Castrate-resistant Prostate Cancer, CRPC, Non-small Cell Lung Cancer With Rearranged ALK Gene/Fusion Protein or KRAS Mutation, NUT Midline Carcinoma, Pancreatic Ductal Adenocarcinoma, Triple Negative Breast Cancer
Conditions
Brief summary
Open-label, phase I, non-randomized, multicentric study of single-agent birabresib (MK-8628) (formerly known as OTX015) administered according to two distinct regimens to participants with selected advanced tumors. The study will be performed in two parts. Dose Escalation Part: This step is designed to determine the maximum tolerated dose (MTD) in each of the two regimens, which will be evaluated in parallel. Participants will receive oral birabresib according to: Continuous Dosing Regimen: continuous, once daily for 21 consecutive days (21-day cycles). OR Days 1-7 Dosing Regimen: once daily on Days 1 to 7, repeated every 3 weeks (21-day cycles; 1 week ON/2 weeks OFF). Participants will be sequentially assigned to Continuous Dosing Regimen or Days 1-7 Dosing Regimen according to the next available place and receive birabresib at escalating doses levels (DL). Cohorts of 3 participants will be treated, and an additional 3 participants will be treated at the first indication of dose-limiting toxicity (DLT). MTD assessment will be based on the tolerability observed during the first 21 days of treatment. Expansion Part: The efficacy of birabresib in each of the five indications (i.e., Bromodomain-Nuclear Protein in Testis \[BRD-NUT\] midline carcinoma, triple negative breast cancer \[TNBC\], non-small cell lung cancer \[NSCLC\] harboring a rearrangement Anaplastic Lymphoma Kinase \[ALK\] gene/fusion protein or Kirsten Ras \[KRAS\] mutation, castrate-resistant prostate cancer, and pancreatic ductal carcinoma) will be assessed in terms of response (Response Evaluation Criteria in Solid Tumors v1.1 \[RECIST v1.1\] or Prostate Cancer Clinical Trials Working Group 2 \[PCWG2\]) using a selected regimen.
Interventions
DRUGBirabresib
Birabresib 10, 20 and/or 40 mg oral capsules
Sponsors
Oncoethix GmbH, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent obtained prior to initiation of any study-specific procedures and treatment; 2. Histologically or cytologically confirmed diagnosis of one of the following advanced or metastatic solid tumors for which standard therapy either does not exist or has proven ineffective, intolerable or inacceptable for the patient: * NUT midline carcinoma (ectopic expression of NUT protein as determined by immunohistochemistry (IHC) and/or detection of BRD-NUT gene translocation as determined by fluorescence In situ hybridization \[FISH\]); * Triple negative breast cancer defined according to American Society of Clinical Oncology (ASCO) recommendations (Hammond et al., 2010; Wolff et al., 2007); * Non-small cell lung cancer harboring a rearranged ALK gene/fusion protein (FISH or IHC) or KRAS mutation (as defined by any molecular analysis); * Castrate-resistant prostate cancer (CRPC); * Pancreatic ductal adenocarcinoma; 3. At least one measurable lesion as per RECIST version 1.1., except for CRPC participants who may be enrolled with objective evidence of disease as per PCWG2 criteria; 4. Age ≥18 years at the time of informed consent; 5. Life expectancy ≥3 months; 6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤1; 7. Adequate bone marrow reserve, renal and liver function: * Absolute neutrophil count ≥1.5 x10\^9/L, * Platelet count ≥150 x10\^9/L, * Hemoglobin ≥9 g/dL, * Creatinine clearance ≥30 mL/min calculated according to the Cockroft and Gault formula or Modification of Diet in Renal Disease (MDRD) formula for participants aged \>65 years, * Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤3 x upper limit of normal (ULN) and total bilirubin ≤1.25 x ULN (in case of liver involvement, ALT/AST ≤5 x ULN and total bilirubin ≤2 x ULN will be allowed), * Serum albumin ≥2.8 g/dL, * International Normalized Ratio (INR) ≤1.5 x ULN or INR \<3 for participants treated with antivitamin K; 8. An interval of ≥3 weeks since chemotherapy (≥6 weeks for nitrosoureas or mitomycin C), immunotherapy, hormone therapy or any other anticancer therapy or surgical intervention resection, or ≥3 half-lives for monoclonal antibodies, or ≥5 half-lives for other non-cytotoxic agents (whichever is longer); 9. CRPC participants must maintain ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analogue, antagonist or orchiectomy providing serum testosterone is \<50 ng/dL (\<1.7 nmol/L); 10. Participants receiving bisphosphonate or denosumab therapy must be on stable doses for at least 4 weeks before initiating study treatment.
Exclusion criteria
1. Inability to swallow oral medications or presence of a gastrointestinal disorder (e.g. malabsorption) deemed to jeopardize intestinal absorption of birabresib; 2. Persistent grade \>1 clinically significant toxicities related to prior antineoplastic therapies (except for alopecia); stable sensory neuropathy ≤ grade 2 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.4.0 is accepted. 3. Known primary central nervous system (CNS) malignancy or CNS involvement; 4. History of prior or concomitant malignancies (other than excised non-melanoma skin cancer or cured in situ cervical carcinoma) within 3 years of study entry; 5. Other serious illness or medical conditions, such as active infection, unresolved bowel obstruction, or psychiatric disorders; 6. Known human immunodeficiency virus (HIV) positivity; 7. Participation in another clinical trial or treatment with any investigational drug within 30 days prior to study entry; 8. Other concomitant anticancer treatment; 9. Concomitant therapy with strong CYP3A4 interfering drugs; 10. Current use of anticoagulants (e.g. warfarin, heparin) at therapeutic levels within 7 days prior to the first dose of birabresib. Low-dose (prophylactic) low molecular weight heparin (LMWH) is permitted; 11. Pregnant or breast-feeding participants, and men and women with childbearing potential not using effective contraception while on study drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1 | Up to Cycle 1 Day 21 (Up to 21 days) | A DLT was defined as any of the following toxicities that were considered by the investigator to be related to MK-8628: Hematologic toxicity: Grade 4 hematologic toxicity or febrile neutropenia, Grade 3 neutropenia with infection, Grade 3 thrombocytopenia with bleeding or lasting \>7 days; Non-hematologic toxicity: Grade 3 or 4 non-hematologic toxicity (regardless of duration) unless it was not optimally managed with supportive care, Grade 3 or 4 laboratory abnormality, with or without symptoms, lasting \>48 hours, Intolerable Grade 2 non-hematologic toxicity resulting in study drug discontinuation or delay \>7 days with or without dose reduction, Designated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) liver test abnormalities; Treatment delay \>2 weeks or dose reduction requirement for initiating Cycle 2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Discontinued Study Treatment Due to an AE | Up to approximately 16.5 months | The number of participants who discontinued study treatment due to an AE is presented. |
| Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Up to approximately 16.5 months | The best overall response was the best response recorded from the start of the study treatment until the end of treatment. RECIST 1.1 response categories included: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. |
| Observed Maximum Plasma Concentration (Cmax) of MK-8628 | Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose | Blood samples were obtained at specified time points for pharmacokinetic (PK) analysis of the observed Cmax of MK-8628. The observed Cmax of MK-8628 after administration is presented. |
| Time to Cmax (Tmax) of MK-8628 | Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose | Blood samples were obtained at specified time points for PK analysis of the Tmax of MK-8628. The Tmax of MK-8628 after administration is presented. |
| Number of Participants Who Experienced at Least One Adverse Event (AE) | Up to approximately 17.5 months (Up to 30 days after last dose of study treatment) | An AE is defined as any untoward medical occurrence associated with use of study treatment in humans, whether or not considered treatment related. The number of participants who experienced at least one AE is presented. |
| Volume of Distribution at Steady State (Vdss) of MK-8628 | Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose | Blood samples were obtained at specified time points for PK analysis of the Vdss of MK-8628. The Vdss of MK-8628 after administration is presented. |
| Terminal Half-Life (t1/2) of MK-8628 | Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose | Blood samples were obtained at specified time points for PK analysis of the t1/2 of MK-8628. The t1/2 of MK-8628 after administration is presented. |
| Total Plasma Clearance (CL) of MK-8628 | Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose | Blood samples were obtained at specified time points for PK analysis of the CL of MK-8628. The CL of MK-8628 after administration is presented. |
| Area Under to Concentration-Time Curve From 0 to Infinity (AUC0-∞) of MK-8628 | Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose | Blood samples were obtained at specified time points for PK analysis of the AUC0-∞ of MK-8628. The AUC0-first is AUC0-∞ which is derived from the post-hoc estimate of CL/F from the population model. The AUC0-∞ of MK-8628 after administration is presented. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MK-8628 Continuous Dosing Regimen 80 mg/Day Participants received MK-8628 capsules at a total daily dose of 80 mg/day once daily in a fasted state in the morning on Days 1-21 of each 21-day cycle. | 20 |
| MK-8628 Continuous Dosing Regimen 100 mg/Day Participants received MK-8628 capsules at a total daily dose of 100 mg/day once daily in a fasted state in the morning on Days 1-21 of each 21-day cycle. | 4 |
| MK-8628 Days 1-7 Dosing Regimen 100 mg/Day Participants received MK-8628 capsules at a total daily dose of 100 mg/day once daily in a fasted state in the morning on Days 1-7 of each 21-day cycle. | 13 |
| MK-8628 Days 1-7 Dosing Regimen 120 mg/Day Participants received MK-8628 capsules at a total daily dose of 120 mg/day once daily in a fasted state in the morning on Days 1-7 of each 21-day cycle. | 3 |
| MK-8628 Days 1-7 Dosing Regimen 160 mg/Day Participants received MK-8628 capsules at a total daily dose of 160 mg/day once daily in a fasted state in the morning on Days 1-7 of each 21-day cycle. | 6 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 | 0 | 0 | 1 |
| Overall Study | Death | 3 | 0 | 1 | 0 | 0 |
| Overall Study | Not Treated | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Progressive Disease | 14 | 2 | 10 | 2 | 5 |
| Overall Study | Treatment Delay >2 wks: Adverse Event | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Treatment Delay >2 wks: Toxicity | 1 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | MK-8628 Continuous Dosing Regimen 100 mg/Day | MK-8628 Days 1-7 Dosing Regimen 100 mg/Day | MK-8628 Days 1-7 Dosing Regimen 120 mg/Day | MK-8628 Days 1-7 Dosing Regimen 160 mg/Day | MK-8628 Continuous Dosing Regimen 80 mg/Day | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 62.5 Years STANDARD_DEVIATION 13.5 | 64.3 Years STANDARD_DEVIATION 9.5 | 63.3 Years STANDARD_DEVIATION 9.3 | 58.5 Years STANDARD_DEVIATION 5.3 | 50.2 Years STANDARD_DEVIATION 18.8 | 57.2 Years STANDARD_DEVIATION 15.3 |
| Race and Ethnicity Not Collected | — | — | — | — | — | 0 Participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 5 Participants | 7 Participants |
| Sex: Female, Male Male | 3 Participants | 13 Participants | 3 Participants | 5 Participants | 15 Participants | 39 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 20 | 2 / 4 | 1 / 13 | 0 / 3 | 0 / 6 |
| other Total, other adverse events | 20 / 20 | 4 / 4 | 13 / 13 | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 15 / 20 | 3 / 4 | 5 / 13 | 3 / 3 | 1 / 6 |
Outcome results
Primary
Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1
A DLT was defined as any of the following toxicities that were considered by the investigator to be related to MK-8628: Hematologic toxicity: Grade 4 hematologic toxicity or febrile neutropenia, Grade 3 neutropenia with infection, Grade 3 thrombocytopenia with bleeding or lasting \>7 days; Non-hematologic toxicity: Grade 3 or 4 non-hematologic toxicity (regardless of duration) unless it was not optimally managed with supportive care, Grade 3 or 4 laboratory abnormality, with or without symptoms, lasting \>48 hours, Intolerable Grade 2 non-hematologic toxicity resulting in study drug discontinuation or delay \>7 days with or without dose reduction, Designated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) liver test abnormalities; Treatment delay \>2 weeks or dose reduction requirement for initiating Cycle 2.
Time frame: Up to Cycle 1 Day 21 (Up to 21 days)
Population: The DLT Evaluable Population consisted of all participants who received ≥85% of the planned dose of study treatment (18 days for Continuous Dosing Regimens, or 6 days for Days 1-7 Dosing Regimens) or experienced a DLT during the first 21-day cycle.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-8628 Continuous Dosing Regimen 80 mg/Day | Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1 | 4 Participants |
| MK-8628 Continuous Dosing Regimen 100 mg/Day | Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1 | 2 Participants |
| MK-8628 Days 1-7 Dosing Regimen 100 mg/Day | Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1 | 0 Participants |
| MK-8628 Days 1-7 Dosing Regimen 120 mg/Day | Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1 | 0 Participants |
| MK-8628 Days 1-7 Dosing Regimen 160 mg/Day | Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1 | 0 Participants |
Secondary
Area Under to Concentration-Time Curve From 0 to Infinity (AUC0-∞) of MK-8628
Blood samples were obtained at specified time points for PK analysis of the AUC0-∞ of MK-8628. The AUC0-first is AUC0-∞ which is derived from the post-hoc estimate of CL/F from the population model. The AUC0-∞ of MK-8628 after administration is presented.
Time frame: Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose
Population: The PK Population consisted of all participants who received MK-8628 on Cycle 1 Day 1 and had blood samples drawn for PK analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-8628 Continuous Dosing Regimen 80 mg/Day | Area Under to Concentration-Time Curve From 0 to Infinity (AUC0-∞) of MK-8628 | 12550 μg*h/L | Standard Deviation 4456 |
| MK-8628 Continuous Dosing Regimen 100 mg/Day | Area Under to Concentration-Time Curve From 0 to Infinity (AUC0-∞) of MK-8628 | 19130 μg*h/L | Standard Deviation 6543 |
| MK-8628 Days 1-7 Dosing Regimen 100 mg/Day | Area Under to Concentration-Time Curve From 0 to Infinity (AUC0-∞) of MK-8628 | 12800 μg*h/L | Standard Deviation 3597 |
| MK-8628 Days 1-7 Dosing Regimen 120 mg/Day | Area Under to Concentration-Time Curve From 0 to Infinity (AUC0-∞) of MK-8628 | 16210 μg*h/L | Standard Deviation 9551 |
| MK-8628 Days 1-7 Dosing Regimen 160 mg/Day | Area Under to Concentration-Time Curve From 0 to Infinity (AUC0-∞) of MK-8628 | 27440 μg*h/L | Standard Deviation 10510 |
Secondary
Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria
The best overall response was the best response recorded from the start of the study treatment until the end of treatment. RECIST 1.1 response categories included: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Time frame: Up to approximately 16.5 months
Population: The Efficacy Population consisted of all participants who received ≥2 complete cycles (6 weeks) of study treatment and underwent baseline assessment and 1 on-study tumor assessment, or who discontinued early due to disease progression.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MK-8628 Continuous Dosing Regimen 80 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Progressive Disease | 4 Participants |
| MK-8628 Continuous Dosing Regimen 80 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Stable Disease | 12 Participants |
| MK-8628 Continuous Dosing Regimen 80 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Complete Response | 0 Participants |
| MK-8628 Continuous Dosing Regimen 80 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Not Evaluable | 0 Participants |
| MK-8628 Continuous Dosing Regimen 80 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Partial Response | 3 Participants |
| MK-8628 Continuous Dosing Regimen 100 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Complete Response | 0 Participants |
| MK-8628 Continuous Dosing Regimen 100 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Progressive Disease | 1 Participants |
| MK-8628 Continuous Dosing Regimen 100 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Stable Disease | 0 Participants |
| MK-8628 Continuous Dosing Regimen 100 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Partial Response | 0 Participants |
| MK-8628 Continuous Dosing Regimen 100 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Not Evaluable | 1 Participants |
| MK-8628 Days 1-7 Dosing Regimen 100 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Not Evaluable | 0 Participants |
| MK-8628 Days 1-7 Dosing Regimen 100 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Complete Response | 0 Participants |
| MK-8628 Days 1-7 Dosing Regimen 100 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Partial Response | 0 Participants |
| MK-8628 Days 1-7 Dosing Regimen 100 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Stable Disease | 7 Participants |
| MK-8628 Days 1-7 Dosing Regimen 100 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Progressive Disease | 5 Participants |
| MK-8628 Days 1-7 Dosing Regimen 120 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Partial Response | 0 Participants |
| MK-8628 Days 1-7 Dosing Regimen 120 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Progressive Disease | 2 Participants |
| MK-8628 Days 1-7 Dosing Regimen 120 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Complete Response | 0 Participants |
| MK-8628 Days 1-7 Dosing Regimen 120 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Not Evaluable | 0 Participants |
| MK-8628 Days 1-7 Dosing Regimen 120 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Stable Disease | 1 Participants |
| MK-8628 Days 1-7 Dosing Regimen 160 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Progressive Disease | 1 Participants |
| MK-8628 Days 1-7 Dosing Regimen 160 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Partial Response | 0 Participants |
| MK-8628 Days 1-7 Dosing Regimen 160 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Not Evaluable | 0 Participants |
| MK-8628 Days 1-7 Dosing Regimen 160 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Stable Disease | 5 Participants |
| MK-8628 Days 1-7 Dosing Regimen 160 mg/Day | Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | Complete Response | 0 Participants |
Secondary
Number of Participants Who Discontinued Study Treatment Due to an AE
The number of participants who discontinued study treatment due to an AE is presented.
Time frame: Up to approximately 16.5 months
Population: The Safety Population consisted of all participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-8628 Continuous Dosing Regimen 80 mg/Day | Number of Participants Who Discontinued Study Treatment Due to an AE | 5 Participants |
| MK-8628 Continuous Dosing Regimen 100 mg/Day | Number of Participants Who Discontinued Study Treatment Due to an AE | 3 Participants |
| MK-8628 Days 1-7 Dosing Regimen 100 mg/Day | Number of Participants Who Discontinued Study Treatment Due to an AE | 2 Participants |
| MK-8628 Days 1-7 Dosing Regimen 120 mg/Day | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| MK-8628 Days 1-7 Dosing Regimen 160 mg/Day | Number of Participants Who Discontinued Study Treatment Due to an AE | 1 Participants |
Secondary
Number of Participants Who Experienced at Least One Adverse Event (AE)
An AE is defined as any untoward medical occurrence associated with use of study treatment in humans, whether or not considered treatment related. The number of participants who experienced at least one AE is presented.
Time frame: Up to approximately 17.5 months (Up to 30 days after last dose of study treatment)
Population: The Safety Population consisted of all participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-8628 Continuous Dosing Regimen 80 mg/Day | Number of Participants Who Experienced at Least One Adverse Event (AE) | 20 Participants |
| MK-8628 Continuous Dosing Regimen 100 mg/Day | Number of Participants Who Experienced at Least One Adverse Event (AE) | 4 Participants |
| MK-8628 Days 1-7 Dosing Regimen 100 mg/Day | Number of Participants Who Experienced at Least One Adverse Event (AE) | 13 Participants |
| MK-8628 Days 1-7 Dosing Regimen 120 mg/Day | Number of Participants Who Experienced at Least One Adverse Event (AE) | 3 Participants |
| MK-8628 Days 1-7 Dosing Regimen 160 mg/Day | Number of Participants Who Experienced at Least One Adverse Event (AE) | 6 Participants |
Secondary
Observed Maximum Plasma Concentration (Cmax) of MK-8628
Blood samples were obtained at specified time points for pharmacokinetic (PK) analysis of the observed Cmax of MK-8628. The observed Cmax of MK-8628 after administration is presented.
Time frame: Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose
Population: The Pharmacokinetics (PK) Population consisted of all participants who received MK-8628 on Cycle 1 Day 1 and had blood samples drawn for PK analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-8628 Continuous Dosing Regimen 80 mg/Day | Observed Maximum Plasma Concentration (Cmax) of MK-8628 | 1466 μg/L | Standard Deviation 566 |
| MK-8628 Continuous Dosing Regimen 100 mg/Day | Observed Maximum Plasma Concentration (Cmax) of MK-8628 | 1867 μg/L | Standard Deviation 241 |
| MK-8628 Days 1-7 Dosing Regimen 100 mg/Day | Observed Maximum Plasma Concentration (Cmax) of MK-8628 | 1514 μg/L | Standard Deviation 377 |
| MK-8628 Days 1-7 Dosing Regimen 120 mg/Day | Observed Maximum Plasma Concentration (Cmax) of MK-8628 | 2052 μg/L | Standard Deviation 1130 |
| MK-8628 Days 1-7 Dosing Regimen 160 mg/Day | Observed Maximum Plasma Concentration (Cmax) of MK-8628 | 2670 μg/L | Standard Deviation 741 |
Secondary
Terminal Half-Life (t1/2) of MK-8628
Blood samples were obtained at specified time points for PK analysis of the t1/2 of MK-8628. The t1/2 of MK-8628 after administration is presented.
Time frame: Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose
Population: The PK Population consisted of all participants who received MK-8628 on Cycle 1 Day 1 and had blood samples drawn for PK analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-8628 Continuous Dosing Regimen 80 mg/Day | Terminal Half-Life (t1/2) of MK-8628 | 4.53 Hours | Standard Deviation 0.866 |
| MK-8628 Continuous Dosing Regimen 100 mg/Day | Terminal Half-Life (t1/2) of MK-8628 | 5.93 Hours | Standard Deviation 2.46 |
| MK-8628 Days 1-7 Dosing Regimen 100 mg/Day | Terminal Half-Life (t1/2) of MK-8628 | 3.97 Hours | Standard Deviation 0.46 |
| MK-8628 Days 1-7 Dosing Regimen 120 mg/Day | Terminal Half-Life (t1/2) of MK-8628 | 3.52 Hours | Standard Deviation 0.593 |
| MK-8628 Days 1-7 Dosing Regimen 160 mg/Day | Terminal Half-Life (t1/2) of MK-8628 | 3.99 Hours | Standard Deviation 0.664 |
Secondary
Time to Cmax (Tmax) of MK-8628
Blood samples were obtained at specified time points for PK analysis of the Tmax of MK-8628. The Tmax of MK-8628 after administration is presented.
Time frame: Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose
Population: The PK Population consisted of all participants who received MK-8628 on Cycle 1 Day 1 and had blood samples drawn for PK analyses.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| MK-8628 Continuous Dosing Regimen 80 mg/Day | Time to Cmax (Tmax) of MK-8628 | 2.0 Hours | Standard Deviation 0.6 |
| MK-8628 Continuous Dosing Regimen 100 mg/Day | Time to Cmax (Tmax) of MK-8628 | 2.4 Hours | Standard Deviation 0.5 |
| MK-8628 Days 1-7 Dosing Regimen 100 mg/Day | Time to Cmax (Tmax) of MK-8628 | 2.9 Hours | Standard Deviation 0.7 |
| MK-8628 Days 1-7 Dosing Regimen 120 mg/Day | Time to Cmax (Tmax) of MK-8628 | 1.9 Hours | Standard Deviation 0.6 |
| MK-8628 Days 1-7 Dosing Regimen 160 mg/Day | Time to Cmax (Tmax) of MK-8628 | 2.5 Hours | Standard Deviation 0.6 |
Secondary
Total Plasma Clearance (CL) of MK-8628
Blood samples were obtained at specified time points for PK analysis of the CL of MK-8628. The CL of MK-8628 after administration is presented.
Time frame: Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose
Population: The PK Population consisted of all participants who received MK-8628 on Cycle 1 Day 1 and had blood samples drawn for PK analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-8628 Continuous Dosing Regimen 80 mg/Day | Total Plasma Clearance (CL) of MK-8628 | 6.98 Liters/Hour | Standard Deviation 1.98 |
| MK-8628 Continuous Dosing Regimen 100 mg/Day | Total Plasma Clearance (CL) of MK-8628 | 5.69 Liters/Hour | Standard Deviation 1.87 |
| MK-8628 Days 1-7 Dosing Regimen 100 mg/Day | Total Plasma Clearance (CL) of MK-8628 | 8.36 Liters/Hour | Standard Deviation 2.16 |
| MK-8628 Days 1-7 Dosing Regimen 120 mg/Day | Total Plasma Clearance (CL) of MK-8628 | 8.97 Liters/Hour | Standard Deviation 4.02 |
| MK-8628 Days 1-7 Dosing Regimen 160 mg/Day | Total Plasma Clearance (CL) of MK-8628 | 7.39 Liters/Hour | Standard Deviation 2.76 |
Secondary
Volume of Distribution at Steady State (Vdss) of MK-8628
Blood samples were obtained at specified time points for PK analysis of the Vdss of MK-8628. The Vdss of MK-8628 after administration is presented.
Time frame: Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose
Population: The PK Population consisted of all participants who received MK-8628 on Cycle 1 Day 1 and had blood samples drawn for PK analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-8628 Continuous Dosing Regimen 80 mg/Day | Volume of Distribution at Steady State (Vdss) of MK-8628 | 44.9 Liters | Standard Deviation 13.4 |
| MK-8628 Continuous Dosing Regimen 100 mg/Day | Volume of Distribution at Steady State (Vdss) of MK-8628 | 44.3 Liters | Standard Deviation 5.59 |
| MK-8628 Days 1-7 Dosing Regimen 100 mg/Day | Volume of Distribution at Steady State (Vdss) of MK-8628 | 46.9 Liters | Standard Deviation 9.2 |
| MK-8628 Days 1-7 Dosing Regimen 120 mg/Day | Volume of Distribution at Steady State (Vdss) of MK-8628 | 44.0 Liters | Standard Deviation 18.3 |
| MK-8628 Days 1-7 Dosing Regimen 160 mg/Day | Volume of Distribution at Steady State (Vdss) of MK-8628 | 41.6 Liters | Standard Deviation 15.1 |