zandelisib (ME-401)

Zandelisib achieved a high rate of durable responses in heavily pretreated patients with relapsed/refractory FL. The intermittent dosing resulted in a relatively low incidence of severe class-related toxicities, which supports the evaluation of zandelisib as a single agent and in combination with indolent B-cell malignancies.

P2, N=61, Active, not recruiting, Kyowa Kirin Co., Ltd. | Trial completion date: Sep 2024 --> May 2028 | Trial primary completion date: Sep 2024 --> May 2028

P1, N=14, Active, not recruiting, Kyowa Kirin Co., Ltd. | Trial completion date: Sep 2024 --> May 2028 | Trial primary completion date: Sep 2024 --> May 2028

The estimated 1-year PFS was 72.3% (95% confidence interval [CI], 51.9-85.1) for FL and 56.3% (95% CI, 28.9-76.7) for MCL (median follow-up: 16.5 and 10.9 months respectively). Zandelisib plus zanubrutinib was associated with high response rates and no increased toxicity compared to either agent alone.

P1/2, N=13, Active, not recruiting, Deepa Jagadeesh | Recruiting --> Active, not recruiting | N=54 --> 13

In this phase 1/II study, encouraging efficacy was observed with zandelisib + R-CHOP, but this should be interpreted with caution as the study was incomplete. There is a potential signal for increased gastrointestinal toxicity (one G3 colitis, one G3 bowel perforation) in this small sample size and larger prospective trials are needed to further assess the toxicity profile of the combination of oral PI3K inhibitors with R-CHOP.

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.

P1/2, N=0, Withdrawn, Jacob Soumerai, MD | N=34 --> 0 | Not yet recruiting --> Withdrawn

This study demonstrates a favorable efficacy and safety profiles consistent with TIDAL study in a Japanese patient population with r/r indolent B-NHL. Zandelisib is being investigated as a potential new therapeutic option for these patients. Marginal zone, Indolent non-Hodgkin's lymphoma, Follicular lymphoma, PI3K

P2, N=169, Terminated, MEI Pharma, Inc. | Trial completion date: Apr 2025 --> Mar 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Mar 2023; discontinuation of zandelisib program

P3, N=82, Terminated, MEI Pharma, Inc. | N=534 --> 82 | Trial completion date: Sep 2031 --> Mar 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Apr 2026 --> Mar 2023; Discontinuation of zandelisib program

P1, N=97, Terminated, MEI Pharma, Inc. | N=177 --> 97 | Trial completion date: Dec 2023 --> Mar 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Aug 2023 --> Mar 2023; discontinuation of zandelisib program

P3, N=534, Active, not recruiting, MEI Pharma, Inc. | Recruiting --> Active, not recruiting

Recent studies have identified altered T cell function as a major contributor to immune related toxicities with idelalisib and duvelisib (Leukemia PMID:34743191, BJH PMID: 35170759). No significant T cell changes were seen among patients who did not develop irAEs by OMIQ analysis. Initial data suggests that low levels of Tregs, and high levels of Th17, Th2 and CD8 Th17 at baseline predispose patients to develop irAEs.

Single agent zandelisib on ID was associated with high rate of durable responses (72.5% ORR, 36.3% CR rate in PEP) in heavily pretreated R/R FL pts, including those with POD24 and refractory disease, and was associated with a relatively lower incidence of Gr ≥3 AESI and AE-related discontinuations, compared with CD. Based on the safety and efficacy profiles observed in this study, these results support further evaluation of zandelisib ID, alone or in combinations, in various B-cell malignancies. Zandelisib plus rituximab vs.

Zandelisib plus zanubrutinib was well tolerated with no increase in the rate or severity of class-related AEs compared to either agent alone. Few pts (4%) have discontinued due to an AE. We observed high response rates in R/R FL (80%) and MCL (76%).

Zandelisib on ID led to high ORR and CR rates in heavily pretreated FL patients and was associated with a low rate of grade 3 AESI and discontinuations due to treatment-related AEs.

Zandelisib 60 mg once daily on an intermittent dosing schedule was safe, with low frequency of grade 3 or worse adverse events, warranting the ongoing global phase 2 and phase 3 trials.

Consistent with the phase Ib study, intermittent dosing with zandelisib led to high ORR and CR rates in heavily pretreated FL pts, and was associated with <10% of pts discontinuing due to treatment-related AEs or grade 3 AESI. These findings support further evaluation of zandelisib alone and in combination in various B-cell malignancies, both in relapsed disease and earlier lines of therapy. Zandelisib plus rituximab vs chemoimmunotherapy is being studied in the phase III COASTAL study in R/R FL and MZL (NCT 04745832).

This profile supports evaluation of zandelisib as a single agent and in combination regimens in various B-cell malignancies, both in R/R disease and in earlier lines of therapy. Zandelisib plus rituximab vs chemoimmunotherapy is being evaluated in the phase 3 study COASTAL in R/R FL and MZL (NCT04745832).

The high ORR and prolonged DOR are encouraging. This profile supports further evaluation of zandelisib on ID as a single agent and in combination in various B-cell malignancies, both in R/R disease and in earlier lines of therapy.

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.

Here, we investigated the dynamic immunomodulatory properties of zandelisib alone or in combination with BTK inhibitor ibrutinib in normal human T cells, as well as the impact of continuous dosing of zandelisib on effector and regulatory immune cells, irAEs, and survival in a preclinical CLL murine model. Zandelisib treatment improved survival of CLL-bearing mice significantly when compared to vehicle group (median survival of zandelisib group 140 days vs. 105 days vehicle). In conclusion, zandelisib treatment reduced Tregs, prevented terminal memory differentiation, and T-cell exhaustion—features that have been shown to permit CLL immune evasion—demonstrated antitumor efficacy, and improved overall survival in a preclinical CLL model.

Eligible pts must have received an anti-CD20 antibody in combination with chemotherapy or lenalidomide (L); at least one bi-dimensionally measured lesion > 1.5 cm; adequate bone marrow, renal and hepatic function; ECOG performance status score of 0 to 1. The trial is open and will enroll approximately 534 pts in ~200 sites globally. Clinical trial information: NCT04745832

Duvelisib is a p110γ/δ inhibitor with a similar efficacy and safety profile to idelalisib. Recent data indicate that umbralisib, a p110δ/CK-1ε dual inhibitor, is safe and effective when administered to patients with CLL.

P3, N=534, Recruiting, MEI Pharma, Inc. | Not yet recruiting --> Recruiting

P3, N=534, Not yet recruiting, MEI Pharma, Inc.