University of Pittsburgh Cancer Institute (UPCI)

Melanoma Clinical Trials

Clinical TrialsWithin UPCI's Melanoma Program (MP) is a multidisciplinary clinical team of medical oncologists, dermatologists, surgical oncologists, radiotherapists, and behavioralists. Surgical subspecialists from multiple disciplines collaborate to accomplish the initial resection or ablation of disease at various primary sites. The mapping of lymphatic drainage from primary sites is routine for intermediate risk melanomas, with the objective of identifying sentinel lymph node(s) (SLN) and planning appropriate follow-up, screening, prevention, and interventions.

The initial assessment of each new primary melanoma patient includes state-of-the art genetic and proteomic profiling in the context of studies designed to identify molecular signatures of melanoma behavior (prognostic risk markers) and sensitivity to therapies (predictive biomarker profiling). The association of atypical (dysplastic) moles with melanoma has prompted the development of a series of studies to identify early risk markers and potential precursors of melanoma. Studies within the MP are also testing the role of nutritional substances (e.g., sulforaphane) that may prevent or reverse the abnormalities in atypical moles associated with melanoma.

For patients with operable, deep primary melanomas or operable lymph node disease, the MP developed the first and only effective FDA-approved immunotherapy treatment (high-dose interferon alfa-2b) that, when given post-surgery (as an adjuvant therapy), reduces the risk of relapse and death. The MP has developed new immunotherapies that may provide greater benefits and less side effects, which are being evaluated in national clinical trials led by UPCI's MP.

For patients with inoperable, advanced melanoma, the recent discovery that both immunotherapies and molecularly targeted therapies provide significant survival-improving benefits has led to a variety of clinical trials which seek to increase and improve the benefits of these treatments for advanced melanoma. The MP has developed molecular inhibitors of multiple melanoma-driving genes (e.g., BRAF, MEK, ERK). Importantly, the recently FDA-approved small molecule inhibitor of BRAF, called vemurafenib, represents the first generation of such therapies being developed and implemented in combination with inhibitors of other genes, both in the same cell signaling pathway (e.g., MEK, ERK) and in other pathways (e.g., AKT, mTor) that may cooperate to drive melanoma progression and may contribute to acquired resistance to therapies aimed against them.

One of the most remarkable recent advances is the discovery that BRAF inhibitors are effective in treating brain metastases, as well as extracranial metastatic melanoma, both of which have historically portended poor prognosis and represented significant hurdles to disease management and cure for patients with advanced metastatic melanoma. This discovery has spurred multiple studies of the effects of newer BRAF inhibitors (e.g., dabrafenib) to evaluate their effectiveness as a treatment for melanoma patients with brain metastases, a population which, despite their crucial need for effective therapies, has historically been excluded from most clinical trials. These important studies will be conducted in the International Melanoma Working Group (IMWG), which was founded and led since 2006 by members of the UPCI MP in collaboration with leaders of major melanoma programs of other prominent cancer centers throughout the world.

The MP's demonstrated translatable immunobiology research has enabled the program to take the lead in developing novel combinations of immunotherapies, such as IFN and anti-CTLA4 blocking antibody, ipilumumab, in phase II trials within UPCI (05-125) and nationally (E3611). These trials have yielded promising results that show improved disease control and survival of melanoma patients treated with these immunotherapy combinations. UPCI's MP faculty is currently leading clinical trials to confirm and extend these results in national cooperative groups. It is the hope and belief of the MP that these trials will lead to more immediately effective and durable treatments for melanoma patients and an improved understanding of the biological basis of the added benefits and the potential side effects of new combinations of immunotherapy.

Newly identified antibody inhibitors to immune checkpoints (e.g., PD-1) are being tested in several trials currently active at UPCI's MP and build upon the success of ipilimumab. In addition, clinical trials establishing the efficacy of combinations of small molecule inhibitors of BRAF (i.e., vemurafenib) and immunotherapy are underway, with the intent of combatting the opposite limitations of each while maximizing the benefits of each (i.e., accurate prediction of patient responders and induction of rapid and dramatic responses, in the case of molecularly targeted agents, and induction of durable responses, including complete responses that may span decades instead of months, in the case of immunotherapy) to complement one another and provide optimal outcomes for melanoma patients.

UPCI's MP has rigorously researched the role of chemotherapy, the oldest established therapy of advanced melanoma, in the context of the evolving melanoma treatment landscape. Drawing on increased understanding of its mechanisms of action and resistance, MP members have made significant strides in the development and design of strategies to improve and extend the positive effects of chemotherapy for melanoma. Towards this end, MP has developed agents that modify the expression of various genes implicated in drug resistance (epigenetic gene regulation), which have demonstrated enhanced anti–tumor effects when given with currently available chemotherapy agents for melanoma. This approach is being studied in order to develop new methods to improve and extend the benefits of chemotherapy in patients with inoperable, advanced melanoma.

Selected Publications

  • A phase II study was conducted to test the hypothesis that the combination of tremelimumab and high dose interferon alfa-2b (HDI), acting via different and possibly synergistic mechanisms, would overcome tumor immune tolerance and lead to significant and durable clinical responses. Out of 35 patients, four had complete responses, five had partial responses, and fourteen had stable disease that lasted up to 21 months. The median progression-free survival was 6.4 months, and the median overall survival was 21 months. Overall, it was found that HDI can be administered combined with tremelimumab with acceptable toxicity and promising durable antitumor efficacy. (Tarhini et.al., J Clin Oncol. 2012;30(3):322-8).
  • During the past 3 decades, the field of clinical research for the treatment of advanced melanoma lacked significant advances. Available drugs had low antitumor activity and no proven benefit in overall survival. Recently, new drugs developed based on an in-depth understanding of the biology of this disease have shown significant benefit. This rapid introduction of new active agents is likely to challenge current notions on how to develop future agents for the treatment of melanoma. In this perspective article, we illustrate the challenges in the choice of endpoints for registrational trials in metastatic melanoma and that, with an improved understanding of the agent being developed, the design of the registrational programs can be informed by earlier mechanistic studies to define the assumptions for definitive clinical testing. (Ribas et.al., Clin Cancer Res. 2012;18(2):336-41).
  • A phase 3, randomized clinical trial was performed to compare treatment with the BRAF kinase inhibitor vemurafenib (PLX4032) versus dacarbazine in patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. We found that vemurafenib produced improved rates of overall (84% vs. 64% of dacarbazine-treated patients) and progression-free survival in this cohort. (Chapman et.al., N Engl J Med. 2011;364(26):2507-16).

Members

Butterfield, Lisa, PhD
Medicine
Rao, Uma, MD
Pathology
Falo, Louis, MD, PhD
Dermatology
Storkus, Walter, PhD
Dermatology
Ferris, Laura, MD, PhD
Dermatology
Tarhini, Ahmad, MD, PhD
Medicine
Ho, Jonhan, MD
Dermatopathology
Tawbi, Hussein, MD, PhD
Medicine
Kirkwood, John M., MD
Medicine
Zarour, Hassane, MD
Medicine, Dermatology
Lin, Yan, PhD
Biostatistics