A Phase 2 Study of Idelalisib Monotherapy in Previously Untreated Patients ≥65 Years with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1986-1986 ◽  
Author(s):  
Andrew D. Zelenetz ◽  
Nicole Lamanna ◽  
Thomas J. Kipps ◽  
Steven E. Coutre ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Lymphoid Tissues ◽  
Small Lymphocytic Lymphoma ◽  
Employment Equity ◽  
Treatment Naïve ◽  
Equity Ownership ◽  
Systemic Therapies

Abstract BACKGROUND: PI3K-delta (δ) is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib (Zydelig, IDELA,), a potent and selective orally administered inhibitor of PI3Kδ, in combination with rituximab weekly x 8 has yielded an ORR of 97% in patients (pts) ≥65 years with previously untreated CLL or SLL (O’Brien, ASCO 2013). This report describes the preliminary experience in treating a similar cohort of pts with IDELA monotherapy. METHODS: Enrollment began in November, 2013. Treatment-naive pts ≥65 yrs with CLL or SLL, requiring treatment per IWCLL 2008 criteria, and with measurable lymphadenopathy, were treated with IDELA 150 mg bid continuously. Response assessment, at pre-determined time points, was investigator determined using either physical exam or CT scans per investigator discretion, using modified IWCLL guidelines (Hallek 2008, Cheson 2012). RESULTS: As of 21 July 2014, 37 pts were enrolled: 78% male; CLL/SLL in 92%/8%; median age 70 years; 73% Rai III or IV; WHO 0-1/2 in 97%/3%. 46% had ≥1 B-symptom. Hepatomegaly and splenomegaly were present in 14% and 57% respectively. Adverse prognostic factors: 14% del(17p) and/or TP53 mutated; 22% del(11q); 41% IGHV unmutated; β-2 microglobulin median 4.35 mg/L (range: 2.1-12.4). The median idelalisib exposure was 4.8 months (range 0.9-8.5). There has been one discontinuation at 3 mo for respiratory distress, assessed as related to a prior condition. The median absolute lymphocyte count was 59.7 K/µl (range: 0.8-294) at baseline peaking at 100 K/µl (range: 2-385) at week 4. 27 pts were evaluable for response, having reached the first evaluation time point of 8 weeks. Of these 27, the ORR was 81% with 9 (33%) PR and 13 (48%) PR with lymphocytosis. Splenomegaly has responded in 88% of 17 evaluable pts and hepatomegaly in 75% of 4 evaluable pts. The most frequent treatment emergent adverse events (TEAE) (% all Grade/% Grade ≥3) were rash (27/3), URI (16/0), constipation (14/0), cough (14/0), nausea (11/0), pyrexia (11/0), arthralgia (8/0), back pain (8/0), diarrhea (8/3), and pneumonia (8/5). Pneumonitis was observed in 2 pts (5%), Gr ≥3 in 1(3%). Gr ≥3 treatment emergent lab abnormalities included transaminase elevation (8%), anemia (5%), and neutropenia (20%); there was no Gr ≥3 thrombocytopenia. One pt had a TEAE leading to dose reduction. CONCLUSIONS: IDELA has substantial single agent activity in treatment-naïve pts with CLL or SLL. Early lymphocytosis is observed with monotherapy in this population, as opposed to an attenuation of lymphocytosis seen in the earlier cohort treated with IDELA plus weekly rituximab. IDELA was well tolerated and had a manageable safety profile in this preliminary analysis. Disclosures Zelenetz: Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Lamanna:Gilead Sciences: Research Funding. Kipps:Gilead Sciences: Research Funding. Coutre:Gilead Sciences: Research Funding. O'Brien:Gilead Sciences: Research Funding. Aiello:Gilead Sciences: Employment, Equity Ownership. Cho:Gilead Sciences: Employment, Equity Ownership. Dubowy:Gilead Sciences: Employment, Equity Ownership. Flinn:Gilead Sciences: Research Funding.

Update on a Phase 2 Study of Idelalisib in Combination with Rituximab in Treatment-Naïve Patients ≥65 Years with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1994-1994 ◽  
Author(s):  
Susan O'Brien ◽  
Nicole Lamanna ◽  
Thomas J. Kipps ◽  
Ian W. Flinn ◽  
Andrew D. Zelenetz ◽  
...  
Keyword(s):  
Research Funding ◽  
Tp53 Mutation ◽  
Lymphocytic Leukemia ◽  
Extension Study ◽  
Primary Study ◽  
Small Lymphocytic Lymphoma ◽  
Employment Equity ◽  
Treatment Naïve ◽  
Equity Ownership ◽  
Systemic Therapies

Abstract Background: The selectivePI3K-delta inhibitor Idelalisib (Zydelig®, IDELA), in combination with rituximab (R), has been previously reported to yield a 97% ORR in treatment naïve patients (pts) ≥65 years with CLL or SLL (O’Brien, ASCO 2013). This report is an update on that initial cohort of study pts. Methods: Treatment-naive pts ≥65 yrs with CLL or SLL were treated with R 375 mg/m2 weekly x 8 and idelalisib 150 mg bid continuously for 48 weeks (primary study). Pts completing 48 weeks without progression could continue to receive idelalisib on an extension study. Response assessment, at pre-determined time points, was investigator determined using either physical exam or CT scans per investigator discretion, based on modified IWCLL guidelines (Hallek 2008, Cheson 2012). Results: 64 pts were enrolled, 59 CLL/5 SLL, median age 71 yrs (range: 65-90), 63% male, Rai stage III/IV 13/30 (%), nodes ≥5 cm in 11%, WHO 0/1/2 in 42/56/2 (%). Adverse risk factors: del(17p) and/or TP53 mutation in 14%, del(11q) in 16%, IGHV unmutated in 58%, median β2-microglobulin 4.0 mg/L (range 1.9-15.8). Disposition: 43 pts completed the 48 wk primary study and 41 entered the extension study. 21 pts discontinued from the primary study (17 AE, 1 withdrawn consent, 3 deaths [pneumonitis; sepsis; metastatic melanoma with pneumonia]); an additional death occurred within 30 days of discontinuation due to pneumonitis. There were 17 discontinuations from the extension study (9 AE, 2 withdrawn consent, 1 investigator request, 4 PD, 1 death [myocardial infarction]), leaving 24 pts ongoing. The median IDELA exposure is 22.9 mos (range 0.8-45.3), with 13 (20%) pts treated for more than 36 months. The ORRis 97% (78% PR, 19% CR) with 3% nonevaluable; median time to response is 1.9 mos (range 1.6-5.7). The Kaplan-Meier (KM) estimated median PFS is not reached (NR), 95% CI (37.3 mo, --). The KM estimated DOR is NR, 95% CI (35.4,--). Of note, 9/9 pts with del(17p) and/or TP53 mutation responded (3 CR, 6 PR); 5 discontinued for AE (4) or investigator request (1) and 4 remain on treatment for 28, 34, 40 and 41 months. The most frequent Gr ≥3 AEs (%) were diarrhea/colitis (42), pneumonia (19), rash (13), dehydration (8), UTI (6), dyspnea (5) and respiratory failure (5). In addition, pneumonitis developed in 2 pts (3%), both Gr 5, and one pt with diverticulitis developed bowel perforation. The median time to onset of Gr ≥3 diarrhea/colitis was 9.5 mo, (range 3-29). Rechallenge was attempted in 21 of the 27 pts with Gr ≥3 diarrhea/colitis, and 12 pts were able to resume IDELA for ≥ 120 days. 15 (23%) pts developed Gr ≥3 ALT or AST elevation, all recovering, with successful resumption of IDELA, at a reduced dose, in 12. In total, 29 (45%) pts had one or more treatment-emergent AEs leading to IDELA dose reduction. Conclusions: IDELA + R is highly active, rapidly inducing responses in 97% of treatment-naïve older pts with CLL and SLL. The responses are durable, including in those with del(17p)/TP53 mutation. Diarrhea/colitis was the most common Gr ≥3 AE, and IDELA was successfully reintroduced in 44% of the affected pts. Ongoing studies are further investigating the role of IDELA in the frontline setting. Disclosures O'Brien: Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Lamanna:Gilead Sciences: Research Funding. Kipps:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Zelenetz:Gilead Sciences: Research Funding. Burger:Gilead Sciences: Research Funding. Holes:Gilead Sciences: Employment, Equity Ownership. Cho:Gilead Sciences: Employment, Equity Ownership. Dubowy:Gilead Sciences: Employment, Equity Ownership. Coutre:Gilead Sciences: Research Funding.

Inhibition Of PI3K-δ and -γ Isoforms By IPI-145 In Chronic Lymphocytic Leukemia Overcomes Signals From PI3K/AKT/S6 Pathway and Promotes Apoptosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4167-4167 ◽  
Author(s):  
Kumudha Balakrishnan ◽  
Marisa Peluso ◽  
Min Fu ◽  
Nathalie Y. Rosin ◽  
Jan A. Burger ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Research Funding ◽  
Therapeutic Potential ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Employment Equity ◽  
Enhanced Production ◽  
Significant Difference ◽  
Equity Ownership

Abstract The functional relevance of the B cell Receptor (BCR) pathway and identification of protein kinases as therapeutic targets have recently shifted the paradigm for treatment of B cell malignancies. Inhibition of protein and lipid kinases (Bruton Tyrosine Kinase [BTK] and phosphoinositide 3-kinase [PI3K]) with ibrutinib and GS-1101 has been shown to be active in treatment of chronic lymphocytic leukemia (CLL). Importantly, differential expression and function of PI3K isoforms support isoform-selective inhibition of this kinase in CLL. Whilst PI3K-α and PI3K-β are ubiquitously expressed, PI3K-δ and PI3K-γ are primarily restricted to leukocytes. Since CLL cells generally express high levels of active PI3K-δ, great interest has been focused on inhibition of PI3K-δ. However, given the distinct and non-overlapping roles of PI3K-δ and PI3K-γ in immune cells, exploration of the therapeutic potential of combined inhibition of both PI3K-δ and PI3K-γ in CLL patients is warranted. IPI-145 is a potent, orally bioavailable, inhibitor of PI3K-δ and PI3K-γ isoforms with KD values of 0.023 nM and 0.24 nM, respectively. Treatment of primary CLL cells (n=51) with IPI-145 (1 µM) resulted in significant apoptosis (median 33%; range 12 – 40%). Patients with mutated (n=13) or unmutated IGHV gene status (n=13), previously untreated (n=21) or treated (n=8), displayed no significant difference in apoptosis from IPI-145. Samples with different prognostic markers such as 13q (del) or FISH negative samples were equally sensitive to IPI-145. Side by side studies of IPI-145 with ibrutinib and GS-1101, revealed that IPI-145 is comparatively potent (IC50 7.6 µM, compared to >10 µM) in promoting apoptosis. Crosslinking with anti-IgM enhanced the survival of primary CLL cells in association with activation of PI3K-δ,γ/AKTSer473/pBadSer136/S6Ser235/236 pathway, which was in turn mitigated upon treatment with IPI-145 (n=9). Consistent with cell death, cleavage of PARP and decrease in anti-apoptotic protein Mcl-1 (but not Bcl-2 or Bcl-xL) was observed. Measurement of the C-C chemokine, CCL3, a biomarker for BCR signaling inhibition in CLL, demonstrated 15 to 48 – fold increase upon anti-IgM stimulation, which was reversed when cells were treated with 1 µM IPI-145 (10 to 80-fold decrease; n=6). Alternatively, co-culturing CLL primary cells with bone marrow stromal cells to mimic the leukemic microenvironment induced the protein levels of all four Class I PI3K isoforms and downstream PI3K/AKT/S6 signaling axis, which was significantly attenuated by IPI-145. To mimic the proliferative state in lymph node pseudofollicles, CLL cells were stimulated to proliferate with CD40L/IL-2/IL-10 and the effect of IPI-145 was measured. Both pAKT and Ki-67 expression were markedly inhibited in primary CLL cells at concentrations of IPI-145 in the low nanomolar range (EC50<10nM; n=2), suggesting a potent anti-proliferative effect of IPI-145 on CLL cells in the nodal environment. Given the significant role of the chemo-attractant, SDF-1, in the directed migration of B-cells, chemotaxis assay demonstrated reduction in migration of CLL cells towards SDF-1 in presence of IPI-145 (% control reduction - median 23%; range 2-42%; n=8). Furthermore, IPI-145 treatment enhanced production of reactive oxygen species (n=6). Taken together, these results demonstrate the potential of combined inhibition of the PI3K-δ and -γ isoforms in CLL, and support clinical investigation of IPI-145 in B-cell malignancies, including CLL. Disclosures: Balakrishnan: Infinity Pharmaceuticals Inc: Research Funding. Peluso:Infinity Pharmaceuticals., Inc.: Employment, Equity Ownership. Faia:Infinity Pharmaceuticals., Inc.: Employment, Equity Ownership. Kutok:Infinity Pharmaceuticals., Inc.: Employment, Equity Ownership. McGovern:Infinity Pharmaceuticals., Inc.: Employment, Equity Ownership. Gandhi:Infinity Pharmaceuticals., Inc: Research Funding.

Correlation Between Serum Ofatumumab Concentrations, Baseline Patient Characteristics and Clinical Outcomes in Patients with Fludarabine-Refractory Chronic Lymphocytic Leukemia (CLL) Treated with Single-Agent Ofatumumab.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3433-3433 ◽  
Author(s):  
Anders Österborg ◽  
Birgitte Biilmann Ronn ◽  
Roxanne C Jewell ◽  
Thomas J Kipps ◽  
Jiri Mayer ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Pivotal Trial ◽  
Employment Equity ◽  
Baseline Factors ◽  
Equity Ownership ◽  
Univariate Analyses

Abstract Abstract 3433 Poster Board III-321 Introduction Monoclonal antibody (mAb) therapies represent an important clinical advance for patients (pts) with CLL, yet little is known about the pharmacokinetics (PK) and pharmacodynamics of mAb therapy in these pts. Ofatumumab is a human mAb targeting a membrane-proximal small-loop epitope on CD20 and mediates efficient complement-dependent cytotoxicity in vitro. Ofatumumab is being evaluated in a pivotal trial for pts with fludarabine-refractory CLL also refractory to alemtuzumab (FA-ref; n=59) or less suitable for alemtuzumab due to bulky (>5 cm) lymphadenopathy (BF-ref; n=79). Overall response rate (ORR; primary endpoint) was 58% in FA-ref and 47% in BF-ref pts at an interim analysis; median progression-free survival (PFS) was 5.7 and 5.9 months, respectively. We evaluated relationships between baseline factors and ofatumumab PK and between PK parameters and treatment outcomes from the pivotal trial. Patients and Methods Pts received 8 weekly infusions of ofatumumab followed by 4 monthly infusions (Dose 1, 300 mg; Doses 2-12, 2000 mg). Response (1996 NCI-WG criteria) was assessed by an Independent Review Committee over 24 weeks of therapy. Blood samples for PK analysis were collected at Dose 1, Dose 8 (last weekly dose), and Dose 12 (last monthly dose). A population PK model was employed that included data from a previous study (Coiffier et al, Blood 2008;111:1094). For Dose 1, Cmax was determined; for Doses 8 and 12, Cmax, Cmin, AUC, clearance (CL), volume of distribution (Vss) and t½ were determined. The relationships between baseline pt characteristics and disease factors and PK parameters were evaluated by multivariate regression analysis. Associations between PK and ORR or PFS were explored using univariate and multivariate logistic regression or Cox regression analyses. Results 90% of the 154 pts received 8 weekly infusions of ofatumumab and 55% received all 12 infusions. PK parameters were similar between FA-ref and BF-ref pts. In multivariate analysis, higher Cmax at Dose 1 was significantly associated with lower % of bone marrow infiltration (p<0.001), lower Rai stage (p=0.002), lower lymphocyte count (p=0.006), smaller BSA (p<0.001) and lower total bilirubin (p=0.013). The majority of responders and non-responders were still receiving treatment at Dose 8; thus, this dose represents an informative time point for analysis. Baseline factors that influenced PK parameters at Dose 8 are shown in the table. Based on univariate analyses, higher Cmax and Cmin at Dose 8 were associated with increased likelihood of response (Table); in addition, significantly higher Cmax, Cmin and AUC were observed in responders versus non-responders (p<0.05 for each; data not shown). Higher Cmax, AUC and Cmin and lower CL at both Doses 8 and 12 were significantly correlated with longer PFS (p<0.05 for each). Based on exploratory multivariate analyses, PK parameters were not independent predictors of ORR or PFS. Conclusions These data demonstrate that baseline factors reflecting disease burden significantly influenced ofatumumab PK. Additionally, higher serum concentrations of ofatumumab at Doses 8 and 12 were associated with positive clinical outcomes in univariate analyses. The pivotal study is ongoing, and further analyses of associations between disease-related factors, PK and treatment response will be performed at study completion. Such analyses will help us to better understand the response kinetics of biological therapy and to optimize the dose. Disclosures Österborg: Celgene: Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding. Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Biilmann Ronn:Genmab: Employment. Jewell:GlaxoSmithKline: Employment, Equity Ownership. Kipps:Physicians' Educational Resource, Educational Concepts: Speakers Bureau; Genmab, Abbott Industries, Celgene, Biogen Idec, Cephalon, sanofi-aventis, Medimmune, Memgem, Genentech: Research Funding. Mayer:GlaxoSmithKline: Consultancy. Stilgenbauer:GlaxoSmithKline, Genmab: Consultancy, Honoraria, Research Funding. Hellmann:Novartis, BMS: Consultancy, Honoraria. Robak:GlaxoSmithKline, Roche: Advisory Board, Research Funding. Furman:GlaxoSmithKline: Consultancy, Speakers Bureau. Hillmen:GlaxoSmithKline: Consultancy, Honoraria for Advisory Boards. Trneny:GlaxoSmithKline: Honoraria. Padmanabhan:GlaxoSmithKline: Consultancy, Honoraria; Celgene, Genentech: Consultancy. Kozak:GlaxoSmithKline, Amgen: Consultancy. Chan:GlaxoSmithKline: Employment. Arning:GlaxoSmithKline: Employment, Equity Ownership. Losic:Genmab: Employment, Stock Ownership. Davis:GlaxoSmithKline: Employment, Stock ownership. Wilms:Genmab: Employment, Equity Ownership. Russell:Genmab: Employment, Equity Ownership. Wierda:Genmab, GlaxoSmithKline: Honoraria, Research Funding.

scholarly journals Duohexabody-CD37, a Novel Bispecific Antibody with a Hexamerization-Enhancing Mutation Targeting CD37, Demonstrates Superior Complement-Dependent Cytotoxicity in Preclinical B-Cell Malignancy Models

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4170-4170
Author(s):  
Simone C. Oostindie ◽  
Hilma J. Van Der Horst ◽  
Marije B. Overdijk ◽  
Kristin Strumane ◽  
Sandra Verploegen ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Bispecific Antibody ◽  
Lymphocytic Leukemia ◽  
Single Point Mutation ◽  
B Cell Malignancies ◽  
Employment Equity ◽  
Healthy Human ◽  
Complement Dependent Cytotoxicity ◽  
Equity Ownership

Abstract CD37 is a tetraspanin plasma membrane protein abundantly expressed on B-cells and represents a promising therapeutic target for the treatment of B-cell malignancies. Although complement-dependent cytotoxicity (CDC) has proven to be a powerful Fc-mediated effector function for killing hematological cancer cells, CD37 antibody-based therapeutics currently in clinical development are poor inducers of CDC. Here we present DuoHexaBody-CD37, a novel humanized IgG1 bispecific antibody targeting two different CD37 epitopes, with an E430G hexamerization-enhancing mutation, for the potential treatment of B-cell malignancies. The natural process of antibody hexamer formation through intermolecular Fc-Fc interactions between IgG molecules after cell surface antigen binding can be improved by introducing a single point mutation such as E430G in the IgG Fc domain, thereby facilitating more efficient C1q binding and complement activation (Diebolder et al., Science 2014; de Jong et al., PLoS Biol 2016). The hexamerization-enhancing mutation E430G was introduced into two humanized CD37 monoclonal antibodies (mAbs) that bind non-overlapping CD37 epitopes. Different antibody formats and combinations, including the single antibodies, combinations of the mAbs and bispecific mAbs were tested for their capacity to induce CDC and antibody-dependent cellular cytotoxicity (ADCC). The bispecific hexamerization-enhanced antibody variant DuoHexaBody-CD37, showed superior CDC activity compared to the single hexamerization-enhanced mAbs and the combination thereof, both in vitro over a range of different B-cell lines, and ex vivo in tumor cell samples obtained from patients with chronic lymphocytic leukemia (CLL). In a CDC assay using tumor cells obtained from a relapsed/refractory CLL patient who received prior treatment with rituximab, ibrutinib and idelalisib, DuoHexaBody-CD37 induced almost complete lysis (84% lysis at a concentration 100 µg/mL), thereby outperforming the single HexaBody molecules (15% and 23% lysis) and the combination (57%) (Figure 1). In addition to its potent CDC activity, DuoHexaBody-CD37 was also capable of inducing potent ADCC of Daudi cells (EC50 = 12.3 ± 9.5 ng/mL), as assessed using peripheral blood mononuclear cells from 8 healthy human donors in a standard chromium release assay. In assays using whole blood from 6 healthy human donors, DuoHexaBody-CD37 showed efficient B-cell binding and potent and specific depletion of the B-cell population (98% ± 1.3% depletion at 10 µg/mL, EC50 = 0.85 ± 0.284 µg/mL). Furthermore, DuoHexaBody-CD37 induced significant inhibition of tumor growth in vivo in Daudi-luc Burkitt's lymphoma and JVM-3 CLL mouse xenograft models, at doses as low as 0.1 and 1 mg/kg (p<0.05), respectively. In summary, we present a novel therapeutic antibody that, for the first time, combines proprietary DuoBody® and HexaBody® platforms. DuoHexaBody-CD37 induced highly potent CDC and efficient ADCC in preclinical models, suggesting that DuoHexaBody-CD37 may serve as a potential therapeutic mAb for the treatment of human B-cell malignancies. Disclosures Oostindie: Genmab: Employment, Equity Ownership. Van Der Horst:Genmab: Research Funding. Overdijk:Genmab: Employment, Equity Ownership. Strumane:Genmab: Employment, Equity Ownership. Verploegen:Genmab: Employment, Equity Ownership. Lindorfer:Genmab: Research Funding. Cook:Genmab: Research Funding. Chamuleau:Gilead: Research Funding; BMS: Research Funding; celgene: Research Funding; Genmab: Research Funding. Mutis:Gilead: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Research Funding; Novartis: Research Funding; OnkImmune: Research Funding. Schuurman:Genmab: Employment, Other: Warrants. Sasser:Genmab: Employment, Equity Ownership. Taylor:Genmab: Research Funding. Parren:Genmab: Equity Ownership; Lava Therapeutics: Employment. Beurskens:Genmab: Employment, Equity Ownership. Breij:Genmab: Employment, Equity Ownership.

scholarly journals Mature Follow up from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating agent)-Refractory Indolent B-Cell Non-Hodgkin Lymphoma (iNHL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1708-1708 ◽  
Author(s):  
Ajay K. Gopal ◽  
Brad S. Kahl ◽  
Sven de Vos ◽  
Nina D. Wagner-Johnston ◽  
Stephen J. Schuster ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Employment Equity ◽  
Non Hodgkin Lymphoma ◽  
Duration Of Response ◽  
Equity Ownership ◽  
Grade 3 ◽  
Systemic Therapies

Abstract Introduction: Rituximab-alkylator combinations are the standard therapies for patients (pts) with iNHL, however, refractory disease nearly uniformly develops. Once iNHL becomes “double-refractory” to both rituximab + alkylating agents, there are limited options to induce durable remissions. PI3K-delta signaling is critical for activation, proliferation and survival of B cells, and is hyperactive in many B-cell malignancies. Idelalisib, a selective oral inhibitor of PI3Kd, demonstrated considerable clinical activity in double-refractory iNHL (Gopal NEJM 2014). FDA granted accelerated approval for Idelalisib (Zydelig®) in patients who have received at least two prior systemic therapies with relapsed FL or SLL. Based on these encouraging initial results, we now describe long-term follow up, safety, and remission durations of this double-refractory iNHL population treated with idelalisib. Methods: Eligible iNHL pts included those with measurable disease refractory to both rituximab and an alkylating agent. Refractory was defined as lack of response to, or progression of lymphoma within 6 months of completion of index therapy, confirmed by imaging. Idelalisib 150 mg PO BID was administered continuously until disease progression or intolerance. Responses were evaluated by an independent review committee, using standard criteria (Cheson, 2007, and Owen 2013). The new data cutoff date for this analysis was June 2014, 20 months after the last patient enrolled. Results: Enrolled pts (N = 125) had a median age of 64 years and included follicular lymphoma (FL) n=72 (58%), small lymphocytic lymphoma (SLL) n=28 (22%), marginal zone lymphoma (MZL) n=15 (12%) and lymphoplasmacytic lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM) n=10 (8%). The median number of prior therapies was 4 [range 2-12], including bendamustine/rituximab (BR) (n=60) and rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=56) and autologous transplant (n=14). 81 pts (65%) had prior bendamustine, of which 61/81 (75%) were refractory. 112 pts (90%) were refractory to their last regimen, and 99 pts (79%) were refractory to ≥2 regimens. 38 pts (30%) had elevated LDH, and 33 pts (26%) had bulky disease >7 cm. The median time to progression from last prior therapy was 3.9 months. With a median exposure of 11.1 months (range 0.7 to 35.4), the overall response rate (ORR) is 56% (95% CI = 46.8-64.9) with 70 responders, comprising 12 CRs (9.6%), 58 PRs (46.4%). The median time to response was 1.9 months (time of first evaluation) and time to CR was 4.5 months. There were 43 pts with stable disease (SD) (34.4%). 90% of pts experienced some decrease in tumor burden. ORR for iNHL subtypes is: FL (54%), SLL (61%), MZL (47%), and LPL/WM (70%). CR rate for iNHL subtypes is: FL (14%), SLL (4%), MZL (7%), and LPL/WM (0%). Among responders, median DOR is 13.9 (0.03-31.3) months. DOR for iNHL subtypes in months (Figure 1) is: FL 11.8, SLL 13.9, MZL 18.4, and LPL/WM (not yet reached). Median PFS for all pts is 11.0 months, in comparison to a median PFS of the last prior regimen of 3.9 months (p<.0001). The median PFS for individual subtypes in months was: FL 11.0, SLL11.1, MZL 6.6, and LPL/WM 22.2. The median overall survival of all patients was 30.8 months. The adverse events include (total%/≥ grade 3%) diarrhea/colitis (50/18), fatigue (30/2), nausea (31/2), cough (32/0), pyrexia (30/2), dyspnea (18/5), rash (14/2), pneumonia (14/11), and pneumonitis (4/3). Based on central laboratory measurements, Grade ≥3 ALT/AST elevations occurred in 18 pts (14%). Drug was temporarily held in these pts, and 11/15 pts (73%) were re-treated without recurrence of ALT/AST elevation. Overall, 30 pts (24%) have discontinued therapy due to adverse events. Conclusions: The prolonged administration of idelalisib was well tolerated, had an acceptable safety profile, and was highly effective in inducing and maintaining remissions in double-refractory iNHL population with an ORR of 56%, PFS of 11 months, and DOR of 13.9 months. The response rate and long term duration of responses in the small number of subjects with LPL/WM is very promising, and will be evaluated in larger trials of this disease. The observed disease control compared to prior regimens suggests the potential for prolonged clinical benefit in this challenging patient population with unmet medical need. Figure 1: Duration of Response by Disease Group. Figure 1:. Duration of Response by Disease Group. Disclosures Gopal: Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Kahl:Gilead Sciences: Research Funding. de Vos:Gilead Sciences: Research Funding. Wagner-Johnston:Gilead Sciences: Research Funding. Schuster:Gilead Sciences: Research Funding. Jurczak:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Flowers:Gilead Sciences: Research Funding. Martin:Gilead Sciences: Research Funding. Viardot:Gilead Sciences: Research Funding. Blum:Gilead Sciences: Research Funding. Goy:Gilead Sciences: Research Funding. Davies:Gilead Sciences: Research Funding. Zinzani:Gilead Sciences: Research Funding. Dreyling:Gilead Sciences: Research Funding. Holes:Gilead Sciences: Employment, Equity Ownership. Sorensen:Gilead Sciences: Employment, Equity Ownership. Godfrey:Gilead Sciences: Employment, Equity Ownership. Salles:Gilead Sciences: Research Funding.

scholarly journals Phase 1b and Pharmacokinetic Study of Idelalisib in Japanese Patients with Relapsed or Refractory (R/R) Indolent B-Cell Non-Hodgkin Lymphoma (iNHL) or Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5089-5089 ◽  
Author(s):  
Tomohiro Kinoshita ◽  
Noriko Fukuhara ◽  
Hirokazu Nagai ◽  
Koji Izutsu ◽  
Yukio Kobayashi ◽  
...  
Keyword(s):  
Neutrophil Count ◽  
Research Funding ◽  
Japanese Patients ◽  
Lymphocytic Leukemia ◽  
Lymphoid Tissues ◽  
Employment Equity ◽  
Histological Transformation ◽  
Equity Ownership ◽  
Grade 3 ◽  
Continuous Dosing

Abstract Background: Increased phosphatidylinositol-3-kinase delta (PI3Kd) activity drives proliferation and survival of malignant B-cells and mediates trafficking to lymphoid tissues. Idelalisib, a first-in-class, selective, oral inhibitor of PI3Kd, is approved in combination with rituximab for patients with relapsed CLL and as monotherapy in patients with relapsed/refractory (R/R) follicular lymphoma (FL) in North America and the EU. Methods: Six Japanese patients were enrolled between October 2014 and November 2014. This is an open-label 6+6 study design for continuous dosing of idelalisib 150mg BID in patients with R/R CLL and iNHL until PD or intolerable toxicity. The primary objective was to evaluate the 28-day safety, tolerability and pharmacokinetics of idelalisib and its metabolite GS-563117. The primary endpoint was the incidence of dose-limiting toxicity (DLT) defined as grade 4 hematological toxicities persisting for >14 days, grade ≥3 non-hematological toxicities, grade >3 laboratory abnormalities, red cell transfusion, and a therapeutic platelet transfusion. Key inclusion criteria were: age ≥20 yrs, patient of Japanese ancestry. Key exclusion criteria were known histological transformation to an aggressive histology, history of iNHL or CLL with CNS involvement. Response assessments as per modified Hallek 2008 and Cheson criteria 2007 were performed using CT scans at pre-determined time points by investigators. Results: Baseline characteristics included 3 patients each with CLL (2/3 refractory, 1/3 relapsed) or FL (3/3 refractory), and median age was 64 years (range 49-74). Median number of prior Rx regimens was 3.5 (range 1-6). Prior therapies included bendamustine plus rituximab (67%), R-CHOP (67%), and R-CVP (33%). No Japanese patients experienced a DLT within the 28-day window. The PK of idelalisib and GS-563117 were comparable between Japanese and non-Japanese patients; non-Japanese PK data predicted from preceding Phase 2 and Phase 3 studies. The most common treatment-emergent any grade/≥ grade 3 AEs in increasing frequency were gastritis (33%/0%), pyrexia (33%/0%), transaminases increased (33%/33%), chest pain (17%/0%), decreased appetite (17%/17%), diarrhea (17%/17%), neutrophil count decreased (17%/17%) and common laboratory abnormalities were decreased WBC (50%/17%), decreased neutrophil count (50%/17%), increased ALT (33%/17%), and increased AST (17%/17%). At the time of this analysis, a total of 3 patients experienced serious AEs (50%); decreased appetite, diarrhea, and increased transaminases. Investigator response assessments were 5/6 (83%) patients achieving partial response (PR) and 1/6 (17%) stable disease. Conclusions: Continuous dosing of idelalisib demonstrated a manageable safety profile with promising efficacy in Japanese patients with R/R CLL and FL. The PK of idelalisib and GS-563117 were comparable between Japanese and non-Japanese patients. The study was registered at ClincalTrials.gov (NCT02242045). Disclosures Kinoshita: Gilead Sciences: Research Funding. Fukuhara:Gilead Sciences: Research Funding. Nagai:Gilead Sciences: Research Funding. Izutsu:Gilead Sciences: Research Funding. Kobayashi:Gilead Sciences: Research Funding. Higuchi:Gilead Sciences: Research Funding. Harigae:Gilead Sciences: Research Funding. Tokunaga:Gilead Sciences: Research Funding. Adewoye:Gilead Sciences: Employment, Equity Ownership. Robeson:Gilead Sciences: Employment, Equity Ownership. Sharma:Gilead Sciences: Employment, Equity Ownership. Fukui:Gilead Sciences: Research Funding. Gao:Gilead Sciences: Employment, Equity Ownership. Christenson:Gilead Sciences: Employment, Equity Ownership. Tobinai:Gilead Sciences: Research Funding.

scholarly journals Improvements in Health-Related Quality of Life and Symptoms in Patients with Previously Untreated Chronic Lymphocytic Leukemia: Results from the Phase II GIBB Study of the Combination of Obinutuzumab and Bendamustine

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 683-683
Author(s):  
Jeffrey P. Sharman ◽  
Habte Yimer ◽  
Michael Boxer ◽  
Nicholas Di Bella ◽  
Sunil Babu ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Induction Treatment ◽  
Future Health ◽  
Employment Equity ◽  
Equity Ownership ◽  
Eortc Qlq

Abstract Introduction: Maintenance and/or improvements in health-related quality of life (HRQoL) are important in patients with chronic lymphocytic leukemia (CLL). GIBB (NCT02320487) is an ongoing, open-label, single-arm Phase II study of the combination of obinutuzumab (GA101; G) and bendamustine (B) (BG) in patients with previously untreated CLL. A previous report from the GIBB study demonstrated an investigator-assessed objective response rate of 89.2%, a complete response rate of 49.0%, and no unexpected safety signals with BG (Sharman et al. ASCO 2017). Here, we present the HRQoL data from GIBB. Methods: In the GIBB trial, patients received BG by intravenous infusion over six 28-day cycles: obinutuzumab 100mg on Day (D)1, 900mg on D2, and 1000mg on D8 and D15 of Cycle 1, then 1000mg on D1 of Cycles 2-6; B 90mg/m2 on D2-3 of Cycle 1, and on D1-2 of Cycles 2-6. The European Organisation for Research and Treatment of Cancer Quality of Life - Core (EORTC QLQ-C30) questionnaire includes a global health status measure, 5 functional scales (physical, emotional, cognitive, social, and role functioning), 8 symptom scales/items (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, and diarrhea), and an item on financial difficulties (Aaronson et al. J Natl Cancer Inst 1993). The EORTC Quality of Life Questionnaire-Chronic Lymphocytic Leukemia 16 (QLQ-CLL16) is a 16-item module, specific to CLL, containing 4 multi-item scales (fatigue, treatment side effects, disease symptoms, and infection) and 2 single items (social activities and future health worries; EORTC website, accessed July 25, 2017). Both questionnaires were completed by patients on D1 of Cycles 1 (baseline), 3, and 6, at the end of induction treatment (defined as +28 days from D1 of Cycle 6 or early treatment termination visit), at the response visit (defined as 2-3 months after the end of induction treatment, for all patients who received study treatment and had not experienced disease progression), and every 3 months thereafter at follow-up visits. HRQoL scores were linear transformed to a 0-100 point scale. Mean baseline scores and mean score changes at each visit were evaluated. A threshold of ≥10-point change in score represents a clinically meaningful difference. Results: Of 102 patients enrolled in the trial, 98 completed a questionnaire at baseline and at least one other questionnaire during a follow-up visit. Questionnaire completion rates were 86.7%, 77.6%, 80.6%, and 86.7% at Cycles 3, 6, at the end of induction treatment, and at the response visit, respectively. Median age was 61 years and 68.4% of patients were male. According to the EORTC QLQ-C30 (Figure 1), clinically meaningful improvements were observed for global health status at the response visit, and for role functioning at the end of induction treatment and at the response visit. A trend was observed for improvement in emotional functioning. The greatest improvement in HRQoL score was observed for fatigue (mean baseline score: 37.64), with mean changes from baseline of −4.01, −5.48, −11.67, and −16.34 at Cycles 3, 6, at the end of induction treatment, and at the response visit, respectively. Improvements were also observed for insomnia (mean baseline score: 33.33), with mean changes from baseline of −6.59, −9.09, −9.7, and −10.98, respectively. There was no worsening in other patient-reported symptoms or functional status over time. Similarly, with the EORTC QLQ-CLL16 (Figure 2), clinically meaningful improvements in symptoms were observed for fatigue, disease symptoms, and future health worries during treatment, at the end of induction treatment and/or at the response visit. The greatest change at the response visit was observed for fatigue (−21.23) and future health worries (−20.24). A positive trend was also observed for improvements in the social activities scale. Conclusions: We previously reported that BG is an effective regimen for first-line treatment of CLL with no unexpected safety signals. In addition, the HRQoL data from the GIBB trial suggest that BG treatment improves patient HRQoL. Several clinically meaningful improvements were observed in HRQoL, including global health status, functioning, symptoms, and future health worries at the time of the response visit. Disclosures Sharman: Acerta: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Other: GIBB is sponsored by Genentech Inc. Third-party editorial support, under the direction of Anthony Masaquel, was provided by Lynda McEvoy of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Yimer: Juno pharma: Equity Ownership; Bellucum Pharma: Equity Ownership. Babu: Alexion: Speakers Bureau; Abbvie: Consultancy. Li: Genentech: Employment, Equity Ownership. Mun: Genentech: Employment, Equity Ownership. Trask: Genentech: Employment, Other: stock. Masaquel: Genentech Inc.: Employment, Other: I Receive Roche stock options. Reyes: Genentech Inc.: Employment, Equity Ownership.

Durable Responses Following Treatment with the PI3K-Delta Inhibitor Idelalisib in Combination with Rituximab, Bendamustine, or Both, in Recurrent Indolent Non-Hodgkin Lymphoma: Phase I/II Results

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3063-3063 ◽  
Author(s):  
Sven de Vos ◽  
Nina D. Wagner-Johnston ◽  
Steven E. Coutre ◽  
Ian Flinn ◽  
Marshall T. Schreeder ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Stable Disease ◽  
Research Funding ◽  
Employment Equity ◽  
Non Hodgkin Lymphoma ◽  
Equity Ownership ◽  
Grade 3 ◽  
Systemic Therapies

Abstract Introduction: PI3K-delta signaling is critical for activation, proliferation and survival of B cells, and is hyperactive in many B-cell malignancies. Idelalisib, a selective oral inhibitor of PI3Kd, demonstrated considerable clinical activity as monotherapy in recurrent (Flinn, Blood 2014) or refractory iNHL subjects (Gopal, NEJM 2014). FDA granted accelerated approval for Idelalisib (ZYDELIG®) in patients who have received at least two prior systemic therapies with relapsed FL or SLL. This study evaluated Idelalisib in combination with rituximab, bendamustine, or both. We now present mature safety and response data with up to 4 years of follow up. Methods: Eligible patients had relapsed/refractory indolent NHL. Idelalisib (Z) was administered continuously with rituximab (R) (375 mg/m2 given weekly for 8 doses) (R/Z regimen), with bendamustine (B) (90 mg/m2 given on Days 1 and 2, for 6 cycles) (B/Z regimen), or in combination with R (375 mg/m2, on Day 1) and B (90 mg/m2 given on Days 1 and 2 of each cycle, for 6 cycles (BR/Z regimen). Initial subjects in the R/Z and B/Z groups (n=8 each), received Idelalisib 100 mg/dose BID. Thereafter, all patients received an Idelalisib dose of 150 mg/dose BID. Tumor response was evaluated according to standard criteria (Cheson 2007). The cutoff date for this analysis was June 2014, 26 months after the last patient enrolled. Results: Between April 2010 and May 2012, 79 subjects with iNHL were enrolled (including 59 with FL, 15 with SLL, and 5 with MZL). Median [range] age was 61 [37-84] years. At baseline patients had elevated beta-2 microglobulin (59%), stage IV disease (58%), bulky adenopathy (> 5cm) (48%), anemia (Hgb <12gm/dL) (41%), and elevated LDH (28%). Patients had a median number of 3 prior therapies (range 1 -11). Most patients had received a rituximab-containing regimen (98%), an alkylating agent (86%), or an anthracycline (53%). Approximately 46% of patients were refractory to their last pre-study therapy and 58% of patients were refractory to rituximab. Frequent adverse events (all grade %/grade 3-4 %) included pyrexia (54/3), nausea (44/0), fatigue (43/4), diarrhea (39/15), rash (38/9), cough (35/0), pneumonia (22/19), pneumonitis (4/3), and febrile neutropenia (3/3). Laboratory abnormalities included lymphopenia (75/62), neutropenia (56/41), anemia (47/10), thrombocytopenia (42/8), and serum transaminase elevations (56/17). Drug was temporarily held for Grade 3/4 ALT/AST elevations, and 8/13 pts (62%) were re-treated without recurrence of ALT/AST elevation. 27% of pts have discontinued therapy due to adverse events. Of the 79 subjects enrolled, 64 had an objective response with an ORR of 81% (95% CI: 70.6-89.0). Complete responses were demonstrated in 26 patients (33%), and partial responses in 38 patients (48%). In addition, 7 patients had stable disease (9%), and 4 patients had progressive disease (5%) as best response on-study. Four patients were non-evaluable, as they did not have follow up CT scans. By treatment subgroup, the ORR were (n=24/32) 75% (95% CI: 57-89) for R/Z, (n=29/33) 88% (95% CI: 72-97) for B/Z, and (n=11/14) 79% (95% CI: 49-95) BR/Z. The CR rates were 25% (n=8/32), 36% (n=12/33), and 43% (n=6/14) respectively; stable disease was noted in 4/32 patients (13%), 3/33 patients (9%), and 0/14 patients in the three groups respectively. ORR/CR by iNHL subtype is: FL (81%/39%), SLL (73%/13%), and MZL (100%/20%). The median progression-free survival is 32.8 months. Median PFS for R/Z group is 29.7 months, B/Z group 32.8 months, and BR/Z group 37.1 months. The PFS at 24 months was 55%, 64%, and 71% for the R/Z, B/Z, and BR/Z groups respectively. The median duration of response has not yet been reached. Median DOR for the R/Z group is 28.6 months, for the B/Z, and BR/Z groups it is not yet reached. The DOR at 24 months was 65%, 67%, and 64% for the R/Z, B/Z, and BR/Z groups respectively. Figure 1: Median overall survival is not yet reached. Conclusions: Idelalisib in combination therapy was well tolerated, had an acceptable safety profile, and was highly effective in this recurrent iNHL population with an ORR of 81%, and CR rate of 33%. Responses are durable beyond 2 years, supporting further evaluation of these combination regimens. Phase 3 trials evaluating the efficacy of Idelalisib in combination with R or BR in iNHL are ongoing (NCT01732913, NCT01732929). Figure 1 Figure 1. Disclosures de Vos: Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Wagner-Johnston:Gilead Sciences: Research Funding. Coutre:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Schreeder:Gilead Sciences: Research Funding. Fowler:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Boccia:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Rai:Gilead Sciences: Research Funding. Boyd:Gilead Sciences: Research Funding. Furman:Gilead Sciences: Research Funding. Holes:Gilead Sciences: Employment, Equity Ownership. Kim:Gilead Sciences: Employment, Equity Ownership. Godfrey:Gilead Sciences: Employment, Equity Ownership. Leonard:Gilead Sciences: Research Funding.

Ibrutinib Plus Bendamustine/Rituximab (BR) Is Associated with Greater Reductions in Fatigue Than Placebo Plus BR Among Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia and Fatigue

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 267-267
Author(s):  
Shana Traina ◽  
Graeme Fraser ◽  
Paula Cramer ◽  
Rodrigo Santucci Silva ◽  
Sebastian Grosicki ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Group Performance ◽  
Eastern Cooperative Oncology Group ◽  
Lymphocytic Leukemia ◽  
Employment Equity ◽  
Fatigue Score ◽  
Travel Grant ◽  
Equity Ownership ◽  
Over Time

Abstract Introduction: Patients with chronic lymphocytic leukemia (CLL) may have reduced health-related quality of life (HRQL) such as severe fatigue during the course of their disease and its treatment. While current treatments aim to increase progression-free survival, it is also important to maintain good HRQL for as long as possible. Methods: Ibrutinib, a first-in-class, once-daily, oral, covalent inhibitor of Bruton's tyrosine kinase, is approved in patients with previously treated CLL and in patients with CLL with del17p, and has recently been shown to reduce the risk of disease progression or death by 80% when added to standard chemoimmunotherapy with BR. In this randomized, double-blind, placebo-controlled, phase 3 study, where patients with active CLL following ≥ 1 prior therapy were randomized 1:1 to receive BR (≤ 6 cycles) with either ibrutinib (420 mg daily) (n = 289) or placebo (n = 289), HRQL and fatigue data were examined. Measures included the FACIT-Fatigue, EORTC QLQ-C30-CLL16, and EQ-5D-5L, which capture general physical and emotional impacts of disease and treatments as well as CLL-specific symptoms. Because examination of mean values may obscure meaningful changes in outcomes, fatigue scores were also examined by baseline quartile with respect to clinical, sociodemographic, and HRQL factors as well as for change over time. Individual CLL symptom items were also examined. The association between changes in hemoglobin levels and fatigue was also examined. Results: Of the 578 patients enrolled, 540 (93%) provided FACIT-Fatigue responses at baseline. No notable mean changes from baseline over time were observed in any HRQL scores within or between the treatment groups. Those in the lowest fatigue score quartile (ie, worst baseline fatigue) were more likely to have an Eastern Cooperative Oncology Group performance score of 1, be in a later stage of disease, have more cytopenias, a greater number of prior therapies, and worse HRQL. Among those with the worst baseline fatigue, unadjusted results indicate apparent improvements in fatigue score over time for both treatments during the first 6 cycles of BR therapy, and subsequently greater continued improvements in fatigue were observed with ibrutinib + BR versus placebo + BR (p < 0.05 at cycle 10) (Figure 1). Similarly, for those with the worst baseline fatigue, mean hemoglobin values appear to increase over time after cycle 2, with comparable changes in each arm (Figure 2). In addition, of the patients who reported feeling ill or unwell at baseline (item 38 on CLL16), a greater proportion reported a return to wellness with ibrutinib + BR (40.0%) versus placebo + BR (27.3%) at cycle 10. This pattern was consistently observed from cycle 2 through cycle 19. Conclusions: These data suggest that addition of ibrutinib to BR is not associated with a negative impact on HRQL and that, among patients with the worst fatigue at baseline, ibrutinib appears to be associated with greater reductions in fatigue versus placebo. Improvements in fatigue appear to be consistent with improvements in hemoglobin and improvements in CLL disease status. Disclosures Traina: Janssen: Employment. Fraser:Hoffman LaRoche: Consultancy, Honoraria; Janssen: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding. Cramer:Astellas: Other: Travel grant; Mundipharma: Other: Travel grant; Glaxo Smith Klein/Novartis: Research Funding; Janssen: Other: Travel grant, Research Funding, Speakers Bureau; Hoffman LaRoche: Other: Travel grant, Research Funding, Speakers Bureau; Gilead: Other: Travel grant, Research Funding. Santucci Silva:Novartis: Other: Travel reimbursement; Merck: Research Funding; Celgene: Research Funding; GSK: Research Funding; Janssen: Other: Travel reimbursement, Research Funding; Hoffman LaRoche: Other: Travel reimbursement, Research Funding. Dilhuydy:Roche: Honoraria, Other: Travel reimbursement; Janssen: Honoraria, Other: Travel reimbursement; Mundipharma: Honoraria. Mahler:Janssen: Employment, Other: Travel reimbursement. Salman:Janssen/J&J: Employment, Equity Ownership. Howes:Janssen/J&J: Employment, Equity Ownership.

scholarly journals Whole-Exome Sequencing Revealed No Recurrent Mutations within the PI3K Pathway in Relapsed Chronic Lymphocytic Leukemia Patients Progressing Under Idelalisib Treatment

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2770-2770 ◽  
Author(s):  
Paolo Ghia ◽  
Viktor Ljungström ◽  
Eugen Tausch ◽  
Andreas Agathangelidis ◽  
Annika Scheffold ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Research Funding ◽  
Somatic Mutations ◽  
Lymphocytic Leukemia ◽  
Employment Equity ◽  
Phase 3 ◽  
Whole Exome ◽  
Equity Ownership

Abstract Introduction: Idelalisib (IDELA) is an ATP-competitive, reversible, and selective small molecule inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3Kδ) approved for the treatment, in combination with rituximab, of patients with relapsed chronic lymphocytic leukemia (CLL). In the relapsed CLL randomized, controlled trials, IDELA + rituximab showed high response rates with improved progression-free and overall survival as compared with placebo + rituximab. While IDELA therapy has significant efficacy, disease progression after response occurs, indicating that escape mechanisms may develop. However, the molecular basis for relapse or progressive disease (PD) in CLL patients treated with IDELA has not yet been characterized. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from 13 CLL patients enrolled in the phase 3 studies; NCT01539512 (study 116; IDELA + rituximab vs placebo + rituximab), 116 extension study NCT01539291 (study 117) and NCT01659021 (study 119; IDELA + ofatumumab). Sample selection criteria included treatment period of at least 180 days (range: 243-703 days), achieving at least partial nodal response followed by PD, PD did not occur within a drug interruption window, PD was not associated with Richter's transformation, and PBMC samples were available from both baseline and time of PD. Whole-exome sequencing (WES) was conducted on the matched samples from 13 subjects fitting the above criteria. In 6/13 cases, DNA was available from CD19+/CD5+ enriched tumor cells, and neutrophils or T-lymphocytes served as a source of germline DNA. These 6 patients were considered as a discovery set for mutational analysis. Established bioinformatics tools were used for detection of somatic mutations and for the comparison of baseline and PD samples. Results: Baseline clinical patient profiles indicated that 12 of 13 patients with PD had unmutated IGHV genes and 8 patients carried TP53 aberrations (ie, 17p deletion and/or TP53 mutation). WES resulted in a mean read depth of 106X within the targeted coding region across samples. In the discovery set, on average 25 somatic mutations (range: 4-44) at baseline and 32 mutations (range: 15-81) at progression were identified. By comparing baseline and PD samples, we identified 88 PD-associated mutations. These specific mutations were tested for in a complete set of 13 patient samples; however, no recurrent progression-associated mutations were identified in more than 1 patient. In particular, no progression-associated mutations were identified in the PI3K signaling pathway or in any other related pathway. Conclusion: Across 3 phase 3 studies in relapsed CLL, WES on 13 samples from patients with PD while on IDELA treatment were evaluated. This analysis detected no relapse-associated mutations in common across this patient set; in particular, no mutations were identified in the drug-binding site (ie, "gateway mutation") or in any other related signaling pathway. Based on these results, we conclude there is no common mutational mechanism of IDELA resistance in this patient group. Disclosures Ghia: Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding; Adaptive: Consultancy; Abbvie: Consultancy, Honoraria. Tausch:Gilead: Other: Travel support, Speakers Bureau; Celgene: Other: Travel support; Amgen: Other: Travel support. Owen:Roche: Honoraria, Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria; Lundbeck: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria; Gilead: Honoraria, Research Funding. Barrientos:Gilead: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy, Research Funding. Munugalavadla:Gilead Sciences: Employment, Equity Ownership. Degenhardt:Gilead Sciences: Employment, Equity Ownership. Kim:Gilead Sciences: Employment, Equity Ownership. Dubowy:Gilead Sciences: Employment, Equity Ownership. Dreiling:Gilead Sciences: Employment, Equity Ownership. Rosenquist:Gilead Sciences: Speakers Bureau. Stilgenbauer:Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding.

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