ALBERT

Description: Introduction: Several prognostic models for overall survival (OS) in chronic lymphocytic leukemia (CLL) have been developed, but none were derived for patients (pts) with relapsed or refractory (R/R) CLL treated in the era of novel agents. We used a comprehensive approach to derive and validate a novel risk model for OS in 2,475 pts with R/R CLL who received therapy in randomized phase 3 trials evaluating ibrutinib (IBR), idelalisib (IDELA), and venetoclax (VEN) vs control arms, or the Mayo Clinic CLL Database (MCCD). Methods: In collaboration with Janssen, Gilead, Pharmacyclics, and Genentech/Roche, the analysis included 2,475 pts from 6 multicenter randomized phase 3 trials or the MCCD. Trials included were: IBR plus bendamustine-rituximab (BR) vs placebo plus BR (HELIOS: NCT01611090), IBR vs ofatumumab (RESONATE: NCT01578707), IDELA plus BR vs placebo plus BR (Study 115: NCT01569295); IDELA plus rituximab vs placebo plus rituximab (Study 116: NCT01539512); IDELA plus ofatumumab vs ofatumumab (Study 119: NCT01659021); VEN plus rituximab vs BR (MURANO: NCT02005471). All pts had R/R CLL and required treatment by iwCLL criteria. The model-building dataset (n=969) included pts from HELIOS and RESONATE, and was randomly assigned to the IBR/chemoimmunotherapy (CIT) training dataset (n=727) and IBR/CIT internal-validation dataset(n=242). Three independent external validation datasets included IDELA/CIT (n=897), VEN/CIT (n=389), and MCCD (n=220). We applied univariate and multivariate analyses (MVA) to 28 candidate clinical/laboratory and genetic prognostic factors to derive the risk model in the training dataset. The primary endpoint was OS. We assessed the need for separate models for targeted agents by interactions with treatment in univariate analyses. We proceeded to develop a single model for all pts with R/R CLL, as only one candidate factor (del(13q), interaction p value

Description: Introduction: Several targeted therapies have been added to the treatment landscape of CLL. These agents have more favorable toxicity profiles compared with chemotherapy, but achieve only low complete remission (CR) rates. However, combination regimens with targeted drugs have the potential for improved duration and depth of response while exhibiting an acceptable safety profile. Tirabrutinib is a selective, irreversible, second generation, small-molecule BTK inhibitor. Tirabrutinib and idelalisib individually have shown promising results as single-agent therapy in patients (pts) with CLL. This study evaluated tirabrutinib and idelalisib together as dual therapy (TI), and as triple therapy adding obinutuzumab (TIO). Methods: This is a prospective, open-label, phase 2 protocol (NCT02968563) at 15 clinical centers in Germany that recruited between April 2017 and September 2018. Pts with relapsed or refractory CLL were eligible, including those who did not progress while treated with any inhibitor of BTK, SYK, PI3K, BCL-2, or with obinutuzumab. Pts received the TI regimen with tirabrutinib 80 mg once daily (QD) + idelalisib 100 mg QD, or TIO adding obinutuzumab at standard dosing, for a total of 8 doses of 1000 mg over 21 weeks. After the implementation of protocol amendment 3, randomization was discontinued and all subsequently enrolled pts received the TIO regimen. The primary endpoint was CR rate at week 25. Results: Thirty-five pts were enrolled, of which 5 were treated with TI and 30 with TIO. Median (range) age was 66 (47-82) years, with a median of 1 (1-1) and 1 (1-4) prior anticancer therapies in those assigned to TI and TIO, respectively. As of 7 June 2019, 1 of 5 pts (20%) on TI and 21 of 30 pts (70%) on TIO continue to receive tirabrutinib on study, while 1 pt (20%) in the TI and 19 pts (63%) in the TIO arm continued with idelalisib. Tirabrutinib dosing as specified per protocol at week 104 was completed by 1 pt (20%) in the TI and 4 pts (13%) in the TIO arm, respectively. No pts receiving TI and 4 pts (13%) on TIO completed idelalisib as specified per protocol. Altogether 3 pts out of 35 (9%) discontinued tirabrutinib and 7 pts (20%) discontinued idelalisib prematurely due to adverse events (AEs). Twenty-eight of 30 (93%) pts completed obinutuzumab dosing as specified per protocol. Four pts (80%) treated with TI and 29 pts (97%) treated with TIO were ongoing in the study. Median duration (range) of exposures to tirabrutinib and idelalisib were 67 (4.3-104.0) and 61 (1.6-95.4) weeks on TI therapy, 49 (0.1-105.4) and 37 (0.1-105.4) weeks on TIO, and 20 (0.1-22.4) weeks for obinutuzumab. CR rate at week 25 was 0% (90% confidence interval [CI] 0-45.1) with TI and 7% (90% CI 1.2-20.2) with the TIO regimen (Table 1).Overall response rates at week 25 were 40% (90% CI 7.6-81.1) and 86% (90% CI 71.2-95.1) with TI and TIO.No pts on TI and 1 pt (3%) on TIO was MRD negative in peripheral blood (PB MRD-) at week 25; no pts were MRD- in bone marrow (BM MRD-) at week 25. Best rates of CR/PB MRD- were 0% (90% CI 0-45.1) and 7% (90% CI 1.2-20.2) for TI and TIO. Median time to first PB MRD- was 42 weeks on TIO. Median progression-free survival (PFS) and overall survival have not yet been reached. Three pts on TI and 1 pt on TIO experienced disease progression (per clinical response assessment) after the end of treatment. Twenty-four month PFS rates were 60% (90% CI 19.0-85.0) and 77% (90% CI 34.0-94.0) in pts receiving the TI and TIO regimens, respectively. Treatment-emergent AEs (TEAEs) grade 3-4 occurred in 3 of 5 (60%) pts with TI and 24 of 30 (80%) pts with TIO (Table 2). Two out of 35 pts had a TEAE leading to death: a 63-year-old male in the TI arm had grade 5 acute cardiac failure (related to tirabrutinib and idelalisib) when on treatment for 45 days, and died on the same date as the AE onset date/last dosing date; a 68-year-old female on TIO had grade 5 cerebral infarction (not related to any study drug as judged by the investigator) when on treatment for only 1 day, and died 27 days after the AE onset date/last dosing date. Conclusion: Combination therapy with tirabrutinib, idelalisib, and obinutuzumab (TIO regimen) had good efficacy with some relevant toxicity in relapsed/refractory CLL. Disclosures Kutsch: Mundipharma, AbbVie, Janssen: Other: Travel, accomodation, expenses; Gilead Sciences, Inc.: Research Funding. Pallasch:Gilead Sciences, Inc.: Honoraria, Research Funding. Decker:Novartis: Consultancy. Graeven:Servier: Honoraria; Amgen: Consultancy; Merck KGaA: Consultancy; Novartis: Consultancy; Hexal: Consultancy; Boehringer Ingelheim: Honoraria; Daiichi Sankyo: Honoraria; Bristol-Myers Squibb: Consultancy; Sirtex Medical: Honoraria; Merck KGaA: Other: Travel, Accommodations; Amgen: Other: Travel, Accommodations. Kroeber:Celgene: Honoraria; Janssen-Cilag: Honoraria; Amgen: Honoraria; Roche: Honoraria. Tausch:Roche: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Speakers Bureau. Wendtner:MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffman-La Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Stilgenbauer:AbbVie, AstraZeneca, Celgene, Gilead Sciences, Inc., GSK, Hoffmann La-Roche, Janssen, Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Huang:Gilead Sciences, Inc.: Employment, Other: Shareholder. Jürgensmeier:Gilead Sciences, Inc.: Employment, Other: Shareholder. Bhargava:Gilead Sciences, Inc.: Employment, Other: Shareholder; Tioma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Dicerna Pharmaceuticals: Consultancy; Sanofi, Aveo Pharma: Patents & Royalties. Hallek:Roche, Gilead Sciences, Inc., Mundipharma, Janssen, Celgene, Pharmacyclics, AbbVie: Honoraria, Research Funding, Speakers Bureau. Eichhorst:Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; BeiGene: Research Funding. OffLabel Disclosure: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia.

Description: Introduction: In CLL, numerous new therapeutic options have been introduced recently, without establishing a definitive standard therapy or cure for most patients (pts). An advantage of targeted therapies is the avoidance of toxicities associated with chemotherapy. However, all new kinase inhibitors used for treatment of CLL have low rates of complete remission (CR). Combinations of targeted agents have the potential to improve outcomes, shorten treatment duration, and reduce toxicity. Tirabrutinib (a BTK inhibitor), and entospletinib (a SYK inhibitor), both show significant single-agent clinical activity in pts with CLL. In this study, we evaluated tirabrutinib and entospletinib as dual therapy (TE), and as triple therapy in combination with obinutuzumab (TEO). Methods: This is a prospective, open-label, phase 2 protocol (NCT02983617) at 15 clinical centers in Germany that recruited pts with relapsed or refractory CLL between April 2017 and September 2018. As of amendment 3, pts who did not progress while on an inhibitor of BTK, SYK, PI3K, BCL-2 or on obinutuzumab were also included. Pts received the TE regimen with tirabrutinib 80 mg once daily (QD) + entospletinib 400 mg QD for up to 104 weeks, or the TEO regimen adding obinutuzumab at standard dosing for a total of 8 doses of 1000 mg over 21 weeks. After the implementation of protocol amendment 3, randomization was discontinued and all subsequently enrolled pts received the TEO regimen. Response was measured by modified iwCLL 2008 criteria. The primary endpoint was the CR rate at week 25. Results: Thirty-six pts were treated, 6 with TE and 30 with TEO. Median (range) age was 68 (45-82) years, with a median of 1 (1-2) and 2 (1-8) prior anticancer therapies in those assigned to TE and TEO, respectively. As of 16 May 2019, 29 of all 36 pts (81%) continue to receive tirabrutinib and entospletinib on study; 2 (6%) pts completed study drug dosing as specified per protocol at week 104. Twenty-eight of 30 pts (93%) in the TEO arm completed obinutuzumab dosing as specified per protocol. Of the 36 pts, 34 (94%) continued the study and 2 (6%) discontinued the study due to adverse events (AEs) or death, both were in the TEO group. Median duration (range) of exposure to tirabrutinib and entospletinib was 99 (90-105) weeks on TE and 50 (4-104) weeks on TEO, including 20 (2-35) weeks for obinutuzumab. At week 25, CR rate was 0% (90% confidence interval [CI] 0-39.3) with TE and 7% (90% CI 1.2-19.5) with TEO (Table 1). Overall response rates at week 25 were 100% (90% CI 60.7-100) and 90% (90% CI 76.1-97.2) for TE and TEO.One pt on the TEO regimen experienced disease progression (per clinical response assessment) after 3.75 months of therapy. Three (10%) pts on TEO were minimal residual disease (MRD) negative in peripheral blood (PB MRD-) at week 25; one (3%) pt was also MRD negative in bone marrow (BM MRD-).No pts showed MRD negativity with TE therapy. Best rate of CR/PB MRD- was 7% (90% CI 1.2-19.5) and for CR/BM MRD- was 3% (90% CI 0.2-14.9) with TEO. Median time to first PB MRD- was 32 weeks on TEO. Median progression-free survival (PFS) and overall survival have not been reached yet, and 24-month PFS rates were not yet estimable in either treatment group. Treatment-emergent AEs (TEAEs) are listed in Table 2. No pt in the TE and 3 pts (10%) in the TEO group discontinued tirabrutinib and entospletinib due to TEAEs, and no pt discontinued obinutuzumab due to TEAEs. Two (7%) pts in the TEO arm died following a TEAE: an 82-year-old male from subdural hematoma (onset within 30 days of last dosing, and death within 68 days) and a 77-year-old male from syncope (onset on the last dosing date, and death at day 35 after last dosing); both deaths were considered unrelated to study treatment by investigators. Conclusion: A triple combination with tirabrutinib, entospletinib, and obinutuzumab (TEO regimen) was tolerable and demonstrated excellent therapeutic activity in pts with relapsed or refractory CLL, but with limited CR rate. Disclosures Kutsch: Gilead Sciences, Inc.: Research Funding; Mundipharma, AbbVie, Janssen: Other: Travel, accomodation, expenses. Pallasch:Gilead Sciences, Inc.: Honoraria, Research Funding. Tausch:AbbVie: Consultancy, Honoraria, Other: travel support, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Boehme:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Glenmark Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Helsinn: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; VioPharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; InCyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant. Ritgen:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding. Wacker:Celgene: Consultancy; Roche: Consultancy; BMS: Consultancy; Incyte: Consultancy; Amgen: Consultancy. Trappe:Celgene, Janssen, Takeda, TEVA: Other: Congress related travel support ; Atara: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche Pharma: Consultancy, Honoraria, Other: Congress related travel support , Research Funding; AbbVie: Consultancy, Other: Congress related travel support . Dreger:AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; Neovii, Riemser: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia. Stilgenbauer:AbbVie, AstraZeneca, Celgene, Gilead Sciences, Inc., GSK, Hoffmann La-Roche, Janssen, Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Zhang:Gilead Sciences, Inc.: Employment, Other: Shareholder. Jürgensmeier:Gilead Sciences, Inc.: Employment, Other: Shareholder. Bhargava:Gilead Sciences, Inc.: Employment, Other: Shareholder; Tioma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Dicerna Pharmaceuticals: Consultancy; Sanofi, Aveo Pharma: Patents & Royalties. Hallek:Roche, Gilead Sciences, Inc., Mundipharma, Janssen, Celgene, Pharmacyclics, AbbVie: Honoraria, Research Funding, Speakers Bureau. Eichhorst:ArQule: Membership on an entity's Board of Directors or advisory committees; BeiGene: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia.

Description: Oral mucositis (OM) is a common complication in cancer patients receiving chemotherapy (CT). OM is characterized by damage to the epithelium of the oral-pharyngeal cavity. CG53135-05, a recombinant human fibroblastic growth factor 20 (rhFGF-20) protein, has demonstrated epithelial and mesenchymal cell proliferation stimulating activity in vitro and reduces OM using single doses in a hamster mucositis model. The goal of this dose-escalating tolerance study was to assess the safety, tolerability and pharmacokinetics of CG53135-05 in cohorts of four patients (pts) at 0.03, 0.1, 0.33, and 1mg/kg (concentrations are determined by the UV method which are equivalent to 0.1, 0.3, 1.0, and 3.0 mg/kg by the Bradford method previously used). Dose escalation was stopped due to tolerability information at 0.33 mg/kg delivered in 15 min (reported in another Phase I study) and the protocol was amended to add a 0.2 mg/kg dose. The World Health Organization (WHO) OM and OMAS scoring systems were used to measure the incidence and severity of OM. The interim results are reported: Ten pts received CG53135-05 at 0.03 mg/kg (n=4) or 0.1 mg/kg (n=6) as a single 100-ml intravenous infusion administered 3 days after completion of the CT. After infusion, CG53135-05 reached maximum plasma concentration within 1h. The mean terminal exponential half-life was 49 min (range: 16.2–87 min, n=5). No pts discontinued the trial due to adverse experiences. Adverse events (number pts) that may be related to the study drug include: nausea (2); chills (2); fever (2); vomiting (1); dizziness (1); vision - “lights flashing” (1) and astigmatism (1); neuropathy (1); tachycardia (1); headache (1); and premature atrial complex (1). All reported incidences were mild to moderate. No grade 3 or 4 laboratory toxicity associated with the study drug was noted. Three serious adverse events deemed unrelated to study drug were noted from two pts including cancer progression, catheter infection, and small intestinal obstruction. Among the treated pts, no grade 3 or 4 OM was observed. Three pts developed Grade 2 mucositis that lasted between 1–5 days. No pts required total parenteral nutrition. Approximately 72–84% of pts receiving CPT-11 experience diarrhea. Of the six pts who received CPT-11 as part of CT in this trial, two pts (both receiving 0.03mg/kg of CG53135-05) experienced mild to moderate diarrhea. Conclusions: CG53135-05 is well tolerated with single dose administration at 0.03 and 0.1 mg/kg. Dosing at 0.2 mg/kg is ongoing. The full results of this study will be presented.