Trial of Vemurafenib/Cobimetinib With or Without Bevacizumab in Patients With Stage IV BRAFV600 Mutant Melanoma

• Sponsor: Melanoma Research Foundation Breakthrough Consortium (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01495988
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 10
• Locations: 14
• Arms: 4
• Duration (Months): 34
• Patients Per Site: 0.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase 2 clinical trial randomizes patients with BRAF mutant melanoma to either (1) standard of care (SOC) - BRAF inhibitor vemurafenib in combination with MEK inhibitor cobimetinib; or, (2) SOC plus bevacizumab, an anti-VEGF antibody that suppresses new blood vessel formation and can stimulate the immune system. Previous clinical studies in melanoma have shown that bevacizumab may improve clinical benefit (progression free survival) if combined with ipilimumab or abraxane. Preclinical studies suggest that VEGF increase plays a role in resistance to BRAF inhibitors. This randomized study will ask whether the addition of bevacizumab to targeted therapy SOC in BRAF mutant melanoma can improve response rates and clinical benefit. Patients may have received no therapy for advanced disease or up to 2 prior therapies, excluding BRAF and MEK inhibitors.

Condition or Disease	Intervention/Treatment	Phase
Melanoma; Metastatic Melanoma	Drug: Vemurafenib; Drug: Bevacizumab; Drug: Cobimetinib	Phase 2

Detailed Description

In this study, the drugs being used are vemurafenib, cobimetinib, and bevacizumab. Vemurafenib has been approved by the FDA for treatment of patients with advanced melanoma that harbors a BRAF mutation. However, vemurafenib in combination with cobimetinib has not been approved by the FDA for the treatment of cancer. Bevacizumab has been approved by the FDA for use in combination with first line chemotherapies for treatment of patients with colorectal, breast and lung cancer. Bevacizumab has not been approved for use in patients with metastatic melanoma.

Vemurafenib and cobimetinib attack different proteins that cause cancer cells to grow. Vemurafenib works by blocking a protein called B-RAF. Researchers have found that a large number of melanomas have mutations (changes) in the BRAF gene. The BRAF gene codes for a protein called B-RAF, which is involved in sending signals in cells that can lead to cell growth. Research has determined that mutations in the BRAF gene at the V600 position cause a change in the B-RAF protein that can drive the growth and spread of melanoma cells. Vemurafenib works by preventing these altered B-RAF proteins from working, and thereby may block the growth and spread of cancer cells in patients with melanoma. Cobimetinib works by blocking a protein called MEK. MEK has been known to promote growth in cancer that carries either a mutation in the BRAF or KRAS genes. The vemurafenib/cobimetinib combination has been used in prior clinical studies. Information from those other research studies suggests that these drugs can shrink melanoma tumors in the majority of patients and slow tumor growth as compared to standard chemotherapy. Another drug to block the BRAF and MEK proteins was recently approved by the FDA in the treatment of patients with B-RAFV600 mutant melanoma. The researchers want to see if using vemurafenib and cobimetinib together will work in a similar way to treat malignant melanoma.

Bevacizumab is a humanized monoclonal antibody (a type of protein that is normally made by the immune system to help defend the body from infection and cancer) produced by using recombinant DNA technology. Bevacizumab is an antibody directed against vascular endothelial growth factor or VEGF. VEGF is a potent, specific growth factor with a well-defined role in normal and abnormal blood vessel formation. It is present in a wide variety of normal tissues, but is produced in excess by most solid cancers (tumors). In the setting of cancer, VEGF promotes the growth of blood vessels that bring nutrients to tumor cells. Its expression by the tumor has been associated with worse outcome in patients with a number of tumors types including melanoma. In laboratory experiments, bevacizumab inhibits the growth of several different types of human cancer cells by blocking the effects of VEGF.

The purpose of this research study is to determine the effectiveness of using the study drugs vemurafenib, cobimetinib, and bevacizumab together relative to vemurafenib and cobimetinib alone. This study will investigate whether using both study drugs lengthens the amount of time before participants' melanoma worsens, increases the number of people whose melanoma responds to treatment and what the side effects are of using the drugs together rather than separately.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Phase II Trial of Vemurafenib (PLX4032/RG7204)/Cobimetinib (GDC-0973) With or Without Bevacizumab in Patients With Stage IV BRAFV600 Mutant Melanoma
• Study Start Date: Aug 1, 2013
• Actual Primary Completion Date: Jan 1, 2016
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Vemurafenib/Cobimetinib Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients. Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Drug: Vemurafenib; Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor.; Other Names: Zelboraf ; Drug: Cobimetinib; Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle.; Other Names: GDC-0973
Experimental: Vemurafenib/Cobimetinib + Bevacizumab Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients. Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Bevacizumab will be administered at the MTD (determined by phase Ib safety lead-in), intravenously, every 2 weeks. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Drug: Vemurafenib; Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor.; Other Names: Zelboraf ; Drug: Bevacizumab; Patients assigned to the combination arm will also receive bevacizumab at 15mg/kg, intravenously, every 3 weeks.; Other Names: Avastin ; Drug: Cobimetinib; Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle.; Other Names: GDC-0973
Active Comparator: Vemurafenib Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Drug: Vemurafenib; Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor.; Other Names: Zelboraf
Experimental: Vemurafenib + Bevacizumab Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients assigned to the combination arm will also receive bevacizumab 15 mg/kg every IV every 3 weeks. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Drug: Vemurafenib; Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor.; Other Names: Zelboraf ; Drug: Bevacizumab; Patients assigned to the combination arm will also receive bevacizumab at 15mg/kg, intravenously, every 3 weeks.; Other Names: Avastin

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose [Until MTD determined (up to 6 months)]

   To establish the maximum tolerated dose (MTD) of bevacizumab in combination with vemurafenib and cobimetinib.

2. Median Progression-free Survival [Time between randomization and disease progression (~10-15 months)]

   To compare median progression-free survival (PFS) of patients with stage IV, BRAFV600E or BRAFV600K melanoma treated with vemurafenib/cobimetinib versus vemurafenib/cobimetinib and bevacizumab.

Secondary Outcome Measures

1. Overall Survival [Time between randomization and death due to any cause (overall survival rates also to be assessed at 12 and 18 months)]

   Compare overall survival (OS) of patients with stage IV, BRAFV600E/K melanoma treated with vemurafenib/cobimetinib versus vemurafenib/cobimetinib and bevacizumab.

2. Response Rates [From time of randomization to time of disease progression (restaging for tumor response to occur every 8 wks until wk 48, then every 12 wks thereafter)]

   Compare response rate (RR) of patients with stage IV, BRAFV600E/K melanoma treated with vemurafenib/cobimetinib versus vemurafenib/cobimetinib and bevacizumab.

3. Toxicity and Safety Profile [Until study completion]

   Describe the toxicity and safety profile of treatment with vemurafenib/cobimetinib versus vemurafenib/cobimetinib and bevacizumab in patients with stage IV, BRAFV600E/K melanoma.

4. Effects of the Addition of Bevacizumab on Tumor Angiogenesis, Resistance Mechanisms and Immune Function [Upon completion of the protocol (3 years)]

   Perform a variety of correlative studies aimed at understanding the effects of vemurafenib/cobimetinib, and bevacizumab administration relative to vemurafenib/cobimetinib on tumor angiogenesis, resistance mechanisms and immune function.

5. Correlate Blood Markers of B-RAFV600 Mutation With Treatment Efficacy [Upon completion of the protocol (3 years)]

   Assess the effectiveness of blood reverse transcription polymerase chain reaction (RT-PCR) assay for BRAFV600 as a surrogate biomarker for tumor response and resistance in patients receiving vemurafenib/cobimetinib +/- bevacizumab.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients must have histological or cytological confirmed melanoma that is metastatic or unresectable stage IIIc and clearly progressive.

2. Patients must have melanoma that is documented to contain a BRAFV600E or BRAFV600K mutation by a FDA-approved test.

3. Age >= 18 years.

4. Women must not be pregnant due to the fact that the effects of vemurafenib, cobimetinib, and/or bevacizumab on the developing human fetus are unknown. For this reason and because antiangiogenic agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence; defined in Appendix G) prior to study entry and for the duration of study participation. Should a woman become pregnant while participating in this study, she should inform her treating physician immediately.

5. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

6. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with bevacizumab, cobimetinib, and vemurafenib, female participants who are breastfeeding must agree to discontinue nursing prior to Day 1 of the study.

7. Patients must have measurable disease as defined in Section 10.1 (cutaneous lesions measuring at least 1 cm will be considered measurable). Baseline CT or MRI scans of measurable disease sites must be performed within 4 weeks of study entry.

8. Patients must have discontinued immunotherapy or other systemic therapy including investigational agents at least 4 weeks prior to entering the study and have recovered from adverse events due to those agents. Patients must agree to not receive any other investigational agents during study participation.

9. Patients must have an ECOG performance status of 0, 1, or 2.

10. Patients must have the following baseline laboratory values:

11. White Blood Count > 3,000/mm3

12. Absolute Neutrophil Count > 1,500/mm3

13. Platelet Count > 100,000/mm3

14. Serum creatinine < 1.5 x upper limit of normal (ULN) or serum creatinine clearance (CrCl)> 40ml/min (CrCl= Wt (kg) x (140-age)*/72 x Cr. level, *female x 0.85)

15. Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) < 3 x ULN (< 5 x ULN for patients with documented liver metastases)

16. Alkaline Phosphatase =< 2 x ULN (=< 5 x ULN for patients with known liver involvement and =< 7 x ULN for patients with known bone involvement)

17. International Normalized Ratio (INR) < 1.5 and aPTT within 1.1 x ULN

18. Total Bilirubin < 1.5 x ULN

19. UPC ratio < 1.0 at screening or 24 hours urine protein < 1 gm (Appendix D)

20. Patients must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Patients may not have received more than 2 prior systemic treatment regimens for distant metastatic disease. The following prior therapy is permitted in either the adjuvant or metastatic disease setting, provided treatment is discontinued at least 4 weeks prior to initiating study treatment:

2. Immunotherapy, such as interferon, interleukin-2, GM-CSF, ipilimumab, anti-PD1 or other experimental agent.

3. Cytotoxic chemotherapy, such as dacarbazine, temozolomide, carboplatin +/-paclitaxel.

4. Patients may not have had radiation therapy within the last 4 weeks prior to initiation of study treatment.

5. Patients who have had prior VEGF pathway inhibitor, BRAF or MEK inhibitor therapy are ineligible.

6. Patients must have no clinical evidence of active brain metastasis. Patients with a history of brain metastases must meet all of the following criteria:

7. Have completed treatment greater than 4 weeks prior to enrollment.

8. Have CNS lesions that are confirmed to be stable or regressing on imaging since the time of the last CNS treatment including the pre-treatment CT or MRI scan for this trial.

9. Patients must have no residual neurologic symptoms while taking no steroids, a stable or decreasing dose of steroids, or a stable dose of anti-seizure medication for the 2 weeks prior to enrollment.

10. Patients must not have other concurrent uncontrolled malignancies, defined as a malignancy that currently requires therapy or other intervention. Patients with suspected cuSCCs should have them excised prior to study registration. Surgical resection should not be performed within 7 days of starting protocol therapy.

11. Patients may not have had a major surgical procedure, open biopsy (excluding skin cancer resection, cutaneous/subcutaneous melanoma metastasis resection or biopsy or vascular access device insertion), or significant traumatic injury within 28 days prior to Day 1, or have an anticipated need for major surgical procedure or a planned elective surgical procedure during the course of the study.

12. Patients may not have had a core biopsy, skin cancer resection, or other minor surgical procedure, including placement of a vascular access device, within 7 days prior to Day 1 of the protocol.

13. Patients must not have a serious intercurrent illness including, but not limited to:

14. Ongoing or active infection requiring parental antibiotics on Day 1

15. A history of malabsorption or other condition that would interfere with absorption of vemurafenib or cobimetinib.

16. History of hemoptysis (>= 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1

17. History of congenital long QT syndrome or mean corrected QTc interval > 450 msec at baseline

18. Clinically significant cardiovascular disease, defined as any of the following conditions:

1. Uncontrolled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg) ii. Prior history of hypertensive crisis or hypertensive encephalopathy iii. Myocardial infarction within 6 months iv. Unstable angina v. New York heart association grade II or greater congestive heart failure (Appendix C) vi. Serious cardiac arrhythmia requiring medication vii. LVEF < 50% or below institutional limit of normal f) History of stroke of TIAs within 6 months prior to Day 1 g) Grade II or greater peripheral vascular disease within 1 year prior to study entry or other significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1 h) Serious, non-healing wound, active ulcer, or untreated bone fracture i) History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1 j) Known hypersensitivity to any component of bevacizumab k) Known CNS disease, except for stable or regressing brain metastases. l) Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation) m) Psychiatric illness/social situations that would limit compliance with study requirements.

1. Significant ocular issues including history of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration. The risk factors for RVO are listed below. Patients should be excluded if they have the following conditions:

1. Uncontrolled glaucoma with intra-ocular pressures >21mm Hg

2. Serum cholesterol >= Grade 2

3. Hypertriglyceridemia >= Grade 2

4. Hyperglycemia (fasting) >= Grade 2

5. Patients must not have the following foods/ supplements at least 7 days prior to initiation of and during study treatment:

6. St. John's wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer)

7. Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor).

8. Because patients with immune deficiency are at increased risk of lethal infections when treated with bone marrow-suppressive therapy, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with bevacizumab, vemurafenib and cobimetinib.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Angeles Clinic	Los Angeles	California	United States	90025
2	University of Colorado Cancer Center	Aurora	Colorado	United States	80045
3	Georgetown Lombardi Comprehensive Cancer Center	Washington, D.C.	District of Columbia	United States	20007
4	Washington Cancer Institute at MedStar Washington Hospital Center	Washington, D.C.	District of Columbia	United States	20010
5	Harry and Jeannette Weinberg Cancer Institute at Franklin Square	Baltimore	Maryland	United States	21237
6	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
7	Beth Israel Deaconess Medical Center (BIDMC)	Boston	Massachusetts	United States	02215
8	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
9	NYU Clinical Cancer Center	New York	New York	United States	10016
10	Columbia University Medical Center	New York	New York	United States	10032
11	OSU Comprehensive Cancer Center	Columbus	Ohio	United States	43210
12	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15232
13	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232
14	University of Washington Medical Center	Seattle	Washington	United States	98109

Sponsors and Collaborators

• Melanoma Research Foundation Breakthrough Consortium
• Genentech, Inc.

Investigators

• Principal Investigator: Michael B Atkins, MD, Beth Israel Deaconess Medical Center
• Principal Investigator: F. Stephen Hodi, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Melanoma Research Foundation Breakthrough Consortium
• ClinicalTrials.gov Identifier: NCT01495988
• Other Study ID Numbers: ML27894; GEN-01
• First Posted: Dec 21, 2011
• Last Update Posted: Oct 24, 2017
• Last Verified: Sep 1, 2017

• Keywords provided by Melanoma Research Foundation Breakthrough Consortium: Metastatic melanoma; BRAF-mutant; Stage IV melanoma; Vemurafenib; Bevacizumab; Cobimetinib
• Additional relevant MeSH terms: Melanoma; Bevacizumab; Vemurafenib

Study Results

Participant Flow

Recruitment Details	Eight subjects were randomized under protocol v2.0 with the first subject enrolled on 8/13/2013. Two subjects were enrolled under protocol v4.0 with the first subject enrolled on 6/19/2015. The study was permanently closed on 6/13/2016. All subjects were recruited from Melanoma Research Foundation Breakthrough Consortium (MRFBC) clinical sites.
Pre-assignment Detail	Participants has to meet the eligibility criteria prior to enrollment into the study.

Arm/Group Title	Vemurafenib/Cobimetinib	Vemurafenib/Cobimetinib + Bevacizumab	Vemurafenib	Vemurafenib + Bevacizumab
Arm/Group Description	Vemurafenib: Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor. Cobimetinib: Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Vemurafenib: Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor. Bevacizumab: Patients assigned to the combination arm will also receive bevacizumab at 15mg/kg, intravenously, every 3 weeks. Cobimetinib: Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter.	Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients assigned to the combination arm will also receive bevacizumab 15 mg/kg every IV every 3 weeks. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter.
Period Title: Vem +/- Bev (Protocol v2.0)
STARTED	0	0	5	3
COMPLETED	0	0	5	3
NOT COMPLETED	0	0	0	0
Period Title: Vem +/- Bev (Protocol v2.0)
STARTED	0	2	0	0
COMPLETED	0	2	0	0
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Vemurafenib/Cobimetinib	Vemurafenib/Cobimetinib + Bevacizumab	Vemurafenib	Vemurafenib + Bevacizumab	Total
Arm/Group Description	Vemurafenib: Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor. Cobimetinib: Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Vemurafenib: Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor. Bevacizumab: Patients assigned to the combination arm will also receive bevacizumab at 15mg/kg, intravenously, every 3 weeks. Cobimetinib: Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter.	Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients assigned to the combination arm will also receive bevacizumab 15 mg/kg every IV every 3 weeks. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter.	Total of all reporting groups
Overall Participants	0	2	5	3	10
Age (Count of Participants)
<=18 years	0 NaN	0 0%	0 0%	0 0%
Between 18 and 65 years	0 NaN	1 50%	3 60%	4 133.3%
>=65 years	2 Infinity	4 200%	0 0%	6 200%
Sex: Female, Male (Count of Participants)
Female	1 Infinity	1 50%	1 20%	3 100%
Male	1 Infinity	4 200%	2 40%	7 233.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 NaN	0 0%	1 20%	1 33.3%
Not Hispanic or Latino	2 Infinity	5 250%	2 40%	9 300%
Unknown or Not Reported	0 NaN	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 NaN	0 0%	0 0%	0 0%
Asian	0 NaN	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 NaN	0 0%	0 0%	0 0%
Black or African American	0 NaN	0 0%	0 0%	0 0%
White	2 Infinity	5 250%	3 60%	10 333.3%
More than one race	0 NaN	0 0%	0 0%	0 0%
Unknown or Not Reported	0 NaN	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	2 Infinity	5 250%	3 60%	10 333.3%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose
Description	To establish the maximum tolerated dose (MTD) of bevacizumab in combination with vemurafenib and cobimetinib.
Time Frame	Until MTD determined (up to 6 months)

Outcome Measure Data

Analysis Population Description

The trial was terminated prematurely during the phase Ib safety lead-in and outcome measures were not analyzed. MTD could not be determined.

Arm/Group Title	Vemurafenib/Cobimetinib	Vemurafenib/Cobimetinib + Bevacizumab	Vemurafenib	Vemurafenib + Bevacizumab
Arm/Group Description	Vemurafenib: Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor. Cobimetinib: Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Vemurafenib: Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor. Bevacizumab: Patients assigned to the combination arm will also receive bevacizumab at 15mg/kg, intravenously, every 3 weeks. Cobimetinib: Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter.	Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients assigned to the combination arm will also receive bevacizumab 15 mg/kg every IV every 3 weeks. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter.
Measure Participants	0	0	0	0

2. Primary Outcome

Title	Median Progression-free Survival
Description	To compare median progression-free survival (PFS) of patients with stage IV, BRAFV600E or BRAFV600K melanoma treated with vemurafenib/cobimetinib versus vemurafenib/cobimetinib and bevacizumab.
Time Frame	Time between randomization and disease progression (~10-15 months)

Outcome Measure Data

Analysis Population Description

The trial was terminated prematurely during the phase Ib safety lead-in and outcome measures were not analyzed due to significantly underpowered data and the MTD being undetermined.

Arm/Group Title	Vemurafenib/Cobimetinib	Vemurafenib/Cobimetinib + Bevacizumab	Vemurafenib	Vemurafenib + Bevacizumab
Arm/Group Description	Vemurafenib: Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor. Cobimetinib: Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Vemurafenib: Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor. Bevacizumab: Patients assigned to the combination arm will also receive bevacizumab at 15mg/kg, intravenously, every 3 weeks. Cobimetinib: Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter.	Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients assigned to the combination arm will also receive bevacizumab 15 mg/kg every IV every 3 weeks. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter.
Measure Participants	0	0	0	0

3. Secondary Outcome

Title	Overall Survival
Description	Compare overall survival (OS) of patients with stage IV, BRAFV600E/K melanoma treated with vemurafenib/cobimetinib versus vemurafenib/cobimetinib and bevacizumab.
Time Frame	Time between randomization and death due to any cause (overall survival rates also to be assessed at 12 and 18 months)

Outcome Measure Data

Analysis Population Description

The trial was terminated prematurely during the phase Ib safety lead-in and outcome measures were not analyzed due to significantly underpowered data and the MTD being undetermined.

Arm/Group Title	Vemurafenib/Cobimetinib	Vemurafenib/Cobimetinib + Bevacizumab	Vemurafenib	Vemurafenib + Bevacizumab
Arm/Group Description	Vemurafenib: Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor. Cobimetinib: Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Vemurafenib: Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor. Bevacizumab: Patients assigned to the combination arm will also receive bevacizumab at 15mg/kg, intravenously, every 3 weeks. Cobimetinib: Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter.	Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients assigned to the combination arm will also receive bevacizumab 15 mg/kg every IV every 3 weeks. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter.
Measure Participants	0	0	0	0

4. Secondary Outcome

Title	Response Rates
Description	Compare response rate (RR) of patients with stage IV, BRAFV600E/K melanoma treated with vemurafenib/cobimetinib versus vemurafenib/cobimetinib and bevacizumab.
Time Frame	From time of randomization to time of disease progression (restaging for tumor response to occur every 8 wks until wk 48, then every 12 wks thereafter)

Outcome Measure Data

Analysis Population Description

The trial was terminated prematurely during the phase Ib safety lead-in and outcome measures were not analyzed due to significantly underpowered data and the MTD being undetermined.

Arm/Group Title	Vemurafenib/Cobimetinib	Vemurafenib/Cobimetinib + Bevacizumab	Vemurafenib	Vemurafenib + Bevacizumab
Arm/Group Description	Vemurafenib: Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor. Cobimetinib: Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Vemurafenib: Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor. Bevacizumab: Patients assigned to the combination arm will also receive bevacizumab at 15mg/kg, intravenously, every 3 weeks. Cobimetinib: Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter.	Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients assigned to the combination arm will also receive bevacizumab 15 mg/kg every IV every 3 weeks. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter.
Measure Participants	0	0	0	0

5. Secondary Outcome

Title	Toxicity and Safety Profile
Description	Describe the toxicity and safety profile of treatment with vemurafenib/cobimetinib versus vemurafenib/cobimetinib and bevacizumab in patients with stage IV, BRAFV600E/K melanoma.
Time Frame	Until study completion

Outcome Measure Data

Analysis Population Description

The trial was terminated prematurely during the phase Ib safety lead-in and outcome measures were not analyzed due to significantly underpowered data and the MTD being undetermined.

Arm/Group Title	Vemurafenib/Cobimetinib	Vemurafenib/Cobimetinib + Bevacizumab	Vemurafenib	Vemurafenib + Bevacizumab
Arm/Group Description	Vemurafenib: Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor. Cobimetinib: Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Vemurafenib: Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor. Bevacizumab: Patients assigned to the combination arm will also receive bevacizumab at 15mg/kg, intravenously, every 3 weeks. Cobimetinib: Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter.	Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients assigned to the combination arm will also receive bevacizumab 15 mg/kg every IV every 3 weeks. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter.
Measure Participants	0	0	0	0

6. Secondary Outcome

Title	Effects of the Addition of Bevacizumab on Tumor Angiogenesis, Resistance Mechanisms and Immune Function
Description	Perform a variety of correlative studies aimed at understanding the effects of vemurafenib/cobimetinib, and bevacizumab administration relative to vemurafenib/cobimetinib on tumor angiogenesis, resistance mechanisms and immune function.
Time Frame	Upon completion of the protocol (3 years)

Outcome Measure Data

Analysis Population Description

The trial was terminated prematurely and outcome measures were not analyzed.

Arm/Group Title	Vemurafenib/Cobimetinib	Vemurafenib/Cobimetinib + Bevacizumab	Vemurafenib	Vemurafenib + Bevacizumab
Arm/Group Description	Vemurafenib: Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor. Cobimetinib: Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Vemurafenib: Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor. Bevacizumab: Patients assigned to the combination arm will also receive bevacizumab at 15mg/kg, intravenously, every 3 weeks. Cobimetinib: Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter.	Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients assigned to the combination arm will also receive bevacizumab 15 mg/kg every IV every 3 weeks. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter.
Measure Participants	0	0	0	0

7. Secondary Outcome

Title	Correlate Blood Markers of B-RAFV600 Mutation With Treatment Efficacy
Description	Assess the effectiveness of blood reverse transcription polymerase chain reaction (RT-PCR) assay for BRAFV600 as a surrogate biomarker for tumor response and resistance in patients receiving vemurafenib/cobimetinib +/- bevacizumab.
Time Frame	Upon completion of the protocol (3 years)

Outcome Measure Data

Analysis Population Description

The trial was terminated prematurely during the phase Ib safety lead-in and outcome measures were not analyzed due to significantly underpowered data and the MTD being undetermined.

Arm/Group Title	Vemurafenib/Cobimetinib	Vemurafenib/Cobimetinib + Bevacizumab	Vemurafenib	Vemurafenib + Bevacizumab
Arm/Group Description	Vemurafenib: Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor. Cobimetinib: Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Vemurafenib: Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor. Bevacizumab: Patients assigned to the combination arm will also receive bevacizumab at 15mg/kg, intravenously, every 3 weeks. Cobimetinib: Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.	Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter.	Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients assigned to the combination arm will also receive bevacizumab 15 mg/kg every IV every 3 weeks. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter.
Measure Participants	0	0	0	0

Adverse Events

Time Frame	Adverse Event data were collected from time of first study drug administration through 30 days following the last administration of study drug or study discontinuation/termination, whichever is earlier.
Adverse Event Reporting Description	Safety assessments will consist of monitoring and reporting the following adverse events (AEs): Serious adverse events Events that lead to drug discontinuation or interruption All grade 3 and 4 toxicities All deaths Adverse events of special interest (AESI)
Arm/Group Title	Vemurafenib/Cobimetinib		Vemurafenib/Cobimetinib + Bevacizumab		Vemurafenib		Vemurafenib + Bevacizumab
Arm/Group Description	Vemurafenib: Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor. Cobimetinib: Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.		Vemurafenib: Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor. Bevacizumab: Patients assigned to the combination arm will also receive bevacizumab at 15mg/kg, intravenously, every 3 weeks. Cobimetinib: Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 weeks until week 48, then every 12 weeks thereafter. Patients will be followed until disease progression.		Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter.		Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients assigned to the combination arm will also receive bevacizumab 15 mg/kg every IV every 3 weeks. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/progression every 6 weeks until week 48, then every 12 weeks thereafter.
All Cause Mortality
	Vemurafenib/Cobimetinib		Vemurafenib/Cobimetinib + Bevacizumab		Vemurafenib		Vemurafenib + Bevacizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		1/2 (50%)		5/5 (100%)		1/3 (33.3%)
Serious Adverse Events
	Vemurafenib/Cobimetinib		Vemurafenib/Cobimetinib + Bevacizumab		Vemurafenib		Vemurafenib + Bevacizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		2/2 (100%)		3/5 (60%)		0/3 (0%)
Cardiac disorders
Myocardial Infarction	0/0 (NaN)	0	0/2 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Gastrointestinal disorders
Incarcerated right femoral hernia	0/0 (NaN)	0	0/2 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Small Intestinal Obstruction	0/0 (NaN)	0	0/2 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Diarrhea	0/0 (NaN)	0	2/2 (100%)	2	0/5 (0%)	0	0/3 (0%)	0
Vomiting	0/0 (NaN)	0	1/2 (50%)	1	0/5 (0%)	0	0/3 (0%)	0
Retroperitoneal Hemorrhage	0/0 (NaN)	0	1/2 (50%)	1	0/5 (0%)	0	0/3 (0%)	0
General disorders
Multi-Organ Failure	0/0 (NaN)	0	1/2 (50%)	1	0/5 (0%)	0	0/3 (0%)	0
Infections and infestations
Sepsis	0/0 (NaN)	0	0/2 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Musculoskeletal and connective tissue disorders
Muscle Weakness Lower Limb	0/0 (NaN)	0	0/2 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Renal and urinary disorders
Acute Kidney Injury	0/0 (NaN)	0	1/2 (50%)	1	0/5 (0%)	0	0/3 (0%)	0
Other (Not Including Serious) Adverse Events
	Vemurafenib/Cobimetinib		Vemurafenib/Cobimetinib + Bevacizumab		Vemurafenib		Vemurafenib + Bevacizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		2/2 (100%)		4/5 (80%)		3/3 (100%)
Blood and lymphatic system disorders
Anemia	0/0 (NaN)	0	0/2 (0%)	0	0/5 (0%)	0	1/3 (33.3%)	1
Cardiac disorders
Myocardial Infarction	0/0 (NaN)	0	0/2 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Gastrointestinal disorders
Diarrhea	0/0 (NaN)	0	2/2 (100%)	2	1/5 (20%)	1	1/3 (33.3%)	1
Incarcerated right femoral hernia	0/0 (NaN)	0	0/2 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Small Intestinal Obstruction	0/0 (NaN)	0	0/2 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Tooth Development Disorder	0/0 (NaN)	0	0/2 (0%)	0	0/5 (0%)	0	1/3 (33.3%)	1
Retroperitoneal Hemorrhage	0/0 (NaN)	0	1/2 (50%)	1	0/5 (0%)	0	0/3 (0%)	0
Vomiting	0/0 (NaN)	0	1/2 (50%)	1	0/5 (0%)	0	0/3 (0%)	0
General disorders
Edema Limbs	0/0 (NaN)	0	0/2 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Fever	0/0 (NaN)	0	0/2 (0%)	0	0/5 (0%)	0	1/3 (33.3%)	1
Multi-Organ Failure	0/0 (NaN)	0	1/2 (50%)	1	0/5 (0%)	0	0/3 (0%)	0
Infections and infestations
Sepsis	0/0 (NaN)	0	0/2 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Injury, poisoning and procedural complications
Fall	0/0 (NaN)	0	1/2 (50%)	1	0/5 (0%)	0	0/3 (0%)	0
Investigations
Lymphocyte Count Decreased	0/0 (NaN)	0	0/2 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Metabolism and nutrition disorders
Hypoalbuminemia	0/0 (NaN)	0	0/2 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Hyponatremia	0/0 (NaN)	0	1/2 (50%)	1	1/5 (20%)	1	0/3 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/0 (NaN)	0	0/2 (0%)	0	0/5 (0%)	0	1/3 (33.3%)	1
Muscle Weakness Lower Limb	0/0 (NaN)	0	0/2 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous Cell Carcinoma	0/0 (NaN)	0	0/2 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Nervous system disorders
Headache	0/0 (NaN)	0	0/2 (0%)	0	0/5 (0%)	0	1/3 (33.3%)	1
Renal and urinary disorders
Acute Kidney Injury	0/0 (NaN)	0	1/2 (50%)	1	0/5 (0%)	0	0/3 (0%)	0
Skin and subcutaneous tissue disorders
Dry Skin	0/0 (NaN)	0	0/2 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Rash Acneiform	0/0 (NaN)	0	0/2 (0%)	0	1/5 (20%)	1	1/3 (33.3%)	1
Rash Maculo-Papular	0/0 (NaN)	0	0/2 (0%)	0	2/5 (40%)	2	2/3 (66.7%)	2
Unknown Rash	0/0 (NaN)	0	0/2 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Vascular disorders
Hypertension	0/0 (NaN)	0	0/2 (0%)	0	1/5 (20%)	1	1/3 (33.3%)	1

Limitations/Caveats

The study was terminated prematurely on June 13, 2016. No further accrual to the study will occur.

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.