Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Uterine Cervical Neoplasms

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Cervical Diseases

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Antineoplastic Agents

All Drugs and Chemicals

Topotecan

Cisplatin

Adavosertib

Topoisomerase I Inhibitors

Enzyme Inhibitors

Part 1: Dose escalation study. adavosertib capsules will be administered in sequentially rising dose levels twice daily for a total of nine doses on Days 1-5 of a 21-day cycle. Topotecan will be administered at a dosage of 0.75 mg/m\^2 by intravenous (IV) infusion over 30 minutes on Days 1-3 . Cisplatin will be administered at a dosage of 50 mg/m\^2 by IV infusion over 30 minutes on Day 1.

Part 2: adavosertib capsules will be administered at the dose determined in Part 1 twice daily for a total of nine doses on Days 1-5 of a 21-day cycle. Topotecan will be administered at a dosage of 0.75 mg/m\^2 by intravenous (IV) infusion over 30 minutes on Days 1-3. Cisplatin will be administered at a dosage of 50 mg/m\^2 by IV infusion over 30 minutes on Day 1.

Part 2: Placebo to adavosertib capsules will be administered twice daily for a total of nine doses on Days 1-5 of a 21-day cycle. Topotecan will be administered at a dosage of 0.75 mg/m\^2 by intravenous (IV) infusion over 30 minutes on Days 1-3. Cisplatin will be administered at a dosage of 50 mg/m\^2 by IV infusion over 30 minutes on Day 1.

Adavosertib capsules are administered in sequentially rising dose levels twice daily for a total of nine doses on Days 1-5 of a 21-day cycle.

adavosertib

Topotecan is administered at a dosage of 0.75 mg/m\^2 by intravenous (IV) infusion over 30 minutes on Days 1-3.

Cisplatin is administered at a dosage of 50 mg/m\^2 by IV infusion over 30 minutes on Day 1.

Placebo to adavosertib capsules are administered in sequentially rising dose levels twice daily for a total of nine doses on Days 1-5 of a 21-day cycle.

Placebo to adavosertib

Medical Director

This study will be conducted in two parts. Part 1 will determine whether administration of adavosertib in combination with topotecan and cisplatin is generally well-tolerated and causes clinical objective responses in patients with cervical cancer. Part 1 will also define the recommended Phase 2 dose and maximum tolerated dose (MTD) of the combination of adavosertib with topotecan and cisplatin. Part 2 of the study will evaluate whether treatment with adavosertib in combination with topotecan and cisplatin causes an improvement in progression-free survival (PFS) compared to treatment with topotecan and cisplatin alone and will further evaluate the tolerability of the combination treatment. The primary hypothesis is the combination of adavosertib, topotecan and cisplatin causes objective radiological responses (assessed per Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1 criteria) in ≥30% of participants. Due to the early termination of the study by the sponsor, no participants were enrolled in Part 2 of the study.

A Study of Adavosertib (MK-1775) in Combination With Topotecan/Cisplatin in Participants With Cervical Cancer (MK-1775-008)

A Two Part, Phase I-IIa Study Evaluating MK1775 in Combination With Topotecan/Cisplatin in Adult Patients With Cervical Cancer

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

On the basis of Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, PR is at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline sum diameters. CR is the disappearance of all extranodal target lesions, where all pathological lymph nodes must have decreased to \<10 mm in the short axis.

A DLT is a protocol-defined, (hematologic and non-hematologic), AE that must be definitely, probably, or possibly related to the study therapy. A DLT is any of the following: Grade 4-5 hematological toxicity; Grade 3 or Grade 4 neutropenia with fever \>38.°C and/or infection requiring antibiotic or anti-fungal treatment. Non-hematologic dose-limiting toxicities are any Grade 3, 4, or 5 non-hematologic toxicity, with specific exceptions. If occurring within the first cycle of combination therapy: unresolved drug-related toxicity, preventing (re) treatment for 3 weeks or more from the date of the next scheduled treatment or any drug-related toxicity preventing the participant from taking at least 75% of the doses of MK-1775 with each administration of chemotherapy.

PFS is the length of time during and after treatment that a participant lives, but whose tumor progression does not worsen. PFS is defined as the time from randomization to progressive disease or death, whichever occurs earlier. Tumor volume changes of +20% for progressive disease was used to be consistent with RECIST 1.1.

Merck Sharp & Dohme LLC

All randomized participants who received at least one dose of study treatment.

Part 1: MK-1775 capsules were administered at 50 mg twice daily on Days 1-4, and once on Day 5 for a total of nine doses per cycle. Each cycle was 21 days. Topotecan was administered at a dosage of 0.75 mg/m\^2 by intravenous (IV) infusion over 30 minutes on Days 1-3 of each cycle. Cisplatin was administered at a dosage of 50 mg/m\^2 by IV infusion over 30 minutes on Day 1 of each cycle. Only a single dose of MK-1775 was administered during Part 1.

Part 1: MK-1775 + Topotecan/Cisplatin

Age, Continuous

Sex: Female, Male

Senior Vice President, Global Clinical Development

The study was prematurely terminated, and data were not collected, so no analyses were performed.

Part 1: Percentage of Participants Whose Best Confirmed Response is Partial Response (PR) or Complete Response (CR)

Participants who completed the first cycle of combination therapy or discontinued from the study due to a DLT attributable to study therapy. One participant who violated the protocol was not assessed for DLTs.

Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)

Due to the early termination of the study Part 2 was not performed.

Part 2: Length of Time for Progression-free Survival (PFS)

Part 2: MK-1775 capsules will be administered at the dose determined in Part 1 twice daily for a total of nine doses on Days 1-5 of a 21-day cycle. Topotecan will be administered at a dosage of 0.75 mg/m\^2 by intravenous (IV) infusion over 30 minutes on Days 1-3. Cisplatin will be administered at a dosage of 50 mg/m\^2 by IV infusion over 30 minutes on Day 1.

Part 2: MK-1775 + Topotecan/Cisplatin

Part 2: Placebo to MK-1775 capsules will be administered twice daily for a total of nine doses on Days 1-5 of a 21-day cycle. Topotecan will be administered at a dosage of 0.75 mg/m\^2 by intravenous (IV) infusion over 30 minutes on Days 1-3. Cisplatin will be administered at a dosage of 50 mg/m\^2 by IV infusion over 30 minutes on Day 1.

Spots Global Cancer Trial Database for placebo to adavosertib