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AMERICAN SOCIETY OF HEMATOLOGY ANNUAL MEETING ● DECEMBER 8-11, 2012 ABSTRACT #1795
Phase 1b Study of TRU-016, an Anti-CD37 SMIP™ Protein, in Combination with Bendamustine in Relapsed Chronic Lymphocytic LeukemiaFarrukh Awan1, Ulrich Jäger2, Robert Rifkin3, Michael Thirman4, John C. Byrd5, Michael Hallek6, Scott Stromatt7, John M. Pagel8 1 Georgia Health Sciences University, Augusta, GA; 2 Medical University of Vienna, Wien, Vienna, Austria; 3 Rocky Mountain Cancer Centers, Denver, CO; , 4 The University of Chicago, Chicago, IL; 5 The Ohio State University, Columbus, OH; 6 University of Cologne, Cologne, Germany; 7 Emergent Product Development, Seattle, WA; 8 Fred Hutchinson Cancer Research Center, Seattle, WA
Introduction
— CD37 is a tetraspanin protein expressed on the surface of normal and transformed B-cells across a wide range of maturational stages and demonstrates death signaling via SHP1.
— TRU-016 is a novel humanized anti-CD37 SMIP™ (mono-specific protein therapeutic).
— In preclinical in vitro and in vivo models of NHL significant activity of TRU-016 against multiple cell lines was observed. In preclinical models, TRU-016 has shown:
– significantly greater direct killing of CLL cells than rituximab.
– greater Fc mediated cellular cytotoxicity of CLL cells than either alemtuzumab or rituximab.
— In a phase 1 study, TRU-016 activity in patients with CLL and NHL was observed.
— This trial of TRU-016 with bendamustine was conducted in patients with relapsed CLL to establish
– maximum tolerated dose
– overall safety
– clinical activity
Figure 1. TRU-016 Targets CD37 on B cells
Study Design
Protocol Design
Phase 1b
— Dose escalation
— MTD determination based on incidence of DLT in Cycle 1
— Safety of TRU-016 and bendamustine
— N=12
Phase 2 (ongoing, results not reported here)
— Randomized controlled trial
— TRU-016 and bendamustine vs. bendamustine alone
— Compare efficacy and safety
— Stratified
– del[17p13.1] or TP53 mutation
– CIRS >6 or ≤6
– CrCl <60 or ≥60
Treatment
— TRU-016 is dosed over six 28-day cycles. Dosing is weekly for the first 2 cycles, then on Day 1 and 15 of the next 4 cycles. Bendamustine is dosed on Day 1 and 2 of each cycle.
— Prophylactic use of growth factors was prohibited during the first cycle.
— Premedication included acetaminophen, diphenhydramine, and hydrocortisone.
Figure 2. Study Design: Phase 1b, Dose Escalation
Entry Criteria
— Relapsed CLL with 1 to 3 prior treatments
— Demonstrated active disease requiring treatment
— No prior bendamustine treatment
— Not refractory to fludarabine or other purines, either as a single agent or in combination. Refractory defined as lack of response to therapy or relapse <6 months after treatment completed.
— Age ≥18 years
— Eastern Cooperative Oncology Group (ECOG) performance status of ≤2
— Serum creatinine, total bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum gluta-mate pyruvate transaminase (SGPT) of ≤2.0 x upper limit of normal (ULN)
— ANC ≥1,200/mm3 (≥1,200/μL)
— Platelets ≥75,000/mm3 (≥75,000/μL)
— Lymphocytes ≥5,000/mm3 (≥5,000/μL) in Phase 1b
— No rituximab (RTX) in prior 30 days or alemtuzumab within prior 12 weeks
— No previous anticancer therapy in prior 30 days
— No investigational drug in prior 30 days
— Must have negative serology for HIV, HCV, or HBV
Efficacy Endpoints
— ORR and CR rate by 2008 IWCLL and 1996 NCI Working Group criteria
— Resolution of disease related symptoms
Table 1. Summary of Baseline Characteristics
Characteristic 15 mg/kg 20 mg/kg Total
Enrolled (n) 6 6 12
Age, median, yrs (range) 67 (57-74) 68.5 (54-81) 67 (54-81)
Median Time since first Diagnosis yrs (range) 7 (2-13) 4 (1-8) 5 (1-13)
Bulky Adenopathy, n (≥7 cm by CT) 1 4 5
Refractory to last treatment, n 2 1 3
Refractory to anti-CD20*, n 2 1 3
Rai Stage, III & IV, n 2 1 3
Number of Previous Treatments
1 2
1 5
6 0
7 5
Time since last CLL Treatment
<6 months 6-12 months >12 months
2 0 4
1 1 4
3 1 8
Previous regimens with anti-CD20
1 2
4 2
6 0
10 2
Hgb <11 g/dL, n 3 1 3
Platelets <100 (10/μL), n 2 1 3
Drugs and regimens received previously (n)
Fludarabine / rituximab Fludarabine / cyclophosphamide / rituximab Fludarabine / cyclophosphamide Rituximab
2 2 2 3
4 2 0 0
6 4 2 3
*Defined as anti-CD20 treatment < 6 months prior to study entry.
Efficacy Results
Table 2. Patient Characteristics and Response
Pati
en
t
Ag
e
Sex
Fit
/ U
nfi
t*
Bu
lky D
isease
(≥
7 c
m)
Rai
Sta
ge
at
Scr
een
ing
Pri
or
Lin
es
o
f Th
era
py
# o
f C
ycl
es
o
f TR
U-0
16
Best
Resp
on
se
(rea
son f
or
dis
continuat
ion)
Resp
on
se p
er
NC
I C
rite
ria
Du
rati
on
of
R
esp
on
se p
er
NC
I C
rite
ria*
*
Node Measurement
(SPD) by CT scan (cm3)
Resp
on
se
per
IWC
LL
Base
lin
e
2 m
on
ths
aft
er
EO
T
Cohort 1: 15 mg/kg TRU-016
1201 69 M Fit No IV 1 3 CR (neutropenia) CR >17 mo 20 No CT No CT
1202 69 M Unfit No I 2 1 PR (autoimmune
hemolytic anemia)DC’d Early 30 No CT No CT
1601 57 M Fit No II 2 6 CR CR >16 mo 30 5 PR
1602 65 F Fit No II 2 6 PR PR 11 mo 38 13 PR
1603 64 F Unfit Yes II 2 4 PR (investigator discretion)
DC’d Early 247 No CT No CT
1604 74 M Unfit No III 2 6 PR PR >15 mo 45 8 PR
Cohort 2: 20 mg/kg TRU-016
1001 62 M Unfit Yes I 1 6 PR PR 14.3 mo 126 20 PR
1203 78 M Unfit Yes II 1 6 CR CR 10.5 mo 48 No CT No CT
1606 54 F Unfit No II 1 6 PR PR >11 mo 37 3 PR
1607 75 M Unfit No I 1 6 CR CR >10 mo 20 4 PR
2101 81 F Unfit Yes I 1 3 PR (neutropenia) PR >11 mo 121 29 PR
8001 56 M Fit Yes IV 1 6 PR PR 4.5 mo 253 180 SD
*Fit = CIRS ≤ 6 and CrCL ≥ 60 mL/min; Unfit = CIRS > 6 and/or CrCL< 60 mL/min
**Follow up ongoing
SPD = sum of product diameters
Figure 3. Absolute Lymphocyte Count 15 mg/kg
Figure 4. Absolute Lymphocyte Count 20 mg/kg
Figure 5. Maximum % Reduction in Target Lesions by CT scan (SPD)
Figure 6. TRU-016 Serum Concentrations vs Time
15 mg/kg 20 mg/kg
Mean Half Life (T ½), days (SD) 12.1 (1.5) 10.28 (3.0)
Mean Cmax, ug/mL (SD) 896.21 (212.0) 1031.53 (311.5)
AUCall, day*ug/mL (SD) 60785 (36646) 79126 (34286)
Response
— Best response at any time according to the investigator was 100% ORR with 33% CR
— 9/12 responses occurred at Cycle 1 assessment
— NCI response: For all patients the ORR was 83% (10/12) and CR 33% (4/12). The median duration of response is >11 months as patients are still in follow-up.
— IWCLL response: CT results were available for 8 patients and 7 had PR and 1 had SD. The 4 CRs by NCI criteria were not confirmed by IWCLL criteria for the following reasons: 1201 did not have a repeat CT scan; 1601 had one node measuring 1.6 cm; 1203 had delayed CT 5 months after end of treatment and had progression; 1607 had one node 1.8 cm.
— There is no apparent dose response relationship.
Safety
Figure 7. Adverse Events Reported by ≥3 Subjects Regardless of Causality (15 mg and 20 mg combined)
Table 3. Number of Patients with Grade 3/4 Adverse Events
15 mg/kg N=6
20 mg/kg N=6
Total N=12
Neutropenia 3 3 6
Febrile neutropenia 2 1 3
Fatigue 0 1 1
Pyrexia 1 0 1
Dyspnea 1 0 1
Autoimmune hemolytic anemia 1 0 1
Myopathy 1 0 1
Leukopenia 0 1 1
Pneumonia 1 0 1
Urinary tract infection 1 0 1
Adverse Events
— Most events were grade 1 and 2.
— Grade 3 and 4 events considered related to TRU-016 and bendamustine were neutropenia (5 patients); febrile neutropenia (2 patients), and urinary tract infection (1 patient).
— 9 serious adverse events were reported by 4 patients.
— Serious adverse events in 3 patients were considered possibly related to TRU-016 and bendamustine by the investigators; febrile neutropenia in 2 patients and urinary tract infection in 1 patient.
— No apparent dose relationship for toxicity.
Conclusions
— TRU-016 in combination with bendamustine was well tolerated.
— The combination produced a response in the majority of patients.
— The Phase 2 trial comparing TRU-016 with bendamustine vs. bendamustine is ongoing.
— TRU-016 is being studied in combination with rituximab in an ongoing frontline CLL trial.
0
50
100
150
200
250
300
0 14
28
42
56
70
84
98
112
126
140
154
168
Lym
ph
ocy
tes,
Ab
solu
te (
10
3/µ
L)
Study Day
1201
1202
1601
1602
1603
1604
0
20
40
60
80
100
120
140
0 14
28
42
56
70
84
98
112
126
140
154
168
Lym
ph
ocy
tes,
Ab
solu
te (
10
3/µ
L)
Study Day
1001 1203 1606 1607 2101 8001
TRU-016 15 mg/kg and Bendamustine 70 mg/m2
N=6
TRU-016 20 mg/kg and Bendamustine 70 mg/m2
N=6
Follow up to 18 months
DLT ≤ 1 so dose was escalated.
-‐100%
-‐90%
-‐80%
-‐70%
-‐60%
-‐50%
-‐40%
-‐30%
-‐20%
-‐10%
0%
Maxim
un % Red
uc.on
in Target Lesion
0 10 20 30 40 50 60 70
nausea
neutropenia
cough
anaemia
decreased appe9te
headache
hypokaelemia
pain in extremity
pruri9s
pyrexia
cons9pa9on
diarrhea
dry mouth
fa9gue
febrile neutropenia
%
Grade 1/2
Grade 3/4
Conflict Of Interest Disclosures
Scott Stromatt is an employee of Emergent Product Development. Ulrich Jaeger is a consultant and received research funding from Emergent Product Development. There are no other relevant conflicts of interest to disclose.
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