Neoplasm
Conditions
Keywords
Advanced Solid Tumor, Programmed Cell Death Receptor 1 (PD-1), Programmed Cell Death Receptor Ligand 1 (PD-L1), PD1, PD-1, PDL1, PD-L1
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 .
Interventions
DRUGpreladenant
Administered as an oral capsule BID on Days 1 through 21 of each 21-day cycle
BIOLOGICALpembrolizumab
Administered as IV infusion on Day 1 of each 21-day cycle
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-limiting Toxicities (DLTs) | 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. |
| Number of Participants Who Experienced at Least One Adverse Event (AE) | 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. |
| Number of Participants Who Discontinued Study Treatment Due to an AE | 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
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 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. |
Countries
Canada, Israel, United States
Participant flow
Pre-assignment details
This study was planned to have 2 parts: a dose escalation/confirmation phase (Part 1) and an expansion phase (Part 2). The expansion phase was not conducted due to early study termination.
Participants by arm
| Arm | Count |
|---|---|
| Preladenant 25 mg BID Participants received 25 mg of preladenant administered by oral capsule BID on Days 1 through 21 of each 21-day cycle. Participants were to receive up to 35 cycles of study treatment. | 3 |
| Preladenant 50 mg BID Participants received 50 mg of preladenant administered by oral capsule BID on Days 1 through 21 of each 21-day cycle. Participants were to receive up to 35 cycles of study treatment. | 4 |
| Preladenant 25 mg BID + Pembrolizumab 200 mg Participants received 25 mg of preladenant administered by oral capsule BID on Days 1 through 21 and pembrolizumab 200 mg administered by IV infusion on Day 1 of each 21-day cycle. Participants were to receive up to 35 cycles of study treatment. | 3 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 |
| Overall Study | Physician Decision | 2 | 0 | 0 |
| Overall Study | Progressive Disease | 1 | 4 | 1 |
Baseline characteristics
| Characteristic | Total | Preladenant 25 mg BID + Pembrolizumab 200 mg | Preladenant 50 mg BID | Preladenant 25 mg BID |
|---|---|---|---|---|
| Age, Continuous | 46.9 Years STANDARD_DEVIATION 17 | 41.3 Years STANDARD_DEVIATION 18.5 | 40.3 Years STANDARD_DEVIATION 16.3 | 61.3 Years STANDARD_DEVIATION 10.8 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS=0 | 6 Participants | 2 Participants | 2 Participants | 2 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS=1 | 4 Participants | 1 Participants | 2 Participants | 1 Participants |
| Prior Line of Therapy Fifth Line | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Prior Line of Therapy First Line | 4 Participants | 0 Participants | 2 Participants | 2 Participants |
| Prior Line of Therapy Fourth Line | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Prior Line of Therapy Second Line | 5 Participants | 3 Participants | 2 Participants | 0 Participants |
| Prior Line of Therapy Third Line | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 3 Participants | 4 Participants | 3 Participants |
| Sex: Female, Male Female | 5 Participants | 1 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 5 Participants | 2 Participants | 2 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 2 / 4 | 0 / 3 |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 3 / 3 |
| serious Total, serious adverse events | 2 / 3 | 1 / 4 | 2 / 3 |
Outcome results
Primary
Number of Participants Who Discontinued Study Treatment Due to an AE
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.
Time frame: Up to approximately 8 months
Population: All participants who received at least one dose of study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preladenant 25 mg BID | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| Preladenant 50 mg BID | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| Preladenant 25 mg BID + Pembrolizumab 200 mg | Number of Participants Who Discontinued Study Treatment Due to an AE | 2 Participants |
Primary
Number of Participants Who Experienced at Least One Adverse Event (AE)
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.
Time frame: Up tp approximately 8 months
Population: All participants who received at least one dose of study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preladenant 25 mg BID | Number of Participants Who Experienced at Least One Adverse Event (AE) | 3 Participants |
| Preladenant 50 mg BID | Number of Participants Who Experienced at Least One Adverse Event (AE) | 4 Participants |
| Preladenant 25 mg BID + Pembrolizumab 200 mg | Number of Participants Who Experienced at Least One Adverse Event (AE) | 3 Participants |
Primary
Number of Participants With Dose-limiting Toxicities (DLTs)
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.
Time frame: Cycle 1 (up to 21 days)
Population: All participants who received at least one dose of study treatment in Cycle 1 (21-day Cycle) and were observed for safety or experienced a DLT during Cycle 1
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preladenant 25 mg BID | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Preladenant 50 mg BID | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Preladenant 25 mg BID + Pembrolizumab 200 mg | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
Secondary
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
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.
Time frame: Up to approximately 8 months
Population: All participants who had a baseline scan that showed measurable disease by investigator assessment and who received at least one dose of study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Preladenant 25 mg BID | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 0.0 Percentage of Participants |
| Preladenant 50 mg BID | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 0.0 Percentage of Participants |
| Preladenant 25 mg BID + Pembrolizumab 200 mg | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 0.0 Percentage of Participants |