Phase II Pharmacological Study With Wee-1 Inhibitor MK-1775 Combined With Carboplatin in Patients With p53 Mutated Epithelial Ovarian Cancer and Early Relapse (< 3 Months) or Progression During Standard First Line Treatment With an Additional Safety and Preliminary Anti-tumor Activity Cohort of Wee-1 Inhibitor AZD1775 Combined With Carboplatin in Patients With Platinum Resistant TP53 Mutated Epithelial Ovarian Cancer

M10MKO / MK1775-009

The purpose of this study is to determine if patients with p53 mutated epithelial ovarian cancer that have been treated with first line treatment (paclitaxel - carboplatin combination therapy) and that have shown early relapse (within 3 months) or progression during treatment will benefit from treatment with Wee-1 inhibitor MK-1775 and carboplatin. Additional safety and preliminary anti-tumor activity cohort (first patient in 2017): To determine the safety and preliminary anti-tumor activity (RECIST 1.1) of AZD1775 in combination with carboplatin in platinum resistant p53 mutated epithelial ovarian cancer (relapse within 6 months), NSCLC, SCLC, cervical, and endometrial cancer, in a 21 day schedule.

2010-07-01

2023-04-01

2023-04-01

Completed

Early phase I

24

Inclusion Criteria: * Histological or cytological proof of epithelial ovarian cancer, and proven p53 mutated pathway by PCR/Sequencing. IHC will also be performed. In the additional safety and efficacy cohort also inclusion of NSCLC, SCLC, cervical and endometrial cancer (only ovarian cancer cohort is pursued) * Measurable disease on a CT-scan or elevated Cancer Antigen (CA)-125 levels that can be monitored. * Patients previously received standard 1st line platinum therapy (combined with paclitaxel) for epithelial ovarian cancer, and showed recurrence on or within 3 months of this treatment (relapse within 6 months in the additional safety and efficacy cohort) * Able and willing to voluntarily give written informed consent. * Able and willing to undergo blood sampling for pharmacokinetics and pharmacodynamics. * Life expectancy ≥ 3 months allowing adequate follow up of toxicity evaluation and anti-tumor activity. * Minimal acceptable safety laboratory values: * Absolute neutrophil count (ANC) of ≥ 1.5 x 109 /L (or 1500/m3). * Platelet count of ≥ 100 x 109 /L (or 100,000/mm3). * Hemoglobin ≥ 5.6 mmol/L (or 9.1 g/dl). * Hepatic function as defined by serum bilirubin ≤ 1.5 x ULN, ALAT and ASAT ≤ 2.5 x ULN, or ALAT and ASAT ≥ 5x ULN in case of liver metastases. * Renal function as defined by serum creatinine ≥ 1.5 x ULN or creatinine clearance ≥ 60 ml/min for patients with creatinine levels ≥ 1.5 x ULN (by Cockcroft-Gault formula). * WHO performance status of ≤ 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. * No radio- or chemotherapy within the last 4 weeks prior to study entry (palliative limited radiation for pain reduction is allowed) * Able and willing to swallow oral medication. * Able and willing to receive iv medication. * Negative pregnancy test (urine/serum) for female patients with childbearing potential. Exclusion Criteria: * Symptomatic cerebral or leptomeningeal metastases. * Current participation or previous participation in a study with an investigational compound, or chemo- and/or radiotherapy within 28 days of receiving first dose of study medication. (Palliative limited radiation for pain reduction is allowed only between day 8 and day 21 of the study, and allowed to a limited area to palliate pain. * No prior radiation therapy to more than 30% of the bone marrow and patient must have recovered for at least 3 weeks from the hematologic toxicity of prior radiotherapy. * More than 1 prior cytotoxic chemotherapy regimen in initial trial. In the additional safety and efficacy cohort: more than 2 prior cytotoxic chemotherapy regimens. * Prior stem cell or bone marrow transplant. * Unresolved (\> grade 1) toxicities of previous chemotherapy, excluding alopecia. * Known hypersensitivity to the components of the combination study therapy or its analogs. * Patient has had prescription or non-prescription drugs or other products known to be metabolized by CYP3A4, or to inhibit or induce CYP3A4 that cannot be discontinued prior to Day 1 of dosing and withheld throughout the study until 2 days after the last dose of study medication * Bowel obstructions or motility disorders that may negatively affect oral drug absorption. * Patients with known alcoholism, drug addiction and/or a history of psychotic disorders who are not suitable for adequate follow up. * Women who are pregnant or breast feeding. * Fertile women who do not agree to use a reliable contraceptive method throughout the study. * Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients. * Patients with a known history of hepatitis B or C. * Neurological disease that may render a patient at increased risk for peripheral or central neurotoxicity. * Clinical history suggestive for Li Fraumeni syndrome.

{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE2'], 'designInfo': {'allocation': 'NA', 'interventionModel': 'SINGLE_GROUP', 'primaryPurpose': 'TREATMENT', 'maskingInfo': {'masking': 'NONE'}}, 'enrollmentInfo': {'count': 24, 'type': 'ACTUAL'}}

2023-09-07