Advanced Lung Cancer Treatment With Metformin and Chemo-Radiotherapy

Study Overview
=================
Brief Summary
-----------------
ALMERA is a randomized, phase II, open label study in patients with locally advanced non-small cell lung cancer (NSCLC) which will compare standard radiotherapy plus concurrent chemotherapy with or without consolidation versus the same treatment plus concurrent Metformin continuing for 12 months. Metformin is a well tolerated and inexpensive drug that has the potential to improve cancer patient outcomes.

Detailed Description
-----------------
This is a randomized, phase II, open label study in patients with locally advanced NSCLC which will compare standard RT (60-63 Gy for 6 weeks) plus concurrent Cisplatin-based chemotherapy (CRT) with or without consolidation (standard arm) vs the same CRT with or without consolidation plus treatment with Metformin concurrent with CRT and continuing for a total of 12 months (experimental arm). Ninety-four eligible and consenting patients will be randomized to one of the two treatment arms. Patients randomized to the experimental arm will receive Metformin (2000 mg/day) for a period of 12 months. Patients will be continuously evaluated for toxicity, will be assessed weekly at clinic visits during concurrent CRT treatment with or without consolidation and at follow up clinic visits at 3, 6, 9 and 12 months (from the date of randomization). Disease progression will be evaluated every 3 months for up to 12 months. All patients will be followed for up to 24 months (2 years) for survival. The primary objective of this study is to determine the effect of Metformin on the proportion of patients free of disease progression at 12 months after initiation of drug treatment.

Official Title
-----------------
A Phase II Study to Investigate a Combination of Metformin With Chemo-Radiotherapy in Patients With Locally Advanced Non-Small Cell Lung Cancer

Conditions
-----------------
Lung Cancer

Intervention / Treatment
-----------------
* Drug: Metformin plus Chemo-radiotherapy
* Radiation: Chemo-radiotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age >/=18 to </= 80 years of age. Unresected and pathologically (histologic) proven Stage 3a or Stage 3b NSCLC of adenocarcinoma, squamous cell, large cell or mixed histology, diagnosed within three months of study randomization. Non-metastatic disease staged by: CT-chest and upper abdomen, brain MRI or contrast-enhanced CT within 12 weeks and physical examination and whole body FDG-PET/CT scan within 8 weeks prior to study randomization. Exclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status >2. More than 10% weight loss in the past 3 months. Diabetic patient or anyone currently taking Metformin, insulin or other anti-hyperglycemic therapy. Pulmonary Function Test (PFTs) (within the last 12 weeks) with Forced Expiratory Volume (FEV)1 < 1.2 litres per second or less than 50% of predicted. Complete Blood Count (CBC) and biochemical renal and liver function profiles that do not permit chemotherapy treatment (as per institutional standard of care). Fasting blood sugar levels of >/= 7.0 mmol per litre (within the last 12 weeks). Prior systemic chemotherapy for lung cancer. Prior radiotherapy that would overlap with the planned treatment area. Prior invasive malignancy within the past 3 years (except non-melanomatous skin cancer non-invasive carcinoma in-situ of the breast, oral cavity or cervix). Known Acquired Immune Deficiency Syndrome (AIDS). Patients with increased risk for lactic acidosis: severe congestive heart failure (NYHA: class III or IV), history of metabolic acidosis, alcoholic intake of > 3 drinks daily, severe liver disease, renal failure Known hypersensitivity or allergy to Metformin. Known pregnancy or lactating female patient. Geographic inaccessibility for follow-up. Inability to provide informed consent.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin plus Chemo-radiotherapy<br>Metformin orally 500 mg twice daily for the first week, 1500 mg a day in week 2 and 2000 mg a day at week 3 and then for a period of 12 months. Cisplatin-based chemotherapy with or without consolidation with standard radiotherapy of 60-63 Gy for 6 weeks. | Drug: Metformin plus Chemo-radiotherapy<br>* Metformin 2000 mg a day for 12 months plus cisplatin-based chemotherapy with or without consolidation with standard radiotherapy of 60-63 Gy for 6 weeks.<br>* Other names: Metformin Hydrochloride;|
| Active Comparator: Chemo-radiotherapy<br>Concurrent cisplatin based chemotherapy with or without consolidation and radiotherapy of 60-63 Gy for 6 weeks. | Radiation: Chemo-radiotherapy<br>* Cisplatin-based chemotherapy with or without consolidation with standard radiotherapy of 60-63 Gy for 6 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Progression free survival illustrates loco-regional disease control and freedom from distant metastasis | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival will be defined from the date of randomization until the date of death due to any cause. | 18-24 months | 
| Time to loco-regional progression | Time to loco-regional progression is defined from the date of randomization until the date of confirmed loco-regional progression | 18-24 months | 
| Distant progression-free survival | Distant progression-free survival is defined from the date of randomization until the date of distant progression, or death due to any cause. | 18-24 months | 
| Toxicities | The adverse event reporting period begins from the time of randomization and ends 30 days after the last treatment (concurrent chemo-radiotherapy plus or minus Metformin). Only adverse events assessed as Grade 3 or higher will be documented. | 12 months plus 30 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Metformin, Non-small cell lung cancer, Locally advanced, Chemo-radiotherapy, Lung cancer treatment