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

Merck Sharp & Dohme (MSD)

Status and phase: Terminated; Phase 2; Phase 1

Conditions: Cervical Cancer

Treatments: Drug: Cisplatin; Drug: Placebo to adavosertib; Drug: Topotecan; Drug: adavosertib

Study type: Interventional

Funder types: Industry

Identifiers

NCT01076400

MK-1775-008 (Other Identifier)

2009-017054-12 (EudraCT Number)

1775-008

Details and patient eligibility

About

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.

Enrollment: 7 patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Has advanced, metastatic, and recurrent squamous cell, adenosquamous, or adeno-carcinoma of the uterine cervix (Stage II - IVb)
• Has received cisplatin in combination with radiation as initial or adjuvant treatment for their cervical cancer
• Has not received any other treatment for their cancer following the cisplatin-based chemo-radiation or targeted therapy except non-cytotoxic targeted therapy
• Recurrence must be at least 6 months post cisplatin-based chemotherapy
• Has measurable disease
• Performance status on the Eastern Cooperative Oncology Group (ECOG) Performance Scale is less than or equal to 1
• Has a negative pregnancy test within 72 hours of the first dose of study medication

Exclusion criteria

• Has had chemotherapy, radiotherapy, or biological therapy within 6 months of entering the study
• Has a history of vascular thrombotic events or vascular reconstruction
• Has active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has a primary CNS tumor
• Requires the use of medications or products that are metabolized by, or inhibit or induce CYP3A4 (Cytochrome P450 3A4)
• Is expecting to reproduce within the duration of the study or is pregnant or breastfeeding
• Is known to be Human Immunodeficiency Virus (HIV)-positive
• Has known active Hepatitis B or C
• Has a known history of interstitial lung disease or pulmonary fibrosis
• Has symptomatic ascites or pleural effusion
• Has a clinical history suggestive of Li-Fraumeni Syndrome

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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7 participants in 3 patient groups, including a placebo group

Part 1: adavosertib + topotecan/cisplatin

Experimental group

Description:

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.

Treatment:

Drug: adavosertib

Drug: Topotecan

Drug: Cisplatin

Part 2: adavosertib + topotecan/cisplatin

Experimental group

Description:

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.

Treatment:

Drug: adavosertib

Drug: Topotecan

Drug: Cisplatin

Part 2: Placebo to adavosertib + topotecan/cisplatin

Placebo Comparator group

Description:

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.

Treatment:

Drug: Topotecan

Drug: Placebo to adavosertib

Drug: Cisplatin