Advances in skin cancer R&D

The last week has seen notable advances in the field of skin cancer research and development, including the initiation of Plexxikon's pivotal Phase III trial of PLX4032 in patients with metastatic melanoma (MM), detailed results of Biofrontera's Phase III comparative study of BF-200 ALA for the treatment of actinic keratosis (AK) and a new study from Stanford University suggesting that an anti-inflammatory prescription drug can reduce the risk of a common skin cancer in humans.

Enrolment has been initiated and the first patient has been dosed in the pivotal Phase III trial of PLX4032, a novel, oral and highly-targeted drug that is designed to inhibit the BRAF cancer-causing mutation that occurs in approximately 50 per cent of melanomas. The randomised, controlled trial, called BRIM3 (BRAF Inhibitor in Melanoma), in previously-untreated patients is part of the planned registration programme for PLX4032. With some tumour shrinkage in nearly all mutation-positive melanoma patients, and 70 per cent of patients achieving at least 30 per cent tumour shrinkage in the company's most recent clinical study, PLX4032 has shown meaningful antitumour activity. BRIM3 is expected to enrol approximately 700 previously-untreated melanoma patients who will be randomised 1:1 with PLX4032 960mg twice daily or dacarbazine.

Separately, detailed results of Biofrontera's Phase III comparative study have confirmed the superiority of BF-200 ALA over Photocure's Metvix (methylaminolevulinate) for the treatment of AK. Patients were treated by photodynamic therapy, combining one of the test compounds or a placebo with a brief red light illumination. With different types of red light sources, BF-200 ALA on average erased all lesions in 78 per cent of the patients, whereas the registered comparator, methylaminolevulinate, only reached a complete healing rate of 64 per cent, and the placebo group of 17 per cent.

Further, according to researchers at Stanford University School of Medicine, a widely-available anti-inflammatory prescription drug can reduce the risk of a common skin cancer in humans. The scientists believe that although oral administration of celecoxib is associated with an increased risk of myocardial infarction and stroke in some people, it is possible that topical application could have a safer, protective effect for people prone to developing basal cell carcinomas (BCCs). The investigators dovetailed studies in mice with a randomised, double-blind, Phase II trial to reach their conclusions.

The researchers enrolled 60 people with a genetic predisposition to BCC in a three-year trial. Approximately half of the patients received celecoxib 200mg twice daily in a tablet format, while the others received a placebo. All patients were monitored at three-month intervals at one of four study sites for the development of new BCCs or the growth of previously-identified cancers. They found that, although both groups continued to develop new cancers during the study, oral celecoxib treatment decreased the growth of skin tumours by approximately 50 per cent, as compared to placebo, in participants who entered the trial with 15 or fewer BCCs. Celecoxib treatment also reduced the overall tumour burden in this group of patients.

Alice Rossiter
Editor, Cancer Drug News

Synta suspends SYMMETRY study

Based on an analysis by an independent Data Monitoring Committee (DMC), Synta Pharmaceuticals has suspended the Phase III SYMMETRY (Synta Metastatic Melanoma Elesclomol Trial) trial, which was comparing elesclomol (STA-4783) in combination with paclitaxel to paclitaxel alone in chemotherapy-naïve patients with Stage IV metastatic melanoma. Following the suspension, shares in Synta fell from US$6.39 at the end of 26th February to close on 27th February at US$1.36, a decrease in value of nearly 79 per cent.

The decision was based on the results of an analysis by the DMC, which identified safety concerns, including an imbalance in overall survival, with a greater number of deaths occurring in the combination arm (elesclomol+paclitaxel) compared to the control arm of paclitaxel alone. The final analysis of the primary endpoint (progression-free survival) as assessed by independent reviewers has not been carried out yet. Elesclomol is an apoptosis stimulator, which acts by inducing oxidative stress in cancer cells by rapidly producing reactive oxygen species. Response to this oxidative stress leads to apoptosis.

Based on these findings, Synta has also revealed that additional ongoing studies with elesclomol, including a study of elesclomol in combination with docetaxel in hormone-refractory metastatic prostate cancer and a monotherapy dose-escalation study, will be suspended pending further analysis of the results of the SYMMETRY trial. Synta is contacting investigators regarding appropriate patient notification and care. The company is also in discussions with its collaborator, GlaxoSmithKline, about the future development of elesclomol. However, it looks likely that GSK will terminate the collaboration.

Such a huge setback could spell the end for Synta, especially in the current economic climate. However, the company has stated that it has both the resources and a diverse pipeline of novel drug candidates in the oncology and anti-inflammatory areas that will allow it to continue operating. The company has recently received two milestone payments that should help its current cash position. These include an up-front payment of US$16 million from Roche for the development of the Synta CRACM (calcium release-activated calcium modulator) programme for the treatment of inflammatory and autoimmune diseases, as well as committed research funding of US$9 million over the next two years. The second payment of US$10 million was received from GSK after Synta achieved a milestone related to the development of elesclomol.

Synta's pipeline includes: STA-9090, a novel heat shock protein 90 inhibitor that is currently in two Phase I studies in solid tumours; STA-5326 (apilimod mesylate), an oral interleukin (IL)-12/IL-23 inhibitor currently in a Phase IIa study in rheumatoid arthritis; STA-9584, a vascular disrupting agent for cancer in preclinical development; and additional programmes in the research and preclinical development stages. Synta shareholders will hope that these programmes prove more successful than elesclomol.

Matthew Dennis - Editor, Cancer Drug News