Content - SAKK 08/14

SAKK 08/14 IMPROVE - Metformin combined with enzalutamide for the treatment of castration resistant prostate cancer

With the phase II trial SAKK 08/14, we investigate the efficacy of a combination of the drug metformin and a treatment with enzalutamide. We compare this combination with a treatment with only enzalutamide. This trial involves patients with castration resistant prostate cancer (prostate cancer that does not react to a hormone therapy anymore).

 

Enzalutamide treatment is a type of hormone therapy and works by stopping the hormone testosterone reaching the prostate cancer cells. Without testosterone, the cancer cells cannot grow, wherever they are in the body.

Metformin is normally used in the treatment of diabetes and is an active substance that constrains the production of glucose in the liver and helps muscles to absorb glucose. However, metformin has demonstrated favorable effects on cancer treatment. There are clues that it may induce disease stabilization and improve metabolic endpoints in patients with castration resistant prostate cancer. Therefore, adding metformin to enzalutamide might have a positive impact.

For this trial, we offer 168 patients with an already spread prostate cancer without small cell features to participate.

Study Chair:

Dr. med Christian Rothermundt, Cantonal Hospital of St.Gallen, +41 71 494 11 63

  • Contacts at the hospitals

  • 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 features
    • 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, ODM201, ARN509),

      • radioisotopes,

      • TKI and other small molecules,

      • immunotherapy or

      • 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 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.

Locations for this trial:

Kantonsspital Aarau
Tellstrasse 25
0 5001 Aarau
Kantonsspital Baden
Im Ergel 1
4600 Baden
Universitätsspital Basel
Petersgraben 4
0 4031 Basel
Kantonsspital Graubünden
Loëstrasse 170
7000 Chur
Istituto Oncologico della Svizzera Italiana IOSI
Via Ospedale
0 6500 Bellinzona
Spital Thurgau, Kantonsspital Frauenfeld
Waldeggstrasse 8A
0 8501 Frauenfeld
Hôpitaux Universitaires de Genève HUG
Rue Gabrielle-Perret-Gentil 4
0 1205 Genève
CCAC Centre de Chimiothérapie Anti-Cancéreuse
Avenue d'Ouchy 35
0 1006 Lausanne
Kantonsspital Luzern
Spitalstrasse
0 6000 Luzern
Kantonsspital Olten
Baslerstrasse 150
0 4600 Olten
Solothurner Spitäler AG (soH)
Schöngrünstrasse 42
0 4500 Solothurn
Kantonsspital St. Gallen
Rorschacher Strasse 95
0 9007 St. Gallen
Kantonsspital Winterthur
Brauerstrasse 15
0 8401 Winterthur
Stadtspital Triemli
Birmensdorferstrasse 497
0 8063 Zürich
UniversitätsSpital Zürich
Rämistrasse 100
0 8091 Zürich
Hôpital du Valais Sion
Avenue du Grand-Champsec 80
0 1951 Sion
CCAC Centre de Chimiothérapie Anti-Cancéreuse
Route de Villars 37
0 1700 Fribourg
Hôpital du Valais Martigny
Av. de la Fusion 27
0 1920 Martigny
Spital Thurgau, Kantonsspital Münsterlingen
Spitalcampus 1
0 8596 Münsterlingen