Dasatinib in Combination With Bevacizumab to Treat Advanced Solid Tumors

BACKGROUND:

Dasatinib is an inhibitor of SRC family kinases, BCR-ABL, c-KIT, EPHA2 and PDGF beta
receptor.

Bevacizumab is a humanized IgG1 monoclonal antibody (MAb) that binds all biologically active
isoforms of human vascular endothelial growth factor (VEGF, or VEGF-A) with high affinity
(k(d) equal to 1.1nM).

This Phase I trial is open to patients with all solid tumors.

OBJECTIVES:

Determine the safety and toxicity of the combination of dasatinib and bevacizumab.

Determine biochemical changes in the src-FAK and src-PLC-. and VEGF signal transduction
pathways in tumor and stromal cells in response to treatment at the MTD, in a pilot fashion,
if those changes are statistically significant.

ELIGIBILITY:

Adults with histologically documented solid tumor malignancy that is metastatic or
unresectable and for which standard curative therapies do not exist or are no longer
effective.

Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or biological
therapy for at least 4 weeks.

All patients enrolling in Group 2 must have at least one lesion amenable to biopsy.

ECOG performance status 0 or 1 and adequate organ and marrow function.

DESIGN:

Group 1 will receive dasatinib and bevacizumab together at the start of study in a dose
escalation fashion.

Group 2 will be randomized as to which agent they receive for cycle one. Cycles 2 and beyond
are treated using both agents.

Tumor biopsies will be obtained from patients in Group 2 before treatment, two weeks into
mono-therapy, and two weeks into combinatorial therapy.

DCE-MRI studies will be obtained on patients in Group 2 before treatment, two weeks into
monotherapy, four weeks into monotherapy, and two weeks into combinatorial therapy.

Patients will be evaluated for toxicity in clinic every 2 weeks for Cycles 1 and 2, and then
every 4 weeks. For patients who have been on the study over 2 years, the cycle may be
lengthened to 6 or 8 weeks at the discretion of the investigator.

Patients will be evaluated for response every 8 weeks using the RECIST criteria. After
patients have completed 2 or more years on study, the interval may be lengthened to 12 or 16
weeks at the discretion of the investigator.

Approximately 48 patients will be needed to achieve the objectives of the trial.

- INCLUSION CRITERIA:

- Patients must have a solid tumor malignancy that is metastatic or unresectable and for
which standard curative therapies do not exist or are no longer effective.

--Patients must have histological documentation of cancer confirmed in the Laboratory
of Pathology/NCI.

- Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or
biological therapy for at least 4 weeks. Patients who were receiving mitomycin C,
nitrosoureas, bevacizumab or carboplatin must be 6 weeks from the last administration
of chemotherapy. Patients with prostate cancer must continue to receive LHRH agonist
(unless orchiectomy has been performed). Patients should not be receiving
complementary/alternative therapy while on study. Any patient who has undergone
therapy with a monoclonal antibody must be at least 4 weeks from the last treatment.

- All patients enrolling in group 2 must have at least one lesion deemed safe to biopsy
and be willing to undergo the three mandatory biopsies. This determination will be
made by a member of the interventional radiology team or surgical associate
investigator and an associate investigator. This requirement is not necessary for
patients in group 1.

- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of dasatinib in combination with bevacizumab in
patients less than 18 years of age, children are excluded from this study, but may be
eligible for future pediatric phase 1 combination trials.

- ECOG performance status 0 or 1. ECOG performance status of 2 will be considered on a
case by case basis with a focused assessment on risk of perforation.

- Life expectancy of greater than 3 months.

- Patients must have adequate organ and marrow function as defined below:

- Inclusion criteria laboratory values

- Leukocytes greater than 3,000/microl

- Hemoglobin greater than or equal to 10g/dl

- Absolute neutrophil count greater than 1,200/microl

- Platelets greater than 100,000/microl

- Total bilirubin less than or equal to 1.5 times institutional upper limits of
normal in the absence of Gilbert s syndrome

- AST(SGOT) and ALT(SGPT) less than or equal to 2.5 times institutional upper limit
of normal

- creatinine less than or equal to 1.5 mg/dL OR Creatinine clearance greater than
45 mL/min/1.73 m(2) for patients with creatinine levels above institutional
normal.

- Activated partial thromboplastin time (PTT) less than or equal 1.25 times
institutional upper limits of normal in the absence of lupus anticoagulant

- Prothrombin Time (PT) OR INR less than or equal to 1.25 times institutional upper
limits of normal

- Spot Urine Protein Creatinine Ratio less than or equal to 0.5; If result is 0.5
or more, a 24-hour urine for protein excretion must be less than or equal to
1000mg

- Patients must have recovered from toxicity related to prior therapy to at least CTEP
grade 1 (defined by CTCAE 3.0). Chronic stable grade 2 peripheral neuropathy secondary
to neurotoxicity from prior therapies may be considered on a case by case basis by the
Principal Investigator.

- As the effect of dasatinib and bevacizumab in combination on the developing human
fetus is not known, women of child-bearing potential and men must agree to use
adequate contraception (abstinence; hormonal or barrier method of birth control) for
the study and at least 3 months after completion. Pregnant women will not be eligible
for study.

- Ability to understand and the willingness to sign a written informed consent document.

- Evaluable disease or measurable disease as defined in section 11.1 of greater than or
equal to 1 cm.

- Patients may not have any clinically significant cardiovascular disease including the
following:

- myocardial infarction or ventricular tachyarrhythmia within 6 months

- prolonged QTc greater than or equal to 480 msec (Fridericia correction)

- ejection fraction less than institutional normal

- major conduction abnormality (unless a cardiac pacemaker is present)

- Patients with any cardiopulmonary symptoms of unknown cause (e.g. shortness of
breath, chest pain, etc.) should be evaluated by a baseline echocardiogram with
or without stress test as needed in addition to electrocardiogram (EKG) to rule
out QTc prolongation. The patient may be referred to a cardiologist at the
discretion of the principal investigator. Patients with underlying
cardiopulmonary dysfunction should be excluded from the

study.

EXCLUSION CRITERIA:

- Brain metastases

- Patients who have a history of remote CNS metastases that have undergone curative
therapy by radiation therapy, gamma knife therapy, or surgery and have remained
without recurrence for a period of greater than or equal 6 months will be
eligible.

- CNS imaging will not be mandated for all patients. However, if there is clinical
suspicion of CNS involvement, a contrast CT or MRI of the brain will be required.
Screening CNS scans should be required for certain tumor types with relatively
high risk of CNS metastases, including but not limited to melanoma, renal cell
carcinoma, breast, lung.

- Thrombotic or embolic events within the past 6 months such as a cerebrovascular
accident (including transient ischemic attacks), pulmonary embolism, unstable angina,
or myocardial infarction. Patients with recent (less than 3 month history) of venous
thrombotic events will be considered on a case by case basis.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure (AHA Class II or worse), unstable
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that
would limit compliance with study requirements.

- Patients with evidence of active infection must have completed antibiotic therapy
and be without clinical or laboratory evidence of infection for seven days after
treatment has concluded.

- QTc prolongation (defined as a QTc interval equal to or greater than 480 msecs)
or other clinically significant EKG abnormalities

- Patients may not have any clinically significant cardiovascular disease including
the following:

- Myocardial infarction or ventricular tachyarrhythmia within 6 months

- Prolonged QTc greater than or equal to 480msec (Fridericia correction)

- Ejection fraction less than institutional normal (should be done if clinically
indicated and for patients with congestive heart failure on medication)

- Major conduction abnormality (unless a cardiac pacemaker is present)

- Patients who have an active pleural effusion may be considered if tapped prior to
study. Patients with pleural effusions that are too small to be removed may be
considered on a case by case basis. Patients with a Grade 2, asymptomatic
pericardial effusion found incidentally on imaging studies may be considered on a
case by case basis.

- Dasatinib is metabolized primarily by the CYP3A4 liver enzyme. Consideration
should be given to using alternative medications not impacting CYP3A4 while on
dasatinib therapy.

- Patients may not be receiving any prohibited potent CYP3A4 inhibitors. For these
drugs, a wash-out period of greater than or equal to 7 days is required prior to
starting dasatinib treatment.

- Category I drugs that are generally accepted to have a risk of causing Torsades
de Pointes. A wash-out period of greater than or equal to 7 days is required for
the following drugs prior to starting dasatinib treatment:

- Quinidine, procainamide, disopyramide

- Amiodarone, sotalol, ibutilide, dofetilide

- Erythromycin, clarithromycin

- Chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide

- Cisapride, bepridil, droperidol, methadone, arsenic, chlorquine,
domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin,
lidoflazine

- HIV-positive patients receiving combination anti-retroviral therapy are excluded from
the study because of possible pharmacokinetic interactions with dasatinib,
bevacizumab, and/or the combination. Appropriate studies will be undertaken in
patients receiving combination antiretroviral therapy when indicated.

- Patients who have been treated with dasatinib (any other Src-family kinase inhibitors)
will be excluded

- Hypertension defined as systolic blood pressure greater than 140 mmHg or diastolic
pressure greater than 90 mmHg despite optimal medical management.

- Proteinuria defined as a spot urine analysis for protein creatinine ratio (UPC) of
greater than 1.0

- Therapeutic anticoagulation with coumadin, heparins, or heparinoids. Prophylaxis doses
are permitted.

- Serious non-healing wounds (including wounds healing by secondary intention), acute or
non-healing ulcers, or bone fractures within 3 months of fracture. History of
abdominal fistula, major surgery, bowel obstruction, or intra-abdominal abscesses
within 28 days will be excluded. Any patient with history of gastrointestinal
perforation will be excluded due to possibility of increased risk of perforation with
bevacizumab.

- Evidence of bleeding diathesis

- Impairment of swallowing that would preclude administration of dasatinib.

- History of hemoptysis or surgery within the past 28 days.

- Patients with squamous cell carcinoma of the lungs will be excluded due to risk of
fatal pulmonary hemorrhage. If a patient has a history of any type primary lung cancer
and hemoptysis, they will be excluded.

- History of high grade varices.

- Use of herbal supplements are not permitted within 7 days of trial commencement and on
study. Vitamin supplement (above a typical single multi-vitamin) usage is discouraged
unless clearly indicated by an existing medical condition. An Associate or Principal
Investigator will have the discretion regarding which vitamin supplements are
permitted.

- Known hypersensitivity to Chinese hamster ovary cell products or recombinant human
antibodies.

- Use of any other concurrent investigational agents for treatment or anticancer agents
including hormonal therapy, except in the case of prostate cancer patients who are
being treated with LHRH agonist at the time of trial entry

- Pregnant women are excluded from this study because bevacizumab is an antibody to VEGF
with the potential for teratogenic or abortifacient effects. Dasatinib is a potential
teratogen. Because there is an unknown but potential risk for adverse events in
nursing infants secondary to treatment of the mother bevacizumab or dasatinib,
breastfeeding should be discontinued if the mother is treated on this study.