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MelanomaPhase 2NCT01754376

Combined BRAF-Targeted Therapy & Immunotherapy for Melanoma

A Phase 2 study testing Aldesleukin and Vemurafenib in people with Melanoma, run by Massachusetts General Hospital at 2 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Melanoma
What is being tested?
Aldesleukin and Vemurafenib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
6 participants
Where
2 sitesUnited States
Study dates
Jan 2013to Mar 2016
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 11Show fewer
  • 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

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Massachusetts General Hospital

    Boston, Massachusetts, 02113

  • Beth Israel Deaconess Medical Center

    Boston, Massachusetts, 02215

Other trials in United States

About this study

Official title: 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.

Read more

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.

Read the 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.

Conditions
Melanoma
Being tested
Aldesleukin, Vemurafenib
Keywords
Metastatic, Unresectable, V600E mutation
Medical subject headings
Melanoma, Neoplasm Metastasis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AldesleukinDrug

    Also called Interleukin 2, IL-2, Proleukin

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

  • VemurafenibDrug

    Also called Zelboraf, PLX4032, RG7204, RO5185426

    Tablets given twice daily.

Study groups in NCT01754376
Study groupRoleWhat they receive
Treatment ArmExperimentalOral 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.
Receives: Drug: Aldesleukin; Drug: Vemurafenib

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 3 years

Secondary outcomes (5)

  1. 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.

    Measured: 2 years

  2. 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.

    Measured: 2 years

  3. 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.

    Measured: 2 years

  4. 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.

    Measured: Approximately 9 months from start of treatment

  5. 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.

    Measured: Up to 8 weeks from start of treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Dec 2012 (estimated)
  2. Study startJan 2013
  3. Primary completionFeb 2015
  4. Study completionMar 2016

Why it stopped: changes in available treatments for melanoma

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
6 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01754376
Sponsor's protocol ID
12-343
Status last verified
Jan 2017
First submitted
16 Dec 2012
Last updated
12 Apr 2017
Data monitoring committee
Yes
Individual data sharing
Yes: All raw analytic data on tumor and blood samples will be shared, upon acceptance of manuscript.

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.

    PubMed 29721378

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Aldesleukin and Vemurafenib in people with Melanoma, run by Massachusetts General Hospital at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 12 Apr 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 9 Mar 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression Free Survival (time frame: 3 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01754376, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Apr 2017.

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