Background: IPI-549 is a first-in-class, oral, potent, and selective PI3K-γ inhibitor being developed as an immuno-oncology therapeutic in multiple cancer indications. Preclinical studies demonstrate a role for PI3K-γ in polarization of immune suppressive myeloid cells in the tumor microenvironment. Inhibition of PI3K-γ by IPI-549 enhanced antitumor immune responses and inhibited tumor growth in syngeneic solid tumor preclinical models. In addition, IPI-549 in combination with immune checkpoint inhibitors showed increased tumor growth inhibition compared to each single agent in multiple pre-clinical models. These data served as the scientific foundation for initiating a clinical trial testing IPI-549 as a potential immuno-oncology therapy. This first-in-human clinical study will evaluate the safety and tolerability, and determine the recommended Phase 2 dose (RP2D) of IPI-549 when administered as a monotherapy and in combination with an anti-PD-! antibody (NCT02637531) in solid tumors.
Methods: This multi-part Phase 1/1b open-label trial will initiate with monotherapy dose escalation cohorts consisting of an accelerated dose escalation phase followed by a standard phase with a 3+3 design. Evaluation of the PK, PD, and safety data in these cohorts will lead to the determination of the maximum tolerated dose (MTD) and RP2D of IPI-549 monotherapy. Subsequently, combination dose escalation cohorts will be initiated in which the combination of IPI-549 and anti-PD-! antibody will be evaluated. Expansion cohorts evaluating the safety, PK, PD, and preliminary clinical activity of IPI-549 as a monotherapy and in combination with an anti-PD-1 antibody will occur following the dose escalation phase.
All subjects in the trial will have advanced and/or metastatic carcinoma or melanoma, and will have failed to respond to standard therapies. Combination expansion cohorts will recruit subjects with non-small cell lung cancer or melanoma who must have received an anti-PD-1 or anti-PD-L1 antibody as their most recent treatment.
This trial is currently enrolling patients in the US. To date, 6 patients have been enrolled and dose escalation is continuing (updated data to be presented).
Citation Format: Anthony Tolcher, David Hong, Ryan Sullivan, James Mier, Geoffrey Shapiro, Joseph Pearlberg, Les Brail, Jahnavi Kharidia, Lixin Han, Claudio Dansky Ullmann, Howard M. Stern, Jedd D. Wolchok. IPI-549-01: A Phase I/Ib first in human study of IPI-549, a PI3K-γ inhibitor, as monotherapy and in combination with an anti-PD-1 antibody in subjects with advanced solid tumors [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B070.
- ©2016 American Association for Cancer Research.