Clinical trial NCT01584297: Ketoconazole as Inhibitor of the Enzyme CYP17 in Locally Advanced or Disseminated Granulosa Cell Tumour of Ovary
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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Granulosa Cell Tumour of the Ovary
Keywords: Granulosa Cell Tumour
Lead sponsor: Grupo Español de Tumores Huérfanos e Infrecuentes
Sponsor class: OTHER
First posted: 2012-04-24
Enrollment: 6
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Overall response rate
timeFrame: Every 8 weeks
Secondary outcomes:
measure: Clinical benefit
timeFrame: Every 8 weeks
measure: Progression-free survival
timeFrame: Every 8 weeks
measure: Overall survival
timeFrame: Untill death
measure: Quality of life
timeFrame: Every 4 weeks
measure: Safety profile
timeFrame: Every 4 weeks
Other outcomes:
Locations:
city: Santiago de Compostela
country: Spain
facility: Complejo Hospitalario Universitario de Santiago de Compostela
state: A Coruña
city: Oviedo
country: Spain
facility: Hospital Central de Asturias
state: Asturias
city: Alcorcón
country: Spain
facility: Hospital Universitario Fundación Alcorcón
state: Madrid
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Cordoba
country: Spain
facility: Hospital Reina Sofía
city: Madrid
country: Spain
facility: Hospital La Paz
city: Murcia
country: Spain
facility: Hospital Morales Meseguer
city: Navarra
country: Spain
facility: Complejo Hospitalario de Navarra
city: Palma de Mallorca
country: Spain
facility: Hospital Son Llatzer
city: Valencia
country: Spain
facility: Hospital Universitario y Politécnico La Fe
Study officials:
affiliation: Hospital Universitario Fundación de Alcorcón, Servicio de Oncología Médica, c/ Budapest, 1,28922 Alcorcón (Madrid), Spain
name: Jesus Garcia-Donas, MD
role: STUDY_DIRECTOR
References: