Study of MK-4464 as Monotherapy and in Combination With Pembrolizumab in Participants With Advanced/Metastatic Solid Tumors (MK-4464-001)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the safety, pharmacokinetics, and preliminary efficacy of MK-4464 as monotherapy and in combination with pembrolizumab in participants with advanced/metastatic solid tumors.

Official Title
-----------------
A Phase 1, Open-label, Multicenter Study of the Safety, Pharmacokinetics, and Pharmacodynamics of MK-4464 as Monotherapy and in Combination With Pembrolizumab in Participants With Advanced/Metastatic Solid Tumors

Conditions
-----------------
Advanced/Metastatic Solid Tumors, Neoplasms

Intervention / Treatment
-----------------
* Biological: MK-4464
* Biological: Pembrolizumab
* Drug: 89Zr-MK-4464


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The key Inclusion Criteria include but are not limited to the following: Have a histologically or cytologically confirmed advanced/metastatic solid tumor by pathology report and have received, been intolerant to, been ineligible for, or refused all treatment known to confer clinical benefit Must submit a baseline tumor sample for analysis Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale Human immunodeficiency virus (HIV) infected participants must have well controlled HIV on antiretroviral therapy (ART) Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks, and have undetectable HBV viral load before randomization. Exclusion Criteria: The key Exclusion Criteria include but are not limited to the following: Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks (2 weeks for palliative radiation) before the first dose of study intervention or has not recovered to CTCAE Grade 1 or better from any AEs that were due to cancer therapeutics administered more than 4 weeks earlier Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years Has clinically active central nervous system (CNS) metastases and/or carcinomatous meningitis Has an active infection requiring therapy History of an allogenic stem cell transplant or a solid organ transplant Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease Has an active autoimmune disease that has required systemic treatment in the past 2 years HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease Has known psychiatric or substance abuse disorders that would interfere with the participant's ability to cooperate with the requirements of the study Has not fully recovered from any effects of major surgery without significant detectable infection Has received radiation therapy to the lung that is >30 gray (Gy) within 6 months of the first dose of study treatment Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention Is currently participating and receiving study intervention in a study of an investigational agent or has participated and received study intervention in a study of an investigational agent or has used an investigational device within 28 days

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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: MK-4464<br>Participants will receive an intravenous (IV) infusion of MK-4464 administered in escalating doses every 3 weeks for up to 35 cycles. Escalation to subsequent MK-4464 doses will be based on safety of previous dose. | Biological: MK-4464<br>* MK-4464 administered as an IV infusion every three weeks according to allocation and dose escalation.<br>|
| Experimental: MK-4464 + Pembrolizumab<br>Participants will receive an IV infusion of MK-4464 administered in escalating doses and a 200 mg IV infusion of Pembrolizumab every 3 weeks for up to 35 cycles. Escalation to subsequent MK-4464 doses will be based on safety of MK-4464 monotherapy arm. | Biological: MK-4464<br>* MK-4464 administered as an IV infusion every three weeks according to allocation and dose escalation.<br>Biological: Pembrolizumab<br>* Pembrolizumab 200 mg administered as an IV infusion every three weeks.<br>|
| Experimental: MK-4464 + Pembrolizumab + Zirconium 89 (89Zr)-MK-4464<br>Participants will receive an IV infusion of 89Zr-MK-4464 + IV infusion of MK-4464 on Cycle 1 Day 1, followed by an IV infusion of MK-4464 + a 200 mg IV infusion of pembrolizumab starting on Cycle 2 Day 1 and every 3 weeks for up to 35 cycles. Each cycle=3 weeks. MK-4464 doses will be based on safety of MK-4464 monotherapy arm. Participants may receive a 200 mg IV infusion of pembrolizumab on cycle 36. | Biological: MK-4464<br>* MK-4464 administered as an IV infusion every three weeks according to allocation and dose escalation.<br>Biological: Pembrolizumab<br>* Pembrolizumab 200 mg administered as an IV infusion every three weeks.<br>Drug: 89Zr-MK-4464<br>* 89ZR-MK-4464 administered as an IV infusion on C1D1.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) | A DLT is any toxicity assessed by the investigator to be possibly, probably, or definitely related to study intervention administration that results in a change to a given dose or a delay in initiating the next cycle. All toxicities will be graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). | Up to approximately 21 days | 
| Number of Participants Who Experience At Least One adverse event (AE) | An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experience at least one AE will be presented. | Up to approximately 27 months | 
| Number of Participants Who Discontinue Study Treatment Due to an AE | An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinue study treatment due to an AE will be presented. | Up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimum Plasma Concentration (Cmin) of MK-4464 | Cmin is the minimum concentration of the drug observed in plasma. Blood samples will be collected pre-dose and post-dose at designated timepoints to determine Cmin of MK-4464. | Once daily on Day 2, 3, 5, 8, 15 of Cycle 1 and 4, Pre-dose and immediately Post-dose Day 1 Cycle 1, 2, 3, 4, Pre-dose Day 1 Cycles 5, 6, 7, 8, and every 4 cycles thereafter through Cycle 35, 30 days post last dose (up to  25 months); Cycle = 21 days | 
| Maximum Plasma Concentration (Cmax) of MK-4464 | Cmax is the maximum concentration of the drug observed in plasma. Blood samples will be collected pre-dose and post-dose at designated timepoints to determine Cmax of MK-4464. | Once daily on Day 2, 3, 5, 8, 15 of Cycle 1 and 4, Pre-dose and immediately Post-dose Day 1 Cycle 1, 2, 3, 4, Pre-dose Day 1 Cycles 5, 6, 7, 8, and every 4 cycles thereafter through Cycle 35, 30 days post last dose (up to  25 months); Cycle = 21 days | 
| Area Under the Plasma Concentration-Time Curve (AUC) of MK-4464 | AUC is a measure of the extrapolated mean concentration in serum. Blood samples will be collected pre-dose and post-dose at designated timepoints to determine AUC of MK-4464. | Once daily on Day 2, 3, 5, 8, 15 of Cycle 1 and 4, Pre-dose and immediately Post-dose Day 1 Cycle 1, 2, 3, 4, Pre-dose Day 1 Cycles 5, 6, 7, 8, and every 4 cycles thereafter through Cycle 35, 30 days post last dose (up to  25 months); Cycle = 21 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 (RECIST 1.1). The percentage of participants who experience CR or PR as assessed by investigator assessment will be presented. | Up to 24 months |