Phase ii open study of ketoconazole as an inhibitor of enzyme

PHASE II OPEN STUDY OF KETOCONAZOLE AS AN INHIBITOR OF ENZYME
CYP17 LOCALLY ADVANCED OR DISSEMINATED GRANULOSA CELL OVARIAN
CANCER. GREKO (GRANULOSA ET KETOCONAZOLE) STUDY

EUDRACT Nº: 2012-001948-21
RATIONALE

Granulosa cell tumours of the ovary are a very uncommon entity. Since 2009 we have been aware that 100% of the cases present a mutation in the FOXL2 gene, which has a protein that indirectly regulates expression of the CYP17 enzyme. This enzyme has been used as a therapeutic target in prostate cancer, so similar results could be obtained in this pathology. The GREKO trial sets out to establish the potential activity of an enzyme CYP17 inhibitor, ketoconazole, in ovarian granulosa cell tumours. INCLUSION CRITERIA

• Patients who have given their written informed consent • Diagnosis of histologically confirmed ovarian granulosa cell carcinoma • Availability of sufficient biopsy material for confirmation of the diagnosis by a central pathologist and determination of the FOXL2 402C→G (C134W) mutation. • Patients with adequate hepatic function, defined by: - AST and ALT serum values ≤ 3 x ULN (except in the presence of metastasis, when values ≤ 5 x ULN) will be permitted • Patients with adequate bone marrow function, defined by: - Absolute neutrophil count ≥1.5 x 109/L, • Patients with adequate renal function: serum creatinine ≤1.5 x ULN • Absence of any impediment to compliance with the study protocol • Sexually active women of fertile age, not subjected to hysterectomy or double adnexectomy, have to comply with the following contraception instructions: - Pregnancy test in serum or urine negative in the 72 hours prior to the start - Use of medically accepted contraceptive method during: the 2 months prior to the start of the study treatment, during the study, 3 months after the last treatment dose.
EXCLUSION CRITERIA

• Patients with primary tumour 2 years prior to starting with the investigational drug, with the exception of properly treated or wholly removed uterine cervix carcinoma in situ or basal cell carcinoma or superficial bladder carcinoma. • Patients who have received radical radiotherapy ≤ 4 weeks prior to starting the study treatment or who have not recovered from the toxicities of radiotherapy. Palliative radiotherapy for painful bone lesions is permitted up to 14 days prior to the start of the investigational treatment. • Patients with heart failure or clinically significant heart disease, including any of - History or presence of uncontrolled severe ventricular arrhythmias. - Clinically significant bradycardia at rest. - LVEF <45% assessed by 2-D echocardiogram (ECO) or MUGA. These tests, however, are not compulsory under the protocol. - Any of the following diseases in the 6 months prior to the start of the • Myocardial infarction (MI), severe or unstable angina, coronary revascularization, congestive cardiac insufficiency (CCI), cerebrovascular accident (CVA), transitory ischemic attack (TIA) • Patients with gastrointestinal function failure or with gastric disease causing significant alteration in ketoconazole absorption, such as for instance: severe ulcerous diseases, uncontrolled nauseas, vomiting, diarrhoea, poor absorption syndrome, extensive small bowel resection (>1m) or inability to swallow oral medication. Prior partial or total gastrectomy is not an exclusion criterion. • Diagnosis of human immunodeficiency virus (HIV) infection. • Women in fertile age not using an effective method of contraception • Patients who do not wish to or are unable to comply with the protocol.
CONTACT DATA, PARTICIPATING RESEARCH CENTRES

• CONTACT

Juan L Sanz
• COORDINATING INVESTIGATOR

Centro Integral Oncológico Clara Campal
Madrid, 28050
Coordinating investigator: Jesus Garcia-Donas, MD +34 91 267 50 62
• PARTICIPATING HOSPITALS

Complejo Hospitalario Universitario de Santiago de Compostela
Santiago de Compostela, A Coruña, 15706
Principal investigator: Juan F Cueva, MD +34 988385471
Hospital Central de Asturias
Oviedo, Asturias, 33006
Principal investigator: Emilio García Esteban, MD +34 985108000
Hospital Universitario Fundación Alcorcón
Alcorcón, Madrid, 28922
Principal investigator: Alicia Hurtado, MD +34 666383649
Hospital del Mar
Barcelona, 08003
Principal investigator: Laia Garrigos, MD +34 93 248 30 00
Hospital Reina Sofía
Cordoba, 14004
Principal investigator: Maria J Rubio, MD +34 957 010 000
Hospital La Paz
Madrid, 28046
Principal investigator: Andrés Redondo, MD +34 917277000 ext 41138
Hospital Morales Meseguer
Murcia, 30008
Principal investigator: Elena García, MD +34 96836520
Complejo Hospitalario de Navarra
Navarra, 31008
Principal investigator: Nuria Lainez, MD
Hospital Son Llatzer
Palma de Mallorca, 07198
Principal investigator: Isabel Bover, MD 871202184
Hospital Universitario y Politécnico La Fe
Valencia, 46026
Principal investigator: Ana Santaballa, MD +34 966616487
Sponsor: Spanish Group for Research on Orphan and Uncommon Tumours (GETHI)
Financing Entity: Ministry of Health,
announcement of grants for fomenting independent clinical research 2011 (project
number EC11-178)

Source: http://www.grupogeico.org/docs/comunicados/estudio_greko_en.pdf