Vandetanib in children and adolescents with multiple endocrine neoplasia type 2B associated medullary thyroid carcinoma

Abstract

Purpose: Medullary thyroid carcinoma (MTC) is a manifestation of multiple endocrine neoplasia type 2 (MEN2) syndromes caused by germline, activating mutations in the RET (REarranged during Transfection) proto-oncogene. Vandetanib, a VEGF and EGF receptor inhibitor, blocks RET tyrosine kinase activity and is active in adults with hereditary MTC.

Experimental design: We conducted a phase I/II trial of vandetanib for children (5-12 years) and adolescents (13-18 years) with MTC to define a recommended dose and assess antitumor activity. The starting dose was 100 mg/m(2) administered orally, once daily, continuously for 28-day treatment cycles. The dose could be escalated to 150 mg/m(2)/d after two cycles. Radiographic response to vandetanib was quantified using RECIST (v1.0), biomarker response was measured by comparing posttreatment serum calcitonin and carcinoembryonic antigen (CEA) levels to baseline, and a patient-reported outcome was used to assess clinical benefit.

Results: Sixteen patients with locally advanced or metastatic MTC received vandetanib for a median (range) 27 (2-52) cycles. Eleven patients remain on protocol therapy. Diarrhea was the primary dose-limiting toxicity. In subjects with M918T RET germline mutations (n = 15) the confirmed objective partial response rate was 47% (exact 95% confidence intervals, 21%-75%). Biomarker partial response was confirmed for calcitonin in 12 subjects and for CEA in 8 subjects.

Conclusion: Using an innovative trial design and selecting patients based on target gene expression, we conclude that vandetanib 100 mg/m(2)/d is a well-tolerated and highly active new treatment for children and adolescents with MEN2B and locally advanced or metastatic MTC.

Conflict of interest statement

Conflict of Interest Statement: No author has disclosed potential conflict of interest.

©2013 AACR.

Figures

Figure 1. Clinical Trial Flow Diagram

The starting dose of vandetanib was 100 mg/m2/d. Adolescents (age 13–18 years of age) were enrolled at the starting dose (100 mg/m2/d) prior to children. Enrollment of the younger age cohort (Children age 5–12 years old) and intrapatient dose escalation in adolescents to 150 mg/m2/d commenced after vandetanib 100 mg/m2/d was demonstrated to be tolerable in adolescents (<33% dose limiting toxicity during cycle 1 and 2). Because of dose limiting diarrhea in subsequent cycles (cycle 5+) in adolescents, intrapatient dose escalation was not permitted in children. One adolescent was enrolled at the starting dose of 150 mg/m2/d, that subject had hypertension and was dose reduced to 100 mg/m2/d in cycle 3. The recommended dose of vandetanib (100 mg/m2/d) was determine based on extended tolerability, pharmacokinetics, and demonstration of activity (objective response).

Figure 2. Adverse Events Attributed to Vandetanib

The percent of patients (n=16) experiencing grade 1 or 2 (solid black) or grade 3 (shaded grey) toxicity during cycle 1 and 2 is presented on left. The percent of cycles (n=346) in which grade 1 or 2 (solid black) or grade 3 (shaded grey) toxicity were reported is presented on the right. For each toxicity in each patient, the highest grade of toxicity during that cycle was recorded. No grade 4 toxicities possibly, probably or definitely related to vandetanib were observed.

Figure 3. Waterfall Plot

Best Overall Response by RECIST v 1 is presented as percent change in the sum of the longest diameter of target lesions for each patient. Black bars indicate radiographic responses that were confirmed >4 weeks after documentation of partial response. The X-axis identifies the corresponding patient number, the cycle number when best response was initially documented and the total number of cycles administered for each patient.

Figure 4. Radiographic Objective Responses in Adolescents and Children with MEN2B and MTC

(A) CT of chest and neck in Patient 1 (15 year old female) and (B) CT Chest in Patient 4 (11 year old male).

Figure 5. Biomarker Response

The percent change from baseline in calcitonin (top) or CEA (bottom) is presented for each evaluation point in each patient. Patients with baseline calcitonin less than the median (