A Phase 1/Phase 2 Study to Evaluate the Safety and Tolerability of MK-1088 as Monotherapy and in Combination with Pembrolizumab in Participants with Advanced Solid Tumors

Trial ID: 2022-502288-40-00
Protocol: MK-1088-002
Sponsor: Merck Sharp & Dohme LLC

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Diseases & Conditions

Neoplasm

Objectives

The primary objective of this study is to determine the **safety** and tolerability of MK-1088, both as a monotherapy and in combination with pembrolizumab, in participants with advanced solid tumors. This includes establishing a preliminary maximum tolerated dose or recommended Phase 2 dose in Part 1 of the study. Understanding the safety profile and optimal dosing is crucial for the development of effective treatment regimens for patients with advanced or metastatic solid tumors.

Secondary objectives include evaluating the pharmacokinetics (PK) of MK-1088 when administered alone and in combination with pembrolizumab in both Part 1 and Part 2 of the study. Additionally, the study aims to assess the antitumor activity, specifically the objective response rate (ORR), of MK-1088 as determined by the investigator. This assessment will be based on PCWG-modified RECIST 1.1 criteria for prostate cancer participants and RECIST 1.1 criteria for all other participants, providing insights into the therapeutic potential of MK-1088 in various cancer types.

Participants

The clinical trial involves a total of **79 participants** diagnosed with advanced or metastatic solid tumors. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on a histologically- or cytologically-confirmed diagnosis of advanced or metastatic solid tumors, having received or been intolerant to treatments known to confer clinical benefit. The trial also includes individuals with metastatic castrate-resistant prostate cancer who have specific prior treatment histories. Participants with well-controlled **HIV** on anti-retroviral therapy are included. The trial population is characterized by a diverse health status, with considerations for those who have been ineligible for other treatments. The selection process ensures a comprehensive representation of individuals affected by these conditions, including vulnerable populations. Lifestyle factors such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the **safety** and **tolerability** of MK-1088, both as a monotherapy and in combination with **pembrolizumab**, in participants with advanced solid tumors. This study is structured as a Phase 1/Phase 2 trial, employing a randomized, double-blind, and controlled methodology to ensure the reliability and validity of the results. The trial is expected to span from June 29, 2022, to November 10, 2025, providing a comprehensive assessment over this period.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically- or cytologically-confirmed diagnosis of advanced/metastatic solid tumors. Following successful screening, participants will be enrolled in the study and will attend regular follow-up visits to monitor their response to the treatment and any potential adverse events. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the overall outcomes of the treatment.

The expected length of participant involvement in the trial is approximately 28 days, corresponding to the maximum treatment period for the investigational products. However, certain conditions may lead to early termination from the study, such as the occurrence of dose-limiting toxicities, adverse events, or discontinuation of study treatment due to adverse events. The primary endpoints include the number of participants experiencing dose-limiting toxicities and adverse events, while secondary endpoints focus on pharmacokinetic parameters such as the area under the plasma concentration-time curve and maximum plasma concentration of MK-1088.

Treatment

The clinical trial involves the administration of **pembrolizumab**, marketed under the name Keytruda, which is provided as a 25 mg/mL concentrate for solution for infusion. This pharmaceutical form is intended for **intravenous** administration. The maximum daily dose of pembrolizumab is 200 mg, with a total maximum dose of 7000 mg over a treatment period of 28 days. Pembrolizumab is a protein-based therapeutic agent, specifically classified as a protein of other origin. The product is authorized in the European Union under the marketing authorization number EU/1/15/1024/002 and is manufactured by Merck Sharp & Dohme BV. Participant compliance with the dosing schedule will be monitored throughout the trial.

Additionally, the trial includes the investigational drug **MK-1088**, which is provided in tablet form for **oral** administration. The maximum daily dose for MK-1088 is 800 mg, with a total maximum dose of 588 g over a 28-day treatment period. MK-1088 is a chemically derived substance, and its development is sponsored by Merck & Co. Inc. The trial aims to evaluate the safety and tolerability of MK-1088 both as a monotherapy and in combination with pembrolizumab. Compliance with the oral dosing regimen will be closely monitored to ensure adherence to the study protocol.

Efficacy

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include the number of participants experiencing dose-limiting toxicities (DLTs), the number of participants experiencing adverse events (AEs), and the number of participants discontinuing study treatment due to AEs. These endpoints are crucial for evaluating the safety and tolerability of the investigational products, MK-1088 and **pembrolizumab**, when administered as monotherapy and in combination.

Secondary endpoints focus on pharmacokinetic parameters and clinical response. These include the area under the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax), and minimum plasma concentration (Cmin) of MK-1088. Additionally, the objective response rate (ORR) will be measured to assess the clinical efficacy of the treatment regimen. These parameters will be collected and analyzed at specified timepoints throughout the trial to provide a comprehensive evaluation of the investigational products' efficacy.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Has a histologically- or cytologically-confirmed diagnosis of advanced/metastatic solid tumor by pathology report and have received, have been intolerant to, or have been ineligible for treatment known to confer clinical benefit
For metastatic castrate-resistant prostate cancer (mCRPC) only: (1) Must have previously received docetaxel, prior treatment with one other chemotherapy is allowed as well as up to 2 second-generation hormonal manipulations and (2) have prostate cancer progression within 6 months before screening, as determined by the investigator
If human immunodeficiency virus (HIV) positive, has well-controlled HIV on anti-retroviral therapy (ART)

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Exclusion Criteria

Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks (2 weeks for palliative radiation) before the first dose of study intervention
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
Has a history of interstitial lung disease
Has a history of (noninfectious) pneumonitis that required steroids or current pneumonitis
Has an active autoimmune disease that has required systemic treatment in the past 2 years
Has concurrent active Hepatitis B and Hepatitis C virus infection
Has HIV with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
Has not fully recovered from any effects of major surgery without significant detectable infection
Has a history or current evidence of a gastrointestinal (GI) condition or impaired liver function or diseases that in the opinion of the investigator may significantly alter the absorption or metabolism of oral medications
Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, including NYHA Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability
Has a QTcF >470 msec
Has history of an allogeneic stem cell transplant or a solid organ transplant
Has received prior systemic anticancer therapy including investigational agents within 4 weeks before allocation
Has received prior radiotherapy within 2 weeks of start of study intervention, or had radiation-related toxicities requiring corticosteroids
Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
Has a "superscan" bone scan