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Altered Tumor Oxygenation by Metformin, a Potential Step in Overcoming Radiotherapy Resistance in LACC (METOXY-LACC)

Primary Purpose

Cervical Cancer

Status

Recruiting

Phase

Phase 2

Locations

Norway

Study Type

Interventional

Intervention

Metformin

Cisplatin

About this trial

This is an interventional treatment trial for Cervical Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

Histologically confirmed cervical cancer (squamous cell carcinoma, adenocarcinoma and adenosquamous carcinoma)
- Planned for radical chemoradiotherapy
- Over 18 years
- Speaks and understands Norwegian
- ECOG 0-1
- Cervical tumor available for biopsy by gynecological examination
- Hemoglobin ≥ 9 g/dL (blood transfusions are allowed)
- Leukocytes ≥ 3,5 x 10^9/L 18
- Absolute neutrophil count ≥ 1,5 x 10^9/L
- Platelets ≥ 100 x 10^9/L
- Total bilirubin ≤ 25 umol/L
- AST/ALT ≤ 2,5 x institutional upper limit
- Creatinine ≤ 90 or creatinine clearance ≥ 60 ml/min/1.73m2 Patients with elevated creatinine secondary to hydronephrosis may be eligible if renal function returns to normal after inserting an internal stent or nephrostomy
- Women of childbearing potential (WOCBP) should have a negative highly sensitive serum pregnancy test within 72 hours prior to receiving the first dose of study medication.

Exclusion Criteria:

Evidence of distant metastasis. Suspicious paraaortic lymph nodes below the renal vessel are allowed if they are covered by the radiation field
Patients who have received other cancer treatments for their cervical cancer
Patients who receive other experimental drugs
Known diabetes mellitus
Currently taking Metformin or any other antidiabetic drugs (sulfonylureas, thiazolidinediones, insulin)
History of allergic reaction attributed to compounds of similar chemical or biologic composition to metformin
Contraindications such as
- Hypersensitivity to the active substance or to any of the excipients listed Section 6.1.
- Severe renal failure (GFR <30 ml / min).
- Acute conditions leading to the risk of renal impairment, eg: dehydration, severe infectious conditions, shock.
- Disease that can cause tissue hypoxia (especially acute illness or exacerbation of chronic illness), such as: acute decompensated heart failure, lung failure, recent heart attack, shock.
- Liver failure, acute alcohol intoxication, alcoholism.
Any condition associated with increased risk of metformin- induced lactic acidosis (congestive heart failure defined as New York Heart Association (NYHA) class III or IV functional status, history of acidosis of any kind)
Uncontrolled intercurrent somatic illness including, but not limited to, ongoing or active serious infections, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, myocardial infarction within 6 months and cerebrovascular disease with previous stroke
Already on medication with increased risk of lactic acidosis
Patients who are pregnant or breastfeeding are excluded due to risk of teratogenic and abortifacient effects of radiotherapy and cisplatin, and the potential risk of adverse effect of nursing infants

Sites / Locations

Oslo University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Standard Chemoradiotherapy +/- metformin

Standard chemoradiotherapy

Arm Description

Metformin will be given orally at doses of 850 mg twice a day. Metformin will be started one week prior to the start of standard cisplatin-based chemoradiotherapy, and will be continued throughout the entire radiation treatment

Standard chemoradiotherapy is given as a combination of EBRT and IGT: 45 Gy in 1.8 Gy/fraction to the pelvis/abdomen, 5 fractions/week 55-57.5 Gy in 2.2-2.3 Gy/fraction to pathological lymph nodes as a simultaneously integrated boost (SIB) 4 fractions of brachytherapy, 7.8 Gy/fraction, to the cervix Concomitant Cisplatin weekly during the external beam radiotherapy (EBRT)

Outcomes

Primary Outcome Measures

Metformin dependent changes in hypoxia-related gene expression.

A hypoxia related 6-gene expression signature analyzed by RNA-sequencing will be obtained before and after one week of metformin The signature consist of the following six genes: ERO1A, DDIT3, KCTD11, P4HA2, STC2, UPK1A

Secondary Outcome Measures

Metformin dependent changes in MRI-parameters.

Diffusion-weighted MRI and Dynamic Contrast-Enhanced MRI will be obtained before and after one week of metformin. Hypoxic tumor fraction on MRI will be calculated using the combined information from DWI- and DCE-MRI

Metformin dependent change in acute toxicity

- Physician-reported acute toxicity will be assessed with validated questionnaires (CTCAE version 3 and 4).

Metformin dependent change in tumor volume during treatment

- Tumor volume will be measured on T2W-MRI before the start of treatment and at the first fraction of brachytherapy

Full Information

NCT ID

NCT04275713

First Posted

February 12, 2020

Last Updated

May 2, 2022

Sponsor

Oslo University Hospital

1. Study Identification

Unique Protocol Identification Number

NCT04275713

Brief Title

Altered Tumor Oxygenation by Metformin, a Potential Step in Overcoming Radiotherapy Resistance in LACC

Acronym

METOXY-LACC

Official Title

Altered Tumor Oxygenation by Metformin, a Potential Step in Overcoming Radiotherapy Resistance in Locally Advanced Cervical Cancer.

Study Type

Interventional

2. Study Status

Record Verification Date

May 2022

Overall Recruitment Status

Recruiting

Study Start Date

May 22, 2020 (Actual)

Primary Completion Date

May 2025 (Anticipated)

Study Completion Date

September 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Oslo University Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

Poor tumor oxygenation (hypoxia) is an established negative prognostic and predictive factor in locally advanced cervical cancer (LACC). Hypoxia-modifying measures implemented in the clinic are lacking. Metformin is a well-known, well-tolerated and low-cost drug used for decades in the treatment of type 2- diabetes. Recent studies suggest an improved tumor oxygenation by metformin potentially improving radiotherapy response and patient outcome. This study is a randomized, phase II, open label study in patients with LACC where patients are randomized to standard cisplatin-based chemoradiotherapy +/- Metformin. Metformin will be started one week prior to the start of chemoradiotherapy, and will be continued throughout the entire radiation treatment. Tumor oxygenation will be evaluated by gene signatures and MRI- parameters.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cervical Cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

Patients are randomized to intervention Group (metformin in combination with radiotherapy) or standard of care.

Masking

None (Open Label)

Allocation

Randomized

Enrollment

90 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Standard Chemoradiotherapy +/- metformin

Arm Type

Experimental

Arm Description

Arm Title

Standard chemoradiotherapy

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Metformin

Intervention Description

Metformin is an oral antidiabetic drug

Intervention Type

Drug

Intervention Name(s)

Cisplatin

Intervention Description

Cisplatin 40 mg/m2 given intravenously once a week, maximum 6 cycles

Primary Outcome Measure Information:

Title

Metformin dependent changes in hypoxia-related gene expression.

Description

Time Frame

baseline and one week

Secondary Outcome Measure Information:

Title

Metformin dependent changes in MRI-parameters.

Description

Time Frame

baseline and one week

Title

Metformin dependent change in acute toxicity

Description

- Physician-reported acute toxicity will be assessed with validated questionnaires (CTCAE version 3 and 4).

Time Frame

baseline, 4 weeks, end of treatment (about 7 weeks), 3 month follow-up

Title

Metformin dependent change in tumor volume during treatment

Description

- Tumor volume will be measured on T2W-MRI before the start of treatment and at the first fraction of brachytherapy

Time Frame

Baseline and about 4 weeks

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Histologically confirmed cervical cancer (squamous cell carcinoma, adenocarcinoma and adenosquamous carcinoma) Planned for radical chemoradiotherapy Over 18 years Speaks and understands Norwegian ECOG 0-1 Cervical tumor available for biopsy by gynecological examination Hemoglobin ≥ 9 g/dL (blood transfusions are allowed) Leukocytes ≥ 3,5 x 10^9/L 18 Absolute neutrophil count ≥ 1,5 x 10^9/L Platelets ≥ 100 x 10^9/L Total bilirubin ≤ 25 umol/L AST/ALT ≤ 2,5 x institutional upper limit Creatinine ≤ 90 or creatinine clearance ≥ 60 ml/min/1.73m2 Patients with elevated creatinine secondary to hydronephrosis may be eligible if renal function returns to normal after inserting an internal stent or nephrostomy Women of childbearing potential (WOCBP) should have a negative highly sensitive serum pregnancy test within 72 hours prior to receiving the first dose of study medication. Exclusion Criteria: Evidence of distant metastasis. Suspicious paraaortic lymph nodes below the renal vessel are allowed if they are covered by the radiation field Patients who have received other cancer treatments for their cervical cancer Patients who receive other experimental drugs Known diabetes mellitus Currently taking Metformin or any other antidiabetic drugs (sulfonylureas, thiazolidinediones, insulin) History of allergic reaction attributed to compounds of similar chemical or biologic composition to metformin Contraindications such as Hypersensitivity to the active substance or to any of the excipients listed Section 6.1. Severe renal failure (GFR <30 ml / min). Acute conditions leading to the risk of renal impairment, eg: dehydration, severe infectious conditions, shock. Disease that can cause tissue hypoxia (especially acute illness or exacerbation of chronic illness), such as: acute decompensated heart failure, lung failure, recent heart attack, shock. Liver failure, acute alcohol intoxication, alcoholism. Any condition associated with increased risk of metformin- induced lactic acidosis (congestive heart failure defined as New York Heart Association (NYHA) class III or IV functional status, history of acidosis of any kind) Uncontrolled intercurrent somatic illness including, but not limited to, ongoing or active serious infections, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, myocardial infarction within 6 months and cerebrovascular disease with previous stroke Already on medication with increased risk of lactic acidosis Patients who are pregnant or breastfeeding are excluded due to risk of teratogenic and abortifacient effects of radiotherapy and cisplatin, and the potential risk of adverse effect of nursing infants

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Kjersti Bruheim, PhD

Phone

+4722934000

UXKJUH@ous-hf.no

First Name & Middle Initial & Last Name or Official Title & Degree

Kjersti Skipar, MD

Phone

+4722934000

kjerstiskipar@gmail.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Kjersti Bruheim, PhD

Organizational Affiliation

Oslo University Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Oslo University Hospital

City

Oslo

ZIP/Postal Code

0379

Country

Norway

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Kjersti Bruheim, PhD

12. IPD Sharing Statement

Learn more about this trial

Altered Tumor Oxygenation by Metformin, a Potential Step in Overcoming Radiotherapy Resistance in LACC

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