Vandetanib and Temozolomide in Treating Patients With Advanced Solid Tumors That Cannot Be Removed By Surgery

Phase I Study of ZD6474 and Temozolomide in Patients With Advanced Cancer

RATIONALE: Vandetanib 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. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving vandetanib together with temozolomide may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of vandetanib and temozolomide in treating patients with advanced solid tumors that cannot be removed by surgery.

Study Overview

• Status: Withdrawn
• Conditions: Unspecified Adult Solid Tumor, Protocol Specific
• Intervention / Treatment: Drug: temozolomide; Other: laboratory biomarker analysis; Other: immunoenzyme technique; Drug: vandetanib

Detailed Description

OBJECTIVES:

• To determine the maximum tolerated dose of concurrently administered vandetanib and temozolomide in patients with unresectable, advanced solid tumors.
• To describe the toxicity profile of this regimen in these patients.
• To describe the response rate in patients treated with this regimen.
• To describe the effects of therapy on angiogenesis-related translational endpoints.

OUTLINE: Patients receive escalating doses of oral vandetanib once daily on days 1-28 and oral temozolomide once daily on days 1-5. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline and prior to each treatment course for correlative laboratory studies, including evaluation of plasma VEGF levels by ELISA, serum angiogenesis assay, and measurement of circulating endothelial cell populations (CD133, CD34, CD146). Frozen serum and plasma samples are also stored for future research studies.

• Study Type: Interventional
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed solid tumor

  • Unresectable, advanced disease
• Measurable or evaluable disease
• No known standard therapy that is potentially curative or definitely capable of extending life expectancy exists
• No intracranial metastatic disease, unless it has been radiologically and clinically stable for the past 3 months

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• ANC ≥ 1,500/μL
• Absolute lymphocyte count > 1,000/μL
• Platelet count ≥ 100,000/μL
• Hemoglobin ≥ 8.0 g/dL
• 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 OR creatinine clearance > 50 mL/min
• Potassium normal
• Serum calcium (ionized or adjusted for albumin) normal
• Magnesium normal
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No uncontrolled infection
• No currently active diarrhea that results in an ongoing need for IV fluids and/or that may affect the ability of the patient to absorb vandetanib or tolerate diarrhea
• No evidence of severe or uncontrolled systemic disease or any concurrent condition that, in the opinion of the treating physician, makes it undesirable for the patient to participate in the study or that would jeopardize compliance with the study
• No other malignancies within the past 5 years, except cervical carcinoma in situ or adequately treated basal cell or squamous cell carcinoma of the skin
• No clinically significant cardiac event, such as myocardial infarction, NYHA class II-IV heart disease within the past 3 months, or presence of cardiac disease that, in the opinion of the treating physician, increases the risk of ventricular arrhythmia

• No history of arrhythmia (i.e., multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) that is symptomatic or requires treatment (CTCAE grade 3)

  • Atrial fibrillation that is controlled on medication allowed
• No asymptomatic sustained ventricular tachycardia
• No history of QTc prolongation as a result of other medication that required discontinuation of that medication
• No congenital long QT syndrome
• No 1st degree relative with unexplained sudden death under 40 years of age
• No left bundle branch block
• No QTc with Bazett's correction that is unmeasurable
• QTc < 480 msec on screening ECG
• No hypertension that is uncontrolled by medical therapy (i.e., systolic blood pressure > 160 mm Hg or diastolic blood pressure > 100 mm Hg)
• No bleeding diathesis (inherited coagulopathy)

PRIOR CONCURRENT THERAPY:

• Recovered from prior therapy
• More than 30 days since prior investigational agents
• More than 4 weeks since prior chemotherapy (6 weeks for mitomycin C or nitrosoureas)
• More than 4 weeks since prior immunotherapy or biologic therapy

• More than 4 weeks since prior major surgery

  • Surgical incision must be completely healed
• More than 4 weeks since prior radiotherapy, except palliative radiotherapy
• No prior radiotherapy to > 25% of bone marrow
• No prior temozolomide or dacarbazine
• No prior enrollment in this study
• More than 2 weeks since prior and no concurrent known potent CYP3A4 inducers, such as rifampin, phenytoin, carbamazepine, barbiturates, or St. John's wort
• More than 2 weeks since prior and no concurrent drugs associated with an increased risk of causing Torsades de Pointes
• No concurrent medication that may cause QTc prolongation
• No concurrent anticoagulants
• No other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time to progression
Time to treatment failure
Toxicity profile
Adverse events profile
Response profile
Maximum tolerated dose of vandetanib and temozolomide
Time until any treatment-related toxicity
Time until treatment-related grade 3+ toxicity
Time until hematologic nadirs
Correlation of changes in VEGF levels, serum angiogenesis, and circulating endothelial cells with response and dose levels

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Cancer Institute (NCI)
• Investigators: Svetomir Markovic, MD, PhD, Mayo Clinic

Study record dates

Study Major Dates

• Study Start: January 1, 2008
• Primary Completion (Anticipated): January 1, 2010

Study Registration Dates

• First Submitted: January 24, 2008
• First Submitted That Met QC Criteria: January 24, 2008
• First Posted (Estimate): January 28, 2008

Study Record Updates

• Last Update Posted (Estimate): March 10, 2014
• Last Update Submitted That Met QC Criteria: March 6, 2014
• Last Verified: March 1, 2014

More Information

Terms related to this study

• Keywords: unspecified adult solid tumor, protocol specific
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide
• Other Study ID Numbers: MC0615; MAYO-MC0615; MAYO-07-004966