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ASH 2018 Highlights Progress in Ongoing Development of Brentuximab Vedotin

As the premier hematology event in malignant and non-malignant hematology, the annual meeting of the American Society of Hematology (ASH), held this year from December 1 – 4, 2018 in San Diego, CA, is expected to present an invaluable educational experience and an opportunity to examine the latest clinical advances on topics covering malignant and non-malignant hematology, explore the year’s most significant scientific discoveries and relevant updates in key areas of the field, build new partnerships, stay current on industry trends and learn about the latest products and services available in research and patient care to meet the need of patients.

Brentuximab vedotin
During the annual meeting, expect to see 31 abstracts featuring data from the broad brentuximab vedotin (Adcetris®) development program.  Brentuximab vedotin is an Antibody-drug Conjugate or ADC directed to CD30, which is expressed on the surface of Hodgkin lymphoma (HL) cells and several types of non-Hodgkin lymphoma.

The drug, being developed by Seattle Genetics and Takeda, is being evaluated globally as the foundation of care for CD30-expressing lymphomas in more than 70 corporate- and investigator-sponsored clinical trials.

The data being presented includes both oral and poster presentations. Some of the presentations includes the latest updated of brentuximab vedotin in combination with other drugs, including Nivolumab (Opdivo®; Bristol-Myers Squibb)

NCT01777152 (ECHELON-2) (CLINICAL TRIAL / BRENTUXIMAB VEDOTIN / SGN-035 / ADCETRIS®)
Schematic 1.0: The phase III ECHELON-2 clinical trial.

ECHELON-2 clinical trial
Data latest, updated from the phase III ECHELON-2 clinical trial evaluating brentuximab vedotin in combination with chemotherapy in previously untreated patients with CD30-expressing peripheral T-cell lymphoma (PTCL) patients will be presented in an oral presentation on Monday, December 3, 2018 at 6:15 p.m. PT.

Seattle Genetics and partner Takeda reported positive top-line results from the ECHELON-2 trial in October 2018. The trial demonstrated a statistically significant improvement in the primary endpoint of progression-free survival (PFS) of brentuximab vedotin in combination with CHP (cyclophosphamide, doxorubicin, prednisone) versus the control arm, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). The brentuximab vedotin plus CHP arm also demonstrated superior overall survival (OS), a key secondary endpoint, compared to CHOP. The ECHELON-2 trial is the first trial to demonstrate an OS advantage in this difficult to treat type of non-Hodgkin lymphoma.

Seattle Genetics expects to submit in November 2018 a supplemental Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for approval of brentuximab vedotin plus CHP in frontline CD30-expressing PTCL.

ECHELON-1 clinical trial

In addition to clinical trial data from the ECHELON-2 trial, expect to see several analyses from the phase III ECHELON-1 clinical trial evaluating brentuximab vedotin in combination with chemotherapy in frontline Stage III or IV classical HL adult patients, which formed the basis of FDA approval in this indication in March 2018.

Data presentations include additional analyses from the ECHELON-1 study, including PFS per investigator and outcomes in younger patients (18-30 years of age). These analyses are consistent with the previously reported modified PFS data and demonstrate improved outcomes in the ADCETRIS plus AVD (doxorubicin, vinblastine, dacarbazine) arm versus ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine).

Preliminary results from a phase II study of brentuximab vedotin in combination with nivolumab among patients with relapsed or refractory primary mediastinal large B-cell lymphoma (CHECKMATE 436 trial), as well as updated results from an ongoing phase I/II study evaluating the combination therapy in relapsed or refractory HL.

“There will be more than 30 data presentations from both corporate- and investigator-sponsored studies presented at the 2018 ASH Annual Meeting evaluating ADCETRIS in a variety of CD30-expressing lymphoma settings. These presentations are reflective of a robust ADCETRIS clinical development program that we, in partnership with the oncology community, are conducting to improve the treatment outcomes for patients,” said Roger Dansey, M.D., Chief Medical Officer of Seattle Genetics.

“[Together with our partner Takeda, we’re looking forward to presentation, on Monday, December 3rd, outlining the] results of the phase III ECHELON-2 clinical trial evaluating brentuximab vedotin in combination with CHP chemotherapy in frontline CD30-expressing peripheral T-cell lymphoma patients.  These data are the basis for our planned supplemental Biologics License Application to the FDA requesting approval of brentuximab vedotin in this setting, which we intend to submit in November 2018,” Dansey concluded.

Oral and poster presentations
Data presented during the meeting includes a series of different presentations:

Saturday, December 1, 2018
Abstract #1647 (poster) Brentuximab Vedotin with Chemotherapy in Adolescents and Young Adults (AYA) with Stage III or IV Hodgkin Lymphoma: A Subgroup Analysis from the Phase 3 ECHELON-1 Study ()
Abstract #1618 (poster) Older Patients (pts) with Previously Untreated Classical Hodgkin Lymphoma (cHL): A Detailed Analysis from the Phase 3 ECHELON-1 Study
Abstract #1635 (poster) Phase 1/2 Study of Brentuximab Vedotin in Combination with Nivolumab in Patients with Relapsed or Refractory Classic Hodgkin lymphoma: Part 3 (Concurrent Dosing) Results and Updated Progression-Free Survival Results from Parts 1 and 2 (Staggered Dosing) ()
Abstract #1636 (poster) Phase 1 Study of MDR1 Inhibitor Plus Brentuximab Vedotin in Relapsed/Refractory Hodgkin Lymphoma
Abstract #1633 (poster) Real World Prevalence of Diagnostic Revision Among Patients with Peripheral T-cell Lymphomas (PTCL) in the US: Results of an Administrative Claims and Electronic Medical Record Analyses
Abstract #1646 (poster) Superior Clinical Benefit of Brentuximab Vedotin in Mycosis Fungoides Versus Physician’s Choice Irrespective of CD30 Level of Large Cell Transformation Status in the Phase 3 ALCANZA Study
Abstract #1654 (poster) A Phase II Study of Brentuximab Vedotin plus Adriamycin and Dacarbazine without Radiation in Non-Bulky Limited Stage Classical Hodgkin Lymphoma.
Abstract #1656 (poster) Treatment Patterns and Outcomes of Relapsed/Refractory Peripheral T-Cell Lymphoma (RR-PTCL) Patients Treated in the Community Oncology Setting.
Abstract #1691 (poster) Nivolumab Combined with Brentuximab Vedotin for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Preliminary Results From the Phase 2 CheckMate 436 Trial.
Abstract #2261 (poster) The Development and Validation of an Electronic Health Record (EHR)-Based Algorithm for Identifying Treatment Failure in Newly Diagnosed Hodgkin Lymphoma (HL) Treated in a US Community Oncology Setting.
Abstract #2268 (poster) Real World Evidence in Relapsed/Refractory Classical Hodgkin Lymphoma Patients Who Are Ineligible for Stem Cell Transplant in the United States (US).
Abstract #1625 (poster) Toxicity Profile of Brentuximab Vedotin in Combination with Chemotherapy for Newly Diagnosed Patients with ALK+ ALCL: a Children’s Oncology Group Study ANHL12P1.
Abstract #1431 (poster) Phase I Study of the Antibody-Drug Conjugate Brentuximab Vedotin Combined with Re-Induction Chemotherapy in Patients with CD30-Expressing Relapsed/Refractory Acute Myeloid Leukemia.
Abstract #1644 (poster) Phase 1 Results from a Phase 1/2 Study to Assess the Safety, Tolerability and Recommended Phase 2 Dose (RP2D) of Brentuximab Vedotin Plus Doxorubicin, Vinblastine and Dacarbazine (A+AVD) in Pediatric Patients (Pts) with Advanced Stage Newly Diagnosed Classical Hodgkin Lymphoma (cHL).
Sunday, December 2, 2018
Abstract #2904 (poster) Brentuximab Vedotin Plus Chemotherapy in Patients with Advanced-Stage Classical Hodgkin Lymphoma (cHL): Evaluation of Modified Progression-Free Survival (mPFS) and Traditional PFS in the Phase 3 ECHELON-1 Study.
Abstract #2921 (poster) Resolution of Peripheral Neuropathy (PN) in Patients Who Received A+AVD or ABVD in the Phase 3 ECHELON-1 Trial.
Abstract #2917 (poster) Interim Analysis Results from an International, Multi-Centre, Non-Interventional Retrospective Study to Describe Treatment Pathways, Outcomes, and Resource Use in Patients with Classical Hodgkin Lymphoma: B-CD30+ Hodgkin Lymphoma International Multi-Centre Retrospective Study of Treatment Practices and Outcomes (B-HOLISTIC).
Abstract #2923 (poster) Combining Brentuximab Vedotin with DHAP as Salvage Treatment in Relapsed/Refractory Hodgkin Lymphoma: the Phase II HOVON/LLPC Transplant BRaVE Study.
Abstract #2938 (poster) Peripheral T-Cell Lymphomas in Spain: Profiling Clinical, Phenotypic and Genetic Characteristics in Spanish Population.
Abstract #2959 (poster) Primary Mediastinal B-Cell Lymphoma: Evaluation of Clinicopathologic Diagnosis Compared to Gene Expression Based Diagnosis in a Clinical Trial with CD30+ B-Cell Lymphomas.
Abstract #2978 (poster) Utilization of a Novel Method of Detection of CD30 Expression in Diffuse Large B-cell Lymphoma.
Abstract #3587 (poster) Health-Related Quality of Life (HRQL) Trajectories during Treatment for Advanced Stage Pediatric Hodgkin Lymphoma (HL).
Monday, December 3, 2018
Abstract #997 (oral presentation at 6:15 p.m. PT) The ECHELON-2 Trial: Results of a Randomized, Double-Blind, Active-Controlled Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Versus CHOP in the Frontline Treatment of Patients with CD30+ Peripheral T-Cell Lymphomas.
Abstract #623 (oral presentation at 8:00 a.m. PT) Longitudinal Adverse Event Assessment of the Combination of Ipilimumab, Nivolumab And Brentuximab Vedotin in Relapsed/Refractory Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Cancer Research Group (E4412: Arms A-F)
Abstract #679 (oral presentation at 10:30 a.m. PT) A Phase I Study with an Expansion Cohort of the Combinations of Ipilimumab, Nivolumab and Brentuximab Vedotin in Patients with Relapsed/Refractory Hodgkin Lymphoma: A trial of the ECOG-ACRIN Research Group (E4412: Arms G-I)
Abstract #926 (oral presentation at 4:45 p.m. PT) B-CAP (brentuximab vedotin, cyclophosphamide, doxorubicin and predniso(lo)Ne) in Older Patients with Advanced-Stage Hodgkin Lymphoma: Results of a Phase II Intergroup Trial By the German Hodgkin Study Group (GHSG) and the Nordic Lymphoma Group (NLG)
Abstract #927 (oral presentation at 5:00 p.m. PT) Response-Adapted Therapy with Nivolumab and Brentuximab Vedotin (BV), Followed by BV and Bendamustine for Suboptimal Response, in Children, Adolescents, and Young Adults with Standard-Risk Relapsed/Refractory Classical Hodgkin Lymphoma.
Abstract #975 (oral presentation at 5:00 p.m. PT) Productivity Loss Among Parent Caregivers is Associated with Poor Health-Related Quality of Life (HRQL) at the Initial Diagnosis Of Pediatric Advanced Stage Hodgkin Lymphoma (HL).
Abstract #2837 (poster) Baseline Tumor Transcriptome Characteristics Associated with the Response of Relapsed/Refractory Hodgkin Lymphoma Patients to Brentuximab Vedotin in Combination with Nivolumab (
Abstract #4786 (poster) Patient and Physician Preferences for First-Line Treatment of Classical Hodgkin Lymphoma in the United States.
Abstract #2907 (poster) Prolonged Overall Survival (OS) in a Subset of Responders to the Combination of Brentuximab Vedotin (Bv) and Bendamustine (B) in Heavily Treated Patients with Relapsed or Refractory Hodgkin Lymphoma (HL): Results of an International Multi-Center Phase I/II Experience.

Editorial Review: November 30, 2018

Featured Image: ASH – San Diego, 2018 #ASH18 Courtesy: © 2010 – 2018 American Society of Hematology. Used with permission.

Copyright © 2018 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Interim Results from Ongoing Studies of Brentuximab Vedotin + Nivolumab in Frontline or Relapsed Hodgkin Lymphoma Presented at ISHL 2018

Multiple presentations evaluating brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda*) across a broad range of Hodgkin lymphoma (HL) settings were presented at the 11th International Symposium on Hodgkin Lymphoma (ISHL) taking place in Cologne, Germany, October 27-29, 2018.  This year’s presentations will highlighted Phase III and other clinical data from brentuximab vedotin and continue to build upon our research in CD30-positive lymphoma.

More than 1,100 delegates from over 70 countries participated in an intensive scientific discourse organized by the German Hodgkin Study Group (GHSG).

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Classical Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.

According to the American Cancer Society, approximately 8,500 cases of Hodgkin lymphoma will be diagnosed in the United States during 2018 and more than 1,000 will die from the disease. Approximately half of all newly diagnosed Hodgkin lymphoma patients have Stage III/IV disease. According to the Lymphoma Coalition, over 62,000 people worldwide are diagnosed with Hodgkin lymphoma each year and approximately 25,000 people die each year from this cancer.


After more than a decade of dedicated clinical research with brentuximab vedotin, we have made significant progress in improving the treatment outcomes for patients with Hodgkin lymphoma…


Trial evaluation
The data presented at the 11th International Symposium on Hodgkin Lymphoma included both encore and additional analyses from the Phase III ECHELON-1 clinical trial evaluating brentuximab vedotin in combination with chemotherapy in frontline Stage III or IV classical HL adult patients, which formed the basis of U.S. Food and Drug Administration (FDA) approval in this indication in March 2018.

Interim results will be presented from two ongoing clinical trials evaluating brentuximab vedotin in combination with nivolumab (Opdivo®; Bristol-Myers Squibb Company), including in newly diagnosed older HL patients.

Finaly, five-year follow-up from the phase III AETHERA clinical trial were presented.

Antibody-drug Conjugate
Bentuximab vedotin is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical HL that plays a role in tumor pathogenesis.  The agent uses a protease-cleavable linker system that is designed to be stable in the bloodstream but to release monomethyl auristatin E (MMAE), a microtubule disrupting agent, upon internalization into CD30-expressing tumor cells.

Brentuximab vedotin is being evaluated globally as the foundation of therapy for HL in more than 50 ongoing clinical trials. Brentuximab vedotin and nivolumab are not approved in combination for the treatment of HL.

Progresss
“After more than a decade of dedicated clinical research with brentuximab vedotin, we have made significant progress in improving the treatment outcomes for patients with Hodgkin lymphoma,” said Nancy Whiting, Pharm.D., Senior Vice President, Clinical Development and Global Medical Affairs at Seattle Genetics.

“At ISHL, we [presented] additional analyses from the ECHELON-1 trial, which demonstrated that Brentuximab vedotin plus AVD improves upon a frontline standard of care regimen, ABVD, in advanced patients and resulted in the first change in advanced stage HL in over 40 years. In addition, three oral presentations will highlight brentuximab vedotin plus nivolumab combination data in frontline and relapsed/refractory HL and five-year data from the phase III AETHERA trial. We are pleased to share these results from our broad brentuximab vedotin clinical development program with the Hodgkin lymphoma community.”

“The presented data a continue to reinforce our dedication to advancing treatment for those affected by Hodgkin lymphoma,” said Jesús Gómez-Navarro, MD, Vice President, Head of Oncology Clinical Research and Development, Takeda.

“[Overal,] the progress we have made in the development of brentuximab vedotin serves as a true testament to the leadership role we have established in the treatment of CD30-positive malignancies, which confirm the long-term benefits of brentuximab vedotin across treatment lines and support its role as an important targeted therapy for Hodgkin lymphoma,” he added.

Analyses
Data from four analyses of the phase III ECHELON-1 clinical trial were be presented at ISHL. Among the presentations are an oral and poster presentation included an analysis from the ECHELON-1 study (Abstract #0038) showing PFS data per investigator that is consistent with the previously reported modified PFS data per Independent Review Facility (IRF).

The ECHELON-1 abstracts included the following:

  • Frontline brentuximab vedotin plus chemotherapy exhibits superior modified progression-free survival vs chemotherapy alone in patients with stage III or IV Hodgkin lymphoma: Phase III ECHELON-1 study (Abstract #0038, oral presentation and poster on Monday, October 29 at 07:30-07:50 CEST)
  • Population pharmacokinetic modeling and exposure-response assessment of brentuximab vedotin efficacy and safety in patients with advanced classical Hodgkin lymphoma from the Phase III ECHELON-1 study (Abstract #0137, poster presentation)
  • Serum sCD30 and TARC do not correlate with PET-based response assessment in patients with stage III or IV classical Hodgkin lymphoma (cHL): phase III ECHELON-1 study of brentuximab vedotin plus chemotherapy vs. chemotherapy alone (Abstract #0159, poster presentation)
  • Brentuximab vedotin plus chemotherapy in high risk advanced-stage classical Hodgkin lymphoma (cHL) patients: Results of pre-specified sub-group analyses from the ECHELON-1 study (Abstract #0136, poster presentation)

Combination
Additional data presentations at 11th International Symposium on Hodgkin Lymphoma also included the results from a follow-up results from the Phase I/II study with brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin Lymphoma  (Abstract #0005, oral presentation on Monday, October 29 at 14:40-14:50 CEST)

Thi presentation included data from 62 patients with relapsed or refractory HL who received the combination regimen of brentuximab vedotin plus nivolumab after failure of frontline therapy. In this study patients were treated once every three weeks, with up to four cycles of combination therapy in the outpatient setting. After completion of the fourth cycle of treatment, patients were eligible to undergo an autologous stem cell transplant (ASCT). The median age of patients was 37 years. The majority of patients (95%) were refractory or had relapsed after receiving the standard of care frontline treatment ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) or some variation of the standard of care (ABVE-PC, R-ABVD). Key findings were presented in an oral presentation by Alex Herrera, M.D., Assistant Professor at the City of Hope Medical Center, Duarte, California.

Herrera showed that of 61 response-evaluable patients, 49 patients (80%) had an objective response, including 37 patients (61%) with a complete response and 12 patients (20 percent) with a partial response.
Of the 61 response-evaluable patients, the estimated 21-month overall survival (OS) and PFS were 95 % and 82%, respectively.

The median follow-up time was 21.8 months and both median OS and PFS were not yet reached. Of 42 patients who underwent ASCT directly after treatment with brentuximab vedotin plus nivolumab, estimated PFS at 21-months was 97 percent and median PFS was not yet reached.

PFS was evaluated by response to treatment. The estimated PFS at 21-months for patients with a complete response was 97%, for patients with a partial response was 83% and patients with stable disease was 50 percent.

As previously reported, the most common adverse events (AEs) of any grade occurring prior to ASCT or subsequent salvage therapy in at least 20% of patients were nausea, infusion-related reaction (IRR), fatigue, pruritus, diarrhea, headache, vomiting, cough, pyrexia, dyspnea and nasal congestion.

Schematic: The AETHERA trial (NCT01100502) is a randomized, double-blind, placebo-controlled, multicenter phase 3 trial to evaluate the efficacy and safety of brentuximab vedotin (SGN-35) and best supportive care (BSC) compared to placebo and BSC in treatment of residual Hodgkin lymphoma (HL) following autologous stem cell transplant (ASCT).

Combination in patients older than 60 years
Another presentation discussed the results from a phase II study of frontline brentuximab vedotin plus nivolumab in patients with Hodgkin Lymphoma aged ≥60 years (Abstract #0153, oral presentation on Monday, October 29 at 15:05-15:15 CEST).

Jonathan Friedberg, M.D., Director of the University of Rochester Medical Center, NY and presented the interim results from an ongoing Phase II clinical trial evaluating brentuximab vedotin in combination with nivolumab as frontline therapy for HL patients age 60 years or older. The reported results included data from 14 patients. The median age of patients was 71.5 years. The majority of patients (79%) had stage III/IV disease at the time of diagnosis.

Friedberg showed that of 11 response-evaluable patients with a median follow-up time of eight months, nine patients (82%) had an objective response, including six patients (55%) with a complete response and three patients (27%) with a partial response. In addition, two patients (18%) had stable disease which equates to all 11 patients (100%) experiencing disease control (complete response + partial response + stable disease) as a result of treatment with brentuximab vedotin in combination with nivolumab.

The most common Adverse Events of any grade occurring in at least 25% of patients were fatigue, diarrhea, constipation, nausea, arthralgia, chills, decreased appetite, pyrexia, IRR, aspartate aminotransferase increased and peripheral sensory neuropathy.

Grade 3 or higher adverse events occurred in seven patients (50%), and the most common were peripheral neuropathy and lipase increased (three patients each); nausea and alanine aminotransferase increased (two patients each).

Five patients (36%) had IRRs, with the majority of symptoms at Grade 1 and there were no Grade 3 or higher symptoms. Four patients (29%) were treated with corticosteroid and no patients discontinued treatment due to an IRR.

Consolidation after Autologous Stem-Cell Transplantation
Five-Year Progression-Free Survival Outcomes from a Pivotal Phase III Study of Consolidative Brentuximab Vedotin after Autologous Stem-Cell Transplantation (ASCT) in Patients with Hodgkin Lymphoma at Risk of Relapse or Progression (AETHERA) (Abstract #0110, oral presentation on Monday, October 29 at 17:10-17:20 CEST)

The five-year follow-up efficacy and safety data from the Phase III AETHERA clinical trial designed to evaluate the potential of single-agent brentuximab vedotin to extend PFS post-ASCT in patients with classical HL who were at high risk of relapse or progression were presented by Craig Moskowitz, M.D., Physician in Chief, Sylvester Comprehensive Cancer Center, University of Miami.

Brentuximab vedotin was approved by the FDA in August 2015 for the treatment of adult patients with classical HL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation.

Moskowitz showed that the five-year PFS rate per investigator was 59% in the brentuximab vedotin arm compared to 41% in the placebo arm. Median PFS per investigator was not yet reached in the brentuximab vedotin arm versus 15.8 months in the placebo arm. The hazard ratio was 0.521 indicating a 48% reduction in the risk of progression or death with treatment of brentuximab vedotin compared to placebo.

Fewer patients in the brentuximab vedotin arm of the study received subsequent anti-cancer therapies versus the placebo arm (32% versus 54%, respectively). In addition, fewer patients in the brentuximab vedotin arm received allogeneic stem-cell transplants versus the placebo arm (17 patients versus 31 patients).

A PFS analysis evaluating subgroups included patients in the brentuximab vedotin arm with either two or more or three or more risk factors, showed patients with a greater number of risk factors for relapse post-ASCT appeared to have the greatest benefit from brentuximab vedotin consolidation therapy. In both subgroups evaluating either two or more or three or more risk factors, median PFS was not reached in the brentuximab vedotin arm and was 9.7 months and 6.3 months, respectively, in the placebo arm.
In the brentuximab vedotin arm, 112 patients (67%) reported peripheral neuropathy.

To date, 90% of these patients had resolution or improvement in symptoms, with 73% having complete resolution.


* Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

Last Editorial Review: November 3 , 2018

Featured Image: Adcetris/Takeda booth at ISHL 2018 . Courtesy: © 2010 – 2018 ISHL/Ralf Juergens. Used with permission.

Copyright © 2018 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Brentuximab Vedotin in Combination with Chemotherapy Approved for Adults with Previously Untreated Stage III or IV Classical Hodgkin Lymphoma

The U.S. Food and Drug Administration (FDA) has approved brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda) in combination with chemotherapy in adult patients with previously untreated Stage III or IV classical Hodgkin lymphoma. This is the first FDA-approved regimen in this disease in more than 40 years

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Classical Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.

According to the American Cancer Society, approximately 8,500 cases of Hodgkin lymphoma will be diagnosed in the United States during 2018 and more than 1,000 will die from the disease. Approximately half of all newly diagnosed Hodgkin lymphoma patients have Stage III/IV disease. According to the Lymphoma Coalition, over 62,000 people worldwide are diagnosed with Hodgkin lymphoma each year and approximately 25,000 people die each year from this cancer.


…this label expansion, based on clinical Trial Results from the Phase III ECHELON-1 Clinical Trial, represents fifth U.S. Food and Drug Administration (FDA) indication for brentuximab vedotin in the United States… and… the ECHELON-1 Clinical Trial also converts prior accelerated approval to regular approval in treatment of relapsed systemic anaplastic large cell lymphoma…


In finding a treatment option for major unmet medical needs, researcher at Seattle Genetics and their global partner Takeda, developed the targeted drug brentuximab vedotin,  an antibody-drug conjugate or ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE).  The drug utilizing Seattle Genetics’ proprietary linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

Successful outcome
The approval is based on the successful outcome of the phase III ECHELON-1 clinical trial that compared brentuximab vedotin plus AVD (Adriamycin, vinblastine and dacarbazine) to ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine).

In addition, data from the ECHELON-1 trial converted the U.S. accelerated approval of brentuximab vedotin for the treatment of adults with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one multi-agent chemotherapy regimen to regular approval.

In October 2017, the FDA granted Breakthrough Therapy Designation (BTD) to brentuximab vedotin in combination with chemotherapy for the frontline treatment of patients with advanced classical Hodgkin lymphoma. The FDA also granted Priority Review for the supplemental Biologics License Application (BLA), and the Prescription Drug User Fee Act (PDUFA) target action date was May 1, 2018.

“The standard of care for treating newly diagnosed advanced Hodgkin lymphoma has not changed in more than four decades. For years, the physician community has been conducting clinical trials to identify improved regimens that are both less toxic and more effective to no avail,” said Joseph M. Connors, M.D., FRCPC, Clinical Director, Center for Lymphoid Cancer at BC Cancer in Vancouver, Canada.

“The ECHELON-1 study results demonstrated superior efficacy of the brentuximab vedotin plus chemotherapy regimen when compared to the standard of care while removing bleomycin, an agent that can cause unpredictable and sometimes fatal lung toxicity, completely from the regimen. This represents a meaningful advance for this often younger patient population,” Connors added.

Approved indications
This is the fifth FDA-approved indication for brentuximab vedotin, which also has regular approval for adult patients with: classical Hodgkin lymphoma (cHL) at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation, cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, sALCL after failure of at least one prior multi-agent chemotherapy regimen, and primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

“Currently, up to 30% of newly diagnosed advanced-stage classical Hodgkin lymphoma patients will experience disease progression after treatment with the current standard of care, representing a significant need for improved treatment options for these often younger patients,” said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

Schematic: The ECHELON-1 trial is a Phase III trial in Frontline Therapy of Patients With Advanced Classical Hodgkin Lymphoma (NCT01712490).

“The ECHELON-1 trial was a bold, five-year effort to redefine the frontline treatment of Stage III/IV classical Hodgkin lymphoma and provide patients with a more effective treatment regimen. In the ECHELON-1 study, brentuximab vedotin plus AVD was shown to have superior efficacy to ABVD. With today’s FDA approval, the physician and patient community have a new treatment option for previously untreated Stage III or IV Hodgkin lymphoma patients. We want to thank all of the patients, physicians and their staff who participated in the ECHELON-1 trial which supported the FDA approval of this novel regimen,” Siegal added.

FDA approval
The FDA approval is based on positive results from a phase 3 trial called ECHELON-1 that were presented at the 59th American Society of Hematology (ASH) annual meeting in December 2017 with simultaneous publication in the New England Journal of Medicine.[1] Results from the ECHELON-1 trial in 1,334 Stage III or IV classical Hodgkin lymphoma patients confirmed that the trial achieved its primary endpoint with the combination of brentuximab vedotin plus AVD resulting in a statistically significant improvement in modified progression-free survival (PFS) versus the control arm of ABVD as assessed by an Independent Review Facility (IRF) (HR 0.77; 95% CI, 0.60-0.98; p-value=0.035). This corresponds to a 23 percent reduction in the risk of progression, death or need for additional anticancer therapy in patients not in complete response (CR) after frontline treatment.

Overall survival (OS) was a key secondary endpoint and the rate of CR per IRF assessment at the end of the randomized regimen was a secondary endpoint. At the time of the modified PFS analysis, an interim OS analysis trended in favor or the brentuximab vedotin plus AVD arm, but did not demonstrate significant difference (HR 0.72; 95% CI, 0.44-1.17; p-value=0.19). The CR rate was 73% on the brentuximab vedotin plus AVD arm and 70 percent on the ABVD arm.

The safety profile of brentuximab vedotin plus AVD in the ECHELON-1 trial was generally consistent with that known for the single-agent components of the regimen.

Adverse events
The most common adverse events of any grade that occurred in at least 10 percent of patients in the ADCETRIS plus AVD arm were: anemia, neutropenia, peripheral sensory neuropathy, constipation, vomiting, diarrhea, pyrexia, decreased weight, stomatitis, abdominal pain, febrile neutropenia, bone pain, insomnia, decreased appetite, back pain, rashes/eruptions/exanthemas, dyspnea, peripheral motor neuropathy, and increased alanine aminotransferase.

In both the brentuximab vedotin plus AVD and ABVD arms, the most common Grade 3 or 4 events were neutropenia, febrile neutropenia, and anemia.

Based on ECHELON-1 clinical trial results, prophylactic growth factors (G-CSF) should be administered starting at cycle one for Stage III or IV classical Hodgkin lymphoma patients receiving brentuximab vedotin plus AVD.

More trials
Brentuximab vedotin is being evaluated broadly in more than 70 clinical trials. This includes two ongoing phase III studies, the ECHELON-2 trial in frontline mature T-cell lymphomas and the CHECKMATE 812 trial of brentuximab vedotin in combination with nivolumab (Opdivo®; Bristol-Myers Squibb Company) for relapsed/refractory Hodgkin lymphoma.


Last Editorial Review: March 20, 2018

Featured Image: Micrograph of Hodgkin lymphoma. Lymph node FNA specimen. Field stain. The micrograph shows a mixture of cells common in Hodgkin Lymphoma, including Eosinophils, Reed-Sternberg cells, Plasma cells and Histocytes.. Courtesy: © 2018 Fotolia. Used with permission.

Copyright © 2013 – 2018 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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U.S. FDA Grants Priority Review for Brentuximab Vedotin in Frontline Advanced Hodgkin Lymphoma

Based on positive results from the Phase III ECHELON-1 clinical trial, the U.S. Food and Drug Administration (FDA) has accepted for filing a supplemental Biologics License Application (BLA) for brentuximab vedotin (Adcetris®; Seattle Genetics) in combination with chemotherapy for the frontline treatment of patients with advanced classical Hodgkin lymphoma.

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Classical Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell.

The Reed-Sternberg cell expresses CD30. Although the currently used standard of care frontline combination chemotherapy can result in durable responses, up to 30% of patients with advanced Hodgkin lymphoma relapse or are refractory to frontline treatment.


…the data demonstrated superior activity of the brentuximab vedotin-containing regimen over standard of care…


According to the American Cancer Society, approximately 8,260 cases of Hodgkin lymphoma will be diagnosed in the United States during 2017 and more than 1,000 will die from the disease. According to the Lymphoma Coalition, over 62,000 people (including early and advanced stage) worldwide are diagnosed with Hodgkin lymphoma each year and approximately 25,000 people die each year from this cancer.

ECHELON-1 trial
The randomized, open-label, Phase III ECHELON-1 trial (NCT01712490) is investigating brentuximab vedotin, an antibody-drug conjugate or ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to the microtubule disrupting agent monomethyl auristatin E (MMAE), using Seattle Genetics’ proprietary technology, plus AVD (Adriamycin, vinblastine, dacarbazine) versus ABVD (AVD + bleomycin) as frontline therapy in patients with advanced classical Hodgkin lymphoma. The primary endpoint is modified PFS per Independent Review Facility assessment using the Revised Response Criteria for Malignant Lymphoma. [1]

Schematic: The ECHELON-1 trial is a Phase III trial in Frontline Therapy of Patients With Advanced Classical Hodgkin Lymphoma (NCT01712490).

Modified PFS is defined as the time to progression, death or receipt of additional anticancer therapy for patients who are not in complete response after completion of frontline therapy per Independent Review Facility. Secondary endpoints include overall survival, complete remission and safety. The multi-center trial was conducted in North America, Europe, South America, Australia, Asia and Africa. The study enrolled 1,334 patients who had a histologically-confirmed diagnosis of Stage III or IV classical Hodgkin lymphoma and had not been previously treated with systemic chemotherapy or radiotherapy. The ECHELON-1 trial was conducted under a Special Protocol Assessment (SPA) agreement from the FDA and the trial also received EMA scientific advice.

The FDA granted Priority Review for the application, and the Prescription Drug User Fee Act (PDUFA) target action date is May 1, 2018. The submission of the supplemental BLA is based on positive results from a Phase III clinical trial called ECHELON-1 that was designed to determine if brentuximab vedotin in combination with chemotherapy could extend modified progression-free survival (modified PFS) in previously untreated advanced classical Hodgkin lymphoma patients. Brentuximab vedotin is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical Hodgkin lymphoma.

Photo 1.0: Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

Foundation of care
Brentuximab vedotin is being evaluated globally as the foundation of care for CD30-expressing lymphomas in more than 70 corporate- and investigator-sponsored clinical trials. Brentuximab vedotin is currently not approved as a frontline therapy for Hodgkin lymphoma.

“The FDA’s filing of our supplemental BLA with Priority Review represents a significant milestone in our goal to redefine the frontline treatment of advanced Hodgkin lymphoma,” said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“We recently reported the primary data from the Phase III ECHELON-1 clinical trial in the Plenary Scientific Session of the [2017 Annual Meeting of the American Society of Hematology (ASH)] with simultaneous publication in the New England Journal of Medicine. The data demonstrated superior activity of the brentuximab vedotin-containing regimen over standard of care, and we are working with the FDA to make this bleomycin-free regimen available to newly diagnosed advanced Hodgkin lymphoma patients as soon as possible,” Siegall concluded.

Breakthrough Therapy Designation
In October 2017, the FDA granted brentuximab vedotin Breakthrough Therapy Designation based on the ECHELON-1 study results. The FDA’s Breakthrough Therapy Designation is intended to expedite the development and review of promising drug candidates for serious or life-threatening conditions. It is based upon clinical evidence of substantial improvement over existing therapies in one or more clinically significant endpoints.

The ECHELON-1 study evaluated a combination of brentuximab vedotin plus AVD compared to a recognized standard of care chemotherapy regimen, ABVD, in frontline advanced classical Hodgkin lymphoma. The positive results from the Phase III ECHELON-1 trial were featured in the Plenary Scientific Session of the 59th American Society of Hematology (ASH) Annual Meeting with simultaneous publication in the New England Journal of Medicine in December 2017.

Results from the ECHELON-1 trial included 1,334 Hodgkin lymphoma patients.

The trial achieved its primary endpoint with the combination of brentuximab vedotin plus AVD resulting in a statistically significant improvement in modified PFS versus the control arm of ABVD as assessed by an Independent Review Facility (IRF) (p-value=0.035). This corresponds to a 23% reduction in the risk of progression, death or need for additional anticancer therapy. Per IRF assessment, the two-year modified PFS rate for patients in the brentuximab vedotin plus AVD arm was 82.1% compared to 77.2% in the control arm.

The investigator assessment of modified PFS also demonstrated a statistically significant advantage for brentuximab vedotin plus AVD versus the control arm of ABVD (p-value <0.01).

All secondary endpoints, including interim analysis of overall survival, trended in favor of the brentuximab vedotin plus AVD arm.

The safety profile of brentuximab vedotin plus AVD in the ECHELON-1 trial was generally consistent with that known for the single-agent components of the regimen.


Last editorial review: January 2, 2018

Featured Image: Micrograph of Hodgkin lymphoma. Lymph node FNA specimen. Field stain. The micrograph shows a mixture of cells common in Hodgkin Lymphoma, including Eosinophils, Reed-Sternberg cells, Plasma cells and Histocytes. Courtesy: © 2017 – 2018. Fotolia | Used with permission. Photo 1.0: Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. Courtesy: © 2017 – 2018. Seattle Genetics. | Used with permission.

Copyright © 2010 – 2018 InPress Media Group, LLC. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Interim Phase I Data from Camidanlumab Tesirine (ADCT-301) Shows Encouraging Preliminary Safety and Efficacy Results

Clinical data from two ongoing Phase I clinical trials evaluating camidanlumab tesirine, also known as ADCT-301* or “Cami-T”, in important subtypes of lymphoma and leukemia show encouraging, preliminary, safety and efficacy results.

The data from these clinical trials was presented at the 59th annual meeting of the American Society of Hematology (ASH), held December 9 – 12, 2017 in Atlanta, Georgia (USA).

Mode of Action
Camidanlumab tesirine is an antibody-drug conjugate or ADC, being developed by ADC Therapeutics, comprising a human monoclonal antibody against CD25 (HuMax®-TAC, licensed from Genmab), stochastically conjugated through a dipeptide cleavable linker to a potent pyrrolobenzodiazepine (PBD) dimer toxin with a drug-antibody ratio (DAR) of 2.3 [1][2]

Once bound to a CD25-expresing cell, camidanlumab tesirine is internalized into the cell where enzymes release the PBD-based payload. After internalizing, the released pyrrolobenzodiazepine (PBD) dimer payload, found among the most cytotoxic agents known, binds in the DNA minor groove and exerts its potent cytotoxic action via the formation of DNA interstrand cross-links. [2] In turn, this eventually results in phosphorylation of histone H2AX, cell-cycle arrest in G2-M, and apoptosis.


Acute myeloid leukemia is the most common leukemia in the adult population in United States. Patients expressing CD25 on their leukemia cells have a particularly poor prognosis.

Camidanlumab tesirine … has shown an acceptable safety profile…


In vivo, single dose of camidanlumab tesirine leads to dose-dependent and targeted antitumor activity against both subcutaneous and disseminated CD25-positive lymphoma models.[2]

Attractive target
CD25, also known as interleukin-2 receptor alpha or IL2R-α, a heterotrimeric protein expressed on the surface of certain immune cells, such as lymphocytes, that binds and responds to a cytokine called interleukin-2 or IL-2, is an attractive target for an antibody-drug conjugate approach as it is expressed on the cell surface of a wide range of hematological malignancies, including Hodgkin lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, and diffuse large B-cell lymphoma lymphoma. Interestingly, the expression of CD25 in healthy organs is restricted. [3][4]

To date, camidanlumab tesirine is being evaluated in two ongoing phase Ia/Ib clinical trials in patients with relapsed or refractory Hodgkin lymphoma and non-Hodgkin lymphoma, and in patients with relapsed or refractory CD25-positive acute myeloid leukemia and acute lymphoblastic leukemia. [5][6]

Poster 1.0: Presented at the 59th (2017) Annual Meeting of the American Society of Hematology. Interim results of a Phase I open label, single agent, dose-escalating study of ADCT-301 evaluating tolerability, safety, pharmacokinetics and efficacy in patients with relapsed or refractory B-cell Hodgkin’s or non-Hodgkin’s lymphoma. Click here to enlarge.

B-cell Hodgkin’s or non-Hodgkin’s lymphoma
The first poster presentation (1510) showed data from 86 evaluable, heavily pre-treated patients who had failed, or were intolerant to, any established therapy known to provide clinical benefit. The median age of patients was 53 years and they had a median of 4 prior therapies.

Data were reported from Part 1 and Part 2 of the Phase I study as of November 1, 2017. In Part 1 (dose escalation), 71 patients were treated at dose ranges from 3-150 µg/kg every three weeks. In Part 2 (dose expansion), 15 Hodgkin Lymphoma patients were treated at 45 µg/kg every 3 weeks. [7]

“Despite considerable advances in the treatment of lymphoma, a significant number of patients still relapse or become refractory to existing therapies and need new treatment options. We are excited by the 77% overall response rate (ORR) in Hodgkin Lymphoma (HL), including a 44% complete response rate,” noted Steven M. Horwitz, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, and Principal Investigator of the study.

“We are also seeing emerging efficacy signals in T-cell lymphomas (ORR: 33%) and B-cell lymphomas (ORR: 19%). Although still early, we are very encouraged by a median duration of response for HL patients of over 5 months to-date. The safety profile appears consistent with what we expect with this target and warhead. We are now working to determine the best dosing regimen for Phase II,” Horwitz added.

Key findings included:

  • For the 27 response-evaluable patients with HL in Part 1, treated at doses greater than or equal to 45 µg/kg, the ORR was 77 percent (21/27 patients) with 12 patients achieving a complete response (44%) and 9 patients achieving a partial response (33%).
  • For the 12 response-evaluable patients with HL in Part 1 and Part 2, treated at the 45 µg/kg dose, the ORR was 100 percent (12/12) with 6 patients achieving a complete response (50 percent) and 6 patients achieving a partial response (50%).
  • For HL patients in Part 1 and Part 2, treated at doses greater than or equal to 45 µg/kg, a complete or partial response was achieved in 21 of 27 patients previously treated with brentuximab vedotin (77%), 13 of 18 patients previously treated with a checkpoint inhibitor (72%), 9 of 14 patients who had previously undergone a stem cell transplantation (64%), and 4 of 8 patients who had previously received all three of these treatments (50%).

Adverse events.
Camidanlumab tesirine has been reasonably well tolerated.

The most common treatment-emergent adverse events of any grade occurring in at least 20 percent of patients in Part 1 and Part 2 were fatigue (30%), rash (26%), elevated gamma-glutamyltransferase (22%), and pyrexia (21%). The most common Grade 3 or 4 adverse events occurring in at least 5 percent of patients, regardless of attribution, were elevated gamma-glutamyltransferase (13%), reduced platelet count (9%), elevated alanine aminotransferase (6%), anemia (6%), and rash (6%). There were three heavily pre-treated patients diagnosed with auto-immune neurotoxicity, including two patients who developed Guillain-Barré syndrome.

Based on the encouraging preliminary safety and efficacy results, the researchers support further characterization of the dosing regime to optimize the therapeutic window in Hodgkin Lymphoma for a Phase II study.

Poster 2.0: Presented at the 59th (2017) Annual meeting of the American Society of Hematology. Interim results of a Phase I open label, single agent, dose-escalating study of ADCT-301 evaluating tolerability, safety, pharmacokinetics and efficacy in patients with relapsed or refractory B-cell acute myeloid leukemia or acute lymphoblastic leukemia. Click here to enlarge.

B-cell acute myeloid leukemia or acute lymphoblastic leukemia
Data were presented from 33 evaluable, heavily pre-treated, patients who had failed, or were intolerant to, any established therapy known to provide clinical benefit.

The median age of patients was 67 years and they had a median of 3 prior therapies.[8]

In Part 1 (dose escalation), 33 patients were treated at dose ranges from 3-92 µg/kg every three weeks, or 30-37.5 µg/kg once weekly.

Key findings:

  • One patient achieved a complete response with incomplete blood count recovery;
  • Camidanlumab tesirine has shown an acceptable safety profile
  • The most common treatment-emergent adverse events of any grade occurring in at least 20 percent of patients were fatigue (30%), nausea (24%), febrile neutropenia (21%), and pneumonia (21%). The most common Grade 3 or 4 adverse events occurring in at least 10 percent of patients, regardless of attribution, were febrile neutropenia (21%), thrombocytopenia (15%), fatigue (12%), reduced neutrophil count (12%), and pneumonia (12%);
  • Dose escalation will continue to investigate weekly dosing.

Earlier this year interim results from an ongoing Phase I, open label, dose-escalating study evaluating ADCT-301, for the treatment of relapsed or refractory Hodgkin’s and non-Hodgkin’s lymphoma, were presented  at the 14th International Conference on Malignant Lymphoma (ICML), held June 14 – 17, 2017 the Lugano Convention Centre, Palazzo dei Congressi, in Lugano, Switzerland, confirming  favorable tolerability and efficacy.

These results were included in a poster showing tolerability, safety, pharmacokinetics and efficacy in patients with relapsed or refractory Hodgkin’s and non-Hodgkin’s lymphoma (r/r HL/NHL). [9]


* Also see: ADC Review | Antibody-drug Conjugates – Drug map

Last editorial review: December 16, 2017

Featured Image:  ADC Therapeutics Booth | 59th Annual Meeting of the American Society of Hematology. Courtesy: © 2017. Sunvalley Communication/Evan Wendt |Used with permission.

Copyright © 2017 InPress Media Group, LLC. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Supplemental Biologics License Application for Brentuximab Vedotin in Frontline Advanced Hodgkin Lymphoma Submitted to FDA

Based on positive results from the Phase III ECHELON-1 Clinical Trial evaluating brentuximab vedotin (Adcetris®; Seattle Genetics) in combination with chemotherapy for the frontline treatment of patients with advanced classical Hodgkin lymphoma, Seattle Genetics has submitted a supplemental Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA)

Brentuximab vedotin is an antibody-drug conjugate or ADC directed to CD30, a defining marker of classical Hodgkin lymphoma. The drug comprises an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.


“…ECHELON-1 study demonstrated superior activity of an brentuximab vedotin-containing regimen over standard of care… [this] resulted in FDA Breakthrough Therapy Designation for brentuximab vedotin in combination with chemotherapy for frontline advanced classical Hodgkin lymphoma…”


Foundation of Care
Brentuximab vedotin is being evaluated globally as the foundation of care for CD30-expressing lymphomas in more than 70 corporate- and investigator-sponsored clinical trials, including four phase III studies: the ECHELON-1 trial in frontline classical Hodgkin lymphoma from which positive top-line results were recently reported and the FDA granted Breakthrough Therapy

Phase III Frontline Therapy Trial in Patients With Advanced Classical Hodgkin Lymphoma (NCT01712490)

Designation in this setting, the ongoing ECHELON-2 trial in frontline mature T-cell lymphomas, the completed ALCANZA trial in cutaneous T-cell lymphoma that supported the supplemental BLA with a Prescription Drug User Fee Act (PDUFA) target action date of December 16, 2017, and the recently initiated CHECKMATE 812 trial of brentuximab vedotin in combination with nivolumab (Opdivo®; Bristol-Myers Squibb Company) for relapsed/refractory Hodgkin lymphoma.

Lymphoma
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Classical Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.

According to the American Cancer Society, approximately 8,260 cases of Hodgkin lymphoma will be diagnosed in the United States during 2017 and more than 1,000 will die from the disease. According to the Lymphoma Coalition, over 62,000 people worldwide are diagnosed with Hodgkin lymphoma each year and approximately 25,000 people die each year from this cancer.

Brentuximab vedotin is currently not approved as a frontline therapy for Hodgkin lymphoma.

Advances in frontline therapy
“There have been no new treatment advances for frontline Hodgkin lymphoma in more than 40 years. Up to 30% of the patients diagnosed with advanced disease will experience disease progression after frontline treatment with the current standard of care chemotherapy regimen, representing a significant unmet need to improve the treatment outcome of these patients who are often young adults,” said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“Results from the ECHELON-1 study demonstrated superior activity of an brentuximab vedotin-containing regimen over standard of care, and resulted in FDA Breakthrough Therapy Designation for brentuximab vedotin in combination with chemotherapy for frontline advanced classical Hodgkin lymphoma. We believe these data represent a significant advance for the patient and physician community and look forward to working with the FDA to complete the review of this new treatment regimen as quickly as possible.”

Clinical trials
About 70-80% of all patients with advanced stage of Hodgkin’s lymphoma are cured with various first-line and second-line treatments, including ABVD  (Adriamycin, Bleomycin, Vinblastine, and Dacarbazine) , BEACOPP, and stem-cell transplantation. Since brentuximab vedotin has shown significant clinical activity, with a manageable safety profile, in patients with relapsed or refractory Hodgkin’s lymphoma.[1]

The ECHELON-1 study evaluated a combination of brentuximab vedotin plus AVD (Adriamycin, Vinblastine, Dacarbazine) compared to a recognized standard of care chemotherapy regimen, ABVD (which also includes Bleomycin), in previously untreated advanced classical Hodgkin lymphoma. The ECHELON-1 study met its primary endpoint of a statistically significant improvement in modified progression-free survival (PFS) of the brentuximab vedotin-containing regimen versus the control arm as assessed by an Independent Review Facility (hazard ratio=0.770; p-value=0.035).

The two-year modified PFS rate for patients in the brentuximab vedotin arm was 82.1% compared to 77.2% in the control arm. Interim analysis of overall survival, the key secondary endpoint, also trended in favor of the brentuximab vedotin plus AVD arm. The safety profile of brentuximab vedotin plus AVD in the ECHELON-1 trial was consistent with that known for the single-agent components of the regimen.

Brentuximab vedotin was recently granted Breakthrough Therapy Designation by the FDA based on data from the phase III ECHELON-1 clinical trial. The FDA’s Breakthrough Therapy Designation is intended to expedite the development and review of promising drug candidates for serious or life-threatening conditions. It is based upon clinical evidence of substantial improvement over existing therapies on one or more clinically significant endpoints.

Trial Design
The randomized, open-label, phase 3 trial is investigating brentuximab vedotin plus AVD versus ABVD as frontline therapy in patients with advanced classical Hodgkin lymphoma. The primary endpoint is modified PFS per Independent Review Facility assessment using the Revised Response Criteria for Malignant Lymphoma. Modified PFS is defined as the time to progression, death or receipt of additional anticancer therapy for patients who are not in complete response after completion of frontline therapy per Independent Review Facility.

This endpoint was chosen as it provides a clearer picture of the efficacy of frontline chemotherapy and eliminates the confounding impact of salvage and consolidation chemotherapies and radiotherapy. Secondary endpoints include overall survival, complete remission and safety. The multi-center trial was conducted in North America, Europe, South America, Australia, Asia and Africa. The study enrolled 1,334 patients who had a histologically-confirmed diagnosis of Stage III or IV classical Hodgkin lymphoma and had not been previously treated with systemic chemotherapy or radiotherapy. The ECHELON-1 trial is being conducted under a Special Protocol Assessment (SPA) agreement from the FDA and the trial also received European Medicines Agency (EMA) scientific advice.

American Society of Hematology
In a statement, Seattle Genetics confirmed that full data from the ECHELON-1 study will be presented in the Plenary Scientific Session at the annual meeting of the American Society of Hematology (ASH) on Sunday, December 10, 2017 from 2:00 – 4:00 p.m. ET in Atlanta, Georgia.


Last Editorial Review: November 2, 2017

Featured Image: Micrograph of Hodgkin lymphoma. Lymph node FNA specimen. Field stain. The micrograph shows a mixture of cells common in Hodgkin Lymphoma, including Eosinophils, Reed-Sternberg cells, Plasma cells and Histocytes.Courtesy: © 2017. Fotolia. Used with permission.

Copyright © 2017 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Positive Results from Phase III ECHELON-1 Trial Evaluating Brentuximab Vedotin in Frontline Advanced Hodgkin Lymphoma

ECHELON-1, a randomized, multicenter, phase III clinical trial evaluating brentiximab vedotin(Adcetris®) as part of a combination chemotherapy regimen in 1,334 patients with advanced Hodgkin Lymphoma, met primary endpoint, demonstrating a statistically significant improvement in modified progression-free survival (PFS) per Independent Review Facility assessment using the Revised Response Criteria for Malignant Lymphoma versus control.[1]

This endpoint was chosen as it provides a clearer picture of the efficacy of frontline chemotherapy and eliminates the confounding impact of salvage and consolidation chemotherapies and radiotherapy. Secondary endpoints include overall survival, complete remission and safety.

The study, conducted in North America, Europe, South America, Australia, Asia and Africa, enrolled 1,334 patients who had a histologically-confirmed diagnosis of Stage III or IV classical Hodgkin lymphoma and had not been previously treated with systemic chemotherapy or radiotherapy.

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Classical Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.

Based on these results, Seattle Genetics and Takeda plan to submit an abstract for presentation during the 2017 annual meeting of the American Society of Hematology, to be held in Atlanta, GA, December 9-12, 2017. The companies are also planning to submit these results to regulatory authorities for approval in their respective territories.

Diagram 1.o: The ECHELON 1 clinical trial (NCT01712490) is an open-label, randomized, 2-arm, multicenter, phase III study has the primary objective of comparing the modified progression-free survival (mPFS) obtained with brentuximab vedotin (Adcetris®) plus AVD (doxorubicin [Adriamycin], vinblastine, and dacarbazine; abbreviated A+AVD) versus that obtained with ABVD (doxorubicin [Adriamycin],bleomycin, vinblastine, and dacarbazine) for the frontline treatment of advanced classical Hodgkin lymphoma(HL).
Brentiximab vedotin is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical Hodgkin lymphoma.

The drug is currently not approved as a frontline therapy for Hodgkin lymphoma.

Patients in ECHELON-1 were randomized to receive either a combination of brentiximab vedotin + AVD (Adriamycin, vinblastine, dacarbazine) or ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine), a recognized standard of care for frontline Hodgkin lymphoma.

Study results
The results of the ECHELON-1 trial demonstrated that combination treatment with brentiximab vedotin resulted in a statistically significant improvement in modified PFS versus the control arm as assessed by an Independent Review Facility (hazard ratio=0.770; p-value=0.035).

The two-year modified PFS rate for patients in the brentiximab vedotin arm was 82.1 percent compared to 77.2% in the control arm. Interim analysis of overall survival (OS), the key secondary endpoint, also trended in favor of the brentiximab vedotin + AVD arm.

Photo 1.0: Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

Safety profile
The safety profile of brentiximab vedotin + AVD in the ECHELON-1 trial was consistent with that known for the single-agent components of the regimen.

The researchers observed an increased incidence of febrile neutropenia and peripheral neuropathy in the brentiximab vedotin + AVD arm. Febrile neutropenia was reduced through the use of prophylactic growth factors in a subset of patients, and peripheral neuropathy was managed through dose modifications. The control arm had an increased rate and severity of pulmonary toxicity.

Positive results
“We are excited about the positive result which shows a statistically significant improvement in the primary endpoint of modified PFS,” said Dirk Huebner, MD., Executive Medical Director, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company. “The results of this trial signify an important step forward in the development of brentiximab vedotin and have the potential to change the treatment approach of frontline advanced Hodgkin lymphoma.”

“The outcome of the Phase III ECHELON-1 trial represents a significant milestone for the Hodgkin lymphoma community,” said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. “Seattle Genetics’ goal is to establish brentiximab vedotin as the foundation of care for CD30-expressing lymphomas, including Hodgkin lymphoma. Notably, this is the first clinical trial in frontline advanced Hodgkin lymphoma to show superior efficacy of a regimen that eliminates bleomycin.”


Last editorial review: June 28, 2017

Featured Image: Micrograph of Hodgkin lymphoma. Lymph node FNA specimen. Field stain. The micrograph shows a mixture of cells common in Hodgkin Lymphoma, including Eosinophils, Reed-Sternberg cells, Plasma cells and Histocytes. Courtesy: © 2017. Fotolia. Used with permission. Photo: Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. Courtesy: © 2017. Seattle Genetics. Used with permission.

Copyright © 2017 InPress Media Group, LLC. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Updates from the 14th International Conference on Malignant Lymphoma (ICML)

Since the inaugurational meeting in 1981, the International Conference on Malignant Lymphoma (ICML), traditionally takes place in Lugano, Switzerland, has become one of the ‘must-attend events’ for anyone involved in the study and treatment of lymphoid neoplasms.

Organized once every two years,in collaboration with the American Association for Cancer Research (AACR), the meeting offers hematologists, clinical oncologists, radio-oncologists, pediatricians, pathologists and leading researchers in the field a great opportunity to to present and discuss the most recent basic and clinical data on a specific morphologic subtype or on a pathways or other biological aspect. Translational and/or pathological aspects are also discussed.

This year a large number of high-quality presentations included the latest updated about Antibody-drug Conjugates.

A New Role for CD37
AGS67E (Astellas Pharma/Agensys) is an antibody-drug conjugate targeting CD37, a tetraspanin expressed on malignant B cells, which includes a fully human monoclonal IgG2 antibody (AGS67C) conjugated to the cytotoxic, microtubule-disrupting, payload monomethyl auristatin E (MMAE) which is linked to reduced cysteines of the antibody via a protease-cleavable linker (maleimidocaproyl-valine-citrulline-p-aminobenzylcarbamoyl). The trial drug is being investigated in patients with relapsed/refractory non-Hodgkin Lymphoma (NHL) in a phase I dose-escalation study.

The data presented this year at the International Conference on Malignant Lymphoma demonstrates a high level of CD37 detection of ≥80% in NHL, including diffuse large B-cell lymphomas (DBCL), making it a potential drug target. But the results also suggest that AGS67E may serve as a potential therapeutic for B-cell malignancies [1][2]

ADCT-301 and ADCT-402
ADCT-301 (ADC Therapeutics), an antibody drug conjugate comprising a human monoclonal antibody against CD25 conjugated to a potent pyrrolobenzodiazepine dimer toxin,  has demonstrated potent anti-tumor activity in pre-clinical studies against CD25-expressing hematological malignancies. Interim results from an ongoing Phase I, open label, dose-escalating study evaluating ADCT-301, included in a poster, confirm that the investigational agent was well tolerated with manageable toxicities. [3]

Interim results from the Phase I, open label, dose-escalating study of ADCT- 402 (ADC Therapeutics), targeting CD19, evaluating tolerability, safety, pharmacokinetics and efficacy in patients with relapsed or refractory non- Hodgkin’s lymphoma (r/r NHL) confirm efficacy and tolerability of ADCT-402. [4]

STRO-001
STRO-001 is a novel CD74-targeting antibody-drug conjugate based on Sutro’s lead human IgG1 antibody (SP7219) conjugated to non-cleavable DBCO-maytansinoid linker-payload with an average drug-antibody ratios (DAR) of 2. The investigational agent, which demonstrates potent in vitro cytotoxicity in NHL cell lines and anti-tumor activity in NHL xenograft models, was developed using  precise site-specific conjugation enabled by Sutro’s cell-free antibody synthesis technology. Study results presented at 14th-ICML confirm potent anti-tumor activity in diffuse large B-cell lymphoma and mantle cell lymphoma tumor models while reducing the potential for toxic secondary effects on adjacent healthy cells. clinical studies of this novel ADC for treatment of B-cell malignancies are under development. [5]

Polatuzumab vedotin
Results from a multicenter, open-label, dose-escalation study evaluating the safety and anti-tumor activity of polatuzumab vedotin (DCDS4501A or RG-7596; Genentech/Roche) in combination with rituximab or obinutuzumab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) in patients with non-Hodgkin’s lymphoma, were presented at 14th-ICML.

CD79b is a signaling component of the B-cell receptor or BCR restricted to the B-cell lineage. In a study published in 2009, Droman et al reported the detection of surface expression of CD79b in almost all non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia patients.  Based on this finding, these researchers concluded that anti-CD79b-vcMMAE could be widely used in these malignancies. [6]

The researchers concluded that a combination of  polatuzumab vedotin at 1.8 mg/kg with R-CHP has an acceptable safety profile and produced promising response rates at the end of treatment, warranting further exploration the investigational drug. [7]

A separate presentation showing updated evaluation of polatuzumab vedotin + bendamustine to polatuzumab vedotinrituximab and substituting obinutuzumab for rituximab shows promising durable responses and an acceptable safety profile in heavily pre-treated transplant ineligible patients with relapsed/refractory (R/R) Follicular or Diffuse Large B-Cell Lymphoma, which generally have poor treatment outcomes.[8]

Brentuximab Vedotin
The complete remission (CR) rate of Hodgkin lymphoma after first line treatment is generally between 80% and 90%. However, about 10% of these patients are refractory and 10% to 30% relapse after achieving a complete remission. The standard of care for suitable patients with relapsed/refractory Hodgkin lymphoma includes high dose chemotherapy followed by autologous stem cell transplant or ASCT.  But patients who relapse after ASCT have a dismal prognosis.

New treatment options including the anti-CD30 antibody-drug conjugate brentuximab vedotin (Adcetris®; Seattle Genetics) are associated with an overall response rate or ORR of 75% and CR rate of 34%.  Results presented during the 14th-ICML report results from a study in which researchers evaluated toxicity, efficacy, and duration of response (DOR) of a combination of brentuximab vedotin and bendamustine, which has demonstrated efficacy in several lymphoproliferative disorders.

The data showed a high response rate (87% ORR and 54% CR) with the combination of brentuximab vedotin and bendamustine, showing a PFS of 80% at 12 months. The median DOR of the CR remission group was 14 months, highlighting durable responses.

The combination of brentuximab vedotin and bendamustine has shown an acceptable toxic profile with only 1 grade 4 adverse event and was able to be delivered as an outpatient regimen. The researchers concluded that the combination is a promising salvage treatment for heavily pretreated patients with R/R Hodgkin lymphoma. They conclude that large investigational trials are necessary to warrant these initial results. [9]

Diagram 1.0: Study of Brentuximab Vedotin (SGN-35) in Pediatric Patients With Relapsed or Refractory Systemic Anaplastic Large-Cell Lymphoma or Hodgkin Lymphoma (NCT01492088)

Trial results from a separate trial confirm that high-dose bendamustine plus brentuximab has shown relevant efficacy and a relatively good safety profile in a setting of heavily pretreated patients with Hodgkin lymphoma.  The combination could be considered as a bridge to second autologous or allogenic stem cell transplant.[10]

In an unrelated study, brentuximab vedotin showed clinically meaningful response rates in patients with this R/R Hodgkin lymphoma and Systemic Anaplastic Large-Cell Lymphoma (sALCL). In this study, 47% of patients proceeded to transplant.

The results of the study show that brentuximab vedotin is a feasible treatment option in pediatric Hodgkin lymphoma and Systemic Anaplastic Large-Cell Lymphoma that can facilitate relapsed patients proceeding to transplant. [11]


Last editorial review: June 16, 2017

Featured Image: Close-up cityscape of Lugano city waterfront along Lugano Lake. Facades of historic houses in front of alp mountains. Courtesy: © 2017. Fotolia. Used with permission.

Copyright © 2017 InPress Media Group, LLC. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Combination of Brentuximab Vedotin and Nivolumab Shows 85% Objective Response Rate and 63% Complete Response Rate in Pre-Transplant Relapsed or Refractory Classical Hodgkin Lymphoma Patients

An updated interim analysis from the ongoing phase I/II clinical trial evaluating  brentuximab vedotin (Adcetris®; Seattle Gentics) and nivolumab (Opdivo®; Bristol-Myers Squibb) in relapsed or refractory (R/R) classical Hodgkin lymphoma presented at the 14th International Conference on Malignant Lymphoma (ICML), held in Lugano, Switzerland, June 14 – 17, 2017, show an 85% Objective Response Rate (ORR) and 63% Complete Response Rate (CRR) with an acceptable safety profile in pre-transplant relapsed or refractory classical Hodgkin lymphoma patients. [1]

During the 14th-ICML, data were reported from 62 patients, including 59 evaluable for response, were be featured in an oral presentation on June 15, 2017.

Most common blood cancer
Lymphoma is a general term for a group of cancers that originate in the lymphatic system and is the most common type of blood cancer. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Hodgkin lymphoma is a cancer that starts in white blood cells called lymphocytes, which are part of the body’s immune system.

The disease is most often diagnosed in early adulthood (ages 20-40) and late adulthood (older than 55 years of age). Classical Hodgkin lymphoma is the most common type of Hodgkin lymphoma, accounting for 95% of all cases. Classical Hodgkin lymphoma is distinguished from other lymphomas by the characteristic presence of CD30-positive Reed-Sternberg cells.

According to the American Cancer Society, more than 8,000 cases of Hodgkin lymphoma will be diagnosed in the United States during 2017 and approximately 1,000 will die from the disease. Furthermore, according to the Lymphoma Coalition, over 62,000 people worldwide are diagnosed with Hodgkin lymphoma each year and approximately 25,000 people die each year from this cancer. In the European Union, about 12,200 new cases and 2,600 deaths occurred in 2012 as a result of Hodgkin lymphoma.

Combination brentuximab vedotin + nivolumab
Brentuximab vedotin is an antibody-drug conjugate or ADC directed to CD30, a defining marker of classical Hodgkin lymphoma. Nivolumab is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to help restore anti-tumor immune respons, and based on recently publsihed data, classical Hodgkin lymphoma (cHL) is ideally suited to therapy with checkpoint inhibitors. One reason being that in Reed-Sternberg cells, the near uniform upregulation of programmed death-ligands 1 and 2 (PD-L1 and PD-L2) result from copy number alterations in chromosome 9p24.1.

The combination of the two agents are not approved in combination for the treatment of relapsed or refractory classical Hodgkin lymphoma or for other indications.

“The phase I/II study combining the antibody-drug conjugate brentuximab vedotin with the PD-1 immune checkpoint inhibitor nivolumab is a promising investigational approach as it combines a targeted therapy with a therapy designed to activate the immune system and the combination may have additive activity,” explained Alex Herrera, M.D., lead trial investigator and assistant professor at the City of Hope, Duarte, California.

“The interim results support further exploration of this novel regimen, free of traditional chemotherapy,” Herrera added.

“We are evaluating [brentuximab vedotin] in novel combinations in order to identify potential treatment regimens for patients with CD30-expressing lymphomas,” noted Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development of Seattle Genetics.

“We are pleased to share updated interim results from this ongoing phase I/II clinical trial evaluating [brentuximab vedotin] in combination with [nivolumab] in relapsed or refractory Hodgkin lymphoma patients. Since our first patient treated with the combination regimen, the data continue to demonstrate encouraging activity with an acceptable safety profile. These updated data support findings first presented at the annual meeting of the American Society of Hematology (ASH) held in December 2016. We have nearly doubled the number of patients in our trial evaluating the [brentuximab vedotin]/[nivolumab] combination strategy and recently announced a collaboration with BMS to initiate a pivotal phase 3 clinical trial in relapsed HL patients in mid-2017.” [2]

“Bristol-Myers Squibb continues to strengthen our broad Immuno-Oncology and hematology development programs for [nivolumab],” noted Fouad Namouni, M.D., head of Oncology Development, Bristol-Myers Squibb.

“Our continued partnership with Seattle Genetics, combines our deep I-O experience and shared commitment to innovative combination treatment options that have the potential to improve the lives of patients impacted by blood cancers. Welook forward to further evaluation of [brentuximab vedotin] in combination with [nivolumab] for the treatment of relapsed Hodgkin lymphoma,” Namouni added.

Trial Design
Data were reported from 62 patients with RR classical HL after failure offrontline therapy who received the combination regimen of [brentuximab vedotin] plus [nivolumab]. Patients were treated once every three weeks with up to four cycles of combination therapy. After completion of the fourth cycle of treatment, patients were eligible to undergo an autologous stem cell transplant (ASCT).

The median age of patients was 36 years. Forty-five percent of patients had primary refractory disease and 55% progressed after responding to frontline therapy, among whom 90% received standard of care frontline treatment ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine).

Key findings
Of 59 response-evaluable patients, 50 patients (85%) had an objective response, including 37 patients (63%) with a complete response and 13 patients (22%) with a partial response. Five patients (8%) had stable disease and four patients (7%) had progressive disease.

Of the 62 patients enrolled, 61 patients (98%) received one or more dose of the study therapies. No patients remain on treatment, 58 patients (94%) have completed treatment and four patients (6%) discontinued prior to the end of treatment.

At the time of data analysis in the ongoing trial, 37 patients (60%) initiated an ASCT and 12 patients (19%) received an alternative salvage therapy subsequent to combination therapy. No unusual post-ASCT adverse events were reported. Preliminary analysis shows no impact of [brentuximab vedotin] and [nivolumab] combination on stem cell mobilization or engraftment.

Prior to ASCT, the most common adverse events of any grade occurring in more than 25% of patients were nausea (56%); fatigue (43%); infusion-related reactions (IRRs, 36%); pruritus (31%); headache (28%); and diarrhea, rash and vomiting (all at 26%). Treatment-related serious adverse events occurred in five patients (8%), including pneumonitis and pyrexia (two patients each) and colitis, malaise, nausea, pneumonia, respiratory failure and sepsis (1% patient each).

Infusion related reactions (IRRs) were observed in 41% of patients. All IRRs were Grade 3 or less, with the rate of Grade 3 IRRs less than 5%.

Ongoing trials
Brentuximab vedotin and nivolumab are being evaluated as combination therapy in multiple ongoing clinical trials. In addition to the study presented during the 14th-ICML, a pivotal phase III clinical trial evaluating brentuximab vedotin in combination with nivolumab compared to brentuximab vedotin alone in relapsed/refractory HL patients is planned to begin enrollment in mid-2017.

In addition, a trial titled “A Safety and Effectiveness Study of Nivolumab in Combination With Brentuximab Vedotin to Treat Non-Hodgkin Lymphomas” is ongoing and focused on patients with relapsed or refractory disease, including diffuse large B-cell lymphoma (DLBCL), and other rare subtypes of B-cell, including mediastinal B-cell lymphoma and mediastinal gray zone lymphoma. The companies recently extended the clinical evaluation of brentuximab vedotin and nivolumab into a clinical trial evaluating the combination as frontline treatment for older Hodgkin lymphoma. patients.


Last editorial review: June 16, 2017

Featured Image: View of Lugano old town with mountains in the background, Switzerland. Courtesy: © 2017. Fotolia. Used with permission.

Copyright © 2017 InPress Media Group, LLC. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Interim Data Shows Favorable Tolerability and Efficacy Results of ADCT-301 in Extensively Pretreated Lymphoma Patients

Interim results from an ongoing Phase I, open label, dose-escalating study evaluating ADCT-301, being developed by ADC Therapeutics for the treatment of relapsed or refractory Hodgkin’s and non-Hodgkin’s lymphoma, presented  at the 14th International Conference on Malignant Lymphoma (ICML), held June 14 – 17, 2017 the Lugano Convention Centre, Palazzo dei Congressi, in Lugano, Switzerland, confirms  favorable tolerability and efficacy. [1]

The results were included in a poster showing tolerability, safety, pharmacokinetics and efficacy in patients with relapsed or refractory Hodgkin’s and non-Hodgkin’s lymphoma (r/r HL/NHL).

Lymphoma is a cancer that begins in cells of the immune system, in particular in the lymph system. The lymph is rich in lymphocytes, a type of white blood cells that help the body fight off infections and other diseases. Lymphoma develops when lymphocytes become cancerous which can occur in both children and adults.

The two main types of lymphomas are Hodgkin lymphoma (HL) and non-Hodgkin lymphomas (NHL), and are differentiated by the type of lymphocytes affected and their appearance under the microscope.

According to the National Cancer Institute around 72,000 new people are diagnosed with non-Hodgkin lymphoma in the United States and around 9’000 new people are diagnosed with Hodgkin lymphoma.

Trial results
The results included data from 37 extensively pretreated patients with a median age of 46 years, a median treatment duration of 43 days and 2 treatment cycles. Among all patients enrolled at the time of the data cutoff for presentation and evaluable for safety, the most common treatment emergent adverse events have been related to skin and decreased blood counts.

The overall response rate for evaluable patients with HL treated with doses 30μg/kg was 38.5% while 8 of 25 (32%) efficacy evaluable patients at all dose levels with HL and NHL have achieved stable disease as their best response. The researchers confirmed that ADCT-301 was well tolerated and toxicities manageable. Dose escalation continues.

Pyrrolobenzodiazepine-based ADC
ADCT- 301 is a novel antibody-drug conjugate (ADC) composed of HuMax®-TAC (licensed from Genmab), a monoclonal antibody directed against CD25 conjugated to ADC Therapeutics’ highly potent proprietary pyrrolobenzodiazepine (PBD)-dimer toxin. Once bound to a CD25-expresing cell, ADCT-301 is internalized into the cell where enzymes release the PBD- based payload.

CD25 is expressed in a wide range of hematological malignancies, including certain forms of lymphomas and leukemias, while its expression in healthy organs is restricted. This makes CD25, as a target, attractive.

“The results seen in this early analysis are impressive for these patients with relapsed or refractory Hodgkin’s and non-Hodgkin’s lymphoma have been heavily pre-treated,’ noted Jay Feingold, Chief Medical Officer and Senior Vice President of Clinical Development at ADC Therapeutics.

“These data, combined with the positive results we have seen in preclinical studies continue to highlight what we believe to be the significant potential of our ADC technology platform based on PBD-warheads,” Feingold added.

“Patients with multiply relapsed or refractory Hodgkin’s or non-Hodgkin’s lymphoma have limited treatment options. These early findings are very encouraging as they demonstrate a clear clinical benefit even at low doses for patients who failed, or are intolerant to any established therapy,” explained principal investigator Steven M. Horwitz, Medical Oncologist at Memorial Sloan Kettering Cancer Center in New York City.

“We look forward to continuing this study to further identify the maximum tolerable dose of ADCT-301 and provide a preliminary assessment of its single-agent anti-tumor activity and toxicity profile,” Horwitz added.

In addition to the ongoing Phase I trial, ADCT-301 is currently being evaluated in an ongoing Phase I clinical trial in Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL). ADC Therapeutics has four PBD- based antibody drug conjugates in six ongoing Phase I clinical trials in the USA and in Europe.


Last editorial review: June 16, 2017

Featured Image: Lugano, Switzerland.Courtesy: © 2017 Lugano Convention Centre, Palazzo dei Congressi, in Lugano, Switzerland Used with permission.

Copyright © 2017 InPress Media Group, LLC. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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