Nivolumab Plus Relatlimab in Patients With Metastatic Uveal Melanoma

A Phase 2 Study of Nivolumab + BMS-986016 (Relatlimab) in Patients With Metastatic Uveal Melanoma

The purpose of this research is to test if a combination treatment of nivolumab and relatlimab will result in tumor reduction in patients with metastatic uveal melanoma.

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Uveal Melanoma
• Intervention / Treatment: Drug: Nivolumab; Drug: Relatlimab

Detailed Description

This is a phase II single-institution trial with a Simon two-stage minimax design with 27 patients (13 in stage 1, 14 in stage 2) setting a 5% type I error and 80% power under true objective response rate (ORR) of 20%. The null hypothesis (ORR=5%) is rejected if 4 or more responses are observed in 27 patients. No prior PD-1, CTLA-4 and/or LAG-3 blocking antibody treatment was allowed. We will also perform single-cell mRNA and T-cell receptor (TCR) variable, diversity, and joining (V[D]J) sequencing pre-treatment and at either progression or response.

Patients will be treated with nivolumab 480 mg/relatlimab 160 mg IV q4wks to progression or intolerable toxicity for up to two years.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Christina Estevez; Phone Number: 305-243-8376; Email: cme101@med.miami.edu
• Study Contact Backup: Name: Edda Bisbal-Loubriel; Phone Number: 305-243-0326; Email: epb61@med.miami.edu

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Have a biopsy-proven diagnosis of metastatic uveal melanoma, previously untreated with anti-PD-1,Cytotoxic T lymphocyte antigen 4 (CTLA-4) and/or lymphocyte activation gene 3 (LAG-3) blocking antibodies.
2. Agree to undergo a pre-treatment and a post-treatment fresh biopsy of the tumor, if easily accessible and low-risk.
3. Have completed all previous therapy for a minimum of 3 weeks before the first dose of experimental treatment. All adverse events of previous therapy must have resolved. Palliative radiation therapy to a limited field is allowed within this 3 week period.
4. Be willing and able to provide written informed consent/assent for the trial.
5. Be ≥ 18 years of age on day of signing informed consent.
6. Have measurable disease based on RECIST 1.1.
7. Have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
8. Left Ventricular Ejection Fraction (LVEF) assessment with documented LVEF 50% by either TTE or Multiple Gated Acquisition (MUGA) (TTE preferred test) within 6 months from first study drug administration

9. Demonstrate adequate organ function as defined in Table 1. All screening labs should be performed within 10 days of treatment initiation:

   • Hematological:

     • Absolute neutrophil count (ANC) ≥1,500 /microliter (mcL)
     • Platelets ≥100,000 / mcL
     • Hemoglobin ≥ 9 g/dL or ≥5.6 mmol/L (within 7 days of assessment)

   • Renal:

     • Serum creatinine ≤ 1.5 X upper limit of normal (ULN) OR
     • Measured or calculated a creatinine clearance ≥30 mL/min for subject with creatinine levels > 1.5 X institutional ULN (GFR can also be used in place of creatinine or CrCl)

   • Hepatic:

     • Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
     • Aspartate Aminotransferase (AST) (SGOT) and Alanine Amino Transferase (ALT) (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
     • Albumin ≥ 2.5 mg/dL

   • Coagulation:

     • International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
     • Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
     • Creatinine clearance should be calculated per institutional standard.
10. If a female of childbearing potential, have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

11. If a female of childbearing potential, be willing to use an adequate method of contraception as outlined in Section 5.8 Contraception, for the course of the study through 24 weeks after the last dose of study medication. Must abstain from ova donation for a minimum of 5 months after the end of treatment.

    Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

12. If a male of childbearing potential, agree to use an adequate method of contraception as outlined in Section 5.8- Contraception, starting with the first dose of study therapy through 7 months after the last dose of study therapy. Must abstain from sperm donation for a minimum of 24 weeks after the end of treatment.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject

Exclusion Criteria:

1. Are currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 3 weeks of the first dose of treatment.
2. Have a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Patients on replacement doses of corticosteroids and patients who received steroids as pre-medication to prevent an imaging contrast allergy are allowed.
3. Have a known history of active tuberculosis (Bacillus Tuberculosis)
4. Have had prior treatment with a PD-1 and/or LAG-3 targeted agent
5. Have hypersensitivity to nivolumab, relatlimab or any of their excipients.
6. Have had a prior anti-cancer monoclonal antibody (mAb) within 3 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from clinically significant adverse events due to agents administered more than 3 weeks earlier.

7. Have had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 3 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from clinically significant adverse events due to a previously administered agent.

   • Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
   • Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
   • Note: Patients will be allowed necessary and palliative radiation therapy to limited fields during the trial, as long as it does not encompass a target lesion.
8. Have a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma or squamous cell carcinoma of the skin that has undergone potentially curative therapy, in situ cervical cancer, ductal carcinoma in situ (DCIS), incidentally discovered asymptomatic thyroid cancer, Prostate Specific Antigen (PSA) recurrence of prostate cancer stable on hormonal therapy with no otherwise detectable disease, and a previous diagnosis of malignancy that has shown no evidence of disease progression for 5 years or longer.
9. Have known active central nervous system (CNS) metastases and/or carcinomatous meningitis as well as a history of previous or current significant brain hemorrhage. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids to treat edema for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis, which will be excluded regardless of clinical stability.
10. Have active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
11. Have known history of, or any evidence of active, non-infectious pneumonitis.
12. Have an active infection requiring systemic therapy.
13. Have a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
14. Have known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
15. Are pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
16. Have a diagnosis or known history of Human Immunodeficiency Virus (HIV), unless controlled on antiretroviral drugs and have undetectable levels of HIV antibodies.
17. Have known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C.
18. Have received a live vaccine within 30 days of planned start of study therapy.
19. Have a history of myocarditis, regardless of etiology

20. Have a troponin T (TnT) or I (TnI)

    • i) > 2x institutional upper limit of normal (ULN) : patient is excluded.
    • ii) between > 1 to 2 x ULN enrollment will be permitted if a repeat assessment remains < 2 x ULN and participant undergoes a cardiac evaluation and is cleared by a cardiologist or cardio-oncologist
21. Are patients with impaired decision-making capacity
22. Are prisoners or participants who are involuntarily incarcerated. (Note: under certain specific circumstances a person who has been imprisoned may be included as a participant. Strict conditions apply and Bristol-Myers Squibb approval is required).
23. Are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
24. Have psychological, familial, sociological, or geographical conditions that potentially hamper compliance with the study protocol and follow-up schedule; those conditions should be discussed with the participant before registration in the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nivolumab Plus Relatlimab Group; Participants in this group will receive Nivolumab and Relatlimab administered together on Day 1 of every 4 week cycle. Both drugs will be administered until disease progression or intolerable toxicity for up to 24 months.	Drug: Nivolumab; Nivolumab 480mg administered intravenously on Day 1 of each 4 week cycle.; Other Names: Opdivo; Drug: Relatlimab; Relatlimab 160 mg administered intravenously on Day 1 of each 4 week cycle.; Other Names: BMS-986016

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	Objective response rate (ORR) will be the proportion of study participants with a confirmed complete response (CR) or partial response PR to study therapy as per treating physician evaluation using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.	Up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Control Rate (DCR)	Disease control rate (DCR) is the proportion of patients with confirmed complete response (CR), partial response (PR), or stable disease (SD) as per treating physician evaluation using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.	Up to 24 months
Progression-Free Survival (PFS)	Progression-free survival (PFS) is defined as the time from the date of enrollment to the date that objective progression disease is documented or death due to any cause, whichever occurs first.	Up to 4 years
Overall Survival (OS)	Overall survival (OS) is defined as the time from the date of enrollment to the date of death.	Up to 4 years
Duration of Response (DOR)	Duration of response is defined as the time from the date of first documented response (CR or PR) until date of documented progression or death in the absence of disease progression.	Up to 4 years
Proportion of Study Participants with Treatment-Related Toxicity	The safety profile of the study therapy will be determined by the proportion of study participants experiencing treatment-related adverse events (AEs) and serious adverse events (SAEs). AEs and SAEs will be tabulated by type, grade, severity, treatment attribution according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.	Up to 25 months

Collaborators and Investigators

• Sponsor: Jose Lutzky, MD
• Collaborators: Bristol-Myers Squibb; United States Department of Defense
• Investigators: Principal Investigator: Jose Lutzky, MD, University of Miami

Study record dates

Study Major Dates

• Study Start (Actual): November 10, 2020
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: September 11, 2020
• First Submitted That Met QC Criteria: September 11, 2020
• First Posted (Actual): September 17, 2020

Study Record Updates

• Last Update Posted (Actual): November 30, 2023
• Last Update Submitted That Met QC Criteria: November 29, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Metastatic Uveal Melanoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Eye Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Uveal Diseases; Neuroendocrine Tumors; Nevi and Melanomas; Eye Neoplasms; Melanoma; Uveal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Relatlimab
• Other Study ID Numbers: 20200847; CA224-094 (Other Identifier: Bristol-Myers Squibb); NCI-2020-11454 (Registry Identifier: NCI Clinical Trials Reporting Program (NCI CTRP))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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.: Yes