ADCP

ADCC

CD19

Macrophage

Natural killer cell

Tumor cell

Direct cytotoxicity

Engineered Fc portion► Enhanced ADCC► Enhanced ADCP

MOR208

A�nity matured CD19 binding site► Direct tumor cell killing

ASCO June 2–6, 2017: Abstract TPS7567

Background• The BTKi, ibrutinib, is an important treatment option for patients with

CLL/SLL.1, 2

• Patients who discontinue treatment with ibrutinib due to progression, transformation or intolerance have a particularly dismal prognosis, as alternative therapeutic options are limited.3-5

• Phosphoinositide-3-kinase δ (PI3K-δ) is hyperactivated in B-cell malig-nancies and plays a pivotal role in the B-cell receptor pathway.6, 7

• Idelalisib is a first-in-class, orally administered, potent, reversible, small-molecule inhibitor of PI3K-δ and is approved in combination with rituximab for the treatment of patients with relapsed CLL and as mono-therapy for patients with relapsed follicular lymphoma or SLL.6

• Venetoclax, an orally administered, small-molecule inhibitor of BCL-2, is currently approved for the treatment of patients with CLL who have a tumor chromosomal 17p deletion and who have received at least one prior therapy.8

• CD19 expression is highly conserved at normal to high levels in most B-cell tumors during the course of disease, including in CLL and B-cell lymphoma.9

• MOR208, an Fc-enhanced monoclonal antibody, binds to CD19 (Figure 1), demonstrating significantly increased tumor cytotoxicity compared with the parental, non-engineered antibody.10,11

• A phase I study showed MOR208 to be generally safe and well tolera-ted, with encouraging single-agent activity in patients with CLL/SLL.12

Figure 1. MOR208 mode of action

ADCC, antibody-dependent cell-mediated cytotoxicity; ADCP, antibody-dependent cell-mediated phagocytosis.

Methods• This is a phase II, two-cohort, open-label, multicenter study to evaluate

the efficacy and safety of MOR208 combined with idelalisib or venetoclax in patients with R/R CLL/SLL previously treated with a BTKi (NCT02639910; Figure 2).

Outcome measuresPrimary endpoint• Overall response rate (based on independent review), defined for

Cohort A as the percentage of patients achieving a complete response (CR), a partial response (PR) or a PR with lymphocytosis, and for Cohort B as the percentage of patients achieving a CR or a PR.

Figure 2. Study design

*1 treatment cycle is 28 days; †Additional loading dose of MOR208 on cycle (C) 1 day (D) 4; ‡Weekly ramp up of venetoclax starting on cycle 1 day 8 (C1D8: 20mg, C1D15: 50mg, C1D22: 100mg, C2D1: 200mg). Venetoclax dose 400 mg up from cycle 2 day 8. BID, twice daily; BTK, Bruton’s tyrosine kinase; Q1W, weekly; Q2W, every second week; Q4W, monthly; QD, daily; R/R CLL, relapsed or refractory chronic lymphocytic leukaemia; R/R SLL, relapsed or refractory small lymphocytic lymphoma.

R/R CLL or R/R SLL pretreated with BTK inhibitor (e.g. ibrutinib)

Cycle 1-3*

Idelalisib 150 mg, BID, PO

Days 1-28

MOR208 12 mg/kg, IV, Q1W

Days 1, 8, 15, 22†

Venetoclax 400 mg, QD, PO

Days 1-28‡

MOR208 12 mg/kg, IV, Q1W

Days 1, 8, 15, 22†

Cycle 4 - 6*

Idelalisib 150 mg, BID, PO

Days 1-28MOR208

12 mg/kg, IV, Q2W Days 1, 15

Venetoclax 400 mg, QD, PO

Days 1-28

MOR208 12 mg/kg, IV, Q2W

Days 1, 15

Cycle 7-24*

Idelalisib 150 mg, BID, PO

Days 1-28MOR208

12 mg/kg, IV, Q4W Day 1

Venetoclax 400 mg, QD, PO

Days 1-28

MOR208 12 mg/kg, IV, Q4W

Day 1

Disease or

survival Follow-Up

Cohort A

Cohort B

COSMOS: MOR208 plus idelalisib or venetoclax in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) previously treated with a Bruton‘s tyrosine kinase inhibitor (BTKi) – a two-cohort phase II studyClemens-Martin Wendtner,1 John Byrd,2 Robin Foà,3 Richard Greil,4 Peter Hillmen,5 Ulrich Jäger,6 Wojciech Jurczak,7 Peter Kelemen,8 Kamel Laribi,9 Talha Munir,5 Johannes Schetelig,10 Philipp B. Staber,6 Stephan Stilgenbauer,11 Jennifer Woyach 21Klinikum Schwabing, Department I of Medicine, Academic Teaching Hospital of University of Munich, Munich, Germany; 2Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA; 3Division of Hematology, ”Sapienza“ University of Rome, Rome, Italy; 4Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, Rheumatology, Oncologic Center, Paracelsus Medical University Salzburg, Salzburg, Austria; 5St James‘s University Hospital, Leeds, United Kingdom; 6Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Vienna General Hospital - Medical University of Vienna, Vienna, Austria; 7Department of Hematology, Jagiellonian University, Kraków, Poland; 8MorphoSys AG, Planegg, Germany; 9Department of Hematology - Centre Hospitalier du Mans, 72037 Le Mans, France; 10Medizinische Klinik und Poliklinik I, TU Dresden, Dresden, Germany; 11Department of Internal Medicine III, Ulm University, Ulm, Germany

Secondary endpoints• Progression-free survival; overall survival; time to progression; time to

treatment failure; time to response.• Duration of response; lymph node response.• Incidence and severity of adverse events.• Detection of anti-MOR208 antibodies (immunogenicity).• MOR208 pharmacokinetics.• Patient-reported quality of life outcomes.

Exploratory endpoints• Proportion of patients with minimal residual disease negativity. Changes

from baseline in B-, T- and natural killer (NK) cell populations. Analysis of exploratory and diagnostic biomarkers from blood (e.g., CD19 expression, BTK and phospholipase C (PLC)γ2 mutational status, CD16 expression on NK cells, antibody-dependent cell-mediated cytotoxicity capacity, cytogenetics and further mutational analysis).

PatientsKey inclusion criteria• Diagnosis of CLL or SLL with an indication for treatment, as defined by

the International Workshop on CLL guidelines.• R/R disease while on BTKi therapy given as a single-agent or as combi-

nation therapy for at least one month, or intolerant to such therapy: – Relapsed disease is defined as progressive disease in patients who

have previously achieved a PR or CR to their most recent BTKi therapy – Refractory disease is defined as progressive disease in patients who

have previously not achieved a PR or CR to their most recent BTKi therapy, or stable disease as the best response after 12 months of receiving their most recent BTKi therapy.

• ECOG performance status of 0–2, adequate bone marrow, hepatic and renal function.

Key exclusion criteria• Non-Hodgkin’s lymphomas other than CLL/SLL; transformed CLL/SLL

or Richter’s syndrome.• Active and uncontrolled autoimmune cytopenia; ongoing systemic

viral, bacterial or fungal infection.

• Treatment with a BTKi within 5 days prior to day 1 dosing. • Prior treatment with a CD19-targeted agent, a PI3K inhibitor (Cohort A)

or a BCL-2 inhibitor (Cohort B).

Current status• Recruitment start date: November 2016.• To date 4 patients have been enrolled.• The study will include a safety run-in phase and there will be an inte-

rim analysis to determine the preliminary safety and efficacy of each combination. The evaluation will be done by an independent data monitoring committee.

References1. Byrd JC, et al. N Engl J Med 2014;371:213-23.2. Burger JA, et al. N Engl J Med 2015;373:2425-37.3. Jain P, et al. Blood 2015;125:2062-7.4. Maddocks KJ, et al. JAMA Oncol 2015;1:80-7.5. Woyach JA, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 7010)6. Yang Q, et al. Clin Cancer Res 2015;21:1537-42.7. Ringshausen I, et al. Blood 2002;100:3741-8.8. Stilgenbauer S, et al. Lancet Oncol 2016;17:768-78.9. Wang K, et al. Exp Hematol Oncol 2012;1:36.10. Awan FT, et al. Blood 2010;115:1204 -13.11. Horton HM, et al. Cancer Res 2008;68:8049-57.12. Woyach JA, et al. Blood 2014;124:3553-60.

AcknowledgmentsThis study is sponsored by MorphoSys AG. Medical writing support was provided by Manuel Krinner and was funded by MorphoSys AG.

DisclosuresDisclosures in relation to MorphoSys AG: CMW, honoraria, consulting/advisory role, research funding, travel/ accommodation/expenses; WJ, consulting/advisory role, research funding; PK, employment, intellectual property interests; TM, consulting/advisory role; PBS, consulting/advisory role; JW, research funding. Other authors had no conflict of interest to disclose in relation to MorphoSys AG.

CorrespondenceClemens-Martin.Wendtner@klinikum-muenchen.de

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