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I NUOVI ANTICORPI ANTI-LINFOMA PIER LUIGI ZINZANI Istituto di Ematologia e Oncologia “L. e A. Seràgnoli” Università degli Studi di Bologna Milano, 28 maggio 2007

I NUOVI ANTICORPI ANTI-LINFOMA - Siematologia · I NUOVI ANTICORPI ANTI-LINFOMA ... Hodgkin’s Lymphoma Study Hx-CD20-001. ... pathway Cytokines; surface markers-CD4+ T cell. Phase

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I NUOVI ANTICORPI

ANTI-LINFOMA

PIER LUIGI ZINZANI

Istituto di Ematologia e Oncologia

“L. e A. Seràgnoli”

Università degli Studi di Bologna

Milano, 28 maggio 2007

CD80 Expression on Lymphoma

CD80NeoplasticB cell

Galiximab Properties

• PRIMATIZED® IgG1monoclonal antibody

• Structurally indistinguishablefrom human antibodies

• Specifically binds CD80

• Anti-tumor effects inpreclinical studies

• Binds Fc RI, Fc RII & FcRIIIa

• Blocks CD80 binding withCD28 but not with CD152(CTLA-4)

Primate variable regions

Human constant regions (IgG1 lambda isotype)

galiximab

0

20

40

60

80

100

10 20 30 40 50 60 70

Days After Implant

Su

rviv

al

(%)

Control (N = 10)

rituximab (200 μg; N = 10)

galiximab (200 μg; N = 10)

galiximab (200 μg)

+ rituximab (200 μg) (N = 10)

Galiximab + Rituximab Increase Survival Human B-Lymphoma Mouse Model (N = 40)

Younes et al., Clinical Lymphoma, 2003 Mar;3(4):257-9

Galiximab Trials in Follicular

NHL

• Study 114-20: Galiximab monotherapy for

relapsed or refractory, follicular NHL

– Enrollment: Jan 2002 - Mar 2003

– 37 patients treated

• Study 114-21: Galiximab + rituximab for

relapsed or refractory, follicular NHL

– Enrollment: Nov 2002 - Mar 2004

– 73 patients treated

114-20: Galiximab Monotherapy

• Phase I/II, dose-escalation study of galiximab(125, 250, 375, or 500 mg/m2/wk x 4)

• Favorable safety profile

– Most common related AEs were fatigue, nausea, andheadache

• Tumor burden reductions in 46% of patients

• Overall response rate = 11% (4 of 37 patients)

– 375 mg/m2 (N = 21): 2 CRs, 1 PR

– 500 mg/m2 (N = 10): 1 PR

• PFS for responders: 11.2, 24.3+, 26.5, and 31 mos.Czuczman et al., J Clin Oncology, 2005

114-21: Galiximab + Rituximab

• Phase I/II, dose-escalation study of

galiximab in combination with a standard

course of rituximab

• 4 treatment groups

375 mg/m2375 mg/m23

375 mg/m2500 mg/m24

375 mg/m2250 mg/m22

375 mg/m2125 mg/m21

Rituximab( 4 infusions)

Galiximab( 4 infusions)

Treatment

Group

Visit Schedule

31 8

Day

15 22

Treatment

Rituximab infusion

Rituximab + galiximab

infusions

Galiximab infusion

On-Study Follow-Up

9 36 4815 4230

Month

123 6

Evaluations

18 21 2450

• Efficacy

• Safety

• Pharmacokinetics

• Immunogenicity

Survival

Day Month

Key Entrance Criteria

• Follicular lymphoma that has relapsed or hasfailed primary therapy

• Patients who received prior rituximab-containingtherapy had to respond with a TTP > 6 months

• WHO Performance Status < 2

• Acceptable hematologic status

– Hemoglobin > 8.0 g/dL

– ANC > 1500 cells/mm3

– Platelet count > 75,000 cells/mm3

Study Status

• 73 patients treated

• 64 treated at 500 mg/m2 galiximab + 375

mg/m2 rituximab weekly x 4

• Median follow up = 20.4 months

Most Common Related

Adverse Events

Incidence >15%; probably, possibly, or unknown relationship to study treatment

0 10 20 30 40 50 60 70 80 90 100

Lymphopenia

Fatigue

Leukopenia

Neutropenia

Chills

Thrombocytopenia

Pyrexia

Anemia 15%

Patients (%)

Grade 1

Grade 2

Grade 3

Grade 4

%

23

47

25

1

21%

21%

27%

22%

36%

36%

48%

Efficacy Results(500 mg/m2 Galiximab Group)

• Responses were evaluated using the

International Workshop Response Criteria

• Overall response rate = 64% (41 of 64

patients)

– 17% CR, 16% CRu, 31% PR

• Median PFS = 12.1 months (95% CI, 9.7

to 15.0 mo.)

Ofatumumab ProgramOfatumumab Program

Type 1

Type 2

ofatumumab

OfatumumabOfatumumab

- Generated from Ig-Transgenic mice- Human IgG1,

- Excellent binding; slow off-rate

- Potent ADCC & CDC

Ofatumumab, a Novel Fully

Human Anti-CD20 Monoclonal

Antibody:

Results of a Phase I/II Trial in

Relapsed or Refractory Follicular Non-

Hodgkin’s Lymphoma

Study Hx-CD20-001

Objectives

To investigate the safety and efficacy ofofatumumab in patients with relapsed orrefractory follicular lymphoma grade 1-2

To determine the pharmacokinetics aftera single dose and after 4 doses ofofatumumab at weekly intervals

Design

An open label, dose-escalating, multicenter

clinical trial

4 cohorts of 10 patients

4 weekly i.v. infusions of 300, 500, 700 or 1000 mg

Patients were premedicated with oral

acetaminophen and i.v. antihistamine

In case of CTC grade 3 adverse events during

infusion i.v. glucocorticosteroids were given

Inclusion criteria

Relapsed or refractory follicular lymphomagrade 1-2, defined according to WHO

Lymphoma verified to be CD20+ from excisionallymph node biopsy

CT in screening phase showing:

2 or more clearly demarcated lesions with alargest diameter 1.5 cm, or

1 clearly demarcated lesion with a largestdiameter 2.0 cm

Age 18 years

57% of adverse events reported on

the infusion days

The use of steroids waslimited to 19% ofinfusions.

N=10

N=10 N=10 N=10

Grade 3Grade 2Grade 1

nu

mb

er

of

pa

tie

nts

1

2

3

4

5

6

7

8

9

10

Infusion noDose group300mg 500mg 700mg 1000mg

1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4

Infections reported in

33% of patients

SAEs

2 unrelated: urinary tract infection, neutropenic sepsis

Non-serious AEs (all grade 1-2)

Unrelated: upper respiratory tract infection (11 events),urinary tract infection (2 events),

herpes (1 event), candidiasis (2 events),

pneumonia (2 events)

Related: Influenza

5305No of patients with infection

10101010No of patients

1000700500300Dose group, mg

Hematological toxicity

Laboratory values

Neutropenia

Grade 1: 2 of 39 patients

Grade 2: 4

Grade 3: 1

Grade 4: None

Thrombocytopenia

Grade 1: 6 of 37 patients

Grade 2: 1 (reported as an adverse event)

Grade 3: None

Pharmacokinetics of

ofatumumab after fourth dose

Summaries are shown as median [range]

For comparison, the mean T of Rituximab

after fourth dose is 208.5 h; SD 95 h

(Berinstein et al., Ann Oncol 9:995-1001, 1998)

n Cmax (_g/ml) T_ (hr) Cl (ml/hr/kg) AUC0-inf (hr*_g / m L )

1 0 1 2 9 [ 1 1 2 – 1 6 1 ] 4 4 6 [ 2 9 3 – 7 1 1 ] 9 [ 1 – 1 7 ] 7 4 6 1 6 [ 4 1 2 8 6 - 2 8 2 5 9 3 ]

9 1 8 5 [ 8 4 – 3 7 3 ] 3 0 3 [ 5 7 – 6 3 2 ] 1 6 [ 4 – 7 8 ] 5 3 2 6 1 [ 6 9 5 7 - 2 0 3 0 6 8 ]

9 3 5 5 [ 2 6 3 – 5 6 0 ] 3 2 2 [ 1 8 9 – 6 2 5 ] 1 0 [ 6 – 2 3 ] 1 8 5 2 5 1 [ 5 1 9 2 5 - 3 8 0 1 8 5 ]

1 0 6 1 0 [ 3 6 2 – 8 5 7 ] 5 6 7 [ 7 7 – 7 2 0 ] 3 [ 1 – 2 9 ] 6 4 4 0 8 0 [ 4 7 1 8 8 - 1 1 0 7 8 4 1 ]

Clinical responseBest objective response

1 Two patients not evaluable due to lack of indicator lesions2 One patient withdrawn before assessment

300 mg 500 mg 700 mg 1000 mg

Patients 81 9

2 10 10

CR 4 1

CRu 1 1

PR 2 2 5

SD 3 6 6 3

PD 2 1

Response rate % (95% CI)

63 (11-100)

33 (0-96)

20 (0-84)

60 (15-100)

Objective responses in patients

previously treated with Rituximab

1 Davis et al., J Clin Oncol; 18: 3135-3143, 2000

9 of 14 (64%) evaluable patients treated withofatumumab after initial response to Rituximabachieved CR (3), CRu (1) or PR (5)

For comparison,

23 of 60 (38%) patients responded (10% CRand 28% PRs) after re-treatment withRituximab1

Bcl-2 conversionperipheral blood

65%67%67%33%80%Bcl-2 conversion

112414

Week 19

Bcl-2 negative

173635

Baseline

Bcl-2 positive

Total1000700500300Dose groups, mg

No correlation to objective response

Time to progressionresponders

Predicted probability (%)

Dose group 300 mg 500 mg 700 mg1000 mg All groups

0

10

20

30

40

50

60

70

80

90

100

Time to progression in responders (days)

0 30 60 90 120 150 180 210 240 270 300 330 360 390

Conclusions

ofatumumab is well tolerated in patients withfollicular non-Hodgkin’s lymphoma’s

All dose levels caused immediate, profound and longlasting B-cell depletion

Objective responses achieved in all dose groups;response rate up to 63%

High objective response in patients previouslytreated with Rituximab

Bcl-2 conversion in the blood in 65% of evaluablepatients

The half-life of ofatumumab is greater than the half-life reported for Rituximab

Data strongly supports further development ofofatumumab in follicular lymphoma

Rationale for Targeting CD4 in CTCL

• CD4 is present on 90% of CTCL T cells

• CD4 expression is lineage-restricted

• CD4 expression is stable

• CD4 is involved in signaling

Zanolimumab

• High affinity, fully human monoclonal IgG1,

antibody (Kd = 5 x10-11 M)

• Activity– Antibody Dependent Cellular Cytotoxicity in vitro

– Depletion CD4+ T-cells in vivo

– The approximate half-life is 40 hours

• Blocks interaction between CD4 and MHC II

ZanolimumabMechanisms of Action

CD4 down-modulation

Inhibition of:

• Signal transduction

• Proliferation

• Cytokine production

• Surface marker expression

ADCC

CDC

Apoptosis

C1q

Fc R

-

Classical

pathway

Cytokines;

surface markers-

CD4+

T cell

Phase II TrialsRefractory Early and Advanced Stage CTCL

• Once weekly i.v. administration for 17 weeks conducted

between April 2003 – June 2004 in 47 CTCL patients

• Initial Regimen: 280 mg

• High Dose Regimen:

- 560 mg in early stage disease (HxCD4-007)

- 980 mg in advanced stage disease (HxCD4-008)

Hx-CD4-007 & Hx-CD4-008

(early and advanced stage CTCL

patients)

A s s e s s m e n t s ( w e e k s)

0 1 2 3 4 5 6 7 8 9 1 1 1 3 1 5 2 0

2 8 0 m g

5 6 0 m g

H x - C D 4 - 0 0 7 P h a s e 2 i n E a r l y S t a g e C T C L

F i n a l : 1 1 + 1 4 p a t i e n t s

2 8 0 m g

9 8 0 m g

H x - C D 4 - 0 0 8 P h a s e 2 i n A d v a n c e d S t a g e C T C L

F i n a l : 1 3 + 9 p a t i e n t s

I n f u s i o n s

17 weekly infusions

17 weekly infusions

Clinical Efficacy in MF Type CTCL (007 – 008)

Early Stage MF280 mg

Advanced Stage MF280 mg

Early Stage MF560 mg

Advanced Stage MF980 mg

0%

10%

20%

30%

40%

50%

60%

70%

80%

1 / 11

2 / 9

7 / 14

3 / 4

Re

sp

on

se

ra

te (

CA

sco

re)

High dose (560 / 980 mg) compared to low dose (280 mg), p=0.016, Fisher's Exact Test

38 MF Patients

Clinical Response in Advanced Stage MF

280 mg50% Reduction in 2 of 9 Patients, 2 Partial

Responses

980 mg50% Reduction in 3 of 4 Patients, 3 Partial

Responses

Zanolimumab Dosing

Response in Stage IB Patient

280 mg

Baseline Week 2

Response in Stage IB Patient

560 mg

Baseline Week 4

Response in Stage IVA Tumor Patient

980mg

Baseline Week 8

Most common AE in CTCL

• Grade 1-2 AE– Flu-like symptoms

– Pruritus

– Infections (no CMV reactivations)

– Eczema (dermatitis)

– Fatigue

– Headache

• SAEs (at 2 yrs follow-up)– 4 patients experienced 6 related SAEs in CTCL trials

4 Infections: Suspected wound infection, groininfection, peri-oral infection, CMV infection (11 monthsafter discontinuation of treatment)

2 cytokine release reactions

Current clinical development

status

• Zanolimumab is currently in phase III

clinical development for MF CD4+

CTCL

• Zanolimumab will soon be tested in

clinical trials as an add-on to standard

front-line combination chemotherapy in

NCTCL.