Phase II Safety Study of Vemurafenib Followed by Ipilimumab in Subjects With V600 BRAF Mutated Advanced Melanoma

• Sponsor: Bristol-Myers Squibb (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01673854
• Collaborator: (none)
• Enrollment: 70
• Locations: 14
• Arm: 1
• Actual Duration (Months): 31.9
• Patients Per Site: 5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the safety profile of vemurafenib, 960 mg, administered for 6 weeks, followed by ipilimumab monotherapy in patients with BRAF V600 mutated advanced/metastatic melanoma.

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Drug: Ipilimumab; Biological: Vemurafenib	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single Arm Open-Label Phase II Study of Vemurafenib Followed by Ipilimumab in Subjects With Previously Untreated V600 BRAF Mutated Advanced Melanoma
• Actual Study Start Date: Sep 13, 2012
• Actual Primary Completion Date: Jul 25, 2014
• Actual Study Completion Date: May 12, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg Participants received vemurafenib, 960 mg, twice daily for 6 weeks (Vem1 Phase). After a washout period of 3-10 days, patients received ipilimumab, 10 mg/kg, every 3 weeks for a maximum of 4 doses. At Week 24, participants received ipilimumab, 10 mg/kg, every 12 weeks until disease progression or unacceptable toxicity. Patients who did not progress or have unacceptable toxicity in the Vem1 Phase were retreated with vemurafenib (Vem 2 Phase) at the last dose level identified at the end of the Vem1 Phase until disease progression or unacceptable toxicity.

Drug: Ipilimumab; Other Names: Yervoy® BMS-734016 ; Biological: Vemurafenib; Other Names: Zelboraf®

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Received Ipilimumab and Who Had Grade 3-4 Drug-related Skin Adverse Events (AEs) [From the first dose date of Vem1 to the last dose of ipilimumab (to a maximum of 3 years) + 90 days or to the first dose date of Vem2, whichever occurred first]

   AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Drug-related=having certain, probable, possible, or unknown relationship to study drug. Grading criteria for AEs: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death.

Secondary Outcome Measures

1. Percentage of Participants Who Received Ipilimumab and Who Had Grade 3-4 Drug-related Gastrointestinal Adverse Events (AEs) [From the first dose date of Vem1 to the last dose of ipilimumab (to a maximum of 3 years) + 90 days or to the first dose date of Vem2, whichever occurred first]

   AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Drug-related=having certain, probable, possible, or unknown relationship to study drug. Grading criteria for AEs: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death.

2. Percentage of Participants Who Received Ipilimumab and Who Had Grade 3-4 Drug-related Hepatobiliary Adverse Events [From the first dose date of Vem1 to the last dose of ipilimumab (to a maximum of 3 years) + 90 days or to the first dose date of Vem2, whichever occurred first]

   AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Drug-related=having certain, probable, possible, or unknown relationship to study drug. Grading criteria for AEs: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death.

Other Outcome Measures

1. Number of Participants Who Died, Who Died Due to Related Adverse Events (AEs), and With Related AEs, Serious Adverse Events (SAEs), Related SAEs, Discontinuations Due to AEs and Related AEs, Immune-related (ir) AEs, and Serious irAEs [From the first dose date of Vem1 to the last dose of ipilimumab (to a maximum of 3 years) + 90 days or to the first dose date of Vem2, whichever occurred first]

   AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or unknown relationship to study drug.

2. Number of Participants With Adverse Events (AEs) Grade 3-4, Related AEs Grade 3-4, Related Serious Adverse Events (SAEs) Grade 3-4, Immune-related (ir) AEs Grade 3-4, and Serious irAEs Grade 3-4 [From the first dose date of Vem1 to the last dose of ipilimumab (to a maximum of 3 years) + 90 days or to the first dose date of Vem2, whichever occurred first]

   AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or unknown relationship to study drug. Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Key Inclusion Criteria:

• Men and women 18 years of age and older

• Histologic diagnosis of malignant melanoma tested positive for the BRAF V600 mutation

• Previously untreated unresectable Stage III or Stage IV melanoma

• Complete set of brain/neck, chest, abdomen/pelvis axial radiographs taken within 28 days of first dose of study drug

• Measurable melanoma by physical or radiographic examination

• Brain metastases stable after radiation for at least 1 month and off corticosteroid therapy for ≥30 days prior to enrollment

• Eastern Cooperative Oncology Group performance status of 0 or 1

• Adequate hematologic parameters and renal and hepatic function

Key Exclusion Criteria:

• Primary ocular melanoma

• Active brain metastases with symptoms or requiring corticosteroid treatment

• Any other malignancy from which the patient has been disease-free for less than 2 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix

• History of or current active autoimmune diseases, including but not limited to inflammatory bowel diseases, rheumatoid arthritis, autoimmune thyroiditis, autoimmune hepatitis, systemic sclerosis, systemic lupus erythematosus, autoimmune vasculitis, autoimmune neuropathies

• History of or current immunodeficiency disease, splenectomy, or splenic irradiation

• Prior anticancer therapy or investigational products <4 weeks prior to enrollment

• Prior therapy with a BRAF or MEK inhibitor and prior investigational anticancer immunotherapies;

• Prior therapies with immunosuppressive agents within the past 2 years

• Concomitant therapy with any anticancer or potent immunosuppressive agent, surgery, radiotherapy, other investigational anticancer therapies, or chronic use of systemic corticosteroids

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beverly Hills Cancer Center	Beverly Hills	California	United States	90211
2	Baptist Cancer Institute	Jacksonville	Florida	United States	32207
3	Orlando Health, Inc	Orlando	Florida	United States	32806
4	Winship Cancer Institute	Atlanta	Georgia	United States	30322
5	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
6	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
7	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
8	University Of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87106
9	Mount Sinai School Of Medicine	New York	New York	United States	10029
10	Levine Cancer Institute	Charlotte	North Carolina	United States	28204
11	Duke University Hospital	Durham	North Carolina	United States	27710
12	Dumc	Durham	North Carolina	United States	27710
13	University Hospitals Of Cleveland	Cleveland	Ohio	United States	44106
14	University Hospitals	Cleveland	Ohio	United States	44106

Sponsors and Collaborators

• Bristol-Myers Squibb

Investigators

• Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• BMS Clinical Trial Patient Recruiting

Publications

None provided.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT01673854
• Other Study ID Numbers: CA184-240; 2012-002054-24
• First Posted: Aug 28, 2012
• Last Update Posted: Jul 24, 2018
• Last Verified: Jun 1, 2018

• Additional relevant MeSH terms: Melanoma; Ipilimumab; Vemurafenib

Study Results

Participant Flow

Pre-assignment Detail	A total of 70 patients were enrolled, and 46 received treatment.

Arm/Group Title	Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg
Arm/Group Description	Participants received vemurafenib, 960 mg, twice daily for 6 weeks (Vem1 Phase). After a washout period of 3-10 days, patients received ipilimumab, 10 mg/kg, every 3 weeks for a maximum of 4 doses. At Week 24, participants received ipilimumab, 10 mg/kg, every 12 weeks until disease progression or unacceptable toxicity. Patients who did not progress or have unacceptable toxicity in the Vem1 Phase were retreated with vemurafenib (Vem 2 Phase) at the last dose level identified at the end of the Vem1 Phase until disease progression or unacceptable toxicity.
Period Title: Vem 1 Phase (Vemurafenib, 960 mg)
STARTED	46
COMPLETED	46
NOT COMPLETED	0
Period Title: Vem 1 Phase (Vemurafenib, 960 mg)
STARTED	46
COMPLETED	19
NOT COMPLETED	27
Period Title: Vem 1 Phase (Vemurafenib, 960 mg)
STARTED	19
COMPLETED	0
NOT COMPLETED	19

Baseline Characteristics

Arm/Group Title	Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg
Arm/Group Description	Participants received vemurafenib, 960 mg, twice daily for 6 weeks (Vem1 Phase). After a washout period of 3-10 days, patients received ipilimumab, 10 mg/kg, every 3 weeks for a maximum of 4 doses. At Week 24, participants received ipilimumab, 10 mg/kg, every 12 weeks until disease progression or unacceptable toxicity. Patients who did not progress or have unacceptable toxicity in the Vem1 Phase were retreated with vemurafenib (Vem 2 Phase) at the last dose level identified at the end of the Vem1 Phase until disease progression or unacceptable toxicity.
Overall Participants	46
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	55.0 (14.20)
Age (Years) [Median (Full Range) ]
Median (Full Range) [Years]	57.5
Sex: Female, Male (Count of Participants)
Female	9 19.6%
Male	37 80.4%
Race/Ethnicity, Customized (Number) [Number]
White	42 91.3%
Other	4 8.7%
M-Stage at Study Entry (Number) [Number]
M0	6 13%
M1A	8 17.4%
M1B	8 17.4%
M1C	24 52.2%
Disease Stage at Study Entry (Number) [Number]
III	8 17.4%
IV	38 82.6%
Number of Disease Sites (Number) [Number]
1	2 4.3%
2	8 17.4%
3	7 15.2%
4	4 8.7%
5 or more	25 54.3%
Eastern Cooperative Oncology Group (ECOG) Performance Status (Number) [Number]
0	35 76.1%
1	11 23.9%
Time from Diagnosis of Advanced /Metastatic Melanoma to First Vem1 Phase Dose (Months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Months]	4.96 (9.38)
Time from Diagnosis of Advanced /Metastatic Melanoma to First Vem1 Phase Dose (Months) [Median (Full Range) ]
Median (Full Range) [Months]	1.86

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Who Received Ipilimumab and Who Had Grade 3-4 Drug-related Skin Adverse Events (AEs)
Description	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Drug-related=having certain, probable, possible, or unknown relationship to study drug. Grading criteria for AEs: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death.
Time Frame	From the first dose date of Vem1 to the last dose of ipilimumab (to a maximum of 3 years) + 90 days or to the first dose date of Vem2, whichever occurred first

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of ipilimumab

Arm/Group Title	Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg
Arm/Group Description	Participants received vemurafenib, 960 mg, twice daily for 6 weeks (Vem1 Phase). After a washout period of 3-10 days, patients received ipilimumab, 10 mg/kg, every 3 weeks for a maximum of 4 doses. At Week 24, participants received ipilimumab, 10 mg/kg, every 12 weeks until disease progression or unacceptable toxicity. Patients who did not progress or have unacceptable toxicity in the Vem1 Phase were retreated with vemurafenib (Vem 2 Phase) at the last dose level identified at the end of the Vem1 Phase until disease progression or unacceptable toxicity. Following the end-of-treatment visit, patients entered the Follow-up Phase.
Measure Participants	46
Number (95% Confidence Interval) [Percentage of participants]	32.6 70.9%

2. Secondary Outcome

Title	Percentage of Participants Who Received Ipilimumab and Who Had Grade 3-4 Drug-related Gastrointestinal Adverse Events (AEs)
Description	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Drug-related=having certain, probable, possible, or unknown relationship to study drug. Grading criteria for AEs: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death.
Time Frame	From the first dose date of Vem1 to the last dose of ipilimumab (to a maximum of 3 years) + 90 days or to the first dose date of Vem2, whichever occurred first

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of ipilimumab.

Arm/Group Title	Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg
Arm/Group Description	Participants received vemurafenib, 960 mg, twice daily for 6 weeks (Vem1 Phase). After a washout period of 3-10 days, patients received ipilimumab, 10 mg/kg, every 3 weeks for a maximum of 4 doses. At Week 24, participants received ipilimumab, 10 mg/kg, every 12 weeks until disease progression or unacceptable toxicity. Patients who did not progress or have unacceptable toxicity in the Vem1 Phase were retreated with vemurafenib (Vem 2 Phase) at the last dose level identified at the end of the Vem1 Phase until disease progression or unacceptable toxicity. Following the end-of-treatment visit, patients entered the Follow-up Phase.
Measure Participants	46
Number (95% Confidence Interval) [Percentage of participants]	21.7 47.2%

3. Secondary Outcome

Title	Percentage of Participants Who Received Ipilimumab and Who Had Grade 3-4 Drug-related Hepatobiliary Adverse Events
Description	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Drug-related=having certain, probable, possible, or unknown relationship to study drug. Grading criteria for AEs: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death.
Time Frame	From the first dose date of Vem1 to the last dose of ipilimumab (to a maximum of 3 years) + 90 days or to the first dose date of Vem2, whichever occurred first

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of vemurafenib and ipilimumab

Arm/Group Title	Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg
Arm/Group Description	Participants received vemurafenib, 960 mg, twice daily for 6 weeks (Vem1 Phase). After a washout period of 3-10 days, patients received ipilimumab, 10 mg/kg, every 3 weeks for a maximum of 4 doses. At Week 24, participants received ipilimumab, 10 mg/kg, every 12 weeks until disease progression or unacceptable toxicity. Patients who did not progress or have unacceptable toxicity in the Vem1 Phase were retreated with vemurafenib (Vem 2 Phase) at the last dose level identified at the end of the Vem1 Phase until disease progression or unacceptable toxicity. Following the end-of-treatment visit, patients entered the Follow-up Phase.
Measure Participants	46
Number (95% Confidence Interval) [Percentage of participants]	4.3 9.3%

4. Other Pre-specified Outcome

Title	Number of Participants Who Died, Who Died Due to Related Adverse Events (AEs), and With Related AEs, Serious Adverse Events (SAEs), Related SAEs, Discontinuations Due to AEs and Related AEs, Immune-related (ir) AEs, and Serious irAEs
Description	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or unknown relationship to study drug.
Time Frame	From the first dose date of Vem1 to the last dose of ipilimumab (to a maximum of 3 years) + 90 days or to the first dose date of Vem2, whichever occurred first

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug

Arm/Group Title	Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg
Arm/Group Description	Participants received vemurafenib, 960 mg, twice daily for 6 weeks (Vem1 Phase). After a washout period of 3-10 days, patients received ipilimumab, 10 mg/kg, every 3 weeks for a maximum of 4 doses. At Week 24, participants received ipilimumab, 10 mg/kg, every 12 weeks until disease progression or unacceptable toxicity. Patients who did not progress or have unacceptable toxicity in the Vem1 Phase were retreated with vemurafenib (Vem 2 Phase) at the last dose level identified at the end of the Vem1 Phase until disease progression or unacceptable toxicity. Following the end-of-treatment visit, patients entered the Follow-up Phase.
Measure Participants	46
Deaths	4 8.7%
Deaths due to related AEs	0 0%
SAEs	31 67.4%
Related SAEs	18 39.1%
Discontinuations due to AEs	18 39.1%
Discontinuations due to related AEs	16 34.8%
irAEs	43 93.5%
Serious irAEs	10 21.7%

5. Other Pre-specified Outcome

Title	Number of Participants With Adverse Events (AEs) Grade 3-4, Related AEs Grade 3-4, Related Serious Adverse Events (SAEs) Grade 3-4, Immune-related (ir) AEs Grade 3-4, and Serious irAEs Grade 3-4
Description	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or unknown relationship to study drug. Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death.
Time Frame	From the first dose date of Vem1 to the last dose of ipilimumab (to a maximum of 3 years) + 90 days or to the first dose date of Vem2, whichever occurred first

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug

Arm/Group Title	Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg
Arm/Group Description	Participants received vemurafenib, 960 mg, twice daily for 6 weeks (Vem1 Phase). After a washout period of 3-10 days, patients received ipilimumab, 10 mg/kg, every 3 weeks for a maximum of 4 doses. At Week 24, participants received ipilimumab, 10 mg/kg, every 12 weeks until disease progression or unacceptable toxicity. Patients who did not progress or have unacceptable toxicity in the Vem1 Phase were retreated with vemurafenib (Vem 2 Phase) at the last dose level identified at the end of the Vem1 Phase until disease progression or unacceptable toxicity. Following the end-of-treatment visit, patients entered the Follow-up Phase.
Measure Participants	46
AEs Grade 3-4	39 84.8%
Related AEs Grade 3-4	30 65.2%
Related SAEs Grade 3-4	17 37%
irAEs Grade 3-4	25 54.3%
Serious irAEs Grade 3-4	9 19.6%

Adverse Events

Time Frame	AEs with onset date on or after Day 1 of study therapy and within the last dose of Vem1 + 14 days, last dose of Ipi Phase + 90 days, last dose of Vem2 + 14 days. Up to July 2014 (approximately 21 months)
Arm/Group Title	Vemurafenib, 960 mg + Ipilimumab,10 mg/kg ab
Arm/Group Description	Participants received vemurafenib, 960 mg, twice daily for 6 weeks (Vem1 Phase). After a washout period of 3-10 days, patients received ipilimumab, 10 mg/kg, every 3 weeks for a maximum of 4 doses. At Week 24, participants received ipilimumab, 10 mg/kg, every 12 weeks until disease progression or unacceptable toxicity. Patients who did not progress or have unacceptable toxicity in the Vem1 Phase were retreated with vemurafenib (Vem 2 Phase) at the last dose level identified at the end of the Vem1 Phase until disease progression or unacceptable toxicity.
All Cause Mortality
	Vemurafenib, 960 mg + Ipilimumab,10 mg/kg ab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Vemurafenib, 960 mg + Ipilimumab,10 mg/kg ab
	Affected / at Risk (%)	# Events
Total	34/46 (73.9%)
Blood and lymphatic system disorders
Anaemia	1/46 (2.2%)
Cardiac disorders
Pericardial effusion	1/46 (2.2%)
Atrial fibrillation	1/46 (2.2%)
Endocrine disorders
Hypothyroidism	1/46 (2.2%)
Hypopituitarism	1/46 (2.2%)
Adrenal Insufficiency	1/46 (2.2%)
Hypophysitis	1/46 (2.2%)
Gastrointestinal disorders
Colitis	3/46 (6.5%)
Pancreatitis	1/46 (2.2%)
Abdominal distension	1/46 (2.2%)
Vomiting	2/46 (4.3%)
Diarrhoea	2/46 (4.3%)
Abdominal pain	2/46 (4.3%)
Dysphagia	2/46 (4.3%)
Autoimmune Colitis	1/46 (2.2%)
General disorders
Abasia	1/46 (2.2%)
Asthenia	3/46 (6.5%)
Pain	2/46 (4.3%)
Fatigue	1/46 (2.2%)
Pyrexia	2/46 (4.3%)
Peripheral Swelling	1/46 (2.2%)
Hepatobiliary disorders
Hepatitis	1/46 (2.2%)
Infections and infestations
Urinary tract infection	1/46 (2.2%)
Pneumonia	1/46 (2.2%)
Cellulitis	1/46 (2.2%)
Injury, poisoning and procedural complications
Wound	1/46 (2.2%)
Fall	1/46 (2.2%)
Investigations
Blood creatine increased	1/46 (2.2%)
Hepatic enzyme increased	1/46 (2.2%)
Blood Creatinine Increased	1/46 (2.2%)
Metabolism and nutrition disorders
Dehydration	2/46 (4.3%)
Musculoskeletal and connective tissue disorders
Pain in extremity	3/46 (6.5%)
Back pain	3/46 (6.5%)
Osteoporosis	1/46 (2.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain	1/46 (2.2%)
Adenocarcinoma of colon	1/46 (2.2%)
Malignant neoplasm progression	5/46 (10.9%)
Squamous cell carcinoma	3/46 (6.5%)
Tumour associated fever	1/46 (2.2%)
Squamous cell carcinoma of skin	1/46 (2.2%)
Malignant melanoma	1/46 (2.2%)
Metastases to Central Nervous System	1/46 (2.2%)
Metastatic Malignant Melanoma	1/46 (2.2%)
Nervous system disorders
Headache	2/46 (4.3%)
Syncope	1/46 (2.2%)
Cerebral ischaemia	1/46 (2.2%)
Haemorrhage Intracranial	2/46 (4.3%)
Renal and urinary disorders
Renal failure	1/46 (2.2%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/46 (2.2%)
Skin and subcutaneous tissue disorders
Pruritus	1/46 (2.2%)
Vascular disorders
Iliac vein occlusion	1/46 (2.2%)
Deep vein thrombosis	1/46 (2.2%)
Hypotension	2/46 (4.3%)
Other (Not Including Serious) Adverse Events
	Vemurafenib, 960 mg + Ipilimumab,10 mg/kg ab
	Affected / at Risk (%)	# Events
Total	44/46 (95.7%)
Blood and lymphatic system disorders
Lymphopenia	5/46 (10.9%)
Anaemia	10/46 (21.7%)
Endocrine disorders
Adrenal insufficiency	3/46 (6.5%)
Hypothyroidism	4/46 (8.7%)
Hypophysitis	7/46 (15.2%)
Eye disorders
Vision blurred	8/46 (17.4%)
Gastrointestinal disorders
Colitis	5/46 (10.9%)
Dyspepsia	4/46 (8.7%)
Gastrooesophageal reflux disease	3/46 (6.5%)
Abdominal distension	3/46 (6.5%)
Constipation	9/46 (19.6%)
Haemorrhoids	3/46 (6.5%)
Vomiting	16/46 (34.8%)
Diarrhoea	23/46 (50%)
Abdominal pain	13/46 (28.3%)
Dysphagia	5/46 (10.9%)
Nausea	22/46 (47.8%)
General disorders
Mucosal inflammation	3/46 (6.5%)
Pain	4/46 (8.7%)
Oedema peripheral	11/46 (23.9%)
Chills	10/46 (21.7%)
Fatigue	24/46 (52.2%)
Pyrexia	14/46 (30.4%)
Infections and infestations
Urinary tract infection	5/46 (10.9%)
Candida infection	4/46 (8.7%)
Sinusitis	4/46 (8.7%)
Cellulitis	3/46 (6.5%)
Investigations
Blood alkaline phosphatase increased	11/46 (23.9%)
Blood sodium decreased	4/46 (8.7%)
Blood calcium decreased	4/46 (8.7%)
Blood creatinine increased	8/46 (17.4%)
Lipase increased	3/46 (6.5%)
Weight decreased	5/46 (10.9%)
Aspartate aminotransferase increased	11/46 (23.9%)
Alanine aminotransferase increased	10/46 (21.7%)
Lymphocyte count decreased	3/46 (6.5%)
Metabolism and nutrition disorders
Dehydration	4/46 (8.7%)
Decreased appetite	19/46 (41.3%)
Hypokalaemia	8/46 (17.4%)
Hyperglycaemia	7/46 (15.2%)
Hypoalbuminaemia	5/46 (10.9%)
Hypomagnesaemia	6/46 (13%)
Hypophosphataemia	3/46 (6.5%)
Hyponatraemia	7/46 (15.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	24/46 (52.2%)
Muscular weakness	7/46 (15.2%)
Groin pain	3/46 (6.5%)
Flank pain	3/46 (6.5%)
Myalgia	9/46 (19.6%)
Pain in extremity	12/46 (26.1%)
Back pain	11/46 (23.9%)
Musculoskeletal pain	3/46 (6.5%)
Nervous system disorders
Dysgeusia	9/46 (19.6%)
Hyperaesthesia	3/46 (6.5%)
Headache	15/46 (32.6%)
Dizziness	11/46 (23.9%)
Psychiatric disorders
Anxiety	3/46 (6.5%)
Insomnia	14/46 (30.4%)
Renal and urinary disorders
Pollakiuria	5/46 (10.9%)
Respiratory, thoracic and mediastinal disorders
Cough	8/46 (17.4%)
Oropharyngeal pain	5/46 (10.9%)
Dyspnoea	9/46 (19.6%)
Skin and subcutaneous tissue disorders
Dry skin	9/46 (19.6%)
Rash	31/46 (67.4%)
Palmar-plantar erythrodysaesthesia syndrome	6/46 (13%)
Rash maculo-papular	6/46 (13%)
Erythema	4/46 (8.7%)
Exfoliative rash	5/46 (10.9%)
Dermatitis acneiform	4/46 (8.7%)
Photosensitivity reaction	7/46 (15.2%)
Pruritus	19/46 (41.3%)
Alopecia	7/46 (15.2%)
Night sweats	3/46 (6.5%)
Hyperkeratosis	4/46 (8.7%)
Vascular disorders
Flushing	4/46 (8.7%)
Hot flush	3/46 (6.5%)
Hypertension	5/46 (10.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.