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

Cervical Cancer Clinical Trial

— METOXY-LACC  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04275713
• Other study ID #: METOXY-LACC
• Status: Recruiting
• Phase: Phase 2
• Start date: May 22, 2020
• Est. completion date: September 2025

Study information

• Verified date: May 2022
• Source: Oslo University Hospital
• Contact: Kjersti Bruheim, PhD
• Phone: +4722934000
• Email: UXKJUH[@]ous-hf.no
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 90
• Est. completion date: September 2025
• Est. primary completion date: May 2025
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cervical Cancer
• Uterine Cervical Neoplasms

Intervention

Drug:
• Metformin
Metformin is an oral antidiabetic drug
• Cisplatin
Cisplatin 40 mg/m2 given intravenously once a week, maximum 6 cycles

Locations

Country	Name	City	State
Norway	Oslo University Hospital	Oslo

Sponsors (1)

Lead Sponsor	Collaborator
Oslo University Hospital

Country where clinical trial is conducted

Norway, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	baseline and one week
Secondary	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	baseline and one week
Secondary	Metformin dependent change in acute toxicity	- Physician-reported acute toxicity will be assessed with validated questionnaires (CTCAE version 3 and 4).	baseline, 4 weeks, end of treatment (about 7 weeks), 3 month follow-up
Secondary	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	Baseline and about 4 weeks