Allovectin-7 Immunotherapy Active in Metastatic Melanoma

NEW YORK—In patients with metastatic cutaneous melanoma who have already failed or are refractory to standard treatment, Allovectin-7, a targeted gene therapy using a nonviral delivery system, can induce both local and systemic responses in tumors injected weekly, results of a multicenter phase II study suggest.

The overall response rate was 14% for evaluable patients, all of whom had stage III or IV disease and had received one or more doses of the treatment. Overall response rate among the intent-to-treat population (77 patients) was about 10%, Ronald Blum, MD, reported at a late-breaking developments session at the Chemotherapy Foundation Symposium XIX.

The toxicity profile for Allovec-tin-7 was "excellent," said Dr. Blum, director of the Cancer Center at Beth Israel Medical Center, New York.

Allovectin-7 is a DNA/lipid complex that contains the human gene encoding HLA-B7 and beta-2 microglobulin, both of which are thought to be downregulated in a number of melanoma patients. The complex is designed to be injected into malignant tumors, which absorb it and express the HLA-B7 antigen.

"The excellent toxicity profile, the ease of manufacture, and routine treatment administration suggest that Allovectin-7 may offer advantages over current modalities of therapy in select subsets of patients," Dr. Blum said.

The phase II study included 78 patients with refractory or relapsed stage III or IV melanoma. The lipid/DNA complex was administered by intratumoral injection into a single tumor lesion weekly for 6 weeks, followed by a 4-week "hiatus" for observation. Additional 10-week treatment cycles (6 weeks injection, 4 weeks hiatus) could continue for patients who were stable or responding.

Response Rate

The overall response rate for injected tumors in 57 evaluable patients (those who had completed one full cycle without progressive disease) was 14%, including two complete responses and six partial responses (median duration of response, 20 weeks). Stable disease was noted for another 17 patients (30%).

"The response rates are there, and if you add them all up, including stable disease, there does seem to be significant tumor activity," Dr. Blum said.

The eight responses were all seen in patients with normal LDH. As is often the case in melanoma trials, females were more likely to respond than males,

Investigators also noted regression of noninjected distant metastases. Of the six partial responders, five had distant lesions that met objective criteria for shrinkage.

In one patient, a 53-year-old woman, the injected site (a subcutaneous metastasis) only regressed 14%, while four non-injected lesions regressed by greater than 50%. Duration of response in this patient was 6 months, with survival 20 months after initiation of therapy. Side effects included mostly injection site reactions (mild to moderate) and flu-like symptoms. All resolved rapidly and were seen most frequently upon first injection. "This is essentially a nontoxic compound," Dr. Blum said.

There was one serious adverse event related to injection (severe dizziness). Also reported were three drug-related serious adverse events (or less than 1% of all reported adverse events). These included abdominal pain and two ascites episodes, all in the same patient. Review of the case record suggested that these adverse events were possibly related to disease progression, not treatment.

Targeted therapy using DNA-based gene transfer is an attractive investigational approach in cutaneous melanoma, Dr. Blum said, particularly since there are no consistently effective therapies in advanced disease. Furthermore, available chemotherapy and nonspecific immunotherapies are associated with significant toxicity.

Allovectin-7 is different from other approaches to gene transfer because it is a "self-contained plasmid DNA" and does not use a viral gene delivery system, he said. Because there is no viral coat protein, there is no immune response to virus, and investigators have found no evidence of integration or replication of plasmid DNA.

"Nonviral DNA-based vectors appear to offer safety advantages compared to viral-based therapies," Dr. Blum said. "Because of the absence of viral protein, plasma DNA may be administered repeatedly."

In another phase II study currently underway, investigators are injecting up to five lesions, in doses 200 times higher than those used in the current trial, in patients with metastases limited to the lung. Investigators think higher doses and multiple injections may improve response rates.