Evaluation of Efficacy, Safety of Vandetanib in Patients With Differentiated Thyroid Cancer

Study Overview
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Brief Summary
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Primary Objective: To determine the efficacy (as assessed by progression-free survival [PFS]) of vandetanib when compared to placebo in participants with differentiated thyroid cancer that is either locally advanced or metastatic who are refractory or unsuitable for radioiodine therapy. Secondary Objectives: To determine the efficacy of vandetanib when compared to placebo in this participant population as assessed by efficacy variables including duration of response (DOR), objective response rate (ORR), change in tumour size (TS) and overall survival (OS). To evaluate the pharmacokinetics (PK) of vandetanib in this participant population and potentially investigate any influence of participant demography and pathophysiology on vandetanib PK. To demonstrate an improvement in time to worsening of pain (TWP) in participants treated with vandetanib when compared to placebo in this participant population. To evaluate the safety and tolerability of vandetanib treatment in this participant population.

Detailed Description
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Participants who were receiving vandetanib as randomized treatment will be allowed, upon re-consent, to continue on open-label vandetanib if in the opinion of the Investigator the participant is still receiving benefit. Placebo participants who experience disease progression within 60 days of unblinding may be offered the option of treatment with open-label vandetanib if, in the Investigator's opinion, such treatment may be of clinical benefit to the participant. Approximately 2 years; duration will vary depending on individual participant response.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Multi-Centre Phase III Study to Assess the Efficacy and Safety of Vandetanib (CAPRELSA™; SAR390530 (Formerly AstraZeneca ZD6474)) 300 mg in Patients With Differentiated Thyroid Cancer That Is Either Locally Advanced or Metastatic Who Are Refractory or Unsuitable for Radioiodine (RAI) Therapy.

Conditions
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Differentiated Thyroid Cancer

Intervention / Treatment
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* Drug: Vandetanib (SAR390530)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent to participate in the study as well as provision of informed consent to provide a sample of a previously obtained archival tumour biopsy. Female or male aged 18 years and older with previously confirmed histological diagnosis of locally advanced or metastatic differentiated (excluding minimally invasive follicular) thyroid cancer not amenable to surgical resection, external beam radiotherapy or local therapy. Measurable disease defined as at least one lesion, not irradiated within 12 weeks of the date of randomisation, that can be accurately measured at baseline. Participants must have experienced progression within 14 months and be RAI-refractory/resistant or unsuitable for RAI. Thyroid-stimulating hormone (TSH) suppression below 0.5 mU/L is required. World Health Organisation (WHO) or Eastern Cooperative Oncology Group (ECOG) Performance status 0-2. Negative pregnancy test (urine or serum) for female participants of childbearing potential. Exclusion Criteria: Inadequate organ function as defined by: (1) Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) greater than 2.5 x upper limit of normal (ULN), or greater than 5.0 x ULN if judged by the Investigator to be related to liver metastases. (2) Serum bilirubin greater than 1.5 x ULN. This criterion does not apply to participants with known Gilbert's Disease. (3) Creatinine clearance <50 mL/min (calculated by Cockcroft-Gault formula). Risk of prolonged interval between Q and T (QT) on an electrocardiogram (ECG) corrected for heart rate (QTc) as defined by: (1) Current therapy with any medication known to be associated with Torsades de pointes or potent inducers of cytochrome CYP3A4. (2) History of QT prolongation. (3) Congenital long QT syndrome. (4) QT interval corrected for heart rate by the Bazett's method (QTcB) correction unmeasurable or greater than 480 ms on screening ECG. Previous therapy with approved or investigational tyrosine kinase or anti- vascular endothelial growth factor (VEGF) receptor inhibitors or targeted therapies (e.g. multi-targeted kinase inhibitors such as sorafenib, AMG-706, sunitinib, pazopanib, lenvatinib). RAI therapy within 12 weeks prior to first dose of study drug, and radiation therapy other than RAI, including external beam, if not completed prior to randomization.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vandetanib<br>Vandetanib 300 mg tablet, orally once daily until disease progression or death. | Drug: Vandetanib (SAR390530)<br>* Pharmaceutical form: tablet Route of administration: oral<br>* Other names: CAPRELSA;|
| Placebo Comparator: Placebo<br>Placebo matched to vandetanib tablet, orally once daily until disease progression or death. | Drug: Placebo<br>* Pharmaceutical form: tablet Route of administration: oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | The PFS was defined as the time (in months) from randomization until the date of first documented disease progression or death (from any cause), whichever came first. Disease progression as per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) was defined as: at least a 20% increase and absolute increase of 5 mm in the sum of the longest diameter (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. Analysis was performed by Kaplan-Meier method. | Randomization until disease progression or death, assessed every 12 weeks (up to 22 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of the Efficacy of Vandetanib When Compared to Placebo in the Patient Population as Assessed by Efficacy Variables Including Duration of Response. | Once 155 progression events have occurred. | Estimated time frame up to 25.5 months (18 months recruitment period plus 7.5 months follow up). RECIST measurements taken every 12 weeks from randomization | 
| Demonstration of an Improvement in Time to Worsening of Pain in Patients Treated With Vandetanib When Compared to Placebo in the Patient Population. | Once 155 progression events have occurred. | Patient assessments at baseline, week 4, 8, 12 and then every 12 weeks thereafter, assess up to 25.5 months | 
| Evaluation of the Safety and Tolerability of Vandetanib Treatment in the Patient Population by Assessment of Adverse Events, Vital Signs, Laboratory Parameters and Electrocardiography. | Once 155 progression events have occurred. | Safety assessments at baseline, Weeks 1, 2, 4, 8, 12 and then every 12 weeks thereafter | 
| Determination of the Efficacy of Vandetanib When Compared to Placebo in the Patient Population as Assessed by Efficacy Variables Including Objective Response Rate. | Once 155 progression events have occurred. | Estimated time frame up to 25.5 months (18 months recruitment period plus 7.5 months follow up). RECIST measurements taken every 12 weeks from randomization | 
| Determination of the Efficacy of Vandetanib When Compared to Placebo in the Patient Population as Assessed by Efficacy Variables Including Change in Tumour Size | Once 155 progression events have occurred. | Assessed tumour size at screening, Weeks 7, 8 and then every 12 weeks thereafter and at Discontinuation visit, estimated time frame at 25.5 months. | 
| Determination of the Efficacy of Vandetanib When Compared to Placebo in the Patient Population as Assessed by Efficacy Variables Including Overall Survival | Once 155 progression events have occurred when 25% of randomized patients have died due to any cause. | Estimated time frame at 20 months after initial 25.5 months. | 
| Evaluation of the Pharmacokinetics of Vandetanib in the Patient Population by Assessment of V/F. | Estimated time frame up to 155 progression events have occurred or up to individual progression of patient. | Blood sampling at 4-6 hours post-dose at Weeks 1, 2, 4, 8, 12 and then every 12 weeks thereafter until discontinuation. | 
| Evaluation of the Pharmacokinetics of Vandetanib in the Patient Population by Assessment of Cmax | Estimated time frame up to 155 progression events have occurred or up to individual progression of patient. | Blood sampling at 4-6 hours post-dose at Weeks 1, 2, 4, 8, 12 and then every 12 weeks thereafter until discontinuation. | 
| Evaluation of the Pharmacokinetics of Vandetanib in the Patient Population by Assessment of AUCss | Estimated time frame up to 155 progression events have occurred or up to individual progression of patient. | Blood sampling at 4-6 hours post-dose at Weeks 1, 2, 4, 8, 12 and then every 12 weeks thereafter until discontinuation. | 
| Evaluation of the Pharmacokinetics of Vandetanib in the Patient Population by Assessment of CL/F | Estimated time frame up to 155 progression events have occurred or up to individual progression of patient. | Blood sampling at 4-6 hours post-dose at Weeks 1, 2, 4, 8, 12 and then every 12 weeks thereafter until discontinuation. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vandetanib, AZD 6474, Differentiated Thyroid Cancer