Neoadjuvant Nivolumab, or Nivolumab in Combination With Ipilimumab, in Resectable Non-Small-Cell Lung Cancer.
Overview
- Phase
- Phase 2
- Intervention
- Nivolumab
- Conditions
- Non-Small Cell Lung Cancer
- Sponsor
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
- Enrollment
- 39
- Locations
- 5
- Primary Endpoint
- Safety as Measured by Number of Participants With Grade 3 and 4 Lab Abnormalities, as Defined by CTCAE v4.03
- Status
- Active, not recruiting
- Last Updated
- 5 months ago
Overview
Brief Summary
The proposed study will evaluate the safety and feasibility of preoperative administration nivolumab +/- ipilimumab in patients with high-risk resectable NSCLC, and will facilitate a comprehensive exploratory characterization of the tumor immune milieu and circulating immune cells and soluble factors in these patients. Data obtained in this study will provide valuable information for planning further prospective clinical trials of anti-PD-1 and other immunotherapies in NSCLC, both in the peri-operative and advanced disease setting.
Detailed Description
The proposed study will evaluate the safety and feasibility of preoperative administration nivolumab +/- ipilimumab in patients with high-risk resectable NSCLC, and will facilitate a comprehensive exploratory characterization of the tumor immune milieu and circulating immune cells and soluble factors in these patients. Data obtained in this study will provide valuable information for planning further prospective clinical trials of anti-PD-1 and other immunotherapies in NSCLC, both in the peri-operative and advanced disease setting. Ultimately, it is highly desirable to discover prospective biomarkers of response and toxicity to allow patients with NSCLC who are most likely to derive benefit to receive anti-PD-1 treatment, and conversely to minimize the risk of toxicity and ineffective treatment for patients who are unlikely to benefit. In addition, an amendment to this study allows evaluation of the combination of nivolumab and the anti-CTLA4 antibody, ipilimumab in the neoadjuvant setting for the treatment of resectable NSCLC. In a large, multicohort, phase 1 trial, the ORR to combination ipilimumab and nivolumab therapy in patients unselected by PD-L1 status ranged from 39-47%. Incidence of grade 3-4 toxicity ranged from 33-37% across the combination ipilimumab and nivolumab cohorts which compares favorably with the rates of toxicity due to platinum doublet chemotherapy in this disease setting. The current amendment includes addition of a third arm (Arm C) combining nivolumab and platinum-doublet chemotherapy in the neoadjuvant setting.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically proven non-small-cell lung cancer (core biopsy required).
- •Squamous or non-squamous histology
- •Diagnostic core biopsy specimens must be reviewed by a faculty pathologist at SKCCC or MSKCC
- •Either a formalin fixed paraffin block or a minimum of fifteen 5-micron tissue sections (slides) of tumor biopsy sample must be available for biomarker evaluation (study pathologist must review for adequacy of sampling). This can be obtained from archived tissues, or from a new biopsy if needed.
- •Stage - High risk NSCLC with resection option for potential cure, as assessed by a faculty surgeon at SKCCC or MSKCC. This may include clinical stage IB (≥4cm), II and IIIA(see Appendix A). Subjects with N3 nodal involvement are not included.
- •ECOG performance status 0-1
- •Adequate organ function as follows:
- •Leukocytes ≥ 2,000/mm3
- •Absolute neutrophil count (ANC) ≥ 1000/mm3
- •Platelet count ≥ 100,000/mm3
Exclusion Criteria
- •Subjects are excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
- •Subjects are excluded if they have a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab-containing regimen.
- •Administration of chemotherapy or any other cancer therapy in the pre-operative period.
- •Subjects with active concurrent malignancies are excluded i.e. cancers other than NSCLC (except non melanoma skin cancers, in situ bladder, gastric, breast, colon or cervical cancers/dysplasia).
- •Subjects with brain metastasis are excluded from this study, and all patients should have brain imaging (either MRI brain or CT brain with contrast) prior to enrollment.
- •Subjects with a history of symptomatic interstitial lung disease.
- •Active systemic infection requiring therapy, positive tests for Hepatitis B surface antigen or Hepatitis C ribonucleic acid (RNA).
- •Known positive history or positive test for Human Immunodeficiency Virus or Acquired ImmunoDeficiency Syndrome (AIDS).
- •History of allergy to study drug components.
- •Women who are pregnant or nursing.
Arms & Interventions
Arm B- Nivolumab
Nivolumab administration: Three doses of nivolumab will be administered to enrolled patients on Day -42, Day -28, and Day-14 (+/- two days) prior to planned surgery on Day 0 or up to +10 days.
Intervention: Nivolumab
Arm C- Nivolumab, Carboplatin, & Paclitaxel
Nivolumab 360 mg IV, Carboplatin AUC 5 or 6 IV, and Paclitaxel 175 or 200 mg/m2 IV every 21 days for 3 cycles prior to planned surgery on Day 0.
Intervention: Nivolumab
Arm C- Nivolumab, Carboplatin, & Paclitaxel
Nivolumab 360 mg IV, Carboplatin AUC 5 or 6 IV, and Paclitaxel 175 or 200 mg/m2 IV every 21 days for 3 cycles prior to planned surgery on Day 0.
Intervention: Carboplatin
Arm C- Nivolumab, Carboplatin, & Paclitaxel
Nivolumab 360 mg IV, Carboplatin AUC 5 or 6 IV, and Paclitaxel 175 or 200 mg/m2 IV every 21 days for 3 cycles prior to planned surgery on Day 0.
Intervention: Paclitaxel
Arm A- Nivolumab and Ipilimumab
One dose of Nivolumab 3mg/kg IV \& Ipilimumab 1mg/kg will be administered to enrolled patients on Day-42, then 2 doses of Nivolumab 3mg/kg will be administered to enrolled patients on Day-28 and Day-14
Intervention: Nivolumab
Arm A- Nivolumab and Ipilimumab
One dose of Nivolumab 3mg/kg IV \& Ipilimumab 1mg/kg will be administered to enrolled patients on Day-42, then 2 doses of Nivolumab 3mg/kg will be administered to enrolled patients on Day-28 and Day-14
Intervention: Ipilimumab
Outcomes
Primary Outcomes
Safety as Measured by Number of Participants With Grade 3 and 4 Lab Abnormalities, as Defined by CTCAE v4.03
Time Frame: 8 weeks
Safety will be measured by drawing safety labs. (CBC and a Chemistry Panel will be drawn at 2 week intervals during Nivolumab administration). Grade 3 and 4 lab abnormalities will be recorded from both participating sites.
Safety as Assessed by Number of Grade 3 and 4 Adverse Events
Time Frame: 8 weeks
Number of Grade 3 and 4 adverse events as defined by CTCAE v4.03 that occur while a subject is participating in the study.
Secondary Outcomes
- Pathologic Response(6 weeks)
- Radiographic Response(5 weeks)