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Duvelisib (IPI-145, INK-1197)

Duvelisib (IPI-145, INK-1197)

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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/small lymphocytic leukemia, 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 adverse events Grade ≥3, and treatment-related adverse events occurring in 11 patients (55%), including five patients (25%) with adverse events 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 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 chronic lymphocytic leukemia/small lymphocytic leukemia 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 chronic lymphocytic leukemia.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 30–June 3, 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 30–June 3, 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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