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

• ClinicalTrials.gov Identifier: NCT01286753
• Recruitment Status: Completed
• First Posted: January 31, 2011
• Results First Posted: September 7, 2016
• Last Update Posted: September 7, 2016
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: January 28, 2011
• First Posted Date: January 31, 2011
• Results First Submitted Date: July 22, 2016
• Results First Posted Date: September 7, 2016
• Last Update Posted Date: September 7, 2016
• Study Start Date: June 2011
• Actual Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 22, 2016)

Best Overall Response Rate in TKI-Naive Participants [ Time Frame: Up to approximately 4 years ]

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.

• Original Primary Outcome Measures (submitted: January 28, 2011): Best overall response rate (BORR) in sorafenib-naïve patients (Cohort 1), assessed by the investigator according to RECIST criteria [ Time Frame: 18 months ]

Current Secondary Outcome Measures (submitted: July 22, 2016)

• Best Overall Response Rate in TKI-Experienced Participants [ Time Frame: Up to approximately 4 years ]
  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.
• Clinical Benefit Rate [ Time Frame: Up to approximately 4 years ]
  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.
• Duration of Response [ Time Frame: From the date of first qualifying response to the date of PD or death for any cause (up to approximately 4 years) ]
  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.
• Progression-Free Survival [ Time Frame: From the day of first treatment until the first documented PD or death (up to approximately 4 years) ]
  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.
• Overall Survival [ Time Frame: From the date of first treatment to the date of death for any cause (up to approximately 4 years) ]
  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.
• Percentage of Participants With Adverse Events [ Time Frame: 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) ]
  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.
• Pharmacokinetics of Vemurafenib: Area Under the Concentration-Time Curve (AUC) [ Time Frame: Up to approximately 4 years ]
  AUC is a measure of the drug or biologic concentration in the body following administration.

Original Secondary Outcome Measures (submitted: January 28, 2011)

• Clinical benefit rate (objective response rate + stable disease) in sorafenib-naïve patients [ Time Frame: 18 months ]
• Duration of response in sorafenib-naïve patients [ Time Frame: 4.5 years ]
• Progression-free survival in sorafenib-naïve patients [ Time Frame: 4.5 years ]
• Overall survival in sorafenib-naïve patients [ Time Frame: 4.5 years ]
• Best overall response rate in sorafenib-exposed patients (Cohort 2) [ Time Frame: 18 months ]
• Clinical benefit rate in sorafenib-exposed patients [ Time Frame: 18 months ]
• Duration of response in sorafenib-exposed patients [ Time Frame: 4.5 years ]
• Progression-free survival in sorafenib-exposed patients [ Time Frame: 4.5 years ]
• Overall survival in sorafenib-exposed patients [ Time Frame: 4.5 years ]
• Safety: Incidence of adverse events [ Time Frame: 4.5 years ]
• Pharmacokinetics (Tmax, Cmax, Cmin, AUC) [ Time Frame: 4.5 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Vemurafenib (RO5185426) in Participants With Metastatic or Unresectable Papillary Thyroid Cancer Positive for the BRAF V600 Mutation
• 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Neoplasms

Intervention

Drug: Vemurafenib

Vemurafenib 960 mg orally twice daily.

Other Names:

• Zelboraf®
• RO5185426

Study Arms

• Experimental: Tyrosine Kinase Inhibitor (TKI) Naive
  Vemurafenib in participants naive to any prior systemic TKI therapy.
  Intervention: Drug: Vemurafenib
• Experimental: TKI Experienced
  Vemurafenib in participants previously treated with TKI therapy active against vascular endothelial growth factor receptor 2 (VEGFR).
  Intervention: Drug: Vemurafenib

• Publications *: Brose MS, Cabanillas ME, Cohen EE, Wirth LJ, Riehl T, Yue H, Sherman SI, Sherman EJ. Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016 Sep;17(9):1272-82. doi: 10.1016/S1470-2045(16)30166-8. Epub 2016 Jul 23.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 23, 2013): 51
• Original Estimated Enrollment (submitted: January 28, 2011): 12
• Actual Study Completion Date: May 2015
• Actual Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France, Italy, Netherlands, United States

Administrative Information

• NCT Number: NCT01286753
• Other Study ID Numbers: NO25530; 2010-024133-23
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Disclosures Group, Hoffmann-La Roche
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: July 2016