Study of Preladenant (MK-3814) Alone and With Pembrolizumab (MK-3475) in Participants With Advanced Solid Tumors (MK-3814A-062)

• ClinicalTrials.gov Identifier: NCT03099161
• Recruitment Status: Terminated
• First Posted: April 4, 2017
• Results First Posted: June 5, 2019
• Last Update Posted: June 5, 2019
• Sponsor: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

Study Description

Brief Summary:

The purpose of this study is to evaluate the safety and preliminary efficacy of preladenant (MK-3814A) alone and in combination with pembrolizumab (MK-3475) (pembro) in participants with advanced solid tumors that have not responded to prior therapy. This study will be done in 2 parts. Part 1 will identify and confirm the recommended Phase 2 dose (RP2D) of preladenant when given alone or in combination with pembrolizumab. Part 2 of the study will determine the safety and efficacy of preladenant in combination with pembrolizumab at the RP2D in participants with select solid tumors .

Condition or disease	Intervention/treatment	Phase
Neoplasm	Drug: preladenant; Biological: pembrolizumab	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 10 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase Ib/II Study to Evaluate the Safety and Tolerability of Preladenant as a Single Agent and in Combination With Pembrolizumab in Subjects With Advanced Malignancies
• Actual Study Start Date: June 27, 2017
• Actual Primary Completion Date: November 24, 2017
• Actual Study Completion Date: February 21, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Preladenant 25 mg Twice a Day (BID); During an initial dose evaluation phase, participants received 25 mg of preladenant orally twice a day (BID) on Days 1 through 21 of each 21-day cycle (for a maximum of 35 cycles) until the RP2D could be established. The RP2D was to be established based on the number of dose limiting toxicities (DLTs) at each dose level administered. Participants continued receiving 25 mg of preladenant BID on Days 1 through 21 of each infusion cycle until discontinuation or receiving a maximum of 35 cycles.	Drug: preladenant; Administered as an oral capsule BID on Days 1 through 21 of each 21-day cycle; Other Name: MK-3814A
Experimental: Preladenant 50 mg BID; During an initial dose evaluation phase, participants received 50 mg of preladenant orally BID on Days 1 through 21 of each 21-day cycle (for a maximum of 35 cycles) until the RP2D could be established. The RP2D was established based on the number of DLTs at each dose level administered. Participants continued receiving 50 mg of preladenant BID on Days 1 through 21 of each infusion cycle until discontinuation or receiving a maximum of 35 cycles.	Drug: preladenant; Administered as an oral capsule BID on Days 1 through 21 of each 21-day cycle; Other Name: MK-3814A
Experimental: Preladenant + Pembrolizumab; During an initial dose evaluation phase, participants received 25 mg of preladenant administered orally BID on Days 1 through 21 in combination with 200 mg pembrolizumab administered as an intravenous (IV) infusion on Day 1 of each 21-day cycle (for a maximum of 35 cycles). Participants continued receiving preladenant 25 mg BID in combination with 200 mg pembrolizumab for each infusion cycle until discontinuation or receiving a maximum of 35 cycles.	Drug: preladenant; Administered as an oral capsule BID on Days 1 through 21 of each 21-day cycle; Other Name: MK-3814A; Biological: pembrolizumab; Administered as IV infusion on Day 1 of each 21-day cycle; Other Names: KEYTRUDA®; MK-3475

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Dose-limiting Toxicities (DLTs) [ Time Frame: Cycle 1 (up to 21 days) ]
   DLTs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4. A DLT was defined as any of the following events: Grade (Gr) 4 non-hematologic toxicity (not laboratory); Gr 4 hematologic toxicity lasting ≥7 days; Gr 4 thrombocytopenia of any duration; Gr 3 thrombocytopenia with bleeding; Gr 3 non-hematologic toxicity (not laboratory) lasting >3 days despite optimal supportive care; Gr 3 or Gr 4 non-hematologic laboratory value requiring treatment, hospitalization, or persisting for >72 hours; alanine aminotransferase (ALT) or aspartate aminotransferase(AST) >3X upper limit of normal (ULN) WITH total bilirubin >2X ULN with no elevation in alkaline phosphatase (<2X ULN); Febrile neutropenia Gr 3 or 4; discontinuation during Cycle 1 or a >2 week delay in initiating Cycle 2 due to treatment-related toxicity; Missing >25% of preladenant doses as a result of adverse events during Cycle 1; or Gr 5 toxicity.
2. Number of Participants Who Experienced at Least One Adverse Event (AE) [ Time Frame: Up tp approximately 8 months ]
   An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. The number of participants who experienced at least one AE is presented.
3. Number of Participants Who Discontinued Study Treatment Due to an AE [ Time Frame: Up to approximately 8 months ]
   An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. The number of participants who discontinued study treatment due to an AE is presented.

Secondary Outcome Measures :

1. Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 8 months ]
   ORR was defined as the percentage of the participants in the analysis population who had a Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) and was assessed using RECIST 1.1 per investigator review. The ORR per RECIST 1.1 for participants is presented.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Has a histologically- or pathologically-documented, locally-advanced or metastatic solid tumor for which standard therapy, either does not exist or has been proven ineffective, intolerable or refused by the participant. Each participant must have received at least one and up to five prior lines of cancer treatment regimens, excluding neo-adjuvant, adjuvant, maintenance treatment and surgery
• Has provided a tumor tissue sample (archival or newly obtained core or excisional biopsy of a tumor lesion)
• Has measurable disease per RECIST 1.1
• Has an Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Females must not be pregnant
• Female and male participants of reproductive potential must agree to use adequate contraception starting from the first dose of study therapy, throughout the study period, and for up to 120 days after the last dose of study therapy

Exclusion Criteria:

• Has disease that is suitable for local treatment administered with curative intent
• Has received previous treatment with an immunomodulatory agent (e.g, anti- Programmed Cell Death Receptor 1/ Programmed Cell Death Receptor Ligand 1 or anti-cytotoxic T-lymphocyte-associated antigen-4) and was discontinued from treatment due to a Grade 3 or higher immune-related adverse event
• Has received previous treatment with an adenosine A2a receptor antagonist (e.g. CPI-444, HTL1071, PBF-509)
• Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks of the first dose of study therapy, or has not recovered to Common Toxicity Criteria for Adverse Events (CTCAE) grade 1 or better from any adverse event
• Is currently participating or has participated in a study with an investigational agent or using an investigational device within 28 days of the first dose of study therapy
• Is currently taking or has taken drugs that interfere with Cytochrome P450 (CYP)3A4 or CYP2C8 or grapefruit and star fruit in diet within 14 days of the first dose of study therapy
• Is currently taking or has taken proton pump inhibitors within 5 days of the first dose of study therapy
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days of the first dose of study therapy
• Is expected to require any other form of systemic or localized antineoplastic therapy while on study
• Has a history of a second malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for 5 years
• Has clinically active central nervous system metastases and/or carcinomatous meningitis
• History of a severe hypersensitivity reaction to treatment with the monoclonal antibody/components of the study drug
• Has an active infection requiring therapy
• History of interstitial lung disease
• History of (non-infectious) pneumonitis that required steroids or current pneumonitis
• History of active tuberculosis
• Has an active autoimmune disease that has required systemic treatment in the past 2 years
• Has received a live-virus vaccine within 30 days of the first dose of study therapy
• Has known Human Immunodeficiency Virus (HIV) (HIV 1 or 2 antibodies) and/or known active and acute Hepatitis B or C infections
• Has known psychiatric or substance abuse disorders that would interfere with the ability to cooperate with the requirements of the study
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study
• Has not fully recovered from any effects of major surgery without significant detectable infection
• Has had surgery that required general anesthesia within 2 weeks of the first dose of study therapy
• Has had surgery that required regional/epidural anesthesia within 72 hours of the first dose of study therapy

Contacts and Locations

Locations

United States, Michigan

START Midwest ( Site 0001)

Grand Rapids, Michigan, United States, 49546

Canada, Ontario

Princess Margaret Hospital ( Site 0010)

Toronto, Ontario, Canada, H9H 4M7

Canada, Quebec

Jewish General Hospital ( Site 0011)

Montreal, Quebec, Canada, H9H 4M7

Israel

Rambam Health Care Campus ( Site 0020)

Haifa, Israel

Tel Aviv Sourasky Medical Center ( Site 0021)

Tel Aviv, Israel

Sponsors and Collaborators

Merck Sharp & Dohme Corp.

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme Corp.

  Study Documents (Full-Text)

Documents provided by Merck Sharp & Dohme Corp.:

Study Protocol and Statistical Analysis Plan  [PDF] March 30, 2017

More Information

• Responsible Party: Merck Sharp & Dohme Corp.
• ClinicalTrials.gov Identifier: NCT03099161
• Other Study ID Numbers: 3814A-062; MK-3814A-062 ( Other Identifier: Merck Protocol Number )
• First Posted: April 4, 2017
• Results First Posted: June 5, 2019
• Last Update Posted: June 5, 2019
• Last Verified: February 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Merck Sharp & Dohme Corp.:

Advanced Solid Tumor; Programmed Cell Death Receptor 1 (PD-1); Programmed Cell Death Receptor Ligand 1 (PD-L1); PD1; PD-1; PDL1; PD-L1

Additional relevant MeSH terms:

Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents