Study of Vibostolimab Alone and in Combination With Pembrolizumab in Advanced Solid Tumors (MK-7684-001) ( KEYVIBE-001)

Merck Sharp & Dohme LLC474 enrolled

Overview

This is a safety, efficacy, and pharmacokinetics (PK) study of vibostolimab (MK-7684) as monotherapy and in combination with pembrolizumab (MK-3475) or pembrolizumab plus pemetrexed and carboplatin in adults with metastatic solid tumors for which there is no available therapy that is expected to convey clinical benefit. Part A of this study is a dose escalation and confirmation phase to estimate the recommended Phase 2 dose (RPTD) for vibostolimab monotherapy or in combination with pembrolizumab, pemetrexed, and carboplatin. Part A will also evaluate the anti-tumor activity of vibostolimab in combination with pembrolizumab plus pemetrexed and carboplatin in participants with non-small cell lung cancer (NSCLC) and vibostolimab (at two dose levels) in combination with pembrolizumab in Japanese participants with gastric cancer. Part B will evaluate the anti-tumor activity of vibostolimab at the RPTD when used as monotherapy and in combination with pembrolizumab in participants with advanced solid tumors in a non-randomized study design. Part B will also evaluate 2 doses of vibostolimab in combination with pembrolizumab in participants with programmed death 1 (PD-1) treatment naïve cancer using a 1:1 randomized study design. Part B is expanded with Amendment 11 to include an additional arm that will compare the safety and PK of a fixed dose of pembrolizumab/vibostolimab coformulation (MK-7684A) to vibostolimab in combination with pembrolizumab administered as separate intravenous infusions. Part A is expanded with Amendment 12 to include an additional arm that will compare the safety and PK of vibostolimab plus pembrolizumab plus the investigator's choice of platinum agent (carboplatin or cisplatin), and etoposide. Part B is expanded with Amendment 12 to include evaluation of efficacy of vibostolimab plus pembrolizumab plus the investigator's choice of platinum agent (carboplatin or cisplatin), and etoposide and efficacy of pembrolizumab/vibostolimab coformulation in participants from mainland China. The primary hypotheses are that vibostolimab administered as monotherapy or in combination with pembrolizumab is safe and tolerable when administered at the RPTD and that pembrolizumab/vibostolimab coformulation is safe and tolerable when administered as a fixed dose.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

Interventions

vibostolimabBIOLOGICAL

Administered as an intravenous (IV) infusion on Day 1 of 21-day infusion Cycles 1-35

pembrolizumabBIOLOGICAL

Administered as an IV infusion on Day 1 of 21-day infusion Cycles 1-35

pemetrexedDRUG

Administered as an IV infusion on Day 1 of 21-day infusion Cycles 1-35

carboplatinDRUG

Administered as an IV infusion on Day 1 of 21-day infusion Cycles 1-4

pembrolizumab/vibostolimab coformulationBIOLOGICAL

Administered as an IV infusion on Day 1 of 21-day infusion Cycles 1-35

cisplatinDRUG

Administered as an IV infusion on Day 1 of 21-day infusion Cycles 1-4

etoposideDRUG

Administered as an IV infusion on Days 1-3 of 21-day infusion Cycles 1-4

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * For Part A participants enrolled prior to Amendment 7, must have a histologically or cytologically confirmed metastatic solid tumor for which there is no available therapy that is expected to convey clinical benefit * For Part A Japanese cohort added with Amendment 7: Must reside in Japan and be of Japanese descent and have adenocarcinoma of the stomach and/or gastric-esophageal junction (GEJ) that is considered inoperable and that has received, and progressed on, at least 1 prior chemotherapy regimen or human epidermal growth factor receptor 2 (HER2)/neu-targeted approved therapy (if HER2/neu-positive). In both cases, participants may be untreated or could have received and progressed on 1 prior regimen, but must not have received prior anti-PD-1/PD-L1 therapy * For Part A participants with non-small cell lung cancer (NSCLC) added with Amendment 7: Must have a histologically or cytologically confirmed diagnosis of stage IV (M1a or M1b per current American Joint Committee on Cancer criteria, edition 8) non-squamous NSCLC * For Part B China participants added with Amendment 12. Must have a histologically or cytologically confirmed metastatic solid tumor for which no more than 2 prior lines of therapy were administered and there is no available therapy that is expected to convey clinical benefit AND be Chinese from mainland China * For Parts A and B: Has histologically or cytologically confirmed metastatic solid tumor * Has measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) * Has an Eastern Cooperative Oncology Group performance status of 0 to 1 * Females must not be pregnant * Women of childbearing potential and male participants must agree to use adequate contraception for the course of the study * Has provided a tumor tissue sample (archival or newly obtained core or excisional biopsy of a tumor lesion) * For Chinese participants enrolled as part of Amendment 12. No tumor tissue samples will be collected Exclusion Criteria: * Has had chemotherapy, radiation, biological cancer therapy or major surgery within 4 weeks prior to the first dose of study treatment * Has not recovered to Common Toxicity Criteria for Adverse Events Grade 1 or better from the adverse events due to cancer therapeutics administered more than 4 weeks prior to the first dose of study treatment * Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment * Has received previous treatment with another agent targeting the T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (TIGIT) receptor * Has received previous treatment with an immunomodulatory agent (e.g., anti-programmed cell death 1, anti-programmed cell death ligand 1 or cytotoxic T-lymphocyte-associated protein 4) and was discontinued from that treatment due to a Grade 3 or higher immune-related adverse event * Is expected to require any other form of antineoplastic therapy while participating in the trial * Is on chronic systemic steroid therapy in excess of replacement doses or on any other form of immunosuppressive medication * Has a history of a previous additional malignancy unless potentially curative treatment has been completed with no evidence of malignancy for 5 years * Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis * Has an active autoimmune disease * Has an active infection requiring systemic treatment * Has interstitial lung disease * Has active or past history of (non-infectious) pneumonitis requiring steroids * Has symptomatic ascites or pleural effusion * Has previously had a hematopoetic stem cell transplant or solid organ transplant * Is known to be human immunodeficiency virus (HIV) positive and/or known to have active chronic or acute Hepatitis B or Hepatitis C * Has a known psychiatric and/or substance abuse disorder that would make it difficult for the participant to cooperate with the requirements of the trial * Is a regular user (including recreational use) of any illicit drugs at the time of providing documented informed consent, or has a recent history (within the last year) of substance abuse * Has received a live virus vaccine within 30 days prior to the first dose of study treatment * Has had hormonal cancer therapy (e.g., tamoxifen, leuprolide). within 4 weeks prior to the first dose of study treatment * For Part A participants with NSCLC added with Amendment 7: Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) other than an aspirin dose ≤1.3 gram per day for a 5-day period (8-day period for long-acting agents, such as piroxicam) * For Part A participants with NSCLC added with Amendment 7: Is unable or unwilling to take folic acid or Vitamin B12 supplementation

Outcomes

Primary Outcomes

Number of Participants With Dose Limiting Toxicities (DLTs) up to 24 Months

A DLT is defined as an event with toxicity including the type, severity, time of onset, time of resolution, and the probable association with study treatment that are not due to pre-existing conditions as defined by the Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE4.0).

Time frame: Up to 24 Months

Number of Participants Who Experienced At Least One Adverse Event (AE)

An AE is defined as any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol specified procedure, whether or not considered related to the medicinal product or protocol specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event.

Time frame: Up to 28 Months

Number of Participants Who Discontinued Study Treatment Due to an AE

Time frame: Up to 24 Months

Secondary Outcomes

Overall Response Rate (ORR) in Participants in Vibostolimab Dose Escalation Phase Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

ORR is the percentage of participants who experience complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions) at any time during the trial using RECIST, version 1.1 as assessed by investigator review. Results for participants treated with vibostolimab dose escalation are presented.

Time frame: Up to 24 Months

ORR in Participants With Programmed Death 1 (PD-1) Refractory Non-small Cell Lung Cancer (NSCLC) Per RECIST 1.1

ORR is the percentage of participants who experience complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions) at any time during the trial using RECIST, version 1.1 as assessed by investigator review. Results for participants with PD-1 refractory NSCLC treated with 200 or 210 mg vibostolimab in dose escalation as well as dose expansion phases are presented.

Time frame: Up to 24 Months

ORR in Participants With PD-1 Naive NSCLC Per RECIST 1.1

ORR is the percentage of participants who experience complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions) at any time during the trial using RECIST, version 1.1 as assessed by investigator review. Results for participants with PD-1 naive NSCLC treated with pembrolizumab and 200 mg vibostolimab from both the dose escalation and expansion phases are presented.

Time frame: Up to 24 Months

ORR in Participants With Extensive-stage Small Cell Lung Cancer (ES-SCLC) Per RECIST 1.1

ORR is the percentage of participants who experience complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions) at any time during the trial using RECIST, version 1.1 as assessed by investigator review. Participants with ES-SCLC treated with vibostolimab in combination with pembrolizumab, carboplatin or cisplatin, and etoposide were analyzed.

Time frame: Up to 24 Months

ORR in Participants With PD-1 Naive Ovarian Cancer Per RECIST 1.1

ORR in Participants With PD-1 Naive Cervical Cancer Per RECIST 1.1

ORR is the percentage of participants who experience complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions) at any time during the trial using RECIST, version 1.1 as assessed by investigator review. Results for participants with PD-1 naive cervical cancer treated with pembrolizumab and either 200 mg or 700 mg vibostolimab are presented.

Time frame: Up to 24 Months

Area Under the Curve From Time 0 to 21 Days Postdose (AUC 0-21 Days) of Plasma Vibostolimab Following Treatment With Increasing Amounts of Vibostolimab Monotherapy or Vibostolimab With 200 mg Pembrolizumab

Blood samples were collected from participants during cycle 1 and cycle 4 of treatment (Cycle length is 21 days) in order to determine the AUC 0-21 days of plasma vibostolimab, Only results from participants treated with increasing amounts of vibostolimab monotherapy or vibostolimab combined with 200 mg pembrolizumab are presented; whereas other treatment groups were not analyzed. Due to terminal fitting issue, non-calculable AUC0-21 days was replaced with AUClast for a few participants.

Time frame: Cycle 1, Cycle 4: Day 1 pre-dose, 0.5, and 2 hours post-dose; once daily on Days 2, 3, 5, 8, 15 and 22.

AUC 0-21 Days of Plasma Vibostolimab Following Treatment With 200 mg Vibostolimab Combined With Various Other Treatments

Blood samples were collected from participants during cycle 1 and cycle 4 of treatment (Cycle length is 21 days) following treatment with 200 mg vibostolimab in order to determine the AUC 0-21 days of plasma vibostolimab, Due to terminal fitting issue, non-calculable AUC0-21 days was replaced with AUClast for a few participants.