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 2

Recruiting

Conditions: high grade uterine sarcoma (HGUtS)
uterine sarcoma
10038594

Registration Number: NL-OMON53073

Lead Sponsor: European Organisation for Research in Treatment of Cancer (EORTC)

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Recruiting

Sex: Not specified

Target Recruitment: 6

Inclusion Criteria

1) At registration, - 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, -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., - 1
formalin fixed paraffin embedded (FFPE) block of tumor tissue (if not
available, at least 1 H/E (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
from the patient according to ICH/GCP, and national/local regulations, allowing
for collection, storage and analysis of tissue and screening procedures., 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 standard chemotherapy (4 to 6 cycles of doxorubicin alone or in
combination with ifosfamide)., - Non-progressive patients (CR, PR, SD) at the
end of the first line standard chemotherapy (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 <= Grade
1 CTCAE v.4.0 from toxicities related to any prior treatments, unless AE(s) are
clinically nonsignificant 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 (ULN). For subjects with known
Gilbert*s disease, bilirubin <= 3.0 mg/dL
* Serum albumin >= 2.8 g/dl
* Serum creatinine <= 1.5 * ULN 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 (ALT) and aspartate aminotransferase (AST) <= 3.0 *
ULN or <= 5.0 x ULN if liver metastases
* Lipase < 2.0 x 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 >= LLN
* Prothrombin time (PT) or international normalized ratio (INR) * 1.2 X upper
limit of normal (ULN), - Clinically normal cardiac function based on the
institutional lower limit of normal (LVEF asses

Exclusion Criteria

At randomization, - 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., - No contraindications to cabozantinib (e.g. no known immediate
or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically
related to cabozantinib), - No planned use of chemotherapy, radiation therapy,
radionuclide treatment, small molecule TKI or hormonal therapy, and any other
investigational agent during the treatment period., - No prior treatment with
cabozantinib, - No concurrent severe, clinically relevant hypothyroidism or
thyroid dysfunction within 7 days before the first dose of study treatment, -
No 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;,
- No concomitant anticoagulation at therapeutic doses with oral anticoagulants
(eg, warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors
(eg, clopidogrel); , - No 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 , - No 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 (including ulcerative colitis and Crohn*s
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 (particularly when associated with delayed or
incomplete healing)
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 treatment with Cabozantinib even
if the abscess occurred more than 6 months before the first dose of study
treatment., - No clinically-significant gastrointestinal bleeding within 6
months before the first dose of study treatment, - No patients with 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)., - No patients
with radiographic evidence of cavitating pulmonary lesion(s)., - No patients
with tumor in contact with, invading or encasing any major blood vessels., - No
evidence of active bleeding or bleeding diathesis.

- No hemoptysis >= 2.5ml of red blood within 3 months before the first dose of
study treatment., - No signs indicative of pulmonary hemorrhage within 3 months
before the first dose of st

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>The primary endpoint is the progression free survival rate at 4 months after<br /><br>randomization to cabozantinib or placebo.</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>* Progression free survival (RECIST 1.1)<br /><br>* Overall survival<br /><br>* Response rate and duration of response to cabozantinib (RECIST 1.1)<br /><br>* Response rate to doxorubicin-based chemotherapy after registration on trial<br /><br>for the patients with measurable disease<br /><br>* Health-related Quality of life (QLQ-C30 + QLQ-EN24)<br /><br>* Safety of Cabozantinib in HGUS according to the Common Terminology Criteria<br /><br>for Adverse events version 4.0 (CTCAE 4.0)</p><br>