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Nivolumab, BMS-936558 in Combination With Relatlimab, BMS-986016 in Patients With Metastatic Melanoma Naïve to Prior Immunotherapy in the Metastatic Setting

Primary Purpose

Melanoma

Status

Active

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Relatlimab

Nivolumab

Relatlimab + Nivolumab

About this trial

This is an interventional treatment trial for Melanoma focused on measuring Stage IIIB, Stage IIIC, Stage IIID, Stage IV, immune checkpoint blockade (ICB), Lymphocyte activation gene-3 (LAG3; CD223), immunotherapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

• Men or women 18 years of age or older meeting AJCC 8th edition criteria for unresectable stage IIIB, stage IIIC, stage IIID, or stage IV melanoma who have not received treatment with immunotherapy in the metastatic setting

Exclusion Criteria:

Known or suspected CNS metastases, with the following exceptions:
- Subjects with controlled brain metastases will be allowed to enroll. Controlled brain metastases are defined as no radiographic progression for at least 4 weeks following radiation and/or surgical treatment at the time of consent. Subjects must be off steroids for at least 2 weeks prior to randomization.
- Subjects with signs or symptoms of brain metastases are not eligible unless brain metastases are ruled out by computed tomography or magnetic resonance imaging.
Active autoimmune disease requiring treatment, with the exception of type 1 diabetes mellitus, vitiligo, resolved childhood asthma/atopy, controlled hyper/hypothyroidism, hypoadrenalism or hypopituitarism.
Prior systemic treatment in the metastatic setting, including anti-PD1, anti-PDL1, anti-PDL2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways; or chemotherapy.
Prior adjuvant treatment with anti-PD1, anti-PDL1, and/or anti-LAG3 antibody. Note that prior adjuvant treatment with targeted therapy (e.g. BRAF/MEK inhibition), anti-CTLA4, or treatment not otherwise specified above would be permitted.
Ocular melanoma

Sites / Locations

UPMC Hillman Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Relatlimab

Nivolumab

Relatlimab + Nivolumab

Arm Description

Cycle 1: Relatlimab (BMS-986016) is supplied as a sterile 10mg/mL formulation to be administered as an intravenous (IV) infusion at 160 mg IV for the first 4 weeks (cycle 1). Cycle 2+: Combination therapy will be administered by sequential infusion. Nivolumab administered at 480 mg IV followed by infusion of relatlimab at 160 mg IV once every 4 weeks.

Cycle 1: Nivolumab (BMS-936558) is supplied as a sterile 10-mg/mL formulation to be administered as an IV infusion at 480 mg IV for the first 4 weeks. Cycle 2+: Combination therapy will be administered by sequential infusion. Nivolumab administered at 480 mg IV followed by infusion of relatlimab at 160 mg IV once every 4 weeks.

Cycle 1+: Combination therapy will be administered by sequential infusion. Nivolumab administered at 480 mg IV followed by infusion of relatlimab at 160 mg IV for the first 4 weeks (Cycle 1), then once every 4 weeks afterwards.

Outcomes

Primary Outcome Measures

Change in LAG3 Expression

LAG3 (cell surface molecule expressed on activated T cells) expression is either positive (present) or not detectable if absent after completion of lead-in phase.

Change in PD1 expression

PD1 (programmed cell death protein 1) expression is either positive (present) or not detectable if absent after completion of lead-in phase

Change in Tumor Size

Tumor size will be assessed per Response Evaluation Criteria in Solid Tumors. Per RECIST 1.1, Tumour lesions: Must be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of: 10 mm by CT scan (CT scan slice thickness no greater than 5 mm; see Appendix II on imaging guidance). 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with calipers should be recorded as non-measurable). 20 mm by chest X-ray.

Overall Response Rate (ORR)

Number of participants experiencing Complete Response (CR) + Number of participants experiencing Partial Response (PR)/total patients assessed. Per RECIST v1.1, CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Secondary Outcome Measures

Clinical Benefit Rate

Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) / total patients assessed per RECIST v1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Duration of Response

Time from first documented Complete Response (CR) or Partial Response (PR) until the first date that progressive disease is objectively documented. Per RECIST v1.1, CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Progression-free Survival (PFS)

Progression-free survival is defined as the time between the date of randomization and the first date of documented progression or death due to any cause, whichever occurs first. Per RECIST v1.1, Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Overall Survival (OS)

Overall survival is defined as the time between the date of randomization and the date of death due to any cause.

LAG3 Expression

LAG3 (cell surface molecule expressed on activated T cells) expression (positive (present) or not detectable if absent) in tumor and peripheral blood of treated participants who experience a complete response, partial response, or stable disease, prior to ultimately experiencing disease progression.

PD-1 Expression

PD-1 (programmed cell death protein 1) expression (positive (present) or not detectable if absent) in tumor and peripheral blood of treated participants who experience a complete response, partial response, or stable disease, prior to ultimately experiencing disease progression.

Change in CD4+ tumor infiltrating lymphocytes

Percentage and number of CD4+ tumor infiltrating lymphocytes present

Change in CD8+ tumor infiltrating lymphocytes

Percentage and number of CD8+ tumor infiltrating lymphocytes present

Change in granzyme B serum levels

Level of granzyme B (a serine protease secreted cells to mediate apoptosis in target cells) in serum.

Change in cell effector/memory status

Measure of cells that have previously encountered and responded to their cognate antigen.

Change in activation and maturation of dendritic cells

Measure of expression of activation and maturation of dendritic cells

Change in T cell count

Number of T cells present in blood and tumor

Change in T cell count

Number of T cells present in blood and tumor in patients that had previously demonstrated complete response (CR), partial response (PR), or stable disease (SD) per RECIST 1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Change in soluble LAG3 levels

Amount of LAG3 (cell surface molecule expressed on activated T cells) protein present in blood and tumor tissue.

Soluble LAG3 levels

Amount of LAG3 (cell surface molecule expressed on activated T cells) protein present in blood and tumor tissue in patients that had previously demonstrated complete response (CR), partial response (PR), or stable disease (SD) per RECIST 1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Change in Regulatory T cell (Treg) marker level

Amount of Regulatory T cell (Treg) markers present in blood and tumor tissue.

Regulatory T cell (Treg) marker levels

Amount of Regulatory T cell (Treg) markers present in blood and tumor tissue.in patients that had previously demonstrated complete response (CR), partial response (PR), or stable disease (SD) per RECIST 1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Full Information

NCT ID

NCT03743766

First Posted

October 18, 2018

Last Updated

September 6, 2023

Sponsor

John Kirkwood

Collaborators

Bristol-Myers Squibb

1. Study Identification

Unique Protocol Identification Number

NCT03743766

Brief Title

Nivolumab, BMS-936558 in Combination With Relatlimab, BMS-986016 in Patients With Metastatic Melanoma Naïve to Prior Immunotherapy in the Metastatic Setting

Official Title

A Phase II Study of Anti-PD1 Monoclonal Antibody (Nivolumab, BMS-936558) Administered in Combination With Anti-LAG3 Monoclonal Antibody (Relatlimab, BMS-986016) in Patients With Metastatic Melanoma Naïve to Prior Immunotherapy in the Metastatic Setting

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

March 29, 2019 (Actual)

Primary Completion Date

July 31, 2027 (Anticipated)

Study Completion Date

July 31, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

John Kirkwood

Collaborators

Bristol-Myers Squibb

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The main goal of this study is to evaluate the antitumor activity of relatlimab and nivolumab in combination in subjects with unresectable or metastatic melanoma who have not received prior treatment with immunotherapy.

Detailed Description

This study will evaluate the antitumor activity of anti-LAG3 monoclonal antibody relatlimab and the anti-PD1 monoclonal antibody nivolumab in combination in subjects with unresectable or metastatic melanoma who have not received prior treatment with immunotherapy. The trial is designed with a lead-in phase of 2 cycles (4 week) treatment of either nivolumab, relatlimab, or the combination of nivolumab/relatlimab, followed by a combination phase of nivolumab/relatlimab treatment in all subjects. This lead-in design with accompanying tumor biopsies and peripheral blood analyses will enable mechanistic analyses of the effect of LAG3 and PD1 blockade alone and in combination to enhance understanding of mechanisms of response and resistance. Duration of response, progression free survival, and safety will be assessed as secondary objectives.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Melanoma

Keywords

Stage IIIB, Stage IIIC, Stage IIID, Stage IV, immune checkpoint blockade (ICB), Lymphocyte activation gene-3 (LAG3; CD223), immunotherapy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

In the 4-week lead-in phase, subjects will be randomized to one of three arms for 1 cycle (4 weeks) of lead-in treatment with nivolumab, relatlimab, or the combination of nivolumab and relatlimab. Following 1 cycle of lead-in treatment, all subjects will be treated with the combination of relatlimab and nivolumab every 4 weeks.

Masking

None (Open Label)

Allocation

Randomized

Enrollment

42 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Relatlimab

Arm Type

Experimental

Arm Description

Arm Title

Nivolumab

Arm Type

Experimental

Arm Description

Arm Title

Relatlimab + Nivolumab

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Relatlimab

Other Intervention Name(s)

BMS-986016

Intervention Description

Relatlimab (BMS-986016) - 10mg/mL formulation to be administered as an intravenous (IV) infusion at 160 mg IV.

Intervention Type

Drug

Intervention Name(s)

Nivolumab

Other Intervention Name(s)

BMS-936558

Intervention Description

Nivolumab (BMS-936558) - 10-mg/mL formulation to be administered as an IV infusion at 480 mg IV.

Intervention Type

Drug

Intervention Name(s)

Relatlimab + Nivolumab

Other Intervention Name(s)

BMS-986016 and BMS-936558

Intervention Description

Combination (Relatlimab + Nivolumab) therapy will be administered by sequential infusion. Nivolumab administered at 480 mg IV followed by infusion of relatlimab at 160 mg IV.

Primary Outcome Measure Information:

Title

Change in LAG3 Expression

Description

LAG3 (cell surface molecule expressed on activated T cells) expression is either positive (present) or not detectable if absent after completion of lead-in phase.

Time Frame

At baseline and at 4 weeks

Title

Change in PD1 expression

Description

PD1 (programmed cell death protein 1) expression is either positive (present) or not detectable if absent after completion of lead-in phase

Time Frame

At baseline and at 4 weeks

Title

Change in Tumor Size

Description

Time Frame

At baseline and at 4 weeks

Title

Overall Response Rate (ORR)

Description

Time Frame

Beginning at 12 weeks post initial treatment, up to 4 years

Secondary Outcome Measure Information:

Title

Clinical Benefit Rate

Description

Time Frame

12 weeks post initial treatment, up to 4 years

Title

Duration of Response

Description

Time Frame

12 weeks post initial treatment, up to 4 years

Title

Progression-free Survival (PFS)

Description

Time Frame

Up to 4 years

Title

Overall Survival (OS)

Description

Overall survival is defined as the time between the date of randomization and the date of death due to any cause.

Time Frame

Up to 4 years

Title

LAG3 Expression

Description

Time Frame

At week 16 (2 weeks post combination treatment (3 cycles))

Title

PD-1 Expression

Description

Time Frame

At week 16 (12 weeks post combination treatment (3 cycles))

Title

Change in CD4+ tumor infiltrating lymphocytes

Description

Percentage and number of CD4+ tumor infiltrating lymphocytes present

Time Frame

At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks

Title

Change in CD8+ tumor infiltrating lymphocytes

Description

Percentage and number of CD8+ tumor infiltrating lymphocytes present

Time Frame

At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks

Title

Change in granzyme B serum levels

Description

Level of granzyme B (a serine protease secreted cells to mediate apoptosis in target cells) in serum.

Time Frame

At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks

Title

Change in cell effector/memory status

Description

Measure of cells that have previously encountered and responded to their cognate antigen.

Time Frame

At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks

Title

Change in activation and maturation of dendritic cells

Description

Measure of expression of activation and maturation of dendritic cells

Time Frame

At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks

Title

Change in T cell count

Description

Number of T cells present in blood and tumor

Time Frame

At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks

Title

Change in T cell count

Description

Time Frame

At the time of disease progression - up to 4 years

Title

Change in soluble LAG3 levels

Description

Amount of LAG3 (cell surface molecule expressed on activated T cells) protein present in blood and tumor tissue.

Time Frame

At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks

Title

Soluble LAG3 levels

Description

Time Frame

At the time of disease progression - up to 4 years

Title

Change in Regulatory T cell (Treg) marker level

Description

Amount of Regulatory T cell (Treg) markers present in blood and tumor tissue.

Time Frame

At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks

Title

Regulatory T cell (Treg) marker levels

Description

Time Frame

At the time of disease progression - up to 4 years

Other Pre-specified Outcome Measures:

Title

Single cell RNA sequencing

Description

The presence and quantity of RNA in in blood and tumor tissue.

Time Frame

2 weeks

Title

Single cell RNA sequencing

Description

The presence and quantity of RNA in in blood and tumor tissue.

Time Frame

At 4 weeks post Cycle 1

Title

Single cell RNA sequencing

Description

The presence and quantity of RNA in in blood and tumor tissue.

Time Frame

At week 16 (12 weeks post combination treatment (3 cycles)

Title

Single cell RNA sequencing

Description

The presence and quantity of RNA in in blood and tumor tissue in patients that had previously demonstrated complete response (CR), partial response (PR), or stable disease (SD) per RECIST 1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Time Frame

At the time of disease progression - up to 4 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: • Men or women 18 years of age or older meeting AJCC 8th edition criteria for unresectable stage IIIB, stage IIIC, stage IIID, or stage IV melanoma who have not received treatment with immunotherapy in the metastatic setting Exclusion Criteria: Known or suspected CNS metastases, with the following exceptions: Subjects with controlled brain metastases will be allowed to enroll. Controlled brain metastases are defined as no radiographic progression for at least 4 weeks following radiation and/or surgical treatment at the time of consent. Subjects must be off steroids for at least 2 weeks prior to randomization. Subjects with signs or symptoms of brain metastases are not eligible unless brain metastases are ruled out by computed tomography or magnetic resonance imaging. Active autoimmune disease requiring treatment, with the exception of type 1 diabetes mellitus, vitiligo, resolved childhood asthma/atopy, controlled hyper/hypothyroidism, hypoadrenalism or hypopituitarism. Prior systemic treatment in the metastatic setting, including anti-PD1, anti-PDL1, anti-PDL2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways; or chemotherapy. Prior adjuvant treatment with anti-PD1, anti-PDL1, and/or anti-LAG3 antibody. Note that prior adjuvant treatment with targeted therapy (e.g. BRAF/MEK inhibition), anti-CTLA4, or treatment not otherwise specified above would be permitted. Ocular melanoma

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

John Kirkwood, MD

Organizational Affiliation

University of Pittsburgh

Official's Role

Principal Investigator

Facility Information:

Facility Name

UPMC Hillman Cancer Center

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15232

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Nivolumab, BMS-936558 in Combination With Relatlimab, BMS-986016 in Patients With Metastatic Melanoma Naïve to Prior Immunotherapy in the Metastatic Setting

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