Clinical Trials

Date: 2017-03-06

Type of information: Halting of the trial

phase: 1-2

Announcement: halting of the trial

Company: Seattle Genetics (USA - WA)

Product: SGN-CD33A (vadastuximab talirine)

Action mechanism:

• antibody drug conjugate. SGN-CD33A is a novel antibody-drug conjugate (ADC) targeted to CD33 utilizing Seattle Genetics’ newest ADC technology. CD33 is expressed on almost all AML cells regardless of subtype, cytogenetic abnormality, or underlying mutations. The CD33 antibody is attached to a highly potent DNA binding agent, a pyrrolobenzodiazepine (PBD) dimer, via a proprietary site-specific conjugation technology to a monoclonal antibody with engineered cysteines (EC-mAb). 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. SGN-CD33A is being evaluated in ongoing phase 1 and phase 1/2 clinical trials for patients with acute myeloid leukemia .

Disease: relapsed or refractory acute myeloid leukemia (AML)

Therapeutic area: Cancer - Oncology

Country: USA

Trial details:

• The phase 1/2, open-label, multi-center, clinical trial is a two-part (A and B) study designed to evaluate the safety and activity of SGN-CD33A administered in patients with relapsed chemotherapy-resistant acute myeloid leukemia (AML). Part A of the study will examine SGN-CD33 as cytoreduction pre-conditioning and Part B will evaluate SGN-CD33A in post-alloSCT as a maintenance regimen. Each part will consist of a phase 1 safety evaluation followed by a phase 2 expansion for activity. (NCT02614560)

Latest news:

• • On June 19, 2017, Seattle Genetics announced that it is discontinuing the phase 3 CASCADE clinical trial of vadastuximab talirine (SGN-CD33A) in frontline older acute myeloid leukemia (AML) patients.
• Seattle Genetics 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 also suspending patient enrollment and treatment in all of its vadastuximab talirine clinical trials including the ongoing phase 1/2 clinical trial in frontline high risk myelodysplastic syndrome (MDS). Seattle Genetics will closely review the data and consult with the FDA to determine future plans for the vadastuximab talirine development program.
• • On March 6, 2017, Seattle Genetics announced that the FDA has lifted the clinical hold announced on December 27, 2016 on phase 1 trials of vadastuximab talirine (SGN-CD33A; 33A) in acute myeloid leukemia. Seattle Genetics will resume two phase 1 trials of vadastuximab talirine. The first is combination treatment with standard of care, or 7+3, chemotherapy in newly diagnosed younger acute myeloid leukemia patients and the second is monotherapy and combination treatment with hypomethylating agents in both newly diagnosed and relapsed acute myeloid leukemia patients. Seattle Genetics will not resume the phase 1/2 trial of vadastuximab talirine monotherapy in pre- and post-allogeneic transplant acute myeloid leukemia patients given the challenges of developing therapies in this specific setting.
• • On December 27, 2016, Seattle Genetics announced that it has received notice from the FDA that a clinical hold or partial clinical hold has been placed on several early stage trials of vadastuximab talirine (SGN-CD33A) in acute myeloid leukemia (AML). The clinical holds were initiated to evaluate the potential risk of hepatotoxicity in patients who were treated with SGN-CD33A and received allogeneic stem cell transplant either before or after treatment. 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 SGN-CD33A 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 SGN-CD33A, to promptly identify appropriate protocol amendments for patient safety and to enable continuation of these trials.
• The phase 1/2 trial of SGN-CD33A monotherapy in pre- and post-allogeneic transplant AML patients has been placed on full clinical hold. Two phase 1 trials have been placed on partial clinical hold (no new enrollment, existing patients may continue treatment with re-consent). These studies are SGN-CD33A monotherapy, including a subset of older AML patients in combination with hypomethylating agents, and SGN-CD33A combination treatment with 7+3 chemotherapy in newly diagnosed younger AML patients. No new studies will be initiated until the clinical holds are lifted.
• • On December  5, 2016, Seattle Genetics highlighted three oral data presentations on vadastuximab talirine (SGN-CD33A; 33A) in patients with acute myeloid leukemia at the 58th American Society of Hematology (ASH) Annual Meeting. The data included updated results from an ongoing phase 1 clinical trial evaluating 33A in combination with hypomethylating agents (HMAs; azacitidine, decitabine) in frontline older AML patients. Further oral presentations focused on results from phase 1 clinical trials evaluating 33A in three distinct settings, including 1) as monotherapy in newly diagnosed older AML patients, 2) in combination with high-dose cytarabine for younger AML patients in first remission and 3) as monotherapy maintenance for younger AML patients who have completed frontline therapy or after allogeneic stem cell transplant. 33A is an investigational antibody-drug conjugate (ADC) targeted to CD33, a protein which is expressed on leukemic cells in nearly all AML patients.
• The following data from the ongoing phase 1 studies evaluating 33A combination therapy or monotherapy in AML patients were presented: Vadastuximab Talirine Plus Hypomethylating Agents: A Well-Tolerated Regimen with High Remission Rate in Frontline Older Patients With Acute Myeloid Leukemia (Abstract #591): 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.
• Data were reported from 53 frontline acute myeloid leukemia 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 percent of patients had evidence of underlying myelodysplasia, 11 percent had FLT3-mutated disease and 43 percent had secondary AML, which is AML that arises from prior chemotherapy, a pre-existing MDS or myeloproliferative disease. Key findings include:
• Of 49 patients evaluable for response, complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) was observed in 36 patients (73 percent). Remissions were observed in higher-risk patients, including 17 of 22 patients (77 percent) with secondary AML, five of five patients (100 percent) who were FLT3/ITD positive and 17 of 26 patients (65 percent) age 75 or older. Eighteen of the 36 patients (50 percent) 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 percent 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. 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. Vadastuximab Talirine Monotherapy in Older Patients with Treatment Naive CD33-Positive Acute Myeloid Leukemia (Abstract #590):  Interim results from 93 patients in the ongoing phase 1 study evaluating 33A monotherapy in AML patients were previously presented at the 2015 ASH Annual Meeting. New results describing the safety and activity of the recommended 33A monotherapy dose of 40 micrograms per kilogram (mcg/kg) in an expansion cohort of treatment-naïve older AML patients were presented by Dr. Anjali Advani, Cleveland Clinic.
• Data were reported from 27 treatment-naïve older AML patients with a median age of 74 years and intermediate or adverse cytogenetic risk of 70 percent and 26 percent, respectively. Regarding additional poor-prognosis indicators, 48 percent of patients had evidence of underlying myelodysplasia and 22 percent had FLT3 mutated disease. Key findings include:
• Of the 26 patients evaluable for response, remission (CR or CRi) was observed in 15 patients (58 percent), with a median time to remission of 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 percent) with underlying myelodysplasia and three of four patients (75 percent) 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 percent 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. A Phase 1b Study of Vadastuximab Talirine as Maintenance and in Combination with Standard Consolidation for Patients with Acute Myeloid Leukemia (Abstract #340): Interim results from an ongoing phase 1b study evaluating 33A in the AML post-remission setting, as a single agent for maintenance therapy or in combination with consolidation therapy (high-dose cytarabine; HiDAC), were presented by Dr. Jay Yang, Karmanos Cancer Institute.
• • On November 23, 2015, Seattle Genetics announced initiation of a phase 1/2 clinical trial of SGN-CD33A (vadastuximab talirine) in patients with relapsed or refractory acute myeloid leukemia. The trial will evaluate SGN-CD33A monotherapy as a pre-conditioning regimen prior to an allogeneic stem cell transplant (alloSCT) and also for use as maintenance therapy following transplant.  The phase 1/2, open-label, multi-center, clinical trial is a two-part (A and B) study designed to evaluate the safety and activity of SGN-CD33A administered in patients with relapsed chemotherapy-resistant AML. The primary endpoints in phase 1 are determination of the maximum tolerated dose (MTD) and the safety and tolerability profiles of SGN-CD33A in both pre- and post-alloSCT settings. The primary endpoints in phase 2 are to evaluate the one-year survival rates of patients treated with SGN-CD33A at the recommended dose pre- and post-alloSCT; to assess the rate of minimal residual disease negativity; and to further assess the safety and tolerability of SGN-CD33A at the recommended dose. The secondary endpoints include assessments of best response on study treatment, duration of response and overall survival. The two-part, phase 1/2 trial will enroll approximately 100 patients at multiple centers in the United States.

Is general: Yes