Targeting CD20 and CD22 in B-cell ALL

Daniel J. DeAngelo, MD, PhD

Harvard/Dana-Farber Cancer Institute

Boston, MA

Disclosures for Daniel J. DeAngelo, MD, PhD

Royalty N/A

Receipt of intellectual property/ Patent holder

N/A

Consulting fee Amgen, Ariad, BMS, Incyte, Novartis

Speakers bureau N/A

Fees for non-CME services N/A

Contracted research N/A

Ownership interest (stocks, stock options)

N/A

Other N/A

N/A = Not Applicable (no conflicts listed) Presentation includes discussion of off-label or unapproved use of a drug or medical device: N/A

CD20 Targeted

Monoclonal Antibodies

CD20 in ALL

• CD20 is expressed in about 40% of patients

with B-cell ALL1

• CD20 expression is associated with an

adverse prognosis in adult ALL

• This suggests that targeting CD20 may

affect outcome2

1Gokbuget N, Hoelzer D. Ann Hematol 2004; 83: 201-5. 2Thomas D et al. Blood 2009; 113: 6330-7.

Induction Therapy

CD20 Is Up-regulated in Pre-B ALL

During Induction Treatment

Dworzak MN et al. Blood 2008; 112: 3982-8.

Thomas DA et al. Blood 113:6330-7, 2009

p=.002

Survival by CD20 Expression with Standard Hyper-CVAD

without Rituximab

0 12 24 36 48 60 72 84 96 108 120

Months

0.0

0.2

0.4

0.6

0.8

1.0

CD20 negative

CD20 positive

No. No. Fail % Relapse

77 31 38

66 42 61

Chemo-immunotherapy with

a Modified HyperCVAD and

Rituximab Regimen

• Patients with Ph neg ALL

• Patients with 20% CD20+ cells received rituximab 375 mg/m2 on Days 1 and 11 of hyperCVAD and Days 1 and 8 of methotrexate/ cytarabine

• Median age was 43 years (range 15-83)

Thomas DA et al. JCO 2010;28:3880-9.

Addition of Rituximab Improves

Outcome in CD20 Positive Patients

Thomas DA et al. JCO 2010;28:3880-9.

Copyrighted material

Rates of MRD for Standard Risk Patients

with CD20+ B-cell ALL

0

20

40

60

80

100

Day 24 Week 16

% o

f P

atients

MR

D N

egative

Rituximab (+)

Rituximab (-)

Hoelzer D et al. Blood 2010; 116: Abstr 170

Summary: ALL and Rituximab

• Encouraging results, but alternative approaches are

needed in patients 60 years of age

• GRAAL-2005 (randomized trial) is pending

• Other anti-CD20 antibodies are in development

• Ofatumumab binds a distinct proximal epitope and

these binding characteristics may positively impact

its ability to kill tumor cells via ADCC

CD22 Targeted

Monoclonal Antibodies

CD22 Is an Attractive Therapeutic Target

• CD22 is expressed on the malignant cells of >

90% of B-lymphoid malignancies

• CD22 is internalized upon antibody binding

• CD22 is not shed into the extracellular

environment

Epratuzumab

• Investigational humanized IgG1 monoclonal

antibody directed against CD22

• More than 300 adults with B-NHL have received

epratuzumab

• ~85 patients with autoimmune disease have

received epratuzumab

• Distinct mechanism of action, modulating B-cell

activation

Carnahan J et al

Molecular Immunology

2007;44:1331-41

Goldenberg DM

Future Drugs 2006

6

C-C

7

C-C

2

C-C

5

C-C

3

C-C

1

C-C

4

C-C CD22

Epratuzumab

Murine

CDRs

Human IgG1

Epratuzumab in Pedi-ALL

• TACL: Introduce new agents at first relapse along with VCR/PEG/PRED/DOXO backbone

• COG study ADVL04P2: – Add weekly or 2x/week epratuzumab, and

antiCD22 MoAb

– Compare to historical controls

• CR rate of 67% with either schedule – No better than historical CR rate=66%

– More pts were MRD negative than expected

Raetz EA et al, ASH 2012, Abstract 573

Study Design

Block 1 Block 2 Block 3

CR2 rate &

MRD

Triple Induction*

Part B Phase 2 Pilot:

B1 Cohort (1X per wk)

Block 1 Block 2 Block 3

Triple Induction* Reduction Phase:

Day -14 to 0

Response

Part A

Feasibility

= Epratuzumab dose (360mg/m2)

CR2 rate &

MRD

*COG AALL01P2; Raetz EA et al. JCO 2008; 26: 3971-8

B2 Cohort (2X per wk)

CD22 Targeting Surface CD22 undetectable by flow

cytometry on peripheral blood

leukemic blasts within 24 hours of

epratuzumab administration in all

but one patient

33 PE molecules bound

1673 PE molecules bound

Pretreatment expression of RFB4

24 hour post-treatment expression of RFB4

1 2 3 4 5 6 7

RFB4 CD22

Epratuzumab

Raetz EA et al. JCO 2008; 26: 3756-3762

B1 Cohort (weekly x 4)

B2 Cohort (twice weekly x 8)

Eligible Patients 54 60

Very Early Relapse (< 18mo) 23 19

Median Age at Relapse (yrs) 10.2 8.4

Extramedullary Disease 3 9

Response Evaluable

Patients 48 50

End Block 1 CR2 Rate 65% (31/48) 66% (33/50)

End Block 1 MRD Available 31 31

End Block 1 MRD Neg (<0.01%)

45% (14/31) 39% (12/31)

End Block 1 MRD Neg Pooled

42% (26/62)*

Responses for B1 and B2 Cohorts

*Significantly higher than the 25% (9/36) with chemotherapy alone on AALL01P2 (one-sided p=0.001)

SWOG0910: Phase 2 Trial of Cytarabine/

Clofarabine/ Epratuzumab for Relapsed/

Refractory ALL

• Clofarabine 40 mg/m2/day IV Days 2-6

• Cytarabine 1 g/m2/ day on Days 1-5

– On Days 2-5, cytarabine was administered four hours after the completion of clofarabine

• Epratuzumab 360 mg/m2 IV Days 4, 11, 18, and 25

SWOG0910: Results

• CR/ CRi 52%, compared to 17% in a prior

trial of cytarabine/ clofarabine

• Encouraging results; but ultimately, a

randomized trial is needed to answer this

question.

• IntReALL (International Study for Treatment

of Childhood Relapsed ALL): phase 3 trial in

children with relapsed ALL

N-Acetyl Calicheamicin

Average loading of calicheamicin derivative on mAb is

5–6 moles of calicheamicin/mole of mAb (range, 3–9) for InO;

~100% of mAbs conjugated

Inotuzumab Ozogamicin (InO)

AcBut Linker:

4-(4’-acetylphenoxy) butanoic acid dimethyl hydrazide

MOA retains activity against tumor cells

with slow cycling times

Intact ADC

Inotuzumab in ALL: Design

Inotuzumab ozogamicin

Pts with refractory ALL and CD22+ by flow cytometry

Weekly dosing for 3 out of 4 weeks (0.8 mg/m2 day #1)

1.2 mg/m2 (0.8 mg/m2 day #1, 0.4 mg/m2 day #15)

1.6 mg/m2 (0.8 mg/m2 day #1, 0.4 mg/m2 day #8 and #15)

1.8 mg/m2 (0.8 mg/m2 day #1, 0.5 mg/m2 day ##8 and #15)

Responding patients continue for up to 6

cycles

DeAngelo D et al, ASH 2012

abstract 2612

Best Overall Response

Response, n (%)

1.2 mg/m2

(n=3)

1.6 mg/m2

(n=12)

1.8 mg/m2

(n=9)

1.8 mg/m2

Expansion (n=13)

Total

(N=37)

CR/CRi

95% CI

2 (67)

(9.4–99.2)

9 (75)

(42.8–94.5)

8 (89)

(51.8–99.7)

6 (46)

(19.2-74.9)

25 (68)

(50.2–82)

CR 1 (33) 7 (58) 4 (44) 2 (15) 14 (38)

CRi 1 (33) 2 (17) 4 (44) 4 (31) 11 (30)

PR 0 2 (17) 0 0 2 (5)

• Median (range) time to hematologic remission (CR or CRi):

29 (20–85) days ORR=overall response rate

Complete remission: Disappearance of all clinical and/or radiologic evidence disease, ANC >1.0 x109/L,

platelet count >100x109/L, normal marrow differential (<5% blasts)

CRi (marrow CR): CR without recovery of ANC or platelet count

Partial remission: Peripheral blood count recovery as for CR, but with decrease in marrow blasts of >50% as compared to

pretreatment value, ≥5% and ≤25% DeAngelo D et al. ASH 2013, Abstract #3906

MRD in Patients with CR/CRi

(n=25)

Response

1.2 mg/m2

(n=2)

1.6 mg/m2

(n=9)

1.8 mg/m2

(n=8)

1.8 mg/m2

Exp

(n=6)

Total

(n=25)

MRD negative, n (%) 2 (100) 8 (89) 8 (100) 6 (100) 24 (96)

Median (range) time

to MRD negativity, d 99 (98–99) 32 (22–64) 30 (22–141) 38 (21-134) 34 (21–141)

MRD negative = <1 abnormal cell out of 104 mononuclear cells in bone marrow by

6 color multiparameter flow cytometry per central lab analysis performed at University of

Washington, Seattle

DeAngelo D et al. ASH 2013, Abstract #3906

Preliminary PK Findings

The “observed Cmin” is the average Cmin across all cycles of treatment that a given patient received (n=19 total)

Not all patients received the same number of cycles of treatment. Plot does not account for cycle-specific differences in Cmin

Note that although 21 patients had evaluable PK data, 19 had PK and corresponding response data

Observed median minimum concentration of inotuzumab ozogamicin vs

response at end of treatment in adults with ALL receiving the

0.8/0.5/0.5-mg/m2 weekly Q4W dosage regimen

(DeAngelo DJ et al. EHA 2013; Abstr S1125)

0

10

20

30

40

50

60

CR=CR or CRi

Fail=All others

Median Cmin

in responders=

40.9 mg/mL

7.65 ng/mL

40.9 ng/mL

Ob

se

rve

d C

min,

ng

/mL

CR FAIL

End of Treatment Response

Inotuzumab in ALL: Schedule

Monthly:

Weekly:

Cycle 1 Cycle 2 1.8mg/m2 1.8mg/m2

D1 D8 D15 D22 D29 D8 D15 D22

Cycle 1 Cycle 2 0.8mg/m2 0.8mg/m2

0.5mg/m2 0.5mg/m2 0.5mg/m2 0.5mg/m2

D1 D8 D15 D22 D29 D8 D15 D22

up to 8 cycles

up to 8 cycles

Inotuzumab in ALL. Response

Response Monthly, N=49

No. (%)

Weekly, N=41

No. (%)

CR 9 (18) 8 (20)

CRp 14 (29) 13 (32)

CRi (marrow CR) 5 (10) 3 (7)

Resistant 19 (39) 15 (37)

Death < 4 wks 2 (4) 2 (5)

OR 28 (57) 24 (59)

Inotuzumab ozogamicin, an anti-CD22-

calecheamicin conjugate, for refractory and

relapsed ALL: a Phase 2 study

• Starting dose of 1.3 mg/m2 was increased to 1.8 mg/m2

Kantarjian H et al. Lancet Oncology 2012; 13: 403-411.

Median age 36 yrs (range 16-80)

Salvage status

S1

S2

> S3

27%

49%

25%

Prior alloHSCT 14%

Poor risk cytogenetics

Ph+

MLL+

Complex

42%

14%

10%

18%

Inotuzumab in ALL. MRD

Parameter

Monthly, N=28

MRD Negative

No. (%)

Weekly, N=24

MRD

Negative

No. (%)

CR 8/9 (89) 6/7 (86)

CRp 9/14 (64) 7/10 (70)

CRi (marrow CR) 0/4 (0) 1/3 (33)

MRD negative

17/28 (63) 19/24 (70)

Inotuzumab in ALL:

Complete Remission Duration &

Progression Free Survival

O’Brien S et al, ASH 2012, abstract 671

Inotuzumab in ALL.

Overall Survival

Inotuzumab in ALL:

Overall Survival

O’Brien S et al, ASH 2012 abstract 671

Inotuzumab in ALL.

Overall Survival by Salvage Number

O’Brien S et al, ASH 2012 abstract 671

Summary: InO – Clinical Data

Relapse/Refractory

Kantarjian H et al. Lancet Oncology 2012;13:403-11

Kantarjian H et al. Cancer 2013;119:2728-36

DeAngelo D et al., ASH 2013, abstract 3906

Phase II MDACC 49 patients Q 4 week

1.8 mg/m2

OR 57%

Phase II MDACC 41 patients Weekly

1.8 mg/m2

(0.8-0.5-0.5)

OR 59%

Phase I/II* Multi-

center

37 pts (I/II)

+

35 pts (II)*

Weekly

1.2 to1.8

mg/m2

(total)

OR 68%

*35 patient Phase II portion of the study in S2+ will be reported at ASH 2014

Medically Important Safety Events

• VOD/SOS

– Especially in patients who proceed to an ablative transplant with high-dose alkylating agents

• Cytopenias

– May lead to delays in subsequent cycles

– Dose reduce once in CR

• Elevated liver function tests

– Seldom Grade 3 or higher

ALL: Conclusions

CD20

Adverse prognostic factor with hyperCVAD

Low single-agent activity

Addition of anti-CD20 monoclonal antibodies (rituximab) to standard chemotherapy seems to improve rates of MRD as well as PFS and OS

CD22

Epratuzumab

Low single-agent activity

May improve MRD rates in combination with chemotherapy

Inotuzumab

Encouraging results. High single-agent activity!!

Weekly and monthly dosing are equivalent with respect to efficacy; however, the tolerability of the weekly schedule appears better

Randomized phase III studies (currently enrolling): Inotuzumab versus SOC

Special Thanks

DFCI Leukemia Team

Richard Stone

Martha Wadleigh

David Steensma

Ilene Galinsky

Susan Buchanan

Kat Edmonds

Adriana Penicaud

Sarah Cahill

Others

All of the Investigators who kindly shared their slides

Patients and their families!!!!