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)

Merck Sharp & Dohme (MSD)

Status and phase: Completed; Phase 2

Conditions: Ovarian Cancer

Treatments: Drug: Placebo; Drug: paclitaxel; Drug: adavosertib; Drug: carboplatin

Study type: Interventional

Funder types: Industry

Identifiers

NCT01357161

2011-002803-13 (EudraCT Number)

1775-004

Details and patient eligibility

About

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.

Enrollment: 136 patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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136 participants in 3 patient groups, including a placebo group

Part 1: adavosertib 225 mg + paclitaxel +carboplatin

Experimental group

Description:

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).

Treatment:

Drug: paclitaxel

Drug: adavosertib

Drug: carboplatin

Part 2: adavosertib 225 mg + paclitaxel +carboplatin

Experimental group

Description:

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).

Treatment:

Drug: paclitaxel

Drug: adavosertib

Drug: carboplatin

Part 2: Placebo + paclitaxel +carboplatin

Placebo Comparator group

Description:

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).

Treatment:

Drug: paclitaxel

Drug: carboplatin

Drug: Placebo