A Phase II Trial Comparing Gemcitabine and Pazopanib Versus Gemcitabine and Docetaxel for Patients With Advanced Soft Tissue Sarcoma

The purpose of this study is to test the effectiveness and safety of Gemcitabine and
Pazopanib compared with Gemcitabine and Docetaxel in participants with soft tissue sarcoma.
Screening tests will be done to ensure subjects are eligible to participate in this study. If
the exams, tests and procedures show that subjects can be in the study, and they choose to
take part, then they will be "randomized" into one of the two study groups: Group 1 or Group
2. Subjects in Group 1 will receive Gemcitabine 1000 mg/m2 intravenously (directly into a
vein) on Day 1 and Day 8 and Pazopanib 800mg by mouth daily. Subjects in Group 2 will receive
Gemcitabine 900 mg/m2 intravenously on Day 1 and Day 8 and Docetaxel 100 mg/m2 intravenously
on Day 8. Both groups will be in 21 day cycles. Both groups will be asked to complete
"quality of life" questionnaires, on their first visit, then at 6 weeks (2nd cycle), 18 weeks
(6th cycle) and at the end of study treatment. Subjects will be followed for up to 2 years.

- 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.
Procedures conducted as part of the subject's routine clinical management (e.g., blood
count, imaging study) 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.

- Age ≥ 18 years or legal age of consent if greater than 18 years.

- Histologically or cytologically confirmed diagnosis of sarcoma of soft tissue.
(Patients with liposarcoma, bone sarcoma or GIST will be excluded).

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

- Subjects must have metastatic and/or locally advanced or locally recurrent disease
that is not amenable to curative surgical resection.

- A minimum of 1 and a maximum of 3 prior chemotherapy regimens for recurrent/metastatic
disease. Patients eligible for an anthracycline should have received a prior
anthracycline containing regimen. Patients who decline or are not eligible for
anthracycline treatment may be considered for this protocol as a first line treatment.

- Patients must have measurable disease by RECIST 1.1. or cutaneous disease amenable to
serial measurements should be present. Measurable disease (a 'target' lesion) is
defined as at least one lesion that can be accurately measured in at least one
dimension (longest diameter to be recorded). Each lesion must be ≥ 10 mm when measured
by CT (CT scan slice thickness no greater than 5 mm); ≥ 10 mm caliper measurement by
clinical exam (lesions which cannot be accurately measured with calipers should be
recorded as non-measurable); and ≥ 20 mm by chest x-ray.

- Able to swallow and retain oral medication.

- Adequate organ system function

- 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

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).

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. Acceptable contraceptive
methods, when used consistently and in accordance with both the product label and the
instructions of the physician, are as follow:

- 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 study drug.

Exclusion Criteria

- Prior therapy with pazopanib, gemcitabine or docetaxel.

- Any concern for hypersensitivity to pazopanib, gemcitabine or docetaxel.

- Prior malignancy. Note: 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.

- History or 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.

- 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 and experiencing the "dumping" syndrome.

- Presence of uncontrolled infection.

- Prior mediastinal radiation

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

- History of any one or more of the following conditions within the past 6 months:

- Cardiac angioplasty or stenting

- Myocardial infarction

- Unstable angina

- Coronary artery bypass graft surgery

- Symptomatic peripheral vascular disease

- Pneumonitis

- Class III or IV congestive heart failure, as defined by the New York Heart
Association (NYHA) (Appendix D).

- Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥ 150
mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg].

Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to
study entry. BP must be re-assessed on two occasions that are separated by a minimum of 1
hour; on each of these occasions, the mean (of 3 readings) SBP/DBP values from each BP
assessment must be < 150/90 mmHg in order for a subject to be eligible for the study.

-History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary
embolism or untreated deep venous thrombosis (DVT) within the past 6 months.

Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating
agents for at least 6 weeks prior to registration and are fully anti-coagulated are
eligible.

- Prior major surgery or trauma within 28 days prior to first dose of study drug and/or
presence of any non-healing wound, fracture, or ulcer (procedures such as catheter
placement not considered to be major).

- Evidence of active bleeding or bleeding diathesis.

- Known endobronchial lesions and/or lesions infiltrating major pulmonary Hemoptysis in
excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose of study drug.

- 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.

- Unable or unwilling to discontinue use of prohibited medications listed in Section
5.2.3 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.

- Treatment with any of the following anti-cancer or non-oncologic investigational
therapies:

- radiation therapy, surgery or tumor embolization within 14 days prior to
registration.

- chemotherapy, immunotherapy, biologic therapy, investigational therapy or
hormonal therapy within 14 days or 2.5 half-lives of a drug (whichever is longer)
prior to registration.

- non-oncologic investigational products within 30 days or 5 halflives, whichever
is longer.

- Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is
progressing in severity, except alopecia.