Study Of Zelboraf (Vemurafenib) in Patients With Locally-Advanced, Unresectable, Stage IIIc Or Metastatic Melanoma and Activating Exon 15 BRAF Mutations Other Than V600E

• Sponsor: Genentech, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01586195
• Collaborator: (none)
• Enrollment: 31
• Locations: 15
• Arm: 1
• Actual Duration (Months): 42
• Patients Per Site: 2.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is an open-label, multicenter, single-agent, phase II study of continuous oral Zelboraf (vemurafenib) in participants with locally-advanced, unresectable, stage IIIc or metastatic melanoma and activating exon 15 BRAF mutations other than V600E.

Condition or Disease	Intervention/Treatment	Phase
Malignant Melanoma	Drug: Vemurafenib	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Multicenter, Phase II Study Of Continuous Oral Zelboraf (Vemurafenib) in Patients With Locally-Advanced, Unresectable, Stage IIIc Or Metastatic Melanoma and Activating Exon 15 BRAF Mutations Other Than V600E
• Actual Study Start Date: Oct 31, 2011
• Actual Primary Completion Date: Apr 30, 2015
• Actual Study Completion Date: Apr 30, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vemurafenib Participants with untreated or previously treated locally advanced, unresectable, Stage IIIc or metastatic melanoma who have an activating exon 15 BRAF mutation other than V600E received vemurafenib 960 milligram (mg) orally twice daily (BID) until disease progression.	Drug: Vemurafenib; Vemurafenib 960 mg BID; Other Names: Zelboraf

Outcome Measures

Primary Outcome Measures

1. Best Objective Response Rate (BORR) [Up to 42 months]

   BORR was assessed by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. BORR was defined as the number of participants whose best overall response was a complete response (CR) or partial response (PR). CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as a >/=30% decrease under baseline of the sum of diameters of all target lesions. BORR was summarized along with the associated exact 95% confidence interval (CI) using the method of Clopper-Pearson.

Secondary Outcome Measures

1. Time to BORR [From start of treatment up to first documentation of confirmed CR or PR (up to 42 months)]

   In participants with a confirmed CR or PR, time to BORR was defined as the interval between the date of first treatment and the date of first documentation of confirmed CR or PR (whichever occurred first). BORR was assessed by the investigators according to RECIST v1.1. CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as a >/=30% decrease under baseline of the sum of diameters of all target lesions. Participants without confirmed CR or PR were censored at the date of last tumor assessment. The time to response was summarized using univariate statistics.

2. Duration of Response [From date of earliest qualifying response up to date of disease progression or death (up to 42 months)]

   In participants with a confirmed CR or PR, duration of response was defined as the time interval between the date of the earliest qualifying response and the date of progressive disease (PD) or death due to any cause. CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as a >/=30% decrease under baseline of the sum of diameters of all target lesions. PD was defined as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions and increase of at least 5 mm in the sum of diameters of target lesions. Duration of response was summarized using Kaplan-Meier method.

3. Progression-free Survival (PFS) [From start of treatment up to first documentation of disease progression or death (up to 42 months)]

   PFS was assessed by the investigators according to RECIST v1.1 and defined as the time interval between the date of the first treatment dose and the date of disease progression or death due to any cause, whichever occurred first. PD was defined as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions and increase of at least 5 mm in the sum of diameters of target lesions. PFS was summarized using Kaplan-Meier method.

4. Overall Survival (OS) [Date of first treatment to date of death due to any cause (up to 42 months)]

   OS was defined as the time from the date of first treatment to the date of death due to any cause. OS was summarized using Kaplan-Meier method.

5. Percentage of Participants With 6-Month Survival [Baseline to Month 6]

6. Percentage of Participants With 12-Month Survival [Baseline to Month 12]

7. Number of Participants With an Adverse Event (AE) [Up to 42 months]

   An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

• Histologically-confirmed metastatic melanoma (unresectable Stage IIIc or IV) with an activating BRAF mutation other than V600E, as detected by DNA sequencing of exon 15 performed at a centralized laboratory

• Measurable disease (as defined by RECIST, v1.1)

• Adequate recovery from most recent systemic or local treatment for cancer

• Adequate organ function within 28 days prior to initiation of treatment

• For women of childbearing potential, agreement to the use of two acceptable methods of contraception, including one barrier method, during the study and for 6 months after discontinuation of vemurafenib

• For men with female partners of childbearing potential, agreement to use a latex condom and to advise their female partner to use an additional method of contraception during the study and for 6 months after discontinuation of vemurafenib

• Negative serum pregnancy test within 7 days of commencement of treatment in premenopausal women. Women who are either surgically sterile or have been post-menopausal for at least 1 year are eligible to participate in this study

• Agreement not to donate blood or blood products during the study and for at least 6 months after discontinuation of vemurafenib; for male participants, agreement not to donate sperm during the study and for at least 6 months after discontinuation of vemurafenib

• Signed informed consent form (prior to study entry and before performing any study-related procedures)

Exclusion Criteria:

• Invasive malignancy other than melanoma at the time of enrollment and within 2 years prior to first study drug administration, except for adequately treated (with curative intent) basal or squamous cell carcinoma, in situ carcinoma of the cervix, in situ ductal adenocarcinoma of the breast, in situ prostate cancer, or limited stage bladder cancer or other cancers from which the patient has been disease-free for at least 2 years

• Pregnant or breast-feeding

• Inability to swallow pills

• Concurrent anti-tumor therapy (e.g., chemotherapy, other targeted therapy, radiation therapy, including participation in an experimental drug study)

• Radiation therapy </= 1 week prior to first administration of vemurafenib and stereotactic radiotherapy </= 1 day prior to first administration of vemurafenib

• Prior treatment with a BRAF or MEK inhibitor

• Either a concurrent condition (including medical illness, such as active infection requiring treatment with IV antibiotics or the presence of laboratory abnormalities) or history of a prior condition that places the patient at unacceptable risk if he/she were treated with the study drug or confounds the ability to interpret data from the study

• History of congenital long QT syndrome or a corrected QT (QTc) interval > 450 ms at baseline

• Ongoing cardiac dysrhythmia >/= Grade 2

• Unwillingness to practice effective birth control

• Inability to comply with other requirements of the protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Cancer Center	Tucson	Arizona	United States	85724
2	UCSD Moores Cancer Center	La Jolla	California	United States	92093
3	UCLA School of Medicine; Hematology/Oncology	Los Angeles	California	United States	90095
4	The Angeles Clinic and Research Institute, Santa Monica Office	Santa Monica	California	United States	90025
5	University of Colorado; Anschutz Cancer Pavilion	Aurora	Colorado	United States	80045
6	Moffitt Cancer Center	Tampa	Florida	United States	33612
7	Emory University; Winship Cancer Institute	Atlanta	Georgia	United States	30308
8	Oncology Specialists, S.C.	Park Ridge	Illinois	United States	60068
9	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
10	Atlantic Health System	Morristown	New Jersey	United States	07960
11	Columbia University Medical Center	New York	New York	United States	10032
12	Mid Ohio Onc Hematology Inc	Columbus	Ohio	United States	43219
13	UPCI Cancer Institute; Cancer Pavillion	Pittsburgh	Pennsylvania	United States	15232
14	Vanderbilt Univ Medical Ctr	Nashville	Tennessee	United States	37232
15	Texas Oncology-Baylor Sammons Cancer Center	Dallas	Texas	United States	75246

Sponsors and Collaborators

• Genentech, Inc.

Investigators

• Study Director: Clinical Trials, Genentech, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT01586195
• Other Study ID Numbers: ML27763
• First Posted: Apr 26, 2012
• Last Update Posted: May 25, 2017
• Last Verified: Apr 1, 2017

• Additional relevant MeSH terms: Melanoma; Vemurafenib

Study Results

Participant Flow

Arm/Group Title	Vemurafenib
Arm/Group Description	Participants with untreated or previously treated locally advanced, unresectable, Stage IIIc or metastatic melanoma who have an activating exon 15 BRAF mutation other than V600E received vemurafenib 960 milligram (mg) orally twice daily (BID) until disease progression.
Period Title: Overall Study
STARTED	31
COMPLETED	5
NOT COMPLETED	26

Baseline Characteristics

Arm/Group Title	Vemurafenib
Arm/Group Description	Participants with untreated or previously treated locally advanced, unresectable, Stage IIIc or metastatic melanoma who have an activating exon 15 BRAF mutation other than V600E received vemurafenib 960 mg orally BID until disease progression.
Overall Participants	31
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.0 (11.39)
Sex: Female, Male (Count of Participants)
Female	4 12.9%
Male	27 87.1%

Outcome Measures

1. Primary Outcome

Title	Best Objective Response Rate (BORR)
Description	BORR was assessed by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. BORR was defined as the number of participants whose best overall response was a complete response (CR) or partial response (PR). CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as a >/=30% decrease under baseline of the sum of diameters of all target lesions. BORR was summarized along with the associated exact 95% confidence interval (CI) using the method of Clopper-Pearson.
Time Frame	Up to 42 months

Outcome Measure Data

Analysis Population Description

ITT population defined as all enrolled participants who received any amount of study drug.

Arm/Group Title	Vemurafenib
Arm/Group Description	Participants with untreated or previously treated locally advanced, unresectable, Stage IIIc or metastatic melanoma who have an activating exon 15 BRAF mutation other than V600E received vemurafenib 960 mg orally BID until disease progression.
Measure Participants	31
Number (95% Confidence Interval) [percentage of participants]	22.6 72.9%

2. Secondary Outcome

Title	Time to BORR
Description	In participants with a confirmed CR or PR, time to BORR was defined as the interval between the date of first treatment and the date of first documentation of confirmed CR or PR (whichever occurred first). BORR was assessed by the investigators according to RECIST v1.1. CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as a >/=30% decrease under baseline of the sum of diameters of all target lesions. Participants without confirmed CR or PR were censored at the date of last tumor assessment. The time to response was summarized using univariate statistics.
Time Frame	From start of treatment up to first documentation of confirmed CR or PR (up to 42 months)

Outcome Measure Data

Analysis Population Description

ITT population defined as all enrolled participants who received any amount of study drug. Participants with a confirmed CR or PR were analyzed.

Arm/Group Title	Vemurafenib
Arm/Group Description	Participants with untreated or previously treated locally advanced, unresectable, Stage IIIc or metastatic melanoma who have an activating exon 15 BRAF mutation other than V600E received vemurafenib 960 mg orally BID until disease progression.
Measure Participants	7
Median (Full Range) [months]	1.7

3. Secondary Outcome

Title	Duration of Response
Description	In participants with a confirmed CR or PR, duration of response was defined as the time interval between the date of the earliest qualifying response and the date of progressive disease (PD) or death due to any cause. CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as a >/=30% decrease under baseline of the sum of diameters of all target lesions. PD was defined as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions and increase of at least 5 mm in the sum of diameters of target lesions. Duration of response was summarized using Kaplan-Meier method.
Time Frame	From date of earliest qualifying response up to date of disease progression or death (up to 42 months)

Outcome Measure Data

Analysis Population Description

ITT population defined as all enrolled participants who received any amount of study drug. Participants with a confirmed CR or PR were analyzed.

Arm/Group Title	Vemurafenib
Arm/Group Description	Participants with untreated or previously treated locally advanced, unresectable, Stage IIIc or metastatic melanoma who have an activating exon 15 BRAF mutation other than V600E received vemurafenib 960 mg orally BID until disease progression.
Measure Participants	7
Median (Full Range) [months]	10.7

4. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	PFS was assessed by the investigators according to RECIST v1.1 and defined as the time interval between the date of the first treatment dose and the date of disease progression or death due to any cause, whichever occurred first. PD was defined as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions and increase of at least 5 mm in the sum of diameters of target lesions. PFS was summarized using Kaplan-Meier method.
Time Frame	From start of treatment up to first documentation of disease progression or death (up to 42 months)

Outcome Measure Data

Analysis Population Description

ITT population defined as all enrolled participants who received any amount of study drug.

Arm/Group Title	Vemurafenib
Arm/Group Description	Participants with untreated or previously treated locally advanced, unresectable, Stage IIIc or metastatic melanoma who have an activating exon 15 BRAF mutation other than V600E received vemurafenib 960 mg orally BID until disease progression.
Measure Participants	31
Median (Full Range) [months]	5.5

5. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from the date of first treatment to the date of death due to any cause. OS was summarized using Kaplan-Meier method.
Time Frame	Date of first treatment to date of death due to any cause (up to 42 months)

Outcome Measure Data

Analysis Population Description

ITT population defined as all enrolled participants who received any amount of study drug.

Arm/Group Title	Vemurafenib
Arm/Group Description	Participants with untreated or previously treated locally advanced, unresectable, Stage IIIc or metastatic melanoma who have an activating exon 15 BRAF mutation other than V600E received vemurafenib 960 mg orally BID until disease progression.
Measure Participants	31
Median (95% Confidence Interval) [months]	NA

6. Secondary Outcome

Title	Percentage of Participants With 6-Month Survival
Time Frame	Baseline to Month 6

Outcome Measure Data

Analysis Population Description

ITT population defined as all enrolled participants who received any amount of study drug.

Arm/Group Title	Vemurafenib
Arm/Group Description	Participants with untreated or previously treated locally advanced, unresectable, Stage IIIc or metastatic melanoma who have an activating exon 15 BRAF mutation other than V600E received vemurafenib 960 mg orally BID until disease progression.
Measure Participants	31
Number (95% Confidence Interval) [percentage of participants]	82.4 265.8%

7. Secondary Outcome

Title	Percentage of Participants With 12-Month Survival
Time Frame	Baseline to Month 12

Outcome Measure Data

Analysis Population Description

ITT population defined as all enrolled participants who received any amount of study drug.

Arm/Group Title	Vemurafenib
Arm/Group Description	Participants with untreated or previously treated locally advanced, unresectable, Stage IIIc or metastatic melanoma who have an activating exon 15 BRAF mutation other than V600E received vemurafenib 960 mg orally BID until disease progression.
Measure Participants	31
Number (95% Confidence Interval) [percentage of participants]	61.6 198.7%

8. Secondary Outcome

Title	Number of Participants With an Adverse Event (AE)
Description	An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution.
Time Frame	Up to 42 months

Outcome Measure Data

Analysis Population Description

Safety population defined as all enrolled participants who received any amount of vemurafenib on study.

Arm/Group Title	Vemurafenib
Arm/Group Description	Participants with untreated or previously treated locally advanced, unresectable, Stage IIIc or metastatic melanoma who have an activating exon 15 BRAF mutation other than V600E received vemurafenib 960 mg orally BID until disease progression.
Measure Participants	31
Number [participants]	30 96.8%

Adverse Events

Time Frame	From the randomization of the first participant to the clinical cutoff date (22 April 2015) (approximately 42 months)
Adverse Event Reporting Description	An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution.
Arm/Group Title	Vemurafenib
Arm/Group Description	Participants received vemurafenib 960 mg orally BID.
All Cause Mortality
	Vemurafenib
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Vemurafenib
	Affected / at Risk (%)	# Events
Total	13/31 (41.9%)
Cardiac disorders
Acute coronary syndrome	1/31 (3.2%)
Gastrointestinal disorders
Abdominal pain	1/31 (3.2%)
Lower gastrointestinal haemorrhage	1/31 (3.2%)
Injury, poisoning and procedural complications
Fall	1/31 (3.2%)
Metabolism and nutrition disorders
Dehydration	1/31 (3.2%)
Hypercalcaemia	1/31 (3.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of skin	6/31 (19.4%)
Basal cell carcinoma	1/31 (3.2%)
Keratoacanthoma	1/31 (3.2%)
Nervous system disorders
Cerebrovascular accident	1/31 (3.2%)
Hemiplegia	1/31 (3.2%)
Peripheral motor neuropathy	1/31 (3.2%)
Tremor	1/31 (3.2%)
Vasogenic cerebral oedema	1/31 (3.2%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/31 (3.2%)
Other (Not Including Serious) Adverse Events
	Vemurafenib
	Affected / at Risk (%)	# Events
Total	30/31 (96.8%)
Blood and lymphatic system disorders
Anaemia	6/31 (19.4%)
Lymphopenia	2/31 (6.5%)
Thrombocytopenia	2/31 (6.5%)
Eye disorders
Vision blurred	3/31 (9.7%)
Dry eye	2/31 (6.5%)
Gastrointestinal disorders
Diarrhoea	8/31 (25.8%)
Nausea	7/31 (22.6%)
Constipation	4/31 (12.9%)
Vomiting	4/31 (12.9%)
Dyspepsia	3/31 (9.7%)
General disorders
Fatigue	19/31 (61.3%)
Pyrexia	4/31 (12.9%)
Chills	2/31 (6.5%)
Cyst	2/31 (6.5%)
Mass	2/31 (6.5%)
Nodule	2/31 (6.5%)
Infections and infestations
Bacterial infection	2/31 (6.5%)
Nasopharyngitis	2/31 (6.5%)
Injury, poisoning and procedural complications
Sunburn	4/31 (12.9%)
Investigations
Blood creatinine increased	5/31 (16.1%)
Weight decreased	5/31 (16.1%)
Alanine aminotransferase increased	4/31 (12.9%)
Aspartate aminotransferase increased	2/31 (6.5%)
Blood bilirubin increased	2/31 (6.5%)
Metabolism and nutrition disorders
Decreased appetite	5/31 (16.1%)
Hypokalaemia	3/31 (9.7%)
Hyperglycaemia	2/31 (6.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	12/31 (38.7%)
Myalgia	6/31 (19.4%)
Musculoskeletal pain	4/31 (12.9%)
Joint swelling	3/31 (9.7%)
Pain in extremity	3/31 (9.7%)
Joint range of motion decreased	2/31 (6.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Seborrhoeic keratosis	7/31 (22.6%)
Skin papilloma	7/31 (22.6%)
Squamous cell carcinoma of skin	7/31 (22.6%)
Squamous cell carcinoma	4/31 (12.9%)
Fibrous histiocytoma	2/31 (6.5%)
Melanocytic naevus	2/31 (6.5%)
Nervous system disorders
Headache	4/31 (12.9%)
Disturbance of attention	2/31 (6.5%)
Dysaesthesia	2/31 (6.5%)
Hyperaesthesia	2/31 (6.5%)
Psychiatric disorders
Anxiety	2/31 (6.5%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	3/31 (9.7%)
Oropharyngeal pain	3/31 (9.7%)
Cough	2/31 (6.5%)
Skin and subcutaneous tissue disorders
Rash	13/31 (41.9%)
Alopecia	9/31 (29%)
Hyperkeratosis	9/31 (29%)
Actinic keratosis	6/31 (19.4%)
Photosensitivity reaction	6/31 (19.4%)
Blister	2/31 (6.5%)
Dry skin	2/31 (6.5%)
Palmar-plantar erythrodysaesthesia syndrome	2/31 (6.5%)
Pruritus	2/31 (6.5%)
Rash generalised	2/31 (6.5%)
Sebaceous hyperplasia	2/31 (6.5%)
Seborrhoeic dermatitis	2/31 (6.5%)
Vascular disorders
Hypertension	5/31 (16.1%)
Hypotension	3/31 (9.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.