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Duvelisib

Duvelisib

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Duvelisib (IPI-145, INK-1197) is a small molecule pan-Class I phosphatidylinositol 3-kinase (PI3K) δ and γ inhibitor with IC50 of 1 nM and 43 nM respectively.1  Duvelisib was discovered by Infinity Pharmaceuticals and is being investigated for use in a range of hematologic malignancies, as well as inflammatory diseases such as mild, allergic asthma and rheumatoid arthritis.

Preliminary safety and efficacy data from an initial Phase I, open-label, dose-escalation study in patients with advanced hematologic malignancies (chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL), N=5; indolent non-Hodgkin lymphoma, N=4; diffuse large B-cell lymphoma, N=2; Richter’s transformation, N=1; multiple myeloma, N=3: Hodgkin lymphoma, N=2; anaplastic large-cell lymphoma, N=2: mantle cell lymphoma, N=1)1,2 suggest duvelisib is well tolerated, with adverse events (AEs) occurring in 13 patients (65%), including seven patients (35%) with AEs Grade ≥3, and treatment-related AEs occurring in 11 patients (55%), including five patients (25%) with AEs Grade ≥3.  New Grade ≥3 hematological laboratory abnormalities included neutropenia [N=6 (30%)] and thrombocytopenia [N=1 (5%)].1  This has been further supported by more recent data from a subset of patients with relapsed/refractory (R/R) CLL (N=44), with no reported dose-related increase in the frequency or severity of AEs.3

In the evaluable patients, responses have been observed at the 8, 15 and 25 mg twice-per-day dose levels for CLL/SLL patients, indolent non-Hodgkin lymphoma patients, and the mantle cell lymphoma patients.  When reported, no responses had been observed for the multiple myeloma or aggressive non-Hodgkin lymphoma patients.  Duvelisib has clinical activity with rapid responses in patients with a variety of hematologic malignancies across the dose range examined.1,4–8  The maximum tolerated dose has been determined at 75 mg twice per day, after two patients experienced a dose-limiting toxicity in cycle 1 (Grade 3 rash, Grade 3 alanine transaminase elevation) when dosed at 100 mg twice per day.8

Based on these emerging data, Infinity Pharmaceuticals is currently recruiting for a Phase II study of IPI-145 in subjects with refractory indolent non-Hodgkin lymphoma,9 and is also investigating duvelisib in combination with bendamustine, rituximab or bendamustine and rituximab in select subjects with lymphoma or CLL.10

Clinical trial

Phase

Indication (N)

Regimen (N)

≥ Grade 3 related AEs (%)

NCT01476657

I

iNHL (13); CLL/SLL (11); T-cell lymphoma (6); aNHL (3); MCL (3); HL (2)1

Duvelisib (38)

Neutropenia (15); febrile neutropenia (2); anemia (2); thrombocytopenia (2); ALT/AST increase (11); rash (4); cellulitis (2); pneumonitis (2); tumor lysis/hyperkalemia (2); nausea (2); dehydration (2); mucosal inflammation (2); hypophosphatemia (2)

CLL (44)3

Duvelisib (44)

Neutropenia (20); anemia (9); febrile neutropenia (7); pneumonitis (7); ALT/AST increase (5)

Table 1: Reported Grade ≥ 3 adverse events1,3,4–8

Lymphoma/CLL clinical trials

NCT01476657: A Phase 1 Study of IPI-145 in Patients With Advanced Hematologic Malignancies – RECRUITING

Study Design
Phase: I
Allocation: Non-randomized
Estimated Enrollment: 250
Intervention Model: Single group assignment
Masking: Open label
Primary Purpose: Treatment
Condition: Hematologic malignancies
Intervention: Drug (IPI-145), escalating oral dose

Results
Full data are not yet available. Available data: Tables 1 and 2

NCT01871675: An Open-label, Phase Ib Study of IPI-145 in Combination With Bendamustine, Rituximab or Bendamustine/Rituximab in Select Subjects With Lymphoma or Chronic Lymphocytic Leukemia – RECRUITING

Study Design
Phase: I
Allocation: Non-randomized
Estimated Enrollment: 70
Intervention Model: Parallel assignment
Masking: Open label
Primary Purpose: Treatment
Condition: Lymphoma; chronic lymphocytic leukemia; non-Hodgkin lymphoma; T-cell lymphoma
Intervention: Study arm 1 – drug (IPI-145), escalating oral dose, with drug (rituximab), 375 mg/m2; study arm 2 – drug (IPI-145), escalating oral dose, with drug (rituximab), 375 mg/m2 and drug (bendamustine) 90 mg/m2; study arm 3 – drug (IPI-145), escalating oral dose, with drug (bendamustine) 120 mg/m2

Results
Full data are not yet available

NCT01882803: A Phase 2 Study of IPI-145 in Subjects With Refractory Indolent Non-Hodgkin Lymphoma – RECRUITING

Study Design
Phase: II
Allocation: Non-randomized
Estimated Enrollment: 120
Intervention Model: Single group assignment
Masking: Open label
Primary Purpose: Treatment
Condition: Indolent non-Hodgkin lymphoma
Intervention: Drug (IPI-145), 25 mg twice daily

Results
Full data are not yet available

Clinical trial

Phase

Indication (N)

Regimen (N)

CR

PR

SD

PD

NE

NCT01476657

I

iNHL (13)

Duvelisib (38)

1/13

7/13

4/13

1/13

0/13

CLL/SLL (11)

0/11

6/11

4/11

1/11

0/11

T-cell lymphoma (6)

1/6

1/6

1/6

3/6

0/6

aNHL (3)

0/3

0/3

1/3

2/3

0/3

MCL (3)

0/3

2/3

0/3

1/3

0/3

HL (2)

1/2

0/2

0/2

1/2

0/2

CLL (44)

Duvelisib (44)

1/44

15/44

14/44

1/44

13/44

Table 2: Reported clinical trial results1,3,4–8

Lymphoma/CLL literature

No publications are currently available

Congress lymphoma/CLL abstracts

ASH 2013
Flinn I, et al. Preliminary Safety and Efficacy Of IPI-145, a Potent Inhibitor of Phosphoinositide-3-Kinase-δ,γ, In Patients With Chronic Lymphocytic Leukemia. 55th ASH Annual Meeting and Exposition. December 7–10, 2013. Oral #677. View

Balakrishnan K, et al. Inhibition of PI3K-δ and -γ Isoforms By IPI-145 In Chronic Lymphocytic Leukemia Overcomes Signals From PI3K/AKT/S6 Pathway and Promotes Apoptosis. 55th ASH Annual Meeting and Exposition. December 7–10, 2013. Poster #4167. View

Douglas M, et al. Treatment With The Potent PI3K-δ,γ Inhibitor IPI-145 Is Associated With Rapid Decreases In Specific Cytokines, Chemokines and Matrix Metalloproteinases In The Serum Of Patients With Chronic Lymphocytic Leukemia and Indolent Non-Hodgkin Lymphoma. 55th ASH Annual Meeting and Exposition. December 7–10, 2013. Poster #1633. View

Campbell V, et al. The Potent PI3K-δ,γ Inhibitor IPI-145 Exhibits Differential Activity In Diffuse Large B-Cell Lymphoma (DLBCL) Cell Lines. 55th ASH Annual Meeting and Exposition. December 7–10, 2013. Poster #1832. View

Quayle SN, et al. Inhibition Of HDAC6 In Combination With Targeted Agents Results In Broad Synergistic Decreases In Viability In Non-Hodgkin’s Lymphoma (NHL) Cells. 55th ASH Annual Meeting and Exposition. December 7–10, 2013. Poster #3071. View

EHA 2013
No data presented

ASCO 2013
Patel MR, et al. Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,γ, in patients with relapsed/refractory CLL. 2013 ASCO Annual Meeting. May 31–June 4, 2013. Poster #7070. View

Horwitz SM, et al. Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,γ, in patients with relapsed/refractory lymphoma. 2013 ASCO Annual Meeting. May 31–June 4, 2013. Poster #8518. View

ICML 2013
Kahl B, et al. Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,-γ, in patients with relapsed/refractory B-cell lymphoma. 12th International Conference on Malignant Lymphoma. June 19–22, 2013. Oral presentation #066.

Flinn IW, et al. Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,-γ, in patients with relapsed/refractory CLL/SLL. 12th International Conference on Malignant Lymphoma. June 19–22, 2013. Oral presentation #145.

Horwitz S, et al. Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,-γ, in patients with relapsed/refractory T-cell lymphoma. 12th International Conference on Malignant Lymphoma. June 19–22, 2013. Poster #294.

Authors: Prof. Anton Hagenbeek, Prof. Ulrich Jäger, Secretariat

References

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