MLN8237 and Pazopanib in Combination for Solid Tumors

Alisertib is taken orally twice a day for the 1st 7 days of a 21 day cycle. Pazopanib is
taken orally once a day continuously beginning on day 10 of cycle 1 to allow for alisertib
pharmacokinetics (PKs). Treatment continues until disease progression, unacceptable
toxicity, or patient refusal. PKs will be done on all patients in association with the last
dose of alisertib cycles 1 and 2.

Inclusion Criteria:

- Diagnosis of advanced non-hematologic solid tumor malignancy that has failed/become
intolerant to standard therapy

- Measurable disease per RECIST

- Age ≥ 18 years

- ECOG PS of 0-2

- Prior systemic chemotherapy, immunotherapy, or biological therapy is allowed; however
prior use of study drugs in combination is not allowed.

- Must have recovered from the reversible effects of previous anti-cancer tx

- Adequate organ function within 14 days of study registration

- Patient must be able to take oral medication and to maintain a fast as required for 2
hrs before and 2 hrs after alisertib admin.

- Subjects agrees to use contraception, as needed

Exclusion Criteria:

- Untreated or symptomatic CNS metastases

- Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is
excluded.

- Prior allogeneic BMT

- >or = Grade 2 peripheral neuropathy within 14 days before enrollment

- Known history of uncontrolled sleep apnea & other conditions that could result in
excessive daytime sleepiness

- Requirement for constant admin. of proton pump inhibitor, H2 antagonist, or
pancreatic enzymes.

- Systemic infection requiring IV antibiotics within 14 days preceding the 1st dose of
study drug, or other severe infection.

- MI within 6 mos. prior to enrollment or has NYHA Class III or IV heart failure,
uncontrolled angina, severe uncontrolled ventricular arrhythmias, CVA, pulmonary
embolism or untreated DVT or evidence of acute ischemia or active conduction system
abnormalities on ECG (e.g., repeated QTc interval > 450 msec)

- Pregnant or breast-feeding.

- Patient has received other investigational drugs with 14 days

- Serious medical/psychiatric illness in the opinion of the PI would likely interfere
with participation

- Diagnosed or treated for another malignancy within 3 years of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.

- Treatment with clinically significant enzyme inducers, such as the enzyme inducing
antiepileptic drugs phenytoin, carbamazepine or phenobarbital, or rifampin,
rifabutin, rifapentine or St. John's wort within 14 days

- Known history of HIV infection, hepatitis B, or hepatitis C.

- Recent (within 6 months) arterial thromboembolic events, including TIA, CVA, unstable
angina, or MI. Pts. with clinically significant PAD are ineligible.

- History of thrombotic or hemorrhagic disorders, not receiving chronic daily treatment
with ASA (>325 mg/day) or NSAIDs known to inhibit platelet function. Treatment with
dipyridamole (persantine), ticlopidine (Ticlid), clopidogrel (Plavix) and/or
cilostazol (Pletal).

- History of abdominal fistula, GI perforation, or intra-abdominal abscess within 28
days prior to beginning study treatment

- Clinically significant GI abnormalities that may affect absorption of IP including,
but not limited to:

- Ongoing nausea or vomiting of any severity

- > grade 1 diarrhea

- Malabsorption syndrome

- Major resection of stomach or small bowel

- Inability to swallow oral medications or inability to take nothing by mouth except
water and prescribed medications for 2 hrs before and 2 hrs after each dose of
alisertib.

- Poorly controlled HTN [SBP of ≥140 mmHg or DBP of ≥ 90mmHg].

- Prior major surgery/trauma within 28 days or presence of any non-healing wound,
fracture, or ulcer

- Evidence of active bleeding

- Known endobronchial lesions or involvement of large pulmonary vessels by tumor or
centrally located pulmonary cavitating lesion

- Hemoptysis within 6 weeks

- Unable or unwilling to D/C use of prohibited medications for at least 14 days prior
to the 1st dose of study drug and for the duration of the study

- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to pazopanib or
alisertib