Combined BRAF-Targeted Therapy & Immunotherapy for Melanoma

NCT01754376 | Terminated Phase 2 Results DMC

• 1 other identifier: 12-343
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Melanoma

Keywords

Metastatic; Unresectable; V600E mutation

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Overall Response Rate

  2 years

• Overall Survival

  2 years

• Number of Participants Experiencing Grade 3 (Severe) Adverse Events

  2 years

• Mean Percentage of Aldesleukin Doses Received Per Participant

  Approximately 9 months from start of treatment

• Ratio of CD8+ T Cells to Regulatory T Cells

  Up to 8 weeks from start of treatment

Study Arms (1)

Treatment Arm

EXPERIMENTAL

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; Drug: Vemurafenib

Interventions

Aldesleukin DRUG

Intravenous therapy given every 8 hours for up to 14 doses per week.

Also known as: Interleukin 2, IL-2, Proleukin

Treatment Arm

Vemurafenib DRUG

Tablets given twice daily.

Also known as: Zelboraf, PLX4032, RG7204, RO5185426

Treatment Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Massachusetts General Hospital: lead

Study Sites (2)

Massachusetts General Hospital

Boston, Massachusetts, 02113, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Related Publications (1)

• 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.

  PMID: 29721378 DERIVED

MeSH Terms

Conditions

Melanoma; Neoplasm Metastasis

Interventions

aldesleukin; Interleukin-2; Vemurafenib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors; Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

The protocol terminated early due to a dramatic change in the treatment landscape for treating BRAF mutant melanoma (e.g. one BRAF/MEK inhibitor combination and two anti-PD1 antibodies were approved by the FDA while this study was open).

Results Point of Contact

• Title: Ryan Sullivan
• Organization: MGH Cancer Center

rsullivan7@mgh.harvard.edu

617-724-4000

Study Officials

• Ryan J Sullivan, MD

  MGH Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 16, 2012
• First Posted: December 21, 2012
• Study Start: January 1, 2013
• Primary Completion: February 1, 2015
• Study Completion: March 1, 2016
• Last Updated: April 12, 2017
• Results First Posted: March 9, 2017

Record last verified: 2017-01

Data Sharing

• IPD Sharing: Will share

Locations

US (2)