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

NCT04275713 | Completed Phase 2 DMC

• 1 other identifier: METOXY-LACC
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 1

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.

Conditions

Cervical Cancer

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Metformin dependent changes in MRI-parameters.

  baseline and one week

• Metformin dependent change in acute toxicity

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

• Metformin dependent change in tumor volume during treatment

  Baseline and about 4 weeks

Study Arms (2)

Standard Chemoradiotherapy +/- metformin

EXPERIMENTAL

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

Drug: Metformin; Drug: Cisplatin

Standard chemoradiotherapy

ACTIVE COMPARATOR

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)

Drug: Cisplatin

Interventions

Metformin DRUG

Metformin is an oral antidiabetic drug

Standard Chemoradiotherapy +/- metformin

Cisplatin DRUG

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

Standard Chemoradiotherapy +/- metformin; Standard chemoradiotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Oslo University Hospital: lead

Study Sites (1)

Oslo University Hospital

Oslo, 0379, Norway

Location

MeSH Terms

Conditions

Uterine Cervical Neoplasms

Interventions

Metformin; Cisplatin

Condition Hierarchy (Ancestors)

Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds

Study Officials

• Kjersti Bruheim, PhD

  Oslo University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal investigator

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

Study Record Dates

• First Submitted: February 12, 2020
• First Posted: February 19, 2020
• Study Start: May 22, 2020
• Primary Completion: June 11, 2024
• Study Completion: November 8, 2024
• Last Updated: January 20, 2025

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

NO (1)