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ADCs – The Dawn of a New Era?

The technology behind antibody-drug conjugates (ADCs) has been around for many years, but so far is without widespread commercial success. Penelope Drake and David Rabuka of Catalent Biologics assess the history and progress to date, and look at what might be preventing ADCs from reaching their full potential.


Abstract
Two decades ago, antibody-drug conjugates or ADCs were hailed as a major breakthrough, especially in the area of oncology therapeutics. The concept of delivering a potent drug payload directly to the site of the tumor for maximum effect with minimal damage caused to non-cancerous cells was viewed as, if not the Holy Grail of cancer treatment, at least a significant advance towards precision medicine. However, the concept has proved difficult to translate into clinical success.

1.0: Introduction
The first ADC reached the market in 2000, but to date, the U.S. Food and drug Administration (FDA) has approved only four ADC therapeutics. The two most recent were granted approval in 2017, and could mark the start of a new era in which ADCs begin to realize their full potential.

The two drugs approved most recently by the FDA are inotuzumab ozogamicin (Besponsa®) and gemtuzumab ozogamicin (Mylotarg®). Mylotarg, the very first marketed ADC, was originally approved in 2000 for treatment of CD33-positive acute myeloid leukemia (AML).

However, treatment-related toxicity concerns led to its withdrawal from the market in 2010, but it has now been re-approved with a lower recommended dose and altered dosing schedule.

Besponsa was approved for treatment of relapsed/refractory acute lymphoblastic leukemia (ALL).[1,2] They join brentuximab vedotin (Adcetris®), an anti-CD30 monomethyl auristatin E (MMAE) conjugate approved in 2011 to treat relapsed/refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, and ado-trastuzumab emtansine (Kadcyla®), an anti-HER2 DM1 conjugate approved in 2013 to treat HER2+ metastatic breast cancer. Kadcyla is currently the only FDA-approved ADC for the treatment of solid tumors.

2.0: An Hybrid Entity
An ADC is very much a hybrid entity, combining both biologic and small molecule characteristics, and consisting of an antibody scaffold covalently modified with a variable number of small-molecule payloads, joined by a chemical linker. The antibody delivers the small molecule specifically to the intended cell type by targeting an antigen that is selectively expressed on tumor cells and internalizes upon antibody engagement. To be an effective therapy, all of these parts of the ADC must be optimized.

Changes to the linker can have a significant effect on the biophysical and functional performance of the ADC, and there are two main conjugation approaches for attaching linkers to antibodies, resulting in either heterogeneous or site-specific payload placement. Currently, the ADC clinical pipeline is still dominated by heterogeneous conjugates, although the functional and analytical advantages of site-specific conjugation [3] are now being recognized.

The average ratio of conjugated payload to antibody is referred to as the drug-to-antibody ratio (DAR) and this has a strong influence on both the efficacy and toxicity of an ADC. High-DAR ADCs can have poor biophysical characteristics that reduce efficacy and increase toxicity, but these effects can be mitigated using certain conjugation and linker technologies.[3]

3.0 Clinically-tested Payloads
To date, the majority of clinically-tested ADC payloads are either antimitotic/microtubule inhibiting, such as auristatins, maytansinoids and tubulysin, or DNA alkylating (e.g., pyrrolobenzodiazepines, indolinobenzodiazepines, calicheamicins, duocarmycins), although a few other interesting payloads with novel mechanisms of action have been introduced (irinotecan derivatives and α-amanitin).

The past five years however, have seen a dramatic change in the ADC clinical pipeline as preclinical technological advances have started to feed into clinical-stage projects. In early 2013, of the 20 ADCs in the clinic, nearly 80% were heterogeneous conjugates with payloads of antimitotic drugs, namely auristatins or maytansinoids. But between 2013 and 2017, the number of ADCs in clinical trials more than tripled [4], with site-specific ADCs accounting for nearly 15% of the total. There has also been a trend away from antimitotic payloads towards more potent cytotoxic drugs, particularly DNA alkylators.

The proportion of antimitotic payloads fell from 80% to 65% overall, and accounted for only one-third of site-specific ADCs. This decline can be attributed in part to the unimpressive clinical results of ADCs bearing antimitotic payloads.

According to a recent review [4], nearly 40% of ADCs bearing maytansine, monomethyl auristatin E (MMAE), or monomethyl auristatin F (MMAF) that entered clinical trials were later discontinued, presumably due to lack of efficacy or (rarely) excessive toxicity.

However, the highly potent DNA alkylating payloads carry an increased risk to patients and the fine line between potency and safety is one that scientists and regulators are still striving to achieve. The first site-specific ADC to reach the clinic, vadastuximab talirine, is an anti-CD33 antibody conjugated through engineered cysteine residues in the heavy chain to yield a DAR 2 molecule and is the first clinical ADC to bear a pyrrolobenzodiazepine (PBD) payload, a highly potent DNA alkylator.

It began clinical phase 1 trials in mid-2013, but the phase 3 trial was recently terminated due to toxicity concerns[5], even though the drug showed a 70% complete remission rate for AML patients.[6]

4.0: Mechanisms of toxicity
Meaningful improvements in ADC technology are expected to continue as preclinical studies focus on understanding the mechanisms of ADC toxicity, developing approaches for reducing off-target toxicities, and improving patient outcomes through changes in both ADC composition and clinical trial study design.

As yet, most clinical experience has been with ADCs carrying antimitotic payloads, which show prominent organ toxicities in the hematopoietic compartments and in the liver. Much less is known about the clinical effects of dosing DNA alkylators, although targeting of the hematopoietic compartments has been shown in clinical trials.

A deeper understanding is needed of the absorption, distribution, metabolism, and excretion (ADME) and drug metabolism and pharmacokinetics (DMPK) fates of both the intact conjugate and its small molecule component. Knowing where the drug goes and how it is processed will enable connections to be drawn with commonly observed clinical toxicities.

A 2015 review of toxicity studies [7] concluded that ADC toxicity was not driven by target antigen but rather by linker/payload: ADCs sharing the same linker/payload composition tended to reach the same maximum tolerated dose, even when their target antigens showed endogenous expression in completely different tissue/organ compartments.

This sobering observation revealed how much progress still needs to be made to achieve specific cytotoxic payload delivery to tumor cells without damaging healthy tissues. But it also offers a possible explanation for the high failure rate of 2013 era ADCs.

It is likely that the lack of clinical benefit observed for some ADCs was the result of an inability to dose to an efficacious level due to off-target toxicities driven by the linker/payload.

If ADC off-target toxicity can be controlled, then it is likely that the maximum tolerated dose can be increased, perhaps leading to better clinical response to treatment.


How to cite:
Drake P, Rabuka D, ADCs – The Dawn of a New Era? (2018),
DOI: 10.14229/jadc.2018.08.27.001.


Original manuscript received: July 25, 2018 | Manuscript accepted for Publication: August 21, 2018 | Published online August 27, 2018 | DOI: 10.14229/jadc.2018.08.27.001.

Last Editorial Review: August 25, 2018

Featured Image: Medical research | Microscope. Courtesy: © Fotolia. Used with permission.

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Phase III CASCADE Clinical Trial of Vadastuximab Talirine in Frontline Acute Myeloid Leukemia Discontinued

Earlier today, Seattle Genetics confirmed that it discontinued the phase III CASCADE clinical trial of vadastuximab talirine (SGN-CD33A) in frontline older acute myeloid leukemia (AML) patients.

The phase III CASCADE clinical trial is a randomized, double-blind, placebo-controlled study evaluating vadastuximab talirine in combination with the hypomethylating agents (HMAs) azacitidine or decitabine compared to an HMA alone in older patients with newly diagnosed AML. Vadastuximab talirine is a novel investigational ADC targeted to CD33 utilizing Seattle Genetics’ proprietary ADC technology. CD33 is expressed on most AML and MDS blast cells.

NCT02785900
Table 1.0: Phase III CASCADE clinical trial of vadastuximab talirine (SGN-CD33A) – NCT02785900.

The company took this action following consultation with the Independent Data Monitoring Committee (IDMC) and after reviewing unblinded data on June 16, 2017.

The data indicated a higher rate of deaths, including fatal infections in the vadastuximab talirine-containing arm versus the control arm of the trial. Based on available data, the safety concerns in this trial do not appear related to hepatotoxicity. Seattle Genetics is suspending patient enrollment and treatment in all of its vadastuximab talirine clinical trials including the ongoing phase I/II clinical trial in frontline high risk myelodysplastic syndrome (MDS).

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

In an announcement today, the company confirmed that it will closely review the data and consult with the U.S. Food and Drug Administration (FDA) to determine future plans for the vadastuximab talirine development program.

“This is a disappointing and unexpected result for the CASCADE trial. Patient safety is our highest priority, and we will closely review the data and evaluate next steps. AML is a devastating disease with a poor prognosis in most patients, and there is a great need for therapeutics against this disease. We thank the patients, caregivers and investigators for their support of this trial,” said Clay Siegall, Ph.D., President and Chief Executive Officer at Seattle Genetics.

Ongoing trials
“We are enthusiastic about the many opportunities across our broad pipeline, including brentuximab vedotin (Adcetris®), enfortumab vedotin (ASG-22ME) and SGN-LIV1A. Notably, we are looking forward to reporting data from our ADCETRIS phase III ECHELON-1 trial in frontline Hodgkin lymphoma, and we are on track to advance enfortumab vedotin into a pivotal trial in metastatic urothelial cancer in the second half of 2017 under our collaboration with Astellas,” Siegall concluded.


Last editorial review: June 19, 2017

Featured Image: Seattle Genetics HQ, Bothel, WA. 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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U.S. FDA Lifts Clinical Hold Phase I Trials of Vadastuximab Talirine

The U.S. Food and Drug Administration (FDA) confirmed today that it has lifted the clinical hold on phase 1 trials of vadastuximab talirine (SGN-CD33A; 33A) in acute myeloid leukemia (AML). The clinical hold was announced on December 27, 2016.

Vadastuximab talirine is a novel investigational antibody-drug conjugate or ADC targeted to CD33 utilizing Seattle Genetics’ proprietary technology. CD33 is expressed on most acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) blast cells. The CD33 engineered cysteine antibody is stably linked to a highly potent DNA binding agent called a pyrrolobenzodiazepine or PBD dimer via site-specific conjugation technology (EC-mAb). PBD dimers are significantly more potent than systemic chemotherapeutic drugs and the EC-mAb technology allows uniform drug-loading onto an ADC. The ADC is designed to be stable in the bloodstream and to release its potent cell-killing PBD agent upon internalization into CD33-expressing cells.

Orphan Drug Designation
Vadastuximab talirine was granted Orphan Drug Designation by both the FDA and the European Commission for the treatment of AML. FDA orphan drug designation is intended to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 individuals in the United States.

“The clinical hold on early-stage vadastuximab talirine clinical trials has been resolved through a comprehensive analysis of the clinical data from over 300 patients treated to date, evaluation by an independent committee of clinical experts, collaborative interactions with the FDA, and protocol amendments designed to further enhance patient safety,” noted Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

“We will resume two phase I trials in AML and plan to initiate a randomized phase II trial during 2017 evaluating vadastuximab talirine in combination with standard of care chemotherapy in frontline, younger AML patients. In addition, we are continuing to enroll our ongoing phase 3 randomized CASCADE trial in frontline older AML patients and our phase I/II trial in frontline high-risk myelodysplastic syndrome (MDS).”

Resuming trials
Following the lifting of the clinical hold, Seattle Genetics will resume two phase I trials of vadastuximab talirine. The first is combination treatment with standard of care, or 7+3, chemotherapy in newly diagnosed younger AML patients. The second is monotherapy and combination treatment with hypomethylating agents in both newly diagnosed and relapsed AML patients.

However, the company will not resume the phase I/II trial of vadastuximab talirine monotherapy in pre- and post-allogeneic transplant AML patients given the challenges of developing therapies in this specific setting.

The randomized global phase III CASCADE trial in frontline older AML and phase I/II trial in frontline MDS were not placed on clinical hold and have continued to enroll patients. Planned studies include a randomized phase II trial of vadastuximab talirine in combination with 7+3 chemotherapy in frontline younger AML patients.

As part of resuming the clinical trial program, additional risk mitigation measures will be implemented in all vadastuximab talirine clinical studies, including revised eligibility criteria and stopping rules for veno-occlusive disease (VOD), which occurs when the small blood vessels that lead into and are inside the liver become blocked.


Last Editorial Review: March 6, 2017

Featured Image: Scientists at Seattle Genetics. Courtesy: © 2017 Seattle Genetics. 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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Clinical Hold on Several Phase I Trials of Vadastuximab Talirine; Enrollment Continues for Phase III CASCADE Trial in AML + Phase I/II Trial in Myelodysplastic Syndrome

Earlier today Seattle Genetics, an innovative biotechnology company that develops and commercializes novel antibody-based therapies for the treatment of cancer, confirmed that it has received notice from the U.S. Food and Drug Administration (FDA) that a clinical hold or partial clinical hold has been placed on several early stage trials of vadastuximab talirine, also known as SGN-CD33A or 33A, in acute myeloid leukemia (AML).

Vadastuximab talirine is a novel investigational ADC targeted to CD33 utilizing Seattle Genetics’ proprietary ADC technology. CD33 is expressed on most AML and MDS blast cells. The CD33 engineered cysteine antibody is stably linked to a highly potent DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer via site-specific conjugation technology (EC-mAb). PBD dimers are significantly more potent than systemic chemotherapeutic drugs and the EC-mAb technology allows uniform drug-loading onto an ADC. The ADC is designed to be stable in the bloodstream and to release its potent cell-killing PBD agent upon internalization into CD33-expressing cells.

The trial drug was granted Orphan Drug Designation by both the FDA and the European Commission for the treatment of AML. FDA orphan drug designation is intended to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 individuals in the United States.

Clinical hold
According to the company, the clinical holds were initiated to evaluate the potential risk of hepatotoxicity, which implies chemical-driven liver damage, in patients who were treated with vadastuximab talirine and received allogeneic stem cell transplant either before or after treatment. Hepatotoxicity and drug-induced liver injury account for a substantial number of compound failures, highlighting the need for drug screening assays, such as stem-cell-derived hepatocyte-like cells, that are capable of detecting toxicity early in the drug development process.[1]

Clinical trial
As part of an extensive clinical trial program, six patients have been identified with hepatotoxicity, including several cases of veno-occlusive disease, with four fatal events. Overall, more than 300 patients have been treated with vadastuximab talirine in clinical trials across multiple treatment settings. Seattle Genetics is working diligently with the FDA to determine whether there is any association between hepatotoxicity and treatment with vadastuximab talirine, to promptly identify appropriate protocol amendments for patient safety and to enable continuation of these trials.

The phase I/II trial of vadastuximab talirine monotherapy in pre- and post-allogeneic transplant AML patients has been placed on full clinical hold. Two phase I trials have been placed on partial clinical hold (no new enrollment, existing patients may continue treatment with re-consent). These studies are vadastuximab talirine monotherapy, including a subset of older AML patients in combination with hypomethylating agents, and vadastuximab talirine combination treatment with 7+3 chemotherapy in newly diagnosed younger AML patients. No new studies will be initiated until the clinical holds are lifted.

Other trials
Seattle Genetics’ other ongoing trials of vadastuximab talirine, including the phase III CASCADE trial in older AML patients and phase I/II trial in myelodysplastic syndrome, are proceeding with enrollment.

The CASCADE Trial is a randomized, double-blind, study being conducted at multiple centers globally to evaluate if vadastuximab talirine in combination with azacitidine or decitabine can extend overall survival compared to azacitidine or decitabine alone in approximately 500 older patients with newly diagnosed AML.

During the 2016 annual meeting of the American Society of Hematology (ASH), data was presented demonstrating that vadastuximab talirine has a promising overall tolerability and activity profile in clinical trials for patients with AML.

Following the annual meeting Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics noted: “Based on the encouraging data presented at ASH, we believe vadastuximab talirine has the potential for clinical development in multiple AML settings, with the goal of providing new treatment options for patients struggling with this aggressive and life-threatening disease.”


Last Editorial Review: December 27, 2016

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Copyright © 2016 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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Vadastuximab Talirine is Well-Tolerated with Rapid, High Remission Rates for AML Patients in Multiple Phase I Trials

Highlighted in three oral data presentations during the 58th annual meeting of the American Society of Hematology, being held in San Diego, CA, December 3 – 6, 2016,  key clinical researchers confirmed that vadastuximab talirine (SGN-CD33A; 33A), a novel, investigational antibody-drug conjugate being developed by Seattle Genetics,  is well-tolerated with rapid, high remission rates for patients with Acute myeloid leukemia or AML.

Acute myeloid leukemia, also called acute myelocytic leukemia or AML, is an aggressive cancer of the bone marrow and blood that progresses rapidly without treatment. Cancerous cells called leukemic blasts multiply and crowd out normal cells in the bone marrow and interfere with normal blood cell production leading to anemia, infection, and bleeding.

According to the SEER database and Kantar Health Sciences, in 2016 approximately 33,000 new cases of AML, the majority in adults, will be diagnosed in the U.S. and Europe.

In the U.S. alone, nearly 10,500 deaths will occur from AML this year. For the last 40 years, treatment has remained virtually unchanged and frontline treatment consists primarily of chemotherapy. A subset of patients (typically those over 60 years of age) cannot tolerate such an aggressive therapy and are typically given lower intensity therapies agents, supportive care, or are recommended for clinical trials.

Investigational drug
Vadastuximab talirine is an investigational antibody-drug conjugate targeted to CD33, a protein also known as Siglec-3 (sialic acid binding Ig-like lectin 3). The protein, a transmembrane receptor, is expressed on leukemic cells in nearly all AML patients. Furthermore, CD33 is expressed on most AML and MDS blast cells.

The novel, investigational drug utilizes Seattle Genetics’ proprietary ADC technology. The CD33 engineered cysteine antibody is stably linked to a highly potent DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer via site-specific conjugation technology (EC-mAb). PBD dimers are significantly more potent than systemic chemotherapeutic drugs and the EC-mAb technology allows uniform drug-loading. One of the unique features of the drug is that it is designed to be stable in the bloodstream and that it only releases the potent cell-killing PBD agent upon internalization into CD33-expressing cells.

Vadastuximab talirine was granted Orphan Drug Designation by both the U.S. Food and Drug Administration (FDA) and the European Commission for the treatment of AML. FDA orphan drug designation is intended to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 individuals in the United States.

Annual Meeting
The data presented during the annual ASH meeting included updated results from an ongoing phase I clinical trial evaluating vadastuximab talirine in combination with hypomethylating agents (HMAs; azacitidine, decitabine) in frontline older AML patients. Further oral presentations focused on results from Phase I clinical trials evaluating vadastuximab talirine in three distinct settings, including as monotherapy in newly diagnosed older AML patients, in combination with high-dose cytarabine for younger AML patients in first remission and as monotherapy maintenance for younger AML patients who have completed frontline therapy or after allogeneic stem cell transplant.

Clinical development
Seattle Genetics is broadly evaluating vadastuximab talirine across multiple lines of therapy in patients with myeloid malignancies. In addition to the clinical trials presented at ASH this year, the trial drug is currently being evaluated in combination with HMAs in the ongoing global phase III CASCADE study.

CASCADE Trial
The CASCADE Trial is a randomized, double-blind, study being conducted at multiple centers globally to evaluate if vadastuximab talirine in combination with azacitidine or decitabine can extend overall survival compared to azacitidine or decitabine alone in approximately 500 older patients with newly diagnosed AML. Additional phase I and II clinical trials for frontline younger AML and frontline myelodysplastic syndrome (MDS) are also underway.

“We are pleased with the growing body of data demonstrating that vadastuximab talirine, also known as 33A, has a promising overall tolerability and activity profile in clinical trials for patients with AML,” said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

“We are committed to improving the therapeutic options for AML patients through innovative, targeted approaches. Our most advanced 33A clinical study, CASCADE, is a randomized phase III trial designed to test vadastuximab talirine in combination with hypomethylating agents, or HMAs, in approximately 500 older patients with newly diagnosed AML. Based on the encouraging data presented at ASH, we believe vadastuximab talirine has the potential for clinical development in multiple AML settings, with the goal of providing new treatment options for patients struggling with this aggressive and life-threatening disease,” Drachman added.

Meaningful change
“AML therapy has not meaningfully changed over the past 40 years, and there is a dire need for improved treatment options. Older AML patients have a particularly poor prognosis with the standard of care, hypomethylating agents or HMAs,” said Amir Fathi, M.D., Massachusetts General Hospital Cancer Center.

These outcomes for AML patients who are older or ineligible to receive standard chemotherapy remain poor. HMAs are frequently used in this setting, but efficacy is limited. Updated results from an ongoing phase 1 study evaluating 33A in combination with HMAs (either azacitidine or decitabine) in newly diagnosed older AML patients were presented by Dr. Amir Fathi, Massachusetts General Hospital Cancer Center.

“I am pleased with the balance of activity and tolerability we have observed in phase I clinical trials evaluating vadastuximab talirine both as monotherapy and combination therapy in AML patients. For older patients with newly diagnosed AML, the 73% remission rate of vadastuximab talirine in combination with hypomethylating agents, with 50% of those patients negative for minimal residual disease, signals promise in improving long-term outcomes,” Fathi added.

During the annual meeting of the American Society of Hematology, scientists demonstrated that vadastuximab talirine in combintion with hypomethylating agents was well-tolerated with high remission rate in frontline older patients with acute myeloid leukemia [1]

Frontline
Data were reported from 53 frontline AML patients with a median age of 75 years and predominantly intermediate or adverse cytogenetic risk who had declined intensive therapy. Regarding additional poor-prognosis indicators, 42% of patients had evidence of underlying myelodysplasia, 11% had FLT3-mutated disease and 43% had secondary AML, which is AML that arises from prior chemotherapy, a pre-existing MDS or myeloproliferative disease.

The result showed that of 49 patients evaluable for response, complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) was observed in 36 patients (73%).
Remissions were observed in higher-risk patients, including 17 of 22 patients (77%) with secondary AML, five of five patients (100%) who were FLT3/ITD positive and 17 of 26 patients (65%) age 75 or older. Eighteen of the 36 patients (50%) who achieved remission (CR or CRi) were negative for minimal residual disease (MRD), which means no cancer could be detected with a sensitive test.

With a median follow-up of 14.7 months, median overall survival for all patients was 11.3 months and 28% of patients remained alive and on study as of last follow-up. The 30- and 60-day mortality rates were two and eight percent, with no treatment-related deaths occurring during that time.

For patients who achieved MRD-negative remission, the median survival had not yet been reached.

Adverse events
The most common Grade 3 or 4 treatment-emergent adverse events occurring in 20 percent or more of patients were thrombocytopenia, febrile neutropenia, anemia and neutropenia.
The most common Grade 1 and 2 treatment-emergent adverse events occurring in 20 percent or more of patients were fatigue, nausea, constipation, peripheral edema and decreased appetite.

Monotherapy
Vadastuximab Talirine Monotherapy in Older Patients with Treatment Naive CD33-Positive Acute Myeloid Leukemia (Abstract #590, oral presentation on Monday, December 5, 2016 at 7:15 a.m. PT)

Interim results from 93 patients in the ongoing phase I study evaluating vadastuximab talirine monotherapy in AML patients were previously presented at the 2015 ASH Annual Meeting. New results describing the safety and activity of the recommended monotherapy dose of 40 micrograms per kilogram (mcg/kg) in an expansion cohort of treatment-naïve older AML patients were presented by Anjali Advani M.D., a staff physician in the Department of Hematologic Oncology and Blood Disorders and Director of the Inpatient Leukemia Program at the Cleveland Clinic in Cleveland, Ohio.

Advani presented data from 27 treatment-naïve older AML patients with a median age of 74 years and intermediate or adverse cytogenetic risk of 70% and 26%, respectively. Regarding additional poor-prognosis indicators, 48% of patients had evidence of underlying myelodysplasia and 22% had FLT3 mutated disease. The data showed that of the 26 patients evaluable for response, remission (CR or CRi) was observed in 15 patients (58%). The median time to remission was 1.4 months.

Forty-three percent of patients who achieved remission were MRD negative.
Responses were observed in higher-risk patients, with remissions achieved in seven of 12 patients (58%) with underlying myelodysplasia and three of four patients (75%) who were positive for FLT3/ITD.

The 30- and 60-day mortality rates were zero and 15 percent, respectively. The median overall survival for all patients was seven months.

The most common Grade 3 or higher treatment-emergent adverse events occurring in 20% or more of patients were thrombocytopenia, febrile neutropenia and anemia. The most common Grade 1 and 2 treatment-emergent adverse events occurring in 20 percent or more of patients were peripheral edema, decreased appetite, fatigue, diarrhea and dizziness.

Maintenance and in Combination with Standard Consolidation
Interim results from an ongoing phase Ib study evaluating vadastuximab talirine as a single dose maintenance therapy and in combination with consolidation therapy with high-dose cytarabine (HiDAC) for patients with AML in the post-remission setting, were presented by Jay Yang M.D., a member of the Malignant Hematology Multidisciplinary Team at the Barbara Ann Karmanos Cancer Institute and assistant professor in the departments of hematology and oncology at Wayne State University, Detroit, Michigan.

Prior to HiDAC administration (3 gm/m2 q12h Day 1, 3, 5), vadastuximab talirine was given on Day 1 for up to 4 cycles (28-day cycle). For maintenance therapy, vadastuximab talirine was given as a single agent on Day 1 for up to 8 cycles (6-wk cycle).

Although the media OS was not yet reached in this study, the researchers concluded that vadastuximab talirine can be safely administered in combination with HiDAC and as monotherapy in the post-remission setting. They also concluded that, in combination with HiDAC, non-hematologic toxicities of vadastuximab talirine were consistent with effects reported with HiDAC alone. Furthermore, the researchers noted that, as a single agent, vadastuximab talirine administered as maintenance post-chemotherapy and/or alloSCT results in predictable on-target myelosuppression, with mild non-hematologic adverse effects.


Last Editorial Review: December 5, 2016

Featured Image: Scientist at Seattle Genetics Courtesy: © Seattle Genetics. Used with permission.

Copyright © 2016 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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Study Shows 76% Objective Response Rate in Newly Diagnosed Acute Myeloid Leukemia Patients Treated with Vadastuximab Talirine Combination Therapy

Phase I clinical data from a study evaluating vadastuximab talirine, also known as SGN-CD33A or 33A in combination with hypomethylating agents (HMAs; azacitidine, decitabine) in frontline patients with acute myeloid leukemia, also called AML who had declined intensive therapy were highlighted at the 21st Congress of the European Hematology Association (EHA) held in Copenhagen, Denmark, June 9-12, 2016. [1]

EHA-Copenhagen_2016The results show a 76% percent objective response rate, including a 41% complete remission rate, in newly diagnosed AML patients treated with vadastuximab talirine combination Therapy. The data supports the recently initiated phase III CASCADE study evaluating vadastuximab talirine in combination with hypomethylating agents in patients with acute myeloid leukemia

Acute myeloid leukemia is an aggressive type of cancer of the bone marrow and blood that progresses rapidly without treatment. AML is a cancer that starts in the cells that are supposed to mature into different types of blood cells. AML starts in the bone marrow (the interior part of bones, where new blood cells are made) and quickly moves into the blood. According to the American Cancer Society, in 2016 approximately 20,000 new cases of AML (mostly in adults) will be diagnosed and nearly 10,500 deaths will occur from AML (almost all will be in adults).[2]

Acute myeloid leukemia is generally a disease of older people and is uncommon before the age of 45. The average age of a patient with AML is about 67 years. The disease is slightly more common among men than among women, but the average lifetime risk in both sexes is less than ½ of 1%. [2]

Investigational drug
Vadastuximab talirine is an novel investigational antibody-drug conjugate or ADC targeted to CD33 utilizing Seattle Genetics’ newest technology.  The trial drug includes an engineered cysteine antibody (EC-mAb) stably linked, via a proprietary site-specific conjugation technology, to a highly potent DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer.

PBD dimers are significantly more potent than systemic chemotherapeutic drugs and the site-specific conjugation technology (EC-mAb) allows uniform drug-loading of the cell-killing PBD agent to the anti-CD33 antibody. The ADC is designed to be stable in the bloodstream and to release its potent DNA binding agent upon internalization into CD33-expressing cells.

The target, CD33, is expressed on leukemic blasts in nearly all patients with acute myeloid leukemia and myelodysplastic syndromes (MDS) with expression generally consistent regardless of age, cytogenetic abnormalities or underlying mutations.

CASCADE Trial
Based on data from the ongoing phase I clinical trial, a phase III clinical trial, called CASCADE, was recently initiated evaluating vadastuximab talirine in combination with HMAs in previously untreated AML patients who where no candidates for intensive induction chemotherapy. [3][4]

The investigational drug is also being evaluated broadly across multiple lines of therapy in patients with myeloid malignancies, including ongoing and planned phase I and II clinical trials for newly diagnosed or relapsed AML and for previously untreated myelodysplastic syndrome (MDS).

Outcomes
The outcomes for patients with AML who are not candidates for intensive chemotherapy or allogeneic stem cell transplant are dismal. Low intensity treatment options, including HMAs, are limited.  During the 21st Congress of the European Hematology Association

Amir Fathi, M.D., investigator of the phase I trial who presented the new study data, showed that from 53 frontline unfit AML patients with a median age of 75 years and intermediate or adverse cytogenetic risk who had declined intensive therapy forty-five percent of patients had evidence of underlying myelodysplasia. Key findings presented by Amir Fathi include:

  • Of 49 efficacy-evaluable patients treated with vadastuximab talirine combined with either azacitidine or decitabine, the overall response rate was 76%. Complete remission (CR) or complete remission with incomplete platelet or neutrophil recovery (CRi) was observed in 35 patients (71%). The remission rate (CR+CRi) was similar between the two vadastuximab talirine and HMA combination treatment groups (71%) combined with azacitidine and 72% combined with decitabine);
  • Responses were observed in higher-risk patients, with remissions achieved in 16 of 22 patients (73%) with underlying myelodysplasia and 15 of 18 patients (83%) with adverse cytogenetics;
  • Patients who achieved minimal residual disease included eight of 19 (42%) CR patients and five of 15 (33%) CRi patients;
  • The median overall survival for all patients in the phase I trial is interim and expected to evolve. The estimated median overall survival for the first 25 patients enrolled in the study was 12.75 months, with a median follow-up of 12.58 months;
  • Median relapse-free survival was 7.7 months (range, 0.0+ and 11.3+) with 27 patients (51%) remaining alive and on study as of last follow-up. The 30- and 60-day mortality rates were two and eight percent, respectively;
  • The most common treatment-related adverse events of any grade occurring in 20% or more of patients were fatigue (57%), thrombocytopenia (53%), nausea (49%), febrile neutropenia (45%), and constipation and anemia (42% each). The most common Grade 3 or 4 treatment-emergent adverse events occurring in 20% or more of patients were febrile neutropenia, thrombocytopenia, neutropenia, anemia and fatigue.

Current standard
“Hypomethylating agents, or HMAs, are the current standard of care for AML patients who are not able to tolerate intensive therapy. HMAs have limited benefit, with low response rates and median

Photo 1.0 Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.
Photo 1.0: Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

overall survival of 10 months or less,” noted Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

“We believe that adding [vadastuximab talirine] to HMAs may improve efficacy and has the potential to redefine the treatment of AML. The clinical data at ASH showing high response rate, manageable tolerability profile and low early mortality reported have been maintained in this larger data set, and support our recently initiated phase III CASCADE clinical trial, which is now enrolling patients,” Drachman added.

Amir Fathi  added: “There is a dire need to improve outcomes for patients with AML. The anti-leukemic activity we have observed in the phase I clinical trial evaluating [vadastuximab talirine] combination therapy in AML patients continues to be encouraging. This is an incredibly difficult disease to treat and the results to-date continue to show a balance of activity and tolerability together with low early mortality rates.”

“The data presented suggest that the addition of [vadastuximab talirine] improves the rates of response and durable remissions in comparison to that seen historically from using the current standard of care alone,” he added.

Orphan Drug Designation
Vadastuximab talirine was granted Orphan Drug Designation by both the U.S. Food and Drug Administration (FDA) and the European Commission for the treatment of AML. The FDA orphan drug designation is intended to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 individuals in the United States.


Last Editorial Review: June 13, 2016

Featured Image: Oncology Nurse talking to a patient. Courtesy: © Fotolia. Used with permission. Photo 1.0: Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. Courtesy: © Seattle Genetics.

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Pivotal Trial with Vadastuximab Talirine Initiated for Treatment of Patients with Newly Diagnosed Acute Myeloid Leukemia

A phase III study called CASCADE, designed to evaluate Seattle Geneticsvadastuximab talirine (SGN-CD33A; 33A) in combination with azacitidine (Vidaza) or decitabine (Dacogen) has been initiated in older patients with newly diagnosed acute myeloid leukemia (AML).

Acute myeloid leukemia, also called acute myelocytic leukemia or AML, is an aggressive type of cancer of the bone marrow and blood that progresses rapidly without treatment. This type of cancer starts in the cells that are supposed to mature into different types of blood cells. As such, AML starts in the bone marrow, the interior part of bones where new blood cells are made,  and quickly move into the blood. According to the American Cancer Society, in 2016 approximately 20,000 new cases of AML will be diagnosed and nearly 10,500 deaths will occur from AML.

Significant unmet need
“Acute myeloid leukemia, or AML, is a devastating disease representing a significant unmet medical need. It impacts approximately 20,000 people in the U.S. each year, with few effective treatment options. Older AML patients have a particularly poor prognosis as the majority have high risk disease characteristics and a median survival of ten months or less with available therapies,” noted Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“We have a robust development strategy, with several ongoing clinical trials across multiple lines of therapy in myeloid malignancies to explore 33A as a treatment option broadly in AML. This pivotal phase 3 CASCADE trial is a significant corporate milestone and an important step in our goal to improve outcomes for AML patients,” Siegall added.

Novel treatment options
Vadastuximab talirine is an antibody-drug conjugate (ADC) targeted to CD33 utilizing Seattle Genetics’ newest technology, comprising an engineered cysteine antibody (EC-mAb) stably linked via a proprietary site-specific conjugation technology, to a highly potent DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer.

PBD dimers are significantly more potent than systemic chemotherapeutic drugs and the site-specific conjugation technology (EC-mAb) allows uniform drug-loading of the cell-killing PBD agent to the anti-CD33 antibody.

These targeted drugs are designed to be stable in the bloodstream and to release its potent DNA binding agent upon internalization into CD33-expressing cells.  In this way, the drug is selectively delivered as a cell-killing agents to tumor cells. This approach is intended to spare non-targeted cells and, thus, reduce many of the toxic effects of traditional chemotherapy while enhancing antitumor activity.

CD33 is expressed on leukemic blasts in nearly all AML patients and expression is generally consistent regardless of age, cytogenetic abnormalities or underlying mutations. Azacitidine and decitabine are hypomethylating agents (HMAs) commonly used in the treatment of older AML patients. CD33 is also expressed on MDS blast cells.

CASCADE-trial
The phase III CASCADE study is a randomized, double-blind, placebo-controlled, global clinical trial. It is designed to evaluate if 33A in combination with azacitidine or decitabine can extend overall survival compared to azacitidine or decitabine alone in older patients with newly diagnosed AML. Patients will be randomized on a 1:1 ratio to be treated with an HMA plus 33A or an HMA plus placebo. The secondary endpoints include the comparison of composite complete remission rate (complete remission and complete remission with incomplete hematologic recovery; CR/CRi), event-free and leukemia-free survival, duration of response, safety, and 30- and 60-day mortality rates. The phase 3 trial will enroll approximately 500 patients globally.

Interim results
Interim results from the ongoing phase I study evaluating 33A in combination with HMAs in frontline AML and as monotherapy in primarily relapsed AML were presented at the 2015 American Society of Hematology (ASH) Annual Meeting and Exposition. Data from the phase 1 33A combination trial demonstrated that 15 of 23 (65 percent) evaluable patients achieved CR/CRi. At a median follow-up of 7.7 months, median survival had not yet been reached, and 72 percent of patients remained alive and on study.

Updated data from the ongoing phase 1 study of 33A in combination with HMAs will be presented in an oral presentation at the 2016 European Hematology Association (EHA) Congress taking place June 9 – 12, 2016, in Copenhagen, Denmark.

Additional trials
In addition to the phase III CASCADE trial, Seattle Genetics is evaluating 33A broadly across multiple lines of therapy in patients with AML and myelodysplastic syndromes (MDS), including the following ongoing trials:

  • A phase 1 trial of 33A monotherapy and in combination with HMAs in AML patients who have relapsed/declined intensive frontline therapy or are newly diagnosed;
  • A phase 1b trial in combination with standard-of-care intensive chemotherapy (7+3), consisting of cytarabine and daunorubicin, for younger fit patients with AML;
  • A phase 1/2 trial in patients with relapsed or refractory AML evaluating 33A monotherapy as a pre-conditioning regimen prior to an allogeneic stem cell transplant and also for use as maintenance therapy following transplant; and,
  • A phase 1/2 trial of 33A in combination with azacitidine in patients with previously untreated MDS.

Data Presented at the 2015 American Society of Hematology Annual Meeting Demonstrated Encouraging Anti-leukemic Activity and Support Advancing 33A into a Registrational Trial.  Additional Phase I data will be featured in an oral presentation during the upcoming at the European Hematology Association Congress in June 2016.


Last Editorial Review: May 25, 2016

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Vadastuximab Talirine (SGN-CD33A) Combination Therapy Evaluates Safety and Activity for Patients with Untreated Myelodysplastic Syndrome

A new phase I/II clinical trial of vadastuximab talirine, also known as SGN-CD33A; 33A (Seattle Genetics), in combination with azacitidine (Vidaza®; Celgene Corporation) in patients with previously untreated myelodysplastic syndrome (MDS) has been initiated to evaluate the safety and activity of the combination therapy.

Myelodysplastic Syndromes, often referred to as a “bone marrow failure disorder,” are a group of diverse bone marrow disorders in which the bone marrow does not produce enough healthy blood cells.  The syndrome starts when abnormal progenitor cells in the bone marrow are damaged and have problems making new blood cells.

Blood cells formed by the abnormal bone marrow cells are defective. These defective cells often have reduced survival and function, resulting in low blood counts and abnormal behavior. In advanced MDS, blast cells (immature blood cells) are detectable in the bone marrow and usually express CD33.

The prognosis is directly related to the number of the bone marrow blast cells, to certain cytogenetic abnormalities, and to the amount of peripheral blood cytopenias.  With fewer healthy blood cells, infection, anemia, or easy bleeding may occur.  In about one-third of patients, MDS can progress to a rapidly growing cancer of the bone marrow cells and is reclassified as acute myeloid leukemia (AML), which broadly expresses CD33, with myelodysplastic features when blood or bone marrow blasts reach or exceed 20%.  Many patients succumb to complications of cytopenias before progression to this stage. And according to the American Cancer Society, in 2016 more than 19,500 new cases of MDS will be diagnosed and more than 10,000 deaths will occur as a result of this disease. [1]

Myelodysplastic syndromes occur predominantly in older patients (usually those older than 60 years), with a median age at diagnosis of approximately 70 years, but patients as young as 2 years have been reported.[1]

Clinical features generally include anemia, bleeding, easy bruising, and fatigue are common initial findings. Splenomegaly or hepatosplenomegaly may indicate an overlapping myeloproliferative neoplasm. In approximately 50% of all patients with MDS a detectable cytogenetic abnormality, most commonly a deletion of all or part of chromosome 5 or 7, or trisomy 8, is observed. Single-nucleotide polymorphism array technology may increase the detection of genetic abnormalities to 80%. Although the bone marrow is usually hypercellular at diagnosis, 10% of patients present with a hypoplastic bone marrow. Hypoplastic myelodysplastic patients tend to have profound cytopenias and may respond more frequently to immunosuppressive therapy. [1]

Vadastuximab talirine, a new approach
A new drug called vadastuximab talirine is expected to change this.  The novel agent is an antibody-drug conjugate (ADC), a monoclonal antibody linked to a cytotoxic agent that is designed to selectively deliver cell-killing agents directly to tumor cells. This approach is intended to spare non-targeted, healthy and non-cancerous cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing antitumor activity.  The novel drug, which targeted targeted to CD33, utilizes Seattle Genetics’ newest technology, comprising an engineered cysteine antibody (EC-mAb) stably linked to a highly potent DNA binding agent known as a pyrrolobenzodiazepine (PBD) dimer. Scientists believe that that this approach may help advance the treatment of AML [2]

Hypomethylating agent
The new trial includes azacitidine, a hypomethylating agent (HMA) commonly used in the treatment of MDS. Although HMAs have significantly improved the outcomes in patients with MDS, on average, prolonging survival by a median of only 9.5 months, only half achieve objective responses. Unfortunately most responders lose response within 1–2 years.

Of the two approved HMAs for the treatment of MDS (azacitidine and decitabine), only azacitidine has been shown to prolong survival in comparison to conventional care regimens. However, because failure of HMA therapy is associated with a very dismal prognosis. The median overall survival, after azacitidine  failure is between 5.6 and 4.3 months, hence novel therapeutic approaches are clearly needed. [3]

Intermediate and high risk
“Most newly diagnosed patients with intermediate or high risk MDS are ineligible for allogeneic stem cell transplant due to age, comorbidities or lack of appropriate donor. For these patients, novel therapies are urgently needed to prolong survival and delay disease progression into AML,” noted Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

“In our phase I AML clinical trial evaluating 33A plus HMAs, we have observed encouraging tolerability and depletion of blasts from the bone marrow in many patients, and we recently presented preclinical data demonstrating synergistic activity of [vadastuximab talirine] plus HMAs (either azacitidine or decitabine). Expanding our clinical evaluation of 33A in MDS is part of a broad clinical development strategy to establish 33A as the foundation of care for patients with myeloid malignancies,” Drachman added.

The phase I/II, open-label, multi-center clinical trial is designed to evaluate the safety and activity of vadastuximab talirine administered in combination with azacitidine in patients with previously untreated International Prognostic Scoring System (IPSS) Intermediate-2 or high risk MDS. Phase I of the study will identify the recommended dose of vadastuximab talirine when combined with azacitidine in this patient population. The phase II portion of the trial will be a randomized, double-blind, placebo-controlled study evaluating azacitidine with or without vadastuximab talirine.

The primary endpoint in phase I is determination of the recommended vadastuximab talirine dose in combination with azacitidine. The primary endpoint in phase II is to compare the overall response rate between the two treatment arms. The secondary endpoints include evaluation of safety, best response, duration of response, progression-free survival and overall survival. The phase I/II trial will enroll approximately 130 patients at approximately 35 centers in North America.

Other trials
As part of a clinical development program Seattle Genetics is evaluating vadastuximab talirine broadly across multiple lines of therapy in patients with acute myeloid leukemia (AML) and MDS. The trials include a phase I trial in combination with HMAs in AML patients who have relapsed/declined intensive frontline therapy or are newly diagnosed, a phase Ib trial in combination with standard of care intensive chemotherapy (including cytarabine and daunorubicin) for younger fit patients with AML, a phase I/II trial in patients with relapsed or refractory AML in which scientists evaluate the novel trial drug as a  monotherapy as a pre-conditioning regimen prior to an allogeneic stem cell transplant and also for use as maintenance therapy following transplant.  A phase III clinical trial to designed to evaluate vadastuximab talirine in combination with HMAs in previously untreated older AML patients is planned to begin by the third quarter of 2016.


Last Editorial Review: February 22, 2016

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Copyright © 2016 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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Vadastuximab Talirine Demonstrates Encouraging Anti-leukemic Activity in Acute Myeloid Leukemia

Several presentations at the 57th American Society of Hematology (ASH) Annual Meeting and Exposition taking place in Orlando, Florida, December 5-8, 2015, evaluating vadastuximab talirine (SGN-CD33A or 33A) in combination with hypomethylating agents (HMAs; azacitidine, decitabine) in frontline acute myeloid leukemia or AML and as monotherapy in primarily relapsed AML shows encouraging anti-leukemic activity.

Acute myeloid leukemia, also called acute myelocytic leukemia or AML, is an aggressive type of cancer of the bone marrow and blood that progresses rapidly without treatment. AML is a cancer that starts in the cells that are supposed to mature into different types of blood cells. AML starts in the bone marrow (the soft inner part of the bones, where new blood cells are made) and quickly moves into the blood. According to the American Cancer Society, in 2015 more than 20,500 new cases of AML (mostly in adults) will be diagnosed and nearly 10,500 deaths will occur from AML (almost all will be in adults).

A novel targeted drug
Vadastuximab talirine is a novel antibody-drug conjugate or ADC targeted to CD33 which is expressed on leukemic blasts in nearly all AML patients and expression is generally not influenced by subtype, cytogenetic abnormality or underlying mutations. The trial drug is based on Seattle Genetics’ newest technology in which a monoclonal antibody with engineered cysteines (EC-mAb) is attached via a proprietary site-specific conjugation technology to a pyrrolobenzodiazepine (PBD) dimer, a highly  potent DNA binding agent.

Pyrrolobenzodiazepine (PBD) dimers
The  PBD dimers are significantly more potent than systemic chemotherapeutic drugs and the site-specific conjugation technology allows uniform drug-loading of the cell-killing PBD agent to the anti-CD33 antibody. Pyrrolobenzodiazepine dimers have been shown to have broad spectrum anti-tumour activity in vivo. These novel drugs exert their activity by binding in the minor groove of DNA and linking the two DNA strands together in a way that cells find difficult to recognise and repair.

Furthermore, pyrrolobenzodiazepine (PBD) dimers combine potency with a demonstrated therapeutic index (unlike other payloads like calicheamycin), are not cross-resistant with widely used chemotherapy agents, and their unique mode of action sets them apart from the tubulin binders such as maytansinoids and auristatins that currently dominate the ADC arena.

Vadastuximab talirine is designed to be stable in the bloodstream and to release its potent DNA binding agent upon internalization into CD33-expressing cells. Vadastuximab talirine is being evaluated in ongoing phase I and phase I/II clinical trials and a planned pivotal phase III clinical trial for patients with AML.

Interim data
Based on interim data from the ongoing phase I clinical trial, a phase III clinical trial is planned to begin in 2016. The phase III study will evaluate vadastuximab talirine in combination with HMAs in previously untreated older AML patients. Seattle Genetics is also evaluating vadastuximab talirine broadly across multiple lines of therapy in patients with myeloid malignancies, including in ongoing and planned phase I and II clinical trials for newly diagnosed or relapsed AML and for newly diagnosed myelodysplastic syndrome or MDS.

Orphan drug designation
Vadastuximab talirine was recently granted Orphan Drug Designation by both the U.S. Food and Drug Administration (FDA) and the European Commission (EC) for the treatment of AML. FDA orphan drug designation is intended to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 individuals in the United States.

“For decades, little progress has been made in improving treatment outcomes for AML patients. Older AML patients have particularly poor outcomes and most do not tolerate intensive therapies,” said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. “Hypomethylating agents are a standard of care for these patients, but deliver low response rates and median overall survival of 10 months or less. We are committed to improving the therapeutic options for AML patients through innovative, targeted approaches. Based on the phase 1 data at ASH, we plan to advance [vadastuximab talirine] into a randomized phase III clinical trial in combination with HMAs for newly diagnosed older AML patients in 2016.”

Improving outcomes
“There is a dire need to improve outcomes for older patients with AML,” said Amir Fathi, M.D., Massachusetts General Hospital Cancer Center. “I am pleased with the anti-leukemic activity we have observed in phase I clinical trials evaluating [vadastuximab talirine] both as monotherapy and combination therapy in AML patients. This is an incredibly difficult disease to treat and the results to-date, especially in combination therapy, show a balance of activity and tolerability together with low early mortality rates. The response rates and durable remissions with [vadastuximab talirine] treatment compare favorably to the current standard of care.”

A Novel, Well-Tolerated Regimen with High Remission Rate
Outcomes for AML patients who are not candidates for intensive chemotherapy or allogeneic stem cell transplant are dismal. Low intensity treatment options, including HMAs (azacitidine and decitabine), are limited with complete remission and complete remission with incomplete platelet or neutrophil recovery (CR/CRi) rates of 17.8 to 27.8% and median overall survival of 7.7 to 10.4 months. Interim results from an ongoing phase I study evaluating vadastuximab talirine in combination with HMAs were presented for the first time. [1]

Data were reported from 25 frontline unfit AML patients with a median age of 77 years and predominantly intermediate or adverse cytogenetic risk who had declined intensive therapy. Forty-eight percent of patients had evidence of underlying myelodysplasia. The key findings presented by Fathi included:

  • Of 23 efficacy-evaluable patients treated with azacitidine or decitabine combination therapy with vadastuximab talirine, the best clinical response by investigator included 15 patients (65%) with a CR or CRi. Responses were observed in higher-risk patients, with remission achieved in eight of 10 patients (80%) with underlying myelodysplasia and eight of nine patients (89%) with adverse cytogenetics.
  • At a median follow-up of 7.7 months, median survival had not yet been reached and 72% of patients remained alive and on study. The 30- and 60-day mortality rates were zero and four percent, with no treatment-related deaths occurring during that time.
  • Ninety-six percent of patients (22 of 23) had reduction in bone marrow blasts, with 87% (20 of 23) experiencing a reduction of 50% or greater.
  • The most common treatment-related adverse events of any grade occurring in 20 percent or more of patients were fatigue (40%), nausea (32%), febrile neutropenia (28%), thrombocytopenia (24%) and neutropenia and anemia (20% each). The most common Grade 3 or 4 treatment-emergent adverse events occurring in 20% or more of patients were febrile neutropenia (56%), thrombocytopenia (32%), neutropenia (28%), anemia (24%) and fatigue (20%).

Monotherapy in Patients with CD33-Positive Acute Myeloid Leukemia
Data were reported from 93 AML patients treated with [vadastuximab talirine] monotherapy with a median age of 74 years and predominantly intermediate or adverse cytogenetic risk. The disease status of the 93 patients was a mixed AML population, consisting of mostly relapsed patients, but also a small percentage of older newly diagnosed patients. Of the 93 patients, 37% had previously received intensive therapy, 44% had received prior non-intensive therapy and 19% had declined intensive therapy. More than 58% of patients had evidence of underlying myelodysplasia. [2]

The key findings presented by Anthony Stein, M.D., City of Hope, include:

  • Of the 85 evaluable patients treated across all dose levels, 48% experienced blast clearance, including 23 patients (27%) with a CR or CRi. Of the 27 response-evaluable patients treated at the recommended monotherapy dose of 40 micrograms per kilogram (mcg/kg), 11 patients (41%) achieved a CR/CRi. Of 12 treatment naïve patients who were treated at 40 mcg/kg, seven patients (58%) achieved CR/CRi.
  • Among all patients treated at the 40 mcg/kg dose level or higher, 91% had a reduction in bone marrow blasts, with a majority experiencing a reduction of 50% or greater. The median overall survival for these predominantly relapsed AML patients was 8.9 months (95% C.I. 3.9, 13.7).
  • For patients achieving CR/CRi, 73% were negative for minimal residual disease.
  • The 30- and 60-day mortality rates were five and 27%.
  • The most common treatment-related adverse events of any grade occurring in 15 percent or more of patients were febrile neutropenia (39%), fatigue (27%), thrombocytopenia (26%), anemia (24%) and neutropenia (16%); the most common Grade 3 or higher adverse events occurring in 20 percent or more of patients were febrile neutropenia (66%), thrombocytopenia (28%) and anemia (24%).

Combination with Hypomethylating Agents is Highly Efficacious in Preclinical Models
A preclinical analysis evaluated the activity of vadastuximab talirine in combination with HMAs, azacitidine and decitabine, in AML models. Data presented in a poster presentation demonstrated enhanced cytotoxicity observed with the combination of vadastuximab talirine and HMAs as well as synergistic mechanisms of action and antitumor activity. In particular, HMA priming appears to increase CD33 expression and enhance DNA incorporation of PBDs released from vadastuximab talirine. [3]

Effective Anti-Leukemic Activity in Multiple Preclinical Models of AML
Preclinical data from a novel ADC called SGN-CD123A, consisting of an anti-CD123 antibody attached to a PBD dimer, were also featured in an oral presentation at ASH. CD123 is expressed across AML subtypes, and is particularly prominent on leukemic stem cells, which are difficult to kill and may be responsible for high relapse rates even following intensive therapy. Data presented in an oral session by Eric Feldman, M.D., Senior Medical Director at Seattle Genetics, demonstrated enhanced anti-leukemic activity observed across multiple AML cell lines, including four out of five multi-drug resistant cell lines, and in 20 of 23 AML patient samples. In addition, antitumor activity was observed in all of the in vivo models tested. These preclinical data support a phase I clinical trial of SGN-CD123A in AML planned to begin in the second-half of 2016. [4]


Last Editorial Review: December 12, 2015

Featured Image: Attendees traverse the Orange County Convention Center at the 2015 ASH Annual Meeting.  Courtesy: © American Society of Hematology. Used with permission.

Copyright © 2015 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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