parsaclisib (INCB50465)

P2, N=25, Completed, Incyte Corporation | Active, not recruiting --> Completed

The compound has a polymeric structure propagated by a screw axis parallel to the b axis with N-H⋯O hydrogen bonding. It is of inter-est with respect to efforts in the synthesis of a candidate anti-cancer drug, parsaclisib.

P1, N=65, Recruiting, Incyte Biosciences Japan GK | Phase classification: P1b/2 --> P1

From the concentration-ΔQTcF analyses, the predicted ΔQTcF (90% CI) for all dose levels was between 0.365 (-1.75 to 2.48) and 7.87 ms (0.921-14.8), with the highest upper limit of CIs well below 20 ms, and therefore, a large QT/QTc effect was ruled out up to the highest dose level (45 mg) investigated. Overall, parsaclisib at the dose ranges studied did not reveal concentration-dependent effects on change in QTcF and did not have a significant effect on HR or cardiac conduction.

P2, N=110, Active, not recruiting, Incyte Corporation | Trial completion date: Dec 2023 --> May 2024

Hemoglobin levels remained steady. The addition of parsaclisib to stable dose ruxolitinib can reduce splenomegaly and improve symptoms, with manageable toxicity in patients with myelofibrosis with suboptimal response to ruxolitinib.

In this phase I study, patients with advanced solid tumors treated with pembrolizumab (PD-1 inhibitor) and either itacitinib (JAK1 inhibitor) or parsaclisib (PI3Kδ inhibitor) experienced limited clinical activity beyond that expected with checkpoint inhibition alone and showed little effect on T-cell infiltration in the tumor. These results do not support continued development of these combinations.

TEAEs led to dose interruptions, reductions, and discontinuations in 56.0%, 16.0%, and 29.0% of all patients, respectively. Durable responses and overall manageable safety profile were demonstrated in patients with R/R MZL treated with parsaclisib monotherapy.

P1/2, N=54, Active, not recruiting, Incyte Corporation | Phase classification: P1b/2a --> P1/2 | Trial completion date: Oct 2023 --> Dec 2024 | Trial primary completion date: Oct 2023 --> Dec 2024

P1/2, N=28, Recruiting, Henan Cancer Hospital | Not yet recruiting --> Recruiting

The combination of parsaclisib with rituximab showed a deep and durable response, with a favorable safety profile and generally good tolerability in patients with previously untreated indolent B-Cell Lymphoma.

P2, N=42, Completed, Incyte Biosciences Japan GK | Active, not recruiting --> Completed

P3, N=13, Active, not recruiting, Incyte Corporation | Trial primary completion date: Apr 2023 --> Oct 2023

P2, N=25, Active, not recruiting, Incyte Corporation | Trial completion date: Sep 2023 --> Mar 2024

P1, N=0, Withdrawn, Innovent Biologics (Suzhou) Co. Ltd. | N=560 --> 0 | Not yet recruiting --> Withdrawn

P3, N=252, Active, not recruiting, Incyte Corporation | N=440 --> 252 | Trial completion date: May 2026 --> Apr 2024 | Trial primary completion date: Nov 2023 --> Aug 2023

Idelalisib is a first-in-class PI3Kδ inhibitor effective in patients with B-cell lymphoid malignancies...Newer drugs are in development to reduce toxicity with novel schedules and/or combinations. The development of novel PI3Kδ inhibitors might help to reduce toxicity and improve efficacy in patients with CLL and other B-cell lymphoid malignancies.

Treatment with parsaclisib demonstrated rapid and durable responses, and a manageable safety profile in patients with R/R FL. Incyte Corporation.

Future development of PI3K inhibitors for NHL will require further investigation of dose optimisation to improve safety and long-term survival. Incyte Corporation.

P1b, N=17, Completed, Incyte Corporation | Active, not recruiting --> Completed

P1b/2a, N=54, Active, not recruiting, Incyte Corporation | N=100 --> 54

Seventeen patients (65.4%) had a complete response and 3 patients (11.5%) had a partial response, for an objective response rate of 76.9%. Overall, results from CITADEL-102 suggest that the combination of parsaclisib with obinutuzumab and bendamustine did not result in unexpected safety events, with little evidence of synergistic toxicity, and demonstrated preliminary efficacy in patients with R/R FL who progressed following prior rituximab-containing regimens.

P2, N=42, Active, not recruiting, Incyte Biosciences Japan GK | Trial completion date: Feb 2024 --> Oct 2023 | Trial primary completion date: Feb 2024 --> Feb 2023

P2, N=162, Active, not recruiting, Incyte Corporation | Trial completion date: Mar 2023 --> Apr 2024

P2, N=110, Active, not recruiting, Incyte Corporation | Trial completion date: Mar 2023 --> Dec 2023

P1, N=560, Not yet recruiting, Innovent Biologics (Suzhou) Co. Ltd.

P1, N=50, Active, not recruiting, Mayo Clinic | Recruiting --> Active, not recruiting

With longer follow-up, parsaclisib demonstrated a high rate of complete response and durable responses, and had an acceptable safety profile. These results demonstrate that parsaclisib has a favorable benefit-risk profile in patients with line 3 or higher Chinese follicular lymphoma. Clinical trial information: NCT04298879 Targeted therapy, Follicular lymphoma, Phase II

Parsaclisib 20 mg QD for 8 weeks followed by 20 mg QW in combination with RIT, RIT+BEN, or IBR in pts with R/R B-cell lymphomas had a manageable tolerability profile with no unexpected safety concerns, and demonstrated promising efficacy.

P1b/2a, N=100, Active, not recruiting, Incyte Corporation | Recruiting --> Active, not recruiting

P1b/2a, N=100, Recruiting, Incyte Corporation | Active, not recruiting --> Recruiting | N=50 --> 100

P1b/2a, N=50, Active, not recruiting, Incyte Corporation | Recruiting --> Active, not recruiting | N=100 --> 50

P1b, N=17, Active, not recruiting, Incyte Corporation | Trial completion date: Jun 2023 --> Mar 2023 | Trial primary completion date: Aug 2022 --> May 2022

Background Patients (pts) with follicular lymphoma (FL) generally respond well to first-line CD20-targeted therapies, such as obinutuzumab or rituximab-based regimens. Median DOR, PFS, and OS were not reached. Conclusion Parsaclisib in combination with bendamustine + obinutuzumab appears to have a manageable safety profile and demonstrated promising efficacy in pts with R/R FL.

Parsaclisib dose interruption or dose reduction due to TEAEs occurred in 75.0% and 18.8% of pts, respectively, in Tmt A; 66.7% and 27.8% of pts, respectively, in Tmt B; and 56.3% and 18.8% of pts, respectively, in Tmt C. Conclusion Parsaclisib 20 mg QD for 8 weeks followed by 20 mg QW can be safely combined with RIT, RIT + BEN, or IBR in pts with R/R B-cell lymphomas. The tolerability profile of the combination regimens was manageable, with no unexpected safety concerns.

P3, N=0, Withdrawn, Incyte Corporation | N=596 --> 0 | Not yet recruiting --> Withdrawn

Parsaclisib demonstrated promising efficacy, and acceptable safety profile. These results suggest that parsaclisib could benefit 3rd or higher line Follicular lymphoma patients.

Two Janus-associated kinase inhibitors (JAKi) (initially ruxolitinib and, more recently, fedratinib) have been approved as treatment options for patients who have intermediate-risk and high-risk myelofibrosis (MF), with pivotal trials demonstrating improvements in spleen volume, disease symptoms, and quality of life. To address such a high unmet therapeutic need, various non-JAKi agents are being actively explored (in combination with ruxolitinib in first-line or salvage settings and/or as monotherapy in JAKi-pretreated patients) in phase 3 clinical trials, including pelabresib (a bromodomain and extraterminal domain inhibitor), navitoclax (a B-cell lymphoma 2/B-cell lymphoma 2-xL inhibitor), parsaclisib (a phosphoinositide 3-kinase inhibitor), navtemadlin (formerly KRT-232; a murine double-minute chromosome 2 inhibitor), and imetelstat (a telomerase inhibitor). The breadth of data expected from these trials will provide insight into the ability of non-JAKi treatments to modify the natural history of MF.

Adverse events with JAK1 inhibition combined with either IDO1 or PI3Kδ inhibition were manageable, but the combinations demonstrated limited clinical activity or enhancement of immune activation in the tumor microenvironment.

P1, N=159, Completed, Incyte Corporation | Active, not recruiting --> Completed

The dual PI3Kδ/γ inhibitor duvelisib is approved for use in CLL patients but with similar toxicities to idelalisib. Umbralisib, a highly selective inhibitor of PI3Kδ and casein kinase-1ε (CK1ε), was found to be efficient and safe in monotherapy and in combination regimens in phase 3 trials in patients with CLL. Novel PI3Kis are under evaluation in early phase clinical trials. In this paper we present the mechanism of action, efficacy and toxicities of PI3Ki approved in the treatment of CLL and developed in clinical trials.

P1b, N=17, Active, not recruiting, Incyte Corporation | Trial completion date: Aug 2022 --> Jun 2023