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EFFICACY AND SAFETY OF ZANDELISIB ADMINISTERED BY INTERMITTENT DOSING (ID) IN PATIENTS WITH RELAPSED OR REFRACTORY (R/R) FOLLICULAR LYMPHOMA: PRIMARY ANALYSIS OF THE GLOBAL PHASE 2 STUDY TIDAL
Author(s): ,
Andrew Zelenetz
Affiliations:
Memorial Sloan Kettering Cancer Institute,New York City,États-unis;Memorial Sloan Kettering Cancer Institute,New York City,Vereinigte Staaten;Memorial Sloan Kettering Cancer Institute,New York City,Stati Uniti;Memorial Sloan Kettering Cancer Institute,New York City,United States;Memorial Sloan Kettering Cancer Institute,New York City,Estados Unidos;Memorial Sloan Kettering Cancer Institute,New Yor
,
Wojciech Jurczak
Affiliations:
Maria Sklodowska Curie National Research Institute of Oncology,Krakow,Pologne;Maria Sklodowska Curie National Research Institute of Oncology,Krakow,Polen;Maria Sklodowska Curie National Research Institute of Oncology,Krakow,Polonia;Maria Sklodowska Curie National Research Institute of Oncology,Krakow,Poland;Maria Sklodowska Curie National Research Institute of Oncology,Krakow,Polonia;Maria Sklodow
,
Vincent Ribrag
Affiliations:
Institut Gustave Roussy,Villejuif,France;Institut Gustave Roussy,Villejuif,Frankreich;Institut Gustave Roussy,Villejuif,Francia;Institut Gustave Roussy,Villejuif,France;Institut Gustave Roussy,Villejuif,Francia;Institut Gustave Roussy,Villejuif,Frankrijk;Institut Gustave Roussy,Villejuif,França;Institut Gustave Roussy,Villejuif,Франция ;Institut Gustave Roussy,Villejuif,Frankrike
,
Kim Linton
Affiliations:
Manchester Cancer Research Centre,Manchester,Royaume-uni;Manchester Cancer Research Centre,Manchester,Vereinigtes Königreich;Manchester Cancer Research Centre,Manchester,Regno Unito;Manchester Cancer Research Centre,Manchester,United Kingdom;Manchester Cancer Research Centre,Manchester,Reino Unido;Manchester Cancer Research Centre,Manchester,Verenigd Koninkrijk;Manchester Cancer Research Centre,Ma
,
Graham Collins
Affiliations:
GenesisCare,Oxford,Royaume-uni;GenesisCare,Oxford,Vereinigtes Königreich;GenesisCare,Oxford,Regno Unito;GenesisCare,Oxford,United Kingdom;GenesisCare,Oxford,Reino Unido;GenesisCare,Oxford,Verenigd Koninkrijk;GenesisCare,Oxford,Reino Unido;GenesisCare,Oxford,Соединённое Королевство;GenesisCare,Oxford,Storbritannien
,
Javier Lopéz-Jiménez
Affiliations:
Hospital Universitario Ramon y Cajal,Madrid,Espagne;Hospital Universitario Ramon y Cajal,Madrid,Spanien;Hospital Universitario Ramon y Cajal,Madrid,Spagna;Hospital Universitario Ramon y Cajal,Madrid,Spain;Hospital Universitario Ramon y Cajal,Madrid,España;Hospital Universitario Ramon y Cajal,Madrid,Spanje;Hospital Universitario Ramon y Cajal,Madrid,Espanha;Hospital Universitario Ramon y Cajal,Madr
,
Nishitha Reddy
Affiliations:
Vanderbilt University,Nashville,États-unis;Vanderbilt University,Nashville,Vereinigte Staaten;Vanderbilt University,Nashville,Stati Uniti;Vanderbilt University,Nashville,United States;Vanderbilt University,Nashville,Estados Unidos;Vanderbilt University,Nashville,Verenigde Staten;Vanderbilt University,Nashville,Estados Unidos;Vanderbilt University,Nashville,United States;Vanderbilt University,Nashv
,
Andrea Mengarelli
Affiliations:
Regina Elena National Cancer Institute,Roma,Italie;Regina Elena National Cancer Institute,Roma,Italien;Regina Elena National Cancer Institute,Roma,Italia;Regina Elena National Cancer Institute,Roma,Italy;Regina Elena National Cancer Institute,Roma,Italia;Regina Elena National Cancer Institute,Roma,Italië;Regina Elena National Cancer Institute,Roma,Itália;Regina Elena National Cancer Institute,Roma
,
Tycel Phillips
Affiliations:
University of Michigan Health System,Ann Arbor,États-unis;University of Michigan Health System,Ann Arbor,Vereinigte Staaten;University of Michigan Health System,Ann Arbor,Stati Uniti;University of Michigan Health System,Ann Arbor,United States;University of Michigan Health System,Ann Arbor,Estados Unidos;University of Michigan Health System,Ann Arbor,Verenigde Staten;University of Michigan Health
,
Gerardo Musuraca
Affiliations:
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori I.R.S.T.,Meldola,Italie;Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori I.R.S.T.,Meldola,Italien;Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori I.R.S.T.,Meldola,Italia;Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori I.R.S.T.,Meldola,Italy;Istituto Scientifico Romagnolo per lo St
,
Oonagh Sheehy
Affiliations:
Belfast Health and Social Care Trust,Belfast,Royaume-uni;Belfast Health and Social Care Trust,Belfast,Vereinigtes Königreich;Belfast Health and Social Care Trust,Belfast,Regno Unito;Belfast Health and Social Care Trust,Belfast,United Kingdom;Belfast Health and Social Care Trust,Belfast,Reino Unido;Belfast Health and Social Care Trust,Belfast,Verenigd Koninkrijk;Belfast Health and Social Care Trust
,
Joanne Li
Affiliations:
MEI Pharma, Inc.,San Diego,États-unis;MEI Pharma, Inc.,San Diego,Vereinigte Staaten;MEI Pharma, Inc.,San Diego,Stati Uniti;MEI Pharma, Inc.,San Diego,United States;MEI Pharma, Inc.,San Diego,Estados Unidos;MEI Pharma, Inc.,San Diego,Verenigde Staten;MEI Pharma, Inc.,San Diego,Estados Unidos;MEI Pharma, Inc.,San Diego,United States;MEI Pharma, Inc.,San Diego,USA
,
Weiming Xu
Affiliations:
MEI Pharma, Inc.,San Diego,États-unis;MEI Pharma, Inc.,San Diego,Vereinigte Staaten;MEI Pharma, Inc.,San Diego,Stati Uniti;MEI Pharma, Inc.,San Diego,United States;MEI Pharma, Inc.,San Diego,Estados Unidos;MEI Pharma, Inc.,San Diego,Verenigde Staten;MEI Pharma, Inc.,San Diego,Estados Unidos;MEI Pharma, Inc.,San Diego,United States;MEI Pharma, Inc.,San Diego,USA
,
Michel Azoulay
Affiliations:
Kyowa Kirin Co.,Princeton,États-unis;Kyowa Kirin Co.,Princeton,Vereinigte Staaten;Kyowa Kirin Co.,Princeton,Stati Uniti;Kyowa Kirin Co.,Princeton,United States;Kyowa Kirin Co.,Princeton,Estados Unidos;Kyowa Kirin Co.,Princeton,Verenigde Staten;Kyowa Kirin Co.,Princeton,Estados Unidos;Kyowa Kirin Co.,Princeton,United States;Kyowa Kirin Co.,Princeton,USA
,
Richard Ghalie
Affiliations:
MEI Pharma, Inc.,San Diego,États-unis;MEI Pharma, Inc.,San Diego,Vereinigte Staaten;MEI Pharma, Inc.,San Diego,Stati Uniti;MEI Pharma, Inc.,San Diego,United States;MEI Pharma, Inc.,San Diego,Estados Unidos;MEI Pharma, Inc.,San Diego,Verenigde Staten;MEI Pharma, Inc.,San Diego,Estados Unidos;MEI Pharma, Inc.,San Diego,United States;MEI Pharma, Inc.,San Diego,USA
Pier Luigi Zinzani
Affiliations:
University of Bologna,Bologna,Italie;University of Bologna,Bologna,Italien;University of Bologna,Bologna,Italia;University of Bologna,Bologna,Italy;University of Bologna,Bologna,Italia;University of Bologna,Bologna,Italië;University of Bologna,Bologna,Itália;University of Bologna,Bologna,Италия;University of Bologna,Bologna,Italien
(Abstract release date: 05/12/22) EHA Library. Zelenetz A. 06/11/22; 357072; S208
Andrew Zelenetz
Andrew Zelenetz
Contributions
Abstract
Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S208

Type: Oral Presentation

Session title: Indolent and mantle cell lymphoma

Background
Zandelisib, a PI3Kδ inhibitor with high target-binding affinity, is administered by intermittent dosing (ID) on days 1 to 7 of 28-day cycles to potentially enable regulatory T-cell repopulation and lower the risk of immune-related adverse events (irAEs) associated with continuous PI3Kδ inhibition. In a phase 1b study in 37 patients (pts) with R/R FL, zandelisib administered daily for two 28-day cycles for tumor debulking then on ID achieved an overall response rate (ORR) of 87% (78% as single agent and 95% with rituximab), a median duration of response (DOR) not reached at median follow-up of 16.9 months, and a low rate (<10%) of grade 3 irAEs (Pagel et al. ICML 2021; #113).  

Aims
We conducted the TIDAL study (NCT03768505) to further evaluate in a global trial the efficacy and safety of zandelisib in larger group of pts with R/R FL and marginal zone lymphoma (MZL). The MZL cohort is still enrolling and not reported here.

Methods

Eligible pts ≥18 years with FL Grade I-IIIA, ECOG performance status 0-1, progressive disease after ≥2 prior therapies including an anti-CD20 antibody and chemotherapy, and no prior PI3Kδ inhibitor, provided consent and then received zandelisib 60 mg daily for two 28-day cycles then on ID.  Another study arm evaluating zandelisib 60 mg daily continuously was closed to enrollment early and is not reported here. The planned sample size in FL was 120 pts on ID, with the primary efficacy population (PEP) pre-defined as the first 91 pts treated and the safety population consisting of all FL pts treated. The primary efficacy endpoint was ORR as assessed by independent review using the Lugano criteria and analyzed 6 months after completing enrollment in the PEP. 

Results
121 FL pts were enrolled. In the PEP (N=91 pts), the median number of prior therapies was 3 (range 2-8), 21 pts (23%) have received prior stem cell transplant, 42 pts (46%) were refractory to last therapy, 31 pts (34%) had tumors ≥5 cm, and 51 pts (56%) were POD24. The ORR was 70.3% (N=64) (95% CI 59.8-79.5%), with 32 pts (35.2%) achieving a complete response (CR). Responses occurred early, with 85.5% (N=56) achieved in the first 2 cycles of therapy and 75% of CRs (N=24) achieved the first 4 cycles. The data are still immature to estimate accurately the DOR. With a median follow-up of 9.4 months (range 0.8-24) in the safety population of 121 pts, 12 pts (9.9%) discontinued therapy due to any drug-related AE. Grade 3 AEs of special interest (AESI) were diarrhea in 6 pts (5%), colitis in 2 (1.7%), cutaneous rash in 4 (3.3%), stomatitis in 3 (2.5%), and 1 (0.8%) each for AST and ALT elevation, and non-infectious pneumonitis. Grade 3 AESIs primarily (15 of 18, 83%) occurred in cycles 1-3, during daily dosing, with only 3 cases reported on ID in Cycles ≥4.

Conclusion
Zandelisib on ID achieved high ORR (70.3%) and CR rate (35.2%) in heavily pretreated R/R FL pts, and was associated with a low rate (<10%) of grade 3 AESI and discontinuations due to AEs, results comparable to the Phase 1b study. Longer follow-up is needed to estimate median DOR. 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).

Keyword(s): Clinical trial, Follicular lymphoma, Phase II, PI3K

Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S208

Type: Oral Presentation

Session title: Indolent and mantle cell lymphoma

Background
Zandelisib, a PI3Kδ inhibitor with high target-binding affinity, is administered by intermittent dosing (ID) on days 1 to 7 of 28-day cycles to potentially enable regulatory T-cell repopulation and lower the risk of immune-related adverse events (irAEs) associated with continuous PI3Kδ inhibition. In a phase 1b study in 37 patients (pts) with R/R FL, zandelisib administered daily for two 28-day cycles for tumor debulking then on ID achieved an overall response rate (ORR) of 87% (78% as single agent and 95% with rituximab), a median duration of response (DOR) not reached at median follow-up of 16.9 months, and a low rate (<10%) of grade 3 irAEs (Pagel et al. ICML 2021; #113).  

Aims
We conducted the TIDAL study (NCT03768505) to further evaluate in a global trial the efficacy and safety of zandelisib in larger group of pts with R/R FL and marginal zone lymphoma (MZL). The MZL cohort is still enrolling and not reported here.

Methods

Eligible pts ≥18 years with FL Grade I-IIIA, ECOG performance status 0-1, progressive disease after ≥2 prior therapies including an anti-CD20 antibody and chemotherapy, and no prior PI3Kδ inhibitor, provided consent and then received zandelisib 60 mg daily for two 28-day cycles then on ID.  Another study arm evaluating zandelisib 60 mg daily continuously was closed to enrollment early and is not reported here. The planned sample size in FL was 120 pts on ID, with the primary efficacy population (PEP) pre-defined as the first 91 pts treated and the safety population consisting of all FL pts treated. The primary efficacy endpoint was ORR as assessed by independent review using the Lugano criteria and analyzed 6 months after completing enrollment in the PEP. 

Results
121 FL pts were enrolled. In the PEP (N=91 pts), the median number of prior therapies was 3 (range 2-8), 21 pts (23%) have received prior stem cell transplant, 42 pts (46%) were refractory to last therapy, 31 pts (34%) had tumors ≥5 cm, and 51 pts (56%) were POD24. The ORR was 70.3% (N=64) (95% CI 59.8-79.5%), with 32 pts (35.2%) achieving a complete response (CR). Responses occurred early, with 85.5% (N=56) achieved in the first 2 cycles of therapy and 75% of CRs (N=24) achieved the first 4 cycles. The data are still immature to estimate accurately the DOR. With a median follow-up of 9.4 months (range 0.8-24) in the safety population of 121 pts, 12 pts (9.9%) discontinued therapy due to any drug-related AE. Grade 3 AEs of special interest (AESI) were diarrhea in 6 pts (5%), colitis in 2 (1.7%), cutaneous rash in 4 (3.3%), stomatitis in 3 (2.5%), and 1 (0.8%) each for AST and ALT elevation, and non-infectious pneumonitis. Grade 3 AESIs primarily (15 of 18, 83%) occurred in cycles 1-3, during daily dosing, with only 3 cases reported on ID in Cycles ≥4.

Conclusion
Zandelisib on ID achieved high ORR (70.3%) and CR rate (35.2%) in heavily pretreated R/R FL pts, and was associated with a low rate (<10%) of grade 3 AESI and discontinuations due to AEs, results comparable to the Phase 1b study. Longer follow-up is needed to estimate median DOR. 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).

Keyword(s): Clinical trial, Follicular lymphoma, Phase II, PI3K

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