Biolyse Pharma is based in Canada, performing its research and developing its products within the country. In 1994, the Canadian Federal Health Protection Branch (HPB) authorized the use of clinical trials to test Paclitaxel for Injection, and in 2001, a Notice of Compliance was issued to Biolyse by Health Authorities.
ONGOING CLINICAL RESEARCH
Previous trials with paclitaxel have pointed towards its use in first, early intervention or possibly in combination with other anticancer agents. Biolyse’s most recent study therefore involves just such an application. In this vein of research, paclitaxel is applied in combination with radiotherapy, used in patients whose cancer has metastasised to the brain.
The mode of action of paclitaxel is unique in that it acts at the cellular level, binding preferentially to microtubules whose action is crucial during cell division. This binding of paclitaxel to microtubules prevents their dissolution and reorganisation, blocking the cells in what are referred to as the G2 and M stages of the cell division cycle. These two phases of the cell cycle are the most sensitive to radiation, so it was theorised that paclitaxel may be a potent “radiosensitizing” agent (i.e. paclitaxel and radiation may boost each other’s effectiveness against cancer cells) (2,5). This theory was demonstrated in vitro, and was approved by an ethics committee at the University of Western Ontario for clinical trials with volunteer patients.
The purpose of our Phase I study is to identify through dose escalation, the maximum amount of paclitaxel which can be safely delivered together with standard radiation therapy, in patients with brain metastases from NSCLC (non-small-cell lung cancer). Additionally, the Phase I trials propose to determine any toxic effects of Paclitaxel given concurrently with radiotherapy. In this open study, escalation of the paclitaxel is achieved by first increasing the number of paclitaxel treatments over the two week course of radiation therapy, then by increasing the dose of paclitaxel in each treatment. Keeping the safety of the patients in mind, the dosage levels are increased only after previous dosage levels are deemed tolerable.
Previous studies combining paclitaxel and radiation therapy have found varying maximum tolerated doses (MTD) in both in vitro and clinical trials. Glantz et al. found that they could successfully administer paclitaxel at 250mg/m2 /week to patients (3) . They stipulated however that patients with brain tumours often have pre-existing neurologic deficits, thus suggesting an optimum dose of 225mg/m2. Similar studies with cervical cancer patients found a 93% response rate to combined treatment using a much lower paclitaxel dosage of 50 mg/m2 /week (1), and in vitro studies with laryngeal carcinoma cells showed a remarkable sensitivity to even lower doses of the drug (2).
Two similar studies by Tishler et al. in 1992 found evidence that time seems to play a role in the concentration-dependent interactions of paclitaxel and radiation therapy (5,6). A fascinating in vitro study performed in Italy follows up on this idea, which has shown evidence that administering paclitaxel 24 hours before either a single radiation shot, or before three days of concomitant radiation had an additive effect to treatment (4). Administering paclitaxel 48 hours before a three day radiation treatment however had supraadditive interactions, which were obtained even with low paclitaxel and radiation doses. This has great promise for future clinical studies, indicating that with proper timing, the same effect can be reached with less toxicity and discomfort for the patient.
Biolyse has committed to fully exploring all the treatment combinations and options provided by paclitaxel, so that future studies at Biolyse will compare this and other combination therapies to the efficacy of radiation treatment alone. Not only will we focus on treating NSCLC, but other cancerous forms such as cervical, colon, ovarian, or breast that have shown early indications of having benefited from this new form of treatment.
- Chen, M.D., et al., 1997. Phase I trial of taxol as a radiation sensitizer with cisplatin in advanced cervical cancer. Gynecol Oncol, Nov;67(2):131-6.
- Elomaa, L., et al., 1995. Squamous cell carcinoma is highly sensitive to taxol, a possible new radiation sensitizer. Acta Otolaryngol, Mar;115(2):340-4.
- Glantz, M.J., et al., 1996. Phase I study of weekly outpatient paclitaxel and concurrent cranial irradiation in adults with astrocytomas. J Clin Oncol, Feb;14(2):600-9.
- Niero, A., et al., 1999. Paclitaxel and radiotherapy: sequence-dependent efficacy- a preclinical model. Clin Cancer Res, Aug;5(8):2213-22.
- Tishler, R.B., et al., 1992. Taxol sensitizes human astrocytoma cells to radiation. Cancer Res, Jun15;52(12):3495-7.
- Tishler, R.B., et al., 1992. Taxol, a novel radiation sensitizer. Int J Radiat Oncol Biol Phys, 22(3):613-617.