A Dose Escalation Study of Adavosertib(MK1775) in Combination With 5-FU or 5-FU/CDDP in Patients With Advanced Solid Tumor (1775-005

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I Dose Escalation Study of MK1775 in Monotherapy, in Combination With 5-Fluorouracil, and in Combination With 5-Fluorouracil and Cisplatin in Patients With Advanced Solid Tumor

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: adavosertib 20 mg
* Drug: 5-FU 1000 mg/m^2/day
* Drug: CDDP
* Drug: adavosertib 65 mg


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: adavosertib 65 mg BID<br>Participants received 65 mg of adavosertib administered orally twice a day (BID) on Days 1-5 of a 21-day cycle. | Drug: adavosertib 65 mg<br>* Adavosertib 65 mg capsule administered orally on days 1-5 of a 21 day cycle.<br>* Other names: MK-1775;|
| Experimental: Part 2 A1: adavosertib 20 mg BID+5-FU 1000 mg<br>Participants received 20 mg of adavosertib 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. | Drug: adavosertib 20 mg<br>* Adavosertib 20 mg capsule administered orally on days 1-5 of a 21 day cycle.<br>* Other names: MK-1775;Drug: 5-FU 1000 mg/m^2/day<br>* 5-FU 1000 mg/m^2/day administered as an intravenous (IV) infusion on Days 1-4 of a 21-day cycle<br>|
| Experimental: Part 2 A2: adavosertib 20 mg QD+5-FU 1000 mg<br>Participants received 20 mg of adavosertib 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. | Drug: adavosertib 20 mg<br>* Adavosertib 20 mg capsule administered orally on days 1-5 of a 21 day cycle.<br>* Other names: MK-1775;Drug: 5-FU 1000 mg/m^2/day<br>* 5-FU 1000 mg/m^2/day administered as an intravenous (IV) infusion on Days 1-4 of a 21-day cycle<br>|
| Experimental: Parts 2B +3: adavosertib+5-FU+CDDP<br>Participants were to receive 20 mg or 65 mg of adavosertib 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. | Drug: adavosertib 20 mg<br>* Adavosertib 20 mg capsule administered orally on days 1-5 of a 21 day cycle.<br>* Other names: MK-1775;Drug: 5-FU 1000 mg/m^2/day<br>* 5-FU 1000 mg/m^2/day administered as an intravenous (IV) infusion on Days 1-4 of a 21-day cycle<br>Drug: CDDP<br>* CDDP 60 mg/m^2 to 100 mg/m^2 administered as an IV infusion on Day 1.<br>* Other names: Cisplatin;Drug: adavosertib 65 mg<br>* Adavosertib 65 mg capsule administered orally on days 1-5 of a 21 day cycle.<br>* Other names: MK-1775;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Cycle 1 (21 days) | 
| 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. | Cycle 1 (21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Cycle 1 (21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Head and Neck Cancer, Esophageal Cancer, Gastric Cancer