BIMET-1: Bicalutamide With or Without Metformin for Biochemical Recurrence in Overweight or Obese Prostate Cancer Patients

• Sponsor: Fox Chase Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02614859
• Collaborator: (none)
• Enrollment: 29
• Locations: 2
• Arms: 2
• Actual Duration (Months): 49.8
• Patients Per Site: 14.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Obesity and metabolic syndrome are prevalent among prostate cancer patients. Having an elevated insulin level in the blood is associated with a shorter median time to cancer progression and median overall survival in patients with an elevated PSA after prior treatment. Androgen deprivation therapy (ADT) with drugs like bicalutamide is frequently used in this patient population,with no proven benefit, which may increase mortality and morbidity.This study evaluates how metformin in combination with bicalutamide affects prostate cancer.

Condition or Disease	Intervention/Treatment	Phase
Cancer of Prostate	Drug: Observation and Bicalutamide; Drug: Metformin and Bicalutamide	Phase 2

Detailed Description

1 Cycle = 28 days = 4 weeks. Treatment will be administered on an outpatient basis ӿ Metformin starting dose is 500 mg BID, will be gradually increased to target dose of 1000mg BID.

Treatment ARM A Cycles 1 - 2: Observation without treatment Cycles 3 - 8: Bicalutamide 50 mg daily, orally, continuously to the end of study (week 32).

Treatment ARM B Cycles 1 - 2: In order to minimize gastrointestinal discomfort, metformin dosing will be ramped up over a period of 2 weeks. Metformin treatment will be started at 500 mg BID (Dose Level -2) and increased by an increment of 500 mg daily every week +/- 2 days provided no grade 2 or higher gastrointestinal toxicity is noted. If grade 2 or greater gastrointestinal toxicity occurs during the first 4 weeks of treatment, the subject will be evaluated every 2 weeks until resolution of toxicity to grade 0 or 1 and, then, the metformin dose will be increased to the next dose level. The target dose of metformin is 1000 mg BID.

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Bicalutamide With or Without Metformin for Biochemical Recurrence in Overweight or Obese Prostate Cancer Patients (BIMET-1)
• Actual Study Start Date: Dec 1, 2015
• Actual Primary Completion Date: Jan 24, 2020
• Actual Study Completion Date: Jan 24, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Observation and Bicalutamide Cycles 1-2: Observation without treatment Cycles 3-8: Bicalutamide 50 mg daily continuously to end of study	Drug: Observation and Bicalutamide; Cycles 1 - 2: Observation without treatment Cycles 3 - 8: Bicalutamide 50 mg daily, orally, continuously to the end of study (week 32).
Experimental: Metformin and Bicalutamide Cycles 1-2: Metformin 1000mg BID Cycles 3-8: Bicalutamide 50 mg daily and Metformin 1000 mg BID	Drug: Metformin and Bicalutamide; Cycles 1-2: Metformin 1000mg BID Cycles 3-8: Bicalutamide 50 mg daily and Metformin 1000 mg BID

Outcome Measures

Primary Outcome Measures

1. Biochemical Response Rate Based on PSA [32 weeks]

   Participants with undetectable PSA after 32 weeks

Secondary Outcome Measures

1. PSA Decline ≥ 85% at 32 Weeks [32 Weeks]

   Number of patients with PSA decline ≥ 85% after 32 weeks

2. PSA Decline [8 Weeks]

   Number of patients with PSA decline after 8 weeks (observation vs metformin)

3. Median PSA Decline [8 weeks]

   Median PSA decline after 8 weeks % (range)

4. BMI Decline After 32 Weeks [32 Weeks]

   Number of patients with BMI decline after 32 weeks

Eligibility Criteria

Criteria

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

Inclusion Criteria:

Ability to understand and the willingness to sign a written informed consent

Male 18 years or older

Histologically or cytologically confirmed diagnosis of prostate cancer

Patient must have had previous treatment with definitive surgery or radiation therapy or cryoablation

Patient may have prior salvage therapy (surgery, radiation or other local ablative procedures) within 6 months prior to randomization if the intent was for cure.Prophylactic radiotherapy to prevent gynecomastia within 4 weeks prior to randomization is allowed BMI > 25 at study entry

Patient may have had prior neoadjuvant and/or adjuvant therapy (chemotherapy, vaccines or experimental agents) within 4 weeks prior to randomization, if the PSA rise and PSADT were documented after the testosterone level was > 150ng/dL.

Patient must have hormone-sensitive prostate cancer as evident by a serum total testosterone level > 150 ng/dL within 12 weeks prior to randomization.

PSA must be < 30 ng/mL at study entry

Patient may not have had therapy modulating testosterone levels (such as luteinizing hormone,releasing-hormone agonists/antagonists and antiandrogens) within 1 year prior to randomization, unless it was in the neoadjuvant and/or adjuvant setting

Patient must have evidence of biochemical failure after primary therapy and subsequent progression. Biochemical failure is declared when the PSA reaches a threshold value after primary treatment and it differs for radical prostatectomy or radiation therapy.

1. For radical prostatectomy the threshold for this study is PSA ≥ 0.2ng/mL

2. For radiation therapy the threshold is a PSA rise of 2 ng/mL above the nadir PSA achieved post radiation with or without hormone therapy (2006 RTOG-ASTRO Consensus definition).

3. PSA progression requires a PSA rise above the threshold measured at any time point since the threshold was reached.

PSA doubling time between 3 and 9 months. PSA calculation requires two consecutive PSA rises (PSA2 and PSA3) above the threshold PSA (total 3 PSA values); PSA2 and PSA3 must be obtained within 12 months of study entry. All baseline PSAs should be obtained at the same reference lab. Patient's PSA doubling time must be calculated using the following formula (http://www.mskcc.org/nomograms/prostate/psa doubling-time):

ECOG performance status less than or equal to 2

Ability to swallow the study drugs

Subjects must have normal organ and marrow function as defined below:

1. Absolute neutrophil count greater than or equal to 1,000/mL

2. Hemoglobin greater than or equal to 10 g/dL

3. Platelets greater than or equal to 100,000/mL

4. Total bilirubin within normal institutional limits

5. AST(SGOT)/ALT(SGPT) less than or equal to 1.5 X institutional ULN

6. Creatinine clearance greater than or equal to 60 mL/min/1.73 m2

7. Hgb A1c ≤ 6.5

Exclusion Criteria:

Evidence of metastatic disease on imaging studies (CT and/or bone scan)

Diagnosis of diabetes mellitus defined as

1. Fasting blood glucose > 126 mg/dl or,

2. Random blood glucose > 200 mg/dl

3. Hemoglobin A1C > 6.5%

Need for treatment with any conventional modality for prostate cancer (surgery, radiation therapy, and hormonal therapy)

Prior hormonal therapy for recurrent prostate cancer (hormonal therapy given in a neoadjuvant or adjuvant setting and greater than 6 months before entry is acceptable)

Treatment within the last 30 days with any investigational drug

Radiation therapy within prior 6 months (prophylactic radiotherapy to prevent gynecomastia within 4 weeks prior to randomization is allowed)

Known hypersensitivity to metformin

Prior history of lactic acidosis

Any history of myocardial infarction in the past 12 months

Subjects who consume more than 3 alcoholic beverages per day Subjects with serious intercurrent illness, including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or other nonmalignant medical or psychiatric illness that is uncontrolled or whose control may be jeopardized by the complications of this therapy or may limit compliance with the study requirements (at the discretion of the investigator)

Patient with previous or concurrent malignancy. Exceptions are made for patients who meet any of the following conditions: Basal cell or squamous cell carcinoma of the skin or prior malignancy that has been adequately treated and patient has been continuously disease free for ≥ 2 years.

Subjects currently treated with metformin and/or bicalutamide or who have been treated with metformin and/or bicalutamide in the past 6 months.

Subjects who have taken 5a-reductase inhibitors (finasteride or dutasteride), saw palmetto, or PC-SPES within the last 6 weeks are ineligible. Subjects will be eligible for the study after the wash out period of 6 weeks.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Cancer Institute	Bethesda	Maryland	United States	20892-9760
2	Fox Chase Cancer Center - Philadelphia	Philadelphia	Pennsylvania	United States	19111-2497

Sponsors and Collaborators

• Fox Chase Cancer Center

Investigators

• Principal Investigator: Daniel Geynisman, MD, Fox Chase Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 5, 2019
• Informed Consent Form - Aug 27, 2019

More Information

Publications

None provided.

• Responsible Party: Fox Chase Cancer Center
• ClinicalTrials.gov Identifier: NCT02614859
• Other Study ID Numbers: GU-079; 15-1015
• First Posted: Nov 25, 2015
• Last Update Posted: Mar 29, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Prostatic Neoplasms; Overweight; Recurrence; Metformin; Bicalutamide

Study Results

Participant Flow

Arm/Group Title	Bicalutamide	Metformin and Bicalutamide
Arm/Group Description	Bicalutamide 50 mg daily beginning at cycle 3 to cycle 8	Metformin 1000mg twice a day Bicalutamide 50 mg daily beginning at cycle 3
Period Title: Overall Study
STARTED	9	20
COMPLETED	9	19
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Bicalutamide	Metformin and Bicalutamide	Total
Arm/Group Description	Bicalutamide 50 mg daily beginning at cycle 3 to cycle 8	Metformin 1000mg twice a day Bicalutamide 50 mg daily beginning at cycle 3	Total of all reporting groups
Overall Participants	9	20	29
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	63	64	63.7
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	9 100%	20 100%	29 100%
Race/Ethnicity, Customized (Count of Participants)
White Non-Hispanic	6 66.7%	19 95%	25 86.2%
Black or African American	3 33.3%	1 5%	4 13.8%
Region of Enrollment (Count of Participants)
United States	9 100%	20 100%	29 100%

Outcome Measures

1. Primary Outcome

Title	Biochemical Response Rate Based on PSA
Description	Participants with undetectable PSA after 32 weeks
Time Frame	32 weeks

Outcome Measure Data

Analysis Population Description

29 patients were found eligible and randomized, 28 patients completed all 32 weeks of the trial, and one patient in Arm B was lost to follow-up.

Arm/Group Title	Bicalutamide	Metformin and Bicalutamide
Arm/Group Description	Bicalutamide 50 mg daily beginning at cycle 3 to cycle 8	Metformin 1000mg twice a day Bicalutamide 50 mg daily beginning at cycle 3
Measure Participants	9	19
Count of Participants [Participants]	3 33.3%	5 25%

2. Secondary Outcome

Title	PSA Decline ≥ 85% at 32 Weeks
Description	Number of patients with PSA decline ≥ 85% after 32 weeks
Time Frame	32 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A	Arm B
Arm/Group Description	Cycles 1-2: Observation without treatment Cycles 3-8: Bicalutamide 50 mg daily continuously to end of study Bicalutamide: Cycles 1 - 2: Observation without treatment Cycles 3 - 8: Bicalutamide 50 mg daily, orally, continuously to the end of study (week 32).	Cycles 1-2: Metformin 1000mg BID Cycles 3-8: Bicalutamide 50 mg daily and Metformin 1000 mg BID Metformin and Bicalutamide: Cycles 1-2: Metformin 1000mg BID Cycles 3-8: Bicalutamide 50 mg daily and Metformin 1000 mg BID
Measure Participants	9	19
Count of Participants [Participants]	6 66.7%	10 50%

3. Secondary Outcome

Title	PSA Decline
Description	Number of patients with PSA decline after 8 weeks (observation vs metformin)
Time Frame	8 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bicalutamide	Metformin and Bicalutamide
Arm/Group Description	Bicalutamide 50 mg daily beginning at cycle 3 to cycle 8	Metformin 1000mg twice a day Bicalutamide 50 mg daily beginning at cycle 3
Measure Participants	9	19
Count of Participants [Participants]	1 11.1%	8 40%

4. Secondary Outcome

Title	Median PSA Decline
Description	Median PSA decline after 8 weeks % (range)
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bicalutamide	Metformin and Bicalutamide
Arm/Group Description	Bicalutamide 50 mg daily beginning at cycle 3 to cycle 8	Metformin 1000mg twice a day Bicalutamide 50 mg daily beginning at cycle 3
Measure Participants	9	19
Median (Full Range) [percent change]	NA	9

5. Secondary Outcome

Title	BMI Decline After 32 Weeks
Description	Number of patients with BMI decline after 32 weeks
Time Frame	32 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A	Arm B
Arm/Group Description	Cycles 1-2: Observation without treatment Cycles 3-8: Bicalutamide 50 mg daily continuously to end of study Bicalutamide: Cycles 1 - 2: Observation without treatment Cycles 3 - 8: Bicalutamide 50 mg daily, orally, continuously to the end of study (week 32).	Cycles 1-2: Metformin 1000mg BID Cycles 3-8: Bicalutamide 50 mg daily and Metformin 1000 mg BID Metformin and Bicalutamide: Cycles 1-2: Metformin 1000mg BID Cycles 3-8: Bicalutamide 50 mg daily and Metformin 1000 mg BID
Measure Participants	9	19
Count of Participants [Participants]	4 44.4%	12 60%

Adverse Events

Time Frame	4 years 1 month
Adverse Event Reporting Description	Participants will be followed every 12 months (+/- 2 months) for up to 4 years 1 month from end of treatment for survival, adverse events, and disease status
Arm/Group Title	Bicalutamide		Metformin and Bicalutamide
Arm/Group Description	Bicalutamide 50 mg daily beginning at cycle 3 to cycle 8		Metformin 1000mg twice a day Bicalutamide 50 mg daily beginning at cycle 3
All Cause Mortality
	Bicalutamide		Metformin and Bicalutamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/19 (0%)
Serious Adverse Events
	Bicalutamide		Metformin and Bicalutamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	Bicalutamide		Metformin and Bicalutamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/9 (100%)		19/19 (100%)
Blood and lymphatic system disorders
Anemia	2/9 (22.2%)		3/19 (15.8%)
Ear and labyrinth disorders
Hearing impaired	1/9 (11.1%)		0/19 (0%)
Tinnitus	0/9 (0%)		1/19 (5.3%)
Vertigo	1/9 (11.1%)		0/19 (0%)
Eye disorders
Blurred vision	1/9 (11.1%)		0/19 (0%)
Gastrointestinal disorders
Diarrhea	1/9 (11.1%)		8/19 (42.1%)
Nausea	0/9 (0%)		4/19 (21.1%)
Constipation	0/9 (0%)		3/19 (15.8%)
Abdominal Pain	0/9 (0%)		2/19 (10.5%)
Bloating	0/9 (0%)		1/19 (5.3%)
Dry Mouth	0/9 (0%)		1/19 (5.3%)
Dyspepsia	0/9 (0%)		1/19 (5.3%)
Gastritis	0/9 (0%)		1/19 (5.3%)
Gastroesophageal reflux disease	0/9 (0%)		1/19 (5.3%)
Gastrointestinal disorders - Other	0/9 (0%)		1/19 (5.3%)
Vomiting	0/9 (0%)		1/19 (5.3%)
General disorders
Fatigue	2/9 (22.2%)		5/19 (26.3%)
General disorders and administration site conditions	2/9 (22.2%)		1/19 (5.3%)
Edema limbs	2/9 (22.2%)		0/19 (0%)
Pain	1/9 (11.1%)		1/19 (5.3%)
Injection site reaction	1/9 (11.1%)		1/19 (5.3%)
Infections and infestations
Infections and infestations - Other	0/9 (0%)		1/19 (5.3%)
Laryngitis	0/9 (0%)		1/19 (5.3%)
Tooth infection	1/9 (11.1%)		0/19 (0%)
Injury, poisoning and procedural complications
Fall	0/9 (0%)		1/19 (5.3%)
Investigations
Alanine aminotransferase increased	2/9 (22.2%)		4/19 (21.1%)
Weight loss	0/9 (0%)		4/19 (21.1%)
Aspartate aminotransferase increased	1/9 (11.1%)		2/19 (10.5%)
Investigations - Other	1/9 (11.1%)		2/19 (10.5%)
Cholesterol high	0/9 (0%)		1/19 (5.3%)
Platelet count decreased	1/9 (11.1%)		0/19 (0%)
Metabolism and nutrition disorders
Hyperglycemia	3/9 (33.3%)		5/19 (26.3%)
Hyperkalemia	0/9 (0%)		5/19 (26.3%)
Hypernatremia	0/9 (0%)		2/19 (10.5%)
Hypophosphatemia	0/9 (0%)		2/19 (10.5%)
Anorexia	0/9 (0%)		1/19 (5.3%)
Dehydration	0/9 (0%)		1/19 (5.3%)
Hypoglycemia	1/9 (11.1%)		0/19 (0%)
Hypokalemia	1/9 (11.1%)		0/19 (0%)
Hyponatremia	0/9 (0%)		1/19 (5.3%)
Musculoskeletal and connective tissue disorders
Back pain	0/9 (0%)		2/19 (10.5%)
Chest wall pain	1/9 (11.1%)		0/19 (0%)
Myalgia	1/9 (11.1%)		0/19 (0%)
Pain in extremity	0/9 (0%)		1/19 (5.3%)
Nervous system disorders
Dizziness	0/9 (0%)		3/19 (15.8%)
Nervous system disorders - Other	0/9 (0%)		1/19 (5.3%)
Peripheral sensory neuropathy	0/9 (0%)		1/19 (5.3%)
Seizure	0/9 (0%)		1/19 (5.3%)
Psychiatric disorders
Anxiety	0/9 (0%)		1/19 (5.3%)
Depression	0/9 (0%)		1/19 (5.3%)
Renal and urinary disorders
Hematuria	2/9 (22.2%)		0/19 (0%)
Cystitis noninfective	1/9 (11.1%)		0/19 (0%)
Renal and urinary disorders - Other	1/9 (11.1%)		0/19 (0%)
Urinary frequency	0/9 (0%)		1/19 (5.3%)
Reproductive system and breast disorders
Reproductive system and breast disorders - Other, specify	2/9 (22.2%)		8/19 (42.1%)
Gynecomastia	3/9 (33.3%)		4/19 (21.1%)
Breast Pain	2/9 (22.2%)		3/19 (15.8%)
Respiratory, thoracic and mediastinal disorders
Cough	0/9 (0%)		1/19 (5.3%)
Dyspnea	1/9 (11.1%)		0/19 (0%)
Nasal congestion	0/9 (0%)		1/19 (5.3%)
Respiratory, thoracic and mediastinal disorders - Other	0/9 (0%)		1/19 (5.3%)
Skin and subcutaneous tissue disorders
Dry skin	1/9 (11.1%)		1/19 (5.3%)
Rash maculo-apular	1/9 (11.1%)		1/19 (5.3%)
Skin and subcutaneous tissue disorders - Other	1/9 (11.1%)		0/19 (0%)
Vascular disorders
Hot flashes	3/9 (33.3%)		3/19 (15.8%)
Hypertension	0/9 (0%)		2/19 (10.5%)
Flushing	0/9 (0%)		1/19 (5.3%)
Hypotension	0/9 (0%)		1/19 (5.3%)

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.