MK-2870 as Monotherapy and in Combination With Pembrolizumab in Participants With Advanced Solid Tumors (MK-2870-008)

Study Overview
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Brief Summary
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This is a phase 1 trial of the safety, tolerability, and pharmacokinetics (PK) of MK-2870 monotherapy, and of MK-2870 in combination with pembrolizumab (MK-3475) or pembrolizumab + carboplatin, in Japanese participants with advanced solid tumors or treatment-naïve advanced or metastatic non-small cell lung cancer (NSCLC).

Official Title
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Phase 1 Trial of MK-2870 as Monotherapy and in Combination With Pembrolizumab ± Chemotherapy in Subjects With Advanced Solid Tumors

Conditions
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Non-small Cell Lung Cancer, Solid Tumors, Programmed Cell Death-1 (PD1, PD-1), Programmed Cell Death 1 Ligand 1(PDL1, PD-L1), Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)

Intervention / Treatment
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* Biological: MK-2870
* Biological: Pembrolizumab
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Arm 1: Histologically or cytologically confirmed advanced/metastatic solid tumor by pathology report and have received, or been intolerant to, all treatment known to confer clinical benefit. Arms 2 and 3: Have a histologically or cytologically confirmed diagnosis of advanced or metastatic NSCLC (Stage IIIB or IIIC disease and not candidates for surgical resection or definitive chemoradiation, or Stage IV NSCLC, AJCC Staging Manual, version 8). Arms 2 and 3: Confirmation that EGFR-, ALK-, or ROS1-directed therapy is not indicated as primary therapy Arm 3: Has tumor tissue that demonstrates PD-L1 TPS ≥ 50% as determined by PD-L1 IHC 22C3 pharmDx assay by local laboratory If capable of producing sperm, the participant agrees to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention (100 days for MK-2870 and 90 days for carboplatin [no restriction for pembrolizumab]) AND agrees to refrain from donating sperm AND is either abstinent and agrees to remain abstinent or uses highly effective contraception For females (assigned at birth), is not pregnant or breastfeeding and ≥1 of the following applies: is not a participant of childbearing potential (POCBP) OR is a POCBP and uses highly effective contraction Arm 1: Participants who have AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline Measurable disease by RECIST 1.1 as assessed by the local site investigator/radiology Archival tumor tissue sample or newly obtained core or incisional biopsy of a tumor lesion not previously irradiated has been provided Have a life expectancy of at least 3 months Have an ECOG performance status of 0 or 1 within 3 days before the start of study intervention Exclusion Criteria: Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible Has Grade ≥2 peripheral neuropathy Has history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or corneal disease that prevents/delays corneal healing Has active inflammatory bowel disease requiring immunosuppressive medication or previous clear history of inflammatory bowel disease Has uncontrolled, significant cardiovascular disease or cerebrovascular disease including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, uncontrolled symptomatic arrhythmia, prolongation of QTcF interval to >480 ms, and/or other serious cardiovascular and cerebrovascular diseases within the 6 months preceding study intervention Received prior treatment with a TROP2-targeted ADC Received prior treatment with a topoisomerase I-containing ADC Arm 1: Has received any prior immunotherapy and was discontinued from that treatment due to a Grade 3 or higher irAE (except endocrine disorders that can be treated with replacement therapy) or was discontinued from that treatment due to Grade 2 myocarditis or recurrent Grade 2 pneumonitis Arms 2 and 3: Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137) Arms 2 and 3: Has received prior systemic chemotherapy or other targeted or biological antineoplastic therapy for their advanced or metastatic NSCLC Arms 2 and 3: Has received radiation therapy to the lung that is >30 Gy within 6 months of the first dose of study intervention Received prior systemic anticancer therapy including investigational agents within 4 weeks before allocation Received prior radiotherapy within 2 weeks of start of study intervention, or radiation-related toxicities, requiring corticosteroids Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention Requires treatment with a strong inhibitor or inducer of CYP3A4 at least 14 days before the first dose of study intervention and throughout the study Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration Arms 2 and 3: Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication Arms 2 and 3: Active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid) Known additional malignancy that is progressing or has required active treatment within the past 3 years Known active CNS metastases and/or carcinomatous meningitis History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease Active infection requiring systemic therapy History of HIV infection Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection History or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator Known psychiatric or substance abuse disorder A severe hypersensitivity reaction to treatment a monoclonal antibody/component of the study intervention

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: MK-2870 Monotherapy<br>Participants receive single doses of MK-2870 monotherapy Q2W. | Biological: MK-2870<br>* MK-2870 injection powder for intravenous (IV) infusion.<br>* Other names: SKB264;Biological: Pembrolizumab<br>* Pembrolizumab solution for IV infusion.<br>* Other names: MK-3475;|
| Experimental: Arm 2: MK-2870 + Pembrolizumab Combination Therapy<br>Participants receive MK-2870 Q2W in combination with pembrolizumab Q6W. | Biological: MK-2870<br>* MK-2870 injection powder for intravenous (IV) infusion.<br>* Other names: SKB264;Biological: Pembrolizumab<br>* Pembrolizumab solution for IV infusion.<br>* Other names: MK-3475;|
| Experimental: Arm 3: MK-2870 + Pembrolizumab/Carboplatin Combination Therapy<br>Participants receive MK-2870 Q2W in combination with pembrolizumab Q6W and carboplatin Q3W. | Biological: MK-2870<br>* MK-2870 injection powder for intravenous (IV) infusion.<br>* Other names: SKB264;Biological: Pembrolizumab<br>* Pembrolizumab solution for IV infusion.<br>* Other names: MK-3475;Drug: Carboplatin<br>* Carboplatin solution for IV infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Dose-Limiting Toxicity (DLT) | A DLT is defined as any of the following: Grade 4 nonhematologic toxicity; Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia or lymphopenia; any nonhematologic AE ≥Grade 3 in severity (with some exceptions); any Grade 3 or Grade 4 nonhematologic laboratory value (if certain criteria are met); febrile neutropenia Grade 3 or Grade 4; a prolonged delay (>2 weeks) in initiating MK-2870 second dose due to intervention-related toxicity; any intervention-related toxicity that causes the participant to discontinue intervention during DLT evaluation period; or any Grade 5 toxicity. All toxicities will be graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0. | Up to 21 days after each dose | 
| Number of Participants Experiencing ≥1 Adverse Event (AE) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to  36 months | 
| Number of Participants Discontinuing from Study Therapy due to AE | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to  36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-Time Curve (AUC) of MK-2870-Antibody-Drug Conjugate (MK-2870-ADC) | The AUC of MK-2870-ADC will be determined in participants from Arm 1. | Day 1: Preinfusion and 0.5, 2, 4, 8, 24, 48, and 72 hours postinfusion | 
| Maximum Plasma Concentration (Cmax) of MK-2870-ADC | The Cmax of MK-2870-ADC will be determined in participants from Arm 1. | Day 1: Preinfusion and 0.5, 2, 4, 8, 24, 48, and 72 hours postinfusion | 
| Minimum Plasma Concentration (Cmin) of MK-2870-ADC | The Cmin of MK-2870-ADC will be determined in participants from Arm 1. | Day 1: Preinfusion and 0.5, 2, 4, 8, 24, 48, and 72 hours postinfusion | 
| Apparent terminal half-life (t½) of MK-2870-ADC | The t½ of MK-2870-ADC will be determined in participants from Arm 1. | Day 1: Preinfusion and 0.5, 2, 4, 8, 24, 48, and 72 hours postinfusion | 
| Time to Maximum Plasma Concentration (Tmax) of MK-2870-ADC | The Tmax of MK-2870-ADC will be determined in participants from Arm 1. | Day 1: Preinfusion and 0.5, 2, 4, 8, 24, 48, and 72 hours postinfusion | 
| Clearance (CL) of MK-2870-ADC | The CL of MK-2870-ADC will be determined in participants from Arm 1. | Day 1: Preinfusion and 0.5, 2, 4, 8, 24, 48, and 72 hours postinfusion | 
| Volume of Distribution (Vz) of MK-2870-ADC | The Vz of MK-2870-ADC will be determined in participants from Arm 1. | Day 1: Preinfusion and 0.5, 2, 4, 8, 24, 48, and 72 hours postinfusion | 
| Accumulation Ratio (Rac) of MK-2870-ADC | The Rac of MK-2870-ADC will be determined in participants from Arm 1. | Day 1: Preinfusion and 0.5, 2, 4, 8, 24, 48, and 72 hours postinfusion | 
| Area Under the Plasma AUC of MK-2870-Total Antibody (MK-2870-TAB) | The AUC of MK-2870-TAB will be determined in participants from Arm 1. | Day 1: Preinfusion and 0.5, 2, 4, 8, 24, 48, and 72 hours postinfusion | 
| Cmax of MK-2870-TAB | The Cmax of MK-2870-TAB will be determined in participants from Arm 1. | Day 1: Preinfusion and 0.5, 2, 4, 8, 24, 48, and 72 hours postinfusion | 
| Cmin of MK-2870-TAB | The Cmin of MK-2870-TAB will be determined in participants from Arm 1. | Day 1: Preinfusion and 0.5, 2, 4, 8, 24, 48, and 72 hours postinfusion | 
| t½ of MK-2870-TAB | The t½ of MK-2870-TAB will be determined in participants from Arm 1. | Day 1: Preinfusion and 0.5, 2, 4, 8, 24, 48, and 72 hours postinfusion | 
| Tmax of MK-2870-TAB | The Tmax of MK-2870-TAB will be determined in participants from Arm 1. | Day 1: Preinfusion and 0.5, 2, 4, 8, 24, 48, and 72 hours postinfusion | 
| CL of MK-2870-TAB | The CL of MK-2870-TAB will be determined in participants from Arm 1. | Day 1: Preinfusion and 0.5, 2, 4, 8, 24, 48, and 72 hours postinfusion | 
| Vz of MK-2870-TAB | The Vz of MK-2870-TAB will be determined in participants from Arm 1. | Day 1: Preinfusion and 0.5, 2, 4, 8, 24, 48, and 72 hours postinfusion | 
| Rac of MK-2870-TAB | The Rac of MK-2870-TAB will be determined in participants from Arm 1. | Day 1: Preinfusion and 0.5, 2, 4, 8, 24, 48, and 72 hours postinfusion | 
| Cmax of MK-2870-ADC Coadministered with Pembrolizumab | The Cmax of MK-2870-ADC when coadministered with pembrolizumab will be determined in participants from Arms 2 and 3. | Cycle 1 and 2: Days 1 and 29 preinfusion and 0.5 hours postinfusion (each cycle is 29 days) | 
| Cmin of MK-2870-ADC Coadministered with Pembrolizumab | The Cmin of MK-2870-ADC when coadministered with pembrolizumab will be determined in participants from Arms 2 and 3. | Cycle 1 and 2: Days 1 and 29 preinfusion and 0.5 hours postinfusion (each cycle is 29 days) | 
| Rac of MK-2870-ADC Coadministered with Pembrolizumab | The Rac of MK-2870-ADC when coadministered with pembrolizumab will be determined in participants from Arms 2 and 3. | Cycle 1 and 2: Days 1 and 29 preinfusion and 0.5 hours postinfusion (each cycle is 29 days) | 
| Cmax of MK-2870-TAB Coadministered with Pembrolizumab | The Cmax of MK-2870-TAB when coadministered with pembrolizumab will be determined in participants from Arms 2 and 3. | Cycle 1 and 2: Days 1 and 29 preinfusion and 0.5 hours postinfusion (each cycle is 29 days) | 
| Cmin of MK-2870-TAB Coadministered with Pembrolizumab | The Cmin of MK-2870-TAB when coadministered with pembrolizumab will be determined in participants from Arms 2 and 3. | Cycle 1 and 2: Days 1 and 29 preinfusion and 0.5 hours postinfusion (each cycle is 29 days) | 
| Rac of MK-2870-TAB Coadministered with Pembrolizumab | The Rac of MK-2870-TAB when coadministered with pembrolizumab will be determined in participants from Arms 2 and 3. | Cycle 1 and 2: Days 1 and 29 preinfusion and 0.5 hours postinfusion (each cycle is 29 days) | 
| Cmax of KL610023 Coadministered with Pembrolizumab | The Cmax of KL610023 (free payload) when MK-2870 is coadministered with pembrolizumab will be determined in participants from Arms 2 and 3. | Cycle 1 and 2: Days 1 and 29 preinfusion and 0.5 hours postinfusion (each cycle is 29 days) | 
| Rac of KL610023 Coadministered with Pembrolizumab | The Rac of KL610023 (free payload) when MK-2870 is coadministered with pembrolizumab will be determined in participants from Arms 2 and 3. | Cycle 1 and 2: Days 1 and 29 preinfusion and 0.5 hours postinfusion (each cycle is 29 days) | 
| Objective Response Rate (ORR) | ORR is defined as the percentage of participants with 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) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST1.1). The percentage of participants who experience CR or PR as assessed by Blinded Independent Central Review (BICR) will be presented. | Up to  36 months | 
| Duration of Response (DOR) | DOR is defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause. | Up to  36 months | 
| Incidence of Antidrug Antibodies (ADA) to MK-2870 | The incidence of ADA will be determined in participants from Arms 2 and 3. | Up to  36 months |