Clinical Trials

Date: 2017-04-01

Type of information: Presentation of results at a congress

phase: 1-1b

Announcement: presentation of results at the American Association for Cancer Research (AACR) Annual Meeting

Company: Infinity Pharmaceuticals (USA - MA)

Product: IPI-549

Action mechanism: phosphoinositide 3-kinase (PI3K) inhibitor. IPI-549 is an orally administered immuno-oncology development candidate that selectively inhibits phosphoinositide-3-kinase gamma (PI3K-gamma), for the treatment of solid tumors. IPI-549 inhibits immune suppressive macrophages within the tumor microenvironment, whereas other immunotherapies such as checkpoint modulators more directly target immune effector cell function. As such, IPI-549 may have the potential to treat a broad range of solid tumors and represents a potentially complementary approach to restoring anti-tumor immunity in combination with other immunotherapies such as checkpoint inhibitors.

Disease: advanced solid tumors

Therapeutic area: Cancer - Oncology

Country: USA

Trial details: This dose-escalation study will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of IPI-549 monotherapy and IPI-549 in combination with nivolumab in subjects with advanced solid tumors. The study includes monotherapy and combination dose-escalation phases, in addition to expansion cohorts, and is expected to enroll approximately 175 patients. (NCT02637531)

Latest news:

• • On April 1, 2017, Infinity Pharmaceuticals reported updated Phase 1 clinical data for IPI-549. These Phase 1 clinical dose-escalation data demonstrated that IPI-549 was well tolerated both as a monotherapy and in combination with Opdivo® (nivolumab). Additionally, data from the more advanced monotherapy module of the study showed IPI-549 has a favorable pharmacokinetic and pharmacodynamic  profile that supports once daily dosing. The data included 15 evaluable patients who received IPI-549 as a monotherapy and six evaluable patients who received IPI-549 in combination with Opdivo®. The data were presented at the American Association for Cancer Research (AACR) Annual Meeting 2017. IPI-549 is believed to be the only selective PI3K-gamma inhibitor in clinical development. The Phase 1 study includes dose-escalation and expansion modules to evaluate IPI-549 as a monotherapy and in combination with Opdivo®. Patient enrollment is complete in five monotherapy does-escalation cohorts with doses of IPI-549 ranging from 10 mg QD to 40 mg QD. Patient enrollment is also complete in two combination dose-escalation cohorts to evaluate IPI-549 20 mg and 30 mg QD in combination with Opdivo®. Infinity expects to complete the monotherapy dose-escalation phase of the study in the first half of 2017 and initiate the monotherapy expansion module in the second half of the year. The company also expects to complete the dose-escalation phase evaluating IPI-549 in combination with Opdivo® and subsequently initiate a combination expansion module in the second half of 2017. The combination expansion module will include patients with non-small cell lung cancer (NSCLC), melanoma, and squamous cell carcinoma of the head and neck (SCCHN) whose tumors show initial resistance or subsequently develop resistance to immune checkpoint therapy. The updated Phase 1 clinical data presented in the educational session will be further detailed in a poster being presented during a poster session taking place at the AACR Annual Meeting 2017 (IPI-549-01 - A Phase 1/1b, First-in-Human Study of IPI-549, a PI3K-Gamma Inhibitor, as Monotherapy and in Combination with Nivolumab in Patients with Advanced Solid Tumors - Abstract number: CT089) In a presentation entitled "Reprogramming Tumor-Associated Macrophages by Targeting PI3K-Gamma through a Small Molecule Approach," Jeffery Kutok , M.D., Ph.D., chief scientific officer at Infinity, discussed the preclinical rationale for targeting PI3K-gamma previously reported in two publications in Nature and summarized updated clinical data from the Phase 1 study of IPI-549 in patients with advanced solid tumors. The clinical data reported today from a March 20, 2017 , data cutoff included 15 evaluable patients who received monotherapy doses of IPI-549 ranging from 10 mg to 40 mg QD and six evaluable patients who received IPI-549 20 mg QD in combination with Opdivo. Summary of Updated Phase 1 Data : The updated data from the monotherapy dose-escalation module demonstrated that IPI-549 treatment was well tolerated. Among the 15 evaluable patients, no dose limiting toxicities or serious drug-related side effects occurred, and no side effects led to treatment discontinuation or dose reduction. The PK and PD properties of IPI-549 appeared favorable, with near-complete and sustained inhibition of PI3K-gamma at doses at or above 20 mg QD, supporting once daily dosing of IPI-549. Of the 15 evaluable patients, six have remained on treatment for at least 24 weeks, and three patients have remained on treatment for more than 32 weeks. The monotherapy dose-escalation module is ongoing to determine the optimal dose for the monotherapy expansion cohort. Preliminary data from the combination dose-escalation module evaluating 20 mg IPI-549 in combination with Opdivo demonstrated that the treatment regimen was well tolerated. Among the six evaluable patients, no dose limiting toxicities or serious drug-related side effects occurred and no side effects led to treatment discontinuation. Additionally, combination treatment did not result in new or unexpected side effects relative to the known safety profile of each treatment when administered as monotherapy. The PK profile of IPI-549 in combination with Opdivo appeared favorable and suggested that Opdivo does not affect the PK properties of IPI-549. The combination dose-escalation module is ongoing to determine the optimal dose for the combination expansion module. Summary of Preclinical Research: Preclinical research has demonstrated that PI3K-gamma is highly expressed in tumor-associated macrophages and that blockade of PI3K-gamma signaling by treatment with IPI-549 results in reprogramming macrophages. This reprogramming shifted macrophages in the tumor microenvironment from the M2, or pro-tumor phenotype, to the M1, or anti-tumor phenotype and increased the number and activity of anti-tumor T cells that attack the tumor and also increased the production of pro-inflammatory cytokines. Preclinical data from multiple solid tumor models demonstrated that IPI-549 was active as a monotherapy and that IPI-549 administered in combination with checkpoint inhibition led to enhanced activity compared to either treatment alone. Additionally, preclinical data demonstrated that M2, pro-tumor macrophages are associated with resistance to checkpoint inhibitor monotherapy and treatment with IPI-549 in combination with checkpoint inhibitors is able to overcome this resistance by reprogramming macrophages from the M2, pro-tumor phenotype to the M1, anti-tumor phenotype. Taken together, these preclinical data demonstrate that PI3K-gamma plays a key role in the immuno-suppressive tumor microenvironment, help to further elucidate the mechanism of action for IPI-549 and provide a strong rationale for the ongoing Phase 1 study of IPI-549.
• • On January 20, 2017, during a plenary session at the Keystone Symposia Conference , "PI3K Pathways in Immunology, Growth Disorders and Cancer," Infinity Pharmaceuticals presented initial Phase 1 monotherapy data from nine patients with advanced solid tumors. These data showed that the safety, pharmacokinetics and pharmacodynamics of IPI-549 monotherapy treatment appeared favorable. As of the September 2016 data cutoff, no dose limiting toxicities and no serious adverse events were observed. Pharmacokinetic and pharmacodynamic data supported once daily dosing of IPI-549 based on the observed half-life and inhibition of the PI3K-gamma pathway. Preclinical data also provide a compelling rationale for Infinity's ongoing Phase 1 clinical study designed to evaluate IPI-549 as a monotherapy and in combination with Opdivo® (nivolumab), a PD-1 immune checkpoint inhibitor, in patients with advanced solid tumors. The combination portion of the Phase 1 study will include patients with non-small cell lung cancer (NSCLC), melanoma, and squamous cell carcinoma of the head and neck (SCCHN) whose tumors show initial resistance or subsequently develop resistance to immune checkpoint therapy. The IPI-549 monotherapy dose-escalation phase is expected to be completed in the first half of 2017, and the monotherapy expansion phase in patients with advanced solid tumors is anticipated to begin in the second half of the year.

Is general: Yes