The Potential for Metformin to Improve Tumor Oxygenation in Locally Advanced Cervix Cancer: A Phase II Randomized Trial

Sponsor

University Health Network, Toronto (Other)

Overall Status

Completed

CT.gov ID

NCT02394652

Collaborator

(none)

Enrollment

Locations

Arms

67.8

Actual Duration (Months)

3.2

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Cervical cancer remains an important health problem worldwide. Poor tumor oxygenation (hypoxia) is associated with inferior survival in cervical cancer and resistance to radiation treatment. Hypoxia-modifying therapies improve survival, but existing therapies are impractical and/or toxic. Metformin, a non-toxic drug for diabetes, has been shown to decrease tumor hypoxia in animal studies and its use is associated with better survival in diabetic cancer patients. It is hypothesized that metformin may decrease cervical tumor hypoxia and thereby improve tumor response to radiation and survival in patients with locally advanced cervix cancer.

This is a randomized, multicenter phase II study of standard chemoradiation in combination with metformin versus standard chemoradiation alone in women with locally advanced cervix cancer. Women randomized to the metformin group will take metformin starting 1 week prior to standard chemoradiation and throughout the duration of external radiation treatment. Tumor hypoxia will be measured by a special X-ray test called positron emission test (PET) performed with a hypoxia dye called FAZA. The main purpose of this study is to see if metformin decreases tumor hypoxia measured on FAZA-PET; information about response and side effects will also be collected.

Condition or Disease	Intervention/Treatment	Phase
Uterine Cervical Neoplasms Squamous Cell Carcinoma Adenocarcinoma Carcinoma, Adenosquamous	Drug: Metformin Drug: Cisplatin Drug: FAZA	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

16 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

The Potential for Metformin to Improve Tumor Oxygenation in Locally Advanced Cervix Cancer: A Phase II Randomized Trial

Actual Study Start Date :

May 21, 2015

Actual Primary Completion Date :

Jan 12, 2021

Actual Study Completion Date :

Jan 12, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental: Metformin with Standard Chemoradiation Metformin: About 1 week prior to the start of chemoradiation, take 850 mg of metformin, orally, once a day for 3 days, followed by 850 mg twice a day and continued for the duration of external radiation. Chemoradiation: Cisplatin will be given intravenously at 40 mg/m2 week for 5 doses, concomitantly with external beam radiation. FAZA-PET scan at baseline and after about 1 week of metformin (just prior to the start of chemoradiation)	Drug: Metformin Metformin is an antidiabetic agent given orally. Drug: Cisplatin Cisplatin is an antineoplastic agent given intravenously. Drug: FAZA FAZA is an investigational imaging agent for positron emission tomography scans indicated for hypoxia. Other Names: 18F-Fluoroazomycin arabinoside
Active Comparator: Standard Chemoradiation Chemoradiation: Cisplatin will be given intravenously at 40 mg/m2 week for 5 doses, concomitantly with external beam radiation. FAZA-PET scan at baseline and about 1 week later (just prior to the start of chemoradiation).	Drug: Cisplatin Cisplatin is an antineoplastic agent given intravenously. Drug: FAZA FAZA is an investigational imaging agent for positron emission tomography scans indicated for hypoxia. Other Names: 18F-Fluoroazomycin arabinoside

Arm

Intervention/Treatment

Experimental: Experimental: Metformin with Standard Chemoradiation

Metformin: About 1 week prior to the start of chemoradiation, take 850 mg of metformin, orally, once a day for 3 days, followed by 850 mg twice a day and continued for the duration of external radiation. Chemoradiation: Cisplatin will be given intravenously at 40 mg/m2 week for 5 doses, concomitantly with external beam radiation. FAZA-PET scan at baseline and after about 1 week of metformin (just prior to the start of chemoradiation)

Drug: Metformin

Metformin is an antidiabetic agent given orally.

Drug: Cisplatin

Cisplatin is an antineoplastic agent given intravenously.

Drug: FAZA

FAZA is an investigational imaging agent for positron emission tomography scans indicated for hypoxia.

Other Names:

18F-Fluoroazomycin arabinoside

Active Comparator: Standard Chemoradiation

Chemoradiation: Cisplatin will be given intravenously at 40 mg/m2 week for 5 doses, concomitantly with external beam radiation. FAZA-PET scan at baseline and about 1 week later (just prior to the start of chemoradiation).

Drug: Cisplatin

Cisplatin is an antineoplastic agent given intravenously.

Drug: FAZA

FAZA is an investigational imaging agent for positron emission tomography scans indicated for hypoxia.

Other Names:

18F-Fluoroazomycin arabinoside

Outcome Measures

Primary Outcome Measures

• Change in fractional hypoxic volume of the tumor on FAZA-PET scan before and after 1 week of metformin. [About 7 days]

Secondary Outcome Measures

Disease-free survival [2 years]
Acute and late gastrointestinal and genitourinary toxicities following metformin and chemoradiation. [2 years]
Effect of metformin on endogenous hypoxia and other markers. [About 7 days]
Biomarkers of response to metformin. [2 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma of the cervix, FIGO stage IB2-IVA
Planned for radical radiotherapy and concurrent cisplatin chemotherapy.
Able to receive weekly cisplatin.
No prior anticancer treatment for cervical cancer
ECOG 0 or 1
Life expectancy of greater than 3 months.
Normal organ and marrow function
Able to take oral medications.
Ability to understand and willing to sign the consent form
Willing to undergo biopsies of cervical tumor.

Exclusion Criteria:

Evidence of distant metastases
Receiving any other investigational agents concurrently or within 4 weeks.
Known diabetes mellitus.
Currently taking metformin, sulfonylureas, thiazolidinediones or insulin.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to metformin or cisplatin.
Any condition associated with increased risk of metformin-associated lactic acidosis
Uncontrolled inter-current illness
Pregnant women
History of another invasive malignancy, except for non-melanoma skin cancer or tumors curatively treated with no evidence of disease for >=5 years.
Known HIV-positive
History of bowel obstruction or malabsorption syndromes
History of active clinically significant bleeding
Contraindications to radiotherapy
Taking drug disulfiram (antabuse).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2N 4N2
2	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
3	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G 2M9
4	Hôpital Maisonneuve-Rosemont	Montréal	Quebec	Canada	H1T 2M4
5	Centre Hospitalier De L'Université de Montréal	Montréal	Quebec	Canada	H2L 4M1