Cervical Cancer
Conditions
Brief summary
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.
Interventions
DRUGadavosertib
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.
DRUGTopotecan
Topotecan is administered at a dosage of 0.75 mg/m\^2 by intravenous (IV) infusion over 30 minutes on Days 1-3.
DRUGCisplatin
Cisplatin is administered at a dosage of 50 mg/m\^2 by IV infusion over 30 minutes on Day 1.
DRUGPlacebo to adavosertib
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.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Percentage of Participants Whose Best Confirmed Response is Partial Response (PR) or Complete Response (CR) | Up to approximately 1 year | 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. |
| Part 1: Number of Participants With Dose Limiting Toxicities (DLTs) | Up to approximately 1 year | 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. |
| Part 2: Length of Time for Progression-free Survival (PFS) | Up to approximately 1 year | 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. |
Participant flow
Recruitment details
Due to the early termination of the study by the sponsor, no participants were enrolled in Part 2 of the study.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: MK-1775 + Topotecan/Cisplatin 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. | 7 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 0 |
| Overall Study | Progressive Disease | 5 | 0 | 0 |
Baseline characteristics
| Characteristic | Part 1: MK-1775 + Topotecan/Cisplatin |
|---|---|
| Age, Continuous | 50.3 Years STANDARD_DEVIATION 3.5 |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 7 / 7 |
| serious Total, serious adverse events | 5 / 7 |
Outcome results
Primary
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.
Time frame: Up to approximately 1 year
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: MK-1775 + Topotecan/Cisplatin | Part 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 2 Number of participants |
Primary
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.
Time frame: Up to approximately 1 year
Population: The study was prematurely terminated, and data were not collected, so no analyses were performed.
Primary
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.
Time frame: Up to approximately 1 year
Population: Due to the early termination of the study Part 2 was not performed.