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Next Generation TKIs and Small Molecule Inhibitors Jennifer R Brown, MD PhD Director, CLL Center

Next Generation TKIs and Small Molecule Inhibitors Jennifer R Brown, MD PhD Director, CLL Center Dana-Farber Cancer Institute Associate Professor of Medicine Harvard Medical School October 24, 2014. Targeting Kinases in the BCR Pathway. Everolimus. Dasatinib. Fostamatinib.

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Next Generation TKIs and Small Molecule Inhibitors Jennifer R Brown, MD PhD Director, CLL Center

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  1. Next Generation TKIs and Small Molecule Inhibitors Jennifer R Brown, MD PhD Director, CLL Center Dana-Farber Cancer Institute Associate Professor of Medicine Harvard Medical School October 24, 2014

  2. Targeting Kinases in the BCR Pathway Everolimus Dasatinib Fostamatinib Idelalisib(GS-1101; CAL-101) Ibrutinib (PCI-32765)

  3. BCR-Directed Agents in Development for CLL

  4. Targeting Kinases in the BCR Pathway IPI-145 TGR-1202 CC-292 (AVL-292) ONO-4059

  5. Ibrutinibis not a very specific BTK inhibitor

  6. Mechanisms of Resistance to Ibrutinib Chang et al., ASCO 2013; Stilgenbauer et al., IWCLL 2013; Woyach NEJM 2014

  7. CC-292 Specificity

  8. Uncoupling PK PD with CC-292:Normal Volunteers, 2 mg/kg dose

  9. Study Design Ongoing phase 1, multicenter, open-label, dose-escalation study (NCT01351935) PART 2 PART 1: Identify RP2D iNHL Dose TBD Dose Escalation DLBCL Dose TBD CLL Expansion Cohort RP2D CLL/SLL 500 mg BID CLL/SLL 750 mg QD • Continuous 28-day oral dosing until PD or intolerable toxicity • 3 + 3 design for cohorts 1-5 • 12 patients per cohort 6a, 6b, and 7 (6 CLL/SLL, 6 NHL/WM) • Reported analyses focused on patients with CLL or SLL Brown et al, EHA 2013

  10. Study Population

  11. Time on Study – All Patients

  12. BTK Occupancy 4 Hrs Post Dose

  13. BTK Occupancy 24 Hrs Post Dose

  14. CC-292 Lymph Node Response by Dose and Time

  15. Efficacy Assessment by Dose Level

  16. Efficacy Assessment (N = 66)

  17. Response Based on Prognostic Factors Efficacy Evaluable Patients at Active Doses (N = 60)

  18. ONO-4059 B cell receptor PIP3 CD79A CD79B BLNK PLCg2 PDK Btk PI3K P AKT P P P P Syk P Y223 Lyn P ONO-4059 PI3K/Akt pathway MAPK/NF-kB pathway B-cell activation and proliferation • ONO-4059 is a highly potent and selective, orally available Btk inhibitor that covalently binds to Cys-481 in Btk. • Very high selectivity towards BTK (IC50 = 2.2 nm/L). • Bio-availability ∼40-50% with half-life of ∼ 5-7 hours and > 90% BTK inhibition at 12 hours in CLL cells in vivo. Yoshizawa T, et al (ICML, 2013)

  19. Study ONO-4059POE001 TUMOR ASSESSMENT 1 month 6 months 3 months • 3+3 phase 1 design • Once daily dosing (QD) • Initial 6 month treatment, with option of additional 18 months, +/- dose escalation • No restrictions on growth factor, anticoagulant use • 6 sites (UK & France) # 1 patient experienced Rash (Grade 2) resulting in 1 week drug interruption during Cycle 1 and another patient enrolled to ensure 3 patients completed the required 28 days drug administration in Cycle 1.

  20. Patient Demographics

  21. 40mg (QD) ONO-4059 Leads to Durable Btk Inhibition (pBtk/PBMCs) Relapsed patient with 17p del; tumour reduction by CT-Scan: 64% (C3); 79% (C6); 86% (C10), 89% (C13); Haematology parameters normal at 3 month time-point

  22. Related Grade 1-2 Adverse Events (in ≥ 2 Patients) *Common Toxicity Criteria Adverse Events Version 4.0 (CTCAEV4.0)

  23. Related Grade 3-4 Adverse Events (in ≥ 2 Patients) • No DLTs observed • Two events of neutropenia (G3 at 20mg/G4 at 320mg) were reversed rapidly using G-CSF • Patient who experienced neutropenia at dose 20mg (Grade 4), also experienced an event of febrile neutropenia which was reported as an SAE. Patient’s neutrophil value at study entry was 0.1 x109/L (CTC Grade 4) *Common Toxicity Criteria Adverse Events Version 4.0 (CTCAE V4.0)

  24. Efficacy: Best Overall Response 84% Best Overall Response is 84% (21/25) based on CT-Scan and Hematological Parameters (IWCLL) * Patient ID 101-202 showed initial response to 20mg ONO-4059 with marked reduction of all palpable disease between D15/28 (based on physical examination). PD on D31 (suspected Richter’s Syndrome). # Patients ID 103-228 and 203-222 by investigator decision by experience of AE during cycle 1. • 17p Deleted patients: Best Overall Response Rate of 89% (8/9) • Refractory patients:Best Overall Response rate of 92% (11/12)

  25. Rapid Lymph Node Reduction Observed

  26. Change in Tumor Burden

  27. Absolute Lymphocyte Count over Time

  28. Improvement in Hematological Parameters from 3 Months on Treatment Mean Platelets (x109/L) Mean Haemoglobin (g/dL) Haemoglobin Platelets N 25 22 16 12 3 2

  29. Durable Responses Observed with ONO-4059 (QD) 20mg 40mg 80mg 160mg 320mg 600mg Median duration of treatment is 11.5 cycles (min 1/max 22) 400mg Withdrawn due to PD Withdrawn due to AE Continuing ONO-4059 Treatment 500mg

  30. Conclusion • ONO-4059 • Was safe with mostly grade 1 and 2 AEs and no DLTs. • Achieved sustained Btk inhibition at doses of ≥ 40mg and has a half-life of 5-7 hours. • Showed good efficacy over a range of doses with a best overall response of 84%in phase I with 21/25 patients. • Showed particularly good efficacy in refractory and in 17p Del patients.

  31. PI3K Signaling Pathway as a Target in B Cells

  32. PI3K Delta: Target for B Cell Diseases Tyrosine Phosphorylation

  33. Phase 1 Trial of IPI-145 in Hematologic MalignanciesPreliminary Outcomes in CLL CLL cohort 1 R/R ≤ 25 mg BID n = 28 Dose Escalation 8 mg BID  100 mg BID MTD = 75 mg BID CLL cohort 2 R/R 75 mg BID n = 24 CLL cohort 3 Tx Naïve 25 mg BID n = 15 • R/R CLL (n=52) • Enrolled in dose-escalation and expansion cohorts (25 mg and 75 mg BID) • Treatment Naïve CLL (n=15) • ≥ 65 years or 17p(del) / p53 mutation • No restriction on cytopenias in CLL expansion cohorts • 40% ≥ Grade 3 cytopenias at baseline in R/R CLL

  34. CLL Patient Characteristics

  35. AEs ≥ Grade 3 in CLL Patients (All Causality, ≥ 5%)IPI-145 at <=25 mg BID

  36. g, d Inhibition: IPI-145 Nodal Responses in CLL R/R CLL • 98% (42/43) of patients had a reduction in adenopathy by CT assessment • 89% (24/27) dosed ≤ 25 mg BID had a nodal response (≥ 50% reduction) • ORR 47%, including in 17p deletion (ORR 50%)

  37. Clinical Responsesin R/R CLL, Including Patients with 17p(del) or p53 Mutation • Median time to response in R/R CLL was < 2 months

  38. Time on Study: R/R CLL Patients Receiving ≤ 25 mg BID IPI-145 Long-term progression free Recently enrolled, data maturing Discontinued Potential to optimize future patient management • 75% (6/8) patients treated for ≥ 1 year remain progression-free on treatment • 8 recently enrolled patients (< 6 months) in early follow-up for PFS

  39. TGR-1202 Second-generation PI3K-delta inhibitor in early clinical development Savona et al., ASH 2013

  40. Preliminary Safety/Efficacy Savona et al., ASH 2013

  41. BCR Pathway Inhibitors In Relapsed CLL

  42. Summary Great enthusiasm for additional BTK and PI3K inhibitors How will they differentiate? BTK: Greater specificity ? Alternative binding site to overcome resistance PI3K: Different isoform specificity Other BCR targets: SYK, mTOR, LYN Other targets: BCL2 et al.

  43. Acknowledgments Ian Flinn; Stephan Stilgenbauer; Gilles Salles; Matthew Davids; David Johnson Brown Lab, DFCI Bethany Tesar Stacey Fernandes Sasha Vartanov Reina Improgo Josephine Klitgaard Clinical Research Karen Francoeur Karen Campbell Shannon Milillo Hazel Reynolds Wu Lab, DFCI Catherine Wu Dan-Avi Landau LiliWang YouzhongWan Broad Institute Eric Lander Gaddy Getz Carrie Sougnez NirHacohen Stacey Gabriel Mike Lawrence PetarStojanov AndreySivachenko KristianCibulskis David Deluca Lymphoma Program, DFCI Arnold S Freedman David C Fisher Ann S LaCasce Eric Jacobsen Philippe Armand Matthew Davids Okonow-Lipton Fund Melton Fund Rosenbach Fund Center for Cancer Genome Discovery, DFCI Megan Hanna Laura Macconaill NIH, NHGRI CLL Research Consortium DFCI Biostatistics Donna Neuberg Lillian Werner Haesook Kim Kristen Stevenson

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