A Phase I Trial of the mTOR Inhibitor RAD001 in Combination With VEGF Receptor Tyrosine Kinase Inhibitor PTK787/ZK 222584 in Patients With Advanced Solid Tumors

Inclusion Criteria

DISEASE CHARACTERISTICS:

- Histologically confirmed solid tumor

- Histologically confirmed metastatic kidney cancer, neuroendocrine carcinoma,
melanoma, or non-small cell lung cancer (cohort 2B)

- Unresectable disease

- No known standard therapy that is potentially curative or definitely capable of
extending life expectancy exists

- Tumor amenable to biopsy (cohort 2A)

- No lymphoma

- No CNS metastases

PATIENT CHARACTERISTICS:

- ECOG performance status 0-2

- Life expectancy ≥ 12 weeks

- ANC ≥ 1,500/μL

- Hemoglobin ≥ 9 g/dL

- Platelet count ≥ 100,000/μL

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST ≤ 3 times ULN (5 times ULN if liver involvement)

- Creatinine ≤ 1.5 times ULN

- INR ≤ 1.4 (cohort 2A)

- Urine protein negative by dipstick OR total urine protein ≤ 500 mg and measured
creatinine clearance ≥ 50mL/min by 24-hour urine collection

- Willing to return to Mayo Clinic Rochester for follow-up visits

- Willing to provide blood specimens for required translational research studies
(cohorts 2A and 2B)

- Willing to undergo brachial artery ultrasound measurements (cohorts 2A and 2B)

- Willing to undergo dynamic contrasted-enhanced MRI (cohort 2A)

- No contraindications for dynamic contrasted-enhanced MRI (e.g., MRI-incompatible
metallic implants or prosthetic heart valves [e.g., pacemakers]) (cohort 2A)

- No uncontrolled infection

- No New York Heart Association class III or IV heart disease

- No uncontrolled hypertension, labile hypertension, or history of poor compliance with
antihypertensive medication

- No active bleeding diathesis

- No seizure disorder

- No concurrent, severe and/or uncontrolled medical condition that would compromise
study participation or pose as unnecessary risk to the patient, including, but not
limited, any of the following:

- Unstable angina

- Myocardial infarction within the past 6 months

- Serious uncontrolled cardiac arrhythmia

- Uncontrolled diabetes

- Interstitial pneumonia or extensive, symptomatic interstitial fibrosis of the
lung

- QTc > 500 msec

- No impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of vatalanib, including any of the following:

- Ulcerative disease

- Uncontrolled nausea, vomiting, or diarrhea

- Malabsorption syndrome

- Bowel obstruction

- Inability to swallow the tablets

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective barrier contraception

PRIOR CONCURRENT THERAPY:

- More than 3 weeks since prior chemotherapy (6 weeks for mitomycin C or nitrosoureas)
and recovered

- More than 2 weeks since prior immunotherapy or biological therapy

- More than 4 weeks since prior investigational therapy

- More than 4 weeks since prior full-field radiotherapy

- Full-field radiotherapy encompasses the entire area of known disease involvement
and surrounding uninvolved, at-risk areas (e.g., sub-total nodal [mantle and
upper abdomen] or total nodal irradiation)

- More than 2 weeks since prior limited-field radiotherapy

- Limited-field radiotherapy is restricted to treating only the known areas of
clinical disease (e.g., involved-field therapy for lymphoma)

- More than 4 weeks since prior major surgery (i.e., laparotomy)*

- More than 2 weeks since prior minor surgery*

- Prior anti-VEGF therapy allowed

- No prior radiotherapy to > 30% of the bone marrow

- No concurrent anticoagulant therapy except heparin for deep venous thrombosis
prophylaxis

- No other concurrent chemotherapy, immunotherapy, radiotherapy, or ancillary therapy
considered investigational (e.g., utilized for a non-FDA-approved indication and in
the context of a research investigation)

- No concurrent chronic treatment with proton pump inhibitors (e.g., omeprazole or
lansoprazole) or H2 antagonists (e.g., ranitidine or famotidine)

- No concurrent prophylactic colony-stimulating factors NOTE: *Insertion of a vascular
access device is not considered major or minor surgery