A Phase II, Multi-Cohort Trial of Combination Nivolumab and Temozolomide in Recurrent/Refractory Small-Cell Lung Cancer and Advanced Neuroendocrine Tumors
Overview
- Phase
- Phase 2
- Intervention
- Nivolumab
- Conditions
- Grade I Neuroendocrine Carcinoma
- Sponsor
- Dwight Owen
- Enrollment
- 55
- Locations
- 2
- Primary Endpoint
- Objective response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
- Status
- Active, not recruiting
- Last Updated
- 4 months ago
Overview
Brief Summary
This phase II trial studies how well nivolumab and temozolomide work in treating patients with small-cell lung cancer that has come back or does not respond to treatment, or neuroendocrine cancer that has spread to other places in the body. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab and temozolomide may work better in treating patients with small-cell lung cancer and neuroendocrine cancer.
Detailed Description
PRIMARY OBJECTIVES: I. To evaluate the efficacy (using response rate per RECIST v1.1) of nivolumab and temozolomide for the treatment of patients with either small cell lung cancer that have progressed or recurred after prior platinum-based chemotherapy and immunotherapy (cohort 1), or progressive metastatic neuroendocrine carcinoma of any grade or primary site in any line of therapy (cohort 2). SECONDARY OBJECTIVES: I. To evaluate the safety profile and toxicity of combination nivolumab and temozolomide as per Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 5.0. II. To evaluate the progression free survival (PFS) and overall survival (OS) of patients treated with combination nivolumab and temozolomide. III. To evaluate the central nervous system (CNS) PFS of patients with small cell lung cancer (SCLC) treated with nivolumab and temozolomide. EXPLORATORY OBJECTIVES: I. To determine whether treatment with nivolumab and temozolomide leads to a decrease in immune-suppressive cell populations (ie myeloid-derived suppressor cells \[MDSC\]) in peripheral blood. II. To determine whether objective response rate (ORR), PFS, OS vary by tumor O6-methylguanine deoxyribonucleic acid (DNA) methyltransferase (MGMT) methylation at baseline. III. To determine whether baseline tumor mutational burden is predictive of response to therapy in patients with SCLC treated with nivolumab and temozolomide. IV. To determine whether changes in blood based mutation burden during treatment may predict clinical benefit. V. To determine whether a composite immune and tumor cell staining score can be developed with or without PD-L1 by immunohistochemistry (IHC) to predict response in the SCLC cohort. OUTLINE: Patients receive nivolumab intravenously (IV) on day 1 of a 28 day cycle. Patients also receive temozolomide orally (PO) on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, every 8 weeks for 12 months, then every 12 weeks thereafter.
Investigators
Dwight Owen
Principal Investigator
Ohio State University Comprehensive Cancer Center
Eligibility Criteria
Inclusion Criteria
- •Be willing and able to provide written informed consent/assent for the trial
- •For Cohort 1: Have histologically or cytologically-documented diagnosis of advanced (metastatic and/or unresectable) small cell lung cancer and have progressed or recurred after platinum-based chemotherapy with immunotherapy. Eligible patients will be defined as follows:
- •Sensitive disease: Patients who had one previous line of chemotherapy and relapsed after \> 90 days of completion of treatment
- •Refractory disease: Patients with no response to first-line chemotherapy or progression \< 90 days after completing treatment.
- •For cohort 1: maximum of 2 prior lines of therapy is allowed (ie second or third line treatment)
- •For Cohort 2: Have histologically or cytologically-documented diagnosis of advanced (metastatic and/or unresectable) neuroendocrine tumor/carcinoma of any grade (World Health Organization \[WHO\] Grade 1-3) of any origin, in any line of therapy (ie both treatment na?ve and pre-treated patients allowed), and have clinical or biochemical or radiographic progression in the 12 months prior to study registration. Concomitant use of a somatostatin analogue is allowed, as long as patients have been on a stable dose for at least 2 months
- •Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.
- •For Cohort 1: Availability of a recent formalin-fixed, paraffin-embedded (FFPE) tumor tissue block. A recently obtained archival FFPE tumor tissue block from a primary or metastatic tumor resection or biopsy can be provided if it was obtained within 1 year of trial screening. Patients with tumor specimens older than 1 year may still be eligible if deemed so by study sponsor. For Cohort 2: archival tissue as above is preferred, but not required for trial entry. Verification of tumor burden in the biopsy is encouraged. For optimal biomarker results, tumor content should be \> 30% of total tissue area
- •Be willing to provide peripheral blood samples at screening and day 1 of cycles 1, 2 and 3 as well as at progressive disease for correlative studies
- •Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
Exclusion Criteria
- •Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
- •Has received prior temozolomide therapy
- •Prior immunotherapy with checkpoint inhibitors (including antibodies to PD-1, PD-L1, is allowed only in Cohort 1 and must have been given in combination with chemotherapy as part of first line treatment. Prior CTLA-4 therapy is excluded in both cohorts.
- •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 a known history of active TB (Bacillus Tuberculosis)
- •Hypersensitivity to nivolumab or temozolomide or any of their excipients
- •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 =\< grade 2 neuropathy due to chemotherapy 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
Arms & Interventions
Treatment (nivolumab, temozolomide)
Patients receive nivolumab IV on day 1 of a 28 day cycle. Patients also receive temozolomide PO on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Nivolumab
Treatment (nivolumab, temozolomide)
Patients receive nivolumab IV on day 1 of a 28 day cycle. Patients also receive temozolomide PO on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Temozolomide
Outcomes
Primary Outcomes
Objective response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
Time Frame: Up to 3 years
Response will be defined by a complete response (CR) or partial response (PR), confirmed or unconfirmed. Response will be defined for patients with measurable disease and who receive at least one dose of combination treatment. Exact binomial 95% confidence intervals for the true PR+CR response rate will be calculated.
Secondary Outcomes
- Progression-free survival (PFS)(The time from allocation to the first documented disease progression according to RECIST 1.1 or death due to any cause, whichever occurs first, assessed up to 3 years)
- Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0(Up to 3 years)
- Overall survival (OS) of patients(Up to 3 years)
- Central nervous system (CNS) PFS(The time from allocation to the first documented disease progression within the CNS according to RECIST 1.1, assessed up to 3 years)