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SAFETY RESULTS OF TERMINATED PHASE 2 STUDY OF IDELALISIB PLUS RITUXIMAB IN TREATMENT NAÏVE CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) WITH DEL(17P)
Author(s): ,
Peter Hillmen
Affiliations:
The Leeds Teaching Hospitals, St. James Institute of Oncology,Leeds,United Kingdom
,
Xavier Badoux
Affiliations:
St. George Hospital,Kogarah,Australia
,
Julio Delgado
Affiliations:
Hospital Clinic de Barcelona,Barcelona,Spain
,
Veronique Leblond
Affiliations:
Hôpital de la Pitié-Salpétrière,Paris,France
,
Anthony Mato
Affiliations:
Hospital of the University of Pennsylvania,Philadelphia,United States
,
Martin Simkovic
Affiliations:
University Hospital and Charles University, Faculty of Medicine,Hradec Králové,Czech Republic
,
Ronald L. Dubowy
Affiliations:
Gilead Sciences, Inc.,Foster City,United States
,
Yeonhee Kim
Affiliations:
Gilead Sciences, Inc.,Foster City,United States
,
Andrzej Pluta
Affiliations:
Specialistic Hospital,Brzozow,Poland
Marco Montillo
Affiliations:
Niguarda Hospital, Hematology Department, Niguarda Cancer Center,Milano,Italy
(Abstract release date: 05/18/17) EHA Library. Hillmen P. 06/24/17; 181752; S465
Prof. Peter Hillmen
Prof. Peter Hillmen
Contributions
Abstract

Abstract: S465

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 17:00 - 17:15

Location: Hall B

Background
Idelalisib (IDELA) is an oral PI3Kδ inhibitor approved in the EU for use with rituximab (R) or ofatumumab in patients (pts) with previously treated CLL or as first-line treatment of CLL with either del(17p) or TP53 mutation in pts unsuitable for other therapies.  Prior single arm studies have suggested that front line use of IDELA may be associated with an increased frequency of transaminase elevations compared to relapsed pts.

Aims
To describe: 1) the safety of IDELA plus rituximab in previously untreated CLL pts with del(17p) in this terminated study, and 2) the relation of key AEs and age. 

Methods
Treatment-naïve pts with CLL and confirmed del(17p) were treated in a single arm study with R 375 mg/m² IV weekly x8 and IDELA 150 mg PO BID continuously until disease progression or intolerability. Informed consent was obtained. The study was fully enrolled when terminated early due to infection related safety concerns observed in a pooled analysis of ongoing Ph3 IDELA trials in front/early line therapy; the planned independent efficacy analysis was not performed, but investigator assessment is available.

Results
102 pts (median age, 66; range, 37-86) were enrolled between Aug 2014 and Jan 2016 and received IDELA for a median (med) duration of 6.4 months (range, 0.7-17.0). The study was terminated in Mar 2016, >8 wks after dosing of the last enrolled pt. 77 pts (75.5%) remained on study at the time of study termination. The reasons for discontinuation from study were death (4.9%), progressive disease (3.9%, 1 fatal), investigator discretion (9.8%), withdrawal of consent (2.9%), other anticancer therapy (2.0%), and lost to follow up (1.0%). The investigator assessed response rate was 79%. 101 pts (99%) had adverse events (AEs); Gr ≥3 occurred in 80.4%, the most frequent Gr ≥3 were ALT increased (27.5%), neutropenia (20.6%), infections (18.6%), and diarrhea (14.7%). Laboratory Gr ≥3 ALT and/or AST elevations were seen in 41.2%, with med time of onset of 8.1 wks (range 4.1-24.1).  The med age of pts both with and without Gr ≥3 ALT/AST was 66 years, and the incidence of Gr ≥3 ALT/AST was similar in younger (43.9%, <65yr) and older (39.3%, ≥65yr) pts. Gr ≥3 diarrhea/colitis occurred in 17.1% of pts <65yr and in 14.8% of pts ≥65yr. Dose interruptions due to AEs occurred in 71 pts (70%), most frequently due to transaminase elevations (37.3%), and diarrhea/colitis (15.7%). Discontinuation due to AEs occurred in 27% of pts, most frequently due to ALT/AST elevation (9.8%). Serious adverse events were reported in 46 (45.1%), including pyrexia (10.8%), diarrhea/colitis (11.8%). AEs of special interest included Gr ≥3 infections in 20 pts (19.6%) of whom 5 had CMV and 3 had PJP (none on prophylaxis),  Gr ≥3 febrile neutropenia in 5 (4.9%) and any grade pneumonitis in 5 (4.9%). Of the 5 pts with CMV, all were CMV IgG+ at screening and 2 also were IgM+. There were 6 on-study deaths, 3 associated with infection, 2 due to CLL progression and 1 due to heart failure.

Conclusion
In IDELA plus rituximab treated front-line CLL, the pattern of AEs was similar to that seen in relapsed CLL studies at similar duration of therapy, however the frequency of Gr ≥3 ALT/AST was increased compared to the relapsed setting.  There was no significant effect of age on the risk of either ALT/AST elevations or diarrhea/colitis. The occurrence of CMV and PJP infections is consistent with current IDELA labeling and speaks to the potential benefit of risk mitigation through PJP prophylaxis and CMV monitoring during treatment. NCT02044822.

Session topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical

Keyword(s): P53, Chronic Lymphocytic Leukemia, Safety, PI3K

Abstract: S465

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 17:00 - 17:15

Location: Hall B

Background
Idelalisib (IDELA) is an oral PI3Kδ inhibitor approved in the EU for use with rituximab (R) or ofatumumab in patients (pts) with previously treated CLL or as first-line treatment of CLL with either del(17p) or TP53 mutation in pts unsuitable for other therapies.  Prior single arm studies have suggested that front line use of IDELA may be associated with an increased frequency of transaminase elevations compared to relapsed pts.

Aims
To describe: 1) the safety of IDELA plus rituximab in previously untreated CLL pts with del(17p) in this terminated study, and 2) the relation of key AEs and age. 

Methods
Treatment-naïve pts with CLL and confirmed del(17p) were treated in a single arm study with R 375 mg/m² IV weekly x8 and IDELA 150 mg PO BID continuously until disease progression or intolerability. Informed consent was obtained. The study was fully enrolled when terminated early due to infection related safety concerns observed in a pooled analysis of ongoing Ph3 IDELA trials in front/early line therapy; the planned independent efficacy analysis was not performed, but investigator assessment is available.

Results
102 pts (median age, 66; range, 37-86) were enrolled between Aug 2014 and Jan 2016 and received IDELA for a median (med) duration of 6.4 months (range, 0.7-17.0). The study was terminated in Mar 2016, >8 wks after dosing of the last enrolled pt. 77 pts (75.5%) remained on study at the time of study termination. The reasons for discontinuation from study were death (4.9%), progressive disease (3.9%, 1 fatal), investigator discretion (9.8%), withdrawal of consent (2.9%), other anticancer therapy (2.0%), and lost to follow up (1.0%). The investigator assessed response rate was 79%. 101 pts (99%) had adverse events (AEs); Gr ≥3 occurred in 80.4%, the most frequent Gr ≥3 were ALT increased (27.5%), neutropenia (20.6%), infections (18.6%), and diarrhea (14.7%). Laboratory Gr ≥3 ALT and/or AST elevations were seen in 41.2%, with med time of onset of 8.1 wks (range 4.1-24.1).  The med age of pts both with and without Gr ≥3 ALT/AST was 66 years, and the incidence of Gr ≥3 ALT/AST was similar in younger (43.9%, <65yr) and older (39.3%, ≥65yr) pts. Gr ≥3 diarrhea/colitis occurred in 17.1% of pts <65yr and in 14.8% of pts ≥65yr. Dose interruptions due to AEs occurred in 71 pts (70%), most frequently due to transaminase elevations (37.3%), and diarrhea/colitis (15.7%). Discontinuation due to AEs occurred in 27% of pts, most frequently due to ALT/AST elevation (9.8%). Serious adverse events were reported in 46 (45.1%), including pyrexia (10.8%), diarrhea/colitis (11.8%). AEs of special interest included Gr ≥3 infections in 20 pts (19.6%) of whom 5 had CMV and 3 had PJP (none on prophylaxis),  Gr ≥3 febrile neutropenia in 5 (4.9%) and any grade pneumonitis in 5 (4.9%). Of the 5 pts with CMV, all were CMV IgG+ at screening and 2 also were IgM+. There were 6 on-study deaths, 3 associated with infection, 2 due to CLL progression and 1 due to heart failure.

Conclusion
In IDELA plus rituximab treated front-line CLL, the pattern of AEs was similar to that seen in relapsed CLL studies at similar duration of therapy, however the frequency of Gr ≥3 ALT/AST was increased compared to the relapsed setting.  There was no significant effect of age on the risk of either ALT/AST elevations or diarrhea/colitis. The occurrence of CMV and PJP infections is consistent with current IDELA labeling and speaks to the potential benefit of risk mitigation through PJP prophylaxis and CMV monitoring during treatment. NCT02044822.

Session topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical

Keyword(s): P53, Chronic Lymphocytic Leukemia, Safety, PI3K

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