Neoadjuvant Combination Biotherapy With Ipilimumab and Nivolumab or Nivolumab Alone

NCT02736123 | Withdrawn Phase 1 DMC

• 1 other identifier: 15-113
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

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.

Conditions

Melanoma

Outcome Measures

Primary Outcomes (1)

• Assess the pathologic complete response rate (absence of viable tumor on histologic assessment)

  5 years

Secondary Outcomes (5)

• Evaluate preoperative clinical/radiologic response rate

  5 years

• Assess progression free survival

  5 years

• Assess overall survival

  5 years

• Assess biomarkers CD8 T cell, PD-L1 and IDO expression by immunohistochemistry

  5 years

• Assess safety and adverse events

  5 years

Study Arms (2)

Arm A consists of 3 phases or steps

EXPERIMENTAL

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

Drug: Nivolumab - Arm A

Arm B consists of 3 phases or steps

EXPERIMENTAL

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

Drug: Nivolumab + Ipilimumab - Arm B

Interventions

Nivolumab - Arm A DRUG

Nivolumab will be given during the induction phase of the study for 6 weeks. This is followed by surgery. Then maintenance therapy (after recovery from surgery).

Arm A consists of 3 phases or steps

Nivolumab + Ipilimumab - Arm B DRUG

Nivolumab + ipilimumab during the induction phase of the study for 6 weeks. This is followed by surgery (week 6-8+). Then maintenance therapy will be initiated for up to one year from study drug initial administration ((after recovery from surgery).

Arm B consists of 3 phases or steps

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Have measurable disease based on RECIST 1.1.
• Have provided tumor tissue from a newly obtained core, punch, incisional or excisional tumor biopsy. Patients must undergo biopsy (core, punch) or open incisional/excisional biopsy (if done as part of a clinically indicated baseline diagnostic procedure) within 4 weeks of registration on the study.
• Patients must have been evaluated by standard-of-care full body imaging studies (CT, PET/CT or MRI) as part of the initial clinical work-up at baseline (no more than 4 weeks prior to study enrollment) and after completion of induction nivolumab-ipilimumab or nivolumab alone (at 6-8 weeks after the first dose of induction and prior to the definitive surgery procedure).
• Required values for initial laboratory tests:
• White blood cell (WBC) 3000/uL

You may not qualify if:

• 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.
• Has received a live vaccine within 30 days prior to the first dose of trial treatment.
• Any underlying medical or psychiatric condition, which in the opinion of the Investigator/Sub-Investigator will make the administration of ipilimumab or nivolumab hazardous or obscure the interpretation of adverse events (AEs), such as a condition associated with frequent diarrhea.
• Patients with underlying heart conditions who are deemed ineligible for surgery by cardiology consult.
• A history of prior treatment with ipilimumab, nivolumab or other cytotoxic T-lymphocyte-associated protein (CTLA-4), progressive disease (PD1) or PD-L1 inhibitor.
• Prior treatment with interferon alfa is allowed.

Sponsors & Collaborators

• University of Pittsburgh: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

UPMC Cancer Center Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

Related Publications (1)

• Gorry C, McCullagh L, O'Donnell H, Barrett S, Schmitz S, Barry M, Curtin K, Beausang E, Barry R, Coyne I. Neoadjuvant treatment for stage III and IV cutaneous melanoma. Cochrane Database Syst Rev. 2023 Jan 17;1(1):CD012974. doi: 10.1002/14651858.CD012974.pub2.

  PMID: 36648215 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

Nivolumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Ahmad Tarhini, MD, PhD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 28, 2016
• First Posted: April 13, 2016
• Study Start: October 1, 2016
• Primary Completion: February 9, 2017
• Study Completion: February 9, 2017
• Last Updated: September 20, 2017

Record last verified: 2017-09

Locations

US (1)