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Clofarabine ODAC Presentation

Clofarabine ODAC Presentation. Pediatric Acute Leukemia December 1, 2004. Clofarabine ODAC Presentation. Steve Weitman, MD, PhD Chief Medical Officer ILEX Oncology, Inc. Sima Jeha, MD St. Jude Children’s Research Hospital Ka Wah Chan, MD M.D. Anderson Cancer Center Laurel Steinherz, MD

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Clofarabine ODAC Presentation

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  1. Clofarabine ODAC Presentation Pediatric Acute Leukemia December 1, 2004

  2. Clofarabine ODAC Presentation Steve Weitman, MD, PhD Chief Medical Officer ILEX Oncology, Inc.

  3. Sima Jeha,MD St. Jude Children’s Research Hospital Ka Wah Chan,MD M.D. Anderson Cancer Center Laurel Steinherz,MD Memorial Sloan-Kettering Cancer Center Robert Arceci,MD, PhD Sidney Kimmel CCC at Johns Hopkins Clofarabine ODAC Consultants Peter Steinherz,MD Memorial Sloan-Kettering Cancer Center Stephen Sallan,MD Dana-Farber Cancer Institute Varsha Gandhi,PhD M.D. Anderson Cancer Center Eric Sandler,MD Nemours Children’s Clinic Peter Adamson, MD Children’s Hospital of Philadelphia

  4. IntroductionSteve Weitman, MD, PhD Pediatric Leukemia:Robert Arceci, MD, PhD Need for New Treatment OptionsSidney Kimmel CCC at Johns Hopkins Clofarabine Pivotal StudiesSteve Weitman, MD, PhD Clinician’s PerspectiveStephen Sallan, MD Dana-Farber Cancer Institute Clofarabine Development PlanSteve Weitman, MD, PhD Agenda

  5. Pediatric Leukemia:Need for New Treatment Options The Challenge Robert Arceci,MD, PhD Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsDepartments of Oncology and Pediatrics

  6. Treatment of Patients with Pediatric Leukemias • Treatments for newly diagnosed patients with ALL & AML use aggressive multi-drug regimens • Overall survival for pediatric ALL and AML has improved, but is approaching a plateau • 20% ALL and 50% AML have disease recurrence

  7. Common Pediatric Cancers De Novo ALL & AML CNS Relapsed/ Refractory ALL & AML Source: SEER Pediatric Monograph Assumes: 75% ALL cases cured and 50% AML cases cured

  8. Challenges in Pediatric Relapsed & Refractory Leukemias • Heterogeneous population • Multi-drug resistance is common in leukemia cells, particularly at relapse • Dose intensification with combination therapies has resulted in significant co-morbidities and organ dysfunction • Transplant is the best curative option but requires disease control and time to identify donor

  9. Survival in Relapsed/ Refractory Pediatric Leukemia Acute Lymphoid Leukemia Acute Myeloid Leukemia Weitman, et. al. J Pediatr Hematol Oncol. 1997;17:197-207

  10. New Agents Needed for Remission Induction in Relapsed/ Refractory Patients • Few agents have been approved for pediatric leukemia • Most commonly used agents approved many years ago • Methotrexate (1953) • 6-Mercaptopurine (1953) • Vincristine (1963) • Ara-C (1969) • Doxorubicin (1974) • Development of new pediatric oncology agents has lagged behind adult oncology drug development

  11. Conclusions • Relapsed leukemia is the third most common childhood cancer • Successful treatment of relapsed and refractory pediatric leukemias remains a major challenge • Patients with multi-drug resistant leukemia are refractory to chemotherapy and have accumulated organ toxicities • New, well tolerated and effective agents are urgently needed

  12. Development OverviewClinical Study Results Clofarabine NDA Steve Weitman,MD, PhD ILEX Oncology, Inc.

  13. Clofarabine Development Overview • Adult Phase I studies started in 1999 • Pediatric Phase I studies started in 2000 • Striking activity in heavily pretreated population with acceptable toxicity profile • Compelling results in pediatric patients with an unmet medical need • Propelled development in pediatrics at a faster rate than adults • Increased the request for expanded access due to lack of alternative studies

  14. Phase I/ II CLO/ ARA-C AML, MDS Phase II AML, ALL, MDS, CML Phase I Leukemia Phase II AML Phase II ALL Phase I Leukemia Phase II AML Clofarabine Development Timeline Adult Studies Phase II/ III CLO/ ARA-C AML In Development 1999 2001 2003 2004 2005 2000 2002 COG Phase II CLO/ ARA-C AML, ALL In Development Pediatric Studies

  15. Phase I Pediatric ALL & AML • Twenty-five patients • Dose levels from 11-70 mg/m2/day x 5 • MTD 52 mg/m2/day IV • DLT was reversible increases in bilirubin and skin rash • Response CR 5/25 (20%) PR 3/25 (12%) • 7 of 25 patients went totransplant Jeha, et. al. Blood. 2004;103:784-789

  16. Pivotal Pediatric ALL & AML • Planned Study Design • Primary Endpoint is Overall Response Rate (CR+CRp) • Fleming 2 stage design - (40% response rate of interest was based on 1 to 2 prior regimens) • Current Clinical Practice • Population was heavily pretreated, having highly resistant leukemia (up to 6 prior regimens) • Patients went to transplant before count recovery • The study size was expanded in collaboration with FDA to understand the true response rate

  17. Chemo Drugs Transplant TBI Pivotal Pediatric ALL Number of Unique Prior Agents Number of Agents Patients

  18. Chemo Drugs Transplant TBI Pivotal Pediatric AMLNumber of Unique Prior Agents Number of Agents Patients

  19. 2000 2001 2002 2003 2004 Induction Regimen 1 Prednisone, Vincristine, Methotrexate Etoposide , Daunorubicin, Cytarabine, Thioguanine Induction Regimen 2 L-Asparaginase, Vincristine, Cytarabine Cyclophosphamide, Etoposide, Thioguanine Post-Induction Regimen L-Asparaginase Cytarabine Induction Regimen 3 Gemcitabine, Topotecan Thiotepa, Vinorelbine Induction Regimen 4 Cytarabine Idarubicin Induction Regimen 5 TBI, Thiotepa, Fludarabine Peripheral Blood SCT Transplant Prep Regimen Clofarabine Cycle 1 Clofarabine Cycle 2 Clofarabine Cycle 3 Clofarabine Cycle 4 Clofarabine Cycle 5 Off Study Bone Marrow Transplant Clofarabine Alive with NED 4 Year Old AML Patient

  20. Safety and EfficacyPediatric Leukemia ALL & AML

  21. NDA Efficacy/ Safety Population • Efficacy data base N=84 • Integrated safety data base N=113

  22. Pivotal Study Endpoints • Key Efficacy Endpoints: Independent Response Review Panel (IRRP) determined response: CR, CRp, PR • Duration of remission • Post-treatment transplants • Survival • Safety

  23. Pivotal Pediatric ALL Efficacy

  24. Pivotal Pediatric ALL Characteristics of Study Group

  25. Pivotal Pediatric ALLIRRP Determined Best Objective Response

  26. Censored Value Pivotal Pediatric ALLDuration of Remission CR + CRp (N=10) Median 20.2 wks CR + CRp + PR (N=15) Median 9.7 wks

  27. Pivotal Pediatric ALLPost-Clofarabine Transplants • 14% of patients went to transplant (7/49) • 2 CR, 2 CRp, 2 PR, 1 NE • Median time to transplant was 32 days (range 16 - 77) • Median number cycles was 2 (range 2 - 3) • 5 of 7 patients alive post-transplant

  28. Censored Value Pivotal Pediatric ALLOverall Survival CR + CRp (N=10) Median 58.6 wks CR + CRp + PR (N=15) Median 42 wks All Pts (N=49) Median 11.7 wks

  29. Pivotal Pediatric AML Efficacy

  30. Pivotal Pediatric AML Characteristics of Study Group

  31. Pivotal Pediatric AML IRRP Determined Best Objective Response

  32. Censored Value Pivotal Pediatric AMLDuration of Remission CR + CRp + PR (N=9) Median 16.2 wks

  33. Pivotal Pediatric AMLPost-Clofarabine Transplants • 34% of patients went to transplant (12/35) • 1 CRp, 6 PR, 3 NE, 2 TF • Median time to transplant was 38 days (range 21 - 75) • Median number of cycles was 2 (range 1 - 5) • 7 of 12 patients alive post-transplant

  34. Censored Value Pivotal Pediatric AMLOverall Survival CR + CRp + PR (N=9) Median 39 wks All Pts (N=35) Median 21 wks

  35. Pivotal ALL & AML Efficacy Summary • Recurrent pediatric acute leukemia is a substantial unmet medical need, especially for patients with AML • Impressive response rates with Clofarabine for pediatric patients with ALL and AML that has become cross-resistant to most currently available agents • The duration of remission was more than sufficient to allow patients with donors the opportunity to proceed to transplant • Long-term survival was observed in patients with ALL and AML who responded to Clofarabine

  36. Integrated Safety Analysis

  37. Grade 3 Grade 4 Integrated Safety All Grade 3 & 4 Adverse Events in > 10% of Pediatric Patients (N=113)

  38. Grade 3 Grade 4 Integrated Safety Drug-Related Grade 3 & 4 Adverse Events in > 5% of Pediatric Patients(N=113)

  39. Grade 3 Grade 4 All Grade 3 & 4 Hepato-Biliary/ Renal Lab Abnormalities

  40. Deaths During Study Includes deaths within 30 days of last dose of study drug

  41. Integrated Safety Summary • Heavily pretreated population • Many adverse events were consistent with underlying leukemia • Events are not unexpected for a cytotoxic agent • Most adverse events were reversible

  42. Clinician’s Perspective Stephen Sallan,MD Dana-Farber Cancer Institute

  43. Childhood Leukemia • ALL 75 - 80% cured with multi-drug chemotherapy • AML 40 - 50% are cured • Successful treatment of relapsed and refractory pediatric leukemias remains a major challenge

  44. Survival in Pediatric Leukemias ALL Five Year Relative Survival Rates AML Year Kersey, Blood. 1997; 90(11):4243-4251

  45. CR After Single Agents in Childhood ALL Adapted from Holland and Frei Cancer Medicine 1974

  46. What Impresses Me As A Clinician • ALL Clofarabine results • 1 in 5 children with multi-drug resistant ALL achieved a CR, affording them a transplant option • AML Clofarabine results • 1 in 3 children with multi-drug resistant AML went to transplant • Transplant is the curative therapeutic option in drug-resistant childhood ALL and AML

  47. What Impresses Me As A Clinician • Clofarabine is Well Tolerated • No overlapping toxicities • Clofarabine provides Clinical Benefit • In a heterogeneous population • No meaningful Alternatives

  48. Commitment to Pediatric Clinical Development Steve Weitman,MD, PhD ILEX Oncology, Inc.

  49. Commitment to Pediatric Clinical Development • This represents a new paradigm in pediatric drug development • The sponsor commits to further develop this drug in children: • Continue survival follow-up on pivotal studies • Moving to less heavily pretreated ALL and AML patients • Proceed to a randomized study in pediatric patients • Our commitment includes working closely with the Children’s Oncology Group and CTEP

  50. Commitment to Pediatric Clinical Development • Children’s Oncology Group (COG)/ CTEP • AML Ara-C/Clofarabine Combination Study • First relapsed patients • Study chairs: Razzouk and Cooper • ALL Cytoxan/Clofarabine and Etoposide/Clofarabine Combination Study • Second relapsed patients • Study chair: Hijiya

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