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

Open Phase II Study of Ketoconazole as Inhibitor of the Enzyme CYP17 in Locally Advanced or Disseminated Granulosa Cell Tumour of Ovary. GreKo Study.

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.

Study Overview

• Status: Terminated
• Conditions: Granulosa Cell Tumour of the Ovary
• Intervention / Treatment: Drug: Ketoconazole

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: Fungarest

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate	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	Every 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical benefit	Clinical benefit defined as stable disease for more than 6 months plus complete and partial response rates, measured by an external evaluator.	Every 8 weeks
Progression-free survival	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.	Every 8 weeks
Overall survival	Overall survival, defined as the time since the start of treatment until the patient dies by any cause.	Untill death
Quality of life	Quality of life measured by the validated in Spanish EORTC QLQ-C30 questionnaire.	Every 4 weeks
Safety profile	Toxicities will be classified according to the NCI-CTCAE v4.03	Every 4 weeks

Collaborators and Investigators

• Sponsor: 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

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): November 1, 2014
• Study Completion (Actual): November 1, 2014

Study Registration Dates

• First Submitted: April 22, 2012
• First Submitted That Met QC Criteria: April 22, 2012
• First Posted (Estimate): April 24, 2012

Study Record Updates

• Last Update Posted (Estimate): January 21, 2015
• Last Update Submitted That Met QC Criteria: January 19, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: Granulosa Cell Tumour
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Neoplasms, Gonadal Tissue; Sex Cord-Gonadal Stromal Tumors; Ovarian Neoplasms; Granulosa Cell Tumor; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Ketoconazole
• Other Study ID Numbers: GETHI 2011-03; 2012-001948-21 (EudraCT Number)