Orteronel (TAK-700) in Metastatic or Advanced Non-resectable Granulosa Cell Ovarian Tumors. The Greko II Study. (Greko II)

Open Label Phase II Clinical Trial of Orteronel (TAK-700) in Metastatic or Advanced Non-resectable Granulosa Cell Ovarian Tumors. The Greko II Study.

Granulosa Cell ovarian carcinoma is an infrequent subtype of neoplasia well differentiated from epithelial tumors. They account for 5% of all ovarian malignancies and, with an incidence of 0.4-1.2 cases per 100000 habitants, is considered as a rare disease.

Though most cases are identified at initial stages and can be cured through surgical resection, distant recurrences have been documented even 10 years after resecting the primary tumor. At advanced stage it is a lethal disease.

Unfortunately because of the low incidence of this disease randomized clinical trials are lacking. In fact current evidence for treatment is provided by case reports, retrospective studies and phase II clinical trials performed one decade ago.

Orteronel, a novel, orally active, selective inhibitor of 17,20-lyase, is being developed as an endocrine therapy for relevant hormone-sensitive cancers such as prostate cancer and breast cancer. Orteronel is expected to suppress sex hormone levels in both circulation and relevant hormone-dependent malignant tissue. Since sex hormone overproduction has been demonstrated in granulosa cell ovarian tumors and seems to play a major role in this disease, this study will assess the efficacy or orteronel treating such tumors.

Study Overview

• Status: Terminated
• Conditions: Metastatic or Advanced Non-resectable Granulosa Cell Ovarian Tumors
• Intervention / Treatment: Drug: Orteronel 300mg BID

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08003
    • Hospital del Mar
  • Córdoba, Spain, 14004
    • Complejo Hospitalario Regional Reina Sofía
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain, 28050
    • Hospital Universitario Madrid Sanchinarro
  • Valencia, Spain, 46026
    • Hospital Universitari i Politecnic La Fe
  • Islas Baleares
    • Palma de Mallorca, Islas Baleares, Spain, 07198
      • Hospital Son Llatzer
  • La Coruña
    • Santiago de Compostela, La Coruña, Spain, 15706
      • Complexo Hospitalario Universitario De Santiago
  • Madrid
    • Alcorcón, Madrid, Spain, 28922
      • Hospital Universitario Fundacion Alcorcon
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Complejo Hospitalario de Navarra

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Voluntary written informed consent.

• Patients, even if surgically sterilized who:

  1. Agree to practice effective barrier contraception during the entire study treatment period and for 4 months after the last dose of study drug, or
  2. Agree to completely abstain from intercourse.
• Patients 18 years or older.
• Screening clinical laboratory values as specified below:
• Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be <=2.5 X ULN.
• Total bilirubin <=1.5 X ULN.
• Estimated creatinine clearance using the Cockcroft-Gault formula must be >40 mL/minute.
• Absolute neutrophil count (ANC) >=1500/mcL and platelet count >=100,000/mcL.
• Histologically confirmed granulosa cell ovarian tumor with locally advanced non-resectable or metastatic disease, measurable or evaluable by RECIST.
• Availability of sufficient biopsy material to confirm the malignant diagnosis of granulosa cell ovarian tumor by a centralized pathologist and to perform the determine the FOXL2 402C mutation → G (C134W). However study entry will be allowed based just on the histological local diagnosis.
• Life expectancy >=12 weeks
• Screening calculated ejection fraction of greater than or equal to normal by multiple gated acquisition (MUGA) scan, or by echocardiogram (ECHO).
• Stable medical condition, including the absence of acute exacerbations of chronic illnesses, serious infections, or major surgery within 4 weeks before first dose of study drug/randomization.

Exclusion Criteria:

• History of myocardial infarction, unstable symptomatic ischemic heart disease, ongoing arrhythmias of Grade > 2 (NCI CTCAE, version 4.02)(56), thromboembolic events (eg, deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), or any other cardiac condition (eg, pericardial effusion restrictive cardiomyopathy) within 6 months prior to first dose of study drug. Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed.
• New York Heart Association Class III or IV heart failure.

• ECG abnormalities of:

  1. Q-wave infarction, unless identified 6 or more months prior to screening
  2. QTc interval > 460 msec
• Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum ?- human chorionic gonadotropin (?-hCG) pregnancy test result obtained during screening.
• Patient has received other investigational drugs within 28 days before enrollment
• Diagnosed or treated for another malignancy within 2 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy.
• Prior therapy with orteronel, ketoconazole, abiraterone, aminoglutethimide or enzalutamide.
• 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.
• Known hypersensitivity to compounds related to orteronel or to orteronel excipients.
• Uncontrolled hypertension despite appropriate medical therapy (BP of greater than 160 mmHg systolic and 90 mmHg diastolic at 2 separate measurements no more than 60 minutes apart during the Screening visit). Note: patients may be rescreened after adjustment of antihypertensive medications.
• Known active chronic hepatitis B or C, life-threatening illness unrelated to cancer, or any serious medical or psychiatric illness that could, in the investigator?s opinion, potentially interfere with participation in this study.
• Likely inability to comply with the protocol or cooperate fully with the investigator and site personnel.
• Known gastrointestinal (GI) disease or GI procedure that could interfere with the GI absorption or tolerance of orteronel, including difficulty swallowing tablets.

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: Orteronel 300mg b.i.d.; Orteronel 300mg BID (600mg per day) will be administered to all included patients in a 28 days cycle schedule.	Drug: Orteronel 300mg BID

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical benefit at 6 months	Clinical benefit is defined as the average of patients with radiological response (partial or complete) plus stable disease longer than 6 months by RECIST 1.1 criteria	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	Overall Response Rate according to RECIST 1.1 criteria.	Every 8 weeks, during 6 months
Progression free survival	Progression Free Survival defined as the time from the administration of the first dose of treatment to disease progression or death from any cause.	Every 8 weeks, during 6 months
Overall Survival	Overall Survival defined as the time from first dose of treatment to patient death from any cause	Every 12 weeks, untill death
Reduction of sex hormones production.	Significant reduction of sex hormones production will be considered as at least a reduction to half the basal level confirmed in one determination one month apart.	Every 8 weeks, during 6 months
Toxicity profile	Frequency of each adverse event per patient	Every 4 weeks, untill end of treatment (6 months estimated)

Collaborators and Investigators

• Sponsor: Grupo Español de Tumores Huérfanos e Infrecuentes
• Collaborators: Takeda
• Investigators: Study Director: Jesús García-Donas, MD, Hospital Universitario Madrid Sanchinarro; Principal Investigator: Alicia Hurtado, MD, Hospital Universitario Fundacion Alcorcon; Principal Investigator: Juan Cueva, MD, Complexo Hospitalario Universitario De Santiago; Principal Investigator: Laia Garrigos, MD, Hospital del Mar; Principal Investigator: María Jesús Rubio, MD, Complejo Hospitalario Regional Reina Sofía; Principal Investigator: Andrés Redondo, MD, Hospital Universitario La Paz; Principal Investigator: Isabel Bover, MD, Hospital Son Llatzer; Principal Investigator: Nuria Lainez, MD, Complejo Hospitalario de Navarra; Principal Investigator: Ana Santaballa, MD, Hospital Universitario La Fe

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Actual): January 11, 2017
• Study Completion (Actual): January 11, 2017

Study Registration Dates

• First Submitted: March 26, 2014
• First Submitted That Met QC Criteria: March 29, 2014
• First Posted (Estimate): April 2, 2014

Study Record Updates

• Last Update Posted (Actual): March 5, 2018
• Last Update Submitted That Met QC Criteria: March 2, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Orteronel, Granulosa Cell Tumour
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Ovarian Neoplasms
• Other Study ID Numbers: GETHI 2013-01; 2013-003128-35 (EudraCT Number)