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

Prostate Cancer Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02640534
• Other study ID #: SAKK 08/14 - IMPROVE
• Status: Terminated
• Phase: Phase 2
• Start date: June 10, 2016
• Est. completion date: March 16, 2023

Study information

• Verified date: June 2023
• Source: Swiss Group for Clinical Cancer Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 169
• Est. completion date: March 16, 2023
• Est. primary completion date: July 1, 2022
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cancer of the Prostate
• Prostate Cancer
• Prostatic Neoplasms

Intervention

Drug:
• Enzalutamide
Enzalutamide 160 mg od until disease progression
• Metformin
850 mg bid until disease progression

Locations

Country	Name	City	State
Switzerland	Kantonsspital Aarau	Aarau
Switzerland	Universitaetsspital Basel	Basel
Switzerland	Istituto Oncologico della Svizzera Italiana (IOSI)	Bellinzona
Switzerland	Kantonsspital Graubuenden	Chur
Switzerland	Spital Thurgau AG	Frauenfeld
Switzerland	Hôpitaux Universitaires de Genève	Genève 14
Switzerland	CCAC Lausanne	Lausanne
Switzerland	Luzerner Kantonsspital	Luzern 16
Switzerland	Hôpital du Valais	Martigny
Switzerland	Kantonsspital Olten	Olten
Switzerland	Hôpital du Valais	Sion
Switzerland	Bürgerspital Solothurn	Solothurn
Switzerland	Kantonsspital St. Gallen	St. Gallen
Switzerland	Kantonsspital Winterthur	Winterthur
Switzerland	Stadtspital Triemli	Zürich
Switzerland	UniversitätsSpital Zürich	Zürich

Sponsors (1)

Lead Sponsor	Collaborator
Swiss Group for Clinical Cancer Research

Country where clinical trial is conducted

Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease control (DC)	The primary endpoint of the trial is disease control (DC) at 15 months.	at 15 months
Secondary	Overall response (OR)	Overall response (OR) according to modified RECIST and PCWG2 recommendations.	at 15 months
Secondary	Event-free survival (EFS)	EFS is defined as the time from randomization until progression or death due to any reason.	at 15 months
Secondary	Adverse events (AEs)	AEs will be assessed according to NCI CTCAE v4.0.	at 15 months
Secondary	Overall survival (OS)	OS will be calculated from randomization until death due any reason.	at 15 months