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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


Phase 1
18 Years
N/A
Open (Enrolling)
Both
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

Thank you

Trial Information

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


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.

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

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of everolimus and vatalanib (Cohort 1) (Closed to enrollment as of 12/6/06)

Safety Issue:

Yes

Principal Investigator

Julian Molina, MD, PhD

Investigator Role:

Study Chair

Investigator Affiliation:

Mayo Clinic

Authority:

United States: Food and Drug Administration

Study ID:

CDR0000592921

NCT ID:

NCT00655655

Start Date:

December 2004

Completion Date:

Related Keywords:

  • 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
  • unspecified adult solid tumor, protocol specific
  • stage IV renal cell cancer
  • recurrent renal cell cancer
  • stage IV melanoma
  • recurrent melanoma
  • stage IV non-small cell lung cancer
  • recurrent non-small cell lung cancer
  • metastatic gastrointestinal carcinoid tumor
  • recurrent gastrointestinal carcinoid tumor
  • gastrinoma
  • glucagonoma
  • insulinoma
  • recurrent islet cell carcinoma
  • pancreatic polypeptide tumor
  • somatostatinoma
  • recurrent neuroendocrine carcinoma of the skin
  • thyroid gland medullary carcinoma
  • metastatic pheochromocytoma
  • recurrent pheochromocytoma
  • stage IV neuroendocrine carcinoma of the skin
  • extra-adrenal paraganglioma
  • Carcinoid Tumor
  • Carcinoma
  • Carcinoma, Merkel Cell
  • Carcinoma, Renal Cell
  • Kidney Neoplasms
  • Head and Neck Neoplasms
  • Lung Neoplasms
  • Melanoma
  • Paraganglioma
  • Paraganglioma, Extra-Adrenal
  • Pheochromocytoma
  • Carcinoma, Neuroendocrine
  • Malignant Carcinoid Syndrome
  • Gastrointestinal Neoplasms
  • Adenoma, Islet Cell
  • Neoplasms
  • Skin Neoplasms
  • Carcinoma, Basal Cell
  • Carcinoma, Basosquamous
  • Carcinoma, Squamous Cell

Name

Location

Mayo ClinicRochester, Minnesota  55905