FDA Grants IPI-549 Fast Track Designation in Urothelial Carcinoma

Jason M. Broderick

Infinity CEO Adelene Perkins

Adelene Perkins

The FDA has granted a Fast Track Designation to IPI-549 for use in combination with nivolumab (Opdivo) for the treatment of patients with advanced urothelial cancer, according to Infinity Pharmaceuticals, Inc., the manufacturer of the PI3K-gamma inhibitor.1

The designation will expedite the development and review of IPI-549 in this setting. Infinity is collaborating with Bristol Myers Squibb on the phase II MARIO-275 trial, which is currently enrolling. The global, randomized trial is evaluating the IPI-549/nivolumab combination in immunotherapy-naive patients with platinum-refractory, advanced urothelial carcinoma.

"Receiving Fast Track designation is an important recognition of the significant unmet need in advanced urothelial cancer and reflects the potential for IPI-549, in combination with Opdivo, to improve outcomes for these patients," said Adelene Perkins, chief executive officer and Chair of Infinity Pharmaceuticals, said in a press release.

"A retrospective analysis of Bristol Myers Squibb’s Checkmate-275 accelerated approval study of Opdivo monotherapy in patients with urothelial cancer revealed an important association between high baseline levels of myeloid derived suppressor cell (MDSC) and poor overall survival. These data, combined with our MARIO-1 data that showed IPI-549, both as a monotherapy and in combination with Opdivo treatment, is associated with a reduction in blood MDSC levels, inspired our MARIO-275 study with the goal of improving outcomes for urothelial cancer patients," added Perkins.

The global phase II MARIO-275 trial is randomizing patients with advanced urothelial carcinoma in a 2:1 ratio to IPI-549/nivolumab or placebo/nivolumab. Patients cannot have received prior checkpoint-inhibitor therapy and must have progressed or recurred following treatment with platinum-based chemotherapy. The targeted enrollment is 160 patients. The primary endpoint is objective response rate, with secondary endpoints including time to response, duration of response, and progression-free survival.

Early data from a phase I/Ib trial (NCT02637531) of IPI-549 plus nivolumab in solid tumors were presented at the 2018 ASCO Annual meeting.2 The study included 30 evaluable patients with advanced solid tumors. The median age was 57 years and the median number of prior therapies was 4.

In a 6+6 design, patients were administered IPI-549 at 20-, 30-, or 40-mg daily in combination with nivolumab at 240 mg every 2 weeks. The maximum-tolerated dose was not reached. The investigators reported that the pharmacokinetics and pharmacodynamics of IPI-549 were not affected by nivolumab.

Partial responses were observed in 2 patients at the first assessment, which occurred 8 weeks after treatment. One occurred in a patient with adrenocortical carcinoma who received a 30-mg dose of IPI-549. The other occurred in a patient with microsatellite-stable gallbladder carcinoma who was treated with the 40-mg dose. Twelve (40%) patients were still on study at ≥12 weeks’ follow-up.

The majority of treatment-emergent adverse events (TEAEs) were grade 1/2. The most common TEAEs across all grades were rash (23%); pruritus (10%); and nausea, anemia, ALT increase, AST increase, and pyrexia (6% each). Dose-limiting toxicities occurred at IPI-549 30 mg (grade 3 rash) and IPI-549 40 mg (grade 3 rash; grade 3 ALT/AST increase). There were no treatment-related deaths. The recommended phase II dose was determined to be 40 mg of IPI-549.

In their poster presented at the ASCO meeting, the researchers also noted that, “On-treatment blood samples showed evidence of immune activation and reduced immune suppression, including upregulation of IFNg-responsive factors, such as PD-L1 and CXCL9/10, and dose-dependent re-invigoration/proliferation of exhausted PD1+CD8+CD45RA- T cells, evidenced by Ki67 increases.”


  1. Infinity Receives Fast Track Designation for IPI-549 in Combination with the Checkpoint Inhibitor Opdivo for the Treatment of Advanced Urothelial Cancer. Published online March 25, 2019. https://yhoo.it/2vOFts9. Accessed March 25, 2019.
  2. Sullivan RJ, Hong DS, Tolcher AW, et al. J Clin Oncol 36, 2018 (suppl; abstr 3013) doi: 10.1200/JCO.2018.36.15_suppl.3013.
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