Phase I Study to Evaluate the Tolerability, Efficacy, and Safety of Pazopanib in Combination With PCI-24781 in Patients With Metastatic Solid Tumors

Inclusion Criteria:

- Patients must provide written informed consent prior to performance of study-specific
procedures or assessments, and must be willing to adhere with treatment and
follow-up.

- Age ≥ 18 years

- Phase Ia: Patients must have histologically or cytologically documented metastatic
solid tumor malignancies.

Phase Ib: Patients must have histologically or cytologically confirmed locally advanced,
unresectable or metastatic sarcoma or renal cell carcinoma, any histologic subtype.

- Measurable disease by RECIST 1.1

- Phase Ia: Patients may have de novo metastatic disease, or documented progression
despite any number of prior therapies. Patients must have no curative or other
effective therapeutic options available.

Phase Ib: Patients with sarcoma and RCC may have had any number of prior treatments,
including 0, or prior pazopanib. Patients with sarcoma must be ineligible for chemotherapy
or must have received at least one standard chemotherapy regimen in the metastatic
setting.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

- Resolution of all chemotherapy or radiation-related toxicities to Grade 1 severity or
lower except for alopecia

- Patient must be at least 2 weeks or five half-lives (whichever is longer) from last
standard or experimental therapy, exceptions listed below

- radiation therapy, surgery or tumor embolization more than 28 days prior to the
first dose of Pazopanib/PCI-24781

- patients who have received prior pazopanib are eligible but must not have
received it in the last two weeks

- 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. GSK
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

- 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.

- Adequate organ system function

Exclusion Criteria:

- Patients with other untreated, current primary malignancies, other than carcinoma in
situ of the cervix or non-melanoma skin cancer

- History or clinical evidence of central nervous system (CNS) metastases or
leptomeningeal carcinomatosis, except for individuals who have previously-treated 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.

- Presence of active HCV or HBV infection, history of HIV, or other uncontrolled
systemic infection

- Corrected QT interval (QTc) > 480 msecs using Friedrichs formula

- Use of medications that are known to prolong cause QT prolongation

- History of any one or more of the following cardiovascular conditions within the past
6 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. 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 <140/90 mmHg in order for a subject to be eligible for the study.

- History of cerebrovascular accident, including transient ischemic attack (TIA)

- History of pulmonary embolism or untreated deep venous thrombosis (DVT) within the
past 6 months Note: Patients with recent DVT who have been treated with therapeutic
anticoagulation including Coumadin or any low molecular weight heparin for at least 6
weeks 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

- 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 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