Neoadjuvant and Adjuvant Anti-PD1 or Combinations for Locoregionally Advanced Melanoma

The purpose of this study is to determine if neoadjuvant (treatment before surgery) immunotherapy treatment based on tumor biomarkers results in better participant outcomes. Immunotherapy is the treatment of disease by using a person's own immune system.

This study is divided into 2 sub-studies/parts designated Part 1 and Part 2 that will enroll in sequence starting with Part 1 followed by Part 2.

Study Overview

• Status: Recruiting
• Conditions: Melanoma; Advanced Melanoma; Melanoma Stage IV; Melanoma Stage III
• Intervention / Treatment: Drug: Nivolumab; Drug: Nivolumab + Relatlimab; Drug: Ipilimumab

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Lina Moreno; Phone Number: 813-745-1060; Email: Lina.Moreno@moffitt.org

Study Locations

• United States
  • Florida
    • Tampa, Florida, United States, 33612
      • Recruiting
      • Moffitt Cancer Center
      • Principal Investigator: Ahmad Tarhini, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• This study is divided into 2 sub-studies/parts designated Part 1 and Part 2 that will enroll in sequence starting with Part 1 followed by Part 2. In Part 2, Part 2 Cohort A and Part 2 Cohort B will enroll simultaneously. Inclusion criteria apply to Part 1 and Part 2 unless otherwise specified.
• Voluntarily agree to participate by giving signed, dated, and written informed consent prior to any study-specific procedures.
• 18 years of age or older
• Histologic diagnosis of melanoma (cutaneous, acral, mucosal or unknown primary) belonging to the following American Joint Committee on Cancer (AJCC) 8th edition TNM stages (Tx or T1-4) and (N1b, N1c, N2b, N2c, N3b or N3c) and/or (M1a).

• Requirements for prior systemic therapy for melanoma are as follows:

  1. Sub-study Part 1: No prior systemic therapy for melanoma (N=30).
  2. Sub-study Part 2 Cohort A: No prior systemic therapy for melanoma (N=20)
  3. Sub-study Part 2 Cohort B: Locoregionally advanced melanoma that is refractory to systemic adjuvant therapy (anti-PD1-based or BRAF-MEK inhibitors) (N=40).

This excludes patients who previously received adjuvant or neoadjuvant anti-PD1 plus anti-LAG3 or anti-PD1 plus anti-CTLA4.

Participants who experienced progression or recurrence after anti-PD1 as monotherapy or other combinations or after BRAF-MEK inhibition would be eligible.

Participants who have previously experienced prior high-grade (grade 3 or 4 by CTCAE criteria) immune related adverse events with immune checkpoint inhibitors are not eligible.

• Must be considered surgically operable and may present as any of the following groups:

  1. Primary melanoma with clinically apparent regional lymph node metastases, confirmed by pathological diagnosis.
  2. Clinically detected recurrence of melanoma at regional lymph node basin(s), confirmed by pathological diagnosis.
  3. Clinically or histologically detected primary melanoma involving multiple regional nodal groups, confirmed by pathological diagnosis.
  4. Clinically detected single site of nodal metastatic melanoma arising from an unknown primary, confirmed by pathological diagnosis.
  5. Participants with in-transit or satellite metastases with or without lymph node involvement are allowed if they are considered surgically resectable at Screening by the treating surgical oncologist.
  6. Participants with distant cutaneous/subcutaneous, soft tissue or nodal metastases with or without regional lymph node involvement are allowed if they are considered potentially surgically resectable and can be biopsied at Screening by the treating surgical oncologist. Elevated LDH is not an exclusion.
  7. Elevated LDH is not an exclusion.
• Participants are eligible for this study either at presentation for primary melanoma with concurrent regional nodal and/or in-transit or distant metastasis, or at the time of clinically detected nodal, in transit, or distant recurrence.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Adequate organ function within 28 days of Cycle 1 Day 1 (C1D1)
• Participants must provide a sufficient and adequate formalin-fixed paraffin-embedded (FFPE) tumor tissue sample from the most recent biopsy of a tumor lesion, obtained within 90 days from signing informed consent form (ICF). If recent tumor tissue is unavailable or inadequate, a fresh biopsy will be required, unless the principal investigator agrees that it is not safe/feasible.
• Participants must be evaluated by standard-of-care full body imaging studies, the choice of which is decided by the treating physician investigator.
• Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test at screening (within 72 hours of first dose of study medication) in accordance with the standard of care for WOCBP.
• WOCBP must agree to use highly effective contraceptive measures starting with the screening visit through 5 months after the last dose of study treatment. Highly effective contraception is as stipulated in national or local guidelines.
• Male participants with a female partner(s) of childbearing potential must agree to use highly effective contraceptive measures throughout the study starting with the screening visit through 5 months after the last dose of study treatment is received. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.
• Willing and able to comply with the requirements of the protocol.

Exclusion Criteria:

• Pregnancy or lactation.
• Treatment with another investigational drug or other systemic intervention for melanoma within 4 weeks of initiation of study drugs. Patients must not have radiotherapy within the preceding 2 weeks. Patients must have recovered from adverse events due to agents administered more than 4 weeks earlier.
• Participants must be at least 4 weeks from major surgery and have fully recovered from any effects of surgery and be free of significant detectable infection.
• Ocular or uveal melanoma.
• Bowel obstruction or impending bowel obstruction within the past 3 months.
• Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 6 months of enrollment, unstable angina, congestive heart failure or serious uncontrolled cardiac arrhythmia requiring medication.
• Active or history of brain metastases or leptomeningeal metastases.
• Concurrent malignancy (present during screening) requiring treatment or history of prior malignancy active within 2 years prior to the first dose of study treatment, i.e., patients with a history of prior malignancy are eligible if treatment was completed at least 2 years before the first dose of study treatment and the patient has no evidence of disease. Participants with history of prior early-stage basal/squamous cell skin cancer, low-risk prostate cancer eligible for active surveillance or noninvasive or in situ cancers who have undergone definitive treatment at any time are also eligible.

• Treatment with one of the following classes of drugs within the delineated time window prior to C1D1:

  1. Cytotoxic, targeted therapy or other investigational therapy within 3 weeks.
  2. mAbs, antibody-drug conjugates, radioimmunoconjugates, or similar therapy, within 4 weeks, or 5 half-lives, whichever is shorter.
  3. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine or booster < 7 days before C1D1. For vaccines requiring more than 1 dose, the full series should be completed prior to C1D1, when feasible. Booster shot not required but also must be administered > 7 days from C1D1 or > 7 days from future cycle on study.
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
• Any evidence of current interstitial lung disease (ILD) or pneumonitis or a prior history of ILD or non-infectious pneumonitis requiring high-dose glucocorticoids.
• History of allogeneic organ transplant.
• Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
• Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) within 14 days or another immunosuppressive medication within 30 days of the first dose of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
• Active autoimmune disease or history of autoimmune disease that required systemic treatment within 2 years before starting treatment, i.e., with use of disease-modifying agents or immunosuppressive drugs.
• History or current evidence of any condition, co-morbidity, therapy, any active infections, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator.
• Pregnant or breastfeeding or WOCBP who are not willing to employ effective birth control from screening to 5 months after the last dose of study treatment (whichever is later).
• Previous SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 20 days for severe/critical illness prior to C1D1.
• Uncontrolled infection with human Immunodeficiency virus (HIV). Patients on stable highly active antiretroviral therapy (HAART) with undetectable viral load and normal CD4 counts for at least 6 months prior to study entry are eligible. Serological testing for HIV at screening is not required.
• Known to be positive for hepatitis B virus (HBV) surface antigen, or any other positive test for HBV indicating acute or chronic infection. Patients who are receiving or who have received anti-HBV therapy and have undetectable HBV DNA for at least 6 months prior to study entry are eligible. Serological testing for HBV at screening is not required. Known active co-infection with hepatitis B and hepatitis C or with hepatitis B and hepatitis D is an exclusion.
• Known active hepatitis C virus (HCV) as determined by positive serology and confirmed by polymerase chain reaction (PCR). Patients on or who have received antiretroviral therapy are eligible provided they are virus-free by PCR for at least 6 months prior to study entry. Serological testing for HCV at screening is not required.
• Dependence on total parenteral nutrition.
• Troponin T (TnT) or I (TnI) > 2× institutional ULN. Participants with TnT or TnI levels between > 1 to 2 × ULN will be permitted if repeat levels within 24 hours are ≤ 1 × ULN. If TnT or TnI levels are between >1 to 2 × ULN within 24 hours, the participant must undergo a cardiology consultation and cardiac evaluation and be considered for treatment, based on a favorable benefit/risk assessment by the Investigator. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are < 2 × ULN, the participant must undergo a cardiology consultation and cardiac evaluation and be considered for treatment, based on a favorable benefit-risk assessment by the Investigator.
• Left ventricular ejection fraction (LVEF) assessment with documented LVEF < 50% by either transthoracic echocardiogram (TTE) or multigated acquisition (MUGA) scan (TTE preferred test) within 6 months prior to start of study treatment.
• Participants with a history of myocarditis and/or current diagnosis of myocarditis, regardless of etiology.
• Participants must not have a history of allergy or hypersensitivity to study intervention components.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1, Arm A: Nivolumab; PD-L1 positive patients will be given Nivolumab 480 mg I.V. over 30 minutes (-/+ 10 minutes) every 4 weeks (every cycle) for 2 a total of 2 cycles.	Drug: Nivolumab; Nivolumab is a fully human immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed death-1 (PD-1, PCD-1) with immune checkpoint inhibitory and antineoplastic activities. Upon administration, nivolumab binds to and blocks the activation of PD-1, an immunoglobulin superfamily (IgSF) transmembrane protein, by its ligands programmed cell death ligand 1 (PD-L1), which is overexpressed on certain cancer cells, and programmed cell death ligand 2 (PD-L2), which is primarily expressed on antigen-presenting cells (APCs). This results in the activation of T cells and cell-mediated immune responses against tumor cells. Activated PD-1 negatively regulates T-cell activation and plays a key role in tumor evasion from host immunity.; Other Names: Opdivo
Experimental: Part 1, Arm B: Nivolumab- Relatlimab-rmbw; PD-L1 negative patients will be given a combination of Nivolumab 480 mg with Relatlimab 160 mg I.V. over 60 minutes (-/+ 10 minutes) every 4 weeks (every cycle) for a total of 2 cycles.	Drug: Nivolumab + Relatlimab; Opdualag (Nivolumab and Relatlimab-rmbw) is a combination formulation composed of nivolumab, a human immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed death-1 (PD-1, PCD-1), and relatlimab-rmbw, a human IgG4 monoclonal antibody directed against the inhibitor receptor lymphocyte activation gene-3 (LAG-3). Nivolumab binds to and blocks the activation of PD-1 by its ligands programmed cell death ligand 1 (PD-L1), which is overexpressed on certain cancer cells, and programmed cell death ligand 2 (PD-L2), which is primarily expressed on antigen-presenting cells (APCs). This prevents PD-1-mediated signaling and PD-1-mediated inhibition of the immune response. Relatlimab binds to LAG-3 on tumor infiltrating lymphocytes (TILs) and prevents LAG-3 binding to major histocompatibility complex (MHC) class II. This prevents LAG-3-mediated signaling and LAG-3-mediated inhibition of the immune response.; Other Names: Opdualag
Experimental: Part 1, Arm C: Nivolumab plus ipilimumab; PD-L1 negative patients will be given 3 mg/kg of Nivolumab plus 1 mg/kg of Ipilimumab I.V. each given over 30 minutes (-/+ 10 minutes) every 4 weeks (every cycle) for a total of 2 cycles.	Drug: Nivolumab; Nivolumab is a fully human immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed death-1 (PD-1, PCD-1) with immune checkpoint inhibitory and antineoplastic activities. Upon administration, nivolumab binds to and blocks the activation of PD-1, an immunoglobulin superfamily (IgSF) transmembrane protein, by its ligands programmed cell death ligand 1 (PD-L1), which is overexpressed on certain cancer cells, and programmed cell death ligand 2 (PD-L2), which is primarily expressed on antigen-presenting cells (APCs). This results in the activation of T cells and cell-mediated immune responses against tumor cells. Activated PD-1 negatively regulates T-cell activation and plays a key role in tumor evasion from host immunity.; Other Names: Opdivo; Drug: Ipilimumab; Ipilimumab is a type of monoclonal antibody and a type of immune checkpoint inhibitor that may block CTLA-4 and help the immune system kill cancer cells. Ipilimumab binds to the protein CTLA-4 to help immune cells kill cancer cells better and is used to treat many different types of cancer. These include cancers that have certain mutations (changes) in genes involved in DNA repair.; Other Names: Yervoy
Experimental: Part 2, Arm A: Ipilimumab + Nivolumab-Relatimab-rmbw; Systemic therapy naïve locoregionally advanced melanoma patients will be given the fixed dose combination of 480 mg of nivolumab with 160 mg of relatlimab I.V. over 60 minutes (-/+ 10 minutes) every 4 weeks (every cycle) for a total of 2 cycles. In addition, a single dose of 1 mg/kg ipilimumab I.V. will be given on C1D1.	Drug: Nivolumab + Relatlimab; Opdualag (Nivolumab and Relatlimab-rmbw) is a combination formulation composed of nivolumab, a human immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed death-1 (PD-1, PCD-1), and relatlimab-rmbw, a human IgG4 monoclonal antibody directed against the inhibitor receptor lymphocyte activation gene-3 (LAG-3). Nivolumab binds to and blocks the activation of PD-1 by its ligands programmed cell death ligand 1 (PD-L1), which is overexpressed on certain cancer cells, and programmed cell death ligand 2 (PD-L2), which is primarily expressed on antigen-presenting cells (APCs). This prevents PD-1-mediated signaling and PD-1-mediated inhibition of the immune response. Relatlimab binds to LAG-3 on tumor infiltrating lymphocytes (TILs) and prevents LAG-3 binding to major histocompatibility complex (MHC) class II. This prevents LAG-3-mediated signaling and LAG-3-mediated inhibition of the immune response.; Other Names: Opdualag; Drug: Ipilimumab; Ipilimumab is a type of monoclonal antibody and a type of immune checkpoint inhibitor that may block CTLA-4 and help the immune system kill cancer cells. Ipilimumab binds to the protein CTLA-4 to help immune cells kill cancer cells better and is used to treat many different types of cancer. These include cancers that have certain mutations (changes) in genes involved in DNA repair.; Other Names: Yervoy
Experimental: Part 2, Arm B1: Triplet Combination Therapy Ipilmumab + Nivolumab-Relatlimab-rmbw; Patients with locoregionally advanced melanoma that is refractory to systemic adjuvant therapy will be given the fixed dose combination of 480 mg of nivolumab with 160 mg or relatlimab I.V. over 60 minutes (-/+ 10 minutes) every 4 weeks (every cycle) for a total of 2 cycles. In addition, a single dose of 1 mg/kg ipilimumab I.V. will be given on C1D1.	Drug: Nivolumab + Relatlimab; Opdualag (Nivolumab and Relatlimab-rmbw) is a combination formulation composed of nivolumab, a human immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed death-1 (PD-1, PCD-1), and relatlimab-rmbw, a human IgG4 monoclonal antibody directed against the inhibitor receptor lymphocyte activation gene-3 (LAG-3). Nivolumab binds to and blocks the activation of PD-1 by its ligands programmed cell death ligand 1 (PD-L1), which is overexpressed on certain cancer cells, and programmed cell death ligand 2 (PD-L2), which is primarily expressed on antigen-presenting cells (APCs). This prevents PD-1-mediated signaling and PD-1-mediated inhibition of the immune response. Relatlimab binds to LAG-3 on tumor infiltrating lymphocytes (TILs) and prevents LAG-3 binding to major histocompatibility complex (MHC) class II. This prevents LAG-3-mediated signaling and LAG-3-mediated inhibition of the immune response.; Other Names: Opdualag; Drug: Ipilimumab; Ipilimumab is a type of monoclonal antibody and a type of immune checkpoint inhibitor that may block CTLA-4 and help the immune system kill cancer cells. Ipilimumab binds to the protein CTLA-4 to help immune cells kill cancer cells better and is used to treat many different types of cancer. These include cancers that have certain mutations (changes) in genes involved in DNA repair.; Other Names: Yervoy
Experimental: Part 2, Arm B2: Doublet Combination Therapy Nivolumab-Relatlimab-rmbw; Patients with locoregionally advanced melanoma that is refractory to systemic adjuvant therapy will be given the fixed dose combination of 480 mg of nivolumab with 160 mg of relatlimab I.V. over 60 minutes (-/+ 10 minutes) every 4 weeks (every cycle) for a total of 2 cycles.	Drug: Nivolumab + Relatlimab; Opdualag (Nivolumab and Relatlimab-rmbw) is a combination formulation composed of nivolumab, a human immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed death-1 (PD-1, PCD-1), and relatlimab-rmbw, a human IgG4 monoclonal antibody directed against the inhibitor receptor lymphocyte activation gene-3 (LAG-3). Nivolumab binds to and blocks the activation of PD-1 by its ligands programmed cell death ligand 1 (PD-L1), which is overexpressed on certain cancer cells, and programmed cell death ligand 2 (PD-L2), which is primarily expressed on antigen-presenting cells (APCs). This prevents PD-1-mediated signaling and PD-1-mediated inhibition of the immune response. Relatlimab binds to LAG-3 on tumor infiltrating lymphocytes (TILs) and prevents LAG-3 binding to major histocompatibility complex (MHC) class II. This prevents LAG-3-mediated signaling and LAG-3-mediated inhibition of the immune response.; Other Names: Opdualag

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic Major Response (pMR)	The pathologic response rate will be measured by evaluation of the residual viable tumor (RVT). Pathologic Major Response (pMR) is defined as near complete response (pCR) measured as ≤10% RVT + complete response (pCR) measured as 0% RVT.	Up to 36 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Preoperative Radiologic Response Rate	The Preoperative Radiologic Response Rate will be measured utilizing RECIST v.1.1.	Up to 8 Weeks
Complete Pathologic Response Rate (pCR)	The pathologic response rate will be measured by evaluation of the residual viable tumor (RVT). Pathologic Complete Response (pCR) is defined as 0% RVT.	Up to 36 Months
Partial Pathologic Response Rate (pPR)	The pathologic response rate will be measured by evaluation of the residual viable tumor (RVT). Pathologic Partial Response (pPR) is defined as 10-50% RVT.	Up to 36 Months
Non-Response Pathologic Response Rate (pNR)	The pathologic response rate will be measured by evaluation of the residual viable tumor (RVT). Pathologic Non-Response (pNR) is defined as 50-100% RVT.	Up to 36 Months
Progression Free Survival (PFS)	Progression Free Survival (PFS) will be measured from the date of start of treatment to the investigator-determined date of progression or death due to any cause, whichever occurs first.	Up to 36 Months
Overall Survival (OS)	Overall Survival (OS) will be measured from the initial date of study registration/randomization to the recorded date of death.	Up to 36 Months

Collaborators and Investigators

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Ahmad Tarhini, MD, PhD, Moffitt Cancer Center

Publications and helpful links

Helpful Links

• Moffitt Cancer Center Clinical Trials Website

Study record dates

Study Major Dates

• Study Start (Actual): May 17, 2024
• Primary Completion (Estimated): November 1, 2028
• Study Completion (Estimated): November 1, 2028

Study Registration Dates

• First Submitted: February 28, 2024
• First Submitted That Met QC Criteria: March 5, 2024
• First Posted (Actual): March 6, 2024

Study Record Updates

• Last Update Posted (Actual): April 1, 2026
• Last Update Submitted That Met QC Criteria: March 31, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Melanoma; Anti-PD1; Locoregionally Advanced Melanoma
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Skin and Connective Tissue Diseases; Melanoma; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Nivolumab; Ipilimumab; relatlimab; Opdualag
• Other Study ID Numbers: MCC-22574

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No