Investigational BCG-refractory NMIBC Tx shows promise

Intravesical recombinant adenovirus interferon alfa with Syn3 (rAd-IFNα/Syn3; Instiladrin) as treatment for high-grade non-muscle-invasive bladder cancer (NMIBC) patients who are unresponsive to bacillus Calmette-Guerin (BCG) demonstrated acceptable toxicity and a clinically meaningful durable response that has been maintained beyond 36 months in some patients when investigated in a phase II study.

The abstract reporting on the results of the open-label, multicenter trial was published online in the Journal of Clinical Oncology (Aug. 23, 2017). The study randomized patients equally into two groups to receive intravesical rAd-IFNα/Syn3 1 × 10¹¹ viral particles (vp)/mL or 3 × 10¹¹ vp/mL. Patients judged to have been cancer free at follow-up visits conducted at months 3, 6, and 9 were retreated at months 4, 7, and 10.

Results of the primary endpoint analysis showed that at 12 months, 14 (35%) of 40 treated patients were high-grade recurrence-free. The response rate was comparable in the two dose groups. In comparison, valrubicin (Valstar), the only treatment approved by the FDA for BCG-refractory disease, has been associated with a 12-month complete response rate of only 8% to 10%.

No patients in the phase II study developed a Grade 4 or 5 adverse event or discontinued treatment because of a drug-related adverse event. There were 10 Grade 3 adverse events that were considered to be serious, but of these, only one episode of diarrhea and one episode of acute renal failure secondary to a urinary tract infection were judged related to the study drug, and both issues resolved with medical therapy.

Urgency and frequency of micturition were the most common adverse events (40%), but they were generally minor, transient, and could be minimized by pretreatment with anticholinergics.

Next: Dr. Dinney discusses findings

“Intravesical immunotherapy with BCG remains frontline therapy for patients with HG NMIBC. Recurrence and progression are common as patients develop BCG-unresponsive disease, and there remains a critical unmet need for effective salvage therapy for BCG-unresponsive NMIBC to avoid cystectomy and improve disease-specific outcomes,” said principal investigator Colin P. N. Dinney, MD, of The University of Texas MD Anderson Cancer Center, Houston. “Intravesical rAd-IFNα/Syn3 gene therapy is one of several agents being evaluated in this space, and in this phase II trial it demonstrated promising efficacy and safety with a convenient dosing schedule. A phase III trial is now underway, and it is important that urologists support this and other studies so that together we can make progress in treating bladder cancer.”

Although monotherapy with intravesical IFNα is well tolerated and has demonstrated dose-related clinical effectiveness for treatment of NMIBC after BCG failure, its durability is insufficient.

“With conventional intravesical IFNα therapy, patients retain the instilled cytokine for no more than 1 to 2 hours, and there is limited local tumor exposure,” said Dr. Dinney.

“rAd-IFNα gene therapy is a breakthrough opportunity for effective local management of BCG-unresponsive NMIBC because it is formulated to allow the adenovirus to penetrate the cells that line the bladder. Once in the cells, the gene it contains causes expression of the therapeutic IFN protein in both normal and cancerous urothelial cells of the patient for up to 3 weeks. So when the cancerous cells are killed rapidly by the treatment, the healthy cells continue to produce the IFN, giving sustained treatment.”

He added, “The schedule for repeating treatment every 90 days is derived from results of preclinical studies showing that it resulted in higher and more protracted levels of expressed urine IFNα than other dosing regimens. Our own work in a phase Ib study found that rapidly repeating the treatment did not improve IFN production.”

Also see: Smoking linked to tumor heterogeneity for bladder Ca

The treatment involves intravesical delivery of 75 mL of fluid using a standard catheter with the patient positioned horizontally. The fluid is retained for 1 hour while the patient is rotated to achieve exposure of the whole bladder.

rAD-IFNα/Syn 3 is being developed with sponsorship from FKD Therapies Oy. The phase II and phase III trials are being conducted by the Society of Urologic Oncology Clinical Trials Consortium. The phase III study design also includes repeat treatments at 3-month intervals for responding patients and is analyzing high-grade recurrence-free survival at 12 months as the primary endpoint. The study has a planned 24-month duration.

The FDA issued guidelines for a single-arm registration trial for AD-IFNα for treatment of carcinoma in situ in the BCG-unresponsive population.

“It is possible that the label could be extended to include prophylaxis of papillary disease,” Dr. Dinney told Urology Times. “What trial and data are sufficient for registration, however, is a decision ultimately in the hands of the FDA.”

Dr. Dinney is independent chairman of the phase III Steering Committee sponsored by FKD and receives research support from the National Cancer Institute and the AIV Institute for Molecular Science.

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