Pazopanib Hydrochloride and Topotecan Hydrochloride in Treating Patients With Metastatic Soft Tissue and Bone Sarcomas

PRIMARY OBJECTIVES:

I. To determine progression free rate at week 12 for patients with soft tissue sarcoma (STS)
treated with pazopanib (pazopanib hydrochloride) plus oral topotecan (topotecan
hydrochloride).

SECONDARY OBJECTIVES:

I. To determine the overall response rate for patients with STS treated with combination
pazopanib and topotecan.

II. To determine the clinical benefit rate (complete response [CR] + partial response [PR] +
stable disease [SD]) for patients with STS treated with combination pazopanib and topotecan.

III. To determine median progression-free rate (PFR) for patients with STS treated with
combination pazopanib and topotecan.

IV. To evaluate overall survival (OS) for patients with STS treated with combination
pazopanib and topotecan.

V. To assess safety and tolerability for patients treated with combination pazopanib and
topotecan.

VI. To estimate the PFR for patients with osteosarcoma treated with combination pazopanib and
topotecan.

VII. To estimate the PFR for patients with liposarcoma treated with combination pazopanib and
topotecan.

TERTIARY OBJECTIVES:

I. To estimate the correlation of PFR and OS to levels of soluble vascular endothelial growth
factor receptor 2 (sVEGFR2) and phosphatidylinositol-glycan biosynthesis class F (PIGF).

OUTLINE:

Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-28 and
topotecan hydrochloride PO on days 1, 8, and 15. Courses repeat every 28 days in the absence
of disease progression or unacceptable toxicity or until discontinuation per patient
preference or physician recommendation.

After completion of study treatment, patients are followed up every 6 months for 2 or 5
years.

Inclusion Criteria:

- Patients 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

- Patients must have a histologically confirmed diagnosis of:

- Metastatic soft tissue sarcomas (non-liposarcoma)

- Metastatic osteosarcoma

- Metastatic liposarcoma- high grade, de-differentiated, or myxoid Note: pathology
is not required to be reviewed at the treating institution; a copy of the
pathology report is sufficient for eligibility purposes

- Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status
of 0-1

- Patients must have measurable disease within 4 weeks prior to registration by Response
Evaluation Criteria In Solid Tumors (RECIST) 1.1, defined as at least one lesion that
can be accurately measured in at least one dimension (longest diameter to be recorded)
as >= 20 mm with conventional techniques or as >= 10mm with spiral computed tomography
(CT) scan

- Patients must have had a minimum of 1 and a maximum of 4 prior chemotherapy regimens
for recurrent/metastatic disease; it will be up to the investigator to determine what
constitutes a "regimen" in each case; the last dose of systemic therapy much have been
given at least 4 weeks prior to initiation of therapy; patients receiving BCNU or
mitomycin C must have received their last dose at least 6 weeks prior to initiation of
therapy

- Patients with brain metastasis are eligible for participation only if they have been
treated with definitive surgery or radiation (surgery ± radiotherapy, radiosurgery, or
gamma knife) and meet both of the following criteria: a) are asymptomatic and b) have
no requirement for steroids or enzyme-inducing anticonvulsants in prior 12 week
interval

- Absolute neutrophil count (ANC) >= 1.5 X 10^9/L (tested within 7 days prior to
Registration)

- Hemoglobin >= 9 g/dL (5.6 mmol/L)

- Subjects may not have had a transfusion within 7 days of screening assessment

- Platelets >= 100 X 10^9/L

- Subjects may not have had a transfusion within 7 days of screening assessment

- Prothrombin time (PT) or international normalized ratio (INR) =< 1.2 X upper limit of
normal (ULN)

- Subjects receiving anticoagulant therapy are eligible if their INR is stable and
within the recommended range for the desired level of anticoagulation

- 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

- Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (upper limit of
normal) are not permitted

- Serum creatinine =< 1.5 mg/dL (133 umol/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

- 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 renal
function assessment is not acceptable

- Females of child-bearing potential (FOCBP) and males must agree to use adequate
contraception prior to study entry, for the duration of study participation, and for
30 days following completion of therapy; should a female patient become pregnant or
suspect she is pregnant while participating in this study, she should inform her
treating physician immediately; Note: a FOCBP is any woman (regardless of sexual
orientation, having undergone a tubal ligation, or remaining celibate by choice) who
meets the following criteria:

- Has not undergone a hysterectomy or bilateral oophorectomy

- Has had menses at any time in the preceding 12 consecutive months (and therefore
has not been naturally postmenopausal for > 12 months)

- FOCBP must have a negative pregnancy test within 7 days prior to registration on study

- Note: female patients 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 study drug

- Are able to swallow and retain oral tablets

Exclusion Criteria:

- Patients with any of the following sarcoma histologic subtypes will not be eligible
for participation:

- Alveolar soft-part sarcoma

- Chondrosarcoma

- Dermatofibrosarcoma

- Ewing sarcoma

- Gastrointestinal stromal tumor (GIST)

- Kaposi sarcoma (non-human immunodeficiency virus [HIV] and HIV related disease)

- Mixed mesodermal tumor/carcinosarcoma

- Low grade (grade 1) sarcomas

- Rhabdomyosarcoma (embryonal, alveolar, pleomorphic)

- Interdigitating dendritic sarcoma

- Giant cell tumor of the bone

- Patients must not have received prior treatment with pazopanib or topotecan

- Patients must not have an active secondary malignancy

- Prior malignancy, unless they have been disease-free for 3 years, or have a history of
completely resected non-melanomatous skin carcinoma or successfully treated in situ
carcinoma

- 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

- 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

- Corrected QT interval (QTc) > 480 msecs using Bazett's formula

- History of any one or more of the following cardiovascular conditions within the past
12 months:

- 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)

- Poorly controlled hypertension [defined as systolic blood pressure (SBP) of >= 140
mmHg or diastolic blood pressure (DBP) of >= 90mmHg Note: 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 deemed safe by principal investigator
[PI] and the quality assurance monitor [QAM]) in order for a patient to be eligible
for the study

- Patients with a history of cerebrovascular accident including transient ischemic
attack (TIA), pulmonary embolism, or untreated deep venous thrombosis (DVT); patients
with DVT must have received appropriate therapy for at least 6 months to be considered
eligible

- 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)

- Evidence of active bleeding or bleeding diathesis

- Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that
increase the risk of pulmonary hemorrhage

- Large protruding endobronchial lesions in the main or lobar bronchi are excluded;
however, endobronchial lesions in the segmented bronchi are allowed

- Lesions extensively infiltrating the main or lobar bronchi are excluded; however,
minor infiltrations in the wall of the bronchi are allowed

- Recent hemoptysis (>= 1/2 teaspoon [2.5 mL]) of red blood within 8 weeks before first
dose of study drug

- Any serious and/or unstable pre-existing medical, psychiatric, or other condition that
could interfere with patient's safety, provision of informed consent, or compliance to
study procedures

- Unable or unwilling to discontinue use of inducers and inhibitors of cytochrome P450
(CYP450) listed for 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;
cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) substrates can be
administered, but investigators will need to be aware of possible increased or
decreased effectiveness of the non-study drug and this should be recorded in
concomitant medications; breast cancer resistance protein (BCRP) and p-glycoprotein
(PgP) inducers and inhibitors will be also prohibited

- Treatment with any of the following anti-cancer therapies:

- Radiation therapy, surgery or tumor embolization within 14 days prior to the
first dose of therapy

- 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 therapy

- 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

- Any ongoing toxicity related to prior anti-cancer therapy that is > grade 1 and/or
that is progressing in severity (exceptions include alopecia, fatigue, and hematologic
toxicities)

- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to pazopanib or topotecan