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CE-01: 1 Efaproxiral (RSR13) as an Adjunct to Whole Brain Radiation Therapy for the Treatment of Brain Metastases Originating from Breast Cancer Oncologic.

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Presentation on theme: "CE-01: 1 Efaproxiral (RSR13) as an Adjunct to Whole Brain Radiation Therapy for the Treatment of Brain Metastases Originating from Breast Cancer Oncologic."— Presentation transcript:

1 CE-01: 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 Meeting May 3, 2004

2 CE-01: 2 RSR13 Introduction Pablo J. Cagnoni, MD Vice President, Clinical Development Allos Therapeutics Pablo J. Cagnoni, MD Vice President, Clinical Development Allos Therapeutics

3 CE-01: 3 Agenda  Introduction Pablo J. Cagnoni, MD  Brain MetastasesJohn H. Suh, MD  Science of RSR13Brian D. Kavanagh, MD  Clinical EfficacyPablo J. Cagnoni, MD  Clinical SafetyPablo J. Cagnoni, MD  ConclusionsPaul A. Bunn, Jr, MD  Introduction Pablo J. Cagnoni, MD  Brain MetastasesJohn H. Suh, MD  Science of RSR13Brian D. Kavanagh, MD  Clinical EfficacyPablo J. Cagnoni, MD  Clinical SafetyPablo J. Cagnoni, MD  ConclusionsPaul A. Bunn, Jr, MD

4 CE-01: 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  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 CE-01: 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  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 CE-01: 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  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 CE-01: 7 RSR13 in Patients with Breast Cancer and Brain Metastases  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  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 Pre-RSR13 Post-RSR13

8 CE-01: 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 RSR mg/kg/d IV over 30 minutes with supplemental oxygen immediately prior to each of 10 fractions of whole brain radiation therapy RSR13 is indicated as an adjunct to whole brain radiation for the treatment of brain metastases originating from breast cancer RSR mg/kg/d IV over 30 minutes with supplemental oxygen immediately prior to each of 10 fractions of whole brain radiation therapy

9 CE-01: 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 John H. Suh, MD Clinical Director of Radiation Oncology Director, Gamma Knife Radiosurgery Center Brain Tumor Institute Cleveland Clinic Foundation Cleveland, Ohio

10 CE-01: 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  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: ;Posner JB Neurologic complications of cancer: 1995.

11 CE-01: 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  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 CE-01: 12 Outcome with Treatment of Brain Metastases

13 CE-01: 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)  Steroids (eg. dexamethasone)  Anticonvulsant medication (symptom control)  Surgical resection (single)  Stereotactic radiosurgery (single)  Chemotherapy (limited use)  Whole brain radiation therapy (gold standard)

14 CE-01: 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  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 CE-01: 15 WBRT-Alternative Fractionation Regimens Lack of Progress StudyN Randomization (Total Dose/# Fractions) MST (months) Harwood et al. (’77) 10130/10 vs. 10/ Kurtz et al. (’81)25530/10 vs. 50/ Borgelt et al. (’81)13810/1 vs. 30/10 vs. 40/ Borgelt et al. (’81)6412/2 vs. 20/ Chatani et al. (’85)7030/10 vs. 50/ Haie-Meder et al. (’93)21618/3 vs. 36/6 vs. 43/ Murray et al. (’97) /34 vs. 30/104.5

16 CE-01: 16 Brain Metastases: Recursive Partitioning Analysis Adapted from: Gaspar L, et al., Int J Radiat Oncol Biol Phys. 1997;37(4): MST 7.1 mos 20% Class I Extra-cranial metastases: No KPS  70 Primary: Controlled Age: <65 MST 4.2 mos 65% KPS  70 MST 2.3 mos 15% Class III KPS <70 Class II KPS  70 Extra-cranial metastases: Yes Age:  65 and / or Primary: Uncontrolled and / or

17 CE-01: 17 StudyN Median Survival (months) Lentzsch et al. (’99) Mizutani et al. (’01) Fokstuen (’00)995.0 Mahmoud-Ahmed (’02)* RTOG BMD (’97) Results of WBRT for Patients with Brain Metastases from Breast Cancer Adapted from: Mahmoud-Ahmed, et al. Int J Radiat Oncol Biol Phys. 2002;54: * 1-yr survival 17%; 2-yr survival 2%

18 CE-01: 18 Survival with WBRT RTOG BMD vs. RT-009 Control Arm RPA Class I MST (months) RPA Class II MST (months) RTOG BMD RT-009 Control7.74.1

19 CE-01: 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  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 CE-01: 20 The Science of RSR13 Drug Design Rationale, Mechanism of Action, and Initial Translation into the Clinic Brian D. Kavanagh, MD, MPH Vice-Chairman Department of Radiation Oncology University of Colorado Comprehensive Cancer Center

21 CE-01: 21 The Science of RSR13  The clinical problem of tumor hypoxia  RSR13 drug design rationale  RSR13-mediated tumor oxygenation  Translation into the clinic  The clinical problem of tumor hypoxia  RSR13 drug design rationale  RSR13-mediated tumor oxygenation  Translation into the clinic

22 CE-01: 22 Oxygen is the Most Efficient Radiosensitizer  The cytotoxicity of radiation is increased by a factor of 3 or more in the presence of O 2  O 2 enhances radiation-induced DNA damage by increasing the half-life of toxic free radicals  Hypoxic regions of low pO 2 exist in all solid tumors  Clinical measurements of tumor hypoxia correlate with lower tumor control rates after radiotherarpy  The cytotoxicity of radiation is increased by a factor of 3 or more in the presence of O 2  O 2 enhances radiation-induced DNA damage by increasing the half-life of toxic free radicals  Hypoxic regions of low pO 2 exist in all solid tumors  Clinical measurements of tumor hypoxia correlate with lower tumor control rates after radiotherarpy

23 CE-01: 23 Hypoxia is Common in Breast Cancer  Substantial hypoxia present in breast cancers  Higher rates have been measured in brain metastases of 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 CE-01: 24 Max Perutz ( ) 1962 Nobel Prize in Chemistry Don Abraham Professor of Medicinal Chemistry Virginia Commonwealth University The Molecular Effect: Allosteric Modification of Hemoglobin N H O O ONa O RSR13

25 CE-01: 25 The Effect of RSR13 on Hemoglobin-Oxygen Binding Affinity pO 2 Percent Hb Saturation RSR13 increases p50 Targeted increase = 10 mm Hg Supplemental O 2

26 CE-01: 26 RSR13 Oxygenates Mammary Tumors in Animal Models Rat Mammary Carcinoma RSR mg/kg IV Control Air Control Oxygen RSR13 Air RSR13 Oxygen Teicher, B. A., et al., Drug Dev. Res. 1996;38:1-11 % Readings < 5 mmHg pO 2

27 CE-01: 27 RSR13 Radiosensitizes Mammary Tumors in Animal Models EMT6 Mouse Mammary Carcinoma RSR mg/kg IP, 1 x 10 Gy Surviving Fraction Rockwell, S. and M. Kelley, Radiat. Oncol. Invest. 1998;6 (5): RSR13RT RSR13 With Oxygen

28 CE-01: 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  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 CE-01: 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  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 CE-01: 30 RSR13 PK/PD Correlation Studies HV-001, RT-002, RT-008 and RT-010 Mean RBC RSR13,  g/mL Mean p50 Shift, mmHg y = x r = 0.90 p50 Target 10 mmHg Desired PK = 10/ = 483  g/mL

31 CE-01: 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  RSR mg/kg selected for future study based on ability to induce desired p50 increase  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  RSR mg/kg selected for future study based on ability to induce desired p50 increase

32 CE-01: 32 RSR13 as Adjunct to WBRT Clinical Efficacy in Patients with Brain Metastases

33 CE-01: 33 RSR13 Clinical Development Program Brain Metastases PK study Phase 3 in brain metastases initiated in Feb. Fast Track granted for brain metastases 1997 Phase 1b in solid tumors Phase 2 in brain metastases completed Enrollment completed in Phase 3 brain metastases trial 2003 RSR13 NDA Phase 3 in brain metastases completed IND 48,171

34 CE-01: 34 Treatment Administration Outpatient clinic Oxygen and pulse oximeter initiated RSR13 is administered via CVAD 30-minute infusion Transfer for radiation treatment 30-minute window Radiation is administered Oxygen tapers off Monitor and release Repeat for 10 days

35 CE-01: 35 Phase 2 Study In Patients with Brain Metastases Study RSR13 RT-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  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 CE-01: 36 Survival All RPA Class II RTOG Database vs. RT-008 RTOG MST = 4.1 mos (N = 1070) RT-008 MST = 6.4 mos (N = 57) p = Months Percent Alive / / / / / / / / / / /

37 CE-01: 37 Survival From RT-008 and RTOG BMD RPA Class II Patients Study and Analysis RTOG MST (months) RT-008 MST (months) Breast5.4 (N = 113) 9.7 (N = 18) NSCLC3.9 (N = 698) 6.4 (N = 33)

38 CE-01: 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 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 CE-01: 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 SpO 2  90% on room air  No cytotoxic chemotherapy (within 7 days)  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 SpO 2  90% on room air  No cytotoxic chemotherapy (within 7 days)

40 CE-01: 40 Study Design Treatment ArmsRandomized 1:1, open label: WBRT 3 Gy fractions x 10 days (30 Gy) with supplemental O 2 +/- RSR13 Stratification (1) RPA Class I (2) RPA Class II NSCLC (3) RPA Class II Breast (4) RPA Class II Other Primary EndpointSurvival Co-Primary Populations All patients: 85% power NSCLC/Breast: 75% power Alpha spending log-rank test

41 CE-01: 41 Amendments and Protocol Versions Protocol Version (Date)NDescription of Change 1 (10Jan2000)2NA 2 (02Mar2000)220Expand MRI/CT specs Omit RSR13 on any day if SpO 2 <90% 3 (05Jun2001)71Sample size up to 538 patients NSCLC/Breast co-primary Dose adjustment for anti-hypertensives, weight and gender 4 (09Oct2001)245Use of Cobalt 60 allowed

42 CE-01: 42 Dosing Adjustment Guideline Initial RSR13WeightWeight (kg) Dose (mg/kg)GroupMaleFemale 75High  95  Low  95  70

43 CE-01: 43 Assumptions for Primary Endpoint RPA Class I : II20% : 80% MST Control Arm4.57 months 35% Improvement6.17 months in RSR13 arm Number Events (deaths)402 All patients 308 NSCLC/Breast 6-month minimum follow-up

44 CE-01: 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)  Primary method: unadjusted log-rank  Primary population: eligible patients  Co-primary populations: Modified Bonferroni adjustment  Cox multiple regression (supportive)

45 CE-01: 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  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 CE-01: 46 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 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 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 Protocol  RPA Class  Primary tumor type  Control of primary  Age  Extent of extra-cranial metastases  KPS  Number of brain metastases

47 CE-01: 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  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 CE-01: 48 Radiology Evaluation CT/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)  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 CE-01: 49 Phase 3 Study RSR13 RT-009 Results

50 CE-01: 50 Patient Enrollment by Region RegionSites Control (N = 267) RSR13 (N = 271) Canada ROW* USA * Includes EU, Israel and Australia

51 CE-01: 51 Patient Characteristics Demographic Control (N = 267) n (%) RSR13 (N = 271) n (%) GenderMale Female 117 (44) 150 (56) 118 (44) 153 (56) RPA ClassI II 24 (9) 243 (91) 22 (8) 249 (92) Age<65  65 Mean 197 (74) 70 (26) (72) 75 (28) 57.1 Tumor TypeNSCLC Breast Other 151 (57) 55 (21) 61 (23) 148 (55) 60 (22) 63 (23)

52 CE-01: 52 Number of Doses Control (N = 267) RSR13 (N = 271) WBRT n (%) WBRT n (%) RSR13 n (%) 04 a (1)5 a (2)8 (3) 1 – 66 (2)9 (3)45 (17) 7 – 93 (1) 77 (28) (95)254 (94)141 (52) Mean a Discontinued study prior to RT Day 1. Not evaluable for safety. Treatment Received

53 CE-01: 53 Ineligible Patients Reason Ineligible Primary Site Control N = 17 RSR13 N = 6 Leptomeningeal MetastasesNSCLC Breast Other No Measurable Brain LesionsNSCLC Breast Dural Disease due to Bone MetsBreast10 Small Cell Lung CancerOther10

54 CE-01: 54 Overall Survival All Eligible Patients Control (N = 250) RSR13 (N = 265) MST Log-rank (01/03)HR = 0.87 (p = 0.16) Log-rank (01/04)HR = 0.87 (p = 0.13)

55 CE-01: 55 Overall Survival Eligible NSCLC/Breast Patients Control (N = 194) RSR13 (N = 203) MST Log-rank (1/03)HR = 0.81 (p = 0.07) Log-rank (1/04)HR = 0.82 (p = 0.05)

56 CE-01: 56 Significant Factors Predictive of Survival All Eligible Patients - Cox Model with 17 Covariates FactorLevelHRp-value KPS70 vs. 80 vs. 90 vs < Extra-cranial Mets0 vs. 1 – 2 vs. > Prior Brain ResectionNo vs. Yes Primary SiteOther vs. Breast Other vs. NSCLC Age <65 vs.  GenderFemale vs. Male Baseline Hgb <12 vs.  Treatment ArmControl vs. RSR

57 CE-01: 57 Significant Factors Predictive of Survival Eligible NSCLC/Breast - Cox Model with 17 Covariates FactorLevelHRp-value KPS70 vs. 80 vs. 90 vs < Extra-cranial Mets0 vs. 1 – 2 vs. > Prior Brain ResectionNo vs. Yes Age <65 vs.  GenderFemale vs. Male Treatment ArmControl vs. RSR

58 CE-01: 58 Stratified Log-rank Survival Analyses Co-primary Populations - Eligible Patients All PatientsNSCLC/Breast StrataHRp-valueHRp-value KPS KPS, Prior Resection KPS, Prior Resection, Extra-cranial Metastases

59 CE-01: 59 Sequence of Survival Analyses Eligible NSCLC/Breast Patients Hazard Ratio (p-value) Test 0.81 (0.07) Log-rank 0.76 (0.017) Cox Eligible NSCLC 0.97 (NS) Log-rank 0.90 (NS) Cox Eligible Breast 0.51 (0.003) Log-rank 0.51 (0.004) Cox

60 CE-01: 60 Overall Survival Eligible Breast Cancer Patients ControlRSR13 MST Died/Total42/4937/58 Log-rankHR = 0.51 (p = 0.003) CoxHR = 0.51 (p = 0.004)

61 CE-01: 61 Survival  12 Months and KPS Eligible Breast Cancer Patients Control (N = 5)RSR13 (N = 11) Survival (months) Alive Y/N Last KPS Survival (months) Alive Y/N Last KPS 17.5Y9026.9Y Y7028.2Y N-24.7Y N-22.9Y N-21.2Y Y Y Y Y N- 13.2N-

62 CE-01: 62 Survival Breast Cancer Patients Minimum Potential Follow Up 18 Months ControlRSR months >24 months Died Still Alive

63 CE-01: 63 Secondary Endpoints All Randomized Patients

64 CE-01: 64 Response Rate in the Brain Protocol-defined Criteria Primary SiteN Control % RSR13 % p-value All Patients NSCLC/Breast Breast All responses were determined by independent central review of all CT/MRI scans

65 CE-01: 65 Confirmed Response Rate in the Brain Primary SiteN Control % RSR13 % p-value All Patients NSCLC/Breast Breast <0.01 All responses were determined by independent central review of all CT/MRI scans

66 CE-01: 66 Response at 3-months Predicts Survival All Patients Response at 3-months n MST * (months) HRp-value Responder Non-responder * Additional survival time beyond 3-month scan

67 CE-01: 67 Response Rate at 3-months All Patients Primary SiteN Control % RSR13 % p-value All Patients NSCLC/Breast Breast

68 CE-01: 68 Secondary Endpoints All Patients EndpointControl (N = 267) RSR13 (N = 271) p-value QoL KPS (% stable/improved at 3 m) Spitzer (% stable/improved at 3 m) Cause of Death (% Neurologic) TTCP (% PF at 3 months) TTRP (% PF at 3 months)

69 CE-01: 69 Secondary Endpoints Breast Cancer Patients EndpointControl (N = 55) RSR13 (N = 60) p-value QoL KPS (% stable/improved at 3 m) Spitzer (% stable/improved at 3 m) Cause of Death (% Neurologic) TTCP (% PF at 3 months) TTRP (% PF at 3 months)

70 CE-01: 70 Treatment Effect Different in Patients with NSCLC and Breast Cancer  Biological differences  Different growth rates  Efficacy of therapy for extra-cranial disease  Body weight differences: RSR13 PK  Biological differences  Different growth rates  Efficacy of therapy for extra-cranial disease  Body weight differences: RSR13 PK

71 CE-01: 71 Body Weight RSR13 Patients by Primary Site and Gender Primary SiteGender Low WeightHigh Weight N%N% NSCLCMale Female BreastFemale

72 CE-01: 72 RSR13 RBC Concentration (µg/mL) By Primary Site, Dose and Weight Group Primary Site Low Weight GroupHigh Weight Group N*MedianN*Median NSCLC Breast *N = number of samples

73 CE-01: 73 Efficacy Conclusions Unprecedented Survival Improvement  Significant reduction in risk of death in pre-specified co-primary populations (Cox multiple regression)  Improvement in response rate and 38% improvement in MST in the eligible NSCLC/Breast population  Eligible Breast cancer patients: Improvement in response rate Clinically meaningful improvement in survival (MST 4.5 vs. 9.0) Higher number of long-term survivors  Significant reduction in risk of death in pre-specified co-primary populations (Cox multiple regression)  Improvement in response rate and 38% improvement in MST in the eligible NSCLC/Breast population  Eligible Breast cancer patients: Improvement in response rate Clinically meaningful improvement in survival (MST 4.5 vs. 9.0) Higher number of long-term survivors

74 CE-01: 74 RSR13 Safety Profile

75 CE-01: 75 RSR13 As Sole Adjunct to RT Safety Database Indication (Doses)StudyPhase Enrolled N Treated N Solid tumors (2-10)RT-0021b20 GBM (30)RT-006 RT-007 RT-007b All 1b Brain Metastases (10)RT-008 RT-009 All / / NSCLC (32)RT All547538

76 CE-01: 76 Allos Hypoxemia Grading Scale Grade NormalO 2 required >3 hours but <4 hours post-end infusion SpO 2 <90% while breathing O 2 4 L/min O 2 required  4 hours post- end infusion Increase in O 2 >4 L/min (during infusion and/or 4-hour recovery) Symptomatic hypoxemia Pre-infusion SpO 2 <90% attributed to RSR13 Decreased SpO 2 requiring hospitalization CPAP and/or mechanical ventilation

77 CE-01: 77 Treatment-Emergent AEs Occurring in  20% RSR13 patients in RT-009 All PatientsBreast Event Control (N = 263) % RSR13 (N = 266) % Control (N = 54) % RSR13 (N = 60) % Fatigue Headache Nausea Hypoxemia Vomiting Radiation dermatitis Constipation Dizziness Infusion symptoms, perioralN/A21N/A32

78 CE-01: 78 Grade 3 AEs in RT-009 (>5% patients) Event All PatientsBreast Control (N = 263) % RSR13 (N = 266) % Control (N = 54) % RSR13 (N = 60) % Hypoxemia21122 Headache3745 Nausea3508 Vomiting3528 Dyspnea6222

79 CE-01: 79 Grade 4 AEs in RT-009 (>2 Patients in Either Arm) Preferred Term All PatientsBreast Control (N = 263) n RSR13 (N = 266) n Control (N = 54) n RSR13 (N = 60) n Pneumonia0500 Renal failure, acute1500 Dyspnea4400 Pulmonary embolism3410 Convulsions3201 Fatigue3010 Headache3010

80 CE-01: 80 RSR13-Related Grade 4 AEs in RT-009 By Primary Site Event NSCLC (N = 144) Breast (N = 60) Other (N = 62) All (N = 266) Renal Failure0033 Vomiting1001 Coma1001 Pneumonia1001 Hypotension0011 Tachycardia0011 Deafness1001

81 CE-01: 81 Hypoxemia  Only 11% patients had a Grade 3 hypoxemia AE  73% of patients in RT-009 who had Grade 3 hypoxemia as an AE were asymptomatic  Hypoxemia was self-limited and easily managed with supplemental oxygen  Only 11% patients had a Grade 3 hypoxemia AE  73% of patients in RT-009 who had Grade 3 hypoxemia as an AE were asymptomatic  Hypoxemia was self-limited and easily managed with supplemental oxygen

82 CE-01: 82 Safety Summary  Data from 535 patients indicate that RSR13 is safe in cancer patients receiving RT  Very low incidence of Grade 3-4 AEs in a heavily pre-treated population of cancer patients in RT-009  All AEs in RT-009 resolved within the 1-month follow-up period and were easily managed with supportive care  Hypoxemia associated with RSR13: Self-limited, requires only supplemental O 2 Asymptomatic in the majority of patients  Data from 535 patients indicate that RSR13 is safe in cancer patients receiving RT  Very low incidence of Grade 3-4 AEs in a heavily pre-treated population of cancer patients in RT-009  All AEs in RT-009 resolved within the 1-month follow-up period and were easily managed with supportive care  Hypoxemia associated with RSR13: Self-limited, requires only supplemental O 2 Asymptomatic in the majority of patients

83 CE-01: 83 Conclusions Paul A. Bunn, Jr., MD Grohne/Stapp Professor and Director University of Colorado Comprehensive Cancer Center Denver, CO

84 CE-01: 84 RSR13 in Patients with Brain Metastases (N = 538) High unmet medical need High incidence High morbidity and mortality Lack of progress High unmet medical need High incidence High morbidity and mortality Lack of progress Pre-RSR13Post-RSR13

85 CE-01: 85 Summary of Survival Results Eligible Patients MST (months) Log-rankCox ControlRSR13HRp-valueHRp-value NSCLC/Breast (N = 397) * NSCLC (N = 290) Breast cancer (N = 107) *Final data with additional follow-up of 12 months

86 CE-01: 86 Breast Cancer Patients Summary Results ControlRSR13p-value MST (months) month K-M Estimate 0%31% Response Rate49%72%0.01 Confirmed RR20%42%0.009 KPS (% stable or improved at 3 months) 18%35%0.002 SQ (% stable or improved at 3 months) 24%37%0.01

87 CE-01: 87 RSR13 as Adjunct to WBRT Risk: Benefit Assessment  Benefit in breast cancer patients: Clinically meaningful improvement in survival Improved quality of life Long term survivors with excellent performance status  Risk in breast cancer patients: Very low incidence of Grade 3-4 AEs No long-term toxicities Most toxicities self-limited and easily managed  Benefit in breast cancer patients: Clinically meaningful improvement in survival Improved quality of life Long term survivors with excellent performance status  Risk in breast cancer patients: Very low incidence of Grade 3-4 AEs No long-term toxicities Most toxicities self-limited and easily managed

88 CE-01: 88 Thank You!


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