New drugs and trials. Andreas Hochhaus

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1 New drugs and trials. Andreas Hochhaus Hadera I Oct 2018

Introduction ABL001 is a potent, specific inhibitor of BCR-ABL1 with a distinct allosteric mechanism of action BCR-ABL1 Protein Binds a distinct and separate region of the kinase domain: the

2 Introduction ABL001 is a potent, specific inhibitor of BCR-ABL1 with a distinct allosteric mechanism of action BCR-ABL1 Protein Binds a distinct and separate region of the kinase domain: the myristate-binding pocket, holding Bcr-Abl in the inactive conformation Has potential to be combined with TKIs that bind to the ATP site for greater pharmacological control of BCR-ABL1 T ABL001 (Myristoyl Site)

3 Mechanism of Action Autoinhibition of ABL1 by Engagement of Myristoyl Binding Site SH2 SH3 Kinase SH2 SH3 Kinase Myristoylated N-terminus INACTIVE ACTIVE Wylie A, et al. Blood. 2014; 124 (21): [abstract 398]. Ottmann O, et al. Blood. 2015; 126(23): [abstract 138]. 3

4 Mechanism of Action Loss of ABL1 Autoinhibition due to BCR-ABL1 Translocation SH3 t(9;22) SH2 Kinase BCR ACTIVE Wylie A, et al. Blood. 2014; 124 (21): [abstract 398]. Ottmann O, et al. Blood. 2015; 126(23): [abstract 138]. 4

5 Mechanism of Action ABL001 Allosterically Inhibits BCR- ABL1 Kinase Activity BCR SH3 SH3 t(9;22) SH2 Kinase SH2 BCR ABL001 Kinase INACTIVE ACTIVE ABL001 Wylie A, et al. Blood. 2014; 124 (21): [abstract 398]. Ottmann O, et al. Blood. 2015; 126(23): [abstract 138]. 5

ABL001 and Classical TKIs Exhibit Complementary Mutation Profiles ATP Binding Site Mutations G250H T315I E255K Y253H F359V I502L Proliferation IC

0001 E255K Myristoyl Binding Site Mutations P465S E255V A337V V299L E459K F359V E355G Nilotinib T3151 A337V ABL001 ATP binding site mutations

6 ABL001 and Classical TKIs Exhibit Complementary Mutation Profiles ATP Binding Site Mutations G250H T315I E255K Y253H F359V I502L Proliferation IC 50 Profiles in Ba/F3 BCR-ABL1 Mutant Lines P223S K294E WT G250H Q252H Y253H V468F E255K Myristoyl Binding Site Mutations P465S E255V A337V V299L E459K F359V E355G Nilotinib T3151 A337V ABL001 ATP binding site mutations P465S V468F Myristoyl binding site mutations 6 Business Use Only ABL001 Backgrounder Wylie A, et al. Blood. 2014; 124 (21): [abstract 398]. Ottmann O, et al. Blood. 2015; 126(23): [abstract 138].

7 ABL001X2101: Study Design A multicenter, phase 1, first-in-human study Dose Escalation Bayesian Logistic Regression CML completed ABL001, po, BID MTD RDE Dose Expansion CML (20 mg, 40 mg) completed T315I mutation (150 mg) ongoing Dose Escalation CML ABL001, po, QD MTD RDE Dose Expansion CML Dose Escalation Ph+ ALL/CML-BP MTD RDE Dose Expansion Ph+ ALL/CML-BP Primary outcome: estimation of MTD/RDE Secondary outcomes: safety, tolerability, preliminary anti-cml activity, pharmacodynamics, pharmacokinetic profile ALL, acute lymphocytic leukemia; BID, twice daily; BP, blast phase; CML, chronic myeloid leukemia; MTD, maximum tolerated dose; Ph+, Philadelphia chromosome-positive; po, peroral; QD, once daily; RDE, recommended dose for expansion Combo Dose Escalation CML ABL001+nilotinib Combo Dose Escalation CML ABL001+imatinib Combo Dose Escalation CML ABL001+dasatinib MTD RDE MTD RDE MTD RDE Expansion Expansion Expansion 7 Business Use Only ABL001 Backgrounder Hughes TP, et al. Blood. 2016; 128 (22): [abstract 625].

8 Demographics and Baseline Characteristics N = 123 Median age (range), years 55 (23-79) Male/female, % 61/39 ECOG performance status 0/1 or 2, % 72/28 Prior lines of therapy, median (range) 3 (1-5) 1 prior TKI, % 5 2 prior TKIs, % 30 3 prior TKIs, % 65 CML-CP/CML-AP/CML-BP/ALL, % 88/4/2/6 TKD non-mutated/mutant a /not evaluable, % 46/30 a /24 a T315I (17), E255K (3), F317L (3), G250E (3), M244V (2), V299L (2) Y253H (2), E279K (1), L248V/G250E/V299L (1), T315I/F359V (1), T315I/M351T (1), T315I/Y253H (1) ALL, acute lymphoblastic leukemia; AP, accelerated phase; BP, blast phase; CML, chronic myeloid leukemia; CP, chronic phase; ECOG, Eastern Cooperative Oncology Group; TKD, tyrosine kinase domain; TKIs, tyrosine kinase inhibitors 8 Hughes TP, et al. Blood. 2016; 128 (22): [abstract 625].

9 Safety: AEs Suspected of Being Related to Study Drug Occurring in 5% of Patients (n = 123) Adverse Event All Grades, n (%) Grade 3/4, n (%) Lipase increase 26 (21) 12 (10) Rash 19 (15) 0 Thrombocytopenia 16 (13) 7 (6) Fatigue 15 (12) 1 (1) Nausea 14 (11) 0 Arthralgia 13 (11) 0 Amylase increased 12 (10) 1 (1) Headache 12 (10) 0 Pruritus 11 (9) 1 (1) Anemia 9 (7) 5 (4) Diarrhea 9 (7) 0 Myalgia 9 (7) 1 (1) Vomiting 9 (7) 0 Hypophosphatemia 7 (6) 1 (1) Neutropenia 7 (6) 5 (4) AE, adverse event 9 Business Use Only ABL001 Backgrounder Hughes TP, et al. Blood. 2016; 128 (22): [abstract 625].

10 Patients With Response, % Responses in Patients With CML Treated With Single-Agent BID ABL001 With 3 Months Exposure on Study Hematologic Response Within 6 mo CHR: 88% (14/16) Hematologic Disease (CHR relapse) Cytogenetic Response Within 6 mo a CCyR: 75% (9/12) MMR: 20% (10/50) Cytogenetic Disease (>35% Ph+) (>0.1% IS) Molecular Response Within 6 mo a,b MMR: 42% (16/38) (>0.1% IS) Disease Status at Baseline CCyR, complete cytogenetic response; CHR, complete hematologic response; IS, International Scale; MMR, major molecular response; mo, months a Patients had 6 months of treatment exposure or achieved response within 6 months b BCR-ABL1 IS reduction achieved c Patients had 12 months of treatment exposure or achieved response within 12 months 1-log reduction: 30% (10/33) Molecular Disease ( 10% IS) Molecular Response Within 12 mo b,c 1-log reduction: 48% (12/25) Molecular Disease ( 10% IS) 10 Hughes TP, et al. Blood. 2016; 128 (22): [abstract 625].

11 Deep Molecular Response % patients Deep Molecular Response % patients Working Concept for ABL001 Add-On Combination Therapy Hypothesis: The combination ABL001+IMA leads to a compelling increase in the proportion of patients reaching DMR becoming potentially eligible for a TFR decision. TTP assumes an absolute increase in DMR from 20% to 45%. Note: All differences shown are relative and are only illustrative ABL001 + IMA ABL001 + NIL or DAS 2 nd generation TKI IMA NIL/DAS Start therapy Molecular Response Milestone Start therapy Molecular Response Milestone 11 Business Use Only

12 ABL001+IMA: Design of Proposed Ph2 CML-CP Study as Add-On in First Line Eligibility CML in chronic phase First-line IMA therapy 2 years on IMA No deep molecular response: BCR-ABL 0.01% <1.0% Stratification 0.1%< BCR-ABL<1.0% vs 0.01% BCR-ABL 0.1% Length on IMA < 5 years, 5 years (TBD) S T R A T I F I C A T I O N A N D R A N D O M I Z A T I O N ABL001 + IMA Stay on IMA Switch to NIL Primary endpoint: 48 weeks Secondary endpoint: 96 weeks Assess TFR in patients choosing to attempt TFR after 2 years (total 4 years of TKI) Assess the safety of the combination as Add-On therapy 12 Business Use Only

13 Treatment Failure/ Intolerance Death/ End of Study Phase III Study to compare efficacy of ABL001 versus bosutinib in patients with CML-CP who have failed a minimum of two prior ATP-binding site TKIs Screening Treatment Period Survival Follow Up ABL001 40mg BID n=148 CML-CP Patients N=222 Two Prior TKIs BCRABLIS 1% 2:1 Stratified by Cytogenetic Response Bosutinib 500mg QID n=74 Key Secondary Endpoints: Primary Endpoint: MMR at 24 Weeks MMR at 96 weeks Other Secondary Endpoints CCyR at and by 24, 48, and 96 weeks, Time to CCyR, Duration of CCyR MMR at 48 weeks; and by 24, 48 and 96 weeks, Time to MMR, Duration of MMR Time to treatment failure; PFS; OS Safety & Tolerability; PK

14 First line pilot phase II cohort study Fascination Nilotinib 300mg bid Asciminib 20 mg bid Newly diagnosed CP-CML Start Asciminib after recovery of normal hematopoiesis (12 weeks) Nilotinib 300mg bid Asciminib 40 mg qd Dasatinib 100mg qd Asciminib 80 mg qd Co-primary endpoints: 1. Safety 2. Rate of MR 4 at 6 mo. Secondary endpoints: 1. Slope of molecular response 2. Rate of EMR 3. MMR, MR 4, MR 4.5 at and by 12 mo. 4. Incidence of AP/BC in 12 mo. Imatinib 400mg qd Study duration: 12 (24) mo. Asciminib 60 mg qd

15 CML-Study V TKI + Interferon trial initiated by the GERman CML Study Group) >36 months therapy Discontinuation Nilotinib 2x300mg/d cont. Nilotinib --- Randomisation Confirmed MMR after > 24 mo. > 12 mo. MR 4 Nilotinib 2x300mg/d PEG-IFN 30(-50)mg/w PEG-IFN 50mg/w --- Induction Maintenance TFR Cure?

16 TIGER-Studie: Stand der Therapie, n=717 Therapiedauer: Median 31 Monate Induktionsphase >24 Mo. Behandlung, MMR bestätigt Dann: Erhaltungsphase >12 mo. MR 4 Dann: Absetzen Nilotinib 2x300 mg cont. Nilotinib --- R Nilotinib + PEG-IFN PEG-IFN --- N=321 N=258 N=138

ENDURE-CML Study (NCT03117816) IFN-a to induce immune surveillance in first or second TKI stop

17 ENDURE-CML Study (NCT ) IFN-a to induce immune surveillance in first or second TKI stop observation 24 months TFR? MR 4 or better R 15 months 9 months TFR? Ropeginterferon observation

18 Weimar 20./

Future of CML: ABL001 and other treatments in the pipeline. Gianantonio Rosti, MD, Department of Hematology, University of Bologna, Italy

Future of CML: ABL001 and other treatments in the pipeline. Gianantonio Rosti, MD, Department of Hematology, University of Bologna, Italy Primitive sleeping BCR-ABL-positive leukemic stem cells are less