Study With Wee-1 Inhibitor AZD1775 (MK-1775) and Carboplatin to Treat p53 Mutated Refractory and Resistant Ovarian Cancer

NCT01164995 | Completed Phase 2

• 1 other identifier: M10MKO / MK1775-009
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Epithelial Ovarian Cancer

Keywords

MK-1775; Carboplatin; epithelial ovarian cancer; p53

Outcome Measures

Primary Outcomes (2)

• Number and percentage of Participants with Adverse Events

  Descriptive tables that summarize the number and percentage of patients that experience adverse events as categorized in the NCI CTCAE version 4.0 will be generated for the overall population. Laboratory assessments: screening/day 1, 8, 15 of each cycle, and regular physical examination at the start of each cycle or on indication will be performed and followed until 30 days after the end of study (defined as disease progression or unacceptable toxicity (AEs) or patient withdrawal or patient death) or in case of AEs or Stable disease until time of progression.

  During treatment with carboplatin and MK-1775 AEs will be recorded up to 30 days after treatment (or until death whatever comes first). Treatment will occur until progressive disease

• Radiological antitumor activity

  Radiological assessment (CT scan or MRI) per RECIST 1.1

  As long as the patient is treated with carboplatin and MK-1775 radiological assessments will be performed every 2 cycles (42 days) until progressive disease occurs, and evaluated in comparison to the baseline scan

Secondary Outcomes (3)

• Pharmacokinetics assessments (not in additional safety and efficacy cohort)

  Cycle 1: day 1, 2, 3

• Pharmacodynamic assessments (not in additional safety and efficacy cohort)

  Cycle 1: Day 1 (pre-dose) and day 3 and Cycle 2: day 1

• In the additional safety and preliminary anti-tumor activity cohort

  From day of first treatment cycle until end of study (progression or death whatever comes first), assessed up to 24 months (estimated)

Other Outcomes (1)

• Biomarker analyses in additional safety and efficacy cohort

  Biopsies will be obtained before treatment (baseline), on treatment in case of response and at time of progression

Study Arms (1)

MK-1775 and carboplatin

EXPERIMENTAL

MK-1775: oral capsules. Carboplatin: intravenous infusion in 30 minutes

Drug: MK-1775 and carboplatin

Interventions

MK-1775 and carboplatin DRUG

Carboplatin will be administered in a dose resulting in AUC5 (i.v. 30 min) at day 1 of each cycle. Concomittantly with the start of the carboplatin infusion 225 mg of MK-1775 will be administered as an oral capsule, followed by 4 additional doses at 12 hour increments ( = 5 BID doses of MK-1775 in 2.5 days in total). One cycle will last 21 days.

Also known as: CBDCA

MK-1775 and carboplatin

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• The Netherlands Cancer Institute: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

FL Opdam

Amsterdam, 1066CX, Netherlands

Location

Related Publications (2)

• Embaby A, Kutzera J, Geenen JJ, Pluim D, Hofland I, Sanders J, Lopez-Yurda M, Beijnen JH, Huitema ADR, Witteveen PO, Steeghs N, van Haaften G, van Vugt MATM, de Ridder J, Opdam FL. WEE1 inhibitor adavosertib in combination with carboplatin in advanced TP53 mutated ovarian cancer: A biomarker-enriched phase II study. Gynecol Oncol. 2023 Jul;174:239-246. doi: 10.1016/j.ygyno.2023.05.063. Epub 2023 May 24.

  PMID: 37236033 DERIVED

• Leijen S, van Geel RM, Sonke GS, de Jong D, Rosenberg EH, Marchetti S, Pluim D, van Werkhoven E, Rose S, Lee MA, Freshwater T, Beijnen JH, Schellens JH. Phase II Study of WEE1 Inhibitor AZD1775 Plus Carboplatin in Patients With TP53-Mutated Ovarian Cancer Refractory or Resistant to First-Line Therapy Within 3 Months. J Clin Oncol. 2016 Dec 20;34(36):4354-4361. doi: 10.1200/JCO.2016.67.5942. Epub 2016 Oct 28.

  PMID: 27998224 DERIVED

MeSH Terms

Conditions

Carcinoma, Ovarian Epithelial

Interventions

adavosertib; Carboplatin

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Ovarian Neoplasms; Endocrine Gland Neoplasms; Neoplasms by Site; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals

Study Officials

• FL Opdam, MD PhD

  The Netherlands Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PhD

Study Record Dates

• First Submitted: July 9, 2010
• First Posted: July 19, 2010
• Study Start: July 1, 2010
• Primary Completion: April 1, 2023
• Study Completion: April 1, 2023
• Last Updated: September 7, 2023

Record last verified: 2023-08

Locations

NL (1)