Error bars represent 25th & 75th percentiles. Paired t-test with Bonferroni correction to evaluate change from baseline: * p<0.005 and ‡ p<0.008. • Some analytes previously reported to be decreased with duvelisib monotherapy treatment in relapsed/refractory iNHL were decreased in this untreated FL population (CCL17, CCL22, CXCL13, TNFα); modulation of these factors may impact tumor cell migration and recruitment of regulatory T cells 10 • The decrease in serum chemokine and cytokine levels provides evidence of biological activity via modulation of the TME • The CONTEMPO study (NCT02391545) is designed to evaluate the safety and clinical activity of duvelisib in combination with rituximab or obinutuzumab in previously untreated CD20 + Follicular Lymphoma (FL) – Disease response assessments (CT scans and physical exams) on Day 1 of C4, C8, C12, C16, C20, and C26 • Mandatory prophylaxis for PJP was added in an amendment to the protocol Part 1: Safety Lead-in • Patients enrolled in alternating fashion in one of two parallel treatment arms – Arm 1: duvelisib 25 mg BID plus rituximab (DR) (n = 6) – Arm 2: duvelisib 25 mg BID plus obinutuzumab (DO) (n = 6) DLTs: any of the following treatment-related events in Cycle 1 Hematologic Toxicities Non-Hematologic Toxicities • Grade 4 neutropenia for ≥ 7 days • ≥ Grade 3 febrile neutropenia • Grade 4 thrombocytopenia ≥ 7 days • ≥ Grade 3 thrombocytopenia associated with ≥ Grade 2 hemorrhage • New ≥ Grade 3 anemia requiring transfusion in a subject previously transfusion-independent • Any ≥ Grade 3 toxicity • Any AE requiring > 25% of scheduled study drug(s) to be withheld during Cycle 1 • Any Grade 4 infusion-related reaction (IRR) • Recurrent IRR ≥ Grade 3 requiring discontinuation of obinutuzumab or rituximab while receiving duvelisib DLT = dose-limiting toxicity. Part 2: Two-Stage Design • Simon 2-stage design for each treatment arm • Total planned enrollment Part 2: 48 patients per arm • The study has been closed to enrollment; 27 patients receive D+O and 28 patients received D+R Dosing • Duvelisib: 25 mg orally BID continuously in 28-day cycles until disease progression or unacceptable toxicity • Rituximab 375 mg/m 2 IV infusion or obinutuzumab 1000 mg IV infusion – Cycle 1: D1, D8, D15, and D22 (Induction Period) – Cycles 4+: Every 2 cycles for up to 2 years (12 doses) (Maintenance Period) Key Inclusion Criteria • Previously untreated CD20 + FL • Stage II with bulky disease (≥ 7 cm lesion), or Stage III-IV disease • At least 1 measurable disease lesion > 1.5 cm • Adequate liver and renal function • No clinical evidence of transformation to a more aggressive subtype of lymphoma or Grade 3B FL Safety, Pharmacokinetics, and Pharmacodynamics of Duvelisib Plus Rituximab or Obinutuzumab in Patients with Previously Untreated CD20 + Follicular Lymphoma C Casulo 1 , JM Sancho 2 *, K Van Eygen 3 *, S de Vos 4 , S Mercadal 5 *, RJ Johnson 6 , K Bouabdallah 7 *, H Holmes 8 , J Lemmens 9 , E Gyan 10 *, M Merli 11 *, RH Advani 12 , L Steelman 13 *, J Pearlberg 13 * and A Goy 14 2979 Background Results Pharmacodynamic Analyses of Serum Chemokine and Cytokine Levels (Part 1 only) Conclusion Study Design • PI3K-δ and PI3K-γ isoforms are central to the growth and survival of certain B- and T-cell malignancies 1-7 • Duvelisib (IPI-145), an oral dual inhibitor of PI3K-δ and PI3K-γ, is being developed for the treatment of hematologic malignancies • Duvelisib disrupts PI3K-δ,γ-mediated signaling within tumor cells and their interactions with the tumor microenvironment (TME), hindering hematologic tumor cell survival 8-9 Presented at 58th Annual Meeting of the American Society of Hematology • December 4, 2016 • San Diego, California 1 Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; 2 Hospital Universitario Germans Trias i Pujol, Badalona, Spain; 3 AZ GROENINGE, Kortrijk, Belgium; 4 Division of Hematology/Oncology, Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA; 5 Department of Hematology, ICO L’Hospitalet-Hospital Duran i Reynals, L’Hospitalet de Ll., Spain; 6 St. James’s Univ. Hospital Trust, Leeds, GBR; 7 University Hospital of Bordeaux, CHU Haut-Leveque, Bordeaux, France; 8 Charles A Sammons Cancer Center, Baylor Research Institute, Dallas, TX, USA; 9 St. Augustinus, Wilrijk, Belgium; 10 Hospital Bretonneau - Regional Center of Oncology, University Hospital of Tours, Tours, France; 11 ASST Sette Laghi, University Hospital Ospedale di Circolo e Fondazione Macchi, Varese, Italy; 12 Stanford Cancer Institute, Stanford University Medical Center, Stanford, CA, USA; 13 Infinity Pharmaceuticals, Inc., Cambridge, MA; 14 John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ, USA Patient Disposition (Part 1 and Part 2) Table 1: Patient Disposition and Analysis Sets Duvelisib + Obinutuzumab Duvelisib + Rituximab Part 1 – Safety Lead-in, n 6 6 Part 2 – Expansion Phase, n 21 22 Full Analysis Set (Parts 1 + 2) Total, n 27 28 Patients On Combination Therapy, n (%) 16 (59) 19 (68) Patients Off Combination Therapy, n (%) 11 (41) 9 (32) Reason for Discontinuation of Duvelisib*, n (%) Adverse event Disease progression Investigator decision Patient withdrawal Death 4 (15) 2 (7) 2 (7) 3 (11) 0 7 (25) 1 (4) 0 0 1 (4) DLT = dose-limiting toxicity * 6 pts off duvelisib remain on O; 1 pt off duvelisib remains on R; no pts discontinued R or O and remained on duvelisib DLT Results (Part 1 only) • 1 DLT occurred on the DO arm: Grade 3 elevated lipase on Day 8 of study treatment; duvelisib interrupted, obinutuzumab continued, AE resolved, and patient continued treatment • No DLTs occurred on the DR arm • Based on observed toxicities in Part 1, Part 2 was initiated for both treatment arms PK Results (Part 1 only) • At C2D1, the mean duvelisib trough concentrations were 613 ng/mL (SD, 598) (DO, n = 6) and 465 ng/mL (SD, 426) (DR, n = 6) • The C2D1 mean duvelisib trough concentrations are comparable to monotherapy, range of 471 – 531 ng/mL (data from Phase 1 study) Extent of Exposure (Part 1 and Part 2) • Median exposure to duvelisib on DR arm was 6.2 mo. (Range: 1-15 months) • Median exposure to duvelisib on DO arm was 6.1 mo. (Range: 1-14 months) • The relative dose intensity of duvelisib for both arms was high (mean 87-91%) Efficacy (Part 1 and Part 2) Study Patients (Part 1 and Part 2) Table 2: Patient Demographics and Disease History Duvelisib + Obinutuzumab (N = 27) Duvelisib + Rituximab (N = 28) Baseline Characteristics Age (years), median 58 58 Male, n (%) 11 (41) 18 (64) ECOG PS, n (%) 0 1 16 (59) 11 (41) 16 (57) 12 (43) Disease History FL Grade at Study Entry, n (%) 1 2 3a Not Reported 13 (48) 9 (33) 4 (15) 1 (4) 6 (21) 18 (64) 3 (11) 1 (4) Time from initial diagnosis to first dose (mo.) Median Min, Max 2.3 0.5, 50 2.3 0.8, 98 Bone marrow involvement, n (%) 17 (63) 15 (54) GELF Criteria ≥ 3 Nodal Sites ≥ 3 cm, n (%) Any nodal/extranodal mass ≥ 7 cm, n (%) B-Symptoms, n (%) 17 (63) 7 (26) 2 (7) 13 (46) 14 (50) 3 (11) Safety (Part 1 and Part 2) • Duvelisib plus obinutuzumab – 25 of 27 (93%) patients had an AE; 22 (82%) patients had an AE assessed as ≥ Grade 3 – Six (22%) patients had an AE that led to duvelisib discontinuation • Duvelisib plus rituximab – 27 of 28 (96%) patients had an AE; 16 (57%) patients had an AE assessed as ≥ Grade 3 – Seven (25%) patients had an AE that led to duvelisib discontinuation Table 4: AEs Occurring in > 15% of Patients on Either Arm Duvelisib + Obinutuzumab (N = 27) Duvelisib + Rituximab (N = 28) Any ≥ Grade 3 Any ≥ Grade 3 ALT increased 12 (44.4) 7 (25.9) 9 (32.1) 7 (25.0) AST increased 11 (40.7) 4 (14.8) 8 (28.6) 3 (10.7) Nausea 9 (33.3) 0 6 (21.4) 0 Pyrexia 8 (29.6) 1 (3.7) 6 (21.4) 0 Diarrhoea 7 (25.9) 3 (11.1) 13 (46.4) 4 (14.3) Fatigue 7 (25.9) 2 (7.4) 9 (32.1) 0 Abdominal pain 6 (22.2) 0 3 (10.7) 0 Decreased appetite 6 (22.2) 2 (7.4) 1 ( 3.6) 1 (3.6) Rash 6 (22.2) 2 (7.4) 8 (28.6) 3 (10.7) Cough 5 (18.5) 0 6 (21.4) 0 Nasopharyngitis 5 (18.5) 0 1 ( 3.6) 0 Neutropenia 6 (22.2) 6 (22.2) 4 (14.3) 3 (10.7) Vomiting 5 (18.5) 1 (3.7) 3 (10.7) 0 Constipation 4 (14.8) 0 5 (17.9) 1 (3.6) Anxiety 3 (11.1) 0 5 (17.9) 0 Asthenia 3 (11.1) 1 (3.7) 5 (17.9) 0 Back pain 3 (11.1) 0 6 (21.4) 0 • Duvelisib plus obinutuzumab – The most common ≥ Grade 3 AEs (>2 pts) were ALT increased (26%), neutropenia (22%), AST increased (15%), diarrhea and colitis (11%, each) – The rate of infection was 56%, with 15% of events ≥ Grade 3: only 1 event of severe opportunistic infection (RSV pneumonia) • Duvelisib plus rituximab – The most common ≥ Grade 3 AEs (>2 pts) were ALT increased (25%) diarrhea (14%), and AST increased, neutropenia, and rash (11%, each) – AEs leading to duvelisib discontinuation were lipase increased (Grade 2, assessed as related) and hepatitis (Grade 4, assessed as related) – The rate of infections was 46%, with 14% ≥ Grade 3: severe opportunistic infections in 2 pts (2 events of PJP pneumonia, and 1 ARDS due to CMV pneumonia); both pts with PJP were not receiving prophylaxis at the time events • Encouraging preliminary results in first-line treatment of FL patients with duvelisib, an oral dual PI3K-δ,γ inhibitor, in combination with rituximab or obinutuzumab • The safety lead-in phase completed successfully; 55 patients have been treated and enrollment has been terminated early by the sponsor • Plasma concentrations of duvelisib with either combination were similar to duvelisib monotherapy, suggesting no drug-drug interaction • The safety profile of duvelisib in combination with either obinutuzumab or rituximab in patients with front line FL is consistent with the previously established safety profile of duvelisib as monotherapy • Preliminary clinical activity with duvelisib plus obinutuzumab (81% ORR, 23% CR) and duvelisib plus rituximab (93% ORR, 22% CR) is encouraging • These preliminary results support the potential therapeutic benefit of duvelisib in combination with an anti-CD20 monoclonal antibody as initial treatment for patients with FL • Serum concentrations of 24 analytes were measured using Luminex xMAP Technologies Table 3: Baseline Serum Analyte Levels (Geometric Mean) Significantly Elevated in Untreated FL Patients Compared to Healthy Donors (p < 0.003) Analyte Healthy Donor pg/mL (N = 33) Previously Untreated FL C1D1 pg/mL (N = 9-12) % Elevated CCL17 6.7 335.4 4936 CCL19 37.6 461.0 1126 CCL22 674.0 2649.5 293 CCL4 6.1 19.9 227 CXCL11 10.0 71.5 615 CXCL13 4.0 145.3 3506 CXCL5 131.0 656.3 401 CXCL9 272.9 2307.7 746 IL-2RA 240.1 1340.7 458 TNFα 7.4 34.5 364 TRAIL 42.7 113.4 166 • Elevated chemokine and cytokine levels in the untreated FL patients likely reflect active communication between malignant cells and non-malignant cells in the FL TME References: 1) Puri and Gold. Front Immunol. 2012; 3: 256 2) Rommel et al. Nature Reviews Immun. 2007; 7:191-201 3) Rückle et al. Nature Reviews Drug Discovery. 2006; 5:903-18 4) Sasaki et al. Science. 2000; 287:1040-6 5) Hirsch et al. Science. 2000; 287:1049-53 6) Laffargue et al. Immunity. 2002; 16, 441–51 7) Balakrishnan et al. ASH 2013 Poster 4167 8) Douglas et al. ASH 2013. Poster 1633 9) Flinn et al. ASH 2013. (oral presentation) 10) Rawal et al. Journal of Immunology. 2013; 190:6681-6693 Median Percent Change CCL17 CCL19 CCL22 CCL4 CXCL11 CXCL13 CXCL5 CXCL9 IL-2RA TNFα TRAIL N= 12 12 11 11 12 12 11 10 11 11 12 12 12 12 9 9 12 12 12 12 12 12 0.6 0.4 0.2 0 -0.2 -0.4 -0.6 -0.8 -1 Cycle 1-Day 8 Cycle 2-Day 1 ‡ * Figure 2: Mean Duvelisib Trough Concentrations 2000 1500 1000 0 500 Duvelisib PK Concentration (ng/mL) DO Arm (n = 6) DR Arm (n = 6) 613 465 Mean Median Figure 1: Best Overall Response Rate (ORR) by Investigator Assessment 0 20 40 60 80 100 DO Arm (n = 26) DR Arm (n = 27) ORR = 81% ORR = 92% Complete Response (CR) Partial Response (PR) Percent Response 23% 58% 22% 70% Figure 3: Median Percent Change from Baseline in Serum Analytes upon DO and DR Treatment (Combined Data) Dr. Casulo has received consultancy and honoraria (CH) from Infinity and research finding from Celgene. Dr. Sancho has received CH from Roche, Gilead, and Janssen, participated with Sanofi in an advisory capacity, and received research finding from Celltrion. Dr. Gyan has received funding from Gilead, Mundipharma, Roche, Celgene, and Novartis, with honoraria from Freseniu Kabi, Pierre Fabre, Sanofi, and Amgen. Dr. Goy has received funding and/or support from Celgene and Takeda. Dr. Pearlberg and Ms. Steelman are employees of Infinity.
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Error bars represent 25th & 75th percentiles. Paired t-test with Bonferroni correction to evaluate change from baseline: * p<0.005 and ‡ p<0.008.
• Some analytes previously reported to be decreased with duvelisib monotherapy treatment in relapsed/refractory iNHL were decreased in this untreated FL population (CCL17, CCL22, CXCL13, TNFα); modulation of these factors may impact tumor cell migration and recruitment of regulatory T cells10
• The decrease in serum chemokine and cytokine levels provides evidence of biological activity via modulation of the TME
• The CONTEMPO study (NCT02391545) is designed to evaluate the safety and clinical activity of duvelisib in combination with rituximab or obinutuzumab in previously untreated CD20+ Follicular Lymphoma (FL)
– Disease response assessments (CT scans and physical exams) on Day 1 of C4, C8, C12, C16, C20, and C26
• Mandatory prophylaxis for PJP was added in an amendment to the protocol
Part 1: Safety Lead-in• Patients enrolled in alternating fashion in one of two parallel treatment arms
– Arm 1: duvelisib 25 mg BID plus rituximab (DR) (n = 6) – Arm 2: duvelisib 25 mg BID plus obinutuzumab (DO) (n = 6)
DLTs: any of the following treatment-related events in Cycle 1
Hematologic Toxicities Non-Hematologic Toxicities
• Grade 4 neutropenia for ≥ 7 days• ≥ Grade 3 febrile neutropenia• Grade 4 thrombocytopenia ≥ 7 days• ≥ Grade 3 thrombocytopenia associated with ≥
Grade 2 hemorrhage• New ≥ Grade 3 anemia requiring transfusion in
a subject previously transfusion-independent
• Any ≥ Grade 3 toxicity• Any AE requiring > 25% of scheduled study
drug(s) to be withheld during Cycle 1• Any Grade 4 infusion-related reaction (IRR) • Recurrent IRR ≥ Grade 3 requiring
discontinuation of obinutuzumab or rituximab while receiving duvelisib
DLT = dose-limiting toxicity.
Part 2: Two-Stage Design• Simon 2-stage design for each treatment arm • Total planned enrollment Part 2: 48 patients per arm• The study has been closed to enrollment; 27 patients receive D +O and 28
patients received D +R
Dosing• Duvelisib: 25 mg orally BID continuously in 28-day cycles until disease
progression or unacceptable toxicity• Rituximab 375 mg/m2 IV infusion or obinutuzumab 1000 mg IV infusion
– Cycle 1: D1, D8, D15, and D22 (Induction Period) – Cycles 4+: Every 2 cycles for up to 2 years (12 doses) (Maintenance Period)
Key Inclusion Criteria• Previously untreated CD20+ FL• Stage II with bulky disease (≥ 7 cm lesion), or Stage III-IV disease• At least 1 measurable disease lesion > 1.5 cm• Adequate liver and renal function• No clinical evidence of transformation to a more aggressive subtype of
lymphoma or Grade 3B FL
Safety, Pharmacokinetics, and Pharmacodynamics of Duvelisib Plus Rituximab or Obinutuzumab in Patients with Previously Untreated CD20+ Follicular LymphomaC Casulo1, JM Sancho2*, K Van Eygen3*, S de Vos4, S Mercadal5*, RJ Johnson6, K Bouabdallah7*, H Holmes8, J Lemmens9, E Gyan10*, M Merli11*, RH Advani12, L Steelman13*, J Pearlberg13* and A Goy142979
Background Results
Pharmacodynamic Analyses of Serum Chemokine and Cytokine Levels (Part 1 only)
Conclusion
Study Design
• PI3K-δ and PI3K-γ isoforms are central to the growth and survival of certain B- and T-cell malignancies1-7
• Duvelisib (IPI-145), an oral dual inhibitor of PI3K-δ and PI3K-γ, is being developed for the treatment of hematologic malignancies
• Duvelisib disrupts PI3K-δ,γ-mediated signaling within tumor cells and their interactions with the tumor microenvironment (TME), hindering hematologic tumor cell survival8-9
Presented at 58th Annual Meeting of the American Society of Hematology • December 4, 2016 • San Diego, California
1 Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; 2Hospital Universitario Germans Trias i Pujol, Badalona, Spain; 3AZ GROENINGE, Kortrijk, Belgium; 4Division of Hematology/Oncology, Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA; 5Department of Hematology, ICO L’Hospitalet-Hospital Duran i Reynals, L’Hospitalet de Ll., Spain; 6St. James’s Univ. Hospital Trust, Leeds, GBR; 7University Hospital of Bordeaux, CHU Haut-Leveque, Bordeaux, France; 8Charles A Sammons Cancer Center, Baylor Research Institute, Dallas, TX, USA; 9St. Augustinus, Wilrijk, Belgium; 10Hospital Bretonneau - Regional Center of Oncology, University Hospital of Tours, Tours, France; 11ASST Sette Laghi, University Hospital Ospedale di Circolo e Fondazione Macchi, Varese, Italy;
12Stanford Cancer Institute, Stanford University Medical Center, Stanford, CA, USA; 13Infinity Pharmaceuticals, Inc., Cambridge, MA; 14John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ, USA
Patient Disposition (Part 1 and Part 2)Table 1: Patient Disposition and Analysis Sets
Duvelisib + Obinutuzumab
Duvelisib + Rituximab
Part 1 – Safety Lead-in, n 6 6Part 2 – Expansion Phase, n 21 22Full Analysis Set (Parts 1 + 2) Total, n 27 28Patients On Combination Therapy, n (%) 16 (59) 19 (68)Patients Off Combination Therapy, n (%) 11 (41) 9 (32)Reason for Discontinuation of Duvelisib*, n (%) Adverse event Disease progression Investigator decision Patient withdrawal Death
4 (15)2 (7)2 (7)3 (11)
0
7 (25)1 (4)
0 0
1 (4)DLT = dose-limiting toxicity* 6 pts off duvelisib remain on O; 1 pt off duvelisib remains on R; no pts discontinued R or O and remained on duvelisib
DLT Results (Part 1 only)• 1 DLT occurred on the DO arm: Grade 3 elevated lipase on Day 8 of study treatment;
duvelisib interrupted, obinutuzumab continued, AE resolved, and patient continued treatment
• No DLTs occurred on the DR arm• Based on observed toxicities in Part 1, Part 2 was initiated for both treatment arms
PK Results (Part 1 only)• At C2D1, the mean duvelisib trough concentrations were 613 ng/mL (SD, 598)
(DO, n = 6) and 465 ng/mL (SD, 426) (DR, n = 6)• The C2D1 mean duvelisib trough concentrations are comparable to monotherapy, range
of 471 – 531 ng/mL (data from Phase 1 study)
Extent of Exposure (Part 1 and Part 2)• Median exposure to duvelisib on DR arm was 6.2 mo. (Range: 1-15 months) • Median exposure to duvelisib on DO arm was 6.1 mo. (Range: 1-14 months)
• The relative dose intensity of duvelisib for both arms was high (mean 87-91%)
Efficacy (Part 1 and Part 2)
Study Patients (Part 1 and Part 2)Table 2: Patient Demographics and Disease History
Duvelisib + Obinutuzumab (N = 27)
Duvelisib + Rituximab (N = 28)
Baseline CharacteristicsAge (years), median 58 58Male, n (%) 11 (41) 18 (64)ECOG PS, n (%) 0 1
16 (59)11 (41)
16 (57)12 (43)
Disease HistoryFL Grade at Study Entry, n (%) 1 2 3a Not Reported
13 (48)9 (33)4 (15)1 (4)
6 (21)18 (64)
3 (11)1 (4)
Time from initial diagnosis to first dose (mo.) Median Min, Max
2.30.5, 50
2.30.8, 98
Bone marrow involvement, n (%) 17 (63) 15 (54)
GELF Criteria ≥ 3 Nodal Sites ≥ 3 cm, n (%) Any nodal/extranodal mass ≥ 7 cm, n (%) B-Symptoms, n (%)
17 (63)7 (26)2 (7)
13 (46)14 (50)
3 (11)
Safety (Part 1 and Part 2)• Duvelisib plus obinutuzumab
– 25 of 27 (93%) patients had an AE; 22 (82%) patients had an AE assessed as ≥ Grade 3
– Six (22%) patients had an AE that led to duvelisib discontinuation• Duvelisib plus rituximab
– 27 of 28 (96%) patients had an AE; 16 (57%) patients had an AE assessed as ≥ Grade 3
– Seven (25%) patients had an AE that led to duvelisib discontinuation
Table 4: AEs Occurring in > 15% of Patients on Either Arm
Duvelisib + Obinutuzumab (N = 27)
Duvelisib + Rituximab (N = 28)
Any ≥ Grade 3 Any ≥ Grade 3ALT increased 12 (44.4) 7 (25.9) 9 (32.1) 7 (25.0)AST increased 11 (40.7) 4 (14.8) 8 (28.6) 3 (10.7)Nausea 9 (33.3) 0 6 (21.4) 0Pyrexia 8 (29.6) 1 (3.7) 6 (21.4) 0Diarrhoea 7 (25.9) 3 (11.1) 13 (46.4) 4 (14.3)Fatigue 7 (25.9) 2 (7.4) 9 (32.1) 0Abdominal pain 6 (22.2) 0 3 (10.7) 0Decreased appetite 6 (22.2) 2 (7.4) 1 ( 3.6) 1 (3.6)Rash 6 (22.2) 2 (7.4) 8 (28.6) 3 (10.7)Cough 5 (18.5) 0 6 (21.4) 0Nasopharyngitis 5 (18.5) 0 1 ( 3.6) 0Neutropenia 6 (22.2) 6 (22.2) 4 (14.3) 3 (10.7)Vomiting 5 (18.5) 1 (3.7) 3 (10.7) 0Constipation 4 (14.8) 0 5 (17.9) 1 (3.6)Anxiety 3 (11.1) 0 5 (17.9) 0Asthenia 3 (11.1) 1 (3.7) 5 (17.9) 0Back pain 3 (11.1) 0 6 (21.4) 0
• Duvelisib plus obinutuzumab – The most common ≥ Grade 3 AEs (>2 pts) were ALT increased (26%), neutropenia (22%), AST increased (15%), diarrhea and colitis (11%, each)
– The rate of infection was 56%, with 15% of events ≥ Grade 3: only 1 event of severe opportunistic infection (RSV pneumonia)
• Duvelisib plus rituximab – The most common ≥ Grade 3 AEs (>2 pts) were ALT increased (25%) diarrhea (14%), and AST increased, neutropenia, and rash (11%, each)
– AEs leading to duvelisib discontinuation were lipase increased (Grade 2, assessed as related) and hepatitis (Grade 4, assessed as related)
– The rate of infections was 46%, with 14% ≥ Grade 3: severe opportunistic infections in 2 pts (2 events of PJP pneumonia, and 1 ARDS due to CMV pneumonia); both pts with PJP were not receiving prophylaxis at the time events
• Encouraging preliminary results in first-line treatment of FL patients with duvelisib, an oral dual PI3K-δ,γ inhibitor, in combination with rituximab or obinutuzumab
• The safety lead-in phase completed successfully; 55 patients have been treated and enrollment has been terminated early by the sponsor
• Plasma concentrations of duvelisib with either combination were similar to duvelisib monotherapy, suggesting no drug-drug interaction
• The safety profile of duvelisib in combination with either obinutuzumab or rituximab in patients with front line FL is consistent with the previously established safety profile of duvelisib as monotherapy
• Preliminary clinical activity with duvelisib plus obinutuzumab (81% ORR, 23% CR) and duvelisib plus rituximab (93% ORR, 22% CR) is encouraging
• These preliminary results support the potential therapeutic benefit of duvelisib in combination with an anti-CD20 monoclonal antibody as initial treatment for patients with FL
• Serum concentrations of 24 analytes were measured using Luminex xMAP Technologies
Table 3: Baseline Serum Analyte Levels (Geometric Mean) Significantly Elevated in Untreated FL Patients Compared to Healthy Donors (p < 0.003)
Analyte Healthy Donor pg/mL (N = 33)
Previously Untreated FL
C1D1 pg/mL (N = 9-12) % Elevated
CCL17 6.7 335.4 4936CCL19 37.6 461.0 1126CCL22 674.0 2649.5 293CCL4 6.1 19.9 227CXCL11 10.0 71.5 615CXCL13 4.0 145.3 3506CXCL5 131.0 656.3 401CXCL9 272.9 2307.7 746IL-2RA 240.1 1340.7 458TNFα 7.4 34.5 364TRAIL 42.7 113.4 166
• Elevated chemokine and cytokine levels in the untreated FL patients likely reflect active communication between malignant cells and non-malignant cells in the FL TME References: 1) Puri and Gold. Front Immunol. 2012; 3: 256 2) Rommel et al. Nature Reviews Immun. 2007; 7:191-201 3) Rückle
et al. Nature Reviews Drug Discovery. 2006; 5:903-18 4) Sasaki et al. Science. 2000; 287:1040-6 5) Hirsch et al. Science. 2000; 287:1049-53 6) Laffargue et al. Immunity. 2002; 16, 441–51 7) Balakrishnan et al. ASH 2013 Poster 4167 8) Douglas et al. ASH 2013. Poster 1633 9) Flinn et al. ASH 2013. (oral presentation) 10) Rawal et al. Journal of Immunology. 2013; 190:6681-6693
Med
ian
Perc
ent C
hang
e
CCL1
7
CCL1
9
CCL2
2
CCL4
CXCL
11
CXCL
13
CXCL
5
CXCL
9
IL-2
RA
TNFα
TRAI
L
N= 12 12 11 11 12 12 11 10 11 11 12 12 12 12 9 912 12 12 12 12 12
0.6
0.4
0.2
0
-0.2
-0.4
-0.6
-0.8
-1
Cycle 1-Day 8Cycle 2-Day 1
‡*
Figure 2: Mean Duvelisib Trough Concentrations2000
1500
1000
0
500Duve
lisib
PK
Conc
entr
atio
n (n
g/m
L)
DO Arm(n = 6)
DR Arm(n = 6)
613465
MeanMedian
Figure 1: Best Overall Response Rate (ORR) by Investigator Assessment
0
20
40
60
80
100
DO Arm(n = 26)
DR Arm(n = 27)
ORR = 81%ORR = 92%
CompleteResponse (CR)
PartialResponse (PR)
Perc
ent R
espo
nse
23%
58%
22%
70%
Figure 3: Median Percent Change from Baseline in Serum Analytes upon DO and DR Treatment (Combined Data)
Dr. Casulo has received consultancy and honoraria (CH) from Infinity and research finding from Celgene. Dr. Sancho has received CH from Roche, Gilead, and Janssen, participated with Sanofi in an advisory capacity, and received research finding from Celltrion. Dr. Gyan has received funding from Gilead, Mundipharma, Roche, Celgene, and Novartis, with honoraria from Freseniu Kabi, Pierre Fabre, Sanofi, and Amgen. Dr. Goy has received funding and/or support from Celgene and Takeda. Dr. Pearlberg and Ms. Steelman are employees of Infinity.
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