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ORLANDO -- Interferon-based gene therapy led to 12-month recurrence-free survival in more than a third of patients with heavily pretreated nonmuscle-invasive bladder cancer (NMIBC), according to a study reported here.

Overall, 14 of 40 patients had high-grade recurrence-free survival (hgRFS) a year after treatment with recombinant adenovirus-linked interferon-alpha (rAd-IFNα/Syn3), including half of patients who had only papillary disease. A majority of patients who attained hgRFS at 3 months maintained the status at 12 months.

About 10% of patients had grade 3 treatment-emergent adverse events (TEAEs), but no grade 4 or 5 TEAEs occurred, and the only two treatment-related serious adverse events resolved with medical therapy, reported , of the Mayo Clinic in Rochester, Minn., at the Genitourinary Cancers Symposium.

"The next step will be a phase III, multicenter, open-label, single-arm trial in patients with BCG (bacillus Calmette-Guerin)-unresponsive nonmuscle-invasive bladder cancer," said Boorjian. "We have a target accrual of 135 patients, and patients who have a complete response at 3 months can be retreated at 3, 6, and 9 months. The primary endpoint is high-grade recurrence-free survival at 12 months. This trial is now open and accruing patients."

A single-arm phase III trial reflects the futility of efforts to find quality treatment for NMIBC that is unresponsive to or progresses during treatment with BCG. The FDA has not approved a new agent for NMIBC since 1998, , of Columbia University in New York City, said during a presentation that preceded Boorjian's report.

"BCG has a success rate of 50% to 65%, which is time dependent," said McKiernan. "Availability and toxicity are issues with the treatment. Radical cystectomy is an undesirable intervention from a quality-of-life perspective."

Efforts to develop new systemic options for BCG-unresponsive disease have encountered multiple barriers, McKiernan added, such as variable definitions of treatment failure; a heterogeneous disease state; "urologist unresponsive" disease (quality of resection influences drug response); and variable endpoints.

A produced by the American Urological Association and Society of Urologic Oncology, stated that after failure or progression of BCG "a clinician should offer radical cystectomy."

"That's about as emphatic a statement you can make that the standard of care for patients with disease that is refractory to BCG is surgical removal of the bladder," said McKiernan.

The only FDA-approved agent for BCG-unresponsive NMIBC is valrubicin (Valstar). The agent is approved for carcinoma in situ (CIS), and has a 1-year disease-free survival of 10%, Boorjian said. Multiple chemotherapeutic agents and combinations have been evaluated, but studies often have been limited by small numbers of patients and modest efficacy.

The rationale for evaluating IFNα begins with the protein's "pleiotropic antitumor effects," Boorjian continued. Studies of intravesical IFNα monotherapy showed insufficient durability, probably owing to inadequate exposure to the protein. Intravesical gene therapy might achieve sustained high levels of IFNα by inducing endogenous production by host cells.

The rationale led to development of the rAd-IFNα recombinant adenovirus with the syn 3 excipient to enhance adenoviral transduction of NMIBC cells. In preclinical models, rAd-IFNα/Syn3 induced regression of human bladder cancer, was associated with sustained high urinary levels of IFNα, and had no evidence of major toxicity.

A of rAd-IFNα/Syn3 demonstrated no dose-limiting toxicity or significant TEAEs, no rAd-IFNα-specific DNA in blood, and measurable levels of IFN in urine with all but the lowest dose evaluated. Subsequently, seven of 17 patients achieved a complete response at 3 months.

Boorjian reported findings from a phase II, multicenter, open-label trial of rAd-IFNα/Syn3 in patients with NIMBC that had progressed after treatment with BCG. The study population included patients with BCG-refractory disease (failure to achieve disease-free state at 6 months) and BCG-relapsed disease (recurrence within 1 year of complete response).

The 40 patients were randomized to two doses of rAd-IFNα/Syn3, and patients who attained a complete response could be retreated every 3 months up to month 12. The primary endpoint was 12-month hgRFS, as determined by biopsy. The goal was a 25% rate of 12-month hgRFS.

The patient population was predominantly male (33:7). The study group comprised 19 patients with relapsed disease and 21 with BCG-refractory NMIBC. Boorjian said 16 patients received three or more courses of BCG. A majority of the patients had CIS and nine others had a CIS component in their disease.

The efficacy data showed no difference in the overall 12-month hgRFS (35%) or the rate in patients treated with the lower doses of rAd-IFNα/Syn3 (33.3%) or the higher dose (36.8%). However, the higher dose was associated with a longer median time to high-grade recurrence (11.7 vs 3.5 months).

Boorjian said 23 of 40 patients achieved hgRFS at 3 months; 17 maintained the status at 6 and 9 months; 14 remained in high-grade relapse-free status at 12 months. The hgRFS status did not differ by patient age or sex or whether the patient had relapsed or refractory disease.

Significant urinary levels of IFNα-2b emerged by posttreatment day 2 in all patients, providing evidence of effective gene transfer. Levels of rAd-IFNα/Syn3 did not correlate with treatment dose or clinical response. Levels of serum IFNα-2b remained low throughout the study (including no measurable IFNα-2b in 31 of 40 patients and no measurable IFNα-2b DNA), suggesting systemic safety.

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