A randomized double-blind phase II study evaluating the role of maintenance therapy with cabozantinib in High Grade Uterine Sarcoma (HGUtS) after stabilization or response to doxorubicin +/- ifosfamide following surgery or in metastatic first line treatment
- Conditions
- High Grade Undifferentiated Uterine Sarcoma (HGUS)Therapeutic area: Diseases [C] - Cancer [C04]MedDRA version: 20.0Level: LLTClassification code 10046821Term: Uterine sarcoma NOSSystem Organ Class: 100000004864
- Registration Number
- EUCTR2013-000762-11-GB
- 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
- 54
1) At registration
- Patients can be register no earlier than 4 weeks prior to start of the 1st line treatment and no later than 4 weeks after last administration of 1st line treatment.Patients who are suitable for treatment with doxorubicin +/- ifosfamide and fall within one of the following patient populations:
. HGUS, HGESS, HGLMS and HG adenosarcoma
. FIGO Stage II and Stage III: if adjuvant chemotherapy is proposed.
. FIGO stage IV: if first line chemotherapy is proposed
- 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
Patients can be randomized within 12 weeks after last administration of 1st line treatment, before the start of protocol treatment.
- Central pathological confirmation: Histological evidence of HGUS, HGESS, HGLMS and HG adenosarcoma
- 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
- Recovery to baseline or - 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 or = 5.0 x ULN if liver metastatses
. 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) > 500 msecs according to Friderica's formula ) and no history of any one or more of the following cardiovascular conditions within the past 6 months:
. Cardiac angioplasty or stenting
Clinically significant arrhythmias
. Myocardial infarction
. Unstable angina
. Coronary artery bypass graft surgery
. Symptomatic peripheral vascular disease
At randomization
- The following tumor types are NOT eligible: low-grade ESS, leiomyosarcoma (low, or intermediate), carcinosarcoma, adenosarcoma, rhabdomyosarcoma (alveolar or embryonal) and soft tissue PNET of uterus/cervix.
- concurrent severe clinically relevant hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment
- patient with concurrent uncontrolled hypertension defined as sustained blood pressure BP > 150 mm Hg systolic or > 100mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment.
- concomitant anticoagulation at therapeutic doses with oral anticoagulants or platelet inhibitors.
- 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 or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction.
- malabsorption syndrome
- ongoing visceral complication from prior therapy
- Prior gastrointestinal surgery
? 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
- Major surgery or trauma within 12 weeks prior to first dose of study drug and/or presence of any non-healing wound, fracture or ulcer. Complete wound healing from major surgery must have occurred one month 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 u
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