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

Melanoma Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03743766
• Other study ID #: 18-071
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: March 29, 2019
• Est. completion date: July 31, 2027

Study information

• Verified date: September 2023
• Source: University of Pittsburgh
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 42
• Est. completion date: July 31, 2027
• Est. primary completion date: July 31, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Melanoma

Intervention

Drug:
• Relatlimab
Relatlimab (BMS-986016) - 10mg/mL formulation to be administered as an intravenous (IV) infusion at 160 mg IV.
• Nivolumab
Nivolumab (BMS-936558) - 10-mg/mL formulation to be administered as an IV infusion at 480 mg IV.
• Relatlimab + Nivolumab
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.

Locations

Country	Name	City	State
United States	UPMC Hillman Cancer Center	Pittsburgh	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
John Kirkwood	Bristol-Myers Squibb

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Single cell RNA sequencing	The presence and quantity of RNA in in blood and tumor tissue.	2 weeks
Other	Single cell RNA sequencing	The presence and quantity of RNA in in blood and tumor tissue.	At 4 weeks post Cycle 1
Other	Single cell RNA sequencing	The presence and quantity of RNA in in blood and tumor tissue.	At week 16 (12 weeks post combination treatment (3 cycles)
Other	Single cell RNA sequencing	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.	At the time of disease progression - up to 4 years
Primary	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.	At baseline and at 4 weeks
Primary	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	At baseline and at 4 weeks
Primary	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.	At baseline and at 4 weeks
Primary	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.	Beginning at 12 weeks post initial treatment, up to 4 years
Secondary	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.	12 weeks post initial treatment, up to 4 years
Secondary	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.	12 weeks post initial treatment, up to 4 years
Secondary	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.	Up to 4 years
Secondary	Overall Survival (OS)	Overall survival is defined as the time between the date of randomization and the date of death due to any cause.	Up to 4 years
Secondary	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.	At week 16 (2 weeks post combination treatment (3 cycles))
Secondary	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.	At week 16 (12 weeks post combination treatment (3 cycles))
Secondary	Change in CD4+ tumor infiltrating lymphocytes	Percentage and number of CD4+ tumor infiltrating lymphocytes present	At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
Secondary	Change in CD8+ tumor infiltrating lymphocytes	Percentage and number of CD8+ tumor infiltrating lymphocytes present	At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
Secondary	Change in granzyme B serum levels	Level of granzyme B (a serine protease secreted cells to mediate apoptosis in target cells) in serum.	At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
Secondary	Change in cell effector/memory status	Measure of cells that have previously encountered and responded to their cognate antigen.	At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
Secondary	Change in activation and maturation of dendritic cells	Measure of expression of activation and maturation of dendritic cells	At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
Secondary	Change in T cell count	Number of T cells present in blood and tumor	At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
Secondary	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.	At the time of disease progression - up to 4 years
Secondary	Change in soluble LAG3 levels	Amount of LAG3 (cell surface molecule expressed on activated T cells) protein present in blood and tumor tissue.	At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
Secondary	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.	At the time of disease progression - up to 4 years
Secondary	Change in Regulatory T cell (Treg) marker level	Amount of Regulatory T cell (Treg) markers present in blood and tumor tissue.	At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
Secondary	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.	At the time of disease progression - up to 4 years