Vandetanib to Treat Children and Adolescents With Medullary Thyroid Cancer

NCT00514046 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 07018907-C-0189
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

Brief Summary

Background:

• Medullary thyroid carcinoma (MTC) is common in people with a genetic disorder called multiple endocrine neoplasia (MEN).
• Vandetanib is an experimental drug that blocks a defective protein receptor (rearranged during transfection (RET) receptor) found on the surface of cancer cells in people with MEN. It is thought that this protein is a primary cause of MTC in people with MEN. Objectives:
• To study the activity of Vandetanib in children and adolescents with MEN-related MTC by measuring the change in tumor size, in blood levels of proteins produced the tumor (calcitonin and carcinoembryonic antigen (CEA) and in tumor-related diarrhea.
• To determine the safety and tolerability of Vandetanib in children and adolescents.
• To study how the body handles Vandetanib in children and adolescents.
• To determine the effect of Vandetanib on the survival of children and adolescents with MTC. Eligibility:
• Children and adolescents 5 to 18 years of age with MTC whose tumor cannot be surgically removed or has grown back after treatment or has metastasized (spread beyond the thyroid gland). Design:
• Patients take Vandetanib once a day in 28-day cycles. The first patients enrolled in the study are started on a low dose of Vandetanib to determine tolerability.
• Patients have periodic blood tests, electrocardiograms, and blood pressure measurements to look for side effects of Vandetanib.
• Blood tests and imaging scans (magnetic resonance imaging (MRI), computed tomography (CT), bone and octreoscan) are done every 8 weeks for the first 32 weeks of treatment and then every 16 weeks for the duration of the treatment period.
• Patients who have tumor-related diarrhea keep a daily record of the number and consistency of bowel movements.

Conditions

Medullary Thyroid Carcinoma; Multiple Endocrine Neoplasia Type 2A; Multiple Endocrine Neoplasia Type 2B

Keywords

Multiple Endocrine Neoplasia; Medullary Thyroid Carcinoma; Molecularly-Targeted Therapy; Pediatric; Pharmacokinetics

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (MTD)

  The MTD is the highest dose of Vandetanib tolerated at which a participant experienced a dose limiting toxicity (DLT) during the first two cycles of drug.

  During Cycle 1 and Cycle 2, approximately 56 days

• Overall Percentage of Participants With an Objective Response Defined as a Complete Response (CR) or Partial Response (PR)

  Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response is disappearance of all target lesions. Partial Response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Stable Disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. Progressive Disease is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

  Patients were evaluated for response after every 2 cycles x 4 (prior to cycles 1, 3, 5, 7, and 9) and then after every 4 cycles X 1 (prior to cycle 13) and then every 6 cycles (prior to cycle 19, 25, 31, etc). Response was followed for an median of 59 mon

Secondary Outcomes (4)

• Number of Participants With an Increase or Decrease in Carcinoembryonic Antigen (CEA) Biomarker Response

  Every 2 cycles x 4 (prior to cycles 1, 3, 5, 7 and 9), prior to cycle 13, and then every 6 cycles (prior to cycle 19, 25, 31, etc). Patients were followed for response for a median of 59 months.

• Percent Change in Calcitonin (CTN) Biomarker Response After Cycle 1

  Cycle 1 (28 days)

• Area Under the Concentration Time Curve (AUC 0-24h)

  Cycle 1, Pre-dose and then 1, 2, 4, 6, 8, 10 and 24 hour post dose.

• Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v3.0)

  Date treatment consent signed to date off study, approximately 142 months and 8 days.

Other Outcomes (1)

• Number of Participants With a Dose Limiting Toxicity (DLT)

  up to Cycle 3 (each Cycle is 28 days)

Study Arms (1)

Vandetanib

EXPERIMENTAL

Vandetanib administered as a once daily dose, continuously (1 cycle = 28 days) at a dose of 150 mg/m\^2/day.

Drug: Vandetanib

Interventions

Vandetanib DRUG

once daily continuously (28 day cycles)

Also known as: Caprelsa

Vandetanib

Eligibility Criteria

• Age: 5 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age: Participants must be 5 to 18 years of age, inclusive. The first cohort of 3 to 6 participants enrolled on the trial will be at least 13 years of age.
• Diagnosis: Hereditary (Multiple endocrine neoplasia, type 2A (MEN 2A) or Multiple endocrine neoplasia, type 2B (MEN 2B) medullary thyroid carcinoma (histologically confirmed) that is unresectable, recurrent or metastatic. Participants must have previously had a characteristic germline mutation in the rearranged during transfection (RET) proto-oncogene documented. Results of the germline mutation testing will be obtained from the referring institution.
• Participants must have measurable disease as defined in Response Evaluation Criteria in Solid Tumors (RECIST) as the presence of at least one lesion that can be accurately measured in at least one dimension with longest diameter of at least 20 mm using conventional techniques or at least 10 mm with spiral computed tomography (CT) scan. Superficial (easily palpable) lymph nodes will be considered measurable.
• Participants must be able to take one of the oral formulations of vandetanib.
• Prior therapy: There are no standard chemotherapy regimens known to be effective for medullary thyroid carcinoma (MTC). Therefore, previously untreated participants are eligible if their tumor(s) are not surgically resectable.
• Participants must be at least 4 weeks from prior surgical procedures and surgical incisions must be healed.
• Participants must have had their last fraction of external beam radiation therapy at least 4 weeks prior to enrollment.
• Participants must have had their last dose of cytotoxic chemotherapy at least 28 days prior to enrollment, their last dose of biological therapy, such as biological response modifiers (e.g., cytokines), immunomodulatory agents, vaccines, differentiating agents, used to treat their cancer at least 7 days prior to enrollment, their last dose of a monoclonal antibody at least 30 days prior to enrollment, and their last dose of any investigational agent at least 30 days prior to enrollment.
• Participants must have received their last dose of short acting colony stimulating factor, such as filgrastim or sargramostim at least 72 hours prior to enrollment and their last dose of long-acting colony stimulating factors, such as polyethylene glycol (PEG)-filgrastim at least 7 days prior to enrollment.
• Participants must have recovered from the acute toxic effects of prior therapy to a grade 1 (Common Terminology Criteria for Adverse Events (CTCAE) v.3.0) level prior to enrollment.
• Performance Status: Lansky (for participants 10 years of age or younger) or Karnofsky (for participants older than 10 years) performance score greater than 50
• Concomitant Medications:
• Participants who have previously had a thyroidectomy should be on thyroid hormone replacement therapy.
• Hematological Function: The peripheral absolute neutrophil count must be at least 1,500 micro liters and the platelet count must be at least 100,000 micro liters within 72 hours prior to enrollment.
• Coagulation: Prothrombin Time (PT) and Partial Thromboplastin Time (PTT) must not be more than 1.5 x ULN within 72 hours prior to enrollment. PT and PTT should drawn by venipuncture, rather than from a central venous catheter when feasible.

You may not qualify if:

• Pregnant or breast feeding females because the anti-angiogenic properties of vandetanib may be harmful to the developing fetus or nursing infant.
• Participants with pheochromocytoma as evidenced by elevated plasma free metanephrines.
• Electrolytes: Participants with a serum potassium less than 3.5 mmol/L or a serum calcium or magnesium below the lower limits of normal. Correction of these electrolyte abnormalities with supplements is allowed.
• Cardiac:
• Participants with a history of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia, uncontrolled atrial fibrillation, left bundle branch block) that is symptomatic or requires treatment (except for controlled atrial fibrillation)
• Participants with a history of congenitally prolonged Corrected QT Interval (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 electrocardiogram (ECG). ECGs should be performed after correction of electrolyte abnormalities. Participants with a prolonged QTc should have a repeat ECG at least 24 hour after the first, and the mean of the 2 QTcs should not exceed 480 msec.
• Participants who experienced QTc prolongation with other medications requiring discontinuation of that medication.
• Participants receiving a medication that has a known risk of QTc prolongation within 14 days (28 days for levomethadyl) of enrollment.
• Hypertension: Diastolic blood pressure above the 95% for age on at least 2 of 3 measurements with an appropriate-size cuff or patients who are currently taking anti-hypertensive therapy.
• Other clinically severe or uncontrolled systemic illness that could compromise the participants ability to tolerate vandetanib or could compromise study procedures or endpoints.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (7)

• Holden SN, Eckhardt SG, Basser R, de Boer R, Rischin D, Green M, Rosenthal MA, Wheeler C, Barge A, Hurwitz HI. Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors. Ann Oncol. 2005 Aug;16(8):1391-7. doi: 10.1093/annonc/mdi247. Epub 2005 May 19.

  PMID: 15905307 BACKGROUND

• Marsh DJ, Learoyd DL, Robinson BG. Medullary thyroid carcinoma: recent advances and management update. Thyroid. 1995 Oct;5(5):407-24. doi: 10.1089/thy.1995.5.407.

  PMID: 8563482 BACKGROUND

• Fox E, Widemann BC, Chuk MK, Marcus L, Aikin A, Whitcomb PO, Merino MJ, Lodish M, Dombi E, Steinberg SM, Wells SA, Balis FM. Vandetanib in children and adolescents with multiple endocrine neoplasia type 2B associated medullary thyroid carcinoma. Clin Cancer Res. 2013 Aug 1;19(15):4239-48. doi: 10.1158/1078-0432.CCR-13-0071. Epub 2013 Jun 13.

  PMID: 23766359 RESULT

• Kraft IL, Akshintala S, Zhu Y, Lei H, Derse-Anthony C, Dombi E, Steinberg SM, Lodish M, Waguespack SG, Kapustina O, Fox E, Balis FM, Merino MJ, Meltzer PS, Glod JW, Shern JF, Widemann BC. Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib. Clin Cancer Res. 2018 Feb 15;24(4):753-765. doi: 10.1158/1078-0432.CCR-17-2101. Epub 2017 Nov 29.

  PMID: 29187393 RESULT

• Allen, T., Bedoya, S.Z., Glod, J., Widemann, B., Wiener, L. Baseline Characteristics of Adolescents and Young Adults with Medullary Thyroid Cancer and MEN-2B: Data from the Rare Tumor Initiative at the National Cancer Institute. International Psycho-Oncology Society's 21st World Congress, Banff, Canada, September, 2019, Journal of Psychosocial Oncology Research and Practice, 1(1): 5.

  RESULT

• Lodish M, Gkourogianni A, Bornstein E, Sinaii N, Fox E, Chuk M, Marcus L, Akshintala S, Balis F, Widemann B, Stratakis CA. Patterns of thyroid hormone levels in pediatric medullary thyroid carcinoma patients on vandetanib therapy. Int J Pediatr Endocrinol. 2015;2015(1):3. doi: 10.1186/1687-9856-2015-3. Epub 2015 Feb 16.

  PMID: 25972901 DERIVED

• Nella AA, Lodish MB, Fox E, Balis FM, Quezado MM, Whitcomb PO, Derdak J, Kebebew E, Widemann BC, Stratakis CA. Vandetanib successfully controls medullary thyroid cancer-related Cushing syndrome in an adolescent patient. J Clin Endocrinol Metab. 2014 Sep;99(9):3055-9. doi: 10.1210/jc.2013-4340. Epub 2014 Mar 11.

  PMID: 24617713 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Carcinoma, Medullary; Multiple Endocrine Neoplasia Type 2a; Multiple Endocrine Neoplasia Type 2b; Multiple Endocrine Neoplasia

Interventions

vandetanib

Condition Hierarchy (Ancestors)

Carcinoma, Neuroendocrine; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms, Ductal, Lobular, and Medullary; Neoplasms, Nerve Tissue; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms, Multiple Primary; Neoplastic Syndromes, Hereditary; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Endocrine System Diseases

Results Point of Contact

• Title: Dr. Brigitte Widemann
• Organization: National Cancer Institute

widemanb@nih.gov

240-760-6203

Study Officials

• Brigitte C Widemann, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 8, 2007
• First Posted: August 9, 2007
• Study Start: July 20, 2007
• Primary Completion: December 10, 2019
• Study Completion: November 1, 2020
• Last Updated: December 22, 2020
• Results First Posted: December 22, 2020

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Indefinitely.

Locations

US (1)