Objective For infants with single ventricle malformations undergoing staged repair, interstage mortality is reported at 2% to 20%. The Single Ventricle Reconstruction trial randomized subjects with a ...single morphologic right ventricle undergoing a Norwood procedure to a modified Blalock–Taussig shunt (MBTS) or a right ventricle-to-pulmonary artery shunt (RVPAS). The aim of this analysis was to explore the associations of interstage mortality and shunt type, and demographic, anatomic, and perioperative factors. Methods Participants in the Single Ventricle Reconstruction trial who survived to discharge after the Norwood procedure were included (n = 426). Interstage mortality was defined as death postdischarge after the Norwood procedure and before the stage II procedure. Univariate analysis and multivariable logistic regression were performed adjusting for site. Results Overall interstage mortality was 50 of 426 (12%)—13 of 225 (6%) for RVPAS and 37 of 201 (18%) for MBTS (odds ratio OR for MBTS, 3.4; P < .001). When moderate to severe postoperative atrioventricular valve regurgitation (AVVR) was present, interstage mortality was similar between shunt types. Interstage mortality was independently associated with gestational age less than 37 weeks (OR, 3.9; P = .008), Hispanic ethnicity (OR, 2.6; P = .04), aortic atresia/mitral atresia (OR, 2.3; P = .03), greater number of post-Norwood complications (OR, 1.2; P = .006), census block poverty level ( P = .003), and MBTS in subjects with no or mild postoperative AVVR (OR, 9.7; P < .001). Conclusions Interstage mortality remains high at 12% and is increased with the MBTS compared with the RVPAS if postoperative AVVR is absent or mild. Preterm delivery, anatomic, and socioeconomic factors are also important. Avoiding preterm delivery when possible and close surveillance after Norwood hospitalization for infants with identified risk factors may reduce interstage mortality.
Duvelisib (IPI‐145) is an oral dual inhibitor of phosphoinositide‐3‐kinase (PI3K)‐δ and ‐γ in clinical development for the treatment of hematologic malignancies, including indolent non‐Hodgkin ...lymphoma (iNHL). In a Phase 1, open‐label study to determine the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, clinical activity, and safety of duvelisib monotherapy in patients with advanced hematologic malignancies, duvelisib was administered at eight dose levels (8‐100 mg BID) in a dose‐escalation phase (n = 31 evaluable patients). Two dose‐limiting toxicities (DLTs), Grade 3 transaminase elevations and Grade 3 rash, occurred at 100 mg BID, and the MTD was determined to be 75 mg BID. Across all doses, 58.1% of iNHL patients had a response (19.4% complete, 35.5% partial, and 3.2% minor); median time to response was 1.84 months and duration of response was 16.9 months. Median progression‐free survival was 14.7 months, and the probability of overall survival at 24 months was 71.7%. Severe (Grade ≥ 3) adverse events included elevated liver enzymes (38.7%), diarrhea (25.8%), and neutropenia (29.0%). Three patients, all in the 75 mg BID cohort, experienced fatal AEs: E. coli sepsis, acute respiratory failure, and fungal pneumonia. No iNHL patients experienced Pneumocystis pneumonia. Duvelisib demonstrated favorable clinical activity and an acceptable safety profile in these high‐risk, heavily pretreated, relapsed/refractory iNHL patients, with 25 mg BID selected for further clinical development.
Duvelisib (IPI‐145), an oral, dual inhibitor of phosphoinositide‐3‐kinase (PI3K)‐δ and ‐γ, was evaluated in a Phase 1 study in advanced hematologic malignancies, which included expansion cohorts in ...relapsed/refractory (RR) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and treatment‐naïve (TN) CLL. Per protocol, TN patients were at least 65 years old or had a del(17p)/TP53 mutation. Duvelisib was administered twice daily (BID) in 28‐day cycles at doses of 8‐75 mg in RR patients (n = 55) and 25 mg in TN patients (n = 18.) Diarrhea was the most common nonhematologic AE (TN 78%, RR 47%); transaminase elevations the most frequent lab‐abnormality AE (TN 33.3%, RR 30.9%); and neutropenia the most common ≥grade 3 AE (RR 44%, TN 33%). The overall response rates were 56.4% for RR patients (1.8% CR, 54.5% PR) and 83.3% for TN patients (all PRs); median response duration was 21.0 months in RR patients but was not reached for TN patients. Based upon phase 1 efficacy, pharmacodynamics, and safety, duvelisib 25 mg BID was selected for further investigation in a phase 3 study in RR CLL/SLL.
Introduction: Peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) are uncommon lymphoid malignancies. Approved agents in the relapsed setting have overall response rates (ORR) in ...the range of 25-35%. Phosphoinositide-3-Kinases (PI3K) are pivotal in cell signaling and regulate multiple cellular functions relevant to oncogenesis. PI3K-δ and PI3K-γ isoforms are preferentially expressed in leukocytes with distinct roles in T-cell function. PI3K-δ and PI3K-γ are central to the growth and survival of certain T-cell malignancies and inhibition of PI3K is a therapeutic strategy for PTCL and CTCL. Duvelisib (IPI-145), an oral inhibitor of PI3K-δ and PI3K-γ, was studied in a phase 1 trial in hematologic malignancies with disease-specific expansion cohorts at the maximum tolerated dose (MTD). Responses were seen in a substantial number of patients with relapsed or refractory PTCL and CTCL.
Methods: This study evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of duvelisib administered twice daily (BID), continuously in 28-day cycles. Patients with relapsed or refractory leukemia or lymphoma received doses ranging from 8 mg to 100 mg BID. A disease-specific cohort at the MTD included PTCL and CTCL patients. The pharmacodynamics of duvelisib were assessed by early positron-emission tomography (PET) in a subset of patients and in serum through evaluation of a panel of cytokines, chemokines, and matrix metalloproteinase.
Results: Thirty-three patients with TCL (17 CTCL, 16 PTCL) received duvelisib primarily at the MTD of 75 mg BID (25 mg, n=1; 50 mg, n=1; 60 mg, n=4; 75 mg, n=25; 100 mg, n=2). The median age was 64 years (range: 34-86), and the median number of prior therapies was 4 (range: 1-11). The median time from last prior therapy to first dose of duvelisib was 1.05 months (range: 0.2-36). Thirty-one patients were evaluable for efficacy, with an ORR of 42% (13/31). The ORR in PTCL was 47% (7/15, 2 complete responses CR, 5 partial responses PR) and in CTCL 38% (6/16, 6 PR). The median time to response was 1.9 months (range: 1.5-3.8). Median overall survival (OS) was 36.4 weeks (95% CI: 18.6, –) for patients with PTCL. The median OS was not yet reached for patients with CTCL. The median number of treatment cycles was 3.1 (range: 0.5-12.5), with 14 (42%) on treatment ≥4 cycles (16 weeks).
Pharmacodynamic results showed that within 8 days of starting treatment with duvelisib, modulation of serum cytokines and chemokines known to play a role in leukocyte migration and support the tumor microenvironment was observed. Furthermore, a reduction in standard uptake value (SUV) from baseline was observed in 6/11 patients evaluated by PET at Cycle 1 Day 22. (All 6 patients with reduction in SUV received duvelisib ≥60 mg BID).
Twenty-six (79%) patients had adverse events (AEs) ≥Grade 3, with the most common (≥10%) being increased ALT/AST (n=12, 36%), rash (combined terms) (n=7, 21%), and neutropenia (n=5, 15%). Ten (30%) patients discontinued treatment due to an AE, with the most common (>1 patient) being increased ALT/AST n=5 (4 CTCL, 1 PTCL), 15%. Three TCL patients died on treatment or within 30 days of the last dose of duvelisib, one due to disease progression, one who declined supportive therapy, and one due to HSV pneumonia (patient was not receiving HSV prophylaxis).
Conclusions: Duvelisib has shown clinical activity in patients with relapsed/refractory TCL (ORR 42%, including 2 CR) with an acceptable safety profile that supports continued assessment in this heavily pretreated patient population. The preliminary results support further evaluation of duvelisib in patients with TCL, including additional studies in both CTCL and PTCL to determine the optimal dose and identify appropriate combination therapy.
Horwitz:Research: Celgene, Millennium, Infinity, Kiowa-Kirin, Seattle Genetics, Spectrum-Consulting: Amgen, Bristol-Myers Squibb, Celgene, Jannsen, Millennium, seattle genetics: Consultancy, Honoraria, Research Funding. Off Label Use: ipi-145 is not an approved drug. Porcu:Actelion (e), Cutaneous Lymphoma Foundation (h), United States Cutaneous Lymphoma Consortium (h), Infinity (d), Celgene (d), : Consultancy, Employment, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Flinn:Infinity Pharmaceuticals: Consultancy. Kahl:Infinity Pharmaceuticals: Consultancy, Research Funding. Sweeney:Infinity Pharmaceuticals: Employment. Stern:Infinity Pharmaceuticals, Inc.: Employment. Douglas:Infinity Pharmaceuticals, Inc.: Employment. Allen:Infinity Pharmaceuticals: Employment. Kelly:Infinity Pharmaceuticals: Employment. Foss:Eisai, Celgene, Seattle Genetics: Consultancy, Research Funding, Speakers Bureau.
Phosphoinositide-3 kinases (PI3Ks) are key cellular signaling proteins that act as a central node, relaying signals from cell surface receptors to downstream mediators such as AKT. The PI3K-δ and ...PI3K-γ isoforms are preferentially expressed in normal and malignant leukocytes where they play critical roles in cell differentiation, migration, and proliferation. IPI-145 is a potent, oral PI3K-δ,γ inhibitor that has shown clinical activity in the Phase 1 trial (IPI-145-02) in patients with advanced hematologic malignancies (ClinicalTrials.gov NCT01476657). Cytokines, chemokines, and matrix metalloproteinases (MMPs) play key roles in the homing, migration and activation of normal immune cells, and can have similar effects on malignant leukocytes. To further explore the biological effects of IPI-145, a panel of cytokines, chemokines, and MMPs were evaluated at several time points in the serum of patients enrolled in the IPI-145-02 trial.
Serum was collected from consenting subjects at baseline, Cycle 1 Day 8 (C1D8), and Cycle 2 Day 1 (C2D1). Serum was frozen and stored at -80°C prior to analysis. Serum proteins were analyzed using Luminex xMAP(®) technology in which analytes are captured on uniquely labeled fluorescent beads, and the amount of analyte is quantified using an LED CCD camera contained in Millipore's MagPix(®) instrument. Multiplex panels of cytokines, chemokines and MMPs covering 72 analytes were evaluated in 30 chronic lymphocytic leukemia (CLL) and 19 indolent non-Hodgkin lymphoma (iNHL) subjects. Each sample was tested in duplicate, and duplicate measurements were averaged. Measurements were excluded from further analysis if duplicate readings exhibited a coefficient of variation of greater than 20% or if all values for a specific analyte and subject were below the limit of detection.
Each analyte was evaluated for evidence of a consistent change (reduction or increase) in serum levels at C1D8 and/or C2D1 compared to baseline. When data were compared between CLL subjects treated with IPI-145 at 25 mg twice daily (BID) and those treated at 75 mg BID, no clear differences in serum analyte levels were observed, although the population subgroups were relatively small. For the purposes of this analysis, all doses were pooled together (n=1 at 8 mg BID, 2 at 15 mg BID, 15 at 25 mg BID, and 13 at 75 mg BID). Likewise, the iNHL dose groups were also pooled (n=1 at 15 mg BID, 12 at 25 mg BID, 1 at 50 mg BID, and 5 at 75 mg BID). In CLL subjects, 9 of 72 analytes decreased after IPI-145 treatment compared to baseline, whereas none increased significantly. Analytes that decreased after IPI-145 treatment include CXCL13, CCL3, CCL4, IL-10, TNFα, IL-12p40, MMP-9, CCL17 and CCL22. Median serum levels of these analytes decreased by C1D8, ranging from 16% to 59% of baseline. In iNHL subjects, median serum levels of 7 analytes decreased by C1D8 (ranging from 32% to 70% of baseline), whereas none increased significantly. Of the 7 analytes that decreased in iNHL subjects, 5 also decreased in CLL subjects (CXCL13, MMP-9, TNFα, CCL17 and CCL22) and 2 were distinct (CCL1 and MMP-12). Interestingly, many of the analytes that decreased with IPI-145 treatment are involved in the communication between malignant B-cells and the microenvironment. CCL3, CCL4, CCL17 and CCL22 are expressed by malignant B-cells and may play a role in recruiting T-cells to interact with the malignant B-cells. CXCL13 is secreted by stromal cells and recruits malignant B-cells to the lymph nodes. In addition, IL-10 is produced by many normal immune cell types as well as by neoplastic B-cells. IL-10 is known to be an autocrine growth factor for B-cell lymphoma cell lines.
These pharmacodynamic data provide further evidence for biological activity of IPI-145 in patients with CLL and iNHL and suggest both similarities and differences in how these two malignancies respond to IPI-145. The association of many of these pharmacodynamic factors with the tumor microenvironment suggests a mechanistic basis for the clinical observation of lymphocytosis and nodal reduction with IPI-145 treatment of CLL subjects. Cytokine, chemokine and MMP levels from patients in IPI-145-02 are being evaluated further for associations with multiple clinical parameters to determine if there is evidence for biomarkers predictive of efficacy and tolerability.
Douglas:Infinity Pharmaceuticals, Inc.: Employment. Allison:Infinity Pharmaceuticals, Inc.: Employment. Ted:Infinity Pharmaceuticals, Inc.: Employment. Allen:Infinity Pharmaceuticals, Inc.: Employment. Kahl:Infinity Pharmaceuticals, Inc.: Consultancy, Research Funding. Horwitz:Celgene, Allos, Seattle Genetics, Bristol-Myers Squibb, Genzyme, Kyowa, Janssen, Johnson & Johnson, Millenium: Consultancy; Celgene, Allos, Seattle Genetics, Kyowa, Infinty, Millenium: Research Funding. Flinn:Infinity Pharmaceuticals, Inc.: Consultancy, Research Funding. Kelly:Infinity Pharmaceuticals, Inc.: Employment. Stern:Infinity Pharmaceuticals, Inc.: Employment.
Introduction: Duvelisib (IPI-145) belongs to an emerging class of therapeutic small molecule kinase inhibitors that target B-cell receptor (BCR) signaling pathways important in various ...lymphoproliferative disorders. Duvelisib, a novel oral inhibitor of PI3K-δ,γ, has shown clinical activity across a range of hematologic malignancies in an ongoing Phase 1 study.
Some patients (pts) treated with ibrutinib (IBR), a BCR inhibitor that targets Bruton’s tyrosine kinase (BTK), have had disease progression and various mechanisms of IBR resistance have been characterized. Since the mechanism of action of duvelisib differs from IBR, duvelisib was evaluated in a subset of pts previously treated with IBR enrolled in an ongoing Phase I study.
Methods: The study was designed to evaluate the safety, maximum tolerated dose, pharmacokinetics, and activity of orally administered duvelisib twice daily in 28-day cycles. Pts with relapsed/refractory (R/R) hematologic malignancies were enrolled, including pts previously treated with IBR with R/R chronic lymphocytic leukemia (CLL) and aggressive B-cell NHL (aNHL including DLBCL and Richter’s transformation RT). Pharmacodynamic studies in CLL pts with measurable disease in the peripheral blood (PB) included flow cytometry to evaluate whether duvelisib inhibits the phosphorylation of AKT (pAKT) at S473 and the CLL cell proliferation index via measurement of Ki67. DNA sequencing on malignant PB cells was performed to determine the mutation status of BTK and other genes involved in hematologic malignancies. Clinical responses were based on IWCLL (2008) criteria and revised IWG (2007) criteria as applicable.
Results: Twelve pts previously treated with IBR were enrolled (R/R CLL, n=6; aNHL, n=6 DLBCL=2; RT=4) and received IPI-145 at 25 mg BID (n=2) or 75 mg BID (n=10). The median age in R/R CLL pts was 58 years (y) (42-76), 67% were male, 100% had ≥3 prior systemic therapies, the median time from prior therapy to first dose of duvelisib was 0.34 months (mo) (0.0-1.6), and 67% started duvelisib within 2 wks of last dose of IBR. The median age in R/R aNHL pts was 62 y (36-81), 67% were male, 50% had ≥3 prior systemic therapies, a median time from last prior therapy to first dose of duvelisib of 0.74 months (0.2-3.7), and 50% started duvelisib within 3 weeks of last dose of IBR.
With a median of 4.1 treatment cycles (range 3.0-9.2) in the R/R CLL pts and 2.5 treatment cycles (range 1.8-5.4) in R/R aNHL pts, the safety profile in these pts previously treated with IBR appears consistent with all pts (n=206) with advanced hematologic malignancies receiving duvelisib. The best response observed in R/R CLL pts includes 1 partial response (PR) and 5 stable disease (SD). Of these 6 pts, 2 pts (1 PR, 1 SD) remain on duvelisib for 8 and 9 months, respectively, and 4 pts have discontinued treatment (progressive disease PD, n=3; physician decision, n=1). The best response observed in R/R aNHL pts included 2 PRs, 1 SD, 2 PD, and 1 not evaluated NE. Three pts remain on duvelisib (1 PR, 1 SD, 1 NE) for 3-5 mo and 3 pts have discontinued treatment (progressive disease, n=2; AE, n=1).
The median baseline proliferative index (Ki67) in R/R CLL pts previously treated with IBR (n=5) was substantially higher (22.2% vs 3.8%) than in non-IBR exposed R/R CLL pts (n=23). Across both R/R CLL populations, Ki67 was reduced with duvelisib treatment by Cycle 2 Day 1 (at steady state); however, the effect was more pronounced in non-IBR treated pts. Despite this apparent difference in baseline proliferative index, the IBR previously treated pts with measureable disease in PB (R/R CLL=5), including 3 pts with a known IBR-resistance mutation in BTK (2 with C481S, 1 with C481F) demonstrated reductions of pAKT that were observed within 1 hour of duvelisib treatment and sustained through 24 hours postdose. This pAKT pharmacodynamic response was consistent with results in R/R CLL pts not previously treated with IBR (n=35).
Conclusions: Pharmacodynamic data demonstrates duvelisib inhibits pAKT in R/R CLL pts, including those with an IBR-resistance mutation in BTK, and is consistent with duvelisib having a non-overlapping MOA with IBR. Baseline Ki67 data suggest a more aggressive clinical phenotype in R/R CLL pts who progress on IBR compared to those without previous IBR treatment. Early evidence of clinical activity and a tolerable safety profile suggest additional studies of duvelisib in pts who have progressed on IBR are warranted.
Porcu:Actelion (e), Cutaneous Lymphoma Foundation (h), United States Cutaneous Lymphoma Consortium (h), Infinity (d), Celgene (d), : Consultancy, Employment, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: IPI-145. Flinn:Infinity Pharmaceuticals: Consultancy. Kahl:Infinity Pharmaceuticals: Consultancy, Research Funding. Horwitz:Research: Celgene, Millennium, Infinity, Kiowa-Kirin, Seattle Genetics, Spectrum-Consulting: Amgen, Bristol-Myers Squibb, Celgene, Jannsen, Millennium, seattle genetics: Consultancy, Honoraria, Research Funding. Oki:Infinity Pharmaceuticals: Research Funding. Byrd:Pharmacyclics, Genentech: Research Funding. Sweeney:Infinity Pharmaceuticals: Employment. Allen:Infinity Pharmaceuticals: Employment. Faia:Infinity Pharmaceuticals, Inc.: Employment. Ni:Infinity Pharmaceuticals: Employment. Stern:Infinity Pharmaceuticals, Inc.: Employment. Kelly:Infinity Pharmaceuticals: Employment.
Introduction: Signaling via PI3K-δ and PI3K-γ is essential for both normal and malignant B-cell and T-cell proliferation, survival, and migration. PI3K-δ and PI3K-γ have distinct and complimentary ...effects on malignant B-cells and nonmalignant immune cells important in tumor immunity and the tumor microenvironment. Duvelisib (IPI-145) is a novel targeted oral PI3K-δ,γ inhibitor in development for the treatment of hematologic malignancies. An ongoing Phase 1 study has demonstrated substantial clinical activity in patients (pts) with advanced hematologic malignancies, including pts with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL).
Methods: This study evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of duvelisib administered continuously in 28-day cycles. The optimal biological dose (supported by pharmacodynamic studies and clinical activity) selected for chronic administration in iNHL (25 mg BID) was further evaluated in expansion cohorts in R/R iNHL pts while additional testing up to the MTD (75 mg BID) was pursued to further characterize safety and activity. iNHL clinical responses were evaluated based on revised IWG (2007) criteria with additional criteria for Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) where appropriate.
Results: A total of 32 pts with R/R iNHL (follicular lymphoma, marginal zone lymphoma and WM/LPL) were enrolled, including 16 pts dosed at 25 mg BID (1 pt received 15 mg BID). The median age was 65 years range: 37-78 and 56% were male. Nineteen (59%) pts had ≥3 prior systemic therapies and 34% were <6 months from their most recent therapy. Baseline cytopenias ≥Grade 1 at study entry were: anemia n=19 (61%), neutropenia n=8 (26%), and thrombocytopenia n=8 (26%).
The R/R iNHL pts received duvelisib at doses ranging from 15 mg BID to 75 mg BID. Pharmacokinetic data demonstrated that exposure (AUC and Cmax) increased across the dose range evaluated. There was evidence of pharmacodynamic modulation based on reductions in serum cytokines and chemokines known to support the malignant B-cell microenvironment. Despite increasing exposure above 25 mg BID, cytokine and chemokine reductions were similar at doses of 25 mg BID or higher.
Consistent with the pharmacodynamic observations, clinical activity was observed in R/R iNHL pts at all doses of duvelisib evaluated (15 mg BID to 75 mg BID). In the efficacy evaluable population (n=31), the ORR was 65% with a best response of 5 complete responses (CR) (all follicular), 14 partial responses (PR), 1 minor response (MR), 9 stable disease (SD) and 2 progressive disease (PD), and with a median time to response of 1.8 months. For the subset of 15 evaluable pts treated at 25 mg BID (1 pt received 15 mg BID), the ORR was 73% (including 4 CRs). This pt subset has received a median of 11 treatment cycles (range: 1.1-28.7), with 47% (7/15) remaining on long-term treatment (1 to >2 years).
The overall safety profile has been consistent across the range of doses studied in R/R iNHL pts (median of 6 treatment cycles range: 0.1-28.7). The majority of adverse events (AEs) were Grade 1-2, reversible and/or clinically manageable. The most common ≥Grade 3 treatment-emergent AEs (≥15%, all causality) were ALT/AST increase (n=13 41%) with a median time to occurrence of 50 days (range: 5-448), and diarrhea (n=7 22%) with a median time to occurrence of 124 days (range: 36-434). In addition, transient ≥Grade 3 neutropenia was reported in 10 pts (31%), including 6 pts who entered the study with baseline neutropenia. The most common reasons for treatment discontinuation included AEs (10/32, 31%) and disease progression (7/32, 22%).
Conclusions: Duvelisib (IPI-145), a novel oral PI3K-δ,γ inhibitor, appears generally well tolerated with an acceptable safety profile across the dose range evaluated. Evidence of clinical activity in pts with R/R iNHL was observed with an ORR of 65% including CRs in 25% (5/20) of responding pts. Based on these promising results which suggest a positive benefit-risk in this pt population, registration trials in pts with iNHL evaluating 25 mg BID as a monotherapy or in combination with rituximab are ongoing or planned, respectively.
Flinn:Infinity Pharmaceuticals: Consultancy. Off Label Use: This is an investigational drug not FDA approved.. Oki:Infinity Pharmaceuticals Inc: Research Funding. Horwitz:Research: Celgene, Millennium, Infinity, Kiowa-Kirin, Seattle Genetics, Spectrum-Consulting: Amgen, Bristol-Myers Squibb, Celgene, Jannsen, Millennium, seattle genetics: Consultancy, Honoraria, Research Funding. Foss:Eisai, Celgene, Seattle Genetics: Consultancy, Research Funding, Speakers Bureau. Sweeney:Infinity Pharmaceuticals: Employment. Allen:Infinity Pharmaceuticals: Employment. Douglas:Infinity Pharmaceuticals, Inc.: Employment. Steelman:Infinity Pharmaceuticals: Employment. Dunbar:Infinity Pharmaceuticals Inc: Employment. Stern:Infinity Pharmaceuticals, Inc.: Employment. Kelly:Infinity Pharmaceuticals: Employment. Kahl:Infinity Pharmaceuticals Inc: Consultancy, Research Funding.
Introduction: Signaling via PI3K-δ and PI3K-γ has distinct and complimentary effects on malignant B-cells and nonmalignant immune cells important in tumor immunity, and on the tumor microenvironment ...involved in the support and maintenance of B-cell neoplasms, including chronic lymphocytic leukemia (CLL). Duvelisib (IPI-145), a novel targeted oral PI3K-δ,γ inhibitor, is in development for the treatment of hematologic malignancies. An ongoing Phase 1 study has demonstrated substantial clinical activity in patient (pts) with relapsed/refractory (R/R) CLL, including those with poor prognostic risk factors.
Methods: This study evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity of duvelisib administered in pts with advanced hematologic malignancies. Pharmacodynamic (PD) studies included peripheral blood (PB) flow cytometry to evaluate whether duvelisib inhibits phosphorylation of AKT (pAKT) and proliferation (Ki67) in CLL cells and serum sampling to evaluate modulation of cytokines and chemokines important for tumor microenvironment signaling. Genomic DNA was isolated from PB at baseline for Sanger sequencing of IGHV and next-generation sequencing of TP53. Following dose escalation, expansion cohorts enrolled CLL pts at 25 and 75 mg BID (MTD). Response was based on IWCLL (2008) criteria.
Results: The median age of the R/R CLL pts (n=54) was 66 y (range 42-82), 78% of whom were male. Forty-four (81.5%) pts received ≥3 prior systemic therapies. The median time from prior therapy to first dose of duvelisib was 3.5 mo (range 0-39.1). Baseline cytopenias ≥ Grade 2 were neutropenia (41%), thrombocytopenia (31%) and anemia (26%). Of the pts with baseline tests for mutations associated with poor CLL prognosis, 49% (23/47) had TP53mut and/or cytogenetic (del)17p and 89% (31/35) had an unmutated IGHV.
Duvelisib dosed at 25 mg BID provided an optimal biologic effect based on maximum pAKT inhibition in CLL cells (<24 hrs after a single dose) and reductions in serum cytokines and chemokines (by Cycle 1 Day 8) known to contribute to CLL growth and survival. In addition, median CLL cell proliferation index (Ki67) was reduced with duvelisib treatment by Cycle 2 Day 1 (at steady state). These PD effects were similar at higher doses (75 mg BID). On-target lymphocytosis had a rapid onset (maximum mean absolute lymphocyte count ALC by Cycle 1 Day 8) across the dose range evaluated (8 to 75 mg BID), returning to baseline (mean ALC) by Cycle 4 Day 1 (12 wks on treatment). In pts with baseline CT assessments, 83% (38/46) achieved >50% reduction in adenopathy by CT scan. The best overall response rate (ORR) by IWCLL criteria was 55% in 49 evaluable pts, including 1 complete response (CR) and 26 partial responses (PR). There were 21 pts with stable disease and 1 pt with progressive disease. Median time to response was 1.9 mo (range 1.7-8.3). The ORR was similar irrespective of dose (52%, ≤25 mg BID n=29; 60%, 75 mg BID n=20), or the presence of TP53mut/(del)17p (48% n=23, including 1 CR) or unmutated IGHV (52%, n=31).
Treatment emergent adverse events (AEs, all causality) were similar across the dose range and were predominantly Grade 1-2. With a median of 7.3 treatment cycles (range 1.0-30.8), the most common AEs ≥Grade 3 (≥10%, all causality) were transient cytopenias (neutropenia 31% and thrombocytopenia 11%), febrile neutropenia (15%), and pneumonia (11%). The most common reasons for treatment discontinuation were AEs (31%) and disease progression (24%).
Conclusions: Pharmacodynamic studies in this ongoing investigation indicate duvelisib, an oral PI3K-δ,γ inhibitor, modulates pAKT in CLL cells, chemokines/cytokines involved in CLL cell survival, and CLL cell proliferation index (Ki67). Early resolution of lymphocytosis and objective lymph node responses suggest survival signals from the tumor microenvironment are affected by inhibition of PI3K-δ,γ pathways. Duvelisib continues to demonstrate clinical activity, with a best ORR of 55% (IWCLL) in a heavily pretreated R/R CLL population, including pts with poor prognostic features. The overall safety profile is generally well tolerated, consistent with underlying disease and suggests a favorable benefit-risk profile in this R/R CLL population. These results support the further development of duvelisib monotherapy, and a randomized Phase 3 study in pts with R/R CLL is ongoing.
Kahl:Infinity Pharmaceuticals: Consultancy, Research Funding. Horwitz:Research: Celgene, Millennium, Infinity, Kiowa-Kirin, Seattle Genetics, Spectrum: Consultancy, Honoraria, Research Funding. Foss:Eisai, Celgene, Seattle Genetics: Consultancy, Research Funding, Speakers Bureau. Porcu:Actelion (e), Cutaneous Lymphoma Foundation (h), United States Cutaneous Lymphoma Consortium (h), Infinity (d), Celgene (d), : Consultancy, Employment, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Sweeney:Infinity Pharmaceuticals: Employment. Allen:Infinity Pharmaceuticals: Employment. Faia:Infinity Pharmaceuticals, Inc.: Employment. Stern:Infinity Pharmaceuticals, Inc.: Employment. Kelly:Infinity Pharmaceuticals: Employment. Flinn:Infinity Pharmaceuticals: Consultancy.
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