Trial Outcomes & Findings for Combined BRAF-Targeted Therapy & Immunotherapy for Melanoma (NCT NCT01754376)

Last Updated: 2017-04-12

Results Overview

To assess the efficacy (as measured by progression-free survival (PFS)) of patients with metastatic melanoma with V600E mutation treated with the combination of vemurafenib and aldesleukin. Progression free survival is defined as the time between the first dose of study drug and the first occurrence of progression of disease or death from any cause. Progression is defined using Response Evaluation Criteria in Solid Tumors (RECIST v.1.1), as at least a 20% increase in the sum of the diameters of target lesions or the appearance of one or more new lesions.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

6 participants

Primary outcome timeframe

3 years

Results posted on

2017-04-12

Participant Flow

Patients were recruited at Massachusetts General Hospital (Boston, MA) between February and November 2013

Participant milestones

Participant milestones
Measure	Treatment Arm Oral vemurafenib twice a day IV infusion of aldesleukin Aldesleukin: Intravenous therapy given every 8 hours for up to 14 doses per week. Vemurafenib: Tablets given twice daily.
Overall Study STARTED	6
Overall Study Completed 2-week Lead in of Vemurafenib	6
Overall Study COMPLETED	3
Overall Study NOT COMPLETED	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Treatment Arm Oral vemurafenib twice a day IV infusion of aldesleukin Aldesleukin: Intravenous therapy given every 8 hours for up to 14 doses per week. Vemurafenib: Tablets given twice daily.
Overall Study Adverse Event	1
Overall Study Lack of Efficacy	2

Baseline Characteristics

Combined BRAF-Targeted Therapy & Immunotherapy for Melanoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Treatment Arm n=6 Participants Oral vemurafenib twice a day IV infusion of aldesleukin Aldesleukin: Intravenous therapy given every 8 hours for up to 14 doses per week. Vemurafenib: Tablets given twice daily.
Age, Continuous	42 years n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	6 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Region of Enrollment United States	6 participants n=5 Participants
Brain Metastasis present	1 Participants n=5 Participants
ECOG Status ECOG Status = 0	3 Participants n=5 Participants
ECOG Status ECOG Status = 1	3 Participants n=5 Participants
Previous treatments Surgery	6 Participants n=5 Participants
Previous treatments Adjuvant interferon-alfa	5 Participants n=5 Participants

PRIMARY outcome

Timeframe: 3 years

Outcome measures

Outcome measures
Measure	Treatment Arm n=6 Participants Oral vemurafenib twice a day IV infusion of aldesleukin Aldesleukin: Intravenous therapy given every 8 hours for up to 14 doses per week. Vemurafenib: Tablets given twice daily.
Progression Free Survival	35.8 weeks Interval 16.0 to 57.0

SECONDARY outcome

Timeframe: 2 years

To determine the overall response rate (as defined as the rate of objective response (Complete Response (CR) or Partial Response (PR)) lasting continuously for 12 or more months, and beginning at any point within 12 months of initiating therapy) in patients treated with aldesleukin and vemurafenib. In this limited cohort, response rate was calculated as the proportion of patients with partial (PR) or complete response (CR) divided by the total number of patients treated. Per Response Evaluation Criteria in Solid Tumors (RECIST v.1.1), 'Complete Response' is the disappearance of all target lesions and 'Partial Response' is at least a 30% decrease in the sum of the diameters of target lesions, as measured via CT (computed tomography). Overally Response (OR) = CR + PR.

Outcome measures

Outcome measures
Measure	Treatment Arm n=6 Participants Oral vemurafenib twice a day IV infusion of aldesleukin Aldesleukin: Intravenous therapy given every 8 hours for up to 14 doses per week. Vemurafenib: Tablets given twice daily.
Overall Response Rate	83.3 percentage of participants Interval 36.0 to 99.0

SECONDARY outcome

Timeframe: 2 years

Population: Median overall survival was not reached

To determine the overall survival in patients treated with aldesleukin and vemurafenib. Overall survival is defined as the time between the first administration of study drug and death due to any cause.

Outcome measures

Outcome measures
Measure	Treatment Arm n=6 Participants Oral vemurafenib twice a day IV infusion of aldesleukin Aldesleukin: Intravenous therapy given every 8 hours for up to 14 doses per week. Vemurafenib: Tablets given twice daily.
Overall Survival	NA months Median overall survival was not reached

SECONDARY outcome

Timeframe: 2 years

To determine the toxicity and safety of concurrent administration of aldesleukin and vemurafenib by assessing adverse events experienced by participants.

Outcome measures

Outcome measures
Measure	Treatment Arm n=6 Participants Oral vemurafenib twice a day IV infusion of aldesleukin Aldesleukin: Intravenous therapy given every 8 hours for up to 14 doses per week. Vemurafenib: Tablets given twice daily.
Number of Participants Experiencing Grade 3 (Severe) Adverse Events	6 Participants

SECONDARY outcome

Timeframe: Approximately 9 months from start of treatment

Population: Six participants started course 1. Only 4 participants started course 2.

To assess whether the number of doses of aldesleukin that can be safely administered is affected by the co-administration of vemurafenib. The total number of planned doses of aldesleukin was 28 in each of course 1 and course 2. A participant receiving all 28 doses in course 1 would be considered as receiving 100 percent of doses.

Outcome measures

Outcome measures
Measure	Treatment Arm n=6 Participants Oral vemurafenib twice a day IV infusion of aldesleukin Aldesleukin: Intravenous therapy given every 8 hours for up to 14 doses per week. Vemurafenib: Tablets given twice daily.
Mean Percentage of Aldesleukin Doses Received Per Participant Course 1 doses	73 percentage of doses Interval 61.0 to 86.0
Mean Percentage of Aldesleukin Doses Received Per Participant Course 2 doses	54 percentage of doses Interval 39.0 to 64.0
Mean Percentage of Aldesleukin Doses Received Per Participant Total doses	55 percentage of doses Interval 32.0 to 70.0

SECONDARY outcome

Timeframe: Up to 8 weeks from start of treatment

Population: Tumor tissue was only analyzed from one participant

Tumor samples were collected pre-treatment, after 1-2 weeks on vemurafenib alone and after administration of aldesleukin (high-dose interleukin 2, HD-IL2). Multi-parameter flow cytometry was performed to measure the frequency of regulatory T cells and of CD8+ T cells. The CD8/Treg ratio was calculated.

Outcome measures

Outcome measures
Measure	Treatment Arm n=1 Participants Oral vemurafenib twice a day IV infusion of aldesleukin Aldesleukin: Intravenous therapy given every 8 hours for up to 14 doses per week. Vemurafenib: Tablets given twice daily.
Ratio of CD8+ T Cells to Regulatory T Cells Pre-treatment	43.9 ratio CD8/T reg cells
Ratio of CD8+ T Cells to Regulatory T Cells After vemurafenib alone	20.5 ratio CD8/T reg cells
Ratio of CD8+ T Cells to Regulatory T Cells After aldesleukin	4.04 ratio CD8/T reg cells

Adverse Events

Treatment Arm

Serious events: 2 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Treatment Arm n=6 participants at risk Oral vemurafenib twice a day IV infusion of aldesleukin Aldesleukin: Intravenous therapy given every 8 hours for up to 14 doses per week. Vemurafenib: Tablets given twice daily.
Psychiatric disorders delirium	16.7% 1/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Cardiac disorders myocarditis	16.7% 1/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.

Other adverse events

Other adverse events
Measure	Treatment Arm n=6 participants at risk Oral vemurafenib twice a day IV infusion of aldesleukin Aldesleukin: Intravenous therapy given every 8 hours for up to 14 doses per week. Vemurafenib: Tablets given twice daily.
Cardiac disorders sinus tachycardia	50.0% 3/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Gastrointestinal disorders diarrhea	100.0% 6/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Gastrointestinal disorders mucositis - oral	66.7% 4/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Gastrointestinal disorders nausea	100.0% 6/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Gastrointestinal disorders vomiting	83.3% 5/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
General disorders fatigue	100.0% 6/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Investigations elevated alanine aminotransferase	50.0% 3/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Investigations elevated aspartate aminotransferase	50.0% 3/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Investigations blood bilirubin increased	33.3% 2/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Musculoskeletal and connective tissue disorders arthralgia	100.0% 6/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Musculoskeletal and connective tissue disorders myalgia	50.0% 3/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Nervous system disorders cognitive disturbance	16.7% 1/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Nervous system disorders headache	33.3% 2/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Psychiatric disorders delirium	33.3% 2/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Skin and subcutaneous tissue disorders erythroderma	33.3% 2/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Skin and subcutaneous tissue disorders rash acneiform	50.0% 3/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Skin and subcutaneous tissue disorders rash maculo-papular	33.3% 2/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Vascular disorders capillary leak syndrome	50.0% 3/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Vascular disorders hypotension	66.7% 4/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Renal and urinary disorders acute kidney injury	33.3% 2/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Renal and urinary disorders acidosis	66.7% 4/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Investigations Platelet count decreased	16.7% 1/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.
Infections and infestations Infection - C. difficile	16.7% 1/6 • 9 months All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit.

Additional Information

Ryan Sullivan

MGH Cancer Center

Phone: 617-724-4000

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place