Clinical trialPhase 3Thyroid cancer

Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial

J Clin Oncol · 2012331 patients (231 vandetanib, 100 placebo)

Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, et al. J Clin Oncol. 2012. 30:134-141

Study type: Clinical trial
Study name: ZETA
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled trial (2:1 randomisation); open-label vandetanib could be received after disease progression
Sample size: 331 patients (231 vandetanib, 100 placebo)
Source: J Clin Oncol · 2012
Trial registration: NCT00410761

In plain words

In this study, patients with advanced medullary thyroid cancer received either vandetanib tablets or a placebo (dummy pill). Vandetanib cut the risk of the disease growing by about half, and most patients had their tumour shrink or a fall in their blood markers. Its common side effects were diarrhoea, skin rash, nausea and high blood pressure.

Key results

Not reached (Weibull model prediction: 30.5 months) vs 19.3 months

Median progression-free survival

HR 0.46; 95% CI 0.31–0.69; P<0.001; 6-month progression-free survival 83% vs 63%

45% vs 13%

Objective response rate

OR 5.48; 95% CI 2.99–10.79; P<0.001; 12 of the 13 responses in the placebo group occurred in the open-label phase while receiving vandetanib

87% vs 71%

Disease control rate at 24 weeks

OR 2.64; 95% CI 1.48-4.69; P=0.001

Calcitonin 69% vs 3%; CEA 52% vs 2%

Biochemical response

Both P<0.001

Immature at data cut-off

Overall survival

HR 0.89; 95% CI 0.48–1.65; 48 deaths (15%) at a median follow-up of 24 months

Dose and schedule cards

Vandetanib (ZETA)

Unresectable locally advanced or metastatic medullary thyroid cancer, symptomatic or progressiveCycle length: ContinuousOn the page “Thyroid cancer” · Advanced or metastatic medullary thyroid cancer

Unresectable locally advanced or metastatic medullary thyroid cancer, symptomatic or progressive

Drug	Dose	Route	Schedule
Vandetanib	300 mg	Oral, with or without food	Once daily, continuously

Cycle length: Continuous
Duration: Until disease progression or unacceptable toxicity

Source: FDA label; ZETA. Boxed warning: QT prolongation, torsades de pointes and sudden death; do not use in patients with hypocalcaemia, hypokalaemia, hypomagnesaemia or long QT syndrome, and correct these abnormalities before starting. ECG and potassium, calcium, magnesium and TSH at baseline, at weeks 2 to 4, at weeks 8 to 12 and then every 3 months; maintain potassium ≥4 mEq/L. QTcF above 500 ms → withhold, then resume at a reduced dose once it falls below 450 ms. Dose reduction levels: 200 mg, then 100 mg. CrCl 30 to less than 50 mL/min: starting dose 200 mg. Avoid QT-prolonging drugs.

On the page “Thyroid cancer” · Advanced or metastatic medullary thyroid cancer

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Vandetanib

Oral vandetanib at a starting dose of 300 mg once daily, continuously until disease progression. General dose reduction for any grade 3 or 4 adverse event (CTCAE): to 200 mg daily, and if grade 3 or 4 toxicity recurred, to 100 mg daily; specific dose-reduction schemes existed for skin and gastrointestinal toxicity and QTc prolongation. 12-lead ECG at screening, weeks 1, 2, 4, 8 and 12, then every 3 months (QTc centrally assessed). Protocol-defined QTc prolongation: a single measurement of 550 ms or more or an increase of 100 ms or more from baseline; two consecutive measurements (within 48 hours) between 500 and less than 550 ms; or an increase of 60 to less than 100 ms to a value of 480 ms or more.

FDA label (CAPRELSA) points: contraindicated in congenital long QT syndrome; in moderate renal impairment (CrCl 30 to less than 50 mL/min) a starting dose of 200 mg; not recommended in moderate and severe hepatic impairment. ECG and potassium, calcium, magnesium and TSH at baseline, at 2 to 4 weeks and 8 to 12 weeks after starting, then every 3 months; keep potassium at 4 mEq/L or more and magnesium and calcium within the normal range; avoid QT-prolonging drugs. If QTcF exceeds 500 ms, stop the drug and resume at a lower dose after it falls below 450 ms.

2Placebo

Oral placebo once daily until disease progression. On objective progression (investigator assessment), study treatment was stopped and unblinded, and the patient could receive open-label vandetanib; 52 of the 56 eligible placebo patients (93%) did so.

Source of the regimen details: Full text of the J Clin Oncol 2012 paper in PMC (PMC3675689): starting dose, dose-reduction scheme and ECG monitoring schedule; FDA label for vandetanib (CAPRELSA, DailyMed) for dose adjustment in renal and hepatic impairment and for QT and electrolyte monitoring.

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with hereditary or sporadic medullary thyroid cancer (MTC) that was unresectable, locally advanced or metastatic and measurable, with WHO performance status 0 to 2 and serum calcitonin of 500 pg/mL or more. Submission of a tumour sample was required, except in hereditary MTC with a documented germline RET mutation. Exclusion criteria: significant cardiac, haematological, hepatic or renal impairment, and chemotherapy or radiotherapy within 4 weeks before randomisation. Characteristics: mean age 52 years; 90% sporadic; 95% metastatic; about 40% had prior systemic therapy; RET mutation was positive in 59% of the vandetanib group and unknown in 40%.

Endpoints

Primary endpoint: progression-free survival by independent central RECIST assessment. Other endpoints: objective response rate, disease control rate, biochemical response and overall survival.

Safety and side effects

Common adverse events (any grade) were more frequent with vandetanib than with placebo: diarrhoea (56% versus 26%), rash (45% versus 11%), nausea (33% versus 16%), hypertension (32% versus 5%) and headache (26% versus 9%).

Grade 3 or higher adverse events (vandetanib versus placebo): diarrhoea 11% versus 2%, hypertension 9% versus 0%, ECG QT prolongation 8% versus 1%, fatigue 6% versus 1%, decreased appetite 4% versus 0% and rash 4% versus 1%. Protocol-defined QTc prolongation occurred in 19 patients (8%), with no torsade de pointes reported. Dose reduction due to adverse events or QTc prolongation: 35% versus 3%; discontinuation due to adverse events: 12% (28 patients) versus 3%. TSH increase requiring a higher thyroid hormone dose: 49.3% versus 17.2%. Five deaths due to adverse events occurred in the vandetanib group (aspiration pneumonia, respiratory arrest, respiratory failure, staphylococcal sepsis, and arrhythmia with acute heart failure) and two in the placebo group. Median duration of treatment in the randomised phase was 90.1 weeks versus 39.9 weeks.

Clinical significance and place in guidelines

ZETA was the first positive phase 3 trial in advanced medullary thyroid cancer. Vandetanib, together with cabozantinib, is recommended in the American Thyroid Association and NCCN guidelines for progressive or symptomatic metastatic medullary cancer.

Limitations

At the time of this analysis, overall survival data were immature, and placebo patients could receive open-label vandetanib after progression; the benefit of vandetanib in asymptomatic or slowly progressing disease must be weighed against its toxicity.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.