Two-Cohort Phase II Study in R/R CLL (COSMOS): First Preliminary Safety and Efficacy Results of Anti-CD19 MOR208 Treatment in Combination with Venetoclax in Patients Who Discontinued Prior BTK Inhibitor Therapy
Authors: Staber Philipp Bernhard , Chanan-Khan Asher A. , Munir Talha , Niederweiser Dietger , Schetelig Johannes , Middeke Jan Moritz , Dirnberger-Hertweck Maren , Kelemen Peter , Weirather Johannes , Parikh Sameer A. , Stilgenbauer Stephan , Wendtner Clemens-Martin , Woyach Jennifer A. 
Published: October 2019

Abstract
Introduction: The CD19 antigen is an attractive therapeutic target as it is highly expressed in chronic lymphocytic leukemia (CLL). CD19 is not down-regulated in patients (pts) pretreated with CD20-targeting agents and has a signaling function that promotes the malignant phenotype. In preclinical studies, the Fc-enhanced, humanized, CD19 antibody MOR208 showed synergistic potential in combination with venetoclax (VEN, a small molecule selective inhibitor of the apoptosis regulator BCL-2). Pts with relapsed or refractory (R/R) CLL who failed treatment with the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib have poor prognosis. A previous phase I study showed that MOR208 was well tolerated, with encouraging single-agent activity in pts with R/R CLL. This ongoing phase II study was designed to assess the safety and preliminary efficacy of MOR208 in combination with idelalisib (Cohort A) or VEN (Cohort B) in pts with R/R CLL previously treated with a BTKi. Results of Cohort A were previously published at EHA 2018 (Poster PF350). Here we report the initial safety and efficacy results for Cohort B.
Methods: Adult pts with R/R CLL without transformation or Richter's syndrome, who progressed on BTKi therapy or were intolerant to a BTKi during their last prior therapy, were eligible if they had ECOG performance status 0-2 and adequate organ function. In Cohort B, pts were treated until progression or for up to 24 cycles (C; 28 days (D)/C). MOR208 was administered intravenously at 12 mg/kg body weight, starting from C1D1, weekly during C1-3 (with an equivalent loading dose on D4 of C1), every other week in C4-6, and monthly in C7-24. Oral VEN was administered daily starting from C1D8 on a weekly ramp up dosing schedule, starting at 20 mg on C1D8, increasing to 50 mg on C1D15, 100 mg C1D22, 200 mg C2D1 and reaching the full daily dose of 400 mg from C2D8 onwards. Primary endpoint is the incidence and severity of adverse events (AEs); secondary endpoints include overall response rate (ORR) as per investigator assessment according to IWCLL 2008 guidelines.
Results: We report preliminary results of Cohort B with a data cutoff date of June 18, 2018 and a median observation time of 4.6 months. Recruitment in Cohort B was completed with 13 pts who received at least one dose of MOR208. Eleven pts started combination treatment with VEN; 10 pts completed at least 5 weeks of combination treatment, reaching the full daily dose of VEN. Baseline characteristics are shown in Table 1. All pts had received ibrutinib therapy and 1 pt had subsequent acalabrutinib treatment. The median number of prior treatment lines, including BTKi therapy in all 13 pts, was 3 (range 1-4). Table 2 summarizes treatment-emergent (TE)AEs. The most common hematological TEAE was neutropenia (38%). Eleven TE serious (S)AEs were reported in 9 pts (69%); all resolved. One grade 3 SAE, tumor lysis syndrome, occurred at ramp up to 50 mg VEN. The pt recovered after treatment and continued VEN 50 mg the day after event onset. Three serious adverse reactions (2 pts with infusion-related reactions, 1 pt with bone pain with pyrexia) were reported in total. Two pts (15%) permanently discontinued study treatment due to an infusion-related reaction arising during MOR208 monotherapy (i.e. before C1D8). One pt (8%) discontinued study participation due to withdrawal of informed consent, when on a dose of 50 mg VEN. The 3 discontinued pts did not undergo a response assessment. Treatment of 10 pts is ongoing and seven pts had at least 1 post-baseline assessment of tumor response on C4D1; all (7/7) had a partial response (PR) based on local investigator assessment.
Conclusions: The novel combination treatment of MOR208 with VEN showed generally acceptable safety and tolerability as well as encouraging antitumor activity in pts with R/R CLL who discontinued prior treatment with a BTK inhibitor.

Disclosures
Staber: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI: 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. Munir:Alexion: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; MorphoSys: Membership on an entity's Board of Directors or advisory committees. Schetelig:Roche: Honoraria; Sanofi: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; Janssen: Consultancy, Honoraria. Middeke:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Dirnberger-Hertweck:MorphoSys: Employment. Kelemen:MorphoSys: Employment. Weirather:MorphoSys: Employment. Parikh:MorphoSys: Research Funding; Gilead: Honoraria; Janssen: Research Funding; Pharmacyclics: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding. Stilgenbauer:Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding. Wendtner:Abbvie: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding.