Phase I/II Study of Nivolumab and Ipilimumab Combined With Nintedanib in Non Small Cell Lung Cancer
Overview
- Phase
- Phase 1
- Intervention
- Nivolumab
- Conditions
- Non Small Cell Lung Cancer
- Sponsor
- H. Lee Moffitt Cancer Center and Research Institute
- Enrollment
- 66
- Locations
- 1
- Primary Endpoint
- Phase 1 - Maximum Tolerated Dose (MTD)
- Status
- Active, Not Recruiting
- Last Updated
- 3 months ago
Overview
Brief Summary
The main purpose of this study is to see if the combination of nivolumab, ipilimumab and nintedanib is effective in people with non- small cell lung cancer. Researchers also want to find out if the combination of nivolumab, ipilimumab and nintedanib is safe and tolerable.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participants must have histologic or cytological diagnosis of advanced/metastatic Non-Small Cell Lung Cancer (NSCLC) with no curative treatment options. For those with mixed histology, there must be a predominant histology.
- •18 years of age or older on day of signing informed consent.
- •Life expectancy of at least 3-6 months.
- •Eastern Cooperative Oncology Group (ECOG) performance status score 0 and 1
- •For phase I trial portion, treatment naïve or patients previously treated with chemotherapy, immunotherapy or targeted therapy for NSCLC are allowed. Patient who underwent curative intent chemotherapy and/radiation in the neoadjuvant or adjuvant setting are allowed to enroll if tumor recurrence occurred greater than 6 months from completion of that therapy (and will be considered treatment naïve in the Stage IV setting). Patients with NSCLC tumor known to harbor a genomic aberration for which FDA approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if they have received prior treatment with the FDA approved targeted therapy.
- •For phase II trial portion, Patients will be enrolled as two parallel cohorts:
- •A.) Arm A (treatment naïve): Patients who are newly diagnosed and treatment naïve. Patient who underwent curative intent chemotherapy and/radiation in the neoadjuvant or adjuvant setting are allowed to enroll if tumor recurrence occurred greater than 6 months from completion of therapy. Patients with NSCLC tumor known to harbor a genomic aberration for which FDA approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if they have received prior treatment with the FDA approved targeted therapy.
- •B.) Arm B (Immunotherapy pre-treated group): Patients who have received prior immunotherapy. Patients who are primary refractory to immunotherapy (i.e., Patients who were previously treated with immunotherapy and did not at least achieve stable disease on first imaging assessment on immunotherapy) or have relapsed disease (i.e., Patients that were treated with immunotherapy, achieved at least stable disease on first imaging assessment and subsequently developed disease progression or relapse). Patients with NSCLC tumor known to harbor a genomic aberration for which FDA approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if they have received prior treatment with the FDA approved targeted therapy
- •At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.
- •QTcB must be \<470 ms for males and \<480 ms for females.
Exclusion Criteria
- •Concurrent use of other anticancer agents including chemotherapy, targeted therapy, radiotherapy or immunotherapy not otherwise specified in the protocol.
- •Concurrent use of other investigational drugs or treatment in another clinical trial with a non- FDA-approved medication within the past 4 weeks before start of therapy.
- •Chemo-, or immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors within the past 2 weeks prior to treatment with the trial drug.
- •Radiotherapy (except for brain and extremities or stereotactic treatment) within the past 2 weeks prior to treatment with the trial drug.
- •In immunotherapy pretreated patients, any history of dose-limiting toxicity with prior immunotherapy agents, including grade 3/4 immune-related adverse events (irAEs); irreversible irAEs; Grade ≥3 irAEs that did not respond to steroid rescue; or neurologic irAE with significant clinical sequelae.
- •Prior treatment with nintedanib (BIBF1120).
- •Known hypersensitivity to nintedanib, nivolumab, ipilimumab, peanut or soy or any other trial drug, or their excipients.
- •Any toxicity (\>CTCAE version 5 grade 3) from previous anti-cancer therapy that has not resolved to a Grade
- •Persistence of clinically relevant therapy related toxicity from previous chemo and/or radiotherapy. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy, alopecia).
- •History of leptomeningeal carcinomatosis.
Arms & Interventions
Phase 1 Nintedanib Dose Escalation 100-200 mg QD to BID
Nivolumab + Ipilimumab + Nintedanib dose escalation. Participants were given the following: Nivolumab: 3 mg/kg IV Q2 weeks. Ipilimumab: 1 mg/kg Q6 weeks. Nintedanib Level -1: 100 mg by mouth (PO) once a day (QD) Days 1-14 (Daily dose =100 mg). Nintedanib Level 0:150 mg by mouth (PO) once a day (QD) Days 1-14 (Daily dose =150 mg) Nintedanib Level 1: 100 mg PO twice daily (BID) Days 2-28 (Daily dose = 200 mg). Nintedanib Level 2: 150 mg PO BID Days 1-14 (Daily dose = 300 mg). Nintedanib Level 3: 200 mg PO BID Days 1-14 (Daily dose = 400 mg).
Intervention: Nivolumab
Phase 1 Nintedanib Dose Escalation 100-200 mg QD to BID
Nivolumab + Ipilimumab + Nintedanib dose escalation. Participants were given the following: Nivolumab: 3 mg/kg IV Q2 weeks. Ipilimumab: 1 mg/kg Q6 weeks. Nintedanib Level -1: 100 mg by mouth (PO) once a day (QD) Days 1-14 (Daily dose =100 mg). Nintedanib Level 0:150 mg by mouth (PO) once a day (QD) Days 1-14 (Daily dose =150 mg) Nintedanib Level 1: 100 mg PO twice daily (BID) Days 2-28 (Daily dose = 200 mg). Nintedanib Level 2: 150 mg PO BID Days 1-14 (Daily dose = 300 mg). Nintedanib Level 3: 200 mg PO BID Days 1-14 (Daily dose = 400 mg).
Intervention: Ipilimumab
Phase 1 Nintedanib Dose Escalation 100-200 mg QD to BID
Nivolumab + Ipilimumab + Nintedanib dose escalation. Participants were given the following: Nivolumab: 3 mg/kg IV Q2 weeks. Ipilimumab: 1 mg/kg Q6 weeks. Nintedanib Level -1: 100 mg by mouth (PO) once a day (QD) Days 1-14 (Daily dose =100 mg). Nintedanib Level 0:150 mg by mouth (PO) once a day (QD) Days 1-14 (Daily dose =150 mg) Nintedanib Level 1: 100 mg PO twice daily (BID) Days 2-28 (Daily dose = 200 mg). Nintedanib Level 2: 150 mg PO BID Days 1-14 (Daily dose = 300 mg). Nintedanib Level 3: 200 mg PO BID Days 1-14 (Daily dose = 400 mg).
Intervention: Nintedanib
Phase 2 - Arm A Nintedanib 100-200 mg BID Treatment-naïve
Arm A: Treatment-naïve defined as newly diagnosed or treatment-naïve patients, with a target overall response rate (ORR) of 50%. Participants were given the following: Nivolumab + Ipilimumab + Nintedanib at RP2D. Nivolumab: Intravenous nivolumab every 2 weeks. Ipilimumab: Intravenous ipilimumab every 6 weeks. Nintedanib: Nintedanib 100-200 mg capsules by mouth twice daily for two-week cycles.
Intervention: Nivolumab
Phase 2 - Arm A Nintedanib 100-200 mg BID Treatment-naïve
Arm A: Treatment-naïve defined as newly diagnosed or treatment-naïve patients, with a target overall response rate (ORR) of 50%. Participants were given the following: Nivolumab + Ipilimumab + Nintedanib at RP2D. Nivolumab: Intravenous nivolumab every 2 weeks. Ipilimumab: Intravenous ipilimumab every 6 weeks. Nintedanib: Nintedanib 100-200 mg capsules by mouth twice daily for two-week cycles.
Intervention: Ipilimumab
Phase 2 - Arm A Nintedanib 100-200 mg BID Treatment-naïve
Arm A: Treatment-naïve defined as newly diagnosed or treatment-naïve patients, with a target overall response rate (ORR) of 50%. Participants were given the following: Nivolumab + Ipilimumab + Nintedanib at RP2D. Nivolumab: Intravenous nivolumab every 2 weeks. Ipilimumab: Intravenous ipilimumab every 6 weeks. Nintedanib: Nintedanib 100-200 mg capsules by mouth twice daily for two-week cycles.
Intervention: Nintedanib
Phase 2 - Arm B Nintedanib 100-200 mg BID Treatment Non-naïve
Arm B: Treatment Non-naïve defined as patients who have been previously exposed to immunotherapy, such as anti-PD-1, anti-PD-L1 or anti-CTLA-4, with a target ORR of 20%. Participants were given the following: Nivolumab + Ipilimumab + Nintedanib at RP2D. Nivolumab: Intravenous nivolumab every 2 weeks. Ipilimumab: Intravenous ipilimumab every 6 weeks. Nintedanib: Nintedanib 100-200 mg capsules by mouth twice daily for two-week cycles.
Intervention: Nivolumab
Phase 2 - Arm B Nintedanib 100-200 mg BID Treatment Non-naïve
Arm B: Treatment Non-naïve defined as patients who have been previously exposed to immunotherapy, such as anti-PD-1, anti-PD-L1 or anti-CTLA-4, with a target ORR of 20%. Participants were given the following: Nivolumab + Ipilimumab + Nintedanib at RP2D. Nivolumab: Intravenous nivolumab every 2 weeks. Ipilimumab: Intravenous ipilimumab every 6 weeks. Nintedanib: Nintedanib 100-200 mg capsules by mouth twice daily for two-week cycles.
Intervention: Ipilimumab
Phase 2 - Arm B Nintedanib 100-200 mg BID Treatment Non-naïve
Arm B: Treatment Non-naïve defined as patients who have been previously exposed to immunotherapy, such as anti-PD-1, anti-PD-L1 or anti-CTLA-4, with a target ORR of 20%. Participants were given the following: Nivolumab + Ipilimumab + Nintedanib at RP2D. Nivolumab: Intravenous nivolumab every 2 weeks. Ipilimumab: Intravenous ipilimumab every 6 weeks. Nintedanib: Nintedanib 100-200 mg capsules by mouth twice daily for two-week cycles.
Intervention: Nintedanib
Outcomes
Primary Outcomes
Phase 1 - Maximum Tolerated Dose (MTD)
Time Frame: Up to 12 months
Dose escalation to determine the MTD and Recommended Phase 2 Dose (RP2D) of concurrent administration of nivolumab, ipilimumab, and nintedanib. The maximum tolerated dose (MTD) is defined as the dose with the dose limiting toxicity (DLT) rate of 30%. Phase 1 began with 100 mg nintedanib, 3 mg/kg IV nivolumab + 1 mg/kg ipilimumab. Dosing of nintedanib increased by 50 mg in each level until dose limiting toxicity.
Phase 2 - Objective Response Rate (ORR) Per Treatment Arm
Time Frame: Up to 36 months
Objective response is defined as confirmed CR or confirmed PR based on modified RECIST guidelines version 1.1. The ORR will be estimated by calculating the proportion of patients who achieve OR; the 80% Confidence Interval (CI) and 95% CI for the OR rate will be estimated using the exact binomial distribution. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Secondary Outcomes
- Phase 2: Disease Control Rate (DCR)(Up to 36 months)
- Phase 2: Overall Survival (OS)(Up to 36 months)
- Phase 2: Progression-free Survival (PFS)(Up to 36 months)