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

• ClinicalTrials.gov Identifier: NCT02115464
• Recruitment Status: Terminated
• First Posted: April 16, 2014
• Last Update Posted: April 22, 2020
• Sponsor: Ontario Clinical Oncology Group (OCOG)
• Collaborator: Canadian Institutes of Health Research (CIHR)
• Information provided by (Responsible Party): Ontario Clinical Oncology Group (OCOG)

Tracking Information

• First Submitted Date: April 14, 2014
• First Posted Date: April 16, 2014
• Last Update Posted Date: April 22, 2020
• Actual Study Start Date: December 17, 2014
• Actual Primary Completion Date: March 9, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 14, 2014)

Progression free survival [ Time Frame: 12 months ]

Progression free survival illustrates loco-regional disease control and freedom from distant metastasis

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: January 28, 2016)

• Overall survival [ Time Frame: 18-24 months ]
  Overall survival will be defined from the date of randomization until the date of death due to any cause.
• Time to loco-regional progression [ Time Frame: 18-24 months ]
  Time to loco-regional progression is defined from the date of randomization until the date of confirmed loco-regional progression
• Distant progression-free survival [ Time Frame: 18-24 months ]
  Distant progression-free survival is defined from the date of randomization until the date of distant progression, or death due to any cause.
• Toxicities [ Time Frame: 12 months plus 30 days ]
  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.

Original Secondary Outcome Measures (submitted: April 14, 2014)

• Overall survival [ Time Frame: 18-24 months ]
  Overall survival will be defined from the date of randomization until the date of death due to any cause.
• Time to loco-regional progression [ Time Frame: 18-24 months ]
  Time to loco-regional progression is defined from the date of randomization until the date of confirmed loco-regional progression
• Distant progression-free survival [ Time Frame: 18-24 months ]
  Distant progression-free survival is defined from the date of randomization until the date of distant progression, or death due to any cause.
• Toxicities [ Time Frame: 12 months plus 30 days ]
  Adverse event reporting period begins from the time of the first dose of Metformin and ends 30 days after the last dose. Only adverse events assessed as Grade 3 or higher will be documented.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Advanced Lung Cancer Treatment With Metformin and Chemo-Radiotherapy
• 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Lung Cancer

Intervention

• 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 Name: Metformin Hydrochloride
• Radiation: Chemo-radiotherapy
  Cisplatin-based chemotherapy with or without consolidation with standard radiotherapy of 60-63 Gy for 6 weeks.

Study Arms

• 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.
  Intervention: Drug: Metformin plus Chemo-radiotherapy
• Active Comparator: Chemo-radiotherapy
  Concurrent cisplatin based chemotherapy with or without consolidation and radiotherapy of 60-63 Gy for 6 weeks.
  Intervention: Radiation: Chemo-radiotherapy

• 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.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: March 8, 2019): 54
• Original Estimated Enrollment (submitted: April 14, 2014): 94
• Actual Study Completion Date: April 21, 2020
• Actual Primary Completion Date: March 9, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada

Administrative Information

• NCT Number: NCT02115464
• Other Study ID Numbers: OCOG-2014-ALMERA
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Ontario Clinical Oncology Group (OCOG)
• Original Responsible Party: Same as current
• Current Study Sponsor: Ontario Clinical Oncology Group (OCOG)
• Original Study Sponsor: Same as current
• Collaborators: Canadian Institutes of Health Research (CIHR)

Investigators

• Principal Investigator: Theodoros Tsakiridis, MD; Juravinski Cancer Centre, Hamilton, Ontario, Canada

• PRS Account: Ontario Clinical Oncology Group (OCOG)
• Verification Date: April 2020