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Neoadjuvant Combination Biotherapy With Ipilimumab and Nivolumab or Nivolumab Alone

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ClinicalTrials.gov Identifier: NCT02736123
Recruitment Status : Withdrawn (PI is closing the trial as he will be leaving the University of Pittsburgh Medical Center)
First Posted : April 13, 2016
Last Update Posted : September 20, 2017
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Ahmad Tarhini, University of Pittsburgh

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.

Condition or disease Intervention/treatment Phase
Melanoma Drug: Nivolumab - Arm A Drug: Nivolumab + Ipilimumab - Arm B Phase 1 Phase 2

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+).


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : October 2016
Actual Primary Completion Date : February 9, 2017
Actual Study Completion Date : February 9, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: 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

Drug: Nivolumab - Arm A
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).

Experimental: 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

Drug: Nivolumab + Ipilimumab - Arm B
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).




Primary Outcome Measures :
  1. Assess the pathologic complete response rate (absence of viable tumor on histologic assessment) [ Time Frame: 5 years ]

Secondary Outcome Measures :
  1. Evaluate preoperative clinical/radiologic response rate [ Time Frame: 5 years ]
  2. Assess progression free survival [ Time Frame: 5 years ]
  3. Assess overall survival [ Time Frame: 5 years ]
  4. Assess biomarkers CD8 T cell, PD-L1 and IDO expression by immunohistochemistry [ Time Frame: 5 years ]
  5. Assess safety and adverse events [ Time Frame: 5 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  • 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
    • Absolute neutrophil count (ANC) 1500/uL
    • Platelets 100 x 103/uL
    • Hemoglobin 10 g/dL
    • Aspartate transaminase/alanine transaminase (AST/ALT) 2.5 x unique learner number (ULN)
    • Bilirubin 1.5 ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
    • Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):

Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL

• No active or chronic infection with HIV, Hepatitis B, or Hepatitis C

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.
  • 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.
  • A history of prior radiotherapy, chemotherapy, including infusion or perfusion therapy for current disease or any immunotherapy including tumor vaccines, interferon-alfa, interleukins, levamisole or other biologic response modifiers within the past 4 weeks.
  • Concomitant therapy with any of the following: IL 2 or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids; unless discontinued ≥ 4 weeks. A history of occasional use of steroid inhalers is allowed.
  • Women of childbearing potential (WOCBP), defined above in Section 3.3, who are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for their entire study period and for at least 23 weeks after cessation of study drug, or have a positive pregnancy test at baseline, or are pregnant or breastfeeding.
  • Melanoma of Uveal Origin

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02736123


Locations
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United States, Pennsylvania
UPMC Cancer Center Hillman Cancer Center
Pittsburgh, Pennsylvania, United States, 15232
Sponsors and Collaborators
University of Pittsburgh
Bristol-Myers Squibb
Investigators
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Principal Investigator: Ahmad Tarhini, MD, PhD University of Pittsburgh

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Responsible Party: Ahmad Tarhini, Principal Investigator, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT02736123     History of Changes
Other Study ID Numbers: 15-113
First Posted: April 13, 2016    Key Record Dates
Last Update Posted: September 20, 2017
Last Verified: September 2017
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents