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

Study Overview
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Brief Summary
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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.

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

Conditions
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Cervical Cancer

Intervention / Treatment
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* Drug: adavosertib
* Drug: Topotecan
* Drug: Cisplatin
* Drug: Placebo to adavosertib


Participation Criteria
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Eligibility Criteria
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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

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: adavosertib + topotecan/cisplatin<br>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. | Drug: adavosertib<br>* 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.<br>* Other names: MK-1775;Drug: Topotecan<br>* Topotecan is administered at a dosage of 0.75 mg/m^2 by intravenous (IV) infusion over 30 minutes on Days 1-3.<br>Drug: Cisplatin<br>* Cisplatin is administered at a dosage of 50 mg/m^2 by IV infusion over 30 minutes on Day 1.<br>|
| Experimental: Part 2: adavosertib + topotecan/cisplatin<br>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. | Drug: adavosertib<br>* 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.<br>* Other names: MK-1775;Drug: Topotecan<br>* Topotecan is administered at a dosage of 0.75 mg/m^2 by intravenous (IV) infusion over 30 minutes on Days 1-3.<br>Drug: Cisplatin<br>* Cisplatin is administered at a dosage of 50 mg/m^2 by IV infusion over 30 minutes on Day 1.<br>|
| Placebo Comparator: Part 2: Placebo to adavosertib + topotecan/cisplatin<br>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. | Drug: Topotecan<br>* Topotecan is administered at a dosage of 0.75 mg/m^2 by intravenous (IV) infusion over 30 minutes on Days 1-3.<br>Drug: Cisplatin<br>* Cisplatin is administered at a dosage of 50 mg/m^2 by IV infusion over 30 minutes on Day 1.<br>Drug: Placebo to adavosertib<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Percentage of Participants Whose Best Confirmed Response is Partial Response (PR) or Complete Response (CR) | 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. | Up to approximately 1 year | 
| Part 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 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. | Up to approximately 1 year | 
| Part 2: Length of Time for Progression-free Survival (PFS) | 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. | Up to approximately 1 year |