Clinical Trials Register

Summary
EudraCT Number:	2012-005050-35
Sponsor's Protocol Code Number:	30102012
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2014-03-19
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2012-005050-35

A.3

Full title of the trial

Phase Ib/II study of metformin in combination with carboplatin/paclitaxel chemotherapy in patients with advanced ovarian cancer

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study to evaluate the safety and effectivity of adding metformin to standard chemotherapy for advanced ovarian cancer

A.4.1

Sponsor's protocol code number

30102012

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University Medical Center Groningen
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	University Medical Center Groningen
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Medical Center Groningen
B.5.2	Functional name of contact point	Medical Oncology
B.5.3	Address:
B.5.3.1	Street Address	Hanzeplein 1
B.5.3.2	Town/ city	Groningen
B.5.3.3	Post code	9713 GZ
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	0031503616161
B.5.5	Fax number	0031503614862
B.5.6	E-mail	m.jalving@umcg.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	carboplatin
D.2.1.1.2	Name of the Marketing Authorisation holder	Hospira Benelux BVBA Antwerpen Belgie
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	carboplatin
D.3.4	Pharmaceutical form	Intravesical solution/solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Carboplatin
D.3.9.3	Other descriptive name	CARBOPLATIN
D.3.9.4	EV Substance Code	SUB06614MIG
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	paclitaxel
D.2.1.1.2	Name of the Marketing Authorisation holder	Fresenius Kabi Oncology PLC, Bordon, UK
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Paclitaxel
D.3.4	Pharmaceutical form	Intravesical solution/solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PACLITAXEL
D.3.9.1	CAS number	33069-62-4
D.3.9.4	EV Substance Code	SUB09583MIG
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Metformin
D.2.1.1.2	Name of the Marketing Authorisation holder	Pharmachemie BV, Haarlem, Netherlands
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Metformin
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	METFORMIN
D.3.9.1	CAS number	657-24-9
D.3.9.4	EV Substance Code	SUB08831MIG
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

advanced ovarian cancer

E.1.1.1

Medical condition in easily understood language

advanced ovarian cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	PT
E.1.2	Classification code	10070908
E.1.2	Term	Ovarian cancer stage IV
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	PT
E.1.2	Classification code	10070907
E.1.2	Term	Ovarian cancer stage III
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Phase I: The primary objective of this phase of the study is to determine the recommended phase II dose of metformin in combination with neoadjuvant carboplatin/paclitaxel chemotherapy in patients with advanced ovarian cancer.

Phase II: 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. Response will be measured according to the GCIG criteria incorporating RECIST 1.1 criteria and/or CA-125 levels as appropriate.

E.2.2

Secondary objectives of the trial

Phase I: The secondary objectives of this phase of the study are:
• To document the safety profile of metformin in combination with carboplatin/paclitaxel chemotherapy
• To document the influence of metformin on the pharmacokinetics of carboplatin/paclitaxel chemotherapy

Phase II: The secondary objectives of the second phase of this study are:
• To determine safety and tolerability
• To describe the effect of metformin on the likelihood of complete tumour debulking
• To describe the effect of metformin on the likelihood of complete pathological response
• To describe the effect of metformin on response in subsets of patients with measurable and non-measurable disease
• To evaluate patient outcome
• To explore the effect of metformin treatment on the tumour expression of immunohistochemical biomarkers.
• To explore the effect of metformin treatment on the levels of serum biomarkers
• To explore the concentration of metformin in tumour cells

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

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 first line treatment eligible for palliative carboplatin/paclitaxel chemotherapy (phase 1 only)
• If an exploratory laparotomy was performed at diagnosis, patients are only eligible if aggressive tumour debulking procedures were not performed. Only minimal tumour resection for the purpose of diagnosis and palliation are allowed. Aggressive tumour debulking procedures include total abdominal hysterectomy, bilateral salpingo-oophorectomy and omentectomy, with or without lymphadenectomy (phase 2 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
• Laboratory Requirements - within 7 days prior to enrolment:
• absolute neutrophil count [ANC] ≥1.5 x 109/L
• platelets > 100 x 109/L
• haemoglobin >9g/dl. Patients may be transfused or use erythropoietin to maintain haemoglobin values ≥ 9 g/dl.
• hepatic function: bilirubin ≤1.5×upper limit of normal (ULN), AST/ALT≤2.5×ULN
• estimated creatinine clearance ≥ 60ml/min
• Before patient registration/randomization, written informed consent for the trial must be given according to ICH/GCP, and national/local regulations.

E.4

Principal exclusion criteria

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.
• Evidence of any other medical conditions, physical examination or laboratory findings that may interfere with the planned treatment, affect patient compliance or place the patient at high risk from treatment related complications.

E.5 End points

E.5.1

Primary end point(s)

Phase I: Recommended phase II dose based on dose-limiting toxicities and maximum tolerated dose of metformin in combination with carboplatin/paclitaxel.

Phase II: The primary end-point 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.

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase 1: The maximum tolerated dose is 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 (6 weeks).

Phase 2: The objective response rate will be evaluated at time of CT scan after 2 cycles of treatment (6 weeks).

E.5.2

Secondary end point(s)

Phase I:
• Plasma levels of carboplatin, paclitaxel and metformin
• Worst grade of AE and laboratory events as determined by CTCAEv4 criteria

Phase II:
• All adverse events and laboratory events coded and graded by the CTCAEv3 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

E.5.2.1

Timepoint(s) of evaluation of this end point

Phase I:
• Plasma levels will be measured during the first 3 days of cycles 1 and 2
• AE and laboratory events will be measured during cycles 1 and 2

Phase II:
• AE and laboratory events during all cycles of therapy
• Percentage of complete debulking and pathological complete response at time of operation (after 3 cycles)
• Objective tumour response at time of CT-scan
• Progression free survival and overall at 6-12 months
• Exploratory translational research analyses after completion of the trial

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

first administration to humans in this combination

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

124

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-03-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-12-01

P. End of Trial
P.	End of Trial Status	Ongoing

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