Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Related Information
Registry Information

Alternate Title

Vandetanib in Treating Young Patients With Medullary Thyroid Cancer

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase II, Phase I Biomarker/Laboratory analysis, Treatment Active 5 to 18 NCI NCI-07-C-0189 07-C-0189, NCT00514046

Special Category: NCI Web site featured trial, NIH Clinical Center trial

Objectives

Primary

1. To assess the activity, in terms of changes in tumor size, tumor biomarkers (calcitonin and CEA), and tumor-related diarrhea, of vandetanib in young patients with hereditary medullary thyroid carcinoma (MTC).
2. To assess the safety and tolerance of vandetanib in young patients at a dose that is equivalent to the recommended dose in adults using a limited intra-patient dose escalation.
3. To assess the pharmacokinetics at a steady state (end of cycle 2) in young patients with hereditary MTC.

Secondary

1. To determine the progression-free survival and overall survival of young patients with hereditary MTC treated with vandetanib.
2. To assess the expression of RET, EGFR, VEGFR, and somatostatin receptor by IHC in archival tissue blocks from young patients.

Entry Criteria

Disease Characteristics:

• Histologically confirmed medullary thyroid carcinoma meeting the following criteria:
  • Hereditary (multiple endocrine neoplasia [MEN] 2A or 2B)
  • Unresectable, recurrent, or metastatic disease
  • Prior characteristic germline mutation in the RET proto-oncogene documented



• Previously untreated patients are eligible if their tumors are not surgically resectable



• Measurable disease, defined by RECIST as at least one lesion that can be accurately measured in at least one dimension with longest diameter of at least 20 mm by conventional techniques or at least 10 mm by spiral CT scan
  • Superficial (easily palpable) lymph nodes will be considered measurable



• No pheochromocytoma as evidenced by elevated plasma-free metanephrines

Prior/Concurrent Therapy:

• Recovered from prior therapy to grade 1 (CTCAE v.3.0)
• At least 4 weeks since prior surgical procedures and surgical incisions must be healed
• At least 4 weeks since prior external beam radiation therapy
• At least 28 days since prior cytotoxic chemotherapy
• At least 7 days since prior anticancer biological therapy (e.g., biological response modifiers [e.g., cytokines], immunomodulatory agents, vaccines, or differentiating agents)
• At least 30 days since prior monoclonal antibody therapy
• At least 30 days since prior investigational agents
• At least 72 hours since prior short-acting colony-stimulating factors (e.g., filgrastim [G-CSF] or sargramostim [GM-CSF])
• At least 7 days since prior long-acting colony-stimulating factors (e.g., pegfilgrastim)
• Patients who have previously undergone a thyroidectomy should be on thyroid hormone replacement therapy
• No other concurrent forms of cancer chemotherapy, radiation therapy, immunotherapy, or investigational agents
• At least 14 days since prior and no concurrent drugs that prolong QTc

Patient Characteristics:

Inclusion criteria:

• Lansky (≤ 10 years of age) or Karnofsky (> 10 years of age) performance status 60-100%
• Peripheral absolute neutrophil count ≥ 1,500/μL
• Platelet count ≥ 100,000/μL
• PT and PTT ≤ 1.5 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 times ULN
• AST and ALT ≤ 2.5 times ULN (5 x ULN if hepatic metastases)
• Creatinine clearance ≥ 60 mL/min OR age-adjusted serum creatinine according to the following schedule:
  • 1 mg/dL (male and female 5 to < 10 years of age)
  • 1.2 mg/dL (male and female 10 to < 13 years of age)
  • 1.5 mg/dL (male 13 to < 16 years of age)
  • 1.4 mg/dL (female 13 to < 16 years of age)
  • 1.7 mg/dL (male ≥ 16 years of age)
  • 1.4 mg/dL (female ≥ 16 years of age)
• Negative pregnancy test
• Patients of child-bearing or child-fathering potential must be willing to use a medically effective form of birth control, which includes abstinence, during and for 2 months after completion of study therapy
• Must be able to take one of the oral formulations of vandetanib
  • Administration of the liquid form of vandetanib via a nasogastric tube or gastrostomy is allowed

Exclusion criteria:

• Pregnant or breastfeeding females
• Serum potassium < 3.5 mEq/L OR serum calcium or magnesium below the lower limits of normal
  • Correction of these electrolyte abnormalities with supplements is allowed
• History of arrhythmia (i.e., multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia, uncontrolled atrial fibrillation, or left bundle branch block) that is symptomatic or requires treatment (except for controlled atrial fibrillation)
• Patients with a history of congenitally prolonged QTc, a first degree relative with unexplained sudden death under 40 years of age, or a measured QTc (Bazett's correction) longer than 480 msec on ECG
• Patients who have experienced QTc prolongation with other medications requiring discontinuation of that medication
• Diastolic blood pressure above 95% for age on at least 2 of 3 measurements with an appropriate size cuff OR patients who are currently taking antihypertensive therapy
• Other clinically severe or uncontrolled systemic illness that would compromise the participants ability to tolerate vandetanib or compromise study procedures or endpoints

Expected Enrollment

Outcomes

Objective response (complete or partial) as assessed by RECIST
Change in tumor markers (calcitonin and CEA)
Change in tumor-related diarrhea
Safety
Maximum tolerated dose
Pharmacokinetics

Toxicity
Progression-free survival
Overall survival
Expression of RET, EGFR, VEGFR, and somatostatin receptor by IHC
Tumor pharmacodynamics

Outline

Patients are stratified according to age (13 to 18 vs 5 to 12).

Patients receive oral vandetanib once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Blood samples are collected from patients periodically for pharmacokinetic, and biological studies, including analysis for concentrations of vandetanib, calcitonin, and CEA by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Previously archived tumor tissue samples are analyzed for RET, VEGFR, EGFR, and somatostatin receptor by IHC and for secondary genetic changes (chromosomal gains/losses of DNA) by comparative genomic hybridization.

After completion of study treatment, patients are followed periodically.

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Frank Balis, MD, Principal investigator		Ph: 301-496-0085 Email: balisf@nih.gov

U.S.A.
Maryland
	Bethesda
	Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
		Clinical Trials Office - Warren Grant Magnusen Clinical Center - NCI Clinical Trials Referral Office	Ph:  888-NCI-1937
Missouri
	Saint Louis
	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
		Samuel Wells, MD, FACS	Ph:  314 454-1898 800-600-3606

Related Information

Featured trial article

Registry Information
Official Title		Phase I/II Trial of Vandetanib (ZD6474, ZACTIMA) in Children and Adolescents With Hereditary Medullary Thyroid Carcinoma
Trial Start Date		2007-06-01
Trial Completion Date		2009-06-01 (estimated)
Registered in ClinicalTrials.gov		NCT00514046
Date Submitted to PDQ		2007-07-11
Information Last Verified		2008-03-30