Solid Tumors
Conditions
Keywords
Head and Neck Cancer, Esophageal Cancer, Gastric Cancer
Brief summary
The study evaluates safety of adavosertib in monotherapy, and in combination with 5-Fluorouracil (5-FU) alone or with 5-FU/cis-diamminedichloroplatinum (CDDP) in Japanese participants with solid tumor. The primary hypothesis is that adavosertib is safe and tolerable in participants with locally advanced or metastatic solid tumors.
Interventions
DRUGadavosertib 20 mg
Adavosertib 20 mg capsule administered orally on days 1-5 of a 21 day cycle.
DRUG5-FU 1000 mg/m^2/day
5-FU 1000 mg/m\^2/day administered as an intravenous (IV) infusion on Days 1-4 of a 21-day cycle
DRUGCDDP
CDDP 60 mg/m\^2 to 100 mg/m\^2 administered as an IV infusion on Day 1.
DRUGadavosertib 65 mg
Adavosertib 65 mg capsule administered orally on days 1-5 of a 21 day cycle.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Parts 1 and 2-A: Patient must have a histologically or cytologically confirmed locally advanced or metastatic solid tumor failed to respond to standard therapy, progressed despite standard therapy, or for which standard therapy does not exist * Parts 2-B and 3: Patient must have a histologically or cytologically confirmed locally advanced or metastatic esophageal, head and neck, or gastric cancer, and be a candidate of 5-Fluorouracil and Cisplatin regimen defined in this study * Patient must have performance status of 0 or 1 on the ECOG Performance Scale
Exclusion criteria
* Patient who has had chemotherapy, radiotherapy, or biological therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to the first dose of study drug or who has not recovered from adverse events due to agents administered more than 4 weeks earlier * Patient with a known primary central nervous system tumor * Patient has known hypersensitivity to any of the components of the combination study therapy or its analogs * Patient is receiving alternative cancer medications such as plant-derived products and their analogs with anti-tumor activity within 1 week prior to entering the study. * Patient must not have prior radiation therapy to more than 30% of the bone marrow and must have recovered for at least 3 weeks from the hematologic toxicity of prior radiotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs) | Cycle 1 (21 days) | DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 and included: any drug-related hematologic toxicity ≥Grade 4 with the exception of Grade 4 neutropenia \<7 days duration; Grade 3 or 4 neutropenia with fever \>38.5 degrees Celsius and/or infection or neutropenia requiring colony-stimulating factor OR non-hematologic DLTs that were any Grade 3, 4, or 5 toxicity with the following exceptions: Grade 3 nausea, vomiting, diarrhea, and dehydration occurring in a setting of inadequate treatment; inadequately treated hypersensitivity reactions; Grade 3 elevated transaminases or urine electrolyte abnormality ≤1 week in duration; Grade 3 serum electrolyte abnormality ≤72 hours in duration. DLTs also included: drug-related adverse experience that lead to a dose modification; unresolved drug-related toxicity preventing treatment for ≥3 weeks or preventing administration of ≥8 of 10 doses in Parts 1 or 2A1 or 4 of 5 doses in Part 2A2. |
| Maximum Tolerated Dose (MTD) of MK1775 in Combination With 5-FU/CDDP Determined by Number of DLTs Per Dose Level: Locally Advanced or Metastatic Esophageal, Head and Neck, or Gastric Cancer | Cycle 1 (21 days) | The maximum tolerated dose (MTD) of MK-1775 in combination with 5-FU/CDDP for participants with locally advanced or metastatic esophageal, head and neck, or gastric cancer was determined based on DLTs that occurred during Cycle 1 of Parts 2B and 3. The MTD for MK-1775 in combination with 5-FU/CDDP was defined as the dose level at which approximately 30% of the participants were expected to experience a DLT for the combination therapy. The study was terminated early and Parts 2B and 3 were not performed. No participants received the 5-FU/CDDP regimen therefore the MTD for MK-1775 in combination with 5-FU/CDDP was not established. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| MTD of MK1775 in Combination With 5-FU/CDDP Determined by Number of DLTs Per Dose Level: Locally Advanced or Metastatic Solid Tumors | Cycle 1 (21 days) | The maximum tolerated dose (MTD) of MK-1775 in combination with 5-FU/CDDP for participants with locally advanced or metastatic solid tumors was determined based on DLTs that occurred during Cycle 1 of Parts 2B and 3. The MTD for MK-1775 in combination with 5-FU/CDDP was defined as the dose level at which approximately 30% of the participants were expected to experience a DLT for the combination therapy. The study was terminated early and Parts 2B and 3 were not performed. No participants received the 5-FU/CDDP regimen therefore the MTD for MK-1775 in combination with 5-FU/CDDP was not established. |
Participant flow
Recruitment details
This study enrolled participants with a confirmed locally advanced or metastatic solid tumor failed to respond to standard therapy, progressed despite standard therapy, or for which standard therapy does not exist with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Additional inclusion and exclusion criteria applied.
Pre-assignment details
Participants received MK-1775 (Part 1), MK-1775 + 5-Fluorouracil (Part 2A), and MK-1775 + 5-Fluorouracil and cis-diamminedichloroplatinum (Parts 2B and 3). The study was terminated early and Parts 2B and 3 were not performed. No participants received the 5-Fluorouracil (5-FU) and cis-diamminedichloroplatinum (CDDP) regimen.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: MK-1775 65 mg BID Participants received 65 mg of MK-1775 administered orally twice a day (BID) on Days 1-5 of a 21-day cycle. | 3 |
| Part 2 A1: MK-1775 20 mg BID + 5-FU 1000 mg Participants received 20 mg of MK-1775 administered orally BID on Days 1-5 of a 21-day cycle and 1000 mg/m\^2/day of 5-FU administered as an intravenous (IV) infusion on Days 1-4 of a 21-day cycle. | 6 |
| Part 2 A2: MK-1775 20 mg QD + 5-FU 1000 mg Participants received 20 mg of MK-1775 administered orally once a day (QD) on Days 1-5 of a 21-day cycle and 1000 mg/m\^2/day of 5-FU administered as an IV infusion on Days 1-4 of a 21-day cycle. | 2 |
| Parts 2B +3: MK-1775 + 5-FU + CDDP Participants were to receive 20 mg or 65 mg of MK-1775 administered either BID or QD on Days 1-5 of a 21-day cycle; 1000 mg/m\^2/day of 5-FU administered as an IV infusion on Days 1-4 of a 21-day cycle; and 60 mg/m\^2 to 100 mg/m\^2 of CDDP administered as an IV infusion on Day 1. | 0 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 1 | 0 |
| Overall Study | Progressive Disease | 2 | 4 | 1 | 0 |
Baseline characteristics
| Characteristic | Part 1: MK-1775 65 mg BID | Part 2 A1: MK-1775 20 mg BID + 5-FU 1000 mg | Part 2 A2: MK-1775 20 mg QD + 5-FU 1000 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 63.0 Years STANDARD_DEVIATION 4.4 | 62.7 Years STANDARD_DEVIATION 7.9 | 59.0 Years STANDARD_DEVIATION 5.7 | 62.1 Years STANDARD_DEVIATION 6.4 |
| ECOG Performance Status ECOG Score = 0 | 2 Participants | 3 Participants | 2 Participants | 7 Participants |
| ECOG Performance Status ECOG Score = 1 | 1 Participants | 3 Participants | 0 Participants | 4 Participants |
| Number of Prior Chemotherapy Regimens | 2.0 Prior regimens STANDARD_DEVIATION 0 | 3.3 Prior regimens STANDARD_DEVIATION 0.8 | 4.0 Prior regimens STANDARD_DEVIATION 0 | 3.1 Prior regimens STANDARD_DEVIATION 0.9 |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 2 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 1 / 2 |
| serious Total, serious adverse events | 0 / 3 | 2 / 6 | 1 / 2 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of MK1775 in Combination With 5-FU/CDDP Determined by Number of DLTs Per Dose Level: Locally Advanced or Metastatic Esophageal, Head and Neck, or Gastric Cancer
The maximum tolerated dose (MTD) of MK-1775 in combination with 5-FU/CDDP for participants with locally advanced or metastatic esophageal, head and neck, or gastric cancer was determined based on DLTs that occurred during Cycle 1 of Parts 2B and 3. The MTD for MK-1775 in combination with 5-FU/CDDP was defined as the dose level at which approximately 30% of the participants were expected to experience a DLT for the combination therapy. The study was terminated early and Parts 2B and 3 were not performed. No participants received the 5-FU/CDDP regimen therefore the MTD for MK-1775 in combination with 5-FU/CDDP was not established.
Time frame: Cycle 1 (21 days)
Population: Participants who received at least one dose of MK-1775 in combination with 5-FU/CDDP and completed Cycle 1 of Parts 2B and 3. No participants received the 5-FU/CDDP regimen due to early termination of the study.
Primary
Number of Participants With Dose Limiting Toxicities (DLTs)
DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 and included: any drug-related hematologic toxicity ≥Grade 4 with the exception of Grade 4 neutropenia \<7 days duration; Grade 3 or 4 neutropenia with fever \>38.5 degrees Celsius and/or infection or neutropenia requiring colony-stimulating factor OR non-hematologic DLTs that were any Grade 3, 4, or 5 toxicity with the following exceptions: Grade 3 nausea, vomiting, diarrhea, and dehydration occurring in a setting of inadequate treatment; inadequately treated hypersensitivity reactions; Grade 3 elevated transaminases or urine electrolyte abnormality ≤1 week in duration; Grade 3 serum electrolyte abnormality ≤72 hours in duration. DLTs also included: drug-related adverse experience that lead to a dose modification; unresolved drug-related toxicity preventing treatment for ≥3 weeks or preventing administration of ≥8 of 10 doses in Parts 1 or 2A1 or 4 of 5 doses in Part 2A2.
Time frame: Cycle 1 (21 days)
Population: The DLT-evaluable population consisted of participants who received at least one dose of MK-1775 and completed Cycle 1 of Parts 1, 2A1, 2A2, or discontinued due to toxicity.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: MK-1775 65 mg BID | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Part 2 A1: MK-1775 20 mg BID + 5-FU 1000 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | 1 Participants |
| Part 2 A2: MK-1775 20 mg QD + 5-FU 1000 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | 1 Participants |
Secondary
MTD of MK1775 in Combination With 5-FU/CDDP Determined by Number of DLTs Per Dose Level: Locally Advanced or Metastatic Solid Tumors
The maximum tolerated dose (MTD) of MK-1775 in combination with 5-FU/CDDP for participants with locally advanced or metastatic solid tumors was determined based on DLTs that occurred during Cycle 1 of Parts 2B and 3. The MTD for MK-1775 in combination with 5-FU/CDDP was defined as the dose level at which approximately 30% of the participants were expected to experience a DLT for the combination therapy. The study was terminated early and Parts 2B and 3 were not performed. No participants received the 5-FU/CDDP regimen therefore the MTD for MK-1775 in combination with 5-FU/CDDP was not established.
Time frame: Cycle 1 (21 days)
Population: Participants who received at least one dose of MK-1775 in combination with 5-FU/CDDP and completed Cycle 1 of Parts 2B and 3. No participants received the 5-FU/CDDP regimen due to early termination of the study.