Combined BRAF-Targeted Therapy & Immunotherapy for Melanoma

COMBAT 1: A Phase II Trial of Combined BRAF-Targeted Therapy and Immunotherapy for Melanoma

This research study is a Phase II clinical trial of an investigational combination of drugs (vemurafenib and aldesleukin) to learn whether the combination works in treating a specific cancer. While both vemurafenib and aldesleukin are approved by the FDA for the treatment of metastatic melanoma, the FDA has not yet approved the combination of vemurafenib and aldesleukin.

Researchers have found that a large number of melanoma cells have mutations in the BRAF gene. It has been shown that vemurafenib blocks the effects of these mutations in the BRAF gene, and, as a result, may help to prevent cancer growth.

Aldesleukin, also referred to as IL-2, is an immunotherapy drug administered via IV infusion that increases the growth of key cells within the immune system that are responsible for targeting cancer cells. Activating more of these key cells, called T-lymphocytes and natural-killer cells, leads to increased cancer cell death.

The BRAF gene is located on a larger pathway called the MAPK pathway. Studies have shown that when a BRAF inhibitor, like vemurafenib is used to block the MAPK pathway, melanocytes, or cancer cells express more proteins on their surfaces, making them easier for T-lymphocytes and natural killer cells to recognize and kill them. This suggests that combining BRAF-targeted therapy with aldesleukin, which activates more of these white blood cells, can lead to an increase in the death of cancer cells.

In this research study, the investigators are looking to see whether the combination of vemurafenib (a BRAF-inhibitor) combined with aldesleukin(an immunotherapy drug) work together to produce a better health outcome in people with metastatic melanoma.

Study Overview

• Status: Terminated
• Conditions: Melanoma
• Intervention / Treatment: Drug: Aldesleukin; Drug: Vemurafenib

Detailed Description

Subjects will take oral vemurafenib twice a day for 2 weeks. Following this lead-in period, subjects will receive aldesleukin via IV infusion on Day 15 of the study. One course of aldesleukin is 12 weeks long; subjects will receive aldesleukin via IV infusion every 8 hours for the first five days. Subjects will be hospitalized for the 5 days that they are receiving aldesleukin.

Week 1 of aldesleukin will be days 15-19 (M-F) of the 12 week cycle. Following Week 1 of therapy, subjects will be discharged from the hospital and only take vemurafenib at home for the following week. Subjects will then come in for one more week of aldesleukin during days 29-33 of the 12 week cycle. This is referred to as Week 2 of aldesleukin.

Subjects will continue to take vemurafenib twice daily during the course of aldesleukin. Their cancer will be evaluated at screening and at Week 12 following the beginning of the first aldesleukin course with a CT scan. After the first cycle, tumors will be evaluated every 8 weeks for the first year, then every 12 weeks for years 2 and 3, every 6 months for year 5, and annually thereafter.

If scans show that the subject's cancer has improved after the first course of aldesleukin, subjects may be allowed to continue on to a second course. In the event of a second course of aldesleukin, subjects will remain on vemurafenib throughout the second course.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02113
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically confirmed metastatic or unresectable melanoma with V600E mutation
• Measurable disease
• May have received prior immunotherapy (excluding interleukin 2)
• Life expectancy greater than 3 months
• Recovered from effects of previous surgery and/or traumatic injury
• Must agree to use effective contraception

Exclusion Criteria:

• Pregnant or breastfeeding
• Psychological, familial or other conditions that could hamper compliance with protocol
• Receiving other study agents
• History of carcinomatous meningitis
• Known active brain metastases
• Have received a BRAF inhibitor
• Uncontrolled intercurrent illness
• HIV positive on antiretroviral therapy
• History of a different malignancy within past 5 years (except cervical cancer in situ or basal/squamous cell carcinoma of the skin)
• Active hepatitis B or C
• Have received allogenic bone marrow transplant or organ transplant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Treatment Arm; Oral vemurafenib 960 milligrams twice a day plus intravenous aldesleukin 600,000 IU/kg every eight hours to tolerance (maximum 14 doses) over five days on days 15-19 of cycle 1 and on days 1-5 of cycle 2. (A cycle is 28 days) The first course of treatment will consist of three 28-day cycles (12 weeks): 2 weeks of lead-in vemurafenib plus 3 weeks on IL-2 plus 7 weeks wait. A second course may be given at the discretion of the investigator, if there is evidence of tumor stability or regression.

Drug: Aldesleukin; Intravenous therapy given every 8 hours for up to 14 doses per week.; Other Names: Proleukin; IL-2; Interleukin 2; Drug: Vemurafenib; Tablets given twice daily.; Other Names: PLX4032; RG7204; Zelboraf; RO5185426

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	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.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	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.	2 years
Overall Survival	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.	2 years
Number of Participants Experiencing Grade 3 (Severe) Adverse Events	To determine the toxicity and safety of concurrent administration of aldesleukin and vemurafenib by assessing adverse events experienced by participants.	2 years
Mean Percentage of Aldesleukin Doses Received Per Participant	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.	Approximately 9 months from start of treatment
Ratio of CD8+ T Cells to Regulatory T Cells	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.	Up to 8 weeks from start of treatment

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Investigators: Principal Investigator: Ryan J Sullivan, MD, MGH Cancer Center

Publications and helpful links

General Publications

• Mooradian MJ, Reuben A, Prieto PA, Hazar-Rethinam M, Frederick DT, Nadres B, Piris A, Juneja V, Cooper ZA, Sharpe AH, Corcoran RB, Flaherty KT, Lawrence DP, Wargo JA, Sullivan RJ. A phase II study of combined therapy with a BRAF inhibitor (vemurafenib) and interleukin-2 (aldesleukin) in patients with metastatic melanoma. Oncoimmunology. 2018 Feb 1;7(5):e1423172. doi: 10.1080/2162402X.2017.1423172. eCollection 2018.

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (ACTUAL): February 1, 2015
• Study Completion (ACTUAL): March 1, 2016

Study Registration Dates

• First Submitted: December 16, 2012
• First Submitted That Met QC Criteria: December 18, 2012
• First Posted (ESTIMATE): December 21, 2012

Study Record Updates

• Last Update Posted (ACTUAL): April 12, 2017
• Last Update Submitted That Met QC Criteria: March 14, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: Metastatic; Unresectable; V600E mutation
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antineoplastic Agents; Protein Kinase Inhibitors; Aldesleukin; Interleukin-2; Vemurafenib
• Other Study ID Numbers: 12-343

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All raw analytic data on tumor and blood samples will be shared, upon acceptance of manuscript.