Advanced Lung Cancer Treatment With Metformin and Chemo-Radiotherapy (ALMERA)

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

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.

Study Overview

• Status: Terminated
• Conditions: Lung Cancer
• Intervention / Treatment: Drug: Metformin plus Chemo-radiotherapy; Radiation: Chemo-radiotherapy

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.

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada
      • Cross Cancer Institute
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Ontario
    • Hamilton, Ontario, Canada
      • Juravinski Cancer Centre
    • Kingston, Ontario, Canada
      • Cancer Centre of Southeastern Ontario At Kingston General Hospital
    • Kitchener, Ontario, Canada
      • Grand River Regional Cancer Centre
    • St. Catharines, Ontario, Canada
      • Walker Family Cancer Centre - Niagara Health System
  • Quebec
    • Montreal, Quebec, Canada
      • Montreal General Hospital - McGill

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age >/=18 to </= 80 years of age.
2. 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.
3. 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:

1. Eastern Cooperative Oncology Group (ECOG) performance status >2.
2. More than 10% weight loss in the past 3 months.
3. Diabetic patient or anyone currently taking Metformin, insulin or other anti-hyperglycemic therapy.
4. 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.
5. Complete Blood Count (CBC) and biochemical renal and liver function profiles that do not permit chemotherapy treatment (as per institutional standard of care).
6. Fasting blood sugar levels of >/= 7.0 mmol per litre (within the last 12 weeks).
7. Prior systemic chemotherapy for lung cancer.
8. Prior radiotherapy that would overlap with the planned treatment area.
9. 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).
10. Known Acquired Immune Deficiency Syndrome (AIDS).

11. 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
12. Known hypersensitivity or allergy to Metformin.
13. Known pregnancy or lactating female patient.
14. Geographic inaccessibility for follow-up.
15. Inability to provide informed consent.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin plus Chemo-radiotherapy; 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; 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.; Other Names: Metformin Hydrochloride
Active Comparator: Chemo-radiotherapy; Concurrent cisplatin based chemotherapy with or without consolidation and radiotherapy of 60-63 Gy for 6 weeks.	Radiation: Chemo-radiotherapy; Cisplatin-based chemotherapy with or without consolidation with standard radiotherapy of 60-63 Gy for 6 weeks.

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

Collaborators and Investigators

• Sponsor: Ontario Clinical Oncology Group (OCOG)
• Collaborators: Canadian Institutes of Health Research (CIHR)
• Investigators: Principal Investigator: Theodoros Tsakiridis, MD, Juravinski Cancer Centre, Hamilton, Ontario, Canada

Publications and helpful links

General Publications

• Tsakiridis T, Pond GR, Wright J, Ellis PM, Ahmed N, Abdulkarim B, Roa W, Robinson A, Swaminath A, Okawara G, Wierzbicki M, Valdes M, Levine M. Metformin in Combination With Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer: The OCOG-ALMERA Randomized Clinical Trial. JAMA Oncol. 2021 Sep 1;7(9):1333-1341. doi: 10.1001/jamaoncol.2021.2328.

Study record dates

Study Major Dates

• Study Start (Actual): December 17, 2014
• Primary Completion (Actual): March 9, 2020
• Study Completion (Actual): April 21, 2020

Study Registration Dates

• First Submitted: April 14, 2014
• First Submitted That Met QC Criteria: April 14, 2014
• First Posted (Estimate): April 16, 2014

Study Record Updates

• Last Update Posted (Actual): April 22, 2020
• Last Update Submitted That Met QC Criteria: April 21, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Metformin; Non-small cell lung cancer; Locally advanced; Lung cancer treatment; Chemo-radiotherapy
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: OCOG-2014-ALMERA

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No