Everolimus and Vatalanib in Treating Patients With Advanced Solid Tumors

OBJECTIVES:

I. To determine the dose limiting toxicity (DLT) and maximally tolerated dose (MTD) of RAD001
and once daily PTK787 when given in combination. (Cohort IA) II. To describe the toxicities
associated with the combination of RAD001 and once daily PTK787. (Cohort IA) III. To evaluate
the therapeutic antitumor activity of the combination of once daily PTK787 with RAD001.
(Cohort IA) IV. To determine the dose limiting toxicity (DLT) and maximally tolerated dose
(MTD) of RAD001 and twice daily PTK787 when given in combination. (Cohort IB) V. To describe
the toxicities associated with the combination of RAD001 and twice daily PTK787. (Cohort IB)
VI. To evaluate the therapeutic antitumor activity of the combination of twice daily PTK787
with RAD001. (Cohort IB) VII. To determine the MTD-Recommended Phase 2 Dose (RP2D) based on
the MTD for Cohorts IA and IB. (Cohorts IA & IB) VIII. To investigate the biological activity
of the combination of PTK787 with RAD001 at the MTD-RP2D. (Cohort II) IX. To evaluate the
therapeutic antitumor activity of the combination of PTK787 with RAD001 at the MTD-RP2D.
(Cohort II) X. To evaluate pharmacogenetic, metabolic and clinical markers that may predict
for hypertension induced by anti-VEGF therapy. (Cohort II) XI. To obtain pilot data on
efficacy outcomes in patients with metastatic kidney cancer, neuroendocrine cancer, NSCLC or
melanoma. (Cohort II)

OUTLINE:

Patients are assigned to 1 of 4 cohorts, according to their disease (cohort IA, IB, or IIA
[any histopathologic diagnosis] vs cohort IIB [metastatic kidney cancer, neuroendocrine
cancer, melanoma, or non-small cell lung cancer). Patients are initially enrolled into
cohorts IA and IB until the maximum tolerated dose (MTD) and recommended phase II dose (RP2D)
are determined. Once the MTD/RP2D of everolimus and vatalanib are determined, subsequent
patients are enrolled and treated in expansion cohorts IIA or IIB.

Cohorts 1A or 1B (dose escalation cohorts; closed to enrollment as of 12/6/06): Patients
receive oral vatalanib once (cohort 1A) or twice (cohort 1B) daily on days 1-28 and oral
everolimus once daily on days 15-28 of course 1. For all subsequent courses, patients receive
oral vatalanib once (cohort 1A) or twice (cohort 1B) daily and oral everolimus once daily on
days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable
toxicity.

Cohort IIA (expansion cohort treated at the MTD/RP2D): Patients receive oral everolimus once
daily for 14 days followed by a 7-day rest period. Patients then receive oral vatalanib twice
daily on days 1-28 and oral everolimus once daily on days 15-28 of course 1. For all
subsequent courses, patients receive oral vatalanib twice daily and oral everolimus once
daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

Cohort IIB (expansion cohort treated at the MTD/RP2D): Patients receive oral vatalanib twice
daily on days 1-28 and oral everolimus once daily on days 15-28 of course 1. For all
subsequent courses, patients receive oral vatalanib twice daily and oral everolimus once
daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed at 3 months.

Inclusion Criteria:

- Histologic proof of cancer that is now unresectable (solid tumors, excluding lymphoma)

- Ability to provide informed consent

- Willingness to return to Mayo Clinic Rochester for follow up

- Life expectancy >= 12 weeks

- Prior anti-VEGF therapy allowed

- Cohort IIA: Patients meeting other eligibility criteria, regardless of histopathologic
diagnosis; tumor that is amenable to biopsy; willingness to provide blood specimens,
undergo DCE-MRI, and undergo brachial artery ultrasound measurements as required by
the protocol

- The following laboratory values obtained =< 14 days prior to registration:

Negative for proteinuria based on dip stick reading OR, if documentation of +1 result for
protein on dip stick reading, then total urinary protein =< 500 mg and measured creatinine
clearance (CrCl) >= 50 mL/min from a 24-hour urine collection

- Cohort IIB: Patients meeting other eligibility criteria AND with pathologic diagnosis
of metastatic kidney cancer, neuroendocrine carcinoma, melanoma, and NSCLC;
willingness to provide blood specimens required and undergo brachial artery ultrasound
measurements

- The following laboratory values obtained =< 14 days prior to registration:

ANC >= 1500/uL; Hgb >= 9 g/dL; PLT >= 100,000/uL; Total bilirubin =< 1.5 x upper limit of
normal (ULN); AST =< 3 x ULN or AST =< 5 x ULN if liver involvement; Creatinine =< 1.5 x
ULN; INR =< 1.4 (Cohort IIA only)

Exclusion Criteria:

- Any of the following prior therapies: Full field radiation therapy =<4 weeks prior to
registration or limited field radiation therapy =< 2 weeks prior to registration;
Radiation to >30% of bone marrow; Major surgery (i.e., laparotomy) =< 4 weeks prior to
registration; Minor surgery =< 2 weeks prior to registration

- New York Heart Association classification III or IV

- Uncontrolled hypertension, labile hypertension or history of poor compliance with
antihypertensive medication

- Active, bleeding diathesis or on any anticoagulant except patients receiving heparin
for deep venous thrombosis prophylaxis (not treatment)

- CNS metastases or seizure disorder

- Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy
considered investigational (utilized for a non-FDA-approved indication and in the
context of a research investigation

- Any concurrent severe and/or uncontrolled medical conditions which could compromise
participation or pose as unnecessary risk to the patient in the study, including, but
not limited, to the following: Unstable angina; Myocardial infarction =< 6 months
prior to registration; Serious uncontrolled cardiac arrhythmia; Uncontrolled diabetes

- Any concurrent severe and/or uncontrolled medical conditions which could compromise
participation or pose as unnecessary risk to the patient in the study, including, but
not limited, to the following: Interstitial pneumonia or extensive and symptomatic
interstitial fibrosis of the lung; QTc > 500 msec; Patients who require chronic
treatment with PPI or H2 antagonist

- Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of PTK787/ZK 222584 (i.e., ulcerative disease, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome, bowel obstruction, or inability to
swallow the tablets)

- Known standard therapy for the patient's disease that is potentially curative or
definitely capable of extending life expectancy

- Chemotherapy =< 3 weeks; Mitomycin C/nitrosoureas =< 6 weeks; Immunotherapy =< 2
weeks; Biologic therapy =< 2 weeks; Prior investigational therapy =< 4 weeks; Full
field radiation therapy =< 4 weeks or limited field radiation therapy =< 2 weeks;
Radiation to > 30% of bone marrow; Major surgery (i.e., laparotomy) =< 4 weeks; or
Minor surgery =< 2 weeks prior to registration

- Any of the following: pregnant women; nursing women; men or women of childbearing
potential who are unwilling to employ adequate barrier contraception

- Patients on whom DCE-MRI is contraindicated (e.g., presence of MRI-incompatible
metallic implants or prosthetic heart valves, pacemakers, etc.) are ineligible

- ECOG performance status (PS) 3 or 4

- Treatment with medications listed in Appendix I for which no safer or more efficacious
alternative is available

- Uncontrolled infection

- Failure to fully recover from acute, reversible effects of prior chemotherapy
regardless of interval since last treatment