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Efaproxiral (RSR13) as an Adjunct to Whole Brain Radiation Therapy for the Treatment of Brain Metastases Originating fr

Efaproxiral (RSR13) as an Adjunct to Whole Brain Radiation Therapy for the Treatment of Brain Metastases Originating from Breast Cancer. Oncologic Drugs Advisory Committee Meeting May 3, 2004. RSR13 Introduction. Pablo J. Cagnoni, MD Vice President, Clinical Development Allos Therapeutics.

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Efaproxiral (RSR13) as an Adjunct to Whole Brain Radiation Therapy for the Treatment of Brain Metastases Originating fr

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  1. Efaproxiral (RSR13) as an Adjunct to Whole Brain Radiation Therapy for the Treatment of Brain Metastases Originating from Breast Cancer Oncologic Drugs Advisory Committee MeetingMay 3, 2004

  2. RSR13Introduction Pablo J. Cagnoni, MD Vice President, Clinical Development Allos Therapeutics

  3. Agenda • Introduction Pablo J. Cagnoni, MD • Brain Metastases John H. Suh, MD • Science of RSR13 Brian D. Kavanagh, MD • Clinical Efficacy Pablo J. Cagnoni, MD • Clinical Safety Pablo J. Cagnoni, MD • Conclusions Paul A. Bunn, Jr, MD

  4. Experts Available for Q&A • Paul A. Bunn, Jr, MD, Director, University of Colorado Cancer Center • Walter J. Curran Jr, MD, Group Chairman, Radiation Therapy Oncology Group • Anthony D. Elias, MD, Medical Director, Breast Cancer Program, University of Colorado Health Sciences Center

  5. Experts Available for Q&A (cont.) • Henry Friedman, MD, Director, James B. Powell Professor of Neuro-oncology, Brain Tumor Center Duke University Medical Center • Marc Gastonguay, PhD, Clinical Pharmacology Consultant • Charles Scott, PhD, Biostatistics, CBS Squared • Baldassarre D. Stea, MD, PhD, Chairman, Department of Radiation Oncology, University of Arizona Health Sciences Center

  6. Experts Available from Allos Therapeutics • Adam P. Boyd, Biostatistics • John O. Hackman, Biostatistics • Markus F. Herzig, Regulatory Affairs • Doug G. Johnson, PhD, CMC • Carrie L. Kass, PharmD, Clinical Safety • Robert P. Steffen, PhD, Pharmacology and Toxicology • Michael E. Saunders, MD, Clinical Development

  7. RSR13 in Patients with Breast Cancer and Brain Metastases Pre-RSR13 • High unmet medical need • High incidence • High morbidity and mortality • Lack of progress • RSR13 • Improves survival in patients with breast cancer • Increases response rate • Excellent safety profile Post-RSR13

  8. Proposed Indication and Dosage RSR13 is indicated as an adjunct to whole brain radiation for the treatment of brain metastases originating from breast cancer RSR13 75-100 mg/kg/d IV over 30 minutes with supplemental oxygen immediately prior to each of 10 fractions of whole brain radiation therapy

  9. Brain Metastases John H. Suh, MD Clinical Director of Radiation Oncology Director, Gamma Knife Radiosurgery Center Brain Tumor Institute Cleveland Clinic Foundation Cleveland, Ohio

  10. Brain Metastases Incidence on the Rise • 170,000 cancer patients develop brain metastases annually in the United States • 20-40% of cancer patients develop brain metastases • Incidence is rising due to: • Longer survival resulting from earlier diagnosis • Better systemic therapy for extracranial disease • Improved neuroimaging techniques contribute to higher detection rate Nussbaum et al. Cancer. 1996;78:1781-1788;Posner JB Neurologic complications of cancer: 1995.

  11. Brain Metastases in Patients With Breast Cancer • Up to 35,000 patients per year • Afflicts younger patients (median age 53) • Systemic agents have benefit for extracranial disease • Current treatment strategies provide limited benefit More effective treatment options are needed

  12. Outcome with Treatment of Brain Metastases

  13. Current Management of Patients With Brain Metastases • Steroids (eg. dexamethasone) • Anticonvulsant medication (symptom control) • Surgical resection (single) • Stereotactic radiosurgery (single) • Chemotherapy (limited use) • Whole brain radiation therapy (gold standard)

  14. Whole Brain Radiation Therapy (WBRT) • Improves survival (approximately 4.5 months) • Improves/stabilizes neurologic function • Standard dosing scheme: 30 Gy in 10 fractions • No benefit to altered fractionation schemes

  15. WBRT-Alternative Fractionation Regimens Lack of Progress

  16. Class I Class II Class III KPS 70 KPS 70 KPS <70 KPS  70 KPS  70 Primary: Controlled Primary: Uncontrolled and / or Age: <65 Age: 65 and / or Extra-cranial metastases: No Extra-cranial metastases: Yes MST 7.1 mos20% MST 4.2 mos65% MST 2.3 mos15% Brain Metastases: Recursive Partitioning Analysis Adapted from: Gaspar L, et al., Int J Radiat Oncol Biol Phys. 1997;37(4):745-51

  17. Results of WBRT for Patients with Brain Metastases from Breast Cancer * 1-yr survival 17%; 2-yr survival 2% Adapted from: Mahmoud-Ahmed, et al. Int J Radiat Oncol Biol Phys. 2002;54:810-817

  18. Survival with WBRT RTOG BMD vs. RT-009 Control Arm

  19. Conclusions • Brain metastases from breast cancer are common • Current treatment options yield poor results • Treatment options are available for extra-cranial metastases • Compelling need for more effective treatment options

  20. The Science of RSR13Drug Design Rationale,Mechanism of Action, andInitial Translation into the Clinic Brian D. Kavanagh, MD, MPH Vice-Chairman Department of Radiation Oncology University of Colorado Comprehensive Cancer Center

  21. The Science of RSR13 • The clinical problem of tumor hypoxia • RSR13 drug design rationale • RSR13-mediated tumor oxygenation • Translation into the clinic

  22. Oxygen is the Most Efficient Radiosensitizer • The cytotoxicity of radiation is increased by a factor of 3 or more in the presence of O2 • O2 enhances radiation-induced DNA damage by increasing the half-life of toxic free radicals • Hypoxic regions of low pO2 exist in all solid tumors • Clinical measurements of tumor hypoxia correlate with lower tumor control rates after radiotherarpy

  23. 12 15% less than 5 mmHg 10 8 Frequency (%) 6 4 2 0 0 20 90 10 30 40 50 60 70 80 100 140 110 120 130 Tissue Oxygen Pressure (mmHg) Hypoxia is Common in Breast Cancer • Substantial hypoxia present in breast cancers • Higher rates have been measured in brain metastases of breast cancer Adapted from: Okunieff et al., Int J Rad Oncol Biol Phys, 1994

  24. O O O O N a N H The Molecular Effect: Allosteric Modification of Hemoglobin Max Perutz(1914-2002)1962 Nobel Prize in Chemistry RSR13 Don Abraham Professor of Medicinal Chemistry Virginia Commonwealth University

  25. Supplemental O2 RSR13 increases p50 Targeted increase = 10 mm Hg The Effect of RSR13 onHemoglobin-Oxygen Binding Affinity 100 75 Percent Hb Saturation 50 25 0 0 20 40 60 80 100 120 pO2

  26. < 5 mmHg pO2 RSR13 Oxygenates Mammary Tumors in Animal Models 13762 Rat Mammary Carcinoma RSR13 150 mg/kg IV 50 45 40 35 30 25 20 15 % Readings 10 5 0 Control Air Control Oxygen RSR13 Air RSR13 Oxygen Teicher, B. A., et al., Drug Dev. Res. 1996;38:1-11

  27. RSR13 Radiosensitizes Mammary Tumors in Animal Models EMT6 Mouse Mammary Carcinoma RSR13 300 mg/kg IP, 1 x 10 Gy 1 Surviving Fraction 0.1 RT RSR13 RSR13 RT With Oxygen Rockwell, S. and M. Kelley, Radiat. Oncol. Invest. 1998;6 (5):199-208

  28. Healthy Volunteer Study HV-001 • Targeted pharmacodynamic endpoint: • p50 increase of 10 mmHg • Phase 1 Study, Single IV dose of RSR13 • RSR13: 10, 25, 50, 75, 100 mg/kg • N = 19 • Result: • an increase in p50 of 10 mmHg was achieved consistently at a dose of 100 mg/kg

  29. RSR13 Pharmacokinetic Summary • Vascular compartment volume of distribution • 50% in RBCs • 50% in plasma • Half-life in RBCs 4.5 hours • Elimination: • RSR13 acyl glucuronide • Renal excretion: Parent and glucuronide

  30. RSR13 PK/PD CorrelationStudies HV-001, RT-002, RT-008 and RT-010 13 y = 0.0207x r = 0.90 12 p50 Target 10 mmHg Desired PK = 10/0.0207 = 483 g/mL 11 10 9 Mean p50 Shift, mmHg 8 7 6 5 300 350 400 450 500 550 600 Mean RBC RSR13, g/mL

  31. Conclusions • Tumor hypoxia is associated with radioresistance • RSR13 reduces tumor hypoxia and increases radiosensitivity • The pharmacodynamic effect of RSR13 is quantified by the increase in p50 • Linear correlation between RSR13 RBC concentration and the p50 increase • RSR13 100 mg/kg selected for future study based on ability to induce desired p50 increase

  32. RSR13 as Adjunct to WBRT Clinical Efficacy in Patients with Brain Metastases

  33. RSR13 Clinical Development ProgramBrain Metastases Enrollment completed in Phase 3 brain metastases trial Phase 3 in brain metastases initiated in Feb. RSR13 NDA Phase 1b in solid tumors IND 48,171 1996 1998 2000 2002 2003 1995 1997 1999 2001 PK study Phase 2 in brain metastases completed Phase 3 in brain metastases completed Fast Track granted for brain metastases

  34. Oxygen and pulse oximeter initiated RSR13 is administered via CVAD 30-minute infusion Monitor and release Oxygen tapers off Transfer for radiation treatment 30-minute window Radiation is administered Treatment Administration Outpatient clinic Repeat for 10 days

  35. Phase 2 Study In Patients with Brain Metastases Study RSR13RT-008 • 69 patients, open label • Breast cancer (n = 21) • NSCLC (n = 39) • Other (n = 9) • 17 sites in the U.S. and Canada • Primary endpoint: Survival • Control group: RTOG BMD

  36. Survival All RPA Class IIRTOG Database vs. RT-008 100 / / 80 RTOG MST = 4.1 mos (N = 1070) RT-008 MST = 6.4 mos (N = 57) 60 Percent Alive p = 0.0174 40 / 20 / / / / / / / / 0 0 6 12 18 24 Months

  37. Survival From RT-008 and RTOG BMD RPA Class II Patients

  38. Study RSR13 RT- 009 A phase 3, randomized, open-label, comparative study of standard whole brain radiation therapy (WBRT) with supplemental oxygen, with or without efaproxiral (RSR13), in patients with brain metastases Study chairs: John H. Suh, MD; Cleveland Clinic Foundation Edward G. Shaw, MD; Wake Forest University

  39. Key Eligibility Criteria • KPS 70 • Excluded histologies: SCLC, NHL, germ cell • No prior treatment for brain metastases (except surgery if only partial resection performed); prior and concurrent corticosteroids allowed • Adequate hematologic, renal, hepatic and pulmonary function • Resting and exercise SpO2 90% on room air • No cytotoxic chemotherapy (within 7 days)

  40. Study Design

  41. Amendments and Protocol Versions

  42. Dosing Adjustment Guideline

  43. Assumptions for Primary Endpoint

  44. Analysis of Survival per SAP • Primary method: unadjusted log-rank • Primary population: eligible patients • Co-primary populations: • Modified Bonferroni adjustment • Cox multiple regression (supportive)

  45. Benefits of Adjusted Survival Analyses • Adjusted analyses provide the most accurate treatment estimate in heterogeneous populations: • Cox multiple regression • Stratified log-rank • RT-009 population very heterogeneous • Omitting strong covariates reduces power to detect treatment effects

  46. RT-009 Protocol RPA Class Primary tumor type Control of primary Age Extent of extra-cranial metastases KPS Number of brain metastases RT-009 Statistical Analysis Plan Gender Hemoglobin Liver metastases Size of brain metastases Previous BM resection Primary disease duration Site location Site size Altitude Weight category Pre-Specified Cox Model Baseline Covariates RT-009 Protocol • RPA Class • Primary tumor type • Control of primary • Age • Extent of extra-cranial metastases • KPS • Number of brain metastases RT-009 Statistical Analysis Plan • Gender • Hemoglobin • Liver metastases • Size of brain metastases • Previous BM resection • Primary disease duration • Site location • Site size • Altitude • Weight category RT-009 Statistical Analysis Plan • Gender • Hemoglobin • Liver metastases • Size of brain metastases • Previous BM resection • Primary disease duration • Site location • Site size • Altitude • Weight category

  47. Secondary Endpoints • Response rate in the brain • Time to radiographic tumor progression in the brain • Time to clinical tumor progression in the brain • Cause of death • Quality of life

  48. Radiology EvaluationCT/MRI Scans of the Brain • Performed at baseline, initial follow-up 1 month after WBRT Day 10, 3 months after WBRT Day 10, and every 3 months thereafter, until progression • Central, independent radiologic review blinded to study arm and treatment outcome conducted for all scans • Neuroimaging Core Laboratory (Cleveland Clinic)

  49. Phase 3 Study RSR13 RT-009 Results

  50. Patient Enrollment by Region * Includes EU, Israel and Australia

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