A randomized double-blind phase II study evaluating the role of maintenance therapy with cabozantinib in High Grade Undifferentiated Uterine Sarcoma (HGUS) after stabilization or response to doxorubicin +/- ifosfamide following surgery or in metastatic first line treatment
- Conditions
- High Grade Undifferentiated Uterine Sarcoma (HGUS)MedDRA version: 17.0Level: LLTClassification code 10046821Term: Uterine sarcoma NOSSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2013-000762-11-IT
- Lead Sponsor
- European Organisation for Research and Treatment of Cancer (EORTC)
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- Female
- Target Recruitment
- 78
1) At registration
- Patients who are suitable for treatment with doxorubicin +/- ifosfamide and fall within one of the following patient populations:
. Locally advanced: newly diagnosed high grade undifferentiated uterine sarcoma with advanced disease (stage III or stage IV) or residual disease after primary surgery
. Metastatic: diagnosed high grade undifferentiated uterine sarcoma with disease relapse after local treatment for primary tumor
- 1 formalin fixed paraffin embedded block of tumor tissue (if not available, at least 1 haematoxylin/eosin and 15 unstained slides) is sent after registration of a patient. Histological central review is mandatory to confirm histology and grade.
- Patients must be at least 18 years old
- Before patient registration, written informed consent for central collection of tissue block or slides and any other trial-specific procedures must be obtained
2) At Randomization
- Central pathological confirmation: Histological evidence of high grade undifferentiated uterine sarcoma
- Non-progressive patients (CR, PR, SD) at the end of the first line treatment (standard chemotherapy consisting of 4 to 6 cycles of doxorubicin alone or in combination with ifosfamide)
- Patients able to swallow and retain oral tablets.
- WHO/ECOG performance status 0-2
- The subject has organ and marrow function and laboratory values as follows before randomization
. Absolute neutrophil count (ANC) = 1500/mm3 without colony stimulating factor support for 7 days
. Platelets = 100,000/mm3
. Hemoglobin = 9 g/dL
. Bilirubin = 1.5 × the upper limit of normal. For subjects with known Gilbert’s disease, bilirubin = 3.0 mg/dL
. Serum albumin = 2.8 g/dl
. Serum creatinine = 1.5 × the upper limit of normal or creatinine clearance (CrCl) = 50 mL/min. For creatinine clearance estimation, the Cockcroft and Gault equation should be used: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72) × 0.85
. Alanine aminotransferase and aspartate aminotransferase = 3.0 × the upper limit of normal
. Lipase < 2.0 × the upper limit of normal and no radiologic or clinical evidence of pancreatitis
. Urine Dipstick: If Urine Dipstick = 2+, determine Urine Protein to Creatinine Ratio (UPCR) by quantitative analysis; if UPCR = 1, then a 24-hour urine protein must be assessed. Any patient with protein > 150 mg over 24 hours would not be eligible.
. Serum phosphorus, calcium, magnesium and potassium = lower limit of normal
. Prothrombin time (PT) or international normalized ratio (INR) = 1.2 × the upper limit of normal
- Clinically normal cardiac function based on the institutional lower limit of normal (LVEF assessed by MUGA or ECHO), normal 12 lead ECG (no prolongation of corrected QT interval (QTc) > 480 msecs) and no history of any one or more of the following cardiovascular conditions within the past 6 months:
. Cardiac angioplasty or stenting
. Myocardial infarction
. Unstable angina
. Coronary artery bypass graft surgery
. Symptomatic peripheral vascular disease
. Class III or IV congestive heart failure, as defined by the New York Heart Association
- Women of child bearing potential must have a negative serum/urine pregnancy test within 3 days prior to the first dose of study treatment.
- Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 4 months after the last study treatment
At randomization
- The following tumor types are NOT eligible: low-grade ESS, leiomyosarcoma (low, intermediate or high grade), carcinosarcoma, adenosarcoma, rhabdomyosarcoma (alveolar or embryonal) and soft tissue PNET of uterus/cervix.
- concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment
- patient with poorly controlled hypertension defined at baseline as blood pressure (BP) >150/90
- patients who have suffered a cerebrovascular accident at any time in the past, patients who have suffered a transient ischemic attack in the past 6 months, patients who have suffered a deep venous thrombosis (DVT) or a pulmonary embolism in the past 6 months
note: Patients with recent DVT who have been treated with therapeutic anti-coagulating agents and remained stable for at least 6 weeks are eligible.
- Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:
? Any of the following within 28 days before the first dose of study treatment
- known intra-abdominal tumor/metastases invading GI mucosa
- active peptic ulcer disease,
- inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis
- malabsorption syndrome
? Any of the following within 6 months before the first dose of study treatment:
- abdominal or vaginal fistula
- gastrointestinal perforation
- bowel obstruction or gastric outlet obstruction
- intra-abdominal abscess. Note: Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating study treatment (Cabozantinib/placebo) even
- patients with radiographic evidence of cavitating pulmonary lesion(s).
- patients with tumor in contact with, invading or encasing any major blood vessels.
- patients evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of study treatment (Cabozantinib/placebo).
- evidence of active bleeding or bleeding diathesis.
- hemoptysis = 0.5 teaspoon (2.5ml) of red blood within 3 months before the first dose of study treatment. Note: Any patient with a prior history of hemoptysis associated with metastatic disease must have a bronchoscopy to rule out endobronchial lesions. A patient with an endobronchial lesion would be excluded from study.
- signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
- clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment
- prior major surgery or trauma within 6 weeks prior to first dose of study drug and any wound, fracture, or ulcer should be completely healed.
- concurrent or planned treatment with strong inhibitors or inducers of cytochrome P450 3A4/5 (a one week wash-out period is necessary for patients who are already on these treatments)
- contraindications to cabozantinib (e.g. no known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to cabozantinib)
- planned use of chemotherapy, radiation therapy, radionuclide treatment, small molecule TKI or hormonal therapy, and any other investigational agent (Cabozantinib/placebo) during the treatment period.
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method