A Study of RO5185426 in Previously Treated Patients With Metastatic Melanoma - Full Text View

Sponsor:	Hoffmann-La Roche
Information provided by (Responsible Party):	Hoffmann-La Roche
ClinicalTrials.gov Identifier:	NCT00949702

Purpose

This open-label single-arm study assessed the efficacy, safety, and tolerability of vemurafenib (RO5185426) in previously treated patients with metastatic melanoma. Patients received oral vemurafenib (RO5185426, RG7204, PLX4032) at a dose of 960 mg bid (bis in die, twice daily) continuously until unacceptable toxicity, disease progression, or withdrawal from the study. Patients were assessed at regular intervals for tumour response and tolerability.

Condition	Intervention	Phase
Malignant Melanoma	Drug: Vemurafenib 960 mg	Phase II

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	An Open-label, Multi-center, Phase II Study of Continuous Oral Dosing of RO5185426 in Previously Treated Patients With Metastatic Melanoma

Resource links provided by NLM:

MedlinePlus related topics: Cancer Melanoma

U.S. FDA Resources

Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:

Best Overall Response (BOR) Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) [ Time Frame: From first treatment through September 27, 2010 ] [ Designated as safety issue: No ]
BOR was defined as a complete response (CR) or partial response (PR) confirmed per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Patients who never received study treatment and treated patients without any post-baseline tumor assessments were considered as non-responders. CR: Disappearance of all target lesions, all non-target lesions, and no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesion.

Secondary Outcome Measures:

Best Overall Response (BOR) Assessed by the Investigator Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) [ Time Frame: From first treatment through September 27, 2010 ] [ Designated as safety issue: No ]
BOR was defined as a complete response (CR) or partial response (PR) confirmed per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Patients who never received study treatment and treated patients without any post-baseline tumor assessments were considered as non-responders. CR: Disappearance of all target lesions, all non-target lesions, and no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesion.
Duration of Response Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) [ Time Frame: From first treatment through September 27, 2010 ] [ Designated as safety issue: No ]
Duration of response was defined as the time interval between the date of the earliest qualifying response and the date of disease progression (PD) or death, only for those patients whose best overall response was complete response or partial response. PD: At least 20% increase in the sum of diameters of target lesions compared to Nadir (smallest sum of diameters on-study), unequivocal progression of existing non-target lesions, or presence of new lesion. For patients who were alive without progression, duration of response was censored on the date of the last evaluable tumor assessment.
Time to Response Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) [ Time Frame: From first treatment through September 27, 2010 ] [ Designated as safety issue: No ]
Time to response was defined as the interval between the date of the first treatment and the date of the first documentation of confirmed complete response (CR) or partial response (PR), whichever occurred first.
Progression Free Survival (PFS) Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) [ Time Frame: From first treatment through September 27, 2010 ] [ Designated as safety issue: No ]
PFS was defined the time interval between the date of the first treatment and the date of progression or death from any cause, whichever occurred first. Deaths that occurred in patients without disease progression were considered to be a PFS event on the date of death. Patients who neither progressed nor died were censored on the date of the last evaluable tumor assessment prior to the data cutoff date.
Overall Survival [ Time Frame: From first treatment through September 27, 2010 ] [ Designated as safety issue: No ]
Overall survival was defined as the time from the date of the first treatment to the date of death, regardless of the cause of death. For patients who were alive at the time of analysis, overall survival was censored at the last date the patient was known to be alive prior to the data cutoff date.
Improvement in Physical Symptoms (Improvement in Physician's Assessment of Global Performance Status and Oxygen Saturation Requirements, and Decrease in Total Dose and Frequency of Narcotic Pain Analgesics) During Treatment in Comparison to Baseline [ Time Frame: From first treatment through September 27, 2010 ] [ Designated as safety issue: No ]
Three parameters were measured. (1) Improvement in the Physician's Assessment of Global Performance status on a 7-point scale (1=very much better to 7=very much worse). (2) Improvement in oxygen saturation requirements, defined as a clinically meaningful increase in oxygen saturation requirement (from a baseline value < 95% to ≥ 95% saturation using a pulse oximeter). (3) A decrease in total dose and frequency of narcotic pain analgesics. The percentage of patients showing improvement (1 and 2) or a decrease (3) are reported.
Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15 of Cycle 1 [ Time Frame: Pre-dose to 8 hours post-dose on Day 15 of Cycle 1 ] [ Designated as safety issue: No ]
Blood samples for assessing the concentration of vemurafenib in plasma were drawn before the morning dose and at 2, 4, 6, and 8 hours post-dose on Day 15 of Cycle 1. Pharmacokinetic parameters were estimated by non-compartmental analysis (Win Non-Lin).
Vemurafenib Plasma Level Area Under the Curve From 0 to 8 Hours (AUC0-8h) on Day 15 of Cycle 1 [ Time Frame: Pre-dose to 8 hours post-dose on Day 15 of Cycle 1 ] [ Designated as safety issue: No ]
Blood samples for assessing the concentration of vemurafenib in plasma were drawn before the morning dose and at 2, 4, 6, and 8 hours post-dose on Day 15 of Cycle 1. Pharmacokinetic parameters were estimated by non-compartmental analysis (Win Non-Lin). AUC0-8h was calculated using the linear trapezoidal rule.
Vemurafenib Plasma Levels at Various Treatment Cycles [ Time Frame: Pre-dose Cycle 1 Day 1 to 4 hours post-dose Cycle 10 Day 1 ] [ Designated as safety issue: No ]
Blood samples for assessing the concentration of vemurafenib in plasma were drawn before the morning dose and 4 hours post-dose at Day 1 of Cycles 1, 2, 3, 4, 6, 8, and 10. Each Cycle was 3 weeks in duration.
Time-matched Change From Baseline in the Study Specific Corrected QT Interval (QTcP) [ Time Frame: Pre-dose Cycle 1 Day 1 to pre-dose Cycle 6 Day 1 ] [ Designated as safety issue: Yes ]
Three electrocardiograms (ECG) were obtained pre-dose and 2, 4, 6, and 8 hours post-dose at Days 1 and 15 of Cycle 1 and again pre-dose and 4 hours post-dose at various Cycles throughout treatment. Five baseline triplicate ECGs were obtained before the start of treatment at the same time points used during treatment. Reported is the largest mean time-matched QTcP change from baseline. QTcP=QT/(60/heart rate)^β (β=mean [calculated separately for males and females] log-transformed QT versus log-transformed RR regression slopes using all available pre-treatment (baseline) ECG values.
Percentage of Patients With Adverse Event [ Time Frame: From first treatment through September 27, 2010 ] [ Designated as safety issue: Yes ]
The intensity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v 4.0 (CTCAE) on a 5-point scale (Grade 1 to 5: Mild, Moderate, Severe, Life-threatening, and Death).

Enrollment:	132
Study Start Date:	September 2009
Estimated Study Completion Date:	December 2012
Primary Completion Date:	September 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Vemurafenib 960 mg Patients received vemurafenib 960 mg (four 240 mg tablets) bid (bis in die, twice daily) orally until disease progression, unacceptable toxicity, withdrawal of consent, or another reason as determined by the investigator.	Drug: Vemurafenib 960 mg Vemurafenib was supplied as 240 mg film-coated tablets packed in bottles. Other Names: Zelboraf RO5185426 RG7204 PLX4032

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion criteria:

adult patients ≥ 18 years of age
histologically confirmed metastatic melanoma (Stage IV, American Joint Committee on Cancer [AJCC])
patients must have completed and failed at least one prior standard of care regimen (eg, dacarbazine, temozolomide, etc)
BRAF V600E positive mutation (by Roche CoDx BRAF mutation assay)
measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) criteria
negative pregnancy test and, for fertile men and women, effective contraception during treatment and for 6 months after completion

Exclusion criteria:

active central nervous system (CNS) metastases on computed tomography/magnetic resonance imaging (CT/MRI) within 28 days prior to enrollment
history of or known carcinomatous meningitis
previous treatment with BRAF (sorafenib allowed) or MEK inhibitor
cardiac dysrhythmias > 2 National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) or treatment with drugs with dysrhythmic potential
uncontrolled hypertension(> 150/100 mmHg) despite optimal medical therapy
infectious disease including human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV)

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00949702

Locations

United States, California

Los Angeles, California, United States, 90095
United States, Colorado

Denver, Colorado, United States, 80220
United States, Florida

Tampa, Florida, United States, 33612-9497
United States, Massachusetts

Boston, Massachusetts, United States, 02114

Boston, Massachusetts, United States, 02115

Boston, Massachusetts, United States, 02215
United States, New York

New York, New York, United States, 10016
United States, Pennsylvania

Philadelphia, Pennsylvania, United States, 19104-4283

Pittsburgh, Pennsylvania, United States, 15232
United States, Tennessee

Nashville, Tennessee, United States, 97232
United States, Texas

Dallas, Texas, United States, 75246

Houston, Texas, United States, 77030
Australia

Melbourne, Australia, 3002

Newcastle, Australia, 2298

Westmead, Australia, 2145

Sponsors and Collaborators

Hoffmann-La Roche

Investigators

Study Director:

Clinical Trials

Hoffmann-La Roche

More Information

No publications provided by Hoffmann-La Roche

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, Reis-Filho JS, Kong X, Koya RC, Flaherty KT, Chapman PB, Kim MJ, Hayward R, Martin M, Yang H, Wang Q, Hilton H, Hang JS, Noe J, Lambros M, Geyer F, Dhomen N, Niculescu-Duvaz I, Zambon A, Niculescu-Duvaz D, Preece N, Robert L, Otte NJ, Mok S, Kee D, Ma Y, Zhang C, Habets G, Burton EA, Wong B, Nguyen H, Kockx M, Andries L, Lestini B, Nolop KB, Lee RJ, Joe AK, Troy JL, Gonzalez R, Hutson TE, Puzanov I, Chmielowski B, Springer CJ, McArthur GA, Sosman JA, Lo RS, Ribas A, Marais R. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012 Jan 19;366(3):207-15.

Responsible Party:	Hoffmann-La Roche
ClinicalTrials.gov Identifier:	NCT00949702 History of Changes
Other Study ID Numbers:	NP22657
Study First Received:	July 28, 2009
Results First Received:	July 29, 2011
Last Updated:	November 17, 2011
Health Authority:	United States: Food and Drug Administration

Additional relevant MeSH terms:

Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas

ClinicalTrials.gov processed this record on February 09, 2012