I NUOVI ANTICORPI ANTI-LINFOMA

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1 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

2 CD80 Expression on Lymphoma

3 Galiximab Properties Neoplastic B cell CD80 galiximab PRIMATIZED IgG 1 monoclonal antibody Structurally indistinguishable from human antibodies Specifically binds CD80 Anti-tumor effects in preclinical studies Binds Fc RI, Fc RII & Fc RIIIa Blocks CD80 binding with CD28 but not with CD152 (CTLA-4) Primate variable regions Human constant regions (IgG 1 lambda isotype)

4 Galiximab + Rituximab Increase Survival Human B-Lymphoma Mouse Model (N = 40) 100 galiximab (200 μg) + rituximab (200 μg) (N = 10) 80 Survival (%) galiximab (200 μg; N = 10) 20 rituximab (200 μg; N = 10) Control (N = 10) Days After Implant Younes et al., Clinical Lymphoma, 2003 Mar;3(4):257-9

5 Galiximab Trials in Follicular NHL Study : Galiximab monotherapy for relapsed or refractory, follicular NHL Enrollment: Jan Mar patients treated Study : Galiximab + rituximab for relapsed or refractory, follicular NHL Enrollment: Nov Mar patients treated

6 114-20: Galiximab Monotherapy Phase I/II, dose-escalation study of galiximab (125, 250, 375, or 500 mg/m 2 /wk x 4) Favorable safety profile Most common related AEs were fatigue, nausea, and headache Tumor burden reductions in 46% of patients Overall response rate = 11% (4 of 37 patients) 375 mg/m 2 (N = 21): 2 CRs, 1 PR 500 mg/m 2 (N = 10): 1 PR PFS for responders: 11.2, 24.3+, 26.5, and 31 mos. Czuczman et al., J Clin Oncology, 2005

7 114-21: Galiximab + Rituximab Phase I/II, dose-escalation study of galiximab in combination with a standard course of rituximab 4 treatment groups Treatment Group Galiximab ( 4 infusions) 125 mg/m mg/m mg/m mg/m 2 Rituximab ( 4 infusions) 375 mg/m mg/m mg/m mg/m 2

8 Treatment Visit Schedule On-Study Follow-Up Survival Day Day Month Month Rituximab infusion Galiximab infusion Rituximab + galiximab infusions Evaluations Efficacy Safety Pharmacokinetics Immunogenicity

9 Key Entrance Criteria Follicular lymphoma that has relapsed or has failed primary therapy Patients who received prior rituximab-containing therapy had to respond with a TTP > 6 months WHO Performance Status < 2 Acceptable hematologic status Hemoglobin > 8.0 g/dl ANC > 1500 cells/mm 3 Platelet count > 75,000 cells/mm 3

10 Study Status 73 patients treated 64 treated at 500 mg/m 2 galiximab mg/m 2 rituximab weekly x 4 Median follow up = 20.4 months

11 Most Common Related Adverse Events Anemia 15% % Pyrexia Thrombocytopenia 21% 21% Grade 1 Grade 2 Grade Chills 27% Grade 4 1 Neutropenia 22% Leukopenia Fatigue 36% 36% Lymphopenia 48% Patients (%) Incidence >15%; probably, possibly, or unknown relationship to study treatment

12 Efficacy Results (500 mg/m 2 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.)

13 Ofatumumab Program Type 1 Type 2 ofatumumab

14 Ofatumumab - Generated from Ig-Transgenic mice - Human IgG1, - Excellent binding; slow off-rate - Potent ADCC & CDC

15 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

16 Objectives To investigate the safety and efficacy of ofatumumab in patients with relapsed or refractory follicular lymphoma grade 1-2 To determine the pharmacokinetics after a single dose and after 4 doses of ofatumumab at weekly intervals

17 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

18 Inclusion criteria Relapsed or refractory follicular lymphoma grade 1-2, defined according to WHO Lymphoma verified to be CD20 + from excisional lymph node biopsy CT in screening phase showing: 2 or more clearly demarcated lesions with a largest diameter 1.5 cm, or 1 clearly demarcated lesion with a largest diameter 2.0 cm Age 18 years

19 57% of adverse events reported on the infusion days number of patients N=10 N=10 N=10 N=10 Grade 3 Grade 2 Grade 1 The use of steroids was limited to 19% of infusions mg 500mg 700mg 1000mg Infusion no Dose group

20 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 Dose group, mg No of patients No of patients with infection

21 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

22 Pharmacokinetics of ofatumumab after fourth dose [ ] [ ] 9 [ ] [ ] [ ] [ ] 1 6 [ ] [ ] [ ] [ ] 1 0 [ ] [ ] [ ] [ ] 3 [ ] [ ] m L ) n C max (_g/ml) T _ (hr) Cl (ml/hr/kg) AUC 0-inf (hr*_g / Summaries are shown as median [range] For comparison, the mean T of Rituximab after fourth dose is h; SD 95 h (Berinstein et al., Ann Oncol 9: , 1998)

23 Clinical response Best objective response 300 mg 500 mg 700 mg 1000 mg Patients CR 4 1 CRu 1 1 PR SD PD 2 1 Response rate % (95% CI) 63 (11-100) 33 (0-96) 20 (0-84) 1 Two patients not evaluable due to lack of indicator lesions 2 One patient withdrawn before assessment 60 (15-100)

24 Objective responses in patients previously treated with Rituximab 9 of 14 (64%) evaluable patients treated with ofatumumab after initial response to Rituximab achieved CR (3), CRu (1) or PR (5) For comparison, 23 of 60 (38%) patients responded (10% CR and 28% PRs) after re-treatment with Rituximab 1 1 Davis et al., J Clin Oncol; 18: , 2000

25 Bcl-2 conversion peripheral blood Dose groups, mg Total Baseline Bcl-2 positive Week 19 Bcl-2 negative Bcl-2 conversion 80% 33% 67% 67% 65% No correlation to objective response

26 Time to progression responders Predicted probability (%) Time to progression in responders (days) Dose group 300 mg 500 mg 700 mg 1000 mg All groups

27 Conclusions ofatumumab is well tolerated in patients with follicular non-hodgkin s lymphoma s All dose levels caused immediate, profound and long lasting B-cell depletion Objective responses achieved in all dose groups; response rate up to 63% High objective response in patients previously treated with Rituximab Bcl-2 conversion in the blood in 65% of evaluable patients The half-life of ofatumumab is greater than the halflife reported for Rituximab Data strongly supports further development of ofatumumab in follicular lymphoma

28 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

29 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

30 Zanolimumab Mechanisms of Action ADCC Fc R Cytokines; surface markers - C1q CDC Inhibition of: Signal transduction Proliferation Cytokine production Surface marker expression - CD4+ T cell Classical pathway CD4 down-modulation Apoptosis

31 Phase II Trials Refractory 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: mg in early stage disease (HxCD4-007) mg in advanced stage disease (HxCD4-008)

32 Hx-CD4-007 & Hx-CD4-008 (early and advanced stage CTCL patients) H x - C D P h a s e 2 i n E a r l y S t a g e C T C L I n f u s i o n s F i n a l : p a t i e n t s m g 17 weekly infusions m g H x - C D 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 : p a t i e n t s m g 17 weekly infusions m g A s s e s s m e n t s ( w e e k s)

33 Clinical Efficacy in MF Type CTCL ( ) 80% 38 MF Patients 3 / 4 Response rate ( CA score) 70% 60% 50% 40% 30% 20% 10% 1 / 11 2 / 9 7 / 14 0% Early Stage MF 280 mg Advanced Stage MF 280 mg Early Stage MF 560 mg Advanced Stage MF 980 mg High dose (560 / 980 mg) compared to low dose (280 mg), p=0.016, Fisher's Exact Test

34 Clinical Response in Advanced Stage MF 280 mg 50% Reduction in 2 of 9 Patients, 2 Partial Responses 980 mg 50% Reduction in 3 of 4 Patients, 3 Partial Responses Zanolimumab Dosing

35 Response in Stage IB Patient 280 mg Baseline Week 2

36 Response in Stage IB Patient 560 mg Baseline Week 4

37 Response in Stage IVA Tumor Patient 980mg Baseline Week 8

38 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, groin infection, peri-oral infection, CMV infection (11 months after discontinuation of treatment) 2 cytokine release reactions

39 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.