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
18 Years
N/A
Female
Epithelial Ovarian Cancer
Trial Information
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.
Inclusion Criteria:
- Histological or cytological proof of epithelial ovarian cancer, and proven p53
mutated pathway by PCR/Sequencing. IHC will also be performed.
- 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.
- 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.
- 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.
Type of Study:
Interventional
Study Design:
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Number and percentage of Participants with Adverse Events
Outcome Description:
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.
Outcome 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
Safety Issue:
Yes
Principal Investigator
JHM Schellens, MD PhD
Investigator Role:
Principal Investigator
Investigator Affiliation:
The Netherlands Cancer Institute
Authority:
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Study ID:
M10MKO / MK1775-009
NCT ID:
NCT01164995
Start Date:
July 2010
Completion Date:
September 2013
Related Keywords:
- Epithelial Ovarian Cancer
- MK-1775
- Carboplatin
- epithelial ovarian cancer
- p53
- Ovarian Neoplasms
- Neoplasms, Glandular and Epithelial
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