Novel Therapeutics for Melanoma

Nagashree Seetharamu; Patrick A Ott; Anna C Pavlick

Disclosures

Expert Rev Anticancer Ther. 2009;9(6):839-849. 

In This Article

Other Targeted Drugs Currently in Clinical Development

Bcl-2

One of the mechanisms for chemotherapy resistance in melanoma is thought to be the overexpression of Bcl-2, an anti-apoptotic protein that blocks the release of cytochrome C, a key player in the apoptotic cascade.[83] Oblimersen sodium (Genasense®, Genta International Inc.) is an 18-base phosphorothioate antisense oligonucleotide that binds the first six codons of the Bcl-2 mRNA open-reading frame and mediates RNA cleavage by RNase, thereby downregulating Bcl-2.[84] Based on the results of a Phase I/II study suggesting that the addition of oblimersen to dacarbazine might improve RRs and OS in patients with advanced melanoma without increasing toxicity,[85] a large Phase III trial of oblimersen in combination with dacarbazine compared with dacarbazine alone was conducted. Among 771 patients randomly assigned, the combination yielded a significant increase in RR (13.5 vs 7.5%) and a small improvement in PFS (2.6 vs 1.6 months), but only a trend toward improved survival at 24-month minimum follow-up (median: 9.0 vs 7.8 months).[86] Interaction between baseline serum lactate dehydrogenase and treatment was observed: In patients with normal serum lactate dehydrogenase, survival was significantly increased with the addition of oblimersen (median OS: 11.4 versus 9.7; p = 0.02). This observation is now being tested prospectively in a Phase III trial. At our institution, the combination of Nab-paclitaxel (paclitaxel protein-bound particles for injectable suspension), temozolomide and oblimersen is currently being investigated in a Phase I/II trial and has shown encouraging clinical activity in an initial cohort of 14 patients.[87]

PARP Inhibitors

Poly-ADP ribose polymerase (PARP) is a key enzyme in DNA repair. Durkacz et al. noted as early as 1980 that ADP ribosylation is involved in DNA excision repair and that inhibition of the enzyme enhances the cytotoxicity of DNA-damaging agents.[88] PARP inhibition as novel targeted cancer therapy gained significantly more interest over recent years when preclinical data demonstrated its exquisite cytotoxic potential in BRCA-1- and -2-deficient cell lines. A number of PARP inhibitors are now in clinical trials in different cancers. In melanoma, PARP-1 overexpression has been reported as a marker for poor prognosis and preclinical data suggest that this enzyme is a potential therapeutic target.[89] AG014699 was the first PARP inhibitor to enter a clinical trial and was studied in combination with temozolomide, a DNA-methylating agent.[90] A Phase I study was completed in 2005 testing this combination in solid-tumor patients. This study concluded that the combination is safe and established the inhibitory dose of the PARP inhibitor using validated immunoblots to measure enzyme activity in both blood cells and tumor biopsies. It also established the maximum tolerated dose of AG014699 in combination with temozolomide.[90] A Phase II study testing the combination of temozolomide and AG014699, in which 40 chemotherapy-naive metastatic melanoma patients were recruited, was reported at the 2006 ASCO meeting.[91] Of the 20 evaluable patients, there were four confirmed PRs and four SDs. In this trial, markedly increased temozolomide-induced myelotoxicity was seen when full-dose temozolomide was used in combination with the PARP inhibitory dose of AG014699, necessitating a 25% dose reduction. The encouraging results of the study have led to the development of a number of PARP inhibiting agents that are now in various stages of clinical testing.

Antibody-drug Conjugate

Glycoprotein NMB (GPNMB) is overexpressed in a variety of cancers including melanoma. CR011-vcMMAE is an antibody-drug conjugate comprised of a fully human monoclonal antibody directed at the extracellular domain of GPNMB linked to a potent tubulin-destabilizing agent, monomethyl auristatin E (MMAE). The enzyme-sensitive linker is designed to be stable in the bloodstream and to release MMAE inside tumor cells, resulting in cancer cell death. Based on promising preclinical data,[92] a Phase I trial is being conducted on patients with advanced melanoma. The trial determined the maximum tolerated dose to be 1.88 mg/kg every 3 weeks and demonstrated dose-dependent anti-tumor activity.[93] Analysis of the pharmacokinetics has resulted in a more frequent dosing schedule. Dose escalations on a 2-week-on, 1-week-off, as well as a continuous weekly dosing schedule, are currently underway. Expansion into a Phase II study is planned once the ideal dose and schedule are identified.[98]

Antibodies Against Integrins

Integrins of the αv family, such as αvb3 and αvb5, are implicated in tumor-induced angiogenesis and are thought to play a role in tumor growth. CNTO 95 is a fully human monoclonal antibody directed against αv integrins, which has demonstrated anti-tumor and anti-angiogenic activities in animal models.[94] Results of a Phase I dose-escalating study to assess the safety and pharmacokinetics of CNTO 95 in patients with advanced refractory solid tumors demonstrated good tolerability at weekly doses of 10 mg/kg and anti-tumor activity.[95] A Phase I/II multicenter, randomized and double-blind study to assess the safety and efficacy of CNTO 95, alone and in combination with dacarbazine, in stage IV melanoma patients has been completed and results are pending.[99]

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