Vandetanib and Everolimus in Treating Patients With Advanced or Metastatic Cancer

Study Overview
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Brief Summary
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This phase I trial studies the side effects and best dose of vandetanib and everolimus when given together in treating patients with cancer that has spread to other places in the body. Vandetanib and everolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) or highest dose level, and the dose-limiting toxicity (DLT) of vandetanib (a multi-kinase inhibitor of epidermal growth factor receptor [EGFR], vascular endothelial growth factor receptor [VEGFR] and ret proto-oncogene [RET] inhibitor) when used in combination with everolimus (a mammalian target of rapamycin [mTOR] inhibitor) in advanced cancer. II. Preliminary descriptive assessment of the anti-tumor efficacy of the combination. III. Preliminary optional assessment of the pharmacokinetic, pharmacodynamic markers of target inhibition and correlates of response. OUTLINE: This is a dose-escalation study. Patients receive vandetanib orally (PO) once daily (QD) and everolimus PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment patients are followed up between 14-28 days at the discretion of the treating physician.

Official Title
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A Phase 1 Trial of Vandetanib (a Multi-Kinase Inhibitor of EGFR, VEGFR, and RET Inhibitor) in Combination With Everolimus (an mTOR Inhibitor) in Advanced Cancer

Conditions
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Advanced Malignant Neoplasm, Metastatic Malignant Neoplasm, Recurrent Malignant Neoplasm, Refractory Malignant Neoplasm

Intervention / Treatment
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* Drug: Everolimus
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Drug: Vandetanib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with advanced or metastatic cancer that is refractory to standard therapy, relapsed after standard therapy, or who have no standard therapy available that improves survival by at least three months. Patients must be at least 3 weeks beyond their previous cytotoxic chemotherapy. Patient must be at least 5 half-lives or 3 weeks, whichever is shorter, from their previous targeted or biologic therapy; In addition, patients must be at least 3 weeks beyond the last session of radiation therapy. Local palliative radiation therapy that is not delivered to all target lesions is allowed immediately before or during treatment. ECOG performance status should be less or equal to 3 Patients must have organ and marrow function defined as: Absolute neutrophil count more or equal to 750/mL; platelets more or equal to 50,000/mL; creatinine less or equal to 3x ULN; total bilirubin less than or equal to 3.0. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence). Exclusion Criteria: Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, uncontrolled asthma, need for hemodialysis, need for ventilatory support. Pregnant or lactating women. History of hypersensitivity to vandetanib, lactose, murine products, or any component of the formulation. History of hypersensitivity to sirolimus, temsirolimus, everolimus. History of hypersensitivity to any component of the formulation. Patients unwilling or unable to sign informed consent document. Presence of cardiac disease that, in the opinion of the Investigator, increases the risk of ventricular arrhythmia. History (within the last 3 months) or presence of stroke/cerebrovascular accident. Congenital long QT syndrome. QTcF interval greater than 500 ms that is not correctable to less than 500ms such as with cessation of a causative medication, etc. History of myocardial infarction within 6 months with a residual arrhythmia that in the opinion of the Investigator, increases the risk of ventricular arrhythmia. Presence of a symptomatic bradyarrhthmia or uncompensated heart failure.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (vandetanib, everolimus)<br>Patients receive vandetanib PO QD and everolimus PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Everolimus<br>* Given PO<br>* Other names: Zortress;Other: Laboratory Biomarker Analysis<br>* Optional correlative studies<br>Other: Pharmacological Study<br>* Optional correlative studies<br>Drug: Vandetanib<br>* Given PO<br>* Other names: ZD6474;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose | Will be defined as the highest dose studied in which the incidence of dose limiting toxicity was less than 33%. Toxicity will be reported by type, frequency, and severity. Worst toxicity grades per patient will be tabulated for selected adverse events and laboratory measurements. | 28 days | 
| Anti-tumor efficacy of the combination in terms of response rate | The response rate will be estimated by dose level and tumor type, along with the exact 95% confidence interval. Efficacy will be evaluated by using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria described in the supplement for response. Patients with lymphoma will be measured per the World Health Organization (WHO) criteria. | Up to 14 years | 
| Maximum observed serum concentration (Cmax) | Will be estimated using standard non-compartmental methods | Days 1 and 21 of course 1 and day 1 of course 3 | 
| Pharmacodynamic (PD) parameters | PD biomarker concentration will be summarized by time points. The relationship between drug concentrations and PD effects will be explored graphically. Based on review of these graphs, analyses to describe the relationship may also be performed. | Up to 14 years | 
| Observed trough serum concentration (Cmin) | Will be estimated using standard non-compartmental methods | Days 1 and 21 of course 1 and day 1 of course 3 | 
| Area under the serum concentration-time curve (AUC) | Will be estimated using standard non-compartmental methods | Days 1 and 21 of course 1 and day 1 of course 3 |