Everolimus and Vatalanib in Treating Patients With Advanced Solid Tumors

• Maximum tolerated dose of everolimus and vatalanib (Cohort 1) (Closed to enrollment as of 12/6/06) [ Designated as safety issue: Yes ]
• Toxicity associated with everolimus and vatalanib (Cohort 1) (Closed to enrollment as of 12/6/06) [ Designated as safety issue: Yes ]
• Therapeutic antitumor activity of everolimus and vatalanib (Cohort 1) (Closed to enrollment as of 12/6/06) [ Designated as safety issue: No ]
• Recommended phase II dose (RPTD) of everolimus and vatalanib (Cohort 1) (Closed to enrollment as of 12/6/06) [ Designated as safety issue: No ]
• Biological activity and therapeutic antitumor activity of everolimus and vatalanib when given at the MTD/RPTD (Cohort 2) [ Designated as safety issue: No ]
• Evaluation of pharmacogenetic, metabolic, and clinical markers that may predict hypertension induced by anti-VEGF therapy (Cohort 2) [ Designated as safety issue: No ]
• Efficacy outcomes in patients with metastatic kidney cancer, neuroendocrine carcinoma, non-small cell lung cancer, or melanoma (Cohort 2) [ Designated as safety issue: No ]

RATIONALE: Everolimus and vatalanib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving everolimus together with vatalanib may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of everolimus and vatalanib in treating patients with advanced solid tumors.

OBJECTIVES:

• To determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of everolimus and vatalanib in patients with advanced solid tumors. (Cohort 1) (Closed to enrollment as of 12/6/06)
• To describe the toxicities of this regimen in these patients. (Cohort 1) (Closed to enrollment as of 12/6/06)
• To evaluate the therapeutic antitumor activity of this regimen in these patients. (Cohort 1) (Closed to enrollment as of 12/6/06)
• To determine the recommended phase II dose (RPTD) of this regimen in these patients. (Cohort 1) (Closed to enrollment as of 12/6/06)
• To investigate the biological activity of this regimen when given at the MTD/RPTD. (Cohort 2)
• To evaluate the therapeutic antitumor activity of this regimen when given at the MTD/RPTD. (Cohort 2)
• To evaluate pharmacogenetic, metabolic, and clinical markers that may predict hypertension induced by anti-VEGF therapy. (Cohort 2)
• To obtain pilot data on efficacy outcomes in patients with metastatic kidney cancer, neuroendocrine carcinoma, non-small cell lung cancer, or melanoma treated with this regimen. (Cohort 2)

OUTLINE: Patients are assigned to 1 of 4 treatment cohorts* according to disease (cohort 1A*, 1B*, or 2A [any histopathologic diagnosis] or cohort 2B [metastatic kidney cancer, neuroendocrine carcinoma, melanoma, or non-small cell lung cancer]). Patients are initially enrolled into cohorts 1A* or 1B* until the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) of everolimus and vatalanib are determined. Once the MTD/RPTD of everolimus and vatalanib are determined, subsequent patients are enrolled and treated at the MTD/RPTD in expansion cohorts 2A or 2B.

NOTE: *Cohorts 1A and 1B are closed to enrollment as of 12/6/06.

• 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.

• Cohorts 2A or 2B (expansion cohorts treated at the MTD/RPTD):

  • Cohort 2A: 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 2B: 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.

Patients in cohorts 2A or 2B undergo blood sample collection periodically for translational research studies. Translational studies include pharmacokinetic studies (cohort 2A only) by high performance liquid chromatography; pharmacogenetic studies; and analysis of plasma levels of VEGF-A and soluble VEGFR-1 by ELISA techniques. Factors predicting the development of hypertension induced by anti-VEGF therapy are also studied in these patients by quantifying plasma levels of ADMA by mass spectrometry and measuring brachial artery flow-mediated vasodilation by brachial artery ultrasound. Formalin-fixed paraffin embedded (FFPE) and fresh tumor tissue samples* are collected and analyzed to assess total and phosphorylated 4E-BP and p70S6 kinase expression and phosphorylated AKT, PTEN, and cyclin D expression by immunohistochemistry. Patients in cohort 2A also undergo dynamic contrast-enhanced MRI periodically to assess changes in tumor perfusion.

NOTE: *FFPE tumor tissue samples are collected from patients enrolled in cohorts 2A or 2B; fresh tumor tissue samples are collected from patients enrolled in cohort 2A only.

• Extra-adrenal Paraganglioma
• Gastrointestinal Carcinoid Tumor
• Head and Neck Cancer
• Islet Cell Tumor
• Kidney Cancer
• Lung Cancer
• Melanoma (Skin)
• Neuroendocrine Carcinoma of the Skin
• Pheochromocytoma
• Unspecified Adult Solid Tumor, Protocol Specific

• Drug: everolimus
• Drug: vatalanib
• Genetic: protein expression analysis
• Other: high performance liquid chromatography
• Other: immunohistochemistry staining method
• Other: laboratory biomarker analysis
• Other: mass spectrometry
• Other: pharmacological study
• Procedure: dynamic contrast-enhanced magnetic resonance imaging
• Procedure: ultrasound imaging

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