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

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 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 (NYHA)
* No history of congenital long QT syndrome, - Minor surgery (including
uncomplicated tooth extractions) within 28 days before the first dose of study
treatment with complete wound healing at least 10 days before the first dose of
study treatment is permitted., - Women of child bearing potential (WOCBP) must
have a negative serum/urine pregnancy test within 72 hours prior to the first
dose of study treatment. Females of childbearing potential are defined as
premenopausal females capable of becoming pregnant (ie, females who have had
any evidence of menses in the past 12 months, with the exception of those who
had prior hysterectomy). However, women who have been amenorrheic for 12 or
more months are still considered to be of childbearing potential if the
amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body
weight, ovarian suppression or other reasons., - 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., - Female subjects who are breast
feeding should discontinue nursing prior to the first dose of study treatment
and until 8 weeks after the last study treatment., - Absence of any
psychological, familial, sociological or geographical condition potentially
hampering compliance with the study protocol and follow-up schedule; those
conditions should be discussed with the patient before registration in the
trial

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 study treatment, - No 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., - Patients with
clinically relevant ongoing complications from prior surgery are not eligible,
- No poor oral hygiene or invasive dental or orofacial procedures within 28
days before the first dose of study treatment., - Prior radiation therapy:, *
No radiation therapy for bone metastasis within 2 weeks, or any other external
radiation therapy within 2 weeks before the first dose of study treatment.
Patient must have fully healed and there are no ongoing sequelae from the
previous radiation therapy before the first dose of study treatment.
* No systemic treatment with radionuclides within 6 weeks before the first dose
of study treatment.
* Patients with clinically relevant ongoing complications from prior radiation
therapy are not eligible., - No 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) , - No other
malignancies within 5 years prior to randomization, with the exception of those
with a negligible risk of metastasis or death, treated with expected curative
outcome (such as adequately treated carcinoma in situ of the cervix, basal or
squamous cell skin cancer, ductal carcinoma in situ treated surgically with
curative intent, and non-muscle invasive urothelial cell carcinoma).