Newly developed photosensitizer safe in patients with solid malignancy

Last Updated: 2016-08-15

By Will Boggs MD

NEW YORK (Reuters Health) - Disulfonated tetraphenyl chlorin (TPCS2a), a newly developed photosensitizer, appears to be safe for photochemical internalization of bleomycin in patients with solid malignancies, according to the results of a first-in-humans trial.

But the treatment turned out to be unexpectedly painful, although the pain dropped to "reasonable" levels after several hours, researchers report in The Lancet Oncology, online July 27.

"There is a light-mediated drug delivery system that enhances chemotherapy effects with minimal morbidity," Dr. Colin Hopper from University College London Hospitals in the U.K. told Reuters Health by email. "In particular, the treatment does not seem to damage nerves, so it is function sparing (as opposed to surgery) and it would seem to be repeatable (unlike radiotherapy)."

Photochemical internalization has been shown in in vitro experiments and in vivo models to enhance cellular uptake of chemotherapeutic agents, especially those like bleomycin that do not readily cross cellular membranes.

Dr. Hopper and colleagues examined the safety and tolerability of TPCS2a-mediated photochemical internalization of bleomycin in a phase 1 clinical trial of 22 patients with advanced or recurrent cutaneous and subcutaneous malignancies.

On the basis of the dose-limiting toxicity and maximum tolerated dose information, they selected an optimal dose of 0.5 mg/kg for further examination.

Administration of TPCS2a and the photochemical internalization treatment did not cause any negative direct effect on any of the monitored body organs, and there were no adverse events within the first 96 hours after TPCS2a injection before the administration of bleomycin and the initiation of the photochemical internalization treatment.

The only unexpected adverse event related to photochemical internalization was localized high pain levels (reported by nine patients), which began a few minutes after initiating the illumination procedure, started to decline one to two hours later, and returned to "reasonable" (clinically expected) levels at five to seven hours, the team reports.

TPCS2a remained detectable in blood 90 days after administration of all evaluable doses.

Overall, at day 28, 11 of 19 patients (58%) achieved complete responses, two patients (11%) achieved partial responses, two had stable disease, and one patient had progressive disease. Target lesions had completely resolved in all four patients in the 0.25 mg/kg cohort and in four of seven (44%) assessed patients in the 0.5 mg/kg cohort.

In patients with cutaneous malignancies, the malignant area turned necrotic after illumination, whereas the surrounding normal skin, although illuminated, remained intact. Results were similar in a patient with a subcutaneous malignancy.

The depth of therapeutic change (i.e., depth of necrosis achieved by photochemical internalization) appeared to be greater in the 0.5 mg/kg cohort than in the 0.25 mg/kg cohort, although the lower-dose cohort had a better overall effect (tumor therapeutic depth and complete response outcome) and fewer photosensitivity reactions, leading the researchers to recommend the 0.25 mg/kg dose for future trials.

"Many solid tumors are resistant to chemotherapy because of the way they metabolize agents," Dr. Hopper explained. "Photodynamic therapy (PDT) allows the negation of these effects and allows chemo drugs to hit their target. Hence, there should be applications to a number of solid tumors - in the study we looked at head and neck cancer, but also metastatic breast cancer and sarcoma and all showed extensive tumor necrosis."

"The obvious limitation is with systemic metastatic disease where photochemical internalization (PCI) can only really help with localized problems," he said.

The researchers note that a multicenter phase 2 trial in patients with head and neck cancer was terminated by the sponsor before being completed, mainly because of strategic commercial considerations. The company is proceeding with a phase 1-2 study using this technology to enhance the effect of gemcitabine in patients with bile duct cancer.

Dr. Steen Madsen from the University of Nevada in Las Vegas, who wrote an accompanying editorial, told Reuters Health by email, "Light-based therapies such as PCI have a role to play in the management of patients with superficial lesions."

"PCI could be of potential benefit to patients with superficial tumors, especially in the head and neck region," he said. "PCI may also play a role as a salvage therapy in cases where conventional treatments have been ineffective. Also, unlike radiation and chemotherapy, retreatments are possible with PCI."

"The excellent response of large tumors was surprising given the relatively limited penetration depth of light in biological tissues," Dr. Madsen said. "The authors postulate that this might be due to immune responses and certainly warrants further investigation in future studies."

Dr. Max Witjes from University Medical Center Groningen in the Netherlands, who has studied the enhancement of bleomycin cytotoxicity using PCI, told Reuters Health by email, "It is a proof of principle that photochemical internalization actually seems to work. I consider that an important step forward, because it provides the basis for new drug delivery strategies."

"When a new PCI strategy has proven to be successful it could grow to a worldwide industry with high turnovers," he said. "In skin cancer, which of course is a huge worldwide problem with millions of patients being diagnosed each year, PDT has evolved to a serious industry."

PCI Biotech of Norway sponsored the trial and employed one of the authors, Dr. Anders Hogset, as its chief scientific officer. Dr. Hogset could not be reached for comments.

SOURCE: http://bit.ly/2aOiqSL and http://bit.ly/2bi3rQf

Lancet Oncol 2016.