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

Phase 1

• Conditions: High Grade Uterine Sarcoma (HGUtS); MedDRA version: 20.0Level: LLTClassification code 10046821Term: Uterine sarcoma NOSSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2013-000762-11-DE
• Lead Sponsor: European Organisation for Research and Treatment of Cancer (EORTC)

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2014-08-22
• Last Update Posted: 15 April 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: Female
• Target Recruitment: 115

Inclusion Criteria

1) At registration:
Patients can be registered 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 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) after first line treatment and at time of randomization.
- Patients able to swallow and retain oral tablets.
- WHO/ECOG performance status 0-2
- Recovery to baseline or = Grade 1 CTCAE v.4.0 from toxicities related to any prior treatments, unless AE(s) are clinically non significant and/or stable on supportive therapy
- 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 metastases
. 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 Fridericia'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 cardiac arrhythmias
. 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
- Minor surgery within 28 days before the first dose of st

Exclusion Criteria

At Registration
? The following tumor types are NOT eligible: low-grade ESS, leiomyosarcoma (low or intermediate), carcinosarcoma, low-grade adenosarcoma, rhabdomyosarcoma (alveolar or embryonal) and soft tissue PNET of uterus/cervix.

At randomization
- Prior treatment with cabozantinib
- history of congenital long QT syndrome
- 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 > 100 mm 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 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: subjects with a venous filter are not eligible for this study
- Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:
- known intra-abdominal tumor/metastases invading GI mucosa
- active peptic ulcer disease,
- inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction.
- malabsorption syndrome
- Ongoing visceral complications 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 even if the abscess occurred more than 6 months before the first dose of study treatment.
- clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment
- patients with evidence of tumor invading the GI tract or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of study treatment
- patients with radiographic evidence of cavitating pulmonary lesion
- patients with tumor in contact with, invading or encasing any major blood vessels.
- patients evidence of tumor invading the GI tract, or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of study trt
- evidence of active bleeding or bleeding diathesis.
- hemoptysis = 0.5 teaspoon 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
- 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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified