Hellmann, Andrzej

Introduction: Patients (pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) who failed treatment with the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib have a poor outcome and are difficult to treat. This ongoing, two-cohort, Phase II trial evaluates the safety and preliminary efficacy of tafasitamab (MOR208), an Fc-enhanced anti-CD19 monoclonal antibody in combination with idelalisib (IDE) (Cohort A) or venetoclax (VEN) (Cohort B) in R/R CLL pts previously treated with a BTKi. Preliminary results were published at EHA 2018 for Cohort A and at ASH 2018 for Cohort B. Here, we report the results of the primary analysis for both cohorts. Methods and Patients: Pts who either progressed or were intolerant to BTKi were enrolled at 12 sites in six countries in Europe and the US from Nov 2016 to Apr 2018. The primary endpoint is the incidence and severity of adverse events (AEs); secondary endpoints include overall response rate (ORR) as per investigator assessment according to International Workshop on CLL (IWCLL) 2008 guidelines. Complete response (CR) was confirmed by computed tomography assessment and by bone marrow (BM) biopsy. The exploratory endpoint minimal residual disease (MRD) was assessed centrally by quantitative allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in peripheral blood (PB) and BM. Each treatment cycle (C) lasts 28 days (D). Dose and administration: tafasitamab intravenous infusion, 12 mg/kg weekly in C1-C3, every other week in C4-C6 and monthly from C7D1; IDE orally, 150 mg twice daily; VEN orally, weekly ramp up starting on C1D8 at 20 mg to full daily dose of 400 mg. Patients: mean time since first CLL diagnosis was 135 months (mos) for pts in Cohort A and 105 mos in Cohort B. Median number of prior therapy lines was five (2-9) and three (1-5), respectively. All pts had received ibrutinib; one pt had subsequent acalabrutinib treatment as last prior therapy line. Mutations of BTK and PLCγ2 were assessed in nine pts in Cohort A and 13 pts in Cohort B. BTK/PLCγ2 mutations were centrally detected in 4/3 pts in Cohort A and in 2/3 pts in Cohort B, respectively. Complex karyotype was observed in six (54.5%) pts in Cohort A and 12 (92.3%) pts in Cohort B. Results with a data cut-off date of 9 Nov 2018 are presented. Results: Cohort A: Median time on study was 9.9 mos (95% confidence interval [CI]: 5.7-not reached). Eleven pts were enrolled and received tafasitamab and IDE. Two pts discontinued treatment due to AEs (aspartate-aminotransferase increased; acute pancreatitis), two due to progressive disease (PD) and one pt by physician's decision. One pt died due to PD and one pt due to cardiac failure. At the cut-off date, treatment was ongoing in four pts. Table 1 summarizes treatment-emergent adverse events (TEAEs) with neutropenia Grade ≥3 being most common (5 [46%]). Fourteen treatment-emergent serious AEs (SAEs) were reported in eight (72.7%) pts. ORR was 90.9% (CR=9.1%, partial response [PR]=81.8%), disease control was achieved in all 11 pts. One of eight pts (12.5%) assessed for MRD status reached MRD-negativity in PB at C14. Cohort B: Median time on study was 12 mos (95% CI: 2.8-not reached). Eleven of 13 enrolled pts received tafasitamab and VEN while two pts received tafasitamab only. Three pts discontinued treatment due to AEs (infusion-related reactions [two pts], diarrhea [one pt], one due to PD and one withdrew consent. At the cut-off date, treatment was ongoing in eight patients. Table 2 summarizes TEAEs, neutropenia Grade ≥3 was most commonly observed (six [46%] pts). Fourteen SAEs were reported in nine (69.2%) pts. The ORR in all 13 pts was 76.9% (CR=23.1%, PR=53.8%, not evaluable=23.1%). Six of seven pts assessed for MRD in PB (46.2% of 13 [100%] pts) reached negative status in PB by C7 at the latest. One of three pts assessed for MRD in BM (7.7% of 13 [100%] pts) reached MRD negative status in BM at C15. Conclusions: This trial demonstrates that in heavily pretreated pts with R/R CLL who failed prior BTKi, tafasitamab in combination with IDE or VEN is a potential therapeutic option. The safety profiles of the combinations are influenced by the combination partner, but both combinations are manageable. The response rates and MRD-negativity rates indicate that combinations of targeted agents with anti-CD19 tafasitamab have valuable antitumor activity and warrant further investigation of tafasitamab-based combinations in CLL. Disclosures Staber: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda-Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jurczak:Celtrion: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Research Funding; Celgene Corporation: Research Funding; Incyte: Research Funding; Servier: Research Funding; Roche: Research Funding; Novo Nordisk: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Gilead: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Brugger:AstraZeneca: Equity Ownership; MorphoSys: Employment. Chanan-Khan:Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding; Xencor: Research Funding; AbbVie: Research Funding. Greil:Mundipharma: Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Sandoz: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Eisai: Honoraria; Janssen-Cilag: Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Boehringer Ingelheim: Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Ratiopharm: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Pfizer: Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; GSK: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Dirnberger-Hertweck:MorphoSys: Employment. Kelemen:MorphoSys: Employment. Middeke:Janssen: Consultancy, Speakers Bureau; MSD: Consultancy; AbbVie: Consultancy, Speakers Bureau; Gilead: Consultancy; Roche: Speakers Bureau; Sanofi: Research Funding, Speakers Bureau. Montillo:Roche: Consultancy, Honoraria, Research Funding; Acerta: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Versatem: Membership on an entity's Board of Directors or advisory committees. Munir:Acerta: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Other: TBC; AbbVie: Honoraria; Alexion: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy. Parikh:Pharmacyclics: Honoraria, Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; MorphoSys: Research Funding; Acerta Pharma: Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Research Funding. Stilgenbauer:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffmann La-Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Weirather:MorphoSys: Employment. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Wendtner:AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffman-La Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Background and purpose of the study: Several reports have documented that histone deacetylase inhibitors induce neoplastic cells to undergo growth arrest, differentiation and/or apoptotic cell death. Among these agents, Givinostat inhibits proliferation of cells bearing the JAK2V617F mutation and has shown clinical significant activity with good tolerability in patients with chronic myeloproliferative neoplasms, including polycythemia vera (PV). In two phase II studies [Rambaldi et al. Br J Haematol 2010;150:446, Finazzi et al. Br J Haematol 2013;161:688] the maximum administered dose (150 mg/day) was generally well tolerated. Assuming a linear relationship between dose and efficacy, greater clinical efficacy could be expected with increased doses of Givinostat. Methods: This is a two-part, multicenter, open label, non-randomized, phase Ib/II study to assess the safety and tolerability, maximum tolerated dose (MTD) and preliminary efficacy of Givinostat in patients with JAK2V617F positive PV. Part A (i.e. phase Ib) is the dose escalation portion of the study, while Part B assesses the preliminary clinical efficacy of Givinostat at the MTD defined in Part A. Eligible patients for this study include JAK2V617F positive PV patients, who have active and/or uncontrolled disease, defined as: (i) Hematocrit (HCT) ≥ 45% or HCT <45% normalized by phlebotomy, and (ii) PLT > 400 x109/L, and (iii) WBC > 10 x109/L. Study therapy is administered in 28 day cycles (cycle is defined as 4 weeks of treatment). Disease response has been evaluated according to the clinico-haematological European LeukemiaNet (ELN) criteria [Barosi et al. Blood 2009;113:4829] at Cycles 3 and 6. Disease-related symptoms have been reported directly by the patients who completed the MPN-SAF QoL form. The study lasts up to a maximum of 24 weeks of treatment. However, after completion of the trial, all patients achieving clinical benefit are allowed to continue treatment with Givinostat in a long-term study (ClinicalTrials.gov ID: NCT01761968). In Part A, the Cycle 1 has been used to define the MTD of Givinostat. Only dose limiting toxicities (DLTs) experienced during Cycle 1 were considered for dose escalation decisions. Part B is the cohort expansion part of the study to assess the preliminary clinical efficacy of Givinostat at the MTD in evaluable patients Results: In Part A, 12 patients with active and/or uncontrolled disease, were treated with Givinostat, 6 patients at DL1 (100 mg b.i.d.), 3 patient at DL6 (150 mg/die) and 3 patients at DL0 (50 mg b.i.d.). Only one DLT .(grade 3 dyspepsia) was observed in the 6 patients treated at DL1 during the Cycle 1. Givinostat treatment was generally well tolerated: one patient developed grade 4 and two patients grade 3 thrombocytopenias at DL1 after the Cycle 1. Complete/partial response was observed in 100% of evaluable patients at Cycle 3 (Figure). At that time, an important reduction of WBC and PLT count (about 50% in both cases), an HCT control without phlebotomy, a net decrease of MPN-SAF total score and JAK2V617F allele burden (about 50% and 30%, respectively) have been noted and generally maintained at Cycle 6. One out of 3 (33%) patients with splenomegaly at baseline normalized the spleen at Cycle 6. PK/PD evaluations are currently under analysis. Part B started on December 2015 and is currently recruiting patients. At the time of ASH Meeting, a presentation of the preliminary results of the interim analysis (IA) is planned. The objective of this IA is to evaluate the response rate of the first 12 treated and evaluable patients. Conclusions: Taking into account the continuous schedule of the drug as prescribed in this current study, the daily dosage of 200 mg has been identified as the MTD of Givinostat in PV patients. Givinostat treatment is generally well tolerated and shows preliminary clinical efficacy in PV patients with an active/uncontrolled disease. Response rate of patients in Part A C3D28 = Cycle 3 Day 28, or three months of treatment. C6D28 = Cycle 6 Day 28, or six months of treatment. Two patients dropped-out the study Part A, due to Informed Consent Form withdrawal, while 1 patient left the study for AE (i.e. grade 3 dyspepsia, DLT). At C3D28, 1 Complete Response (CR) and 8 Partial Response (PR) have been observed. At C6D28, 1 Complete Response (CR), 7 Partial Response (PR) and 1 No Response (NR) have been observed Figure Figure. Disclosures McMullin: Novartis: Honoraria, Speakers Bureau. Vannucchi:Novartis: Honoraria, Speakers Bureau. Mesa:Ariad: Consultancy; CTI: Research Funding; Galena: Consultancy; Celgene: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Incyte Corporation: Research Funding; Gilead: Research Funding. Tibes:Italfarmaco S.p.A.: Consultancy, Honoraria. Bettica:Italfarmaco S.p.A.: Employment. DI Tollo:Italfarmaco S.p.A.: Employment.