Study With Wee-1 Inhibitor MK-1775 and Carboplatin to Treat p53 Mutated Refractory and Resistant Ovarian Cancer (M10MKO)
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.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|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|
- Number and percentage of Participants with Adverse Events [ Time Frame: 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 ] [ Designated as safety issue: Yes ]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.
- Radiological antitumor activity [ Time Frame: 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 ] [ Designated as safety issue: No ]Radiological assessment (CT scan or MRI)
- Laboratory anti-tumor activity [ Time Frame: As long as the patient is treated with carboplatin and MK-1775 CA-125 laboratory assessments will be performed every 2 cycles (42 days) until progressive disease occurs, and evaluated in comparison to baseline CA-125. ] [ Designated as safety issue: No ]CA-125 will be assessed according to the Gynecologic Cancer Intergroup (GCIG) CA-125 response criteria.
- Pharmacokinetics assessments [ Time Frame: Cycle 1: day 1, 2, 3 ] [ Designated as safety issue: Yes ]
Pharmacokinetic analysis will be performed by using nonlinear mixed effect modeling (NONMEM).
The pharmacokinetic profile of MK-1775, when given in combination with carboplatin, will be determined in plasma and dry blood on day 1,2,3 of cycle 1. Pharmacokinetics of carboplatin, when given in combination with MK-1775, will be determined in plasma and ultrafiltrates on day 1 of cycle 1.
Correlations between pharmacokinetic data and toxicity are subsequently analyzed for their significance.
- Pharmacodynamic assessments [ Time Frame: Cycle 1: Day 1 (pre-dose) and day 3 and Cycle 2: day 1 ] [ Designated as safety issue: No ]
Pharmacodynamic changes induced by MK-1775 in combination with carboplatin, measured as changes in pCDC2, will be determined in surrogate tissue (skin). Skin biopsies will be performed on day 1 of cycle 1 (pre-dose) and on day 3 of cycle 1 within 2 hours of the last intake of MK-1775.
The relationship of various pharmacokinetic parameters to the pharmacodynamic endpoints will also be explored. Disease response, accompanied by available p53-pathway status, will be descriptively summarized.
|Study Start Date:||July 2010|
|Estimated Study Completion Date:||September 2013|
|Estimated Primary Completion Date:||July 2013 (Final data collection date for primary outcome measure)|
Experimental: MK-1775 and carboplatin
MK-1775: oral capsules. Carboplatin: intravenous infusion in 30 minutes
Drug: MK-1775 and carboplatin
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.
Other Name: CBDCA
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.
|Contact: JHM Schellens, MD PhD||+3120-512 ext firstname.lastname@example.org|
|Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital||Recruiting|
|Amsterdam, Netherlands, 1066CX|
|Contact: Jan HM Schellens, MD, PhD email@example.com|
|Principal Investigator: Jan HM Schellens, MD, PhD|
|Principal Investigator:||JHM Schellens, MD PhD||The Netherlands Cancer Institute|