FARYDAK (Panobinostat) for the Treatment of Patients With Previously Treated Multiple Myeloma
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1 CI-1 FARYDAK (Panobinostat) for the Treatment of Patients With Previously Treated Multiple Myeloma Oncologic Drugs Advisory Committee Meeting November 6, 2014
2 CI-2 FARYDAK (Panobinostat) for the Treatment of Patients With Previously Treated Multiple Myeloma Renaud Capdeville, MD Novartis Pharma
3 CI-3 Pressing Need for New Treatment Options Despite improvements over the last 10 years, MM remains incurable in the vast majority of patients Salvage therapy relapse or toxicity next salvage option classes of agents are currently approved (chemotherapy, IMiDs, proteasome inhibitors) 1. Kumar SK, et al. Mayo Clin Proc. 2004;79(7): ; 2. Kumar SK, et al. Leukemia. 2012;26(1): ; 3. Richardson PG, et al. Blood. 2014;123(12):
4 Panobinostat: A Novel, Highly Potent Inhibitor of Histone and Non-Histone Deacetylases 1 Panobinostat CI-4 Activation of tumor suppressor genes (eg, p21, p27) Histone (epigenetic) HDAC Non-histone Accumulation of misfolded proteins (critical to MM) HDAC1,2,3 HDAC1,2 HDAC6 Histones p53 Tubulin HSP90 Aggresome Cell Death 1. Atadja P. Cancer Letters. 2009;280:
5 CI-5 Strong Rationale for Panobinostat in MM Synergy of PAN+BTZ+Dex Combination In vitro synergy with combination indexes of 0.06 to 0.4 at concentrations of PAN and BTZ ranging from 4 to 20 nm 1 In vivo MM1S mouse model: greater antitumor activity with the triple combination PAN-BTZ-Dex 2 Tumor volume (mm 3 ) Control BTZ Dex BTZ+Dex PAN * PAN+Dex * PAN+BTZ ** PAN+BTZ+Dex * P <.05 related to singles. ** P <.05 related to doubles. Days of treatment 1. Catley L, et al. Blood. 2006;108: ; 2. Ocio EM, et al. Haematologica. 2010;95(5):
6 CI-6 Development of Panobinostat-BTZ in Myeloma Phase 1 hematologic malignancies (B2102) N = 176 Phase 2 in MM (B2203) Single-agent PAN N = 38 Phase 1b in MM (B2207) Combination PAN-BTZ-Dex Oct 07 N = 62 Pivotal phase 3 in R/R MM (D2308) N = 768 Jan 10 Sep 13 Mar 12 Phase 2 BTZ-refractory MM (DUS71) N = 55 Jun 10 Dec 12 Aug 11 Note: shaded areas represent enrollment periods.
7 CI-7 Regulatory Interactions Date Aug 2012 Feb 2012 Feb 2014 Mar 2014 May 2014 Regulatory Interaction Orphan designation Reached agreement on endpoints and SAP Pre-NDA meeting NDA submitted Priority review granted SAP, statistical analysis plan.
8 CI-8 Overview of Panobinostat NDA Novel mechanism of action relevant to MM Significant and clinically meaningful prolongation of PFS ( 3.9 months) Consistent HR demonstrated across all prespecified sensitivity analyses 28% (PAN) vs 16% (PBO) CR/nCR 38 months (PAN) vs 35 months (PBO) median OS in interim analysis 1 Well-characterized and manageable safety profile 1. Not statistically significant (HR = 0.87).
9 CI-9 Proposed Indication Panobinostat, in combination with bortezomib and dexamethasone, for treatment of patients with multiple myeloma who have received at least one prior therapy
10 CI-10 Panobinostat Presentation Overview Introduction Multiple Myeloma Treatment Landscape Clinical Efficacy and Safety Clinical Perspective Renaud Capdeville, MD Novartis Pharma Keith Stewart, MB, ChB Mayo Clinic Renaud Capdeville, MD Novartis Pharma Paul Richardson, MD Dana-Farber Cancer Institute
11 CI-11 Experts Keith Stewart, MB, ChB Mayo Clinic Paul Richardson, MD Dana-Farber Cancer Institute Peter Voorhees, MD UNC Lineberger Comprehensive Cancer Center Jatin Shah, MD MD Anderson Cancer Center ASH/FDA panel on endpoints in MM member 1 IMWG 2 guidelines Author Mayo msmart guidelines 3 Author PI for trial DSU71, Co-Chair for trial D2308 ASH/FDA panel on endpoints in MM member 1 IMWG 2 guidelines Author Chair of the Independent Review Committee IMWG member Member of the Independent Review Committee IMWG member John Ware, PhD Ware Research Group, Inc. Chief of Outcomes Measurement Division Dept of Quantitative Sciences Massachusetts Medical School Expert in patient-reported outcomes 1. Anderson K, et al. 2009; 2. IMWG: International Myeloma Working Group; 3. Mikhael JR, et al. Mayo Clin Proc. 2013;88(4):
12 CU-1 Multiple Myeloma Treatment Landscape Keith Stewart, MB, ChB Professor of Hematology and Oncology
13 CU-2 Disclosure Statement My employer has received compensation for my participation in today s proceedings, and I have personally received compensation for pre-meeting preparation, but have no financial interest in the outcome of this meeting
14 CU-3 Multiple Myeloma Epidemiology Multiple myeloma represents 10% to 15% of all hematologic malignancies 1 Incidence in US: Estimated 24,050 new cases in Median age at diagnosis is 69 years Prevalence in US: 83,367 people living with myeloma 2,a a Prevalence data are for Raab MS, et al. Lancet. 2009;374: ; 2. SEER Cancer Statistics Factsheets: Myeloma. National Cancer Institute. Bethesda, MD,
15 Multiple Myeloma Is Characterized by Multiple Relapses and Accumulating Drug Resistance CU-4 M-protein, g/l Asymptomatic MGUS or Smoldering MM Active MM Plateau Remission Symptomatic Relapse Refractory disease 1st-line therapy 2nd- to 4th-line therapy Late-line therapy Time MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma. Reprinted from Borrello I. Leuk Res. 2012;36(suppl 1):S3-S12.
16 CU-5 Endpoints Used in Relapsed MM Studies PFS as a primary endpoint Recommended by FDA/ASH panel 1 More conservative endpoint than TTP as it includes deaths Disease progression: 1 of the following criteria 2 Serum or urine M-protein levels Variability of assay requires confirmatory test and a minimum increase Bone marrow plasma cells New or size of existing lytic bone lesions or extramedullary disease 1. Anderson KC, et al. Leukemia. 2008;22: ; 2. Rajkumar SJ, et al. Blood. 2011;117(18):
17 CU-6 Therapies Approved for MM in the US Newly Diagnosed (No prior therapy) Proteasome inhibitors Bortezomib (Velcade 2008) Relapsed (Median 1-2 prior therapies) Bortezomib (Velcade 2003) Refractory (Median 5 prior therapies) Carfilzomib (Kyprolis 2012) Immunomodulatory drugs (IMiDs) Thalidomide (Thalomid 2006) Lenalidomide (Revlimid 2006) Pomalidomide (Pomalyst 2013) Chemotherapy Cyclophosphamide (Cytoxan 1959) Carmustine (BiCNU 1977) Liposomal doxorubicin (Doxil 2007) Melphalan (for palliative treatment of MM) (Alkeran 1964)
18 Basis of Approval in Relapsed Multiple Myeloma CU-7 Drug Trial Type Approval Basis Δ TTP, mo Survival Benefit Bortezomib IV 1 RCT vs Dex (N = 669) 2.7 HR = 0.57 P <.05 Lenalidomide 2 (+dexamethasone) RCT vs Dex (N = 351) 3.9 No RCT vs Dex (N = 341) NE No Liposomal doxorubicin 3 (+bortezomib) RCT vs Bortezomib (N = 646) 2.8 No 1. Velcade (bortezomib) US PI; 2. Revlemid (lenalidomide) US PI; 3. Doxil (doxorubicin HCl liposome injection) US PI; RCT, randomized clinical trial.
19 CU-8 Common Treatment Sequences in the US 1st-Line 1st Relapse 2nd Relapse BTZ-Dex LEN-Dex BTZ-Dex LEN-BTZ-Dex LEN-Dex BTZ-Dex BTZ-Dex PAN-BTZ-Dex was studied in a setting where BTZ-Dex is commonly used
20 Basis of Approval in Refractory Multiple Myeloma a CU-9 Approval Basis Drug Trial Type ORR mdor Survival Carfilzomib 1a Single-arm N = % 7.8 mo NE Pomalidomide 2 (+dexamethasone) RCT vs Pom N = % vs 7% 7.4 mo for Pom+Dex NE A phase 2 supportive study (DUS71) of PAN-BTZ-Dex was conducted in this setting a Subpart H approvals. 1. Kyprolis (carfilzomib) US PI; 2. Pomalyst (pomalidomide) US PI; RCT, randomized clinical trial.
21 CU-10 Side Effects of Currently Used Regimens Immunomodulatory agents 1,2 Myelosuppression: Neutropenia, anemia Infections (pneumonia) Venous thrombosis and pulmonary embolism Fatigue Gastrointestinal effects: Constipation, diarrhea Second primary malignancy Proteasome inhibitors 3,4 Peripheral neuropathy (bortezomib) Infections: Pneumonia, herpes zoster Thrombocytopenia Gastrointestinal effects: Nausea, diarrhea Cardiovascular and renal effects (carfilzomib) BTZ, bortezomib; CFZ, carfilzomib; IMiDs, immunomodulatory drugs. 1. Dimopoulos ME, et al. Leukemia. 2014;28(8): ; 2. Dimopoulos ME, et al. Leukemia. 2011;25(5): ; 3. San Miguel J, et al. Oncologist. 2006;11(1):51-61; 4. Harvey RD. Clin Pharmacol. 2014;6:87-96.
22 Multiple Myeloma Survival Improving With New Drugs: But Almost All Still Relapse Early Deaths in High Risk CU-11 No Plateau Adapted from Kumar SK, et al. Leukemia. 2014;28:
23 Important Need for Efficacious Drugs With Non-overlapping MOA in Relapsed MM CU-12 Despite new effective drugs, almost all patients will relapse Available treatment options at relapse are limited Alkylating agents and steroids Only 2 classes of compounds introduced in the last decade With each new relapse, therapeutic options become progressively limited by drug resistance or intolerance
24 CE-1 FARYDAK (Panobinostat) for the Treatment of Patients With Previously Treated Multiple Myeloma Renaud Capdeville, MD Novartis Pharma
25 CE-2 Presentation Overview Dosing Rationale Efficacy Results Supportive Phase 2 Study DUS71 Pivotal Phase 3 Study D2308 Safety Results Summary & Conclusions
26 CE-3 Dosing Rationale Panobinostat 20 mg PO + BTZ 1.3 mg/m 2 IV 1 as MTD in phase 1b B2207 Highest ORR (73%) Longest duration of treatment (5.2 mo) Individualized dose titration to manage toxicity % of patients Overall Response Rate Dose Expansion 2 wks on/ 1 wk off PAN dose (mg/day) BTZ dose (mg/m 2 ) n = Bortezomib [package insert] Cambridge, MA: Millennium; 2009.
27 CE-4 Treatment Schedule in Phase 2 & 3 Trials Two Treatment Phases Similar to the APEX BTZ Registration Trial 1 Treatment phase 1 (Cycles 1-8) 3-week cycles Treatment phase 2 (Cycles 9-12) 6-week cycles Dose Schedule: 2 weeks on / 1 week off Panobinostat 20 mg Three times/week Three times/week Bortezomib 1.3 mg/m 2 Twice weekly Once weekly Dexamethasone 20 mg Day of/after BTZ Day of/after BTZ 24 weeks 24 weeks 1. Richardson PG, et al. N Engl J Med. 2005;352:
28 CE-5 Phase 2 Study in BTZ-Refractory Patients Study DUS71 Heavily Pretreated and Advanced Population PAN+BTZ+Dex n = 55 Sex, % M/F 53/47 Age, yr Median (range) 61 (41-88) Race, % Caucasian/Black 78/22 Prior lines of therapy Median (range) 4 (2-11) BTZ refractoriness, % 100 Progressed on BTZ therapy 73 Progressed 60 days after last BTZ therapy 27 BTZ in last line of therapy 49 Prior non-btz therapies, % ASCT 64 Lenalidomide 98 Thalidomide 69
29 Overcoming Resistance to BTZ With PAN Phase 2 Study DUS71 CE-6 35% overall response rate (ORR, PR) ORR of 43% among the 14 patients with high-risk cytogenetics (del[17p], t[4;14], t[14;16]) Median PFS: 5.4 months Median DoR: 6.0 months Median OS: 17.5 months
30 Panobinostat Phase 3 Trial in Myeloma Study D2308 Key Eligibility Criteria CE-7 Inclusion criteria Relapsed or relapsed-and-refractory MM 1 to 3 prior lines of therapy Adequate organ function ECOG performance status 0 to 2 Exclusion criteria Patients refractory to bortezomib
31 Panobinostat Phase 3 Trial in Myeloma Study D2308 Largest Trial Done in Previously Treated MM CE-8 Maximum duration of treatment = 48 weeks N = 768 PAN + BTZ + Dex Placebo + BTZ + Dex PFS (primary) OS Randomization stratification Prior lines of therapy Prior BTZ NO CROSSOVER IDMC safety analyses every 6 months BTZ, bortezomib; Dex, dexamethasone; OS, overall survival; PAN, panobinostat; PFS, progression-free survival.
32 CE-9 Efficacy Endpoints Study D2308 Endpoints Primary Key secondary PFS by mebmt criteria Investigator assessment, local laboratory OS Secondary ORR, ncr/cr rate, DoR, TTP, QoL Exploratory ORR by IMWG response criteria DoR, duration of response; EBMT, European Bone Marrow Transplant Organization; IMWG, International Myeloma Working Group; ncr/cr, near complete response/complete response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; QoL, quality of life; TTP, time to progression
33 CE-10 Baseline Demographics Study D2308 PAN+BTZ+Dex n = 387 PBO+BTZ+Dex n = 381 Age, median, yr (range) 63 (28-84) 63 (32-83) Age category, % < 65 yr yr Sex, % Male Female Race, % Caucasian Asian Black 1 5 Other 1 3
34 CE-11 Baseline Disease Characteristics Study D2308 PAN+BTZ+Dex n = 387 PBO+BTZ+Dex n = 381 Time from diagnosis Median, months (range) 37 (2-308) 39 (2-300) ISS clinical stage, % Stage II-III MM category, % Relapsed Relapsed and refractory Prior ASCT, % Prior lines of therapy, % 1 line lines Bortezomib Thalidomide Lenalidomide Cytogenetic risk Optional central assessment n = 120 n = 124 Standard Poor 20 10
35 CE-12 Patient Disposition Study D2308 All Patients Have Completed or Discontinued Therapy PAN+BTZ+Dex PBO+BTZ+Dex Primary reason for end of treatment n = 387, % n = 381, % Disease progression Treatment duration completed Adverse event(s) Patient withdrew consent 9 5 Death 5 4 New cancer therapy 1 2 Abnormal test procedures result(s) Protocol deviation Administrative problems Lost to follow-up 0.3 0
36 CE-13 Primary Endpoint: PFS by Investigator (ITT) 3.9-Month PFS Benefit, 37% Risk Reduction Progression-free survival probability, % PAN+BTZ+Dex PBO+BTZ+Dex Events, n/n PAN+BTZ+Dex 207/387 PBO+BTZ+Dex 260/381 Median PFS, mo (95% CI) 12.0 (10.3, 12.9) (7.6, 9.2) 3.9 mo HR (95% CI) P value (0.52, 0.76) Time, months Patients at risk PAN+BTZ+Dex PBO+BTZ+Dex <.0001
37 CE-14 Prespecified Sensitivity Analyses of PFS Support the robustness and consistency of the primary endpoint Conducted to assess: M-protein methods (IRC) Non-measurable disease at baseline (per protocol) Alternative censoring methods Not designed to estimate the true treatment effect
38 CE-15 PFS - Sensitivity Analyses Independent Review Committee (IRC) IRC instituted prior to database lock To independently assess responses in all patients To assess the impact of different methods of M-protein measurement IRC process: 77% of patients assessed by PEP, 23% with 1 visit using alternative standard methods (PEP globulin fractions, nephelometry, turbidimetry) Blinded to treatment assignment and investigator assessment Assessed response following mebmt criteria in all patients IRC recorded response visit-by-visit, until 2 consecutive values of M-protein qualified for progression per mebmt criteria mebmt, modified European Bone Marrow Transplant; PEP, protein electrophoresis.
39 CE-16 PFS Sensitivity Analyses (IRC & Per Protocol) Consistent Hazard Ratios Across All Analyses Median PFS, months PAN PBO HR (95%CI) Primary analysis a (0.52, 0.76) IRC assessment (0.52, 0.76) Per protocol (INV) (0.49, 0.75) Per protocol (IRC) (0.48, 0.74) HR All analyses include a requirement for PD confirmation per mebmt criteria. FDA briefing document reports only the IRC analysis without PD confirmation. P value <.0001 for all sensitivity analyses.
40 CE-17 PFS Sensitivity Analyses for Alternative Censoring Consistent Hazard Ratios Across All Analyses Median PFS, months PAN PBO HR (95%CI) Primary analysis * (0.52, 0.76) Actual event a (0.56, 0.79) Backdating date b (0.58, 0.81) Dropout c (0.61, 0.83) HR * P value <.0001 for all sensitivity analyses. a Includes the event whenever it occurred even after 2 missing adequate assessments. b Uses the date of next scheduled assessment for events occurring after 1 missing adequate assessment. c Includes subsequent antineoplastic therapy, reason for end of treatment as disease progression without investigator documentation, and disease progression after 2 missing adequate assessments as events.
41 CE-18 Post-Hoc Sensitivity Analysis Time-to-treatment failure is not recommended to assess treatment benefit 1 Does not distinguish efficacy from safety variables Ignores long progression-free period after treatment discontinuation 1. FDA Guidance to Industry on Clinical Trial Endpoints for Approval of Cancer Drugs and Biologics. May 2007.
42 CE-19 PFS by Baseline Characteristics (ITT) Study D2308 Median PFS, months PAN+BTZ+Dex PBO+BTZ+Dex All patients (N = 768) Race Caucasian (n = 499) Asian (n = 232) Other (n = 37) Sex Male (n = 407) Female (n = 361) Age group < 65 yr (n = 445) yr (n = 323) Clinical staging by ISS Stage I (n = 308) Stage II and III (n = 359) Favors PAN+BTZ+Dex Favors PBO+BTZ+Dex Hazard ratio (95% CI)
43 CE-20 PFS by Treatment History (ITT) Study D2308 Median PFS, months PAN+BTZ+Dex PBO+BTZ+Dex All patients (N = 768) Prior lines anti-mm therapy 1 (n = 352) or 3 (n = 416) Prior use of BTZ No (n = 432) Yes (n = 336) Prior stem cell transplantation No (n = 329) Yes (n = 439) Prior use of IMiDs No (n = 283) Yes (n = 485) Prior use of IMiDs and BTZ No (n = 570) Yes (n = 198) MM characteristics Relapsed (n = 482) Relapsed & refractory (n = 275) Favors PAN+BTZ+Dex Favors PBO+BTZ+Dex Hazard ratio (95% CI)
44 CE-21 Overall Survival 2nd Interim Analysis (86% of Events) Study D2308 Longer Median Survival With PAN+BTZ+Dex Overall survival probability, % HR (95% CI) = 0.87 (0.70, 1.07) Log-rank P =.1783 Kaplan-Meier medians PAN+BTZ+Dex: mo PBO+BTZ+Dex: mo PAN+BTZ+Dex PBO+BTZ+Dex 0 Patients at risk Time, months PAN+BTZ+Dex PBO+BTZ+Dex Cut-off date: August
45 CE-22 Secondary Endpoints Study D2308 Response by mebmt criteria PAN+BTZ+Dex n = 387 PBO+BTZ+Dex n = 381 P value ORR (CR/nCR/PR), % (95% CI) 61 (56, 66) 55 (49, 60).087 Median duration, mo (95% CI) 13 (12, 15) 11 (9, 12) CR/nCR, % (95% CI) 28 (23, 32) 16 (12, 20) a Median duration, mo (95% CI) 16 (12, 25) 12 (11, 15) Consistent findings using the IMWG response criteria (exploratory endpoint) a Statistical analysis of P value was not prespecified in the analysis plan
46 CE-23 Panobinostat Efficacy Conclusions Largest double-blind, randomized, phase 3 study in previously treated MM PFS: Median prolonged by 3.9 months 37% risk reduction (HR = 0.63, P <.0001) All sensitivity analyses support the primary analysis Benefit observed in all subgroups Trend for prolonged OS favoring panobinostat a Numerically higher ORR (61% vs 55%) Higher rate of CR/nCR (28% vs 16%) Longer duration of responses Efficacy supported by phase 2 in BTZ-refractory patients a Not statistically significant.
47 CS-1 FARYDAK (Panobinostat) for the Treatment of Patients With Previously Treated Multiple Myeloma Renaud Capdeville, MD Novartis Pharma
48 CS-2 Drug Exposure and Treatment-Free Period Study D2308 Duration of study treatment, mo PAN+BTZ+Dex n = 381 PBO+BTZ+Dex n = 377 Median (range) 5.0 (0.1, 13) 6.1 (0.1, 15) Treatment-free period, mo a Mean (95% CI) 7.5 (6.1, 8.6) 3.9 (3.0, 4.7) a Time between end of treatment and PFS estimated using PFS partitioning analysis Zee B, et al. J Clin Oncol. 1998;16:
49 CS-3 AEs Leading to Discontinuation ( 1% Patients) Most Frequent AEs: Diarrhea and Peripheral Neuropathy Preferred term PAN+BTZ+Dex n = 381 PBO+BTZ+Dex n = 377 Discontinuation due to AEs, % Diarrhea 5 2 Peripheral neuropathy 4 2 Asthenia 3 0 Fatigue 3 3 Thrombocytopenia Pneumonia 1 2
50 CS-4 Overview of Mortality Study D2308 PAN-BTZ-Dex n = 387 a PBO-BTZ-Dex n = 381 a 169 (44%) deaths 30 (8%) on-treatment b 4 Myeloma progression 10 Infection 5 Hemorrhage 3 Myocardial infarct 2 Acute renal failure 2 Cardiac arrest/cva 4 Other 190 (50%) deaths 18 (5%) on-treatment b 6 Myeloma progression 6 Infection 1 Hemorrhage 0 Myocardial infarct 0 Acute renal failure 2 Cardiac arrest 3 Other 139 (36%) post-treatment 172 (45%) post-treatment Treatment-related: 11 (2.8%) PAN vs. 7 (1.8%) PBO a All the frequencies are based on the patients in the full analysis set; Cut-off August b Deaths during or within 28 days after having discontinued therapy.
51 CS-5 Non-Hematologic AEs Irrespective of Relationship Study D2308 AE in 15% of Patients PAN+BTZ+Dex n = 381 PBO+BTZ+Dex n = 377 Preferred term, % All grades Grade 3/4 All grades Grade 3/4 Diarrhea Peripheral neuropathy a Asthenia/fatigue Nausea Peripheral edema Decreased appetite Constipation Pyrexia Vomiting Upper respiratory tract infection Pneumonia a Combined incidence of hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, paraesthesia, peripheral sensory neuropathy, polyneuropathy.
52 CS-6 Hematologic Laboratory Abnormalities Study D2308 PAN+BTZ+Dex n = 381 PBO+BTZ+Dex n = 377 Laboratory abnormality, % All grades Grade 3/4 All grades Grade 3/4 Thrombocytopenia Lymphopenia Neutropenia Anemia Platelet counts PAN+BTZ+Dex PBO+BTZ+Dex
53 CS-7 Hemorrhagic Events Study D2308 Patients with severe hemorrhage 16 (4%) on PAN 9 (2%) on PBO On-treatment deaths due to hemorrhage 5 (1.3%) on PAN 1 patient with cerebral bleeding with brain myelomatosis 2 patients with GI hemorrhage 2 patients with pulmonary hemorrhage 1 (0.3%) on PBO (CVA)
54 Incidence of Thrombocytopenia Decreases Following PAN and BTZ Dose Titration CS-8 Median Actual Dose-Intensity of PAN & BTZ Thrombocytopenia (Grade 3-4 AE) in PAN Arm 6 Treatment Phase 1 Treatment Phase Treatment Phase 1 Treatment Phase 2 Panobinostat dose, mg/day Panobinostat Bortezomib Bortezomib dose, mg/m 2 /day % of patients at risk Treatment cycle Treatment cycle N N PAN: DI of 5.7 mg/day corresponds to 20 mg TIW on the 2 wks on/1 wk off schedule. BTZ: DI of 0.24 mg/m 2 /day corresponds to 1.3 mg/m 2 twice-a-week on same schedule.
55 CS-9 Diarrhea Study D2308 Median time to onset of 2 months Low rate of discontinuation 5% PAN vs 2% PBO Grade 3-4 AE 25% PAN vs 8% PBO Median duration of 4 days 65% of patients had a single episode
56 CS-10 Elderly Patients Increased Risk of Thrombocytopenia, Diarrhea, and Fatigue PAN n = 221 % < 65 years 65 years PBO n = 217 % RR PAN n = 160 % PBO n = 160 % RR Discontinuation due to AE On-treatment death Grade 3-4 AE Thrombocytopenia Pneumonia Diarrhea Fatigue Increased toxicity confirmed in a multivariate analysis of risk factors 1 RR, relative risk. 1. Rogatko A, et al. Clin Canc Res. 2004;10(15):
57 CS-11 Conclusions Novel mechanism of action Positive and clinically important benefit-risk profile in patients with previously treated MM Met primary endpoint in large, double-blind, randomized, phase 3 trial Median PFS prolonged by 3.9 months, 37% risk reduction (HR = 0.63) Consistent HR across all preplanned sensitivity & subgroup analyses CR/nCR rate: 28% vs. 16% OS: 38 months vs. 35 months favoring PAN Well-characterized safety profile Most frequent AEs are thrombocytopenia, diarrhea, and fatigue Manageable with monitoring, dose adjustments, supportive care Supportive phase 2 study BTZ refractory disease
58 CB-1 Clinical Perspective on Panobinostat for the Treatment of Patients With Previously Treated Multiple Myeloma Paul Richardson, MD RJ Corman Professor of Medicine Harvard Medical School Dana-Farber Cancer Institute Boston, MA
59 CB-2 Disclosure Statement I have not received any compensation for my participation or for time spent in preparation for today s proceedings, and I have no financial interest in the outcome of this meeting.
60 Medical Need in Previously Treated Multiple Myeloma CB-3 Patients relapse and become refractory to available therapies Increased symptom burden due to disease and cumulative side effects with each line of therapy Balance between disease control and quality of life Treatment options include 2 major classes of compounds Proteasome inhibitors (bortezomib, carfilzomib) IMiDs (thalidomide, lenalidomide, pomalidomide) Urgent need for drugs with a new mechanism of action
61 CB-4 Panobinostat Improves Outcomes in Bortezomib-Refractory Disease Study DUS71 55 heavily pretreated patients Multicenter study and all enrolled in the USA High ORR: 35%, CBR ( MR): 53% Adverse cytogenetics (n = 14), ORR: 43% and CBR: 71% Median OS: 17.5 mos Median PFS: 5.4 mos Median DoR: 6.0 mos Manageable toxicity CBR, clinical benefit rate; DoR, duration of response; MR, minor response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival. Richardson PG, et al. Blood. 2013;122(14): ; Kumar SK, et al. Leukemia. 2012;26:
62 CB-5 Primary Endpoint: PFS by Investigator (ITT) 37% Risk Reduction, 3.9-Month PFS Benefit Progression-free survival probability, % PAN+BTZ+Dex PBO+BTZ+Dex Events, n/n PAN+BTZ+Dex 207/387 PBO+BTZ+Dex 260/381 Median PFS, mos (95% CI) 12.0 (10.3, 12.9) (7.6, 9.2) 3.9 mos HR (95% CI) P value (0.52, 0.76) < Time, months Patients at risk PAN+BTZ+Dex PBO+BTZ+Dex San-Miguel JF, et al. Lancet Oncol. 2014;15(11): Elsevier 2014.
63 Panobinostat is Associated With Deep and Durable Responses Study D2308 CB-6 PAN+BTZ+Dex n = 387 D2308 Pbo+BTZ+Dex n = 381 P value CR/nCR rate, % a ORR, % Median DoR, months a Statistical analysis of P value was not prespecified in the analysis plan. 1. San-Miguel JF, et al. Lancet Oncol. 2014;15(11):
64 PFS Benefit Regardless of Patient Characteristics CB-7 Hazard ratio All patients (N = 768) 0.63 Race Caucasian (n = 499) 0.69 Asian (n = 232) 0.54 Other (n = 37) 0.77 Sex Male (n = 407) 0.54 Female (n = 361) 0.76 Age group < 65 yr (n = 445) yr (n = 323) 0.72 Clinical staging by ISS Stage I (n = 308) 0.62 Stage II and III (n = 359) 0.61 Cytogenetics risk group Standard risk (n = 167) 0.88 Poor risk (n = 37) 0.47 Favors PAN+BTZ+Dex Favors PBO+BTZ+Dex Hazard ratio (95% CI) 1. San-Miguel JF, et al. Lancet Oncol. 2014;15(11): Elsevier 2014.
65 PFS Benefit Regardless of Prior Treatment CB-8 Hazard ratio All patients (N = 768) 0.63 Prior lines anti-mm therapy 1 (n = 352) or 3 (n = 416) 0.64 Prior use of BTZ No (n = 432) 0.68 Yes (n = 336) 0.58 Prior stem cell transplantation No (n = 329) 0.64 Yes (n = 439) 0.64 Prior use of IMiDs No (n = 283) 0.78 Yes (n = 485) 0.54 Prior use of IMiDs and BTZ No (n = 570) 0.68 Yes (n = 198) 0.53 MM characteristics Relapsed (n = 482) 0.70 Relapsed & refractory (n = 275) San-Miguel JF, et al. Lancet Oncol. 2014;15(11): Elsevier Favors PAN+BTZ+Dex Favors PBO+BTZ+Dex Hazard ratio (95% CI)
66 *From published data. BTZ, bortezomib; Dex, dexamethasone; NR, not reported; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; TTP, time to progression. 1. PANORAMA1 Study CLBH589D2308 Clinical Study Report; 2. Velcade (bortezomib) US PI; 3. DOXIL (doxorubicin HCl liposome injection) US PI. Bortezomib-Containing Therapies for Relapsed Disease CB-9 Median, months Regimen N PFS/TTP OS Primary endpoint PANORAMA1 1 PFS PAN + BTZ IV + Dex Δ 4 mos PBO + BTZ IV + Dex APEX 2 TTP BTZ IV * Δ 3 mos Dex * MMY ORR BTZ SC NR 53% vs 51% BTZ IV 74 8 NR MMY TTP BTZ IV + PLD NR Δ 2.8 mos BTZ IV NR
67 CB-10 Therapies for Refractory Disease Median, mos Regimen N ORR, % DoR PFS OS Primary endpoint PAN + BTZ + Dex ORR Pom + Dex a 14.7 a ORR CFZ a 15.6 a ORR a From published data. BTZ, bortezomib; CFZ, carfilzomib; Dex, dexamethasone; DoR, duration of response; ORR, overall response rate (partial response or better); OS, overall survival; PAN, panobinostat; PBO, placebo; PFS, progression-free survival; POM, pomalidomide. 1. PANORAMA2 Study CLBH589DUS71 Clinical Study Report; 2. Pomalyst (pomalidomide) US PI; 3. Kyprolis (carfilzomib) US PI.
68 Side-Effects of Current Treatment Options CB-11 IMiDs + Dex: Severe neutropenia, infections and DVT and/or PE Carfilzomib: Significant cardiovascular, pulmonary, and renal AEs BTZ+Doxil: Significant neutropenia, hand-foot syndrome, cardiovascular AEs PAN+BTZ+Dex: Severe thrombocytopenia, fatigue, and diarrhea Manageable with dose reduction and supportive care
69 On-Treatment Mortality With Current Therapies CB-12 Regimen Trial Overall Treatment-related Len + Dex MM Len + Dex MM BTZ IV APEX 3 BTZ IV ± Dex MMY BTZ SC ± Dex MMY BTZ IV + PLD MMY PBO + BTZ + Dex D PAN + BTZ + Dex D CFZ PX Pom + LoDex MM-002/003 8,9 PAN + BTZ + Dex DUS NR % of patients % of patients BTZ, bortezomib; CFZ, carfilzomib; Dex, dexamethasone; Len, lenalidomide; LoDex, low-dose Dex; NR, not reported; PAN, panobinostat; PBO, placebo; Pom, pomalidomide. 1. Dimopoulos M, et al. N Engl J Med. 2007;357: ; 2. Weber D, et al. N Engl J Med. 2007;357: ; 3. Richardson PG, et al. Blood. 2007;110: ; 4. Richardson PG, et al. N Engl J Med. 2005;352: ; 5. Orlowski RZ, et al. J Clin Oncol. 2007;25: ; 6. PANORAMA1 Study CLBH589D2308 Clinical Study Report; 7. Siegel D, et al. Blood. 2012;120: ; 8. Richardson PG, et al. Blood. 2014;123(12): ; 9. San Miguel J, et al. Lancet Oncol. 2013;14: ; 10. PANORAMA2 Study CLBH589DUS71 Clinical Study Report.
70 CB-13 Bortezomib Therapy Has Evolved Bortezomib IV and dexamethasone is a standard of care Subcutaneous bortezomib is commonly used Equivalent efficacy to intravenous Reduced rate of important adverse events Weekly bortezomib use is a major advance Improved management of GI toxicity, peripheral neuropathy, thrombocytopenia, and fatigue
71 CB-14 Managing Therapy in Older Patients Older patients ( 65 years) are at increased risk of AEs Result in higher frequency of treatment discontinuations and on-treatment deaths EMN and IMWG guidance 1,2 More frequent monitoring Early intervention with dose adjustment and supportive care Guidance on managing diarrhea 3 Prompt initiation of loperamide, adequate fluid intake, and dose adjustments EMN, European Myeloma Network; IMWG, International Myeloma Working Group. 1. Palumbo A, et al. Blood. 2011;118(17): ; 2. Palumbo A, et al. J Clin Oncol. 2014;32(6): ; 3. Andreyev J, et al. Lancet Oncol. 2014;15(10):e447-e460.
72 Conclusion: Clinically Relevant Benefit With PAN+BTZ+Dex CB-15 Higher quality responses ncr/cr: 28% vs 16%; P = % reduction in risk of progression or death (HR = 0.63, P <.0001) Prolonged median PFS (12 vs 8.1 months) PFS benefit across all sub-groups Trend towards improved OS (HR = 0.87) Active in high-risk and refractory disease DUS71: ORR 35%, CBR ( MR) 53% Adverse cytogenetics: ORR 43%, CBR 71%
73 CB-16 Clinical Perspective Urgent need for additional therapies with novel mechanisms of action Panobinostat: Produces a clinically relevant prolongation of PFS Trend towards prolonged OS Effective in patients who have received multiple prior therapies and are both relapsed and refractory Adverse events are predictable Managed with dose adjustment and supportive care Offers an important new option for patients with relapsed/refractory disease and who have received at least 1 prior therapy
74 BR-23 Quality Adjusted Toxicity free and Progression free time (TWiST) Study D2308 PAN + BTZ + Dex PBO + BTZ + Dex PAN + BTZ +Dex PBO + BTZ + Dex Difference Toxicity free and Progression free time, months 11.9 [ 10.4, 13.2] 8.6 [ 7.6, 9.6] 3.3 [1.6, 5.0] 23 Presentation Title Presenter Name Date Subject Business Use Only
75 CL-31 Censoring in Phase III Registration Trials in Relapsed MM TTP for BTZ, LEN and L-doxorubicin, and PFS for D % of patients randomized BTZ APEX LEN Trial 1 LEN Trial 2 L-Doxo Column1 D Experimental Arm Control Arm Source: Published FDA summary of approval for relapsed or Relapsed/Refractory MM (Kane RC et al., Clin. Canc. Res, 2006 / Hazarika M et al., The Oncologist, 2008 / Ning YM et al., Oncology, 2007)
76 DE-5 On-Treatment Deaths: Time to onset (< 60 days) 28 days post treatment follow-up Principal cause of death, n PAN+BTZ+Dex N=30* PBO+BTZ+Dex N=18* Deaths due to study indication 4 6 Deaths due to AE Early deaths (< 60 days) 10 6 Infection 4 3 Hemorrhage 4 1 Myocardial infarction 1 - Cerebrovascular accident 1 - Acute respiratory failure - 1 Cardiopulmonary failure - 1 * Based on 28 days post-treatment follow-up
77 DE-6 On-Treatment Deaths: Time to onset ( 60 days) 28 days post treatment follow-up Principal cause of death, n PAN+BTZ+Dex N=30* PBO+BTZ+Dex N=18* Deaths due to study indication 4 6 Deaths due to AE Deaths 60 days 16 6 Infection 6 3 Hemorrhage 1 - Myocardial infarction 2 - Acute renal failure 2 - Cardiac arrest 1 2 Pulmonary edema 1 - Pulmonary embolism - 1 Intestinal ischemia 1 - Death unknown 1 - Drug intoxication 1 - * Based on 28 days post-treatment follow-up
78 DE-12 Summary of death 45 days of last dose Days from last dose PAN + BTZ + Dex N = 381 PBO + BTZ + Dex N = 377 Within 28 days 30 (7.9) 18 (4.8) Within 30 days 31 (8.1) 19 (5.0) Within 45 days 33 (8.7) 25 (6.6)
79 EF-21 Prior Treatment of Multiple Myeloma Study D2308 US patients Prior lines of antineoplastic medication with a PAN+BTZ+Dex N = 22 Patients, % PBO+BTZ+Dex N = 32 Bortezomib Lenalidomide Thalidomide Alkylators Combined bortezomib+lenalidomide Combined bortezomib+imids Combined bortezomib+dexamethasone Steroids Other a Drugs with 10% of patients and drugs and combinations of interest. Combinations include at least the 2 drugs but combinations with any additional 3rd drug or more is included in the row.
80 EF-45 Censoring Reasons for PFS as per INV Study D2308 PAN+BTZ+ Dex N = 387 Patients, n (%) PBO+BTZ+ Dex N = 381 All N = 768 Total number of censored patients 180 (47) 121 (32) 301 (39) Ongoing 35 (19) 15 (12) 50 (17) Adequate response assessment not 86 (48) 54 (45) 140 (47) available Lost to follow-up 3 (2) 1 (1) 4 (1) Withdrew consent 74 (41) 45 (37) 119 (40) Other 9 (5) 8 (7) 17 (6) New cancer therapy added 23 (13) 24 (20) 47 (16) Event documented after 2 missing adequate response assessments 36 (20) 28 (23) 64 (21) Total number of censored patients used as denominator to calculate percent rates for each censoring reason.
81 Duration of Exposure and PFS in BTZ Phase III Trials Medians EF-87 Duration of exposure (median) PFS/TTP (median) Time (months) APEX 1 MMY Vantage Moreau Study D2308: PBO-BTZ-Dex PAN-BTZ-Dex 1. Richardson 2005 & 2007; 2. Orlowski 2007; 3. Dimopoulos 2012; 4. Moreau 2011
82 EF-94 Post-treatment Anti-neoplastic Therapy (1) Study D2308 PAN+BTZ+Dex N = 387 % PBO+BTZ+Dex N = 381 % Total Alkylators Cyclophosphamide Melphalan 5 7 Bendamustine 2 4 Bendamustine hydrochloride IMIDs Lenalidomide Thalidomide 7 7 Pomalidomide 0 0.3
83 EF-174 PFS by Investigator Assessment (mebmt criteria) at 18 Weeks by CR/nCR and Responders Study D PAN Treatment Group, Full Analysis Set 100 Events, n/n Median PFS, mo Progression-free Survival probability, % CR/nCR PR CR/nCR 40/ PR 77/ Time, months Patients at risk CR/nCR PR
84 Median PFS, months IRC-11 PFS Sensitivity Analyses Study D2308 Consistent HR Across All Analyses Conducted PAN+BTZ+Dex PBO+BTZ+Dex HR (95%CI) Primary analysis a (0.52, 0.76) IRC Assessment (0.52, 0.76) Per Protocol (INV) (0.49, 0.75) Per Protocol (IRC) (0.48, 0.74) Pts w M-protein (0.51, 0.78) HR All analyses include a requirement for PD confirmation per mebmt criteria P value <.0001 for all sensitivity analyses.
85 IRC-18 Drop out and censoring Study D2308 PAN+BTZ+ Dex N = 387 Patients, n (%) PBO+BTZ+ Dex N = 381 All N = 768 Total number of censored patients* 180 (47) 121 (32) 301 (39) Ongoing 35 (19) 15 (12) 50 (17) Adequate response assessment not available 86 (48) 54 (45) 140 (47) Lost to follow-up 3 (2) 1 (1) 4 (1) Withdrew consent 74 (41) 45 (37) 119 (40) Other 9 (5) 8 (7) 17 (6) Administrative problems 7 (4) 5 (4) 12 (4) Disease progression (clinical) 2 (1) 1 (1) 3 (1) Protocol Deviation 0 (0) 2 (2) 2 (1) New cancer therapy added 23 (13) 24 (20) 47 (16) Event documented after 2 missing adequate response assessments *Total number of censored patients used as denominator to calculate percent rates for each censoring reason. 36 (20) 28 (23) 64 (21)
86 IRC-20 PFS Sensitivity Analyses Study D2308 Consistent HR Across All Analyses Conducted Sensitivity analysis Median PFS, months PAN+BTZ+Dex PBO+BTZ+Dex HR (95%CI) Primary analysis (0.52, 0.76) Actual event a (0.56, 0.79) Alternative Censoring methods Backdating date b (0.58, 0.81) Hazard ratio (95% CI) P value <.0001 for all sensitivity analyses. a Includes the event whenever it occurred even after 2 missing adequate assessments. b Uses the date of next scheduled assessment for events occurring after 1 missing adequate assessment.
87 Last adequate response assessment of patients censored due to withdrawal of consent Study D2308 IRC-31 Last adequate response assessment PAN+BTZ+Dex N = 74 n (%) PBO+BTZ+Dex N = 45 n (%) Complete response (CR) 3 ( 4.1) 2 ( 4.4) Near-complete response (ncr) 8 (10.8) 4 ( 8.9) Partial response (PR) 31 (41.9) 16 (35.6) Minimal response (MR) 8 (10.8) 2 ( 4.4) No change (NC) 1 ( 1.4) 6 (13.3) No adequate assessment 23 (31.1) 15 (33.3)
88 IRC-32 Reasons for end of treatment for patients censored due to withdrawal of consent Study D2308 PAN+BTZ+Dex N = 74 n (%) PBO+BTZ+Dex N = 45 n (%) Discontinued treatment due to AE 36 (48.6) 22 (48.9) Discontinued treatment due to WOC 29 (39.2) 14 (31.1) Discontinued treatment due to protocol deviations Discontinued treatment due to administrative problems Discontinued treatment due to abnormal test procedures 4 (5.4) 4 (8.9) 1 (1.4) 0 (0) 1 (1.4) 2 (4.4) Treatment completed as per protocol 3 (4.0) 3 (6.7)
89 Censoring reason for patients censored at Day 1 Study D2308 IRC-33 PAN+BTZ+Dex N = 50 n (%) PBO+BTZ+Dex N = 37 n (%) Ongoing 1 (2) 1 (3) Lost to follow-up 0 (0) 0 (0) Withdrew consent* 23 (46) 15 (41) Other 4 (8) 2 (5) New cancer therapy added 5 (10) 5 (14) Event documented after 2 missing adequate response assessments 17 (34) 14 (38) *Median Duration from randomization until WOC date 1.4 mo 2.0 mo
90 IRC-35 Last adequate response assessment of patients censored due to event after >= 2 missing assessments Study D2308 Last adequate response assessment PAN+BTZ+Dex N = 36 n (%) PBO+BTZ+Dex N = 28 n (%) Complete response (CR) 1 (2.8) 0 (0.0) Near-complete response (ncr) 2 (5.6) 1 (2.8) Partial response (PR) 12 (33.3) 9 (32.1) Minimal response (MR) 4 (11.1) 3 (10.7) No change (NC) 0 (0.0) 1 (3.6) No adequate assessment 17 (47.2) 14 (50.0) Median time from last response assessment until actual event date 107 days 116 days
91 IRC-41 Last adequate response assessment in patients considered event in worst case analysis (discontinuation due to AE) Study D2308 Last adequate response assessment PAN+BTZ+Dex N = 101 n (%) PBO+BTZ+Dex N = 64 n (%) Complete response (CR) 7 ( 6.9) 1 ( 1.6) Near-complete response (ncr) 14 (13.9) 5 ( 7.8) Partial response (PR) 41 (40.6) 27 (42.2) Minimal response (MR) 8 ( 7.9) 4 ( 6.3) No change (NC) 0 ( 0.0) 4 ( 6.3) No adequate assessment 31 (30.7) 23 (35.9)
92 Time from treatment discontinuation due to AE until end of disease follow-up Study D2308 Patients who discontinued due to AE [days] PAN+BTZ+Dex N=130 PBO+BTZ+Dex N=66 n Mean Median (Min, Max) 52 (0, 631) 29 (0, 955) IRC-43
93 Illustrative Patient from Study D2308 Assessment of Response by Investigator and IRC IRC-47 M-protein by spep in g/dl 3.5 Baseline Nadir Jul 2011 Oct 2011 INV PR PR PR PR PR PR PR PR PD PD IRC PR PR PR PD PR PR PR PR PD PD
94 PFS - Sensitivity Analyses Analysis of PFS with Investigator and IRC assessments IRC-48 spep in g/dl 3.5 Baseline Nadir 0.5 Primary Analysis (INV) PFS event Median PFS (months) PAN PBO Investigator assessed PFS as confirmed PD per mebmt Initial Analysis with IRC PFS event Incorrect analysis, counting PFS despite unconfirmed PD Analysis with IRC (with confirmation) PFS event Correct analysis, counting PFS with confirmed PD per mebmt
95 Three PRO instruments were administered in the PANORAMA-1 trial QL-2 General cancer-specific quality of life and functioning questionnaire (EORTC-QLQ-C30), 18 measures Myeloma-specific quality of life module (QLQ-MY20),4 measures Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity (FACT/GOG-Ntx), 5 measures Instruments were administered at screening, cycle1 day1 and every 6 weeks thereafter, while patients were on treatment Due to missing data patient reported outcome results should be interpreted with caution
96 PANORAMA-1 HR-QoL Summary of Results QL-3 FACT/GOG-Ntx neurotoxicity subscale was similar in both treatment arms, suggesting no difference in symptoms of peripheral neuropathy Initial improvement followed by stabilization in the myeloma specific disease symptom score (QLQ-MY20) with no difference between arms EORTC QLQ-C30 Global Health Score declined initially in both treatment arms Larger decline in the PAN+BTZ+Dex arm Recovery toward baseline scores observed in both arms after week 18 EORTC QLQ-C30 Symptom scores (diarrhea, fatigue, appetite loss) worsened initially in both treatment arms Increased worsening in the PAN+BTZ+Dex arm At all time points EORTC QLQ-C30 Global Health Scores were found to be associated with toxicity
97 QL-10 Comparison with APEX Trial APEX Trial BTZ vs. DEX PANORAMA-1 High dose dexamethasone was used in the APEX trial Bortezomib single agent; no dexamethasone Improvement could be attribute to experience in clinical practice
98 Multivariate Risk Factors Analysis using Toxicity Index Risk Factors Included in the Model SA-92 Covariates Age Gender Race Description < 65 years vs. 65 years Male vs. Female Asian vs. Caucasian vs. Other ECOG performance status 0 vs. 1 Prior stem cell transplant Yes vs. No Prior lines of multiple myeloma therapy 1 vs. > 1 Baseline platelet count Baseline hemoglobin Baseline neutrophil count 150 x 10 9 /L vs. >150 x 10 9 /L* 123 g/l vs. >123 g/l* 1.8 x 10 9 /L vs. >1.8 x 10 9 /L* *Cut-off is determined based on median lower limit of normal
99 Multivariate Risk Factors Analysis using Toxicity Index All-grade Clinically Notable AE and On-treatment Deaths SA-94 Significant increase in toxicity in elderly and pts with low baseline platelet count Baseline Age Platelet Count 5 Mean Toxicity Index (95 % CI) < <150 (years) (x 10 9 /L) (Factors significant at nominal two-sided 5% p-value)
100 Relative Dose Intensity by Treatment Cycle in PAN+BTZ+Dex Study D2308 SO-6 Median Relative dose intensity % 100 PAN BTZ Treatment Cycles Patients at risk at the start of each cycle: N QC by TD D2308 CSR Table
101 SO-10 Patients with 90% Relative Dose Intensity of PAN by Treatment Cycle in PAN+BTZ+Dex Study D PAN % of patients with RDI 90% Treatment Cycle N QC by TD ODAC table
102 SO-28 Summary of Dose Modification Study D2308 AE/Grade PAN/placebo BTZ Thrombocytopenia G3 with bleeding or G4 Neutropenia (ANC) ANC < G4 neutropenia (ANC <0.5) G3 febrile neutropenia Anemia G2, G3/4 Diarrhea G2, G3, G4 Peripheral neuropathy Herpes zoster reactivation Non-hematologic AEs (GI, fatigue, LFTs, total bilirubin) Other non-hematologic toxicity G2 Other non-hematologic toxicity G2
103 Median (days) Study B2207: Endpoint by Dose Cohort Duration of treatment (median) Dose Expansion 2 wks on/ 1 wk off 159 PAN dose (mg/day) SO n=7 n=7 n=17 n=9 n=7 n=15 BTZ dose (mg/m 2 ) QC by TD B2207 CSR Table 12-1, 12-2
104 Patients with 90% Relative Dose Intensity by Treatment Cycle SO-73 Median relative dose intensity % Treatment cycle PAN+BTZ+Dex: PAN PAN+BTZ+Dex: BTZ PBO+BTZ+Dex: BTZ N QC by TD ODAC table
105 Median dose intensity of BTZ in PBO+BTZ+Dex arm by treatment cycle Study D2308 SO-75 Bortezomib dose (mg/m^2/day) Treatment Cycle BTZ: DI of 0.24 mg/m 2 /day corresponds to 1.3 mg/m 2 twice-a-week on same schedule
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