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Kinase Inhibitors in B-cell Lymphomas: What Does the Future Hold?

Kinase Inhibitors in B-cell Lymphomas: What Does the Future Hold?. Peter Martin, MD. Bruton ’ s Tyrosine Kinase (BTK) A critical kinase for lymphoma cell survival and proliferation. BTK is expressed and functional across non-T-cell hematopoietic lineages

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Kinase Inhibitors in B-cell Lymphomas: What Does the Future Hold?

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  1. Kinase Inhibitors in B-cell Lymphomas:What Does the Future Hold? Peter Martin, MD

  2. Bruton’s Tyrosine Kinase (BTK)A critical kinase for lymphoma cell survival and proliferation • BTK is expressed and functional across non-T-cell hematopoietic lineages • BTK functions downstream in a variety of receptors • Essential element of B-cell receptor signaling • Chemokine mediated migration & adhesion • Toll Like Receptor signaling • B-cell tumors may be dependent upon BTK for proliferation and survival

  3. Ibrutinib (PCI-32765) • 4/2006 – Pharmacyclics acquires Celera’s BTK program • 2007 – Publication describing irreversible inhibitors of BTK (including PCI-32765) in ChemMedChem • 12/2007 – Poster at ASH describing activity in B-cell lymphoma • 2/2009 – Phase I trial in B-NHL initiated • 12/2009 – Poster at ASH describing preliminary results from phase I trial • 12/8/11 – Pharmacyclics partners with Janssen

  4. Ibrutinib (PCI-32765) • 1/2013 – Publication of phase I trial in JCO • 2/12/13 - FDA grants Breakthrough Therapy Designation for MCL and WM • 4/8/13 – FDA grants Breakthrough Therapy Designation for CLL • 6/2013 – Publication of two phase II trials (CLL, MCL) in NEJM • 8/29/13 – FDA accepts NDA applications for MCL and CLL • >40 trials have been initiated to date in clinicaltrials.gov, 3 publications in peer-reviewed journals

  5. First-Line DLBCL • DBL3001 - A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, PCI-32765 (Ibrutinib), in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Subjects With Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma(NCT01855750) • Primary outcome: EFS • Key eligibility: Stage >2 histologically confirmed non-GC DLBCL, IPI >1, ECOG <2 • Estimated enrollment: 800, 218 study locations, international • Start date: August 2013, open to accrual • Estimated completion date: June 2018

  6. Previously Treated DLBCL • PCYC-1106 - A Multicenter, Open-label, Phase 2, Safety and Efficacy Study of the Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI-32765, in Subjects With Relapsed or Refractory or de Novo Diffuse Large B-cell Lymphoma (DLBCL) (NCT01325701) • Primary outcome: Response rate • Key eligibility: relapsed/refractory non-GC DLBCL (central IHC by Hans method) • Estimated enrollment: 125, 15 sites in US • Start date: May 2011, open to accrual • Estimated completion date: June 2015

  7. First-Line FL • A051103 - A Phase I Study of Rituximab, Lenalidomide, and Ibrutinib in Previously Untreated Follicular Lymphoma (NCT01829568) • Primary outcome: MTD • Key eligibility: untreated, stage >2 FL • Estimated enrollment: 33, 5 sites in US • Start date: June 2013, open to accrual • Estimated completion date: January 2014

  8. Previously Treated FL • FLR2002 - An Open-Label, Multicenter, Single-Arm, Phase 2 Study of PCI-32765 (Ibrutinib) in Subjects With Refractory Follicular Lymphoma (NCT01779791) • Primary outcome: Response rate • Key eligibility: FL, >2 prior lines of therapy, last prior line must be rituximab-chemo regimen, progression within 12 months of last prior line. • Estimated enrollment: 110, 59 sites, international • Start date: April 2013, open to accrual • Estimated completion date: September 2016

  9. First-Line MCL • MCL3002 - A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, PCI-32765 (Ibrutinib), in Combination With Bendamustine and Rituximab (BR) in Subjects With Newly Diagnosed Mantle Cell Lymphoma (NCT01776840) • Primary outcome: Progression-free survival • Key eligibility: untreated stage >2 MCL • Estimated enrollment: 520, 268 sites, international • Start date: May 2013, open to accrual • Estimated completion date: March 2018

  10. Previously Treated MCL • MCL3001 - A Randomized, Controlled, Open-Label, Multicenter Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, Versus Temsirolimus in Subjects With Relapsed or Refractory Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy (NCT01646021) • Primary outcome: Progression-free survival • Key eligibility: Previously treated MCL, at least 1 prior rituximab-containing regimen • Estimated enrollment: 280, 138 sites outside US • Start date: December 2012, open to accrual • Estimated completion date: August 2014

  11. First-Line CLL/SLL >65 years • PCYC-1115 - A Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor PCI-32765 Versus Chlorambucil in Patients 65 Years or Older With Treatment-naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (NCT01722487) • Primary outcome: Progression-free survival • Key eligibility: Untreated CLL, age >65 • Estimated enrollment: 111 • Start date: January 2013, open to accrual • Estimated completion date: June 2015

  12. First-Line CLL/SLL • A041202 - A Randomized Phase III Study of Bendamustine Plus Rituximab Versus Ibrutinib Plus Rituximab Versus Ibrutinib Alone in Untreated Older Patients (>65 Years of Age) With Chronic Lymphocytic Leukemia (CLL) (NCT01886872) • Primary outcome: Progression-free survival • Key eligibility: Untreated CLL, Age >65 • Estimated enrollment: 523, all Alliance sites in US • Start date: July 2013, not yet recruiting • Estimated completion date: March 2018

  13. Previously Treated CLL/SLL • CLL3001 - Randomized, Double-blind, Placebo-controlled Phase 3 Study of Ibrutinib, a Bruton's Tyrosine Kinase (BTK) Inhibitor, in Combination With Bendamustine and Rituximab (BR) in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (NCT01611090) • Primary outcome: Progression-free survival • Key eligibility: Previously treated CLL • Estimated enrollment: 580, 155 sites, international • Start date: September 2012, open to accrual • Estimated completion date: August 2015

  14. Previously Treated CLL/SLL • PCYC-1112 - The purpose of the study is to evaluate whether treatment with ibrutinib as a monotherapy results in a clinically significant improvement in progression free survival (PFS) as compared to treatment with ofatumumab in patients with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) (NCT0157807) • Primary outcome: Progression-free survival • Key eligibility: Previously treated CLL • Estimated enrollment: 391, international • Start date: June 2012, closed to accrual • Estimated completion date: July 2015

  15. Previously Treated CLL/SLL with 17p Deletion • PCYC-1117 - An Open-label, Single arm, Multicenter Phase 2 Study of the Bruton's Tyrosine Kinase Inhibitor PCI-32765 (Ibrutinib) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma with 17p Deletion (NCT01744691) • Primary outcome: Response rate • Key eligibility: Previously treated CLL, deletion of 17p • Estimated enrollment: 111 • Start date: January 2013, closed to accrual • Estimated completion date: March 2016

  16. MCL 1st line DLBCL 1st line R/R non-GC DLBCL CLL 1st line R/R CLL MCL R/R R-chemo FL WM? PCYC1104 PCYC1102 WM MCL3001 FLR2002 DBL3001 PCYC1106 PCYC1115 A041202 MCL3002 CLL3001 PCYC1112 PCYC1117 Phase I in B-NHL ‘09 ‘10 ‘11 ‘12 ‘18 ‘17 ‘13 ‘15 ‘16 ‘14

  17. Ibrutinib Future Challenges • Patient selection • DLBCL: non-GC • Current trials require central pathology. How will this work in community setting? • Resistance • BTK mutations (C481S). Role for other BTK inhibitors? • Other mutations in CLL: PLCg2 • Other mutations in DLBCL: CD79B, not CARD11, MYD88? • Role for rational combinations?

  18. Ibrutinib Future Challenges • Adverse events • Bleeding? • Leukocytosis? Is it significant? • Duration of therapy?

  19. Ibrutinib Future Opportunities • Other lymphomas • Untreated FL • Compared to R-chemo? Compared to R-len? Added to R-X? • Untreated WM • Compared to R-X? • MZL • HCL

  20. AVL-292 (CC-292) • 2009- Avila presents data on Btk inhibitors • 6/2011 – Phase I trial initiated in B-NHL • 3/7/12 – Celgene acquires Avila • 11/2012 – Phase Ib plus lenalidomide initiated in CLL • 5 trials have been initiated in clinicaltrials.gov, no publications in peer-reviewed journals

  21. Previously Treated NHL • Phase 1b, Escalating Dose Study of AVL-292, a Bruton's Tyrosine Kinase (Btk) Inhibitor, as Monotherapy in Subjects With Relapsed and/or Refractory B Cell Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, and Waldenstrom'sMacroglobulinemia (NCT01351935) • Primary outcome: Safety • Key eligibility: Previously treated B-cell NHL • Estimated enrollment: 60, 13 sites in US • Start date: June 2011, open to accrual • Estimated completion date: December 2013

  22. Previously Treated NHL • A phase IB study of the BTKi CC-292 combined with lenalidomide in adult patients with relapsed/refractory B-cell lymphomas (NCT01766583) • Primary outcome: RP2D • Key eligibility: Previously treated B-NHL except CLL/SLL and WM • Estimated enrollment: 60, 6 sites in France • Start date: February 2013, open to accrual • Estimated completion date: April 2015

  23. AVL-292-003 CLEAR ‘09 ‘10 ‘11 ‘12 ‘18 ‘17 ‘13 ‘15 ‘16 ‘14

  24. CC-292 Future Challenges • Comparison to ibrutinib • Specific subtypes? • Efficacy? • Safety?

  25. PI3K Stromal cell T-cell Signaling stimulus IL-6 BAFF CXCL13 BCR IL-6R CD40 CXCR5 Malignant B-cell membrane BAFFR LYN gp130 gp130 JAK TRAF6 JAK SYK  LYN/SYK   PI3K Delta STAT STAT BTK BTK PLC2 PLC2 AKT T308 S473 NF-k pathway PKC GSK-3 mTOR p70s6k elf4E Lannutti, Blood, 2011

  26. Idelalisib (CAL-101, GS-1101) • 5/12/05 – Patent filed for PI3Kd inhibitor • 06/2008 – Phase I trial initiated • 2/22/11 – Gilead acquires Calistoga Pharmaceuticals • 9/11/13 – Gilead submits NDA for indolent NHL • 10/9/13 – Gilead halts phase III CLL trial, everyone crosses over to idelalisib • 16 studies have been initiated in clinicaltrials.gov, no publications in peer-reviewed journals

  27. Rituximab/Alkylator-refractory iNHL • CAL-101-09 - A Phase 2 Study to Assess the Efficacy and Safety of CAL-101 in Patients With Indolent B-Cell Non-Hodgkin Lymphoma Refractory to Rituximab and Alkylating Agents (NCT01282428) • Primary outcome: Response rate • Key eligibility: Previously treated FL, SLL, LPL/WM, MZL • Estimated enrollment: 120, 55 sites, international • Start date: January 2011, closed to accrual • Estimated completion date: October 2013

  28. Previously Treated iNHL • GS-312-0124 - A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib (GS-1101) in Combination With Rituximab for Previously Treated Indolent Non-Hodgkin Lymphomas(01732913) • GS-312-0125 - A Phase 3, Randomized, Double-Blind, Placebo Controlled Study Evaluating the Efficacy and Safety of Idelalisib (GS-1101) in Combination With Bendamustine and Rituximab for Previously Treated Indolent Non-Hodgkin Lymphomas (NCT01732926) • Primary outcome: Progression-free survival • Key eligibility: Previously treated FL, SLL, LPL/WM, MZL • Estimated enrollment: 375/450, >40 sites, international • Start date: December 2012, open to accrual • Estimated completion date: December 2016/April 2016

  29. Previously Treated FL • A051202 - A Phase I Trial of Lenalidomide, Rituximab and Idelalisib in Recurrent Follicular Lymphoma (NCT01644799) • Primary outcome: MTD • Key eligibility: Previously treated FL • Estimated enrollment: 30, 6 sites in US • Start date: July 2013, open to accrual • Estimated completion date: November 2013

  30. Previously Treated MCL • A051201 - A Phase I/Randomized Phase II Trial of Idelalisib, Lenalidomide and Rituximab in Patients With Relapsed/Refractory Mantle Cell Lymphoma (NCT01838434) • Primary outcome: MTD • Key eligibility: Previously treated MCL • Estimated enrollment: 99 • Start date: July 2013, open to accrual • Estimated completion date: August 2017

  31. Previously Treated CLL/SLL • GS-312-0116 - A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib (GS-1101) in Combination With Rituximab for Previously Treated Chronic Lymphocytic Leukemia (NCT01539512) • Primary outcome: Progression-free survival • Key eligibility: Previously treated CLL/SLL, not fit to receive chemo • Estimated enrollment: 200 • Start date: February 2012, closed to accrual • Estimated completion date: February 2014

  32. Previously Treated CLL/SLL • GS-312-0115 - A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib (GS-1101) in Combination With Bendamustine and Rituximab for Previously Treated Chronic Lymphocytic Leukemia (NCT01569295) • Primary outcome: Progression-free survival • Key eligibility: Previously treated CLL/SLL • Estimated enrollment: 390 • Start date: May 2012, open to accrual • Estimated completion date: October 2015

  33. Previously Treated CLL/SLL • GS-312-0119 - A Phase 3, Randomized, Controlled Study Evaluating the Efficacy and Safety of GS-1101 (CAL-101) in Combination With Ofatumumab for Previously Treated Chronic Lymphocytic Leukemia (NCT01659021) • Primary outcome: Progression-free survival • Key eligibility: Previously treated CLL/SLL • Estimated enrollment: 210 • Start date: November 2012, open to accrual • Estimated completion date: December 2014

  34. R/R R-alkylator iNHL R/R iNHL R/R CLL GS-312-0116 Phase I GS-312-0119 CAL-101-07 CAL-101-09 0125 GS-312-0115 0124 ‘09 ‘10 ‘11 ‘12 ‘18 ‘17 ‘13 ‘15 ‘16 ‘14

  35. Idelalisib Future Challenges • Adverse effects • Hepatic toxicity • Lymphocytosis • Mechanisms of resistance • Unclear, no published mutations in PI3Kd

  36. Idelalisib Future Opportunities • Novel combinations • Ibrutinib resistant patients • Front-line CLL • Front-line iNHL • Aggressive lymphomas

  37. Duvelisib (IPI-145) • 10/31/11 – Phase I trials initiated • 9 studies initiated in clinicaltrials.gov, only 3 in hematologic malignancies, no publications in peer reviewed journals

  38. Previously Treated iNHL • IPI-145-02 - A Phase 1 Study of IPI-145 in Patients With Advanced Hematologic Malignancies (NCT01476657) • Primary outcome: Safety • Key eligibility: Previously treated • Estimated enrollment: 250, 7 sites in US • Start date: October 2011,open to accrual • Estimated completion date: September 2014

  39. Previously Treated iNHL • IPI-145-06 - A Phase 2 Study of IPI-145 in Subjects With Refractory Indolent Non-Hodgkin Lymphoma (NCT01882803) • Primary outcome: Response rate • Key eligibility: previously treated FL, MZL, SLL, rituximab refractory • Estimated enrollment: 120, 3 sites in US • Start date: May 2013, open to accrual • Estimated completion date: May 2015

  40. Previously Treated iNHL • Phase Ib Study of IPI-145 in Combination With Bendamustine, Rituximab or Bendamustine/Rituximab in Hematologic Malignancies (NCT01871675) • Primary outcome: Safety • Key eligibility: Previously treated B-cell NHL • Estimated enrollment: 70 • Start date: May 2013, open to accrual • Estimated completion date: June 2014

  41. B+R+D IPI-145-02 IPI-145-06 ‘09 ‘10 ‘11 ‘12 ‘18 ‘17 ‘13 ‘15 ‘16 ‘14

  42. Duvelisib Future Challenges • Comparison to other PI3k inhibitors • Adverse events • Myelosuppression? • Hepatic toxicity?

  43. SYK

  44. GS-9973 • 2012 – Preclinical data • 04/2013 – combination with idelalisib is safe in healthy volunteers • 3 trials have been initiated in clinicaltrials.gov, no publications in peer reviewed journals

  45. Previously Treated B-Cell NHL • GS-US-339-0102 - A Phase 2, Open-Label Study Evaluating the Efficacy, Safety, Tolerability, and Pharmacodynamics of GS-9973 in Subjects With Relapsed or Refractory Hematologic Malignancies (NCT01799889) • Primary outcome: Progression-free survival • Key eligibility: Previously treated B-NHL • Estimated enrollment: 280, 30 sites in US • Start date: March 2013, open to accrual • Estimated completion date: February 2015

  46. Previously Treated B-Cell NHL • GS-US-339-0103 - A Phase 2 of GS-9973 in Combination With Idelalisib in Subjects With Relapsed or Refractory Hematologic Malignancies (NCT01796470) • Primary outcome: Response rate • Key eligibility: Previously treated B-NHL • Estimated enrollment: 200, 11 sites in US • Start date: April 2013, open to accrual • Estimated completion date: December 2015

  47. 0102 0103 ‘09 ‘10 ‘11 ‘12 ‘18 ‘17 ‘13 ‘15 ‘16 ‘14

  48. GS-9973 Future • Challenges • Comparison to fostamatinib • Opportunities • Combination with idelalisib

  49. Conclusions • Potential near term FDA approval • Ibrutinib: MCL, CLL, WM • Idelalisib: iNHL, CLL • Pivotal trials underway • Ibrutinib: DLBCL, CLL, MCL, FL • Idelalisib: CLL, iNHL • Expect about 5000 patients to be treated on pivotal trials over 5 years • Very limited data in peer-reviewed journals • Opportunities to improve depend on understanding of resistance, so far unclear

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