A Phase I/II Study to Determine Feasibility and Safety MK-3475 Alone or in Combination With Copanlisib in Relapsed or Refractory NK and T-cell Non-Hodgkin Lymphoma
Overview
- Phase
- Phase 1
- Intervention
- MK-3475
- Conditions
- Lymphoma, T-Cell, Peripheral
- Sponsor
- Fox Chase Cancer Center
- Enrollment
- 17
- Locations
- 1
- Primary Endpoint
- Recommended Phase II Dose of the Combination of Pembrolizumab and Copanlisib
- Status
- Terminated
- Last Updated
- 3 years ago
Overview
Brief Summary
This is a multicenter, single-arm, open label, study consisting of two cohorts. Cohort 2 explores the combination of copanlisib and pembrolizumab in patients with relapsed or refractory NKTCL, who have received at least 1 prior systemic therapy. Cohort 2 will include a phase 1 portion (cohort 2a) to determine the recommended phase 2 dose (RP2D) utilizing a standard 3+3 design, followed by a phase II portion where patients will be treated at the RP2D (cohort 2b). The primary endpoint for cohort 1 was progression-free survival; the primary endpoint for cohort 2a will be to determine RP2D for the combination therapy; and overall response rate at the end of 4 treatment cycles for cohort 2b. Patients will be assessed for response with PET CT or CT every 12 weeks using the revised Cheson criteria. Correlative endpoints will be exploratory and assess PD-1 expression on peripheral blood lymphocytes; peripheral blood T-cell and NK-cell functional assays; PD-1 and PD-L1 expression on tumor tissue; tumor infiltrating lymphocytes and gene expression panels using the nanostring technology as prognostic and predictive biomarkers, as well as monitoring of minimal residual disease via high-throughput sequencing of cell free tumor DNA, and exosome analysis.
Detailed Description
Patients with relapsed or refractory (RR) NK and T-cell Lymphoma (NKTCL), who have received at least 1 prior systemic therapy, were enrolled in cohort 1. The study design for cohort 1 was a single arm phase II 2-stage design, to explore monotherapy with the PD-1 antibody pembrolizumab (or MK-3475) given intravenously at a fixed dose of 200mg every 3 weeks for up to 36 cycles. Enrollment to this cohort has been completed.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Have a histologically or cytologically confirmed relapsed/refractory mature T-cell lymphoma that has progressed after a minimum of 1 systemic therapy with any of the following T-cell histologies:
- •Peripheral T-cell NHL, not other wise specified (PTCL, NOS)
- •Anaplastic large cell T-cell lymphoma (ALCL)
- •Anaplastic lymphoma kinase positive or negative
- •Angioimmunoblastic T-cell lymphoma
- •Subcutaneous panniculitis like T-cell lymphoma
- •Follicular T-cell lymphoma
- •Nodal peripheral T-cell lymphoma with TFH phenotype
- •Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)
- •Enteropathy associated T-cell lymphoma
Exclusion Criteria
- •Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 2 weeks of the first dose of treatment.
- •Patients diagnosed with Adult T-cell Leukemia/Lymphoma (ATLL) or T-cell PLL
- •Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
- •Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., worse than Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
- •Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
- •Note: Subjects with worse than Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
- •Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
- •Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
- •Has known active intraparenchymal lymphomatous central nervous system (CNS) lesions and/or lymphomatous meningitis. Subjects with previously treated CNS involvement by lymphoma may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain lesions, and are not using steroids for at least 7 days prior to trial treatment.
- •Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjoegren's syndrome will not be excluded from the study.
Arms & Interventions
Treatment
MK-3475 given intravenously at a fixed dose of 200mg every 3 weeks for up to 36 cycles
Intervention: MK-3475
Combination
MK-3475 is given intravenously at a fixed dose of 200mg every 3 weeks Copanlisib is given intravenously at RP2D determined from Phase I study
Intervention: MK-3475
Combination
MK-3475 is given intravenously at a fixed dose of 200mg every 3 weeks Copanlisib is given intravenously at RP2D determined from Phase I study
Intervention: Copanlisib
Outcomes
Primary Outcomes
Recommended Phase II Dose of the Combination of Pembrolizumab and Copanlisib
Time Frame: 6 months
Progression Free Survival
Time Frame: 3 Months
Based on RECIST v1.1
Determine Overall Response Rate by 4 Cycles of Combination of Pembrolizumab and Copanlisib
Time Frame: 6 months
Secondary Outcomes
- Maximum Tolerated Dose of Pembrolizumab and Copanlisib(6 months)
- Expression of PD-1, PD-L1 and Tumor Infiltrating Lymphocytes (TIL) in Pre-treatment Tumor Specimens(1 year)
- Overall Survival(6 Months)