Targeting CD20 and CD22 in B-cell ALL Daniel J. DeAngelo, MD, PhD

Transcription

1 Targeting CD20 and CD22 in B-cell ALL Daniel J. DeAngelo, MD, PhD Harvard/Dana-Farber Cancer Institute Boston, MA

2 Disclosures for Daniel J. DeAngelo, MD, PhD Royalty Receipt of intellectual property/ Patent holder Consulting fee Speakers bureau Fees for non-cme services Contracted research Ownership interest (stocks, stock options) Other N/A N/A Amgen, Ariad, BMS, Incyte, Novartis N/A N/A N/A N/A 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

3 CD20 Targeted Monoclonal Antibodies

4 CD20 in ALL CD20 is expressed in about 40% of patients with B-cell ALL 1 CD20 expression is associated with an adverse prognosis in adult ALL This suggests that targeting CD20 may affect outcome 2 1 Gokbuget N, Hoelzer D. Ann Hematol 2004; 83: Thomas D et al. Blood 2009; 113:

5 CD20 Is Up-regulated in Pre-B ALL During Induction Treatment Induction Therapy Dworzak MN et al. Blood 2008; 112:

6 Survival by CD20 Expression with Standard Hyper-CVAD without Rituximab CD20 negative CD20 positive No. No. Fail % Relapse p= Months Thomas DA et al. Blood 113:6330-7, 2009

7 Chemo-immunotherapy with a Modified HyperCVAD and Rituximab Regimen Patients with Ph neg ALL Patients with 20% CD20+ cells received rituximab 375 mg/m 2 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:

8 Addition of Rituximab Improves Outcome in CD20 Positive Patients Copyrighted material Thomas DA et al. JCO 2010;28:

9 % of Patients MRD Negative Rates of MRD for Standard Risk Patients with CD20+ B-cell ALL Rituximab (+) Rituximab (-) Day 24 Week 16 Hoelzer D et al. Blood 2010; 116: Abstr 170

10 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

11 CD22 Targeted Monoclonal Antibodies

12 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

13 Epratuzumab CD22 7 C-C 6 C-C 5 C-C 4 C-C 3 C-C 2 C-C 1 C-C Investigational humanized IgG1 monoclonal antibody directed against CD22 More than 300 adults with B-NHL have received epratuzumab Epratuzumab Murine CDRs ~85 patients with autoimmune disease have received epratuzumab Distinct mechanism of action, modulating B-cell activation Human IgG1 Carnahan J et al Molecular Immunology 2007;44: Goldenberg DM Future Drugs 2006

14 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

15 Study Design Part A Feasibility Reduction Phase: Day -14 to 0 Triple Induction* Block 1 Block 2 Block 3 Response CR2 rate & MRD Part B Phase 2 Pilot: B1 Cohort (1X per wk) B2 Cohort (2X per wk) Block 1 Block 2 Block 3 CR2 rate & MRD Triple Induction* = Epratuzumab dose (360mg/m 2 ) *COG AALL01P2; Raetz EA et al. JCO 2008; 26:

16 CD22 Targeting 1673 PE molecules bound Surface CD22 undetectable by flow cytometry on peripheral blood leukemic blasts within 24 hours of epratuzumab administration in all but one patient Pretreatment expression of RFB4 Epratuzumab 33 PE molecules bound 24 hour post-treatment expression of RFB RFB4 CD22 Raetz EA et al. JCO 2008; 26:

17 Responses for B1 and B2 Cohorts B1 Cohort (weekly x 4) Eligible Patients Very Early Relapse (< 18mo) Median Age at Relapse (yrs) Extramedullary Disease 3 9 Response Evaluable Patients B2 Cohort (twice weekly x 8) End Block 1 CR2 Rate 65% (31/48) 66% (33/50) End Block 1 MRD Available End Block 1 MRD Neg (<0.01%) 45% (14/31) 39% (12/31) End Block 1 MRD Neg 42% (26/62)* Pooled *Significantly higher than the 25% (9/36) with chemotherapy alone on AALL01P2 (onesided p=0.001)

18 SWOG0910: Phase 2 Trial of Cytarabine/ Clofarabine/ Epratuzumab for Relapsed/ Refractory ALL Clofarabine 40 mg/m 2 /day IV Days 2-6 Cytarabine 1 g/m 2 / day on Days 1-5 On Days 2-5, cytarabine was administered four hours after the completion of clofarabine Epratuzumab 360 mg/m 2 IV Days 4, 11, 18, and 25

19 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

20 Inotuzumab Ozogamicin (InO) AcBut Linker: 4-(4 -acetylphenoxy) butanoic acid dimethyl hydrazide MOA retains activity against tumor cells with slow cycling times Intact ADC 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

21 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/m 2 day #1) 1.2 mg/m 2 (0.8 mg/m 2 day #1, 0.4 mg/m 2 day #15) 1.6 mg/m 2 (0.8 mg/m 2 day #1, 0.4 mg/m 2 day #8 and #15) 1.8 mg/m 2 (0.8 mg/m 2 day #1, 0.5 mg/m 2 day ##8 and #15) Responding patients continue for up to 6 cycles DeAngelo D et al, ASH 2012 abstract 2612

22 Best Overall Response Response, n (%) 1.2 mg/m 2 (n=3) 1.6 mg/m 2 (n=12) 1.8 mg/m 2 (n=9) 1.8 mg/m 2 Expansion (n=13) Total (N=37) CR/CRi 95% CI 2 (67) ( ) 9 (75) ( ) 8 (89) ( ) 6 (46) ( ) 25 (68) ( ) 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) (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 x10 9 /L, platelet count >100x10 9 /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

23 MRD in Patients with CR/CRi (n=25) Response 1.2 mg/m 2 (n=2) 1.6 mg/m 2 (n=9) 1.8 mg/m 2 (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 10 4 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

24 Observed C min, ng/ml Preliminary PK Findings 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/m 2 weekly Q4W dosage regimen (DeAngelo DJ et al. EHA 2013; Abstr S1125) ng/ml CR=CR or CRi Fail=All others Median C min in responders= 40.9 mg/ml ng/ml 0 CR FAIL End of Treatment Response The observed C min is the average C min 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 C min Note that although 21 patients had evaluable PK data, 19 had PK and corresponding response data

25 Inotuzumab in ALL: Schedule Monthly: Cycle 1 Cycle 2 1.8mg/m 2 1.8mg/m 2 up to 8 cycles D1 D8 D15 D22 D29 D8 D15 D22 Weekly: Cycle 1 Cycle 2 up to 8 cycles 0.8mg/m 2 0.8mg/m 2 0.5mg/m 2 0.5mg/m 2 0.5mg/m 2 0.5mg/m 2 D1 D8 D15 D22 D29 D8 D15 D22

26 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)

27 Inotuzumab ozogamicin, an anti-cd22- calecheamicin conjugate, for refractory and relapsed ALL: a Phase 2 study Starting dose of 1.3 mg/m 2 was increased to 1.8 mg/m 2 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% Kantarjian H et al. Lancet Oncology 2012; 13:

28 Parameter Inotuzumab in ALL. MRD 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)

29 Inotuzumab in ALL: Complete Remission Duration & Progression Free Survival O Brien S et al, ASH 2012, abstract 671

30 Inotuzumab in ALL. Overall Survival

31 Inotuzumab in ALL: Overall Survival O Brien S et al, ASH 2012 abstract 671

32 Inotuzumab in ALL. Overall Survival by Salvage Number O Brien S et al, ASH 2012 abstract 671

33 Summary: InO Clinical Data Relapse/Refractory Phase II MDACC 49 patients Q 4 week 1.8 mg/m2 Phase II MDACC 41 patients Weekly 1.8 mg/m2 ( ) OR 57% OR 59% Phase I/II* Multicenter 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 Kantarjian H et al. Lancet Oncology 2012;13: Kantarjian H et al. Cancer 2013;119: DeAngelo D et al., ASH 2013, abstract 3906

34 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

35 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

36 DFCI Leukemia Team Richard Stone Martha Wadleigh David Steensma Special Thanks Others All of the Investigators who kindly shared their slides Ilene Galinsky Susan Buchanan Kat Edmonds Adriana Penicaud Sarah Cahill Patients and their families!!!!