Ketoconazole as Inhibitor of the Enzyme CYP17 in Locally Advanced or Disseminated Granulosa Cell Tumour of Ovary (GreKo)

Study Description

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Brief Summary:

Our proposal is to conduct an open phase II clinical trial that allows us to explore the activity of ketoconazole, an inhibitor of the enzyme CYP17, in ovarian granulosa tumors similar to what has been done in prostate cancer. The rational is based on dysregulation that FOXL2 mutations present in almost all granulosa tumors result in the expression of CYP17 that appears to be key in the development and progression of the disease.

This work would represent the first attempt to address the treatment of ovarian granulosa cancer with a molecular solid rational, drawing on the recent identification of the mutation "leader" of this tumor. If succeed provide a widely available therapeutic alternative compared with current cancer therapies, with low toxicity. In addition it would open a new line of research with CYP17 enzyme inhibitors that could alter the course and outcome, usually fatal, in advanced stages of disease.

Condition or disease	Intervention/treatment	Phase
Granulosa Cell Tumour of the Ovary	Drug: Ketoconazole	Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	6 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Open Phase II Study of Ketoconazole as Inhibitor of the Enzyme CYP17 in Locally Advanced or Disseminated Granulosa Cell Tumour of Ovary. GreKo Study.
Study Start Date :	October 2012
Actual Primary Completion Date :	November 2014
Actual Study Completion Date :	November 2014

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Ketoconazole; Patients will receive ketoconazole, 400 mg three times a day. Study treatment period will be during 6 months or up to progression disease, unacceptable toxicity, death or withdraw from the study for any reason.	Drug: Ketoconazole; Patients will receive ketoconazole, 400 mg three times a day. Study treatment period will be during 6 months or up to progression disease, unacceptable toxicity, death or withdraw from the study for any reason.; Other Name: Fungarest

Outcome Measures

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Primary Outcome Measures :

1. Overall response rate [ Time Frame: Every 8 weeks ]
   The primary endpoint is overall response rate, defined as the proportion of patients with response defined as complete or partial response according to RECIST CRITERIA 1.1 measured by an external evaluator

Secondary Outcome Measures :

1. Clinical benefit [ Time Frame: Every 8 weeks ]
   Clinical benefit defined as stable disease for more than 6 months plus complete and partial response rates, measured by an external evaluator.
2. Progression-free survival [ Time Frame: Every 8 weeks ]
   Progression-free survival is defined as the time since the start of treatment until progressive disease assessed (through evaluation by an external radiologist) according to RECIST 1.1, or death by any cause.
3. Overall survival [ Time Frame: Untill death ]
   Overall survival, defined as the time since the start of treatment until the patient dies by any cause.
4. Quality of life [ Time Frame: Every 4 weeks ]
   Quality of life measured by the validated in Spanish EORTC QLQ-C30 questionnaire.
5. Safety profile [ Time Frame: Every 4 weeks ]
   Toxicities will be classified according to the NCI-CTCAE v4.03

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Patients obtained their written informed consent.
• Women ≥18 years old.
• ECOG ≤ 1.
• Histologically confirmed carcinoma of granulosa cell in ovary.
• Availability of sufficient biopsy material to confirm the diagnosis by a centralized pathologist and determination of the FOXL2 402C mutation → G (C134W).
• Metastatic or unresectable disease.
• Imaging measurable disease.
• Life expectancy ≥ 12 weeks.
• Patients with adequate hepatic function, defined by:
• Serum values of AST and ALT ≤ 3 x UNL (except in the presence of metastases then allowed values ≤ 5 x UNL)
• Total bilirubin ≤ 1.5 x UNL
• Patients with adequate bone marrow function, defined by:
• Absolute neutrophil count ≥ 1.5 x 10*9 / L
• Platelets ≥ 100 x 10*9 / L
• Hb > 9 g / dL
• Patients with adequate renal function: serum creatinine ≤ 1.5 x UNL.
• Absence of any impediment to comply with the study protocol.
• Women of childbearing potential, sexually active, not under hysterectomy or bilateral adnexectomy, should follow the following guidelines on contraception:
• Negative serum or urine pregnancy test within 72 hours before the start of treatment.
• Use of a medically accepted contraceptive method during: the 2 months prior to study treatment, during the study and 3 months after the last dose of study treatment.

Exclusion Criteria:

• Patients with another primary tumor 2 years before starting the study drug, with the exception of cervical carcinoma in situ or adequately treated or removed completely or basalioma or superficial bladder carcinoma.
• Patients received radical radiotherapy ≤ 4 weeks before starting the study treatment or who have not recovered from the toxicities of radiotherapy. Palliative radiotherapy of painful bone lesions is allowed up to 14 days before the start of study treatment.
• Patients with heart failure or clinically significant heart disease, including any of the following:
• History or presence of uncontrolled severe ventricular arrhythmia.
• Clinically significant bradycardia at rest.
• LVEF <45% assessed by 2-D echocardiogram (ECHO) or MUGA.
• Any of the following diseases within 6 months prior to the start of study drug: Myocardial infarction (MI), severe or unstable angina, coronary revascularization, congestive heart failure (CHF), stroke (CVA), transient ischemic attack (TIA).
• Patients with gastrointestinal function failure or gastric disease that significantly alter the ketoconazole absorption, for example, severe ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption, extensive resection (> 1m) of the small intestine or inability to swallow oral medication. The partial or total gastrectomy is not an exclusion criteria.
• Diagnosis of infection with human immunodeficiency virus (HIV).
• Pregnant women or nursing.
• Women of childbearing potential not using effective contraceptive method.
• Patients who are unwilling or unable to comply with the protocol.

Contacts and Locations

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Locations

Spain
Complejo Hospitalario Universitario de Santiago de Compostela
Santiago de Compostela, A Coruña, Spain, 15706
Hospital Central de Asturias
Oviedo, Asturias, Spain, 33006
Hospital Universitario Fundación Alcorcón
Alcorcón, Madrid, Spain, 28922
Hospital del Mar
Barcelona, Spain, 08003
Hospital Reina Sofía
Cordoba, Spain, 14004
Hospital La Paz
Madrid, Spain, 28046
Hospital Morales Meseguer
Murcia, Spain, 30008
Complejo Hospitalario de Navarra
Navarra, Spain, 31008
Hospital Son Llatzer
Palma de Mallorca, Spain, 07198
Hospital Universitario y Politécnico La Fe
Valencia, Spain, 46026

Sponsors and Collaborators

Grupo Español de Tumores Huérfanos e Infrecuentes

Investigators

Study Director:	Jesus Garcia-Donas, MD	Hospital Universitario Fundación de Alcorcón, Servicio de Oncología Médica, c/ Budapest, 1,28922 Alcorcón (Madrid), Spain

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Grupo Español de Tumores Huérfanos e Infrecuentes
ClinicalTrials.gov Identifier:	NCT01584297 History of Changes
Other Study ID Numbers:	GETHI 2011-03; 2012-001948-21 ( EudraCT Number )
First Posted:	April 24, 2012
Last Update Posted:	January 21, 2015
Last Verified:	January 2015

Keywords provided by Grupo Español de Tumores Huérfanos e Infrecuentes:

Granulosa Cell Tumour

Additional relevant MeSH terms:

Granulosa Cell Tumor; Ovarian Neoplasms; Sex Cord-Gonadal Stromal Tumors; Neoplasms, Gonadal Tissue; Neoplasms by Histologic Type; Neoplasms; Endocrine Gland Neoplasms; Neoplasms by Site; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Genital Neoplasms, Female; Urogenital Neoplasms; Endocrine System Diseases	Gonadal Disorders; Ketoconazole; Antifungal Agents; Anti-Infective Agents; 14-alpha Demethylase Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Steroid Synthesis Inhibitors; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Cytochrome P-450 CYP3A Inhibitors