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

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tes,

Ab

solu

te (

10

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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 (

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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.