Phase II Clinical Trial of Pazopanib to Evaluate the Activity and Tolerability in Patients With Advanced and/or Metastatic Liposarcoma Who Have Relapsed Following Standard Therapies or for Whom no Standard Therapy Exists
1. Subjects must provide written informed consent prior to performance of study-specific
procedures or assessments and must be willing to comply with treatment and follow-up.
Informed consent must be obtained prior to start of the specified screening window.
Procedures conducted as part of the subject's routine clinical management (e.g.,
blood count, imaging study such as bone scan) and obtained prior to signing of
informed consent may be utilized for screening or baseline purposes provided these
procedures are conducted as specified in the protocol.
2. Age ≥ 18 years or legal age of consent if greater than 18 years
3. Histological confirmed diagnosis of high or intermediate grade malignant liposarcoma
with metastatic or locally advanced disease. Formalin fixed paraffin embedded tumour
block and/or representative H/E (haematoxylin/eosin) slides must be available for
central pathologic review to classify tumors in the 2 eligible subtypes:
Well-differentiated liposarcoma/de-differentiated liposarcoma (ALT-WD) Myxoid/round
4. Patient must have documentation of disease progression within 6 months prior to study
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
6. Measurable disease by RECIST v1.1 criteria. At least one measurable lesion located
outside of a previously irradiated area. If the only measurable lesion is in a
previously irradiated area, RECIST progression should be documented after
radiotherapy, in the previous 6 months before study entry.
7. The patient should not be considered eligible for surgery or radical radiotherapy.
e.g. Patients to whom surgery/radiotherapy can not be performed with a curative
intent due to the extension of the disease. In the case of radiotherapy, it may also
be limited due to a previous treatment with radiotherapy in the same area.
8. The patient must have either been considered ineligible for systemic chemotherapy or
received at least one previous regimen for relapsed, refractory or metastatic
disease. A maximum of three previous lines for advanced/metastatic disease are
Patients not eligible for systemic chemotherapy:
Because of age, a biological condition or patient-refusal Generally, patients that
received anthracyclines in the adjuvant setting are not eligible for first line
therapy with this agent for advanced disease.
Patients with a solitary kidney or >60 years old are usually not the best candidates
for treatment with regular doses of ifosfamide.
9. Tumor tissue must be provided for all subjects for biomarker analysis before/during
treatment with investigational product.
10. The patient should be able to swallow and retain study drug
11. Adequate organ system function as defined:
Absolute neutrophil count (ANC)≥ 1.5 X 109/L Hemoglobin ≥ 9 g/dL (5.6 mmol/L)
Platelets ≥ 100 X 109/L Prothrombin time (PT) or international normalized ratio
(INR)≤ 1.2 X ULN Activated partial thromboplastin time (aPTT)≤ 1.2 X ULN Total
bilirubin≤ 1.5 X ULN Alanine amino transferase (ALT) and Aspartate aminotransferase
(AST) ≤ 2.5 X ULN Serum creatinine ≤ 1.5 mg/dL (133 µmol/L)Or, if >1.5 mg/dL:
Calculated creatinine clearance (ClCR)≥ 30 mL/min to ≥ 50 mL/min Urine Protein to
Creatinine Ratio (UPC) <1 Or, 24-hour urine protein <1g
1. Subjects may not have had a transfusion within 7 days of screening assessment.
2. Subjects receiving anticoagulant therapy are eligible if their INR is stable and
within the recommended range for the desired level of anticoagulation.
3. Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (upper limit of
normal) are not permitted.
4. If UPC ≥ 1, then a 24-hour urine protein must be assessed. Subjects must have a
24-hour urine protein value <1 g to be eligible. Use of urine dipstick for
baseline renal function assessment is not acceptable.
12. A female is eligible to enter and participate in this study if she is of:
Non-childbearing potential (i.e., physiologically incapable of becoming pregnant),
including any female who has had:
A hysterectomy A bilateral oophorectomy (ovariectomy) A bilateral tubal ligation Is
post-menopausal Female subjects not using hormone replacement therapy (HRT) must have
experienced total cessation of menses for ≥ 1 year and be greater than 45 years in
age, OR, in questionable cases, have a follicle stimulating hormone (FSH) value >40
mIU/mL and an estradiol value < 40pg/mL (<140 pmol/L).
Female subjects using HRT must have experienced total cessation of menses for ≥ 1
year and be greater than 45 years of age OR have had documented evidence of menopause
based on FSH and estradiol concentrations prior to initiation of HRT
Childbearing potential, including any female who has had a negative serum pregnancy
test within 2 weeks prior to the first dose of study treatment, preferably as close
to the first dose as possible, and agrees to use adequate contraception. The
acceptable contraceptive methods, when used consistently and in accordance with both
the product label and the instructions of the physician, are as follows:
Complete abstinence from sexual intercourse for 14 days before exposure to
investigational product, through the dosing period, and for at least 21 days after
the last dose of investigational product Oral contraceptive, either combined or
progestogen alone Injectable progestogen Implants of levonorgestrel Estrogenic
vaginal ring Percutaneous contraceptive patches Intrauterine device (IUD) or
intrauterine system (IUS) with a documented failure rate of less than 1% per year
Male partner sterilization (vasectomy with documentation of azoospermia) prior to the
female subject's entry into the study, and this male is the sole partner for that
subject Double barrier method: condom and an occlusive cap (diaphragm or
cervical/vault caps) with a vaginal spermicidal agent
(foam/gel/film/cream/suppository) Female subjects who are lactating should
discontinue nursing prior to the first dose of study drug and should refrain from
nursing throughout the treatment period and for 14 days following the last dose of
13. LVEF above the lower limit of normal for the institution, based on ECHO or MUGA.
1. Prior history of malignancies other than liposarcoma. Subjects who have had another
malignancy and have been disease-free for 3 years, or subjects with a history of
completely resected non-melanomatous skin carcinoma or successfully treated in situ
carcinoma are eligible.
2. Clinical evidence of central nervous system (CNS) metastases or leptomeningeal
carcinomatosis, except for individuals who have previously-treated CNS metastases,
are asymptomatic, and have had no requirement for steroids or anti-seizure medication
for 6 months prior to first dose of study drug. Screening with CNS imaging studies
(computed tomography [CT] or magnetic resonance imaging [MRI]) is required only if
clinically indicated or if the subject has a history of CNS metastases.
3. Clinically significant gastrointestinal abnormalities that may increase the risk for
gastrointestinal bleeding including, but not limited to:
Active peptic ulcer disease Known intraluminal metastatic lesion/s with risk of
bleeding Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or
other gastrointestinal conditions with increased risk of perforation History of
abdominal fistula, gastrointestinal perforation, or intra‑abdominal abscess within 28
days prior to beginning study treatment.
4. Clinically significant gastrointestinal abnormalities that may affect absorption of
investigational product including, but not limited to:
Malabsorption syndrome Major resection of the stomach or small bowel.
5. Corrected QT interval (QTc) > 480 msecs
6. History of any one or more of the following cardiovascular conditions within the past
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 (NYHA)
7. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 mmHg
or diastolic blood pressure (DBP) of ≥ 90mmHg].
Initiation or adjustment of antihypertensive medication(s) is permitted prior to
study entry. Following antihypertensive medication initiation or adjustment, blood
pressure (BP) must be re-assessed three times at approximately 2-minute intervals. At
least 24 hours must have elapsed between anti-hypertensive medication initiation or
adjustment and BP measurement. These three values should be averaged to obtain the
mean diastolic blood pressure and the mean systolic blood pressure. The mean SBP /
DBP ratio must be <140/90 mmHg (OR 150/90 mm Hg, if this criterion is approved by
Safety Review Team) in order for a subject to be eligible for the study.
8. History of cerebrovascular accident including transient ischemic attack (TIA),
pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6
Subjects with recent DVT who have been treated with therapeutic anti-coagulating
agents for at least 6 weeks are eligible
9. Major surgery or trauma within 28 days prior to first dose of investigational product
and/or presence of any non-healing wound, fracture, or ulcer (procedures such as
catheter placement not considered to be major surgery).
10. Evidence of active bleeding or bleeding diathesis.
11. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that
increase the risk of pulmonary hemorrhage.
Lesions infiltrating major pulmonary vessels (contiguous tumour and vessels) are
excluded; however, the presence of a tumor that is touching, but not infiltrating
(abutting) the vessels is acceptable (CT with contrast is strongly recommended to
evaluate such lesions).
12. Recent hemoptysis (≥ ½ teaspoon of red blood within 8 weeks before first dose of
13. Any serious and/or unstable pre-existing medical, psychiatric, or other condition
that could interfere with subject's safety, provision of informed consent, or
compliance to study procedures.
14. Unable or unwilling to discontinue use of prohibited medications listed in section
7.4 of this protocol or at least 14 days or five half-lives of a drug (whichever is
longer) prior to the first dose of study drug and for the duration of the study.
15. Treatment with any of the following anti-cancer therapies:
radiation therapy, surgery or tumor embolization within 14 days prior to the first
dose of Pazopanib chemotherapy, immunotherapy, biologic therapy, investigational
therapy or hormonal therapy within 14 days or five half-lives of a drug (whichever is
longer) prior to the first dose of Pazopanib
16. Administration of any non-oncologic investigational drug within 30 days or 5 half
lives whichever is longer prior to receiving the first dose of study treatment
17. Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is
progressing in severity, except alopecia.