E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally advanced cervical cancer |
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E.1.1.1 | Medical condition in easily understood language |
Locally advanced cervical cancer |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008229 |
E.1.2 | Term | Cervical cancer |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The overall study objective is to investigate whether metformin can induce molecular changes, cell death and/or improved oxygenation in the tumor tissue, especially in hypoxic areas, and thereby improve tumor response with acceptable added acute toxicity. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Histologically confirmed cervical cancer (squamous cell carcinoma, adenocarcinoma and adenosquamous carcinoma)
•Planned for radical chemoradiotherapy
•Included in the MIMB-protocol
•Over 18 years
•Speaks and understands Norwegian
•ECOG 0-1
•Cervical tumor available for biopsy by gynecological examination
•Able to receive weekly cisplatin
•Able to take oral medication
•Ability to understand and willing to sign a written informed consent
•Willing to undergo biopsies of cervical tumor
•Willing to be included in the Embrace 2- protocol if randomized to the control group
•Negative pregnancy test in women with childbearing potential
•Normal bone marrow and organ function ≤ 14 days before inclusion |
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E.4 | Principal exclusion criteria |
•Evidence of distant metastasis. Suspicious paraaortic lymphnodes below the renal wessel is 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
•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
•Psychiatric illness /social situations limiting study compliance
•Prior radiotherapy to the pelvis
•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
•Patients with other invasive malignancies except non-melanoma skin cancers
•Known HIV-positive patients on antiretroviral therapy
•Known conditions limiting absorption of study drug (bowel obstruction, malabsorption syndromes)
•Patients taking the drug disulfiram (antabus)
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E.5 End points |
E.5.1 | Primary end point(s) |
To determine if one week of metformin treatment can change tumor hypoxia-related gene expression signature |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluated after one week of metformin prior to start of chemoradiotherapy. |
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E.5.2 | Secondary end point(s) |
1. To detect changes in tumor cell density, extracellular space, vascularity and hypoxia evaluated by DW- and DCE-MRI after one week of metformin before start of chemoradiotherapy.
2. To determine if metformin- treated patients have increased tumor shrinkage during external radiation treatment, estimated by the percentage decrease in tumor volume on T2W- and DW-MRI at the time of brachytherapy.
3. To determine acute toxicity following metformin and chemoradiotherapy.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. After one week of metformin prior to start of chemoradiotherapy.
2. At the time of brachytherapy.
3. Ongoing |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
possible change of hypoxia gene score |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
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 | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Standard chemotherapy alone |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |