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
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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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
JHM Schellens, MD PhD
The Netherlands Cancer Institute
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
M10MKO / MK1775-009