Ixabepilone and Sunitinib Malate in Treating Patients With Progressive Advanced Solid Tumors

OBJECTIVES:

Primary

- To determine the safety and toxicity profile of ixabepilone in combination with
sunitinib malate in patients with progressive, advanced non-hematologic malignancies.

- To determine the recommended phase II dose of ixabepilone given weekly versus once
every three weeks in combination with a fixed dose of sunitinib malate in these
patients.

Secondary

- To evaluate the pharmacokinetic profiles of the combination of ixabepilone and
sunitinib malate and correlate them with activity and/or toxicity.

- To obtain preliminary efficacy data (complete response, partial response, or stable
disease) of these treatment combinations.

- To correlate changes in angiogenesis biomarkers with clinical (safety and efficacy) and
pharmacokinetic parameters in patients treated with these drug combinations.

- To estimate the optimal biological dose.

OUTLINE: This is a dose escalation study of ixabepilone. Patients are assigned to 1 of 2
treatment groups.

- Schedule A: Patients receive ixabepilone IV on days 1, 8, and 15. Beginning on day 8 of
course 1, patients also receive oral sunitinib malate once daily. Courses repeat every
28 days in the absence of disease progression or unacceptable toxicity.

- Schedule B: Patients receive ixabepilone IV on day 1. Beginning on day 8 of course 1,
patients also receive oral sunitinib malate once daily. Courses repeat every 21 days in
the absence of disease progression or unacceptable toxicity.

Blood samples are collected periodically for biomarker and pharmacokinetic studies by flow
cytometry.

After completion of study therapy, patients are followed at 30 days and every 3 months for 1
year.

INCLUSION CRITERIA:

- Non-hematological malignancy that has progressed on standard therapy.

- Age > 18.

- ECOG Performance Status (PS) 0, 1, or 2.

- Life expectancy of > 3 months.

- More than three prior systemic therapy regimens (a period of 4 weeks from
chemotherapy or immunotherapy ("washout period"), must have elapsed; and 2 weeks for
prior tyrosine kinase inhibitors).

- Prior treatment with sunitinib in a 4 weeks on/2weeks off schedule is acceptable.

- Women of Child Bearing Potential (WOCBP) must use adequate method of contraception
throughout and up to 4 weeks after the study.

- Patients must have either measurable disease (defined in Section 9.0) or evaluable
disease (bony lesions, pleural effusion, ascites)

- Required laboratory values obtained <= 7 days prior to registration:

- Granulocytes (ANC) >= 1500/mm3

- PLT >= 100,000/mm3

- Hgb >= 9.0 g/dL

- Direct bilirubin <= 1.0 x ULN

- Alkaline phosphatase <= 2.5 x ULN (<= 5 x if liver metastasis is present)

- AST/ALT <= 2.5 x ULN (<= 5 x if liver metastasis is present)

- Creatinine < 1.5 x ULN

- Pregnancy Test Negative (For WOCBP*)

- Urinalysis - Urine protein/creatinine ratio < 1, or < 1+ protein**

- TSH = WNL

- INR <= 1.5, unless the patient is on full dose warfarin or stable dose of LMW
heparin with a therapeutic INR of > 1.5, <= 3.

- Urine protein should be screened by random urine protein:creatinine ratio.
For urine protein: creatinine ratio >1.0, 24-hour urine protein should be
obtained and the level should be < 1000 mg for patient enrollment.

- Capable of understanding the investigational nature, potential risks and benefits of
the study and able to provide valid informed consent.

- Willingness to donate blood for correlative marker studies.

- If a patient is on full-dose anticoagulants, the following criteria should be met for
enrollment:

- The subject must have an in-range INR (usually between 2 and 3) on a stable dose of
warfarin or on stable dose of LMW heparin.

- No active bleeding or pathological conditions that carry high risk of bleeding (e.g.
tumor involving major vessels, known varices).

EXCLUSION CRITERIA:

- Patients with symptomatic/untreated CNS metastases. Patients with known CNS
metastases can be enrolled if:

- CNS metastases have been appropriately treated. Treatment for brain metastases may
include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, LINAC, or
equivalent) or resection as deemed appropriate by the treating physician. Patients
who had surgical resection of CNS metastases or brain biopsy within 3 months prior to
Day 1 will be excluded.

- No ongoing requirement for dexamethasone, as ascertained by clinical examination and
brain imaging (MRI or CT) during the screening period.

- No evidence of progression or hemorrhage after treatment (brain imaging study within
4 weeks of treatment start).

- CTC Grade 2 or greater neuropathy (motor or sensory) at study entry.

- Inability to swallow capsules.

- History of gastrointestinal disease, malabsorption, or requiring use of a feeding
tube.

- Patients who have received any investigational compound within the past 28 days
(within 2 weeks for prior RTKI treated patients).

- Patients who have received radiotherapy for any cause less than 4 weeks prior to
study entry.

- Patients taking cytochrome P450 (CYP) 3A4 enzyme-inducing or enzyme-inhibitor
medications like: antiepileptic drugs (phenytoin, carbamazepine or phenobarbital), St
John's Wort, ketoconazole, dexamethasone, dysrhythmic drugs (terfenadine, quinidine,
procainamide, sotalol, probucolol, bepridil, indapamide, or flecainide), haloperidol,
risperidone, rifampin, grapefruit (or juice) within two weeks of registration and
during the course of therapy. Topical and inhaled steroids are permitted. Please
refer to Appendix VI for a complete list of CYP34A inducers and inhibitors.

- Patients with known HIV infection are excluded due to the possibility of unknown side
effects on the immune system by these agents. The potential impact of pharmacokinetic
interactions of anti-retroviral therapy with ixabepilone or sunitinib is unknown.
Appropriate studies may be undertaken in patients with HIV and those receiving
combination anti-retroviral therapy in the future.

- Invasive procedures defined as follows:

- Major surgical procedure, open biopsy or significant traumatic injury <= 28 days
prior to registration.

- Anticipation of need for major surgical procedures during the course of the
study.

- Core biopsy <= 7 days prior to registration.

- Port placement <= 7 days prior to registration.

- Serious or non-healing wound, ulcer or bone fracture.

- History of abdominal fistula, gastrointestinal perforation or intra-abdominal
abscess <= 28 days.

- Evidence of bleeding diathesis or coagulopathy.

- Ongoing hemoptysis, or cerebrovascular accident <= previous 6 months, or peripheral
vascular disease with claudication on < 1 block, or history of clinically significant
bleeding.

- Significant cardiovascular disease defined as congestive heart failure (New York
Heart Association Class II, III or IV), angina pectoris requiring nitrate therapy, or
recent myocardial infarction (<= the last 6 months). Patients must have an absolute
baseline left ventricular ejection fraction (LVEF) >= 50% by MUGA scan within 4 weeks
prior to registration

- Uncontrolled hypertension (defined as a blood pressure of > 150 mmHg systolic and/or
> 90 mmHg diastolic on medication).

- A currently active second malignancy other than non-melanoma skin cancer. Patients
are not considered to have a currently active malignancy if they have completed
anti-cancer therapy and are considered by their physician to be at less than 30% risk
of relapse.

- Any of the following, as this regimen may be harmful to a developing fetus or nursing
child:

- Pregnant women

- Breastfeeding women

- Men or women of childbearing potential or their sexual partners who are
unwilling to employ adequate contraception (diaphragm, birth control pills,
injections, intrauterine device [IUD], surgical sterilization, subcutaneous
implants, or abstinence, etc.) NOTE: The effects of the agent(s) on the
developing human fetus at the recommended therapeutic dose are unknown.

- Other uncontrolled serious medical or psychiatric condition (e.g. cardiac
arrhythmias, diabetes, etc.)

- Patients must not have ongoing ventricular cardiac dysrhythmias of NCI CTCAE Version
3.0 grade >= 2. Patients with a history of serious ventricular arrhythmia (VT or VF
>= 3 beats in a row) are also excluded. Additionally, patients with ongoing atrial
fibrillation are not eligible.

- Patients must have a QTc interval < 500 msec on baseline EKG.

- Prior treatment with ixabepilone.

- History of chronic or recurrent infection that requires continuous use of anti-viral,
anti-fungal or anti-bacterial therapy; or foreseeable need to receive anti-infective
therapy within 14 days of Cycle 1 Day 1 treatment.

- History of Grade 3/4 hypersensitivity reaction to Cremophor EL or its derivatives
(polyoxyethylated castor oil).

- Non-small cell lung cancer (NSCLC) of squamous cell type, or NSCLC of any histology
that involves a major blood vessel (e.g. aorta, pulmonary artery, etc)