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Clinical Trials, Emerging New Drugs and Future Concepts in the Treatment of Lymphoma

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Audio and slides for this presentation are available on YouTube: http://youtu.be/Q_wdfcJO3XE

Ann LaCasce, MD, MMSc, of Dana-Farber/Brigham and Women's Cancer Center Adult Lymphoma Program, talks about new clinical trials and treatments available for lymphoma patients. This presentation was originally given at the Lymphoma Research Foundation North American Forum on Sept. 28, 2013. http://www.dana-farber.org | http://www.lymphoma.org

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Clinical Trials, Emerging New Drugs and Future Concepts in the Treatment of Lymphoma

  1. 1. Clinical Trials, Emerging New Drugs and Future Concepts in the Treatment of Lymphoma Ann S. LaCasce, MD, MMSc Medical Oncologist, Dana-Farber/Brigham and Women’s Cancer Center Adult Lymphoma Program Assistant Professor, Harvard Medical School Director, Dana-Farber/Partners CancerCare Hematology-Medical Oncology Fellowship Program
  2. 2. What is a clinical trial? • Test the safety and how well a new drug works in a particular disease • Test the safety and how well an established drug works in a new disease • Compare a new medication to standard treatment • Goal for FDA approval of a drug for a particular use
  3. 3. History of clinical trials Established rules for clinical trial – • drug must be used on simple, not composite disease • quality of drug must correspond with strength of disease • must be tested on two contrary diseases • time action must be observed • must be performed on humans Avicenna, Persian physician and philosopher (1025)
  4. 4. History of clinical trials sailors with scurvy sailors with scurvy 1747
  5. 5. History of clinical trials sailors with scurvy sailors with scurvy 1747
  6. 6. NIH – types of trials Prevention Prevention Screening Screening Diagnostic Diagnostic Treatment Treatment Quality Quality of Life of Life Compassionate Compassionate use use
  7. 7. Pre-clinical studies In vitro studies Animal studies
  8. 8. New drug clinical trials Phase 1 Phase 1 Safety Safety 20-100 pts 1st in humans dose, schedule
  9. 9. New drug clinical trials Phase 1 Phase 1 Safety Safety 20-100 pts 1st in humans dose, schedule Phase 2 Phase 2 Efficacy Efficacy 100-500 pts How well does it work?
  10. 10. New drug clinical trials Phase 1 Phase 1 Safety Safety 20-100 pts 1st in humans dose, schedule Phase 2 Phase 2 Efficacy Efficacy 100-500 pts How well does it work? Phase 3 Phase 3 Confirm Confirm >1,000 pts Compare with standard of care & study safety
  11. 11. New drug clinical trials Phase 1 Phase 1 Safety Safety 20-100 pts 1st in humans dose, schedule Phase 2 Phase 2 Efficacy Efficacy 100-500 pts How well does it work? Phase 3 Phase 3 Confirm Confirm >1,000 pts Compare with standard of care & study safety FDA review FDA review Phase 4 Phase 4 Safety in typical patients
  12. 12. Phase I • In non-cancer studies performed in healthy volunteers • In drugs directed against cancer, typically given to patients with different types of cancer • Establish safe dose and schedule • Evaluate side effects • Give preliminary information regarding if the drug works
  13. 13. Phase I clinical trial of anti-CD20 monoclonal antibody in recurrent B-cell lymphoma 3 pts 3 pts 10 mg/m2 10 mg/m2 3 pts 3 pts 50 mg/m2 50 mg/m2 3 pts 3 pts 100 mg/m2 100 mg/m2 3 pts 3 pts 250 mg/m2 250 mg/m2 3 pts 3 pts 500 mg/m2 500 mg/m2 Side effects: fever (5); nausea (2), chills(2), low blood pressure (2), wheezing (1), low platelets (1) Lymphoma responded in more than half of patients
  14. 14. Phase II The drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety
  15. 15. Rituximab therapy for relapsed indolent lymphoma • 166 patients • IDEC-C2B8 375 mg/m2 intravenously weekly for four doses • Fever and chills were the most common events • Low incidence of serious side effects • Approximately half of patients responded • FDA approves the drug
  16. 16. Phase III clinical trial In cancer studies, typically no placebo except in certain circumstances
  17. 17. CHOP plus rituximab versus CHOP in older patients with diffuse large-B-cell lymphoma 399 pts Age 60-80
  18. 18. CHOP plus rituximab versus CHOP in older patients with diffuse large-B-cell lymphoma RCHOP 399 pts Age 60-80
  19. 19. CHOP plus rituximab versus CHOP in older patients with diffuse large-B-cell lymphoma RCHOP 399 pts Age 60-80 CHOP RCHOP superior and becomes standard treatment
  20. 20. Phase IV After drug approved by FDA Collect additional information on side effects Identify any rare or long term toxicity
  21. 21. Oversight • Studies may be conducted by pharmaceutical companies, single or group of investigators (including cooperative groups) • Careful oversight to ensure ethical and safe conduct • Institutional Review Board (IRB) – Evaluate protocol – Review consent form – Oversee ongoing conduct of trial
  22. 22. FDA definitions Standard Review Standard Review 10 months 10 months
  23. 23. FDA definitions Standard Review Standard Review 10 months 10 months Priority Review Priority Review 6 months 6 months
  24. 24. FDA definitions Accelerated Accelerated Approval: Approval: Standard Review Standard Review 10 months 10 months Priority Review Priority Review 6 months 6 months Surrogate Surrogate endpoint endpoint Requires Requires confirmation confirmation
  25. 25. FDA definitions Fast Track: Fast Track: Frequent meetings with Frequent meetings with FDA re drug FDA re drug development plan development plan Eligible for accelerated Eligible for accelerated approval and priority approval and priority review, if relevant review, if relevant criteria are met criteria are met Rolling review Rolling review
  26. 26. FDA definitions Fast Track: Fast Track: Breakthrough Therapy: Breakthrough Therapy: Frequent meetings with Frequent meetings with FDA re drug FDA re drug development plan development plan All Fast Track features All Fast Track features Eligible for accelerated Eligible for accelerated approval and priority approval and priority review, if relevant review, if relevant criteria are met criteria are met Rolling review Rolling review Intensive guidance on Intensive guidance on drug development drug development program, beginning as program, beginning as early as Phase 1 early as Phase 1 Organizational Organizational commitment involving commitment involving senior managers senior managers
  27. 27. Clinical trial process
  28. 28. Targeting CD30 in Hodgkin Lymphoma
  29. 29. SGN-30 CD30 Anti-CD30 antibody • Phase 2 study in patients with HL or CD30+ anaplastic large cell lymphoma • Several patients with T-cell lymphoma experienced disease improvement but activity disappointing • Favorable side effect profile CD 30 positive lymphoma cell
  30. 30. Brentuximab vedotin Antibody drug conjugate (ADC) Chemotherapy drug (MMAE) Antibody CD-30 ADC binds to CD30 ADC-CD30 complex taken into cell MMAE is released MMAE disrupts microtubule network G2/M cell cycle arrest Cell dies
  31. 31. Brentuximab vedotin FDA approval Hodgkin lymphoma Hodgkin lymphoma Phase 2 study Phase 2 study Relapsed disease Relapsed disease Anaplastic large cell Anaplastic large cell lymphoma lymphoma Phase 2 study Phase 2 study Relapsed disease Relapsed disease Extremely active drug in both diseases Manageable side effect profile with peripheral neuropathy as predominant issue
  32. 32. Brentuximab vedotin FDA approval Hodgkin lymphoma Hodgkin lymphoma Phase 2 study Phase 2 study Relapsed disease Relapsed disease Anaplastic large cell Anaplastic large cell lymphoma lymphoma Phase 2 study Phase 2 study Relapsed disease Relapsed disease Extremely active drug in both diseases Manageable side effect profile with peripheral neuropathy as predominant issue
  33. 33. Brentuximab development HL Phase 3 Phase 3 Previous untreated Previous untreated Stage III/IV Stage III/IV
  34. 34. Brentuximab development HL BV+AVD BV+AVD Phase 3 Phase 3 Previous untreated Previous untreated Stage III/IV Stage III/IV
  35. 35. Brentuximab development HL BV+AVD BV+AVD Phase 3 Phase 3 Previous untreated Previous untreated Stage III/IV Stage III/IV ABVD ABVD
  36. 36. Brentuximab development NHL Phase 2 Phase 2 relapsed CD30+ relapsed CD30+ NHL NHL
  37. 37. Brentuximab development NHL Phase 2 Phase 2 relapsed CD30+ relapsed CD30+ NHL NHL Phase 3 Phase 3 CD30+ CD30+ NHL NHL
  38. 38. Brentuximab development NHL Phase 2 Phase 2 relapsed CD30+ relapsed CD30+ NHL NHL BV+CHP BV+CHP Phase 3 Phase 3 CD30+ CD30+ NHL NHL
  39. 39. Brentuximab development NHL Phase 2 Phase 2 relapsed CD30+ relapsed CD30+ NHL NHL BV+CHP BV+CHP Phase 3 Phase 3 CD30+ CD30+ NHL NHL CHOP CHOP
  40. 40. Learning from the past • Thalidomide with a checkered past • Introduced in the late 50’s as a sedative thought to be safe for pregnant women with morning sickness • Tragic toxicity of limb deformities • 1990’s found to have activity in leprosy and HIV • Later found to be active in multiple myeloma and approved as initial therapy by FDA in 2006 • Prominent side effects of neuropathy and fatigue
  41. 41. Lenalidomide
  42. 42. Drugs active in other disease Approved for mantle cell lymphoma Approved for MDS 5q2006 2005 Approved for multiple myeloma 2013
  43. 43. Lenalidomide Aggressive Aggressive lymphoma lymphoma
  44. 44. Lenalidomide Indolent Indolent lymphoma lymphoma Aggressive Aggressive lymphoma lymphoma
  45. 45. Lenalidomide Indolent Indolent lymphoma lymphoma Aggressive Aggressive lymphoma lymphoma Mantle cell Mantle cell lymphoma lymphoma Phase 2 studies in lymphoma demonstrate activity in multiple subtypes Numerous recent and on-going studies in combination or as maintenance after chemotherapy
  46. 46. Evolution of front-line therapy in follicular lymphoma CHOP or CVP conventional chemotherapy
  47. 47. Evolution of front-line therapy in follicular lymphoma CHOP or CVP conventional chemotherapy CHOP or CVP plus rituximab
  48. 48. Evolution of front-line therapy in follicular lymphoma CHOP or CVP conventional chemotherapy CHOP or CVP plus rituximab Bendamustine plus rituximab
  49. 49. Evolution of front-line therapy in follicular lymphoma CHOP or CVP conventional chemotherapy CHOP or CVP plus rituximab Bendamustine plus rituximab Lenaliomide plus rituximab
  50. 50. Evolution of front-line therapy in follicular lymphoma CHOP or CVP conventional chemotherapy CHOP or CVP plus rituximab Bendamustine plus rituximab Lenaliomide plus rituximab Lenaliomide plus rituximab ? + additional novel agent
  51. 51. Targeting the B-cell receptor
  52. 52. Targeting the B-cell receptor
  53. 53. Ibrutinib CLL CLL MCL MCL Oral drug Favorable side effect profile Extremely active in both CLL and mantle cell lymphoma FDA will meet in early 2014 to consider approval in both
  54. 54. Idelalisib
  55. 55. Idelalisib
  56. 56. Idelalisib Submitted to Submitted to the FDA the FDA in rituximab in rituximab refractory refractory iNHL iNHL On-going On-going clinical trials clinical trials oral drug favorable side effect profile CLL CLL MCL MCL iNHL iNHL
  57. 57. Personalized medicine in lymphoma Targeting ABC Targeting ABC DLBCL DLBCL Ibrutinib Ibrutinib Tissue biopsy to Tissue biopsy to determine DLBCL determine DLBCL subtype subtype lenalidomide lenalidomide
  58. 58. Drugs approved in NHL Before 1990 bleomycin chlorambucil cyclophosphamide dacarbazine doxorubicin IFN alpha methotrexate procarbazine vinblastine vincristine 1990-1999 2000-2010 After 2010 bendamustine bendamustine denileukin difitox bortezomib bortezomib ibritumomab ibritumomab liposomal cytarabine rituximab pralatrexate pralatrexate romidepsin romidepsin tositumumab tositumumab vorinostat vorinostat brentuximab brentuximab lenalidomide lenalidomide
  59. 59. Drugs approved in CLL Before 1990 1990-1999 2000-2010 chlorambucil chlorambucil alemtuzumab alemtuzumab cyclophosphamide cyclophosphamide bendamustine bendamustine fludarabine fludarabine ofatumumab ofatumumab After 2010
  60. 60. Drugs approved in HL Before 1990 bleomycin chlorambucil cyclophosphamide dacarbazine doxorubicin IFN alpha methotrexate procarbazine vinblastine vincristine 1990-1999 2000-2010 After 2010 brentuximab brentuximab
  61. 61. Clinical trials are the future … to more effective and less toxic treatments for lymphoma
  62. 62. Clinical trials are the future … to more effective and less toxic treatments for lymphoma
  63. 63. Clinical trials are the future … to more effective and less toxic treatments for lymphoma
  64. 64. How to find a clinical trial Talk to your oncologist
  65. 65. How to find a clinical trial Call the LRF Helpline Talk to your oncologist
  66. 66. How to find a clinical trial Call the LRF Helpline Talk to your oncologist cancer.gov ClinicalTrials.gov Cancertrials.org

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