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Nivolumab and Metformin Hydrochloride in Treating Patients With Stage III-IV Non-small Cell Lung Cancer That Cannot Be Removed by Surgery

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03048500
Recruitment Status : Active, not recruiting
First Posted : February 9, 2017
Results First Posted : October 14, 2020
Last Update Posted : October 14, 2020
Sponsor:
Collaborators:
Bristol-Myers Squibb
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Young Kwang Chae, Northwestern University

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Recurrent Non-Small Cell Lung Carcinoma
Stage III Non-Small Cell Lung Cancer
Stage IIIA Non-Small Cell Lung Cancer
Stage IIIB Non-Small Cell Lung Cancer
Stage IV Non-Small Cell Lung Cancer
Interventions Other: Laboratory Biomarker Analysis
Drug: Metformin Hydrochloride
Biological: Nivolumab
Enrollment 17
Recruitment Details The first patient started treatment July 12, 2017. The study was designed to enroll patients with/without prior PD-1/PD-L1 inhibitor treatment. The study closed enrollment to patients without prior treatment with PD-1/PD-L1 inhibitor April 30, 2018. The study was suspended for IA and subsequently closed to further enrollment August 13, 2019.
Pre-assignment Details  
Arm/Group Title Treatment (Metformin Hydrochloride, Nivolumab)
Hide Arm/Group Description

Induction: Patients receive treatment with metformin monotherapy PO QD on Day -7 to -1.

Main treatment starting Day 1 of Cycle 1: Patients receive metformin PO QD (Days 1-28 of a 28 days cycle) and nivolumab IV every 14 days (on Days 1 and 15 of a 28 day cycle) for the first 4 cycles and then every 28 days, starting Cycle 5 (Day 1 of a 28 day cycle).

28 day cycles continue in the absence of disease progression, unacceptable toxicity, or withdrawal of consent.

Laboratory Biomarker Analysis: Correlative studies

Metformin Hydrochloride: Given PO

Nivolumab: Given IV

Period Title: 2 Cycles of Treatment
Started 17
Attempted 1st Cycle 17
Attempted 2nd Cycle 16
Completed 16
Not Completed 1
Reason Not Completed
Withdrawal by Subject             1
Period Title: Reached 1st Response/Continued Treatment
Started 16
Assessed for First Response 16
Went on to Cycle 3 and Beyond 9
Completed 9
Not Completed 7
Reason Not Completed
Progressive Disease             4
Death             1
Withdrawal by Subject             1
Physician decision, Patient PS declining             1
Period Title: Follow up for 3 Years
Started [1] 16 [2]
Completed 0
Not Completed 16
Reason Not Completed
Currently in Follow-up             4
Death             12
[1]
All patients that are treated on study go into the follow-up period.
[2]
1 patient died whilst on study.
Arm/Group Title Treatment (Metformin Hydrochloride, Nivolumab)
Hide Arm/Group Description

Induction: Patients receive treatment with metformin monotherapy PO QD on Day -7 to -1.

Main treatment starting Day 1 of Cycle 1: Patients receive metformin PO QD (Days 1-28 of a 28 days cycle) and nivolumab IV every 14 days (on Days 1 and 15 of a 28 day cycle) for the first 4 cycles and then every 28 days, starting Cycle 5 (Day 1 of a 28 day cycle).

28 day cycles continue in the absence of disease progression, unacceptable toxicity, or withdrawal of consent.

Laboratory Biomarker Analysis: Correlative studies

Metformin Hydrochloride: Given PO

Nivolumab: Given IV

Overall Number of Baseline Participants 17
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 17 participants
<=18 years
0
   0.0%
Between 18 and 65 years
8
  47.1%
>=65 years
9
  52.9%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 17 participants
Female
11
  64.7%
Male
6
  35.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 17 participants
Hispanic or Latino
0
   0.0%
Not Hispanic or Latino
16
  94.1%
Unknown or Not Reported
1
   5.9%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 17 participants
American Indian or Alaska Native
0
   0.0%
Asian
1
   5.9%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
3
  17.6%
White
12
  70.6%
More than one race
0
   0.0%
Unknown or Not Reported
1
   5.9%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 17 participants
17
1.Primary Outcome
Title Objective Response Rate (ORR) of Patients With Non-small Cell Lung Cancer Treated With Nivolumab and Metformin Combination Using RECIST 1.1
Hide Description

Anti-tumor activity will be assessed by ORR (defined as the sum of Complete Responses (CR) and/or Partial Responses (PR)) as measured by CT or MRI scan approximately every 8 weeks and assessed by Response Evaluation Criteria in Solid Tumors, RECIST criteria v1.1 using the patients best response to treatment where:

CR=Disappearance of all lesions PR=At least a 30% decrease in the sum of the diameters of the target lesions, taking as reference the baseline sum diameters

Time Frame up to a maximum of 24 weeks from start of treatment (Range of cycles that best response was seen was 2-5 cycles of treatment where 1 cycle =28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
All patients who received treatment are considered evaluable (even those who did not complete CT scans for RECIST measurement) except those removed from the study for adverse drug reactions.
Arm/Group Title Treatment (Metformin Hydrochloride, Nivolumab)
Hide Arm/Group Description:

Induction: Patients receive treatment with metformin monotherapy PO QD on Day -7 to -1.

Main treatment starting Day 1 of Cycle 1: Patients receive metformin PO QD (Days 1-28 of a 28 days cycle) and nivolumab IV every 14 days (on Days 1 and 15 of a 28 day cycle) for the first 4 cycles and then every 28 days, starting Cycle 5 (Day 1 of a 28 day cycle).

28 day cycles continue in the absence of disease progression, unacceptable toxicity, or withdrawal of consent.

Laboratory Biomarker Analysis: Correlative studies

Metformin Hydrochloride: Given PO

Nivolumab: Given IV

Overall Number of Participants Analyzed 17
Measure Type: Count of Participants
Unit of Measure: Participants
1
   5.9%
2.Secondary Outcome
Title Depth of Response
Hide Description Depth of response (stable disease or partial response) defined as the change in the sum of the largest tumor diameters per RECIST v1.1 and irRECIST criteria.
Time Frame 24 weeks from start of treatment
Outcome Measure Data Not Reported
3.Secondary Outcome
Title Duration of Response
Hide Description Duration of response will be evaluated using RECIST v1.1 and irRECIST criteria.
Time Frame Up to 3 years
Outcome Measure Data Not Reported
4.Secondary Outcome
Title Persistence of Response
Hide Description Persistence of response will be assessed using RECIST v1.1 and irRECIST criteria.
Time Frame Up to 3 years
Outcome Measure Data Not Reported
5.Secondary Outcome
Title Disease Control Rate (DCR)
Hide Description DCR will be evaluated using RECIST v1.1 and irRECIST criteria.
Time Frame 24 weeks from start of treatment
Outcome Measure Data Not Reported
6.Secondary Outcome
Title Progression-Free Survival (PFS)
Hide Description PFS will be assessed using RECIST v1.1 and irRECIST criteria.
Time Frame At 1 year than at 2 years
Outcome Measure Data Not Reported
7.Secondary Outcome
Title Overall Survival (OS)
Hide Description OS will be assessed using RECIST v1.1 and irRECIST criteria.
Time Frame At 1 year than at 2 years
Outcome Measure Data Not Reported
8.Secondary Outcome
Title Objective Response Rate (ORR) of Patients With Non-small Cell Lung Cancer Treated With Nivolumab and Metformin Combination Using irRECIST.
Hide Description

Anti-tumor activity will be assessed by ORR (defined as the sum of Complete Responses (CR) and/or Partial Responses (PR)) as measured by CT or MRI scan approximately every 8 weeks and assessed by irRECIST criteria using the patients best response to treatment where:

CR=Disappearance of all lesions PR=At least a 30% decrease in the sum of the diameters of the target lesions, taking as reference the baseline sum diameters

But also new measurable lesions are incorporated in the tumor burden, which is used to determine immune-related progressive disease (irPD), immune-related partial response (irPR), and immune-related complete response (irCR). New non-measurable lesions preclude irCR. Under RECST v1.1, there is no confirmation for PD. Under irRECIST, responses and irPDs must be confirmed by consecutive scans at least 4 weeks apart, assuming no clinical deterioration.

Time Frame up to a maximum of 24 weeks from start of treatment (Range of cycles that best response was seen was 2-6 cycles of treatment where 1 cycle =28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
All patients who received treatment are considered evaluable (even those who did not complete CT scans for RECIST measurement) except those removed from the study for adverse drug reactions.
Arm/Group Title Treatment (Metformin Hydrochloride, Nivolumab)
Hide Arm/Group Description:

Induction: Patients receive treatment with metformin monotherapy PO QD on Day -7 to -1.

Main treatment starting Day 1 of Cycle 1: Patients receive metformin PO QD (Days 1-28 of a 28 days cycle) and nivolumab IV every 14 days (on Days 1 and 15 of a 28 day cycle) for the first 4 cycles and then every 28 days, starting Cycle 5 (Day 1 of a 28 day cycle).

28 day cycles continue in the absence of disease progression, unacceptable toxicity, or withdrawal of consent.

Laboratory Biomarker Analysis: Correlative studies

Metformin Hydrochloride: Given PO

Nivolumab: Given IV

Overall Number of Participants Analyzed 17
Measure Type: Count of Participants
Unit of Measure: Participants
2
  11.8%
9.Secondary Outcome
Title Incidence of Adverse Events
Hide Description Assess the safety and tolerability of the combination treatment of metformin with nivolumab by evaluating the number, frequency, and severity of adverse events using CTCAE version 4.03.
Time Frame Up to 3 years
Outcome Measure Data Not Reported
Time Frame Adverse events (AEs) were collected from Day -7 of Induction with Metformin until 30 days post the last dose of treatment (or at time of initiation of new treatment) for a maximum of 14 cycles for any patient (where 1 cycle = 28 days).
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Treatment (Metformin Hydrochloride, Nivolumab)
Hide Arm/Group Description

Induction: Patients receive treatment with metformin monotherapy PO QD on Day -7 to -1.

Main treatment starting Day 1 of Cycle 1: Patients receive metformin PO QD (Days 1-28 of a 28 days cycle) and nivolumab IV every 14 days (on Days 1 and 15 of a 28 day cycle) for the first 4 cycles and then every 28 days, starting Cycle 5 (Day 1 of a 28 day cycle).

28 day cycles continue in the absence of disease progression, unacceptable toxicity, or withdrawal of consent.

Laboratory Biomarker Analysis: Correlative studies

Metformin Hydrochloride: Given PO

Nivolumab: Given IV

All-Cause Mortality
Treatment (Metformin Hydrochloride, Nivolumab)
Affected / at Risk (%)
Total   13/17 (76.47%)    
Hide Serious Adverse Events
Treatment (Metformin Hydrochloride, Nivolumab)
Affected / at Risk (%) # Events
Total   8/17 (47.06%)    
Cardiac disorders   
Pericardial effusion  1 [1]  1/17 (5.88%)  1
Cardiac arrest and subsequent death  1  1/17 (5.88%)  1
Gastrointestinal disorders   
Constipation  1  1/17 (5.88%)  2
Infections and infestations   
Lung infection  1  1/17 (5.88%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Disease progression  1  2/17 (11.76%)  2
Non-small Cell Lung Cancer  1 [2]  1/17 (5.88%)  1
Respiratory, thoracic and mediastinal disorders   
Pneumonitis  1  1/17 (5.88%)  1
Hemoptysis and acute chronic obstructive pulmonary disease exacerbation  1  1/17 (5.88%)  1
1
Term from vocabulary, CTCAE (4.03)
Indicates events were collected by systematic assessment
[1]
Patient reported to also have spesis at the same time as the event
[2]
This resulted in death
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Treatment (Metformin Hydrochloride, Nivolumab)
Affected / at Risk (%) # Events
Total   17/17 (100.00%)    
Blood and lymphatic system disorders   
Anemia  1  6/17 (35.29%) 
Cardiac disorders   
Cardiac arrest  1  1/17 (5.88%) 
Sinus tachycardia  1  2/17 (11.76%) 
Endocrine disorders   
Endocrine disorders - Other, specify  1  1/17 (5.88%) 
Hypothyroidism  1  1/17 (5.88%) 
Eye disorders   
Eye disorders - Other, specify  1  1/17 (5.88%) 
Gastrointestinal disorders   
Abdominal distension  1  1/17 (5.88%) 
Constipation  1  2/17 (11.76%) 
Diarrhea  1  9/17 (52.94%) 
Flatulence  1  2/17 (11.76%) 
Gastrointestinal disorders - Other, specify  1  2/17 (11.76%) 
Nausea  1  6/17 (35.29%) 
Vomiting  1  2/17 (11.76%) 
General disorders   
Edema limbs  1  3/17 (17.65%) 
Fatigue  1  7/17 (41.18%) 
Fever  1  2/17 (11.76%) 
General disorders and administration site conditions - Other, specify  1  4/17 (23.53%) 
Non-cardiac chest pain  1  2/17 (11.76%) 
Infections and infestations   
Lung infection  1  1/17 (5.88%) 
Sinusitis  1  1/17 (5.88%) 
Urinary tract infection  1  1/17 (5.88%) 
Injury, poisoning and procedural complications   
Fracture  1  1/17 (5.88%) 
Investigations   
Alkaline phosphatase increased  1  2/17 (11.76%) 
Aspartate aminotransferase increased  1  1/17 (5.88%) 
INR increased  1  1/17 (5.88%) 
Investigations - Other, specify  1  2/17 (11.76%) 
Lymphocyte count decreased  1  7/17 (41.18%) 
Lymphocyte count increased  1  1/17 (5.88%) 
Weight loss  1  8/17 (47.06%) 
White blood cell decreased  1  1/17 (5.88%) 
Metabolism and nutrition disorders   
Anorexia  1  7/17 (41.18%) 
Hypercalcemia  1  2/17 (11.76%) 
Hyperglycemia  1  5/17 (29.41%) 
Hyperkalemia  1  2/17 (11.76%) 
Hypoalbuminemia  1  9/17 (52.94%) 
Hypocalcemia  1  2/17 (11.76%) 
Hypokalemia  1  4/17 (23.53%) 
Hypomagnesemia  1  3/17 (17.65%) 
Hyponatremia  1  5/17 (29.41%) 
Hypophosphatemia  1  6/17 (35.29%) 
Musculoskeletal and connective tissue disorders   
Back pain  1  2/17 (11.76%) 
Flank pain  1  1/17 (5.88%) 
Generalized muscle weakness  1  2/17 (11.76%) 
Musculoskeletal and connective tissue disorder - Other, specify  1  3/17 (17.65%) 
Pain in extremity  1  2/17 (11.76%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify  1  1/17 (5.88%) 
Nervous system disorders   
Dizziness  1  4/17 (23.53%) 
Headache  1  2/17 (11.76%) 
Hypersomnia  1  1/17 (5.88%) 
Memory impairment  1  2/17 (11.76%) 
Nervous system disorders - Other, specify  1  2/17 (11.76%) 
Paresthesia  1  1/17 (5.88%) 
Peripheral motor neuropathy  1  1/17 (5.88%) 
Psychiatric disorders   
Anxiety  1  1/17 (5.88%) 
Confusion  1  1/17 (5.88%) 
Depression  1  1/17 (5.88%) 
Insomnia  1  1/17 (5.88%) 
Renal and urinary disorders   
Hematuria  1  1/17 (5.88%) 
Proteinuria  1  1/17 (5.88%) 
Renal and urinary disorders - Other, specify  1  2/17 (11.76%) 
Urinary frequency  1  1/17 (5.88%) 
Respiratory, thoracic and mediastinal disorders   
Cough  1  3/17 (17.65%) 
Dyspnea  1  4/17 (23.53%) 
Pleural effusion  1  1/17 (5.88%) 
Pneumonitis  1  1/17 (5.88%) 
Productive cough  1  1/17 (5.88%) 
Respiratory, thoracic and mediastinal disorders - Other, specify  1  4/17 (23.53%) 
Wheezing  1  1/17 (5.88%) 
Skin and subcutaneous tissue disorders   
Rash acneiform  1  3/17 (17.65%) 
Skin and subcutaneous tissue disorders - Other, specify  1  3/17 (17.65%) 
Urticaria  1  0/17 (0.00%) 
Vascular disorders   
Hypertension  1  10/17 (58.82%) 
1
Term from vocabulary, CTCAE (4.03)
Indicates events were collected by systematic assessment
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Young Chae, MD
Organization: Northwestern University
Phone: 312-695-1301
EMail: young.chae@northwestern.edu
Layout table for additonal information
Responsible Party: Young Kwang Chae, Northwestern University
ClinicalTrials.gov Identifier: NCT03048500    
Other Study ID Numbers: NU 16L04
STU00204354 ( CTRP (Clinical Trial Reporting Program) )
NU 16L04 ( Other Identifier: Northwestern University )
P30CA060553 ( U.S. NIH Grant/Contract )
NCI-2017-00060 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
First Submitted: February 7, 2017
First Posted: February 9, 2017
Results First Submitted: July 27, 2020
Results First Posted: October 14, 2020
Last Update Posted: October 14, 2020