Metformin Plus Modified FOLFOX 6 in Metastatic Pancreatic Cancer

• Sponsor: Case Comprehensive Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01666730
• Collaborator: (none)
• Enrollment: 50
• Locations: 2
• Arm: 1
• Actual Duration (Months): 65.3
• Patients Per Site: 25
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This phase II trial studies how well metformin hydrochloride, leucovorin calcium, fluorouracil, and oxaliplatin work in treating patients with metastatic pancreatic cancer. Metformin hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving metformin hydrochloride together with combination chemotherapy may kill more tumor cells

Condition or Disease	Intervention/Treatment	Phase
Acinar Cell Adenocarcinoma of the Pancreas; Duct Cell Adenocarcinoma of the Pancreas; Recurrent Pancreatic Cancer; Stage IV Pancreatic Cancer	Drug: metformin hydrochloride; Drug: oxaliplatin; Drug: leucovorin calcium; Drug: fluorouracil; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine if metformin (metformin hydrochloride) when added to FOLFOX ( leucovorin calcium, fluorouracil, oxaliplatin) improves overall survival in patients with metastatic pancreatic cancer.

SECONDARY OBJECTIVES:

1. To assess response rate (RR). II. To assess progression free survival (PFS). III. To assess toxicity in patients with metastatic pancreatic cancer receiving FOLFOX and metformin.
2. To identify tumor/serum correlative markers.

OUTLINE: Patients receive metformin hydrochloride orally (PO) twice daily (BID) on days 1-7 for an introductory period before the addition of FOLFOX. After the introductory period, patients will continue metformin twice daily and FOLFOX therapy comprising leucovorin calcium intravenously (IV) over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for periodically.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Metformin Plus Modified FOLFOX 6 in Patients With Metastatic Pancreatic Cancer
• Actual Study Start Date: Feb 21, 2013
• Actual Primary Completion Date: Aug 1, 2018
• Actual Study Completion Date: Aug 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (metformin hydrochloride, FOLFOX) Patients receive metformin hydrochloride PO BID on days 1-14 and FOLFOX therapy comprising leucovorin calcium IV over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Drug: metformin hydrochloride; Given PO; Other Names: Glucophage ; Drug: oxaliplatin; Given IV; Other Names: 1-OHP Dacotin Dacplat Eloxatin L-OHP ; Drug: leucovorin calcium; Given IV; Other Names: CF CFR LV ; Drug: fluorouracil; Given IV; Other Names: 5-fluorouracil 5-Fluracil 5-FU ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Median Overall Survival (OS) [Time from first day of treatment to death from any cause, assessed up to 1 year]

   Calculated using Kaplan Meier methods and the median will be estimated assuming an exponential distribution.

Secondary Outcome Measures

1. Response Rate (RR) Objective Tumor Response Based on Computed Tomography (CT) Scans or Magnetic Resonance Imaging (MRI) Scans According to Response Evaluation Criteria in Solid Tumors (RECIST) [1 year]

   CBR is the number of participants of the total analysis population who experience confirmed complete (CR) or partial response (PR) per RECIST CR = all detectable tumor has disappeared PR = a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum Stable Disease (SD) = small changes that do not meet previously given criteria. Progressive disease (PD) = a >=20% increase in target lesions The true response rate of the combination therapy for this patient population will be estimated based on the number of response using a binomial distribution and its confidence intervals will be estimated using Wilson's method.

2. Clinical Benefit Rate (CBR) Based on Computed Tomography (CT) Scans or Magnetic Resonance Imaging (MRI) Scans According to RECIST [1 year]

   CBR is the number of participants of the total analysis population who experience a CR, PR, or SD per RECIST CR = all detectable tumor has disappeared PR = a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum SD = small changes that do not meet previously given criteria. PD = a >=20% increase in target lesions

3. Progression Free Survival According to RECIST 1.1 Criteria [Time from first day of treatment received to the earlier documented disease progression or death from any cause, assessed up to 1 year]

   Calculated using Kaplan Meier methods and the median will be estimated assuming an exponential distribution.

4. Number of Grade 3 and 4 Toxicities According to NCI CTCAE Version 4.0 [Up to 1 year]

   The toxicity profile of the combination will be tabulated.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed metastatic pancreatic adenocarcinoma (or any mixed pathology if adenocarcinoma is predominant)

• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm with conventional techniques or as > 10 mm with spiral computed tomography (CT) scan

• Patient must have not received systemic chemotherapy for metastatic disease; prior chemotherapy, radiation therapy, concurrent chemoradiation are allowed if used for treatment of non-metastatic disease; prior palliative radiation for symptom management is allowed; any chemotherapy must have been completed 4 weeks prior to enrollment; any radiotherapy must have been completed 2 weeks prior to enrollment

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Absolute neutrophil count ≥ 1,500/L

• Platelets ≥ 100,000/L

• Hemoglobin ≥ 9 g/dL

• Total bilirubin ≤ 2 mg/dL

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) ≤ 2.5 x institutional upper limit of normal

• Creatinine ≤ 1.5

• Women of childbearing potential and men must agree to use adequate contraception (double barrier method of birth control or abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect that she is pregnant while she or her partner is participating in this study, she should inform the treating physician immediately

• Subjects must have the ability to understand and the willingness to sign a written informed consent document

• Patients with diabetes are eligible for this trial; all diabetic patients who are enrolled on this study should discuss the need to change their diabetes management regimen with their primary care physician or endocrinologist prior to enrollment

• Diabetic patients who are on metformin are eligible as long as they have been on metformin for less than 6 months (estimated 6 months or less duration of metformin therapy from start of metformin to enrollment on study)

Exclusion Criteria:

• Chemotherapy within 4 weeks prior to entering the study, radiotherapy within 2 weeks prior to entering the study or failure to recover from adverse events due to agents administered more than 4 weeks earlier

• Prior treatment toxicities must be resolved to ≤ grade 1 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

• Current use of metformin for more than 6 months prior to enrollment on study

• Use of any other investigational agents

• Patients with untreated brain metastases should be excluded from this clinical trial

• History of allergic reactions attributed to compounds of similar chemical or biological composition to metformin or oxaliplatin or fluorouracil (5-FU)

• Active second primary malignancy or history of second primary malignancy within the last 3 years, with the exception of basal cell skin cancers or carcinoma in situ that have been adequately treated

• Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Pregnant or nursing women

• Human immunodeficiency virus (HIV)-positive patients

• Chronic or planned acute alcohol use of three or more drinks per day

• Metabolic acidosis, acute or chronic, including ketoacidosis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44106
2	Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44195

Sponsors and Collaborators

• Case Comprehensive Cancer Center

Investigators

• Principal Investigator: David Bajor, MD, University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 23, 2015
• Informed Consent Form - Nov 4, 2019

More Information

Publications

None provided.

• Responsible Party: Case Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT01666730
• Other Study ID Numbers: CASE1212
• First Posted: Aug 16, 2012
• Last Update Posted: Aug 10, 2021
• Last Verified: Jul 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Adenocarcinoma; Pancreatic Neoplasms; Carcinoma, Acinar Cell; Leucovorin; Metformin; Fluorouracil; Oxaliplatin; Calcium; Levoleucovorin

Study Results

Participant Flow

Arm/Group Title	Treatment (Metformin Hydrochloride, FOLFOX)
Arm/Group Description	Patients receive metformin hydrochloride PO BID on days 1-14 and FOLFOX therapy comprising leucovorin calcium IV over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. metformin hydrochloride: Given PO oxaliplatin: Given IV leucovorin calcium: Given IV fluorouracil: Given IV laboratory biomarker analysis: Correlative studies
Period Title: Overall Study
STARTED	50
COMPLETED	0
NOT COMPLETED	50

Baseline Characteristics

Arm/Group Title	Treatment (Metformin Hydrochloride, FOLFOX)
Arm/Group Description	Patients receive metformin hydrochloride PO BID on days 1-14 and FOLFOX therapy comprising leucovorin calcium IV over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. metformin hydrochloride: Given PO oxaliplatin: Given IV leucovorin calcium: Given IV fluorouracil: Given IV laboratory biomarker analysis: Correlative studies
Overall Participants	50
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	19 38%
>=65 years	31 62%
Sex: Female, Male (Count of Participants)
Female	32 64%
Male	18 36%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 2%
Not Hispanic or Latino	49 98%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 8%
White	46 92%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	50 100%

Outcome Measures

1. Primary Outcome

Title	Median Overall Survival (OS)
Description	Calculated using Kaplan Meier methods and the median will be estimated assuming an exponential distribution.
Time Frame	Time from first day of treatment to death from any cause, assessed up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Metformin Hydrochloride, FOLFOX)
Arm/Group Description	Patients receive metformin hydrochloride PO BID on days 1-14 and FOLFOX therapy comprising leucovorin calcium IV over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. metformin hydrochloride: Given PO oxaliplatin: Given IV leucovorin calcium: Given IV fluorouracil: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	50
Median (95% Confidence Interval) [Months]	7.1

2. Secondary Outcome

Title	Response Rate (RR) Objective Tumor Response Based on Computed Tomography (CT) Scans or Magnetic Resonance Imaging (MRI) Scans According to Response Evaluation Criteria in Solid Tumors (RECIST)
Description	CBR is the number of participants of the total analysis population who experience confirmed complete (CR) or partial response (PR) per RECIST CR = all detectable tumor has disappeared PR = a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum Stable Disease (SD) = small changes that do not meet previously given criteria. Progressive disease (PD) = a >=20% increase in target lesions The true response rate of the combination therapy for this patient population will be estimated based on the number of response using a binomial distribution and its confidence intervals will be estimated using Wilson's method.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Patients that were evaluable for clinical response

Arm/Group Title	Treatment (Metformin Hydrochloride, FOLFOX)
Arm/Group Description	Patients receive metformin hydrochloride PO BID on days 1-14 and FOLFOX therapy comprising leucovorin calcium IV over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. metformin hydrochloride: Given PO oxaliplatin: Given IV leucovorin calcium: Given IV fluorouracil: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	31
Count of Participants [Participants]	4 8%

3. Secondary Outcome

Title	Clinical Benefit Rate (CBR) Based on Computed Tomography (CT) Scans or Magnetic Resonance Imaging (MRI) Scans According to RECIST
Description	CBR is the number of participants of the total analysis population who experience a CR, PR, or SD per RECIST CR = all detectable tumor has disappeared PR = a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum SD = small changes that do not meet previously given criteria. PD = a >=20% increase in target lesions
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Patients that were evaluable for clinical response

Arm/Group Title	Treatment (Metformin Hydrochloride, FOLFOX)
Arm/Group Description	Patients receive metformin hydrochloride PO BID on days 1-14 and FOLFOX therapy comprising leucovorin calcium IV over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. metformin hydrochloride: Given PO oxaliplatin: Given IV leucovorin calcium: Given IV fluorouracil: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	31
Count of Participants [Participants]	14 28%

4. Secondary Outcome

Title	Progression Free Survival According to RECIST 1.1 Criteria
Description	Calculated using Kaplan Meier methods and the median will be estimated assuming an exponential distribution.
Time Frame	Time from first day of treatment received to the earlier documented disease progression or death from any cause, assessed up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Metformin Hydrochloride, FOLFOX)
Arm/Group Description	Patients receive metformin hydrochloride PO BID on days 1-14 and FOLFOX therapy comprising leucovorin calcium IV over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. metformin hydrochloride: Given PO oxaliplatin: Given IV leucovorin calcium: Given IV fluorouracil: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	50
Median (95% Confidence Interval) [Months]	5.1

5. Secondary Outcome

Title	Number of Grade 3 and 4 Toxicities According to NCI CTCAE Version 4.0
Description	The toxicity profile of the combination will be tabulated.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Metformin Hydrochloride, FOLFOX)
Arm/Group Description	Patients receive metformin hydrochloride PO BID on days 1-14 and FOLFOX therapy comprising leucovorin calcium IV over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. metformin hydrochloride: Given PO oxaliplatin: Given IV leucovorin calcium: Given IV fluorouracil: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	50
Grade 3	60
Grade 4	2

Adverse Events

Time Frame	AEs will be collect up to 1 year
Arm/Group Title	Treatment (Metformin Hydrochloride, FOLFOX)
Arm/Group Description	Patients receive metformin hydrochloride PO BID on days 1-14 and FOLFOX therapy comprising leucovorin calcium IV over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. metformin hydrochloride: Given PO oxaliplatin: Given IV leucovorin calcium: Given IV fluorouracil: Given IV laboratory biomarker analysis: Correlative studies
All Cause Mortality
	Treatment (Metformin Hydrochloride, FOLFOX)
	Affected / at Risk (%)	# Events
Total	45/50 (90%)
Serious Adverse Events
	Treatment (Metformin Hydrochloride, FOLFOX)
	Affected / at Risk (%)	# Events
Total	9/50 (18%)
Blood and lymphatic system disorders
Febrile neutropenia	1/50 (2%)	1
Cardiac disorders
Atrial fibrillation	1/50 (2%)	1
Chest pain - cardiac	1/50 (2%)	1
Gastrointestinal disorders
Abdominal pain	1/50 (2%)	1
Mucositis oral	1/50 (2%)	1
General disorders
Death	1/50 (2%)	1
Edema limbs	1/50 (2%)	1
Fever	1/50 (2%)	2
Hepatobiliary disorders
Bile duct stenosis	1/50 (2%)	1
Hepatobiliary disorder	1/50 (2%)	1
Infections and infestations
Infection- Klebsiella Bacteremia	1/50 (2%)	1
Mucosal infection	1/50 (2%)	1
Sepsis	1/50 (2%)	2
Injury, poisoning and procedural complications
Fall	1/50 (2%)	1
Fracture	1/50 (2%)	1
Head Injury	1/50 (2%)	1
Investigations
Blood bilirubin increased	1/50 (2%)	1
Creatinine increased	1/50 (2%)	1
Lymphocyte count decreased	1/50 (2%)	1
Neutrophil count decreased	1/50 (2%)	1
Platelet count decreased	1/50 (2%)	1
White blood cell decreased	1/50 (2%)	1
Metabolism and nutrition disorders
Dehydration	1/50 (2%)	1
Hypoalbuminemia	1/50 (2%)	1
Hypokalemia	1/50 (2%)	2
Hyponatremia	1/50 (2%)	1
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	1/50 (2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Death related to disease	1/50 (2%)	1
Nervous system disorders
Cognitive disturbance	1/50 (2%)	1
Renal and urinary disorders
Acute kidney injury	1/50 (2%)	1
Vascular disorders
Hematoma	1/50 (2%)	1
Hypotension	2/50 (4%)	3
Thromboembolic event	1/50 (2%)	1
Pulmonary embolism	1/50 (2%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Metformin Hydrochloride, FOLFOX)
	Affected / at Risk (%)	# Events
Total	33/50 (66%)
Blood and lymphatic system disorders
Anemia	24/50 (48%)	46
Gastrointestinal disorders
Abdominal pain	10/50 (20%)	21
Bloating	4/50 (8%)	4
Constipation	13/50 (26%)	18
Diarrhea	17/50 (34%)	32
Dyspepsia	3/50 (6%)	3
Gastroesophageal reflux disease	4/50 (8%)	4
Mucositis oral	6/50 (12%)	9
Nausea	20/50 (40%)	35
Vomiting	13/50 (26%)	18
General disorders
Chills	4/50 (8%)	4
Edema limbs	7/50 (14%)	10
Fatigue	28/50 (56%)	59
Pain	5/50 (10%)	7
Infections and infestations
Mucosal infection	3/50 (6%)	3
Urinary tract infection	4/50 (8%)	9
Injury, poisoning and procedural complications
Bruising	3/50 (6%)	3
Fall	4/50 (8%)	5
Investigations
Alanine aminotransferase increased	10/50 (20%)	12
Alkaline phosphatase increased	17/50 (34%)	32
Aspartate aminotransferase increased	11/50 (22%)	19
Blood bilirubin increased	3/50 (6%)	4
Lymphocyte count decreased	16/50 (32%)	29
Neutrophil count decreased	12/50 (24%)	23
Platelet count decreased	17/50 (34%)	38
Weight loss	20/50 (40%)	32
White blood cell decreased	16/50 (32%)	24
Metabolism and nutrition disorders
Dehydration	6/50 (12%)	7
Hyperglycemia	16/50 (32%)	30
Hypernatremia	3/50 (6%)	3
Hypoalbuminemia	18/50 (36%)	48
Hypocalcemia	9/50 (18%)	28
Hypoglycemia	4/50 (8%)	5
Hypokalemia	13/50 (26%)	26
Hypomagnesemia	8/50 (16%)	10
Hyponatremia	10/50 (20%)	16
Hypophosphatemia	3/50 (6%)	5
Musculoskeletal and connective tissue disorders
Back pain	4/50 (8%)	4
Generalized muscle weakness	9/50 (18%)	10
Nervous system disorders
Dizziness	7/50 (14%)	8
Dysgeusia	8/50 (16%)	12
Paresthesia	5/50 (10%)	5
Peripheral sensory neuropathy	10/50 (20%)	21
Psychiatric disorders
Anxiety	8/50 (16%)	8
Depression	5/50 (10%)	6
Insomnia	10/50 (20%)	10
Respiratory, thoracic and mediastinal disorders
Dyspnea	8/50 (16%)	10
Skin and subcutaneous tissue disorders
Alopecia	11/50 (22%)	11
Vascular disorders
Hot flashes	3/50 (6%)	3
Hypertension	14/50 (28%)	18

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.