novel approaches for transplant ineligible high risk...

ELASTIC

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

AZA-001: Randomised PhIII study of Aza v CCR

Fenaux et al. Lancet Oncol 2009

Overall Survival: Azacitidine vs CCR

0 5 10 15 20 25 30 35 40

Time (months) from Randomization

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Prop

ortio

n Su

rviv

ing

CCR AZA

Difference: 9.4 months

24.4 months 15 months

50.8%

26.2%

OS by CCR Treatment

Median OS (mo) ∆ OS (mo)

Hazard Ratio

Log-rank P

AZA (N=117) vs BSC (N=105)

21.1

11.5 9.6 0.56 0.002 AZA (N=45) vs LDAC (N=49)

24.5

15.3 9.2 0.58 0.075 AZA (N=17) vs Stand Chemo (N=25)

25.1

15.7 9.4 0.87 0.75

Hazard Ratios for OS ITT Subgroups Total - Event / N

Cytopenias: 0/1 20 / 53

WHO: RAEB-1 15 / 31

0.125 0.250 0.500 1 2 4

Favors Azacitidine Favors CCR

≥ 65 150 / 258

Female 61 / 107 FAB: RAEB 95 / 207

RAEB-T 80 / 123

RAEB-2 102 / 193 IPSS: INT-2 71 / 146

High 98 / 167 Cytogenetics: Good 80 / 167

Intermediate 38 / 76 Poor 67 / 100

2/3 167 / 290

Karyotype: -7/del (7q) 42 / 57

≥ 21% to < 31% 58 / 99

AGE: < 65 45 / 100

LDH: ≤ 240 U/I 97 / 208

RAEB & RAEB-T: AGE ≥ 65 138 / 240

> 240 U/I 94 / 145

ITT 195 / 358

≥ 75 50 / 87

≥ 11% to < 21% 98 / 192

Male 134 / 251

BM Blasts: ≥ 5% to < 11% 34 / 61

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

Secondary Endpoints: IWG (2000) RR and HI

Response

AZA N=179

(%)

CCR N=179

(%) P Value Overall (CR+PR) 29 12 0.0001 CR 17 8 0.02

PR 12 4 0.009

IWG HI Major+Minor 49 29 <0.0001 HI-E Major 40 11 <0.0001

HI-P Major 33 14 0.0003

HI-N Major 19 18 0.87

Conclusions

• AZA prolongs OS compared with CCR • Consistent effect across demographic and risk

subgroups • AZA was well tolerated

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

Azacitidine failure

Prebet et al JCO 2011

Improving on Azacitidine

Novel agents • small molecules • antibody therapy Aza combinations • Aza+Vorinostat (RAvVA) • Aza+Lenalidomide (VIOLA) • Aza+Eltrombopag (ELASTIC)

Eltrombopag

ELASTIC – clinical rationale

• Aza failure associated with appalling prognosis • Response to Aza is dose duration dependent • Median of 3 cycles before see response

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

Platelet doubling after 1st cycle of Azacitidine as a predictor of survival

Van der Helm et al. BJH 2011

Predictive response based on platelet doubling after first cycle

Van der Helm et al. BJH 2011

Use of TpoR agonists outside of ITP

• MDS/AML • Aplastic anaemia

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%)

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

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

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)

Eltrombopag and aplastic anaemia

Olnes M et al NEJM 2012

Olnes M et al NEJM 2012

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

A Phase Ib Study of Eltrombopag and Azacitidine in Patients with High Risk

Myelodysplastic Syndromes and Related Disorders

ELASTIC ELASTIC

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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



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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 – 2nd gen thrombopoietin receptor (TpoR) agonist

Improve tri-lineage response Anti-leukaemic effect?



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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



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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



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3+3 Cohort Trial Design Single arm, multicentre, phase 1b dose finding study

Cohort 2 Recruit 3 patients at 50mg od

Cohort 2 Recruit another 3 patients at 50mg od

Discontinue Dose Escalation & Review


Cohort 1 Recruit another 3 patients at 25mg od 0 out of 3 has DLT

1 of 3 has DLT

>1 of 6 has DLT

1 of 6 has DLT

>1 of 3 has DLT

Discontinue Dose Escalation: MTD = 25mg od



Cohort 5* Recruit 3 patients at 300mg od

Dose Escalation process repeated

Dose Escalation process repeated

>1 of 3 has DLT

>1 of 6 has DLT 0 out of 3 has DLT

1 of 3 has DLT

*An extra 3 patients will be recruited (if necessary) so that 6 patients will be treated at the proposed MTD

1 of 6 has DLT Safety Committee • Minimum 1 azacitidine cycle • Review DLTs, possible interactions, AEs

and lab parameters

MTD - Additional 10 patients recruited



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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



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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



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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*



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Treatment All patients If continuing eltrombopag

Week: Baseline 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

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/m2 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



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Sample collection

Sample

Timepoint1

(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 Blood samples for EPO and TPO levels (5ml in serum separated tube) Store serum at -80°C after centrifugation

X X X X X X

Blood samples for trough eltrombopag levels (2-4ml in EDTA tube) Store plasma at -20°C after centrifugation

X X X X

Peripheral blood sample for research (10ml in EDTA tube) Send same day in First Class Safebox

X X X X

Bone marrow aspirate (2-10ml in EDTA tube) Send same day in Special Delivery Safebox

X X X

20 nail clippings (sterile pot) X

1Timepoints

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)



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IMPs – Eltrombopag and Azacitidine

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/m2 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

All patients If continuing eltrombopag

Week: Baseline 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Eltrombopag

Azacitidine Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6



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Progress to date

Final approvals Oct 2014 3 sites now open Rest to open in next few months First patient recruited Dec 2014



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Acknowledgements

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

novel approaches for transplant ineligible high risk...

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