A Study of Adavosertib (MK-1775) in Combination With Paclitaxel and Carboplatin Versus Paclitaxel and Carboplatin Alone for Participants With Platinum-Sensitive Ovarian Tumors With the P53 Gene Mutation (MK-1775-004)

Study Overview
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Brief Summary
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This is a study of the safety and efficacy of adavosertib in combination with paclitaxel plus carboplatin in the treatment of ovarian, fallopian tube, and primary peritoneal tumors with the P53 mutation. In Part 1, a small group of participants will receive adavosertib along with paclitaxel plus carboplatin to establish the tolerability of adavosertib with this combination. In Part 2, participants will be randomly assigned to receive either adavosertib plus paclitaxel and carboplatin OR placebo plus paclitaxel and carboplatin to assess efficacy of adavosertib compared to placebo. The primary hypothesis of the study (Part 2) is that administration of adavosertib in combination with paclitaxel plus carboplatin in participants with platinum sensitive p53 mutant ovarian cancer will result in improvement in progression free survival (PFS) per enhanced Response Evaluation Criteria In Solid Tumors version 1.1 (enhanced RECIST 1.1) compared to participants treated with paclitaxel plus carboplatin alone.

Official Title
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A Randomized, Phase II Study Evaluating MK-1775 in Combination With Paclitaxel and Carboplatin Versus Paclitaxel and Carboplatin Alone in Adult Patients With Platinum Sensitive p53 Mutant Ovarian Cancer

Conditions
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Ovarian Cancer

Intervention / Treatment
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* Drug: adavosertib
* Drug: Placebo
* Drug: paclitaxel
* Drug: carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed non-low grade, non-borderline (low malignant potential) ovarian, fallopian tube, or primary peritoneal cancer which has progressed after paclitaxel / platinum-based therapy. Platinum-sensitive disease. Radiological progression must have occurred 6 months or more after the completion of the most recent platinum-based treatment. Measurable disease. Available tumor sample(s). Performance status of ≤1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. Adequate organ function. Exclusion Criteria: Pregnancy or the intention to become pregnant during the course of the study. Participation in a study with an investigational compound or device within 28 days of receiving first dose of study medication. Active central nervous system (CNS) metastases and/or carcinomatous meningitis. Primary CNS tumor. Known hypersensitivity or contraindications to the components of potential study therapy (paclitaxel, carboplatin, adavosertib) or its analogs (i.e., cremophor, mannitol, etc.). Participant requires the use of medications or products that are metabolized by, or inhibit, or induce Cytochrome P450 3A (CYP3A4). Ongoing peripheral neuropathies ≥Grade 2 and related to previous treatment. Known psychiatric or substance abuse disorders. Regular use (including recreational use) of any illicit drugs or recent history (within the last year) of drug or alcohol abuse. HIV positive. Active Hepatitis B or C. Symptomatic ascites or pleural effusion. Clinical history suggestive of Li Fraumeni Syndrome.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: adavosertib 225 mg + paclitaxel +carboplatin<br>During the open-label run-in, participants receive 225 mg adavosertib twice daily (BID) starting on Day 1 of Cycle 1 (cycle=21 days) for a total of 5 doses. Participants receive adavosertib in combination with paclitaxel (175 mg/m2) and carboplatin (area under the curve [AUC] 5). | Drug: adavosertib<br>* Adavosertib capsules, orally, twice a day (BID) for a total of 5 doses starting on Day 1 of each 3-week cycle<br>* Other names: MK-1775;Drug: paclitaxel<br>* paclitaxel, intravenous (IV) infusion on Day 1 of each 3-week cycle<br>* Other names: Taxol;Drug: carboplatin<br>* carboplatin, IV infusion on Day 1 of each 3-week cycle<br>* Other names: paraplatin;|
| Experimental: Part 2: adavosertib 225 mg + paclitaxel +carboplatin<br>During Part 2, participants receive 225 mg adavosertib BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants receive adavosertib in combination with paclitaxel (175 mg/m2) and carboplatin (AUC 5). | Drug: adavosertib<br>* Adavosertib capsules, orally, twice a day (BID) for a total of 5 doses starting on Day 1 of each 3-week cycle<br>* Other names: MK-1775;Drug: paclitaxel<br>* paclitaxel, intravenous (IV) infusion on Day 1 of each 3-week cycle<br>* Other names: Taxol;Drug: carboplatin<br>* carboplatin, IV infusion on Day 1 of each 3-week cycle<br>* Other names: paraplatin;|
| Placebo Comparator: Part 2: Placebo + paclitaxel +carboplatin<br>During Part 2, participants receive matched placebo to adavosertib BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants receive placebo in combination with paclitaxel (175 mg/m2) and carboplatin (AUC 5). | Drug: Placebo<br>* placebo to adavosertib, capsule, orally, BID for a total of 5 doses, starting on Day 1 of each 3-week cycle<br>Drug: paclitaxel<br>* paclitaxel, intravenous (IV) infusion on Day 1 of each 3-week cycle<br>* Other names: Taxol;Drug: carboplatin<br>* carboplatin, IV infusion on Day 1 of each 3-week cycle<br>* Other names: paraplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2: Median Progression-free Survival (PFS) in Weeks Based on Enhanced Response Evaluation Criteria In Solid Tumors Version 1.1 (Enhanced RECIST 1.1) by Independent Radiology Review | PFS was defined as the time from randomization to progressive disease (based on blinded independent central radiologic review) or death, whichever occurred earlier. Tumor response was evaluated every 6 weeks during treatment by diagnostic anatomic imaging and objective response assessments were performed based on enhanced RECIST 1.1 criteria. According to enhanced RECIST 1.1, progressive disease was the appearance of one or more new lesions, OR an unambiguous increase in the sum of target lesion volumes with both 1) >20% increase in the sum of volumes (SOV) of all target lesions (taking as reference the nadir) and 2) greater than two times the variability of the measurements estimated by the sponsor and/or its designees. PFS was analyzed for Part 2 participants only using the Kaplan-Meier method and median PFS was reported in weeks. Per protocol, Part 1 participants were not included in this analysis. | Up to 57 months | 
| Part 1: Number of Participants With a Dose Limiting Toxicity (DLT) | DLTs assessed during first 21-day cycle of Part 1 and defined as toxicities that met pre-defined severity criteria, were possibly, probably, or definitely related to triplet therapy, and could possibly result in a change in the given dose. Hematologic DLTs included Grade (Gr) 3 or Gr 4 neutropenia with fever >38.5°C and/or infection requiring antibiotic or anti-fungal treatment, and any Gr 4-5 hematological toxicity EXCEPT Gr 4 anemia, leukopenia, lymphopenia, neutropenia lasting <7 days, and thrombocytopenia lasting <4 days, except if a platelet transfusion was required. Non-hematologic DLT defined as any Gr 3, 4, or 5 nonhematologic toxicity EXCEPT: Gr 3 nausea, vomiting, diarrhea, or dehydration judged by Investigator and SPONSOR to occur in setting of inadequate compliance with supportive care measures and last for less than 48 hours, alopecia of any grade, inadequately treated hypersensitivity reactions, or clinically non-significant, treatable or reversible lab abnormalities. | During Cycle 1 of Part 1 (first 21 days) | 
| Parts 1 and 2: Percentage of Participants That Experienced an Adverse Event (AE) | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's products, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product was also an AE. The percentage of participants that experienced at least one AE was reported for each treatment arm. | Part 1: Day 1 through Post Study (286 days total). Part 2: Day 1 through Post Study (479 days total) | 
| Parts 1 and 2: Percentage of Participants That Discontinued Study Treatment Due to an AE | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's products, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product was also an AE. The percentage of participants that discontinued study treatment (paclitaxel, carboplatin, or MK-1775) due to an AE was reported for each treatment arm. | Part 1: Day 1 through Post Study (286 days total). Part 2: Day 1 through Post Study (479 days total) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Objective Response Rate (ORR) Per Gynecological Cancer Intergroup (GCIG) Criteria Based on Both RECIST 1.1 and Cancer Antigen 125 (CA-125) Level by Independent Radiology Review | ORR was defined as the percentage of participants whose best response was confirmed partial response (PR) or complete response (CR) based both on imaging per RECIST 1.1 and on serum marker CA-125 level according to GCIC criteria. CR was defined by RECIST 1.1 as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have had reduction in short axis to <10 mm. PR was defined by RECIST 1.1 as at least a 30% decrease in the sum of the diameters (SOD) of target lesions, taking as reference the baseline SOD. A response according to CA-125 had occurred if there was ≥50% reduction in CA-125 levels from a pretreatment sample. The response must have been confirmed and maintained for at least 28 days. Participants could be evaluated according to CA-125 only if they had a pretreatment sample that was ≥2 times the upper limit of normal and within 2 weeks prior to starting treatment. Only evaluable Part 1 participants were included in this analysis. | Up to 57 months | 
| Part 2: Median PFS in Weeks Based on RECIST 1.1 by Independent Radiology Review | PFS was defined as the time from randomization to progressive disease (based on blinded independent central radiologic review) or death, whichever occurred earlier. Tumor response was evaluated every 6 weeks during treatment by diagnostic anatomic imaging and objective response assessments were performed based on RECIST 1.1 criteria. According to RECIST 1.1, progressive disease was the appearance of one or more new lesions, OR a ≥20% increase in the sum of target lesion diameters (SOD) taking as reference the nadir (smallest SOD recorded since treatment started). PFS was analyzed for all randomized participants in Part 2 using the Kaplan-Meier method and median PFS was reported in weeks. Per protocol, Part 1 participants were not included in this analysis. | Up to 57 months | 
| Part 2: ORR Per GCIG Criteria Based on Both Enhanced RECIST 1.1 and CA125 Level by Independent Radiology Review | ORR defined as the percentage of participants with best response of confirmed PR or CR based both on imaging per enhanced RECIST 1.1 and on serum marker CA-125 level according to GCIC criteria. CR defined by enhanced RECIST 1.1 as disappearance of all target lesions. Any pathological lymph nodes (target or non-target) must have had reduction in short axis to <10 mm. PR was defined by enhanced RECIST 1.1 as ≥30% decrease in SOV of target lesions, taking as reference baseline SOV. Response according to CA-125 had occurred if there was ≥50% reduction in CA-125 levels from pretreatment sample. Response must have been confirmed and maintained for ≥28 days. Participants could be evaluated according to CA-125 only if they had a pretreatment sample that was ≥2 times the upper limit of normal and within 2 weeks prior to starting treatment. All randomized participants in Part 2 were analyzed. Per protocol, Part 1 participants were not included in this analysis. | Up to 57 months | 
| Part 2: Median Overall Survival (OS) in Months | OS was defined as the time from randomization to death due to any cause, reported in months. Participants without documented death at the time of analysis were censored at the date last known to be alive. For this endpoint, all randomized participants in Part 2 were analyzed. Per protocol, Part 1 participants were not evaluated for OS. | Up to 57 months |