Study With Wee-1 Inhibitor AZD1775 (MK-1775) and Carboplatin to Treat p53 Mutated Refractory and Resistant Ovarian Cancer — M10MKO  

Epithelial Ovarian Cancer Clinical Trial

Official title: 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

Status Completed

Clinical Trial 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.

Clinical Trial Description

Platinum-based drugs are used in first line treatment of epithelial ovarian cancer. Despite high overall initial response rates, resistance or early relapse can occur. MK-1775 is a potent and selective inhibitor of Wee-1 kinase, a kinase that regulates the G2/M checkpoint. Since most human cancers retain p53-related G1 checkpoint abnormalities, they are dependent on the G2 checkpoint. Annulment of the G2 checkpoint may therefore make p53 deficient tumor cells more susceptible to anti-cancer agents. The Phase I study with MK-1775 combined with gemcitabine, carboplatin or cisplatin in patients with advanced solid tumors already confirmed target engagement of MK-1775.

In this study Carboplatin will be administered in combination with MK-1775 in a 21 day cycle. Ovarian cancer patients with a p53 mutation based on PCR/sequencing will be eligible for the study. p53 immunohistochemistry (IHC) wil also be performed.

This study is a proof of concept (POC) study. To proof the hypothesis that MK-1775 is more effective in tumors harboring p53 mutations a single stage study with 21 patients will be performed. The final conclusion will then be made as follows: Applying a A'Hern's Single Stage Phase II Design, a minimum of 6 responses (RECIST 1.0 or CA125) out of 21 patients will provide a 61% power to declare an efficacy of at least a 30% (α=0.05). A response of 13% or less would definitively indicate no efficacy of interest.

Patients will remain on treatment until they no longer have clinical benefit from treatment or when toxicity leads to patient withdrawal. Patients will be followed for at least 30 days following their last dose of study therapy, or until death, whichever comes first.

For patients with stable disease follow-up will take place at least until disease progression has been documented = until time of progression. Patients discontinued from the study for unacceptable adverse experiences will be followed until time of progression and until the resolution or stabilization of the adverse experience. These patients with stable disease at the end of treatment or who discontinued for unacceptable adverse experiences will be evaluated every 2 months at the outpatient department, and CA-125 will be determined. In case of CA-125 increase a CT scan will be performed. In patients for whom CA-125 is not a good marker, a CT-scan will need to be performed every 2 cycles (42 days), until disease progression.

In the additional safety and preliminary anti-tumor activity cohort a minimum of 10 patients will be recruited per tumor type. If no partial responses have been documented in a defined tumor type that tumor type will be closed for further recruitment. If at least one patient shows a PR recruitment may continue until 29 (evaluable) patients have been included per tumor type. ;

Related Conditions & MeSH terms

• Carcinoma, Ovarian Epithelial
• Epithelial Ovarian Cancer
• Ovarian Neoplasms

• NCT number: NCT01164995
• Study type: Interventional
• Source: The Netherlands Cancer Institute
• Status: Completed
• Phase: Phase 2
• Start date: July 2010
• Completion date: April 2023