Combined BRAF-Targeted Therapy & Immunotherapy for Melanoma

Melanoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01754376
• Other study ID #: 12-343
• Status: Active, not recruiting
• Phase: Phase 2
• First received: December 16, 2012
• Last updated: March 20, 2016
• Start date: January 2013

Study information

• Verified date: March 2016
• Source: Massachusetts General Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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, we 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.

Description:

You will take oral vemurafenib twice a day for 2 weeks. Following this lead-in period, you will receive aldesleukin via IV infusion on Day 15 of the study. One course of aldesleukin is 12 weeks long; you will receive aldesleukin via IV infusion every 8 hours for the first five days. Youi will be hospitalized for the 5 days that you are receiving aldesleukin. This week that you are hospitalized will be referred to as Week 1. Week 1 of aldesleukin will be days 15-19 (M-F) of the 12 week cycle. Following Week 1 of therapy, you will be discharged from the hospital and only take vemurafenib at home for the following week. You wil 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.

You will continue to take vemurafenib twice daily during the course of aldesleukin. Your 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, your tumor 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.

During the research study, you will come into the clinic weekly for various tests and procedures.

If scans show that your cancer has improved after the first course of aldesleukin, your doctor may allow you to continue on the a second course. In the event of a second course of aldesleukin, you will remain on vemurafenib throughout the second course. If your doctor decides you will not receive a second course of aldesleukin, you may still remain on vemurafenib until one of the following events occurs: Your cancer becomes worse, you experience serious side effects that are from taking vemurafenib, you request to discontinue taking vemurafenib/withdraw from the study, you develop another illness that prevents you from being able to take vemurafenib, the study is terminated by the sponsor or your study doctor decides it is in your best interest to discontinue treatment with vemurafenib.

In some cases if your cancer does get worse, but you and your study doctor believe you are still benefitting from vemurafenib in some way, you may continue receiving it after you consult with the study director.

After the final dose of the study drug we would like to keep track of your medical condition for the rest of your life. We would like to do this by calling you on the telephone once a year to see how you are doing. Keeping in touch with you and checking your condition every year helps us look at the long-term effects of the research study.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 49
• Est. primary completion date: February 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Melanoma

Intervention

Drug:
• Aldesleukin
Intravenous therapy given every 8 hours for up to 14 doses per week.
• Vemurafenib
Tablets given twice daily.

Locations

Country	Name	City	State
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Massachusetts General Hospital

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Efficacy of Vemurafenib + Aldesleukin	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 in comparison to an historic control of vemurafenib alone	2 years	No
Secondary	Determine Response Rates (Complete, Partial and Durable)	To determine the complete response (CR), partial response (PR), and durable response (DR) rates (as defined as the rate of objective response (CR or PR) lasting continuously for 12 or more months, as compared to control therapy, and beginning at any point within 12 months of initiating therapy) in patients treated with aldesleukin and vemurafenib	2 years	No
Secondary	Overall Survival	To determine the overall survival in patients treated with aldesleukin and vemurafenib	2 years	No
Secondary	Toxicity and Safety of Aldesleukin and Vemurafenib	To determine the toxicity and safety of concurrent administration of aldesleukin and vemurafenib	2 years	Yes
Secondary	Confirm Pre-Clinical Data	To confirm preclinical data indicating that pharmacologic inhibition of mutated BRAF enhances the immunogenicity of melanoma without adversely affecting the cellular immune response. To assess whether the number of doses of aldesleukin that can be safely administered is affected by the co-administration of vemurafenib	2 years	No
Secondary	Exploration of Biomarkers	To explore biomarkers that may be relevant: to further predict responsiveness to vemurafenib and aldesleukin, to explain primary or acquired resistance to vemurafenib, to indicate pharmacodynamic effects of vemurafenib and to monitor the disease.	2 years	No