Download Phase IIa study of single-agent MOR208 in patients

Phase IIa study of single-agent MOR208 in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma
Wojciech Jurczak,1 Pier Luigi Zinzani,2 Gianluca Gaidano,3 Andre Goy,4 Mariano Provencio,5 Zsolt Nagy,6 Tadeusz Robak,7 Kami Maddocks,8 Christian Buske,9 Roman P. Korolkiewicz,10 Frank Striebel,10 Kristie A. Blum8
1
Department of Hematology, Jagiellonian University, Kraków, Poland; 2Institute of Hematology “L. e A. Seràgnoli”, University of Bologna, Bologna, Italy; 3Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy; 4John Theurer Cancer Center, Hackensack
University Medical Center, Hackensack, USA; 5Department of Medical Oncology, University Hospital Puerta De Hierro, Madrid, Spain; 6First Department of Internal Medicine, Semmelweis University, Budapest, Hungary; 7Department of Hematology, Medical University of Lodz, Lodz, Poland; 8Department of Internal Medicine,
Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, USA; 9Comprehensive Cancer Center Ulm, Institute of Experimental Cancer Research, University Hospital of Ulm, Ulm, Germany; 10MorphoSys AG, Martinsried, Germany
ASH December 5–8, 2015: Abstract 1528
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Introduction
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CD19, a B-lymphocyte lineage specific surface antigen, is the earliest and most
broadly expressed of the selective B-cell markers, and is highly expressed in most
B-cell non-Hodgkin’s lymphomas (NHLs).1,2
Consequently, a CD19 antibody may have clinical utility as a new therapeutic
approach to NHL treatment.
MOR208 is an Fc-engineered humanized monoclonal antibody that targets CD19
(Figure 1).
A phase I study has shown MOR208 to be generally safe and well-tolerated, with
encouraging single-agent activity in patients with chronic lymphocytic leukemia
(CLL) – recommended intravenous dose, 12 mg/kg, weekly.3
Figure 1. MOR208 mode of action
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2-stage design:
– Stage 1: 10 patients to be enrolled into each of 4 NHL subtype cohorts; diffuse
large B-cell lymphoma (DLBCL), follicular lymphoma (FL), other indolent (i)NHL,
mantle cell lymphoma (MCL)
– Stage 2: cohorts with ≥2 responses (complete or partial) expanded by at least
20 additional patients:
• Cohorts with <2 responses not expanded.
Key Inclusion criteria:
– Aged ≥18 years
– Histologically confirmed DLBCL, FL, other iNHL or MCL
– NHL progressed after at least one prior rituximab-containing therapy
– Eastern Cooperative Oncology Group performance status ≤2
– Adequate bone marrow, renal and liver function.
All patients provided written informed consent prior to study entry.
Results
Efficacy
Safety
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Response data are presented in Table 2 and Figures 4 & 5.
Median progression-free survival time was 6 months (Figure 6).
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Table 2. Response
DLBCL
n=35
iNHL†
n=45
MCL
n=12
Total
n=92
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Best overall response,* n (%)
Complete response
Partial response
Stable disease
Progressive disease
Not evaluable‡
ORR (all patients)
ORR (evaluable patients§)
2 (6)
7 (20)
5 (14)
11 (31)
10 (29)
9 (26)
9 (36)
5 (11)
7 (16)
21 (47)
7 (16)
5 (11)
12 (27)
12 (30)
0
0
6 (50)
5 (42)
1 (8)
0
0
7 (8)
14 (15)
32 (35)
23 (25)
16 (17)
21 (23)
21 (28)
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*Investigator assessed. †Includes follicular lymphoma and other indolent NHLs. ‡Post-baseline
response assessment not performed/data unavailable. §n=25, 40, 11 and 76, respectively.
CR, complete response; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma;
iNHL, indolent non-Hodgkin’s lymphoma; MCL, mantle cell lymphoma; ORR (CR + PR), objective
response rate; PR, partial response.
Figure 4. Duration of response
Patients
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Data cutoff November 11, 2015.
Two cohorts were expanded (DLBCL and FL) leading to an overall enrollment of 92
patients (Figure 3):
– Other iNHL cohort not expanded as response was deemed too heterogeneous
between different lymphoma subtypes: data are presented for the combined
FL/other iNHL cohort.
Patient baseline characteristics are summarized in Table 1.
*Includes follicular lymphoma and other indolent NHLs.
CR, complete response; DLBCL, diffuse large B-cell lymphoma; NHL, non-Hodgkin’s lymphoma;
PR, partial response.
Objectives
Grade 3/4,* n (%)
Hematological
Any
Neutropenia
Anemia
Thrombocytopenia
Non-hematological
Dyspnea
Fatigue
Hypokalemia
Pneumonia
DLBCL
n=35
iNHL†
n=45
MCL
n=12
Total
n=92
9 (26)
6 (17)
3 (9)
2 (6)
4 (9)
2 (4)
0
1 (2)
1 (8)
0
0
1 (8)
14 (15)
8 (9)
3 (3)
4 (4)
2 (6)
1 (3)
1 (3)
2 (6)
1 (2)
1 (2)
1 (2)
0
1 (8)
0
0
0
4 (4)
2 (2)
2 (2)
2 (2)
Figure 5. Tumor shrinkage
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Methods
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Non-randomized phase IIa multicenter study (Figure 2).
Figure 2. Study design
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*Until disease progression.
DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; iNHL, other indolent non-Hodgkin’s
lymphoma; iv, intravenous infusion; MCL, mantle cell lymphoma; PR, partial response; R-R relapsed
or refractory; SD, stable disease.
Age, years
Sex
Ann Arbor stage
Median
Male
I–II
III–IV
Missing
ECOG PS
0–1
2
Prior lines of therapy
1
2
≥3
Last rituximab dose <6 months
Prior stem cell transplant
Yes
MCL
n=12
Total
n=92
71
24 (69)
4 (11)
30 (86)
1 (3)
32 (91)
3 (9)
15 (43)
8 (23)
12 (34)
14 (40)
2 (6)
66
21 (47)
5 (11)
40 (89)
0
44 (98)
1 (2)
17 (38)
7 (16)
21 (47)
6 (13)
7 (16)
64.5
11 (92)
1 (8)
11 (92)
0
11 (92)
1 (8)
3 (25)
1 (8)
8 (67)
1 (8)
1 (8)
66.5
56 (61)
10 (11)
81 (88)
1 (1)
87 (95)
5 (5)
35 (38)
16 (17)
41 (45)
21 (23)
10 (11)
Data are n (%) unless otherwise stated.
DLBCL, diffuse large B-cell lymphoma; ECOG PS, Eastern Cooperative Oncology Group
performance status; iNHL, indolent non-Hodgkin’s lymphoma (follicular lymphoma and other iNHL);
MCL, mantle cell lymphoma.
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Encouraging single-agent activity for MOR208, an Fc-engineered CD19 antibody,
in patients with relapsed or refractory NHL.
Promising objective response rates observed; 26% in the DLBCL cohort and 27%
in the combined FL/iNHL cohort:
– 2 complete responses in the DLBCL cohort
– 5 complete responses in the combined iNHL cohort.
Longest DoR to date is 20.3 months for DLBCL and 20.3 months for iNHL
(both ongoing).
MOR208 was well tolerated – infusion-related reactions reported only in 10%
of patients and were typically grade 1/2.
Favorable pharmacokinetic profile and very low immunogenicity.
Protocols are being developed for trials which combine MOR208 with other
antilymphoma therapies (e.g. lenalidomide and bendamustine).
References
1. Wang K, et al. Exp Hematol Oncol 2012;1:36.
2. Schuurman HJ, et al. Am J Pathol 1988;131:102-11.
3. Woyach JA, et al. Blood 2014;124:3553-60.
Acknowledgments
This study was sponsored by MorphoSys AG. Medical writing support was provided
by Jim Heighway PhD, Cancer Communications and Consultancy Ltd (Knutsford, UK)
and was funded by MorphoSys AG.
Table 1. Baseline characteristics
iNHL
n=45
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*Response was deemed too heterogeneous between different lymphoma subtypes. †No responses.
DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; iNHL, indolent non-Hodgkin’s
lymphoma; MCL, mantle cell lymphoma.
DLBCL
n=35
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Estimated mean terminal elimination half-life: 15 days.
Steady state (Cmax ~500 µg/mL, trough ~250 µg/mL) was reached after
approximately 40–50 days (around the seventh dose; Figure 7).
No significant target mediated drug disposition (at 12 mg/kg weekly) observed for
most patients based on time-concentration data.
No significant immunogenicity detected:
– Only 1 of 92 patients has so far tested positive for anti-drug antibodies during
treatment with MOR208.
Figure 7. Overview of pharmacokinetics in patients with NHL
Characteristic
Conclusions
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Antitumor activity of single-agent MOR208 in adult patients with relapsed or
refractory NHL who had received at least one prior therapy containing the CD20
antibody, rituximab:
– Primary endpoint: objective response rate.
Duration of response (DoR) and progression-free survival (PFS).
Safety and tolerability.
Potential immunogenicity.
Pharmacokinetics and pharmacodynamics.
AUC, area under the concentration-time curve; CLL, chronic lymphocytic leukemia; DLBCL, diffuse
large B-cell lymphoma; PD, progressive disease; PR, partial response; SD, stable disease.
Pharmacokinetics
Secondary
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Figure 8. Exposure vs response after 2 cycles of treatment
Table 3. Adverse events
Primary
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The MOR208 exposures showing clinical efficacy are mainly reached at 12 mg/kg
with an initially weekly dosing.
*Treatment emergent adverse events reported in two or more patients overall at grade ≥3 according
to MedDRA preferred terms. †Includes follicular lymphoma and other indolent NHLs.
DLBCL, diffuse large B-cell lymphoma; iNHL, indolent non-Hodgkin’s lymphoma; MCL, mantle cell
lymphoma.
Figure 3. Study profile
ADCC, antibody-dependent cell-mediated cytotoxicity; ADCP, antibody-dependent cell-mediated
phagocytosis.
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The employed dosing regimen at 12 mg/kg was safe and well tolerated and will be
tested further in future clinical trials.
The most common treatment emergent adverse events (>10%) were headache and
upper respiratory tract infection.
Infusion-related reactions were reported in 9 (10%) of 92 patients:
– Grade 1/2 in 8 patients; grade 4 dyspnea in 1 patient.
The most common grade ≥3 treatment emergent adverse events are summarized
in Table 3.
There were no treatment-related deaths.
*Includes follicular lymphoma and other indolent NHLs.
DLBCL, diffuse large B-cell lymphoma; NHL, non-Hodgkin’s lymphoma.
Disclosures
Figure 6. Progression-free survival*
Disclosures in relation to MorphoSys AG: WJ, research funding; GG, honoraria: TR,
consultancy, honoraria and research funding; RPK, FS, employment; KAB, research
funding. Other authors had no conflict of interest to disclose in relation to MorphoSys AG.
Correspondence
Mean values +/– SD are shown for the observed MOR208 concentrations (lower error bars not shown
for 161 and 203 days).
q2w, every 2 weeks; q4w, every 4 weeks; SD, standard deviation.
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*All subtypes of non-Hodgkin’s lymphoma; patients without confirmed progression were censored at
the time of last tumor response assessment.
PFS, progression-free survival.
For patients with relapsed or refractory DLBCL (current study) or relapsed or
refractory CLL/small lymphocytic lymphoma (phase I dose escalation study3), all
of those with a partial response after cycle 2 showed exposure with MOR208 above
a certain exposure level (Figure 8).
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