Neoadjuvant Combination Biotherapy With Ipilimumab and Nivolumab or Nivolumab Alone in Patients With Locally/Regionally Advanced/Recurrent Melanoma: A Randomized Efficacy, Safety and Biomarker Study
Overview
- Phase
- Phase 1
- Intervention
- Nivolumab - Arm A
- Conditions
- Melanoma
- Sponsor
- University of Pittsburgh
- Locations
- 1
- Primary Endpoint
- Assess the pathologic complete response rate (absence of viable tumor on histologic assessment)
- Status
- Withdrawn
- Last Updated
- 8 years ago
Overview
Brief Summary
This study plans to test the pathologic complete response (pCR) rate of the combination biotherapy regimen consisting of nivolumab plus ipilimumab versus nivolumab alone in patients with advanced but operable melanoma. Evaluation of the presence of tumor-infiltrating CD8+ T cells as well as that of PDL1 expression and IDO expression will be associated with clinical response (pathologic and/or radiologic). The study will test the radiologic/clinical preoperative response rate, recurrence free survival (RFS) and overall survival (OS). It will evaluate the safety of neoadjuvant nivolumab and neoadjuvant nivolumab-ipilimumab. Up to 66 patients will be randomized in 1:1 ratio.
Detailed Description
The study has 2 study arms: * Nivolumab alone (Arm A) * Induction phase: nivolumab 3 mg/kg IV infusion every 2 weeks x3 doses. Followed by Definitive Surgery. * Maintenance phase: nivolumab 3 mg/kg IV infusion every 3 weeks for up to one year from study treatment initiation. * Ipilimumab + nivolumab (Arm B) * Induction phase: Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV every 3 weeks x2. Followed by Definitive Surgery. * Maintenance phase: nivolumab 3 mg/kg IV infusion every 2 weeks for up to one year from study treatment initiation. Definitive Surgery consists of complete lymph node dissection/ lymphatic, cutaneous, subcutaneous or other distant disease resection (week 6-8+).
Investigators
Ahmad Tarhini
Principal Investigator
University of Pittsburgh
Eligibility Criteria
Inclusion Criteria
- •Men and women at least 18 years of age
- •Willing and able to give written informed consent
- •Performance status Eastern Cooperative Oncology Group (ECOG) zero or 1
- •Histologic diagnosis of melanoma belonging to the following AJCC Tumor Node and Metastasis (TNM) stages: Tx or T1-4 and N1b or N2 or N2c or N3 and/or M0 or M1 (if considered surgically operable)
- •Patients are eligible for this trial either at presentation for primary melanoma with concurrent regional nodal and/or in-transit metastasis and/or distant metastasis, or at the time of clinically detected nodal and/or in-transit recurrence and/or distant metastasis and may belong to any of the following groups: Primary melanoma with clinically apparent (overt) regional lymph node metastases.
- •Clinically detected recurrence of melanoma at the proximal regional lymph node(s) basin.
- •Clinically detected primary melanoma involving multiple regional nodal groups.
- •Clinically detected site of nodal metastatic melanoma arising from an unknown primary.
- •Patients with intransit or satellite metastases with or without lymph node involvement are allowed if they are considered surgically resectable at baseline.
- •Patients with distant metastases with or without intransit or lymph node involvement are allowed if they are considered potentially surgically resectable at baseline. NOTE: All patients must be determined to be surgically resectable at baseline to be eligible for this neoadjuvant study.
Exclusion Criteria
- •Subject will be excluded from participating in the trial if they meet any of the following criteria:
- •Patients are excluded if they have a history of central nervous system (CNS)metastases.
- •Patients who have had a history of acute diverticulitis, intra-abdominal abscess, GI obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation.
- •Any other malignancy from which the patient has been disease-free for less than 3 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix.
- •Patients will be excluded if they have an active, known or suspected autoimmune disease. Autoimmune disease: Patients with a history of inflammatory bowel disease are excluded from this study, as are patients with a history of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, autoimmune vasculitis e.g., Wegener's Granulomatosis); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome).
- •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.
- •Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
- •Patients should be 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.
- •Has an active infection requiring systemic therapy.
Arms & Interventions
Arm A consists of 3 phases or steps
Induction Phase Nivolumab 3 mg/kg IV infusion every 2 weeks for 3 doses Definitive Surgery Complete lymph node dissection/ lymphatic, cutaneous, subcutaneous disease resection (week 6-8+) Maintenance Phase (after recovery from surgery) Nivolumab 3 mg/kg IV infusion every 3 weeks
Intervention: Nivolumab - Arm A
Arm B consists of 3 phases or steps
Nivolumab 1 mg/kg IV infusion every 3 weeks for 2 doses given concurrently with Ipilimumab 3 mg/kg IV infusion every 3 weeks for 2 doses Definitive Surgery Complete lymph node dissection/ lymphatic, cutaneous, subcutaneous disease resection (week 6-8+) Maintenance Phase (after recovery from surgery) Nivolumab 1 mg/kg IV infusion every 3 weeks for 2 doses given concurrently with Ipilimumab 3 mg/kg IV infusion every 3 weeks for 2 doses; then, Nivolumab 3 mg/kg IV infusion every 3 weeks
Intervention: Nivolumab + Ipilimumab - Arm B
Outcomes
Primary Outcomes
Assess the pathologic complete response rate (absence of viable tumor on histologic assessment)
Time Frame: 5 years
Secondary Outcomes
- Assess biomarkers CD8 T cell, PD-L1 and IDO expression by immunohistochemistry(5 years)
- Evaluate preoperative clinical/radiologic response rate(5 years)
- Assess progression free survival(5 years)
- Assess overall survival(5 years)
- Assess safety and adverse events(5 years)