The primary objective of the phase I part of the study is to determine the recommended phase II dose of metformin in combination with carboplatin/paclitaxel chemotherapy in patients with advanced ovarian cancer. The secondary objectives the phase I…
ID
Source
Brief title
Condition
- Reproductive neoplasms female malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary end-point of the phase I study is the recommended phase II dose
based on dose-limiting toxicities and maximum tolerated dose of metformin in
combination with carboplatin/paclitaxel.
The primary end-point of the phase II study is objective response rate in
patients with measureable disease and CA-125 response as defined by the
Gynaecologic Cancer Intergroup (GCIG) for non-measurable disease.
Secondary outcome
The secondary end-points are:
• All adverse events and laboratory events coded and graded by the CTCAEv4
criteria
• Percentage of patients in which complete debulking is achieved (residual
disease <1cm)
• Percentage of patients with a complete pathological response
• Objective tumour response by RECIST version 1.1 in patients with measurable
disease
• Objective tumour response by CA-125 criteria in patients without measurable
disease
• Progression free survival and overall survival distributions
• Exploratory analysis of paired pre-and post treatment immunohistochemical
tumour tissue biomarker expression as described in translational research
section
• Exploratory analysis of paired pre-and-post treatment serum biomarker levels
as described in the translational research section
• Exploratory analysis of metformin concentrations in tumour cells as described
in the translational research section
Background summary
Molecularly targeted agents which inhibit the mTOR pathway and/or circumvent
p53 in the induction of apoptosis are exciting potential targets in ovarian
cancer. Metformin is a biguanide, widely used in the treatment of type 2
diabetes mellitus, that has shown anti-cancer activity in preclinical models of
ovarian cancer. The main mechanism of metformin*s effect is mTOR pathway
inhibition and, in addition, it has been shown to circumvent p53-induced
apoptosis making it an exciting, potentially effective drug in ovarian cancer.
Study objective
The primary objective of the phase I part of the study is to determine the
recommended phase II dose of metformin in combination with
carboplatin/paclitaxel chemotherapy in patients with advanced ovarian cancer.
The secondary objectives the phase I study are to document the safety profile
of metformin in combination with carboplatin/paclitaxel chemotherapy and to
document the influence of metformin on the pharmacokinetics of
carboplatin/paclitaxel chemotherapy.
The primary objective of the second phase of this study is to determine the
activity of adding metformin to carboplatin/paclitaxel neoadjuvant chemotherapy
in patients with advanced stage ovarian cancer. The secondary objectives are to
determine safety and tolerability, likelihood of complete tumour debulking,
likelihood of complete pathological response and the patient outcome and to
explore tumour and serum biomarkers and intratumoral metformin concentrations.
Study design
A phase Ib, single-centre, dose-escalation trial of metformin given in
combination with carboplatin and paclitaxel chemotherapy in patients with
advanced ovarian cancer, with a traditional escalation rule with fixed dose
levels (*3 + 3* rule). The recommended phase II dose will be defined as the
maximum predefined dose level at which 0 of 3 or <= 1 of 6 subjects experience a
drug-related DLT during cycle 1 and 2 of treatment. An estimated 10-20 patients
will be required for this part of the study.
An open-label, single-centre, randomised, controlled phase II study in advanced
ovarian cancer patients eligible for neoadjuvant chemotherapy followed by
surgical debulking and adjuvant chemotherapy. The control arm will receive
three 21-day cycles of paclitaxel/carboplatin neoadjuvant chemotherapy followed
by cytoreductive surgery and thereafter three adjuvant cycles. The treatment
arm will additionally receive continuous dosing of metformin, at the
recommended phase II dose as determined in the phase I part of this trial,
during chemotherapy treatment. 44 patients will be included initially, if
sufficient responses are seen an additional 60 patients will be entered
Intervention
Phase I: Carboplatin/paclitaxel chemotherapy in combination with escalating
doses of metformin
Phase II: Carboplatin/paclitaxel chemotherapy with or without metformin at
recommended phase II dose
Study burden and risks
Metformin is a widely prescribed, safe oral anti-diabetic drug with a known,
relatively mild side-effect profile. There is preclinical evidence for an
anti-cancer effect. In combination with standard carboplatin/paclitaxel
chemotherapy it may enhance response rates and improve outcome. Burden of
participation will be kept to a minimum with the majority of the study visits
coinciding with routine treatment visits. Besides blood sampling, no additional
diagnostic procedures are required.
Hanzeplein 1
Groningen 9700 RB
NL
Hanzeplein 1
Groningen 9700 RB
NL
Listed location countries
Age
Inclusion criteria
•Patients with advanced stage (FIGO III-IV), histologically confirmed and documented epithelial ovarian carcinoma
•Patients eligible for neoadjuvant carboplatin/paclitaxel chemotherapy prior to surgical debulking (phase 1 or 2) OR patients with relapsed or progressive ovarian cancer after initial treatment eligible for palliative carboplatin/paclitaxel chemotherapy (phase 1 only)
•Measurable tumour according to RECISTv1.1 or GCIG CA125 criteria (phase 2 only)
•Eastern Cooperative Oncology Group-performance status (ECOG-PS) of 0-2
•Age >= 18 years
•Adequate blood count, hepatic and renal function
•Written informed consent
Exclusion criteria
•Prior chemotherapy, immunotherapy, targeted agents or radiotherapy to abdomen or pelvis (phase 2 only)
•Current or recent (within 30 days of first study dosing) treatment with another investigational drug or participation in another investigational study.
•Metformin within 4 weeks prior to enrolment.
•Other malignancy within the last 5 years, except for adequately treated carcinoma in situ of the cervix or squamous carcinoma of the skin, or adequately controlled limited basal cell skin cancer (phase 2 only)
•Symptomatic CNS metastasis
•Pre-existing peripheral neuropathy >= CTC grade 2.
•Pregnant or lactating females. Serum pregnancy test to be assessed within 7 days prior to study treatment start, or within 14 days with a confirmatory urine pregnancy test within 7 days prior to study treatment start.
•Women of childbearing potential (defined as <2 years after last menstruation and not surgically sterile) not using effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly) during the study and for 6 months after the last study medication.
•Known hypersensitivity to any of the study drugs or excipients.
•Serious active infection requiring i.v. antibiotics at enrolment.
•Unstable medical conditions.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-005050-35-NL |
| CCMO | NL47539.042.14 |