A Phase Ib Multi-Cohort Trial of MK-3475 in Subjects with Hematologic Malignancies
B Douglas Smith
The primary objectives of the trial are to determine safety, tolerability, and efficacy of MK-3475 in subjects with hematologic malignancies. Secondary objectives include further analysis of various efficacy parameters (TTP/PFS/OS) for each respective indication, as well as an analysis of PD-L1 expression and corresponding efficacy. The pharmacokinetic (PK) properties of MK-3475 and the relationship of candidate efficacy/resistance biomarkers and anti-tumor activity of MK-3475 will be investigated as exploratory objectives.
This is a multicenter, nonrandomized trial of MK-3475 in subjects with intermediate-1, intermediate-2, or high risk MDS who have failed to respond to at least 4 cycles of prior treatment with a hypomethylating agent (Cohort 1). Cohort 1: MDS 1. Be willing and able to provide written informed consent/assent for the trial. The subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research. 2. Be greater than or equal to 18 years of age on day of signing informed consent. 3. Have primary or secondary MDS with IPSS score of Intermediate-1, Intermediate-2, or High and has failed (defined as worsening of cytopenias, increase in percentage of bone marrow blasts, or progression to more advanced MDS FAB subtype than pretreatment) to respond to at least 4 cycles of prior treatment with a hypomethylating agent (azacitidine and decitabine). Per IWG criteria, progression is defined as: ï?· Less than 5% blasts: greater than or equal to 50% increase in blasts to greater than 5% blasts ï?· 5%-10% blasts: greater than or equal to 50% increase to greater than 10% blasts ï?· 10%-20% blasts: greater than or equal to 50% increase to greater than 20% blasts ï?· 20%-30% blasts: greater than or equal to 50% increase to greater than 30% blasts Or any of the following: ï?· At least 50% decrement from maximum remission/response in granulocytes or platelets ï?· Reduction in Hgb by greater than or equal to 2 g/dL ï?· Transfusion dependence 4. Be expected to survive long enough to assess for response or benefit from treatment at investigatorâ??s discretion. 5. Have a performance status of 0 or 1 on the ECOG Performance Scale. 6. Be able to provide bone marrow biopsy/aspirate material for biomarker analysis or is willing to provide a newly obtained bone marrow biopsy/aspirate. 7. Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 10 days of treatment initiation.
Approximately 100 subjects will be enrolled in this trial to examine the safety and efficacy of a 10 mg/kg dose of MK-3475 administered every 2 weeks (Q2W). Adverse events will be monitored every two weeks throughout the trial and graded in severity according to the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Treatment with MK-3475 will continue until documented disease progression, unacceptable adverse event(s), intercurrent illness that prevents further administration of treatment, investigatorâ??s decision to withdraw the subject, subject withdraws consent, pregnancy of the subject, noncompliance with trial treatment or procedure requirements, or administrative reasons.
07/29/2014 04:02 AM