Current guidelines for management of INT- 2/high risk MDS

Transcription

1 ELASTIC

2 Current guidelines for management of INT- 2/high risk MDS If fit (i.e. HCT-CI and performance status< 3), consider for early allo BMT with/without prior AML induction therapy If unfit consider Azacitidine

3 AZA-001: Randomised PhIII study of Aza v CCR Fenaux et al. Lancet Oncol 2009

4 Overall Survival: Azacitidine vs CCR Proportion Surviving Difference: 9.4 months 50.8% 24.4 months 15 months 26.2% Time (months) from Randomization AZA CCR

5 OS by CCR Treatment AZA (N=117) vs BSC (N=105) AZA (N=45) vs LDAC (N=49) AZA (N=17) vs Stand Chemo (N=25) Median OS (mo) 21.1 OS (mo) Hazard Ratio Logrank P

6 ITT Subgroups Hazard Ratios for OS Total - Event / N ITT 195 / 358 RAEB & RAEB-T: AGE / 240 AGE: < / / / 87 Male 134 / 251 Female 61 / 107 FAB: RAEB 95 / 207 RAEB-T 80 / 123 WHO: RAEB-1 15 / 31 RAEB / 193 IPSS: INT-2 71 / 146 High 98 / 167 Cytogenetics: Good 80 / 167 Intermediate 38 / 76 Poor 67 / 100 Karyotype: -7/del (7q) 42 / 57 Cytopenias: 0/1 20 / 53 2/3 167 / 290 BM Blasts: 5% to < 11% 34 / 61 11% to < 21% 98 / % to < 31% 58 / 99 LDH: 240 U/I 97 / 208 > 240 U/I 94 / Favors Azacitidine Favors CCR

7 Secondary Endpoints Time to AML or death 13 mos AZA vs 7.6 mos, p=0.003 Time to AML 26.1 mos AZA vs 12.4, p=0.004 RBC Transfusion Independence 45% vs 11%, p<0.0001

8 Secondary Endpoints: IWG (2000) RR and HI Response AZA N=179 (%) CCR N=179 (%) P Value Overall (CR+PR) CR PR IWG HI Major+Minor < HI-E Major < HI-P Major HI-N Major

9 Conclusions AZA prolongs OS compared with CCR Consistent effect across demographic and risk subgroups AZA was well tolerated

10 Current practice BCSH guidance 2013: Fit with absence of adverse karyotype: Discussion of Azacitidine v intensive chemotherapy Azacitidine recommended for IPSS INT-2, HR MDS, CMML-2 or low blast % AML Assess response after six cycles Continue Azacitidine until response lost

11 Prebet et al JCO 2011 Azacitidine failure

12 Improving on Azacitidine Novel agents small molecules antibody therapy Aza combinations Aza+Vorinostat (RAvVA) Aza+Lenalidomide (VIOLA) Aza+Eltrombopag (ELASTIC)

13 Eltrombopag

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15 ELASTIC clinical rationale Aza failure associated with appalling prognosis Response to Aza is dose duration dependent Median of 3 cycles before see response

16 AZA-001 and thrombocytopenia G3,4 thrombocytopenia in 85% G1,2 G3,4 thrombocytopenia 74% 14% of patients dose reduced 46% of cycles delayed Major platelet improvement seen in 33% First cycle doubling in platelet count

17 Platelet doubling after 1 st cycle of Azacitidine as a predictor of survival Van der Helm et al. BJH 2011

18 Predictive response based on platelet doubling after first cycle Van der Helm et al. BJH 2011

19 Use of TpoR agonists outside of ITP MDS/AML Aplastic anaemia

20 Romiplostim and MDS/AML Amgen single agent study of Romiplostim v placebo in low risk/int-1 MDS Aim n=240 but terminated at n=219 Significant reduction in Grade 3+ bleeding Significant reduction in platelet Tx if baseline <20 15% of Romiplostim group developed transient PB blast >10% 6% of Romiplostim and 2.4% of placebo developed AML (later amended to 6% v 4.9%)

21 Eltrombopag and MDS/AML In vitro suggests anti-proliferative effect possibly mediated by mobilisation of intracellular iron/block in G1 of cell cycle Single agent study in HR MDS/AML ineligible to further chemo Single agent study of LR-INT-2 MDS currently under way Combination studies in MDS/AML underway

22 Eltrombopag AML/MDS Single agent in untreatable MDS/AML 2:1 randomisation 98 patients Well-tolerated One AML went into CR on Eltrombopag Trend to reduced bleeding events, platelet Tx and improved OS

23 Eltrombopag in aplastic anaemia 43 patients with refractory SAA 40% response rate after 3.5 months Bi- and tri-lineage responses Durable and improving 5 discontinued and maintained counts 8/43 showed clonal evolution (monosomy 7) No evolution to AML (yet)

24 Eltrombopag and aplastic anaemia Olnes M et al NEJM 2012

25 Olnes M et al NEJM 2012

26 Summary of Eltrombopag data to date Platelet responses in MDS/AML Tri-lineage responses in severe aplastic anaemia In vitro evidence for anti-proliferative effect in AML Single case report of remission in AML

27 ELASTIC ELASTIC A Phase Ib Study of Eltrombopag and Azacitidine in Patients with High Risk Myelodysplastic Syndromes and Related Disorders

28 Trial Infrastructure Sponsor: University of Birmingham Chief Investigator: Dr Alexander Sternberg Co-Investigators: Profs. Paresh Vyas,David Bowen, Sten Eirik Jacobsen Trial Management: CRCTU, University of Birmingham Funders: LLR, (Trials Acceleration Programme) Celgene, GSK 28

29 Background & Objectives Limited therapeutic options for MDS Azacitidine first approved by NICE in 2011 Aza + Eltrombopag combination treatment Prevent treatment delays/dose reduction Improve baseline azacitidine efficacy Eltrombopag 2 nd gen thrombopoietin receptor (TpoR) agonist Improve tri-lineage response Anti-leukaemic effect? 29

30 Primary Outcome Measure To evaluate the safety and tolerability, including establishing the Maximum Tolerated Dose (MTD), of Eltrombopag in combination with Azacitidine in patients with MDS/AML 30

31 Secondary outcome measures 1. To establish the Optimal Biological Dose (OBD) of Eltrombopag where not limited by the MTD 2. To evaluate the effect of Eltrombopag on: Platelet count Platelet transfusions Bleeding complications Azacitidine treatment delays and dose modifications Bone marrow blast percentage IWG 2006 response criteria for MDS Dose effect on leukaemia stem/progenitor subset numbers, fate, and karyotype 31

32 3+3 Cohort Trial Design Single arm, multicentre, phase 1b dose finding study Cohort 1 Recruit 3 patients at 25mg od >1 of 3 has DLT 1 of 3 has DLT Discontinue Dose Escalation & Review 0 out of 3 has DLT Cohort 1 Recruit another 3 patients at 25mg od >1 of 6 has DLT 1 of 6 has DLT Cohort 2 Recruit 3 patients at 50mg od >1 of 3 has DLT 1 of 3 has DLT Discontinue Dose Escalation: MTD = 25mg od 0 out of 3 has DLT Cohort 2 Recruit another 3 patients at 50mg od >1 of 6 has DLT 1 of 6 has DLT Cohort 3 Recruit 3 patients at 100mg od Cohort 4 Recruit 3 patients at 200mg od Dose Escalation process repeated Dose Escalation process repeated Safety Committee Minimum 1 azacitidine cycle Review DLTs, possible interactions, AEs and lab parameters MTD - Additional 10 patients recruited Cohort 5* Recruit 3 patients at 300mg od *An extra 3 patients will be recruited (if necessary) so that 6 patients will be treated at the proposed MTD 32

33 Eligibility Inclusion Criteria Age 16 years of age Platelet count at baseline <150 x 109/l Myelodysplastic Syndromes (MDS) classified as Intermediate 2-risk or high risk according to the International Prognostic Scoring System (IPSS) at registration [2] OR Chronic Myelomonocytic Leukaemia (CMML) with 10-29% bone marrow blasts without proliferation (peripheral white blood cell count <13 x 109/l) OR Acute Myeloid Leukaemia (AML) with 20-30% bone marrow blasts Subjects must have platelet count and platelet transfusion data available over a period of 4 weeks prior to registration. A baseline bone marrow examination to evaluate blast percentage, karyotype and assessment of fibrotic change within 8 weeks of registration ALT/AST < 3 x upper limit of normal ECOG 2 Valid informed consent 33

34 Eligibility Exclusion Criteria AML with >30% blasts Known HIV positive Known liver cirrhosis Uncontrolled infection (grade 4 CTCAE v4) Previous exposure to azacitidine Previous exposure to thrombomimetic agents Use of prior investigational agents within 6 weeks Other severe, concurrent diseases or mental disorders Concurrent active or previous malignancy within the last 3 years except controlled, localised prostate cancer on hormone therapy or non-melanoma skin malignancy or cervical carcinoma in situ or completely resected colonic polyps carcinoma in situ 34

35 Eligibility Exclusion Criteria (continued) Bone marrow fibrosis Clinical evidence of splenomegaly Known hypersensitivity to study drugs or any of their excipients Pregnant and lactating patients (patients of childbearing potential must have a negative pregnancy test prior to study entry) Females of childbearing potential (i.e. not post-menopausal or surgically sterilised) who are not willing to use adequate methods of contraception to prevent pregnancy or abstain from heterosexual activity for the duration of the trial and for at least 3 months following treatment discontinuation. Male patients who are not willing to use an adequate method of contraception for the duration of the trial treatment if engaged in sexual activity with a female of childbearing potential and for at least 3 months following treatment discontinuation Patients of east Asian ancestry* 35

36 Treatment All patients If continuing eltrombopag Week: Baseline Eltrombopag Azacitidine Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Eltrombopag Starting dose dependent on Cohort Start treatment on day 1 Wash out period - cycle 3 Patients may continue eltrombopag after week 13 if: Investigator believes platelet response is due to eltrombopag And patient is considered to be in need of eltrombopag to receive adequate azacitidine dose Azacitidine Dose: 75mg/m 2 subcutaneous for 7 days (5+2+2 schedule) Minimum 3 cycles starting on day 8 (week 2) Up to 6 cycles on trial Treatment with azacitidine to be continued as per its licences at investigator discretion 36

37 Sample collection Timepoint 1 Sample Blood samples for EPO and TPO levels (5ml in serum separated tube) Store serum at -80 C after centrifugation Blood samples for trough eltrombopag levels (2-4ml in EDTA tube) Store plasma at -20 C after centrifugation Peripheral blood sample for research (10ml in EDTA tube) Send same day in First Class Safebox Bone marrow aspirate (2-10ml in EDTA tube) Send same day in Special Delivery Safebox (Samples should be taken in reference to Azacitidine treatment. Week numbers may be subject to change if treatment is delayed) Baseline Day 8 Week 6 Week 10 Week 13 Week 25 X X X X X X X X X X X X X X X X X 20 nail clippings (sterile pot) X 1 Timepoints Baseline - within 4 weeks of registration Day 8 - immediately prior to cycle 1 of Azacitidine Week 10 - immediately prior to cycle 3 of Azacitidine Week 6 - immediately prior to cycle 2 of Azacitidine Week 13 - end of cycle 3 of Azacitidine Week 25 - end of cycle 6 of Azacitidine (only for patients who have continued with azacitidine treatment beyond 3 cycles) 37

38 IMPs Eltrombopag and Azacitidine All patients If continuing eltrombopag Week: Baseline Eltrombopag Azacitidine Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Eltrombopag Supplied free of charge by GlaxoSmithKline (GSK), and labelled, QP released and distributed by Catalent 35 film coated tablets per bottle (25mg and 50mg) Cohorts: 25mg OD, 50mg OD, 100mg OD, 200mg OD, 300mg OD Azacitidine To be taken from normal hospital stock as per local practice 75mg/m 2 daily subcutaneous for 7 days (5 on + 2 off + 2 on) BSA should be calculated using the Mosteller Formula Injected subcutaneously into upper arm, thigh or abdomen 38

39 Progress to date Final approvals Oct sites now open Rest to open in next few months First patient recruited Dec

40 Acknowledgements MDS CTC Leukaemia and Lymphoma Research CRCTU: University of Birmingham Sonia Fox Harriet Bell Sten Eirik Jacobsen Paresh Vyas 40