A Study of Vemurafenib (RO5185426) in Participants With Metastatic or Unresectable Papillary Thyroid Cancer Positive for the BRAF V600 Mutation

Study Overview
=================
Brief Summary
-----------------
This open-label, multi-center study will evaluate the safety and efficacy of Vemurafenib (RO5185426) in participants with metastatic or unresectable papillary thyroid cancer (PTC) positive for the BRAF V600 mutation and resistant to radioactive iodine therapy. Participants will receive vemurafenib 960 milligrams (mg) orally twice daily until progressive disease or unacceptable toxicity occurs.

Official Title
-----------------
An Open-Label, Multi-Center Phase II Study of the BRAF Inhibitor Vemurafenib in Patients With Metastatic or Unresectable Papillary Thyroid Cancer (PTC) Positive for the BRAF V600 Mutation and Resistant to Radioactive Iodine

Conditions
-----------------
Neoplasms

Intervention / Treatment
-----------------
* Drug: Vemurafenib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult participants. >/= 18 years of age Histologically confirmed metastatic or unresectable papillary thyroid cancer for which standard curative or palliative measures do not exist or are no longer effective; participants whose tumors exhibit areas of other histology may be enrolled, provided the tumor histology remains predominantly papillary Positive for BRAF V600 mutation (Roche Cobas 4800 BRAF V600 Mutation Test) Radioactive Iodine resistant disease Prior therapy excluding (Cohort 1, TKI Naive) or including (Cohort 2, TKI Experienced) TKI Clinically relevant disease progression according to RECIST criteria within the prior 14 months Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Adequate hematological, renal and liver function Exclusion Criteria: Histological diagnosis other than papillary PTC, including squamous cell variants of PTC or PTC with areas of squamous metaplasia Active or untreated central nervous system metastases History of or known carcinomatous meningitis Anticipated or ongoing administration of any anti-cancer therapies other than those administered in the study Active squamous cell skin cancer that has not been excised or adequately healed post excision Previous treatment with any agent that specifically and selectively targets the MEK or BRAF pathway Prior radiotherapy to the only measurable lesion Clinically relevant cardio-vascular disease or event within the prior 6 months

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tyrosine Kinase Inhibitor (TKI) Naive<br>Vemurafenib in participants naive to any prior systemic TKI therapy. | Drug: Vemurafenib<br>* Vemurafenib 960 mg orally twice daily.<br>* Other names: RO5185426;|
| Experimental: TKI Experienced<br>Vemurafenib in participants previously treated with TKI therapy active against vascular endothelial growth factor receptor 2 (VEGFR). | Drug: Vemurafenib<br>* Vemurafenib 960 mg orally twice daily.<br>* Other names: RO5185426;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response Rate in TKI-Naive Participants | Best overall response rate was assessed by the investigators according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Best overall response rate: the percentage of participants with best objective response of complete response (CR) or partial response (PR) (calculated as the number of participants with best response CR or PR divided by the total number of efficacy-evaluable participants). CR: disappearance of all target lesions with reduction in target/non-target pathological lymph nodes to < 10 millimeters (mm). PR: ≥ 30% decrease in the sum of diameters of target lesions, compared to the baseline sum diameters. | Up to approximately 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response Rate in TKI-Experienced Participants | Best overall response rate was assessed by the investigators according to RECIST v1.1. Best overall response rate: the percentage of participants with best objective response of CR or PR (calculated as the number of participants with best response CR or PR divided by the total number of efficacy-evaluable participants). CR: disappearance of all target lesions with reduction in target/non-target pathological lymph nodes to < 10 mm. PR: ≥ 30% decrease in the sum of diameters of target lesions, compared to the baseline sum diameters. | Up to approximately 4 years | 
| Clinical Benefit Rate | Clinical benefit rate: the percentage of participants with confirmed CR, PR, or stable disease (SD; maintained for at least 6 months) as assessed by investigators according to RECIST v1.1. CR: disappearance of all target lesions with reduction in target/non-target pathological lymph nodes to < 10 mm. PR: ≥ 30% decrease in the sum of diameters of target lesions, compared to the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, compared to the baseline sum diameters. | Up to approximately 4 years | 
| Duration of Response | Duration of response (for participants with confirmed best response CR or PR): the interval between earliest qualifying response and date of progression of disease (PD) or death for any cause, whichever occurred first; participants with no documented progression after CR or PR were censored at the date of last known CR or PR, respectively. CR: disappearance of all target lesions with reduction in target/non-target pathological lymph nodes to < 10 mm. PR: ≥ 30% decrease in the sum of diameters of target lesions, compared to the baseline sum diameters. PD: ≥ 20% increase in the sum of diameters of target lesions, compared to the smallest sum on study. | From the date of first qualifying response to the date of PD or death for any cause (up to approximately 4 years) | 
| Progression-Free Survival | Progression-free survival: the interval between the day of first treatment and the first documentation of PD or death; participants who were withdrawn from the study without documented progression were censored at the date of the last tumor assessment when the participant was known to be progression-free; participants without post baseline tumor assessments were censored at the time of enrollment. PD: ≥ 20% increase in the sum of diameters of target lesions, compared to the smallest sum on study. | From the day of first treatment until the first documented PD or death (up to approximately 4 years) | 
| Overall Survival | Overall survival: the interval between the date of first treatment to the date of death, regardless of the cause of death; participants who were alive at the time of the analysis were censored at the date of the last known alive; participants with no post baseline information were censored at the time of enrollment. | From the date of first treatment to the date of death for any cause (up to approximately 4 years) | 
| Percentage of Participants With Adverse Events | An adverse event was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. | Baseline until 28 days after the last dose of study treatment or until initiation of another anti-cancer therapy, whichever occurred first (up to approximately 4 years) | 
| Pharmacokinetics of Vemurafenib: Area Under the Concentration-Time Curve (AUC) | AUC is a measure of the drug or biologic concentration in the body following administration. | Up to approximately 4 years |