Melanoma Clinical Trials
Within Hillman'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 Hillman's MP. UPMC Hillman Cancer Center has also led the national adjuvant studies of new anti-CTLA-4 blocking antibodies conducted in the ECOG ACRIN cooperative group, and has participated in the development of anti-PD1 antibodies that are ongoing.
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 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 Hillman 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 UPMC Hillman Cancer Center (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. Hillman'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 Hillman'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.
The development of vaccines to induce and strengthen immune resistance to melanoma has been a longstanding goal of the MP, and our current trials in the context of the Specialized Program of Research Excellence (SPORE) in Melanoma and Skin Cancers is developing two new approaches to vaccination of patients with melanoma and cutaneous T cell lymphoma. The development of specific vaccines in combination with the immunostimulants and other immunotherapies under investigation in the MP is an ongoing theme of the program.
Hillman's MP has previously 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 role 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.
- Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade with ipilimumab prolongs survival in patients with metastatic melanoma. CTLA-4 blockade and granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccine combinations demonstrate therapeutic synergy in preclinical models. A key unanswered question is whether systemic GM-CSF (sargramostim) enhances CTLA-4 blockade. Results show that among patients with unresectable stage III or IV melanoma, treatment with ipilimumab plus sargramostim vs ipilimumab alone resulted in longer overall survival and lower toxicity, but no difference in progression free survival. (Hodi et. al., JAMA. 2014 Nov 5;312(17):1744-53.)
- Recent phase III trials have shown an overall survival benefit in metastatic melanoma. After screening 1649 reports and meeting abstracts, 12 eligible randomized trials were identified that enrolled 4416 patients with metastatic melanoma. Irrespective of weighting strategy, a strong correlation between the treatment effects for progression free survival (PFS) and overall survival was noted, which seemed independent of treatment type. It was concluded that PFS can be regarded as a robust surrogate for overall survival in dacarbazine-controlled randomized trials of metastatic melanoma, and postulated that this association will hold as treatment standards evolve and are adopted as the control arm in future trials. (Flaherty et. al., Lancet Oncol. 2014 Mar;15(3):297-304.)
- High-dose interferon (IFN) for 1 year (HDI) is the US FDA-approved adjuvant therapy for patients with high-risk melanoma. Efforts to modify IFN dose and schedule have not improved efficacy. Results now show that a shorter course of biochemotherapy (dacarbazine, cisplatin, vinblastine, interleukin-2, IFN alfa-2b and granulocyte colony-stimulating factor given every 21 days for three cycles) provides statistically significant improvement in relapse free survival but no difference in overall survival and more toxicity compared with HDI for patients with high-risk melanoma. (Flaherty et. al., J Clin Oncol. 2014 Nov 20;32(33):3771-8.)
- The use of graded-dose peginterferon α-2b (Peg-IFN) in patients with stage IV melanoma overexpressing basic fibroblast growth factor (FGF-2) was investigated, with primary objective being suppression of plasma FGF-2 to within reference range (≤ 7.5 pg/mL). Results showed that graded-dose Peg-IFN suppresses FGF-2 in patients with metastatic melanoma who overexpress FGF-2. Over one third of patients had complete suppression of plasma FGF-2, which correlated with clinical response to this therapy. (Go et. al., Clin Cancer Res. 2013 Dec 1;19(23):6597-604.)
| Butterfield, Lisa, PhD
| Kirkwood, John, MD|
|Davar, Diwakar, MD
|Lin, Yan, PhD|
| Falo, Louis, MD, PhD
|Rao, Uma, MD|
|Ferris, Laura Korb, MD, PhD
| Storkus, Walter, PhD|
|Ho, Jonhan, MD
|Zarour, Hassane, MD|
|Holtzman, Matthew, MD