Investigation of Metformin in Patients With Castration Resistant Prostate Cancer in Combination With Enzalutamide vs. Enzalutamide Alone

Sponsor

Swiss Group for Clinical Cancer Research (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02640534

Collaborator

(none)

169

Enrollment

Locations

Arms

140.7

Anticipated Duration (Months)

10.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this trial is to test if the combination of enzalutamide and metformin in patients with castration resistant prostate cancer CRPC progressing on androgen deprivation therapy ADT is more effective compared to enzalutamide alone. The half of the patients will receive the experimental treatment combination, enzalutamide and metformin, while the other half will receive enzalutamide alone.

Condition or Disease	Intervention/Treatment	Phase
Cancer of the Prostate Prostate Cancer	Drug: Enzalutamide Drug: Metformin	Phase 2

Detailed Description

One in seven men will be diagnosed with cancer of the prostate during his lifetime . Accordingly, prostate cancer (PC) is the most common cancer amongst men in the western world and worldwide. PC ranks second in cancer incidence and sixth in cancer mortality in men. The current standard of care for patients with metastatic castration resistant prostate cancer (mCRPC) and disease progression is either treatment with abiraterone acetate and prednisone in asymptomatic or mildly symptomatic patients without visceral metastases, or treatment with docetaxel in more symptomatic patients and in the presence of visceral metastases.

Rothemundt et al. previously demonstrated favorable effects of metformin in a phase II trial:

it yields objective Prostate specific antigen PSA responses and may induce disease stabilization and improve metabolic endpoints in patients with CRPC. Therefore addition of metformin to enzalutamide might have positive impact on tumor progression, on body composition, and insulin sensitivity.

Study Design

Study Type:

Interventional

Actual Enrollment :

169 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Investigation of Metformin in Patients With Castration Resistant Prostate Cancer in Combination With Enzalutamide vs. Enzalutamide Alone (IMPROVE TRIAL): A Randomized, Open Label, Phase II Trial

Actual Study Start Date :

Jun 10, 2016

Anticipated Primary Completion Date :

Mar 1, 2028

Anticipated Study Completion Date :

Mar 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Enzalutamide + Metformin Enzalutamide 160 mg od + metformin 850 mg bid until disease progression	Drug: Enzalutamide Enzalutamide 160 mg od until disease progression Drug: Metformin 850 mg bid until disease progression
Active Comparator: Enzalutamide Enzalutamide 160 mg od until disease progression	Drug: Enzalutamide Enzalutamide 160 mg od until disease progression

Arm

Intervention/Treatment

Experimental: Enzalutamide + Metformin

Enzalutamide 160 mg od + metformin 850 mg bid until disease progression

Drug: Enzalutamide

Enzalutamide 160 mg od until disease progression

Drug: Metformin

850 mg bid until disease progression

Active Comparator: Enzalutamide

Enzalutamide 160 mg od until disease progression

Drug: Enzalutamide

Enzalutamide 160 mg od until disease progression

Outcome Measures

Primary Outcome Measures

Disease control (DC) [at 15 months]
The primary endpoint of the trial is disease control (DC) at 15 months.

Secondary Outcome Measures

Overall response (OR) [at 15 months]
Overall response (OR) according to modified RECIST and PCWG2 recommendations.
Event-free survival (EFS) [at 15 months]
EFS is defined as the time from randomization until progression or death due to any reason.
Adverse events (AEs) [at 15 months]
AEs will be assessed according to NCI CTCAE v4.0.
Overall survival (OS) [at 15 months]
OS will be calculated from randomization until death due any reason.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Inclusion Criteria:

Written informed consent according to ICH/GCP regulations before registration and prior to any trial-related investigations
Histologically or cytological confirmed adenocarcinoma of the prostate without small cell carcinoma or small cell components
Asymptomatic or minimally symptomatic patients in relation to disease
Metastatic adenocarcinoma of the prostate documented by imaging (CT/MRI and/or bone scan)
Ongoing androgen deprivation therapy with Gonadotropin-releasing hormone GnRH analogues or bilateral orchiectomy (i.e. surgical or medical castration)
Total testosterone levels ≤ 1.7 nmol/L (corresponding to ≤ 50 ng/dL)
Tumor progression at the time of registration, defined as per protocol.
Completed baseline QoL and pain questionnaires
Male patients ≥ 18 years
WHO performance status 0-2
Adequate hematologic values: hemoglobin ≥ 90 g/L, neutrophils ≥ 1.0 x 109/L, platelets ≥ 75 x 109/L
Adequate hepatic function: ALT and AST ≤ 2.5 x ULN, bilirubin ≤ 1.5 x ULN (exception if Gilbert's syndrome ≤ 2.5 x ULN)
Adequate renal function: calculated creatinine clearance ≥ 50 mL/min, according to the formula of Cockcroft-Gault
Patient is able to swallow the trial drugs and comply with trial requirements
Patient agrees not to father a child during participation in the trial and during 3 months thereafter
Patient agrees to participate to the mandatory translational research part of the trial with exception of Pyruvate dehydrogenase sub-study.

Exclusion Criteria:

Known or suspected Central nervous system CNS metastases or active leptomeningeal disease
Previous malignancy within 2 years prior to registration, with the exception of localized non-melanoma skin cancer and Ta and Tis bladder cancer
Prior treatment for prostate cancer with
novel endocrine agents (including abiraterone acetate, enzalutamide, TAK-700, TAK-683, TAK-448, VT464, darolutamide, apalutamide),
radioisotopes,
TKI and other small molecules,
immunotherapy,
chemotherapy (with the exception of docetaxel chemotherapy in hormone sensitive prostate cancer)
Treatment with experimental drugs or treatment within a clinical trial within 30 days prior to registration (except the clinical trial SAKK 96/12, PEACE-4 and/or the biobank project SAKK 63/12)
Clinically significant cardiovascular disease including:
Myocardial infarction within 6 months prior to registration,
Uncontrolled angina within 3 months prior to registration,
Congestive heart failure NYHA class III or IV,
QTc interval > 480 ms,
History of clinically significant ventricular arrhythmias (e.g. ventricular tachycardia, ventricular fibrillation, torsades de pointes),
History of Mobitz II second or third degree heart block without a permanent pacemaker in place,
Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg OR diastolic blood pressure > 105 mmHg
Severe concurrent disease, infection, or co-morbidity that, in the judgment of the investigator, would make the patient inappropriate for enrollment (e.g. uncontrolled or acute severe infection, advanced chronic obstructive pulmonary disease, heart failure)
Known history of HIV, hepatitis B, hepatitis C
Major surgery within 4 weeks prior to registration
Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer disease within 3 months prior to registration)
Treatment with metformin within the last 6 months prior to registration
Patients on pharmacotherapy for diabetes mellitus
History of diabetic ketoacidosis, diabetic coma and pre-coma
Known history of seizures or any conditions that may predispose to seizure. History of loss of consciousness or transient ischemic attack within 12 months prior to registration
Concurrent anticoagulation with rivaroxaban or warfarin
Known hypersensitivity to the IMPs or hypersensitivity to any of their components
Any concomitant drugs contraindicated for use with the IMPs according to the Swissmedic approved product information
Any psychological, familial, sociological or geographical condition potentially hampering compliance with the trial protocol and follow-up.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Kantonsspital Aarau	Aarau	Switzerland	5001
2	Universitaetsspital Basel	Basel	Switzerland	4031
3	Istituto Oncologico della Svizzera Italiana (IOSI)	Bellinzona	Switzerland	6500
4	Kantonsspital Graubuenden	Chur	Switzerland	7000
5	Spital Thurgau AG	Frauenfeld	Switzerland	CH-8500
6	Hôpitaux Universitaires de Genève	Genève 14	Switzerland	1211
7	CCAC Lausanne	Lausanne	Switzerland	1004
8	Luzerner Kantonsspital	Luzern 16	Switzerland	6000
9	Hôpital du Valais	Martigny	Switzerland	1920
10	Kantonsspital Olten	Olten	Switzerland	CH-4600
11	Hôpital du Valais	Sion	Switzerland	1951
12	Bürgerspital Solothurn	Solothurn	Switzerland	CH-4500
13	Kantonsspital St. Gallen	St. Gallen	Switzerland	9007
14	Kantonsspital Winterthur	Winterthur	Switzerland	8401
15	Stadtspital Triemli	Zürich	Switzerland	8063
16	UniversitätsSpital Zürich	Zürich	Switzerland	8091