METformin With a Cargohydrate Restricted Diet in Combination With Platinum Based Chemotherapy in Stage IIIB/IV Non-squamous Non-small Cell Lung Cancer

Carcinoma, Non-squamous Non-small-cell Lung Clinical Trial

Official title:

METformin With a Carbohydrate Restricted Diet in Combination With Platinum Based Chemotherapy in Stage IIIB/IV Non-squamous Non-small Cell Lung Cancer (NS-NSCLC) - METRO Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02254512
• Other study ID #: 090-13
• Status: Recruiting
• Phase: Phase 2
• First received: September 25, 2014
• Last updated: November 22, 2016
• Start date: September 2013
• Est. completion date: September 2017

Study information

• Verified date: November 2016
• Source: Beth Israel Medical Center
• Contact: Benjamin Levy, MD
• Phone: 212-604-6017
• Email: belevy[@]chpnet.org
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

Subjects, who are eligible for the study, will be treated with four cycles of carboplatin AUC of 5 IV and pemetrexed 500mg/m2 IV every 21 days +/- 2 days as per the standard of care. Subjects who have not progressed after four cycles by radiological assessment (partial response or stable disease) will receive single agent pemetrexed 500mg/m2 IV q 21 days +/- 2 days as maintenance therapy and as the standard of care until disease progression or subject cannot tolerate.

Metformin will be given as 500 mg pills starting on day 1 of chemotherapy. Starting dose will 500mg po bid (1000mg/day). If tolerating (see below for dose reduction), the dose will be escalated to 1000mg po qam and 500mg po qpm (1500mg/day) from days 8 to 14. If still tolerating, the dose will be escalated to 2 500mg pills twice a day for a total dose of 2000mg/day from days 15 until end of the study. This dose has been found to be safe in healthy controls and in subjects treated with chemotherapy.

Description:

Metformin, an oral biguanide agent used for the treatment of non-insulin-dependent diabetes mellitus, is now prescribed to more than 120 million people worldwide. Its glucose lowering effects result from both inhibition of liver gluconeogenesis and increased insulin sensitivity in peripheral tissue[5]. Metformin has limited adverse effects with little or no risk of hypoglycemia in healthy, nondiabetic controls. In addition to its anti-diabetic properties, metformin has demonstrated both chemopreventative and therapeutic effects in both prostate and breast cancer.

The role of metformin as a preventative and therapeutic agent in lung cancer is beginning to be assessed. A recent epidemiological study from Taiwan demonstrated a 39-45% decreased risk of lung cancer in diabetic patients being treated with antidiabetic drugs including metformin versus those not taking these agents[12]. These studies have triggered preclinical and clinical observational trials that further support metformin's potential as an antineoplastic agent. Two observational studies in humans have reinforced metformin's potential role as a therapeutic agent in lung cancer. In the first, Mezzone et al. showed that diabetic patients with lung cancer previously treated with metformin or thiazolidinediones had a lower incidence of metastatic disease at the time of diagnosis and a reduced risk of death compared to those who did not receive the same treatment[15]. More recently, a retrospective study performed by Tan et al. evaluated the outcomes of three groups of diabetic patients with NSCLC treated with first line chemotherapy and receiving various diabetic drugs. In this study, patients treated with chemotherapy with metformin had superior outcomes compared to those patients treated with chemotherapy with insulin or with drugs other than metformin (OS, 20 months vs. 13.1 months vs 13.0 months, respectively, p=0.007)[16]. The remarkable activity of this agent in both preclinical and clinical lung cancer models as well as its low toxicity and tolerability in non- diabetic patients warrants further prospective studies evaluating the therapeutic efficacy with platinum based chemotherapy in NSCLC.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: September 2017
• Est. primary completion date: June 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• • Able to provide written consent and is amenable to compliance with protocol schedules and testing

• Subject is > 18 years of age

• Pathologically proven (either histologic or cytologic) diagnosis of Stage IIIB or IV non-squamous non-small cell lung cancer

• No prior, palliative chemotherapy for stage IV lung cancer Subjects who have received adjuvant chemotherapy post surgery for curative intent more than 12 months prior to development of stage IV disease are allowed.

• Measurable disease as RECIST criteria 1.1 (Response Evaluation Criteria in Solid Tumors, Version 1.1)

• CT Scan of the chest/abdomen/pelvis or PET Scan within 30 days of study entry

• An MRI of the brain or Head CT Scan with contrast within 30 days of study entry if clinically indicated

• ECOG Performance Status 0-2.

• CBC/differential obtained within 2 weeks prior to registration on study, with adequate bone marrow function defined as follows:

• Absolute neutrophil count (ANC) >1,500 cells/ul

• Platelets > 100,000 cells/ul

• Hemoglobin > 9.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb > g/dl is acceptable.)

• Serum creatinine < 1.5 x ULN

• Total bilirubin < 2.0 times the institutional Upper Limit of Normal (ULN)

• AST and ALT < 3.0 x the ULN

• Women of childbearing potential must have:

• A negative serum or urine pregnancy test (sensitivity </=25IU HCG/L) within 14 days prior to the start of study drug administration

• Persons of reproductive potential must agree to use and utilize an adequate method of contraception throughout treatment and for at least 90 days after study drug is stopped prior to study enrollment, women of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy.

• Ability to take oral medication

Exclusion Criteria:

• • The subject has a diagnosis of squamous cell carcinoma. Adenosquamous (mixed) histologies are allowed

• The subject has a history of type I or type II diabetes

• Weight of less than 80% of (IBW) ideal body weight

• Creatinine clearance less than 45 l/min as calculated by the Cockcroft-Gault equation

• Known EGFR or ALK mutation in which targeted therapy with erlotinib or crizotinib would be the standard of care. Those subjects whose tissue is not tested or have insufficient material are eligible

• The subject is currently taking or has previously taken metformin in the past 6 months

• The subject has received previous chemotherapy for NSCLC except in instances of adjuvant therapy post surgical resection more than 12 months prior to enrollment

• The subject has undergone major surgery within four weeks prior to randomization.

• The subject has undergone palliative radiation (chest, brain) to tumor sites within two weeks of randomization (except palliative radiation to the bone which can be within one week

• Uncontrolled (untreated) brain metastasis.

• Subject who has NCI-CTCAE Version 4 Grade > 2 diarrhea

• That subject has clinically relevant CAD or uncontrolled CHF

• The subject has ongoing or active infection (requiring antibiotics) that would limit the administration of chemotherapy including active TB. HIV is allowed in this study

• The subject has a history of neurological or psychological disorder that may interfere with the compliance of the protocol

• Women who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 weeks after cessation of study drug, or have a positive pregnancy test at baseline, or are pregnant or breastfeeding

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Carcinoma, Non-squamous Non-small-cell Lung
• Lung Neoplasms

Intervention

Drug:
• Metformin
Metformin by mouth twice daily with meals
• Carboplatin
Carboplatin AUC of 5, IV day 1 of every 21 days times 4 cycles
• Pemetrexed
Pemetrexed 500 mg/m2, IV day 1 of every 21 days until PD

Locations

Country	Name	City	State
United States	Moun Sinai Beth Israel Comprehensive Cancer Center	New York	New York
United States	Mount Sinai Beth Israel Phillips Ambulatory Care Center	New York	New York
United States	Mount Sinai Roosevelt	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Beth Israel Medical Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To determine the safety and efficacy (progression free survival)	To determine the safety and efficacy (progression free survival) of metformin and a carbohydrate restricted diet in addition to standard platinum-pemetrexed based chemotherapy for advanced stage (IIIB/IV) non-squamous, non-small cell lung cancer subjects (NS-NSCLC)	48 months, up to March 2017 (anticipated)	Yes
Secondary	To determine the overall survival of subjects	To determine the overall survival of subjects treated with metformin and a carbohydrate restricted diet in addition to standard platinum-pemetrexed based chemotherapy for advanced stage IIIB/IV non-sqaumous cell lung cancer	48 months, up to March 2017 (anticipated)	Yes
Secondary	To evaluate LKBI mutations as a potential biomarker	To evaluate LKBI mutations as a potential biomarker to predict subjects who will benefit most from metformin in combination with a carbohydrate restricted diet	48 months, up to March 2017 (anticipated)	Yes
Secondary	To evaluate tolerability in fasting serum glucose, insulin levels and subject BMI	To evaluate baseline and changes in fasting serum glucose, insulin levels and subject BMI during treatment as potential host makers to predict clinical outcomes from this intervention	48 months, up to March 2017 (anticipated)	Yes