Phase I/Ib Study of Nivolumab and Veliparib in Patients With Advanced Solid Tumors and Lymphoma With and Without Alterations in Selected DNA Repair Genes
Overview
- Phase
- Phase 1
- Intervention
- Laboratory Biomarker Analysis
- Conditions
- Advanced Solid Neoplasm
- Sponsor
- Northwestern University
- Enrollment
- 15
- Locations
- 1
- Primary Endpoint
- Maximum Tolerated Dose (MTD)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
The purpose of this research study is to determine the highest and safest dose of the experimental drug veliparib when combined with nivolumab. We will also study how safely this combination of medication can be given in advanced cancer and lymphoma and benefits of receiving this therapy. Nivolumab is currently approved in certain cancers such as melanoma, lung cancer and kidney cancer. Veliparib is not yet approved for use in the United States, and is considered experimental. Veliparib inhibits (blocks) the activity of the enzyme PARP. This blocking activity may prevent the cancer cell from repairing itself and resume growing. Nivolumab increases T cells in your immune system, which allows your immune system to attack the cancer. We think the combination of these drugs will be more effective against your cancer.
Detailed Description
PRIMARY OBJECTIVES: I. To identify maximum tolerated dose (MTD) for the combination treatment of nivolumab and veliparib in patients with advanced refractory solid cancers and lymphoma. SECONDARY OBJECTIVES: I. To evaluate the safety and tolerability of nivolumab and veliparib in patients with advanced refractory solid cancers and lymphoma with and without mutations in selected DNA repair genes. II. To evaluate the efficacy of treatment with nivolumab and veliparib in this population by objective response rate (ORR, defined as partial response \[PR\] + complete response \[CR\]), clinical benefit rate (CBR, defined as stable disease \[SD\] for \>= 12 weeks, PR, + CR), and progression free survival (PFS, defined as the time from treatment initiation to documented disease progression) using Response Evaluation Criteria in Solid Tumors (RECIST) criteria version (v)1.1 or Lugano criteria. III. To evaluate efficacy of treatment with nivolumab and veliparib in this population by ORR, CBR, and immune-related PFS (irPFS) using irRECIST criteria. IV. To evaluate overall survival (OS) in this population at 3 years from the start of treatment. V. To evaluate the proportion of patients alive and progression free at 24 weeks in this population. VI. To evaluate ORR to nivolumab and veliparib in patients with prior exposure to single agent PD-1/PD-L1 inhibitors. TERTIARY OBJECTIVES: I. To evaluate if any of the following predict response to veliparib in combination with nivolumab: tissue PD-L1 protein expression, immune cell infiltration markers. II. To demonstrate the pharmacodynamic effects of veliparib and nivolumab on biomarkers including PD-L1, TILs, T cell subpopulations, and T cell receptor genotype. III. To explore the pattern of clonal changes through circulating cell free DNA assay. IV. To assess the dynamic change in both immune and genomic biomarkers in blood that may correlate with response to veliparib. OUTLINE: This is a dose-escalation study of veliparib. Patients receive veliparib orally (PO) twice daily (BID) on day 1 and nivolumab intravenously (IV) over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 3, 6, 9, and 12 months and then every 6 months for 3 years.
Investigators
Young Kwang Chae
Principal Investigator
Northwestern University
Eligibility Criteria
Inclusion Criteria
- •Patients must have a histologically documented (either primary or metastatic site) diagnosis of advanced solid tumor cancer (stage IV or unresectable) or aggressive lymphoma (diffuse large B cell lymphoma, mantle cell lymphoma, T cell lymphoma, and natural killer \[NK\] cell lymphoma)
- •NOTE: The following histologies will be excluded given known response to PD-1/PD-L1 inhibitor monotherapy: non-small cell lung cancer, squamous cell carcinoma of head and neck, melanoma, renal cell carcinoma, bladder cancer, Hodgkin's lymphoma, Merkel cell carcinoma, and high-frequency microsatellite instability (MSI-H) colorectal cancer
- •All patients must have received, and be relapsed/refractory to at least one line of systemic therapy
- •NOTE: This does not include surgery or radiation alone; patients may have received any number of systemic therapies
- •All patients with relapsed/refractory lymphoma must have received or be ineligible for autologous stem cell transplant or be ineligible for allogeneic stem cell transplant
- •NOTE: Patients must not have had a prior allogeneic stem cell transplant
- •Patients must have measurable disease as per appropriate guidelines:
- •Solid tumors: by RECIST v1.1
- •Lymphoma: patient has at least one measurable nodal lesion (\>= 2 cm) according to Lugano classification; if the patient has no measurable nodal lesions \>= 2 cm in the long axis at screening, then the patient must have at least one measurable extra-nodal lesion
- •Patients must have the ability to understand and the willingness to sign a written consent prior to registration in the study
Exclusion Criteria
- •Patients who have had chemotherapy or radiotherapy =\< 14 days prior to entering the study are not eligible
- •NOTE: Patients may not have had systemic chemotherapy within 28 days
- •Patients are not eligible who have had major surgery =\< 14 days of registration; please contact principle investigator (PI) and quality assurance monitor (QAM) for questions about specific surgical procedures
- •Patients are not eligible who have received prior PARP inhibitors (including but not limited to veliparib, talazoparib, rucaparib, and olaparib)
- •Patients are not eligible who have received systemic chemotherapy or investigational agents =\< 28 days prior to registration
- •Patients are not eligible who have received prior immunotherapy including interleukin-2 and immune checkpoint antagonists and/or agonists (including but not limited to PD-1, PD-L1, CD137, or OX40)
- •NOTE: Single agent anti-CTLA4 monoclonal antibody treatments are permitted; cancer vaccine therapies are permitted
- •Patients with the following histologies are not eligible for either study cohort given known response to PD-1/PD-L1 inhibitor monotherapy:
- •Non-small cell lung cancer, squamous cell carcinoma of head and neck, melanoma, renal cell carcinoma, bladder cancer, Hodgkin's lymphoma, Merkel cell carcinoma, and MSI-H colorectal cancer
- •Patients are not eligible who have had a prior allogeneic stem cell transplant
Arms & Interventions
Treatment (veliparib, nivolumab)
Patients receive veliparib PO BID on day 1 and nivolumab IV over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Treatment (veliparib, nivolumab)
Patients receive veliparib PO BID on day 1 and nivolumab IV over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Nivolumab
Treatment (veliparib, nivolumab)
Patients receive veliparib PO BID on day 1 and nivolumab IV over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Pharmacological Study
Treatment (veliparib, nivolumab)
Patients receive veliparib PO BID on day 1 and nivolumab IV over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Veliparib
Outcomes
Primary Outcomes
Maximum Tolerated Dose (MTD)
Time Frame: First Cycle of Treatment with velaparib and nivolumab (28 days)
The MTD will be defined as the highest dose that causes dose-limiting toxicities (DLTs) in \<2 of 6 patients. Toxicity will be assessed using CTCAEv4.03. A DLT is defined as an Adverse Event (AE) or abnormal laboratory value assessed as at least possibly related to the study medication, occurs ≤ 28 days (1 cycle) following the first dose of veliparib and nivolumab and meets any of the following criteria: Grade ≥ 3 non-hematologic toxicities that represent at least a 2-grade increase from baseline excluding Nausea, vomiting, diarrhea lasting ≤48 hours, Electrolyte abnormalities resolving within ≤24 hours, Hypersensitivity reactions,and Alopecia. Grade 4 thrombocytopenia (platelets \< 25.0 x 109 /L) Grade 3 thrombocytopenia with bleeding (platelets \< 0.5 x 109 /L) 5. Grade 3 febrile neutropenia with fever lasting for \> 7 days 6. Grade 4 febrile neutropenia of any duration 7. Dosing delay due to toxicity for \> 14 consecutive days from the date nivolumab or veliparib is due.
Secondary Outcomes
- Progression Free Survival (PFS)(From the start of treatment and every 2 cycles during treatment, and up to three years, where 1 cycle =28 days, and range of cycles is 1-12.)
- Number of Participants With Adverse Events Possibly Related to Study Drugs Graded 3, 4, and 5(Up to 30 days after treatment discontinuation, where 1 cycle =28 days, and range of cycles is 1-12.)
- ORR (Overall Response Rate)(after 2 cycles at first response time point (1 cycle = 28 days))
- Clinical Benefit Rate (CBR)(From the start of treatment and every 2 cycles during treatment where 1 cycle =28 days, average number of cycles is 4 and range of cycles is 1-12.)
- Overall Survival (OS)(From the start of treatment and up to 3 years, where 1 cycle =28 days, and range of cycles is 1-12.)
- Number of Patients Alive and Progression Free at 24 Weeks(At 24 weeks)