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)

NCT01357161 | Completed Phase 2 Results

• 2 other identifiers: 1775-0042011-002803-13
• Study Type: interventional
• Target: 136
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Ovarian Cancer

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (4)

• 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

  Up to 57 months

• Part 2: Median PFS in Weeks Based on RECIST 1.1 by Independent Radiology Review

  Up to 57 months

• Part 2: ORR Per GCIG Criteria Based on Both Enhanced RECIST 1.1 and CA125 Level by Independent Radiology Review

  Up to 57 months

• Part 2: Median Overall Survival (OS) in Months

  Up to 57 months

Study Arms (3)

Part 1: adavosertib 225 mg + paclitaxel +carboplatin

EXPERIMENTAL

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; Drug: paclitaxel; Drug: carboplatin

Part 2: adavosertib 225 mg + paclitaxel +carboplatin

EXPERIMENTAL

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; Drug: paclitaxel; Drug: carboplatin

Part 2: Placebo + paclitaxel +carboplatin

PLACEBO COMPARATOR

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; Drug: paclitaxel; Drug: carboplatin

Interventions

adavosertib DRUG

Adavosertib capsules, orally, twice a day (BID) for a total of 5 doses starting on Day 1 of each 3-week cycle

Also known as: MK-1775

Part 1: adavosertib 225 mg + paclitaxel +carboplatin; Part 2: adavosertib 225 mg + paclitaxel +carboplatin

Placebo DRUG

placebo to adavosertib, capsule, orally, BID for a total of 5 doses, starting on Day 1 of each 3-week cycle

Part 2: Placebo + paclitaxel +carboplatin

paclitaxel DRUG

paclitaxel, intravenous (IV) infusion on Day 1 of each 3-week cycle

Also known as: Taxol

Part 1: adavosertib 225 mg + paclitaxel +carboplatin; Part 2: Placebo + paclitaxel +carboplatin; Part 2: adavosertib 225 mg + paclitaxel +carboplatin

carboplatin DRUG

carboplatin, IV infusion on Day 1 of each 3-week cycle

Also known as: paraplatin

Part 1: adavosertib 225 mg + paclitaxel +carboplatin; Part 2: Placebo + paclitaxel +carboplatin; Part 2: adavosertib 225 mg + paclitaxel +carboplatin

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Links

• Merck Clinical Trials Information

MeSH Terms

Conditions

Ovarian Neoplasms

Interventions

adavosertib; Paclitaxel; Carboplatin

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Coordination Complexes

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 18, 2011
• First Posted: May 20, 2011
• Study Start: July 26, 2011
• Primary Completion: August 8, 2016
• Study Completion: August 8, 2016
• Last Updated: September 21, 2023
• Results First Posted: September 7, 2017

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will share