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Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib.

ABSTRACT: Purpose: Vandetanib is well-tolerated in patients with advanced medullary thyroid carcinoma (MTC). Long-term outcomes and mechanisms of MTC progression have not been reported previously.Experimental Design: We monitored toxicities and disease status in patients taking vandetanib for hereditary, advanced MTC. Tumor samples were analyzed for molecular mechanisms of disease progression.Results: Seventeen patients [8 male, age 13 (9-17)* years] enrolled; 16 had a RET p.Met918Thr germline mutation. The duration of vandetanib therapy was 6.1 (0.1-9.7+)* years with treatment ongoing in 9 patients. Best response was partial response in 10, stable disease in 6, and progressive disease in one patient. Duration of response was 7.4 (0.6-8.7+)* and 4.9 (0.6-7.8+)* years in patients with PR and SD, respectively. Six patients died 2.0 (0.4-5.7)* years after progression. Median progression-free survival (PFS) was 6.7 years [95% confidence interval (CI): 2.3 years-undefined] and 5-year overall survival (OS) was 88.2% (95% CI: 60.6%-96.9%). Of 16 patients with a RET p.Met918Thr mutation, progression-free survival was 6.7 years (95% CI: 3.1-undefined) and 5-year overall survival was 93.8% (95% CI: 63.2%-99.1%). No patients terminated treatment because of toxicity. DNA sequencing of tissue samples (n = 11) identified an increase in copy number alterations across the genome as a potential mechanism of drug resistance [*median (range)].Conclusions: This study demonstrates that vandetanib is safe and results in sustained responses in children and adolescents with hereditary MTC. Our preliminary molecular data suggest that an increase in copy number abnormalities may be associated with tumor progression in hereditary MTC patients treated with vandetanib. Clin Cancer Res; 24(4); 753-65. ©2017 AACR.

SUBMITTER: Kraft IL

PROVIDER: S-EPMC5815946 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib.

Kraft Ira L IL Akshintala Srivandana S Zhu Yuelin Y Lei Haiyan H Derse-Anthony Claudia C Dombi Eva E Steinberg Seth M SM Lodish Maya M Waguespack Steven G SG Kapustina Oxana O Fox Elizabeth E Balis Frank M FM Merino Maria J MJ Meltzer Paul S PS Glod John W JW Shern Jack F JF Widemann Brigitte C BC

Clinical cancer research : an official journal of the American Association for Cancer Research 20171129 4

Purpose: Vandetanib is well-tolerated in patients with advanced medullary thyroid carcinoma (MTC). Long-term outcomes and mechanisms of MTC progression have not been reported previously.Experimental Design: We monitored toxicities and disease status in patients taking vandetanib for hereditary, advanced MTC. Tumor samples were analyzed for molecular mechanisms of disease progression.Results: Seventeen patients [8 male, age 13 (9-17)* years] enrolled; 16 had a RET p.Me ...[more]

PMID: 29187393

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Project description:BACKGROUND:Tyrosine kinase inhibitors (TKIs) have been associated with elevated TSH as a drug class effect. Prior studies of vandetanib in adults with medullary thyroid carcinoma (MTC) described an increase in levothyroxine (LT) requirement. We studied TSH, free T4, and LT dosing in children and adolescents enrolled in the phase I/II trial of vandetanib for medullary thyroid cancer (MTC). METHODS:Data from 13 patients with multiple endocrine neoplasia type 2B (MEN 2B) and MTC were analyzed [6 M, 7 F, median age 13.0 y (9.1-17.3)] Eleven patients (85%) had undergone prior thyroidectomy and all received single-drug therapy with vandetanib for?>?6 months. Confirmed compliance with vandetanib (67-150 mg/m(2)/day) and LT was a necessary inclusion criterion. RESULTS:While on vandetanib treatment, all 11 athyerotic patients exhibited significantly increased TSH levels. The baseline TSH level was 4.37 mclU/ml (0.08 - 23.30); in comparison, the first peak TSH concentration on vandetanib was 15.70 mclU/ml (12.50 - 137.00, p?=?0.0010). The median time to reach the initial peak of elevated TSH was 1.8 months (0.3 - 9.3). Free T4 levels remained within the normal reference range. An increase from a baseline LT dose of 91 mcg/m(2)/day (±24) to 116 mcg/m(2)/day (±24) was required in order to resume normative TSH levels (p?=?0.00005), equal to an increase of 36.6% (±16.56) in the dosage of LT in mcg/day. For the 2 patients with intact thyroid glands, free T4 and TSH remained normal over a combined 6 patient years of follow up. CONCLUSIONS:In our cohort of pediatric MTC patients, athyreotic patients with preexisting hypothyroidism developed increased TSH and reduced free T4 during the first few months of treatment with vandetanib, necessitating an increase in LT dosage. Additional patients with normal thyroid function before treatment and intact glands (n?=?2) maintained normal thyroid function tests during treatment. Elevated TSH in athyreotic patients may be due to an indirect effect of vandetanib on the metabolism of thyroid hormone, or to altered TSH sensitivity at the pituitary. Proper recognition and management of abnormal thyroid hormone levels is critical in growing children on TKIs. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT00514046.

Project description:LESSONS LEARNED:Vandetanib at a dose of 300 mg orally every day plus bortezomib 1.3 mg/m2 intravenously on days 1, 4, 8, and 11 could be administered safely.Assessing outcomes in 17 patients with medullary thyroid cancer, investigators considered the combination to be more difficult to administer than single-agent vandetanib and that achieving better outcomes was unlikely. Consequently, a planned phase II study was terminated early. BACKGROUND:The proto-oncogene RET (REarranged during Transfection) has a critical role in the pathogenesis of medullary thyroid cancer (MTC). Vandetanib (V), a multitargeted tyrosine kinase inhibitor approved for the treatment of MTC, is thought to inhibit RET in MTC. Supported by preclinical studies demonstrating that bortezomib (B) administration lowered RET mRNA and protein levels, we conducted a phase I study in advanced solid tumors of vandetanib in combination with bortezomib. The goal was to establish an RP2D (recommended phase II dose) for the combination of vandetanib plus bortezomib, a regimen envisioned as a dual strategy for targeting RET in MTC. METHODS:Patients with advanced solid tumors were treated with escalating doses of bortezomib or vandetanib to assess the safety and tolerability of daily oral vandetanib and intravenous (IV) bortezomib administered on days 1, 4, 8, and 11 of a 28-day cycle. Intrapatient dose escalation was allowed. RESULTS:Twenty-two patients were enrolled and received escalating mg/m2 bortezomib and mg vandetanib (number of patients) at initial doses of 1 and 100 (3), 1.3 and 100 (6), 1.3 and 200 (6), and 1.3 and 300 (7), respectively. Patients received a median of four cycles of bortezomib/vandetanib (range: 1-10), with 13 patients escalating to 1.3/200 and 10 to 1.3/300. G3 toxicities occurring in more than one patient included hypertension (24%), fatigue (19%), thrombocytopenia (10%), diarrhea (10%), and arthralgia (10%). There were no drug-related G4/5 toxicities. There was one dose-limiting toxicity, G3 thrombocytopenia, at bortezomib/vandetanib doses of 1.3/200 in cycle 2 that resolved without intervention. Four patients with a diagnosis of MTC (27%) had a partial response (PR). CONCLUSION:The MTD of the combination was established as bortezomib, 1.3 mg/m2 IV days 1, 4, 8, and 11 with vandetanib 300 mg p.o. daily. RECIST responses were observed in patients with a diagnosis of MTC.

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Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib.

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Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib.

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