A new multi-center trial of high dose Interleukin-2 (HD rIL-2; Aldesleukin for Injection/Proleukin?; Prometheus Laboratories Inc, San Diego, CA/Novartis Vaccines and Diagnostics, Emeryville, CA)[1] plus vemurafenib (Zelboraf?, Genentech/Roche) therapy in patients with BRAFV600mutation-positive metastatic melanoma (mM) is enrolling patients. In the Proclivity-01 trial (NCT01683188)[A] HD rIL-2 therapy is administered in specialized hospitals as inpatient therapy while vemurafenib is given as an oral outpatient therapy. The Phase IV study is currently open in 12 sites and will be conducted in approximately 25 sites in the United States.

While skin cancer is the most common of all cancers melanoma accounts for less than 5% of skin cancer cases. However, of al skin cancers, melanoma causes the most skin cancer related deaths. The number of new cases of melanoma in the United States has been increasing for at least 30 years.According to the American Cancer Society, an estimated 76,690 new cases of metastatic melanoma will be diagnosed this year with 9,480 Americans expected to die of the disease.[1]

Immune-based therapy: meaningful responses
“Metastatic melanoma is a rapidly progressing cancer for which approved systemic therapy has been limited until the past 2 years,” explained James Lowder, MD, Senior Director of Oncology Clinical Development and Medical Affairs at Prometheus. “Immune-based therapy with the FDA-approved HD IL-2 has long been shown to produce meaningful and durable responses in a small percentage of patients with metastatic melanoma.[3] The recently FDA-approved vemurafinib produces rapid, but temporary, reductions in tumor size in a majority of patients with an activating mutation of the BRAF signaling protein. The rationale for this trial is based on data suggesting that the activity of vemurafenib and rIL-2 is potentially synergistic.”[4]

Interleukin-2 or IL-2 is a naturally occurring cytokine protein and plays an important role in activating the immune system. Proleukin or Aldesleukin is a recombinant version of IL-2 (rIL-2). The drug possesses the same properties as naturally occurring IL-2 and, when administered to patients with metastatic melanoma (mM) and metastatic kidney cancer (mRCC), activates the immune system to recognize and eliminate cancer cells. rIL-2 has been used for over 15 years in mM and over 20 years in the treatment of mRCC. Complete plus partial response rates were 15% in mRCC patients and 16% in mM patients.

Treatment Schedule
The open-label, two-arm study is enrolling mM patients with BRAFV600oncogene mutations. Patients will initially receive treatment with vemurafenib sequenced with two courses of HD IL-2. Cohort one, on which the study’s statistics are based, will consist of 135 patients naive to vemurafenib and HD IL-2 therapy. These patients will be initially treated with 6 weeks of vemurafenib alone followed by two courses of HD IL-2 sequenced with continued vemurafenib. Cohort two patients will have received 7-18 weeks of vemurafenib prior to adding HD IL-2 and can be enrolled after starting vemurafenib. The second cohort will explore the effect of more prolonged vemurafenib treatment on adverse events and efficacy.

Importance of study
“The importance of BRAF mutations in melanoma and the continuing increase in FDA approved agents with different mechanisms makes clinical trials studying the sequential administration of several agents vital,” said Stan Adler, a melanoma patient. “Combining immunotherapy with targeted therapy may both improve outcomes and personalize care for patients with metastatic melanoma.”

Primary Outcome Measures
The study’s primary endpoint is complete response (CR) at 26 weeks (+/-3 weeks) from the start of HD IL-2. Patient assessment of overall response rate (OSS), progression-free survival (PFS) and overall survival (OS) will be followed in the Proclaim study.

Advances in Understanding
“The past decade has been marked by significant advances in understanding the key molecular signaling events underlying the pathogenesis of melanoma,” explained Dr. Lowder. “We now know that the BRAFV600mutation is found in approximately 50% of melanomas, especially in younger individuals.[4] If, by combining BRAF inhibition with immunotherapy, we could improve the durable complete response rate over that seen with high-dose interleukin-2 alone, it would be viewed as a significant advance in the management of metastatic melanoma.”

For more information
[1] American Cancer Society. Cancer Facts & Figures 2013. Atlanta, GA: American Cancer Society; 2013.
[2] Proleukin (Aldesleukin for Injection). Prescribing Information (USA)
[3] Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin-2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999; 17:2105-16.
[4] Frederick DT, Piris A, Cogdill AP, et al. BRAF Inhibition Is Associated with Enhanced Melanoma Antigen Expression and a More Favorable Tumor Microenvironment in Patients with Metastatic Melanoma. Clin Cancer Res. 2013 Mar 1;19(5):1225-31. doi: 10.1158/1078-0432.CCR-12-1630. Epub 2013 Jan 10.
[5] Vemurafenib (Zelboraf?, Genentech) Highlights of Prescribing Information

Clinical Trials
[A]NCT01683188 – HD IL-2 + Vemurafenib in Patients With BRAF Mutation Positive Metastatic Melanoma (PROCLIVITY-01)

Other Clinical Trials with HD rIL-2 + Vemurafenib
NCT01659151 – Vemurafenib With Lymphodepletion Plus Adoptive Cell Transfer & High Dose IL-2 Metastatic Melanoma
NCT01585415 – Vemurafenib and White Blood Cell Therapy for Advanced Melanoma
NCT01754376 – Combined BRAF-Targeted Therapy & Immunotherapy for Melanoma

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