Advanced or Metastatic Solid Tumors
Conditions
Keywords
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)
Brief summary
The purpose of this study is to assess the efficacy and safety and establish a preliminary recommended Phase 2 dose (RP2D) of MK-6598 administered as monotherapy and in combination with pembrolizumab (MK-3475) in adult participants with advanced or metastatic solid tumors.
Interventions
DRUGMK-6598
Oral tablet
BIOLOGICALPembrolizumab
Intravenous (IV) infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has a histologically- or cytologically-confirmed advanced/metastatic solid tumor by pathology report and has received, or been intolerant to, all treatment known to confer clinical benefit. * Has measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by the local site investigator/radiology. * Has one or more discrete malignant lesions that are amenable to a minimum of 2 separate biopsies. * Has a baseline tumor sample that can be submitted for analysis. * Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy (ART). * A participant assigned male sex at birth who receives MK-6598 must agree to use contraception and should refrain from donating sperm during the specified period(s) of at least 102 days after study interventions. * A participant assigned female sex at birth is eligible to participate if not pregnant or breastfeeding and at least 1 of the following: not a participant of childbearing potential (POCBP) or a POCBP who agrees to follow the contraceptive guidance during the treatment period and for up to 120 days after study intervention.
Exclusion criteria
* Received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention or has not recovered to CTCAE Version 5.0 Grade 1 or better from any AEs that were due to cancer therapeutics administered more than 4 weeks earlier (this includes participants with previous immunomodulatory therapy with residual immune-related AEs). * Known additional malignancy that is progressing or has required active treatment within 2 years. * Clinically active central nervous system (CNS) metastases and/or carcinomatous meningitis. * A severe hypersensitivity (≥Grade 3) reaction to treatment with a monoclonal antibody/components of the study intervention. * Active infection requiring therapy. * History of interstitial lung disease. * History of (noninfectious) pneumonitis that required steroids or current pneumonitis. * Active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid) is allowed. * Has known hepatitis B or C infections or known to be positive for hepatitis B surface antigen (HBsAg)/hepatitis B virus (HBV) deoxyribonucleic acid (DNA) or hepatitis C antibody or ribonucleic acid (RNA). * Has a 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. * Received prior radiotherapy within 2 weeks of start of study intervention, has radiation-related toxicities requiring corticosteroids, or had a history of radiation pneumonitis. * Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed. * Has 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 co-inhibitory T-cell receptor (eg, cytotoxic T-lymphocyte-associated protein 4 \[CTLA-4\], OX 40, CD137), and was discontinued from that treatment due to a ≥Grade 3 immune-related AE (irAE). * Has a 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 before the start of study treatment. * Has had an allogeneic tissue/solid organ transplant in the last 5 years or has evidence of graft-versus-host disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Dose-Limiting Toxicity (DLT) Graded Using National Cancer Institute Common Terminology Criteria for Adverse Events (AEs) Version 5.0 | Up to approximately 21 days | DLT is defined as any of the following toxicities, unless assessed by investigator as due to the underlying disease or extraneous causes: Grade (Gr) 4 nonhematologic toxicity (not laboratory); Gr 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia; Gr 4 thrombocytopenia of any duration; Gr 3 thrombocytopenia associated with clinically significant bleeding lasting ≥7 days; Gr 4 anemia of any duration; Nonhematologic AE Gr ≥3 in severity, with exceptions; Any Gr 3/4 nonhematologic lab abnormality if it requires clinically significant medical intervention, leads to hospitalization, persists for \>72 hours, or results in certain drug-induced liver injuries, with some exceptions; Gr 3 or 4 febrile neutropenia; \>2 week delay in initiating Cycle 2 due to treatment-related toxicity; Treatment-related toxicity resulting in study treatment discontinuation during Cycle 1 (C1), 1 cycle = 21 days; Missing \>25% of MK-6598 doses due to treatment-related AE during C1; Gr 5 toxicity. |
| Number of Participants Who Experienced At Least One AE | Up to approximately 24 months | 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who experienced an AE will be reported. |
| Number of Participants Who Discontinue Study Treatment Due to an AE | Up to approximately 24 months | 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinued study treatment due to an AE will be reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve From Time 0 to Last Quantifiable Sample (AUC0-last) of MK-6598 | Days 1, 8, and 15 of Cycle 1: predose, postdose at 30 minutes (min), 45 min, 60 min, 2 hours (hrs), 6 hrs. Days 2 and 9 of Cycle 1: predose. | Blood samples were collected at pre-specified time points to determine the AUC0-last of MK-6598 in participant's plasma. AUC0-last of MK-6598 was defined as the area under the concentration-time curve from time 0 to the time of the last quantifiable (above lower limit of quantitation) concentration. AUC0-last was calculated using noncompartmental analysis. Geometric coefficient of variation is calculated in the natural log-scale with the equation:100 x sqrt(exp(σ\^2) - 1), where σ\^2 is the observed variance on the natural log scale. |
| Minimum Serum Concentration (Cmin) of MK-6598 | Days 8 and 15 of Cycle 1: predose, postdose at 30 min, 45 min, 60 min, 2 hrs, 6 hrs. Days 2 and 9 of Cycle 1: predose. | Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine Cmin. Geometric coefficient of variation is calculated in the natural log-scale with the equation:100 x sqrt(exp(σ\^2) - 1), where σ\^2 is the observed variance on the natural log scale. |
| Maximum Serum Concentration (Cmax) of MK-6598 | Days 1, 8, and 15 of Cycle 1: predose, postdose at 30 min, 45 min, 60 min, 2 hrs, 6 hrs. Days 2 and 9 of Cycle 1: predose. | Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine Cmax. Geometric coefficient of variation is calculated in the natural log-scale with the equation:100 x sqrt(exp(σ\^2) - 1), where σ\^2 is the observed variance on the natural log scale. |
| Tumor Phenylpyruvate Concentration | Approximately Day 22 | Tumor core biopsy sample collected during screening period and cycle 2 (21 day cycles) day 1 to determine tumor phenylpyruvate concentration (pmol/mg). |
| Time to Maximum Concentration (Tmax) of MK-6598 | Days 1, 8, and 15 of Cycle 1: predose, postdose at 30 min, 45 min, 60 min, 2 hrs, 6 hrs. Days 2 and 9 of Cycle 1: predose. | Tmax was defined as the time to maximum concentration of MK-6598 observed in plasma. Blood samples were collected pre-dose and post-dose at designated timepoints to determine Tmax of MK-6598. |
Countries
Canada, Switzerland, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 58.9 Years STANDARD_DEVIATION 11.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 35 Participants |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 4 | 3 / 4 | 2 / 3 | 3 / 9 | 6 / 7 | 4 / 6 | 6 / 6 | 2 / 3 | 2 / 5 |
| other Total, other adverse events | 4 / 4 | 3 / 4 | 3 / 3 | 9 / 9 | 7 / 7 | 6 / 6 | 6 / 6 | 3 / 3 | 5 / 5 |
| serious Total, serious adverse events | 1 / 4 | 1 / 4 | 1 / 3 | 3 / 9 | 4 / 7 | 4 / 6 | 4 / 6 | 0 / 3 | 2 / 5 |
Outcome results
None listed