3CLL: Pertinent Topics ASH treatment updates FCR treatment expectations James DF, et al. ASH Abstract 291.Foa R, et al. ASH Abstract 294.Badoux XC, et al. ASH Abstract 980.FCR treatment expectationsFink A, et al. ASH Abstract 977.Rational therapeutic targets and novel agents
4Rituximab + Lenalidomide for Patients With Previously Untreated CLL: Phase II Patients with previously untreated CLL (n = 69)Patients younger than 65 yrs of age: n = 40Patients 65 yrs of age or older: n = 29Primary endpoint: CR in patients <65 yrs vs. > 65 yrsSecondary endpointsSafety, ORR, PFSCLL, chronic lymphocytic leukemia; CR, complete response; ORR, overall response rate; PFS, progression-free survival.James DF, et al. ASH Abstract 291.
5Rituximab + Lenalidomide in Previously Untreated CLL: Study Design Treatment protocol: 7 cyclesCycle 1: lenalidomide on 21 of 35 daysCycles 2-7: lenalidomide on 21 of 28 daysRituximab50 mg/m2 on Day 29 of C 1325 mg/m2 on Day 31 of C 1375 mg/m2 on Day 33 of C 1375 mg/m2/wk x 4 for cycle 2375 mg/m2 on Day 1 of C 3-7LenalidomideDay 1: Starting dose: mg/dayDay 8: Escalated to 5 mg/dayDay 1 cycle 3: increase to mg/dayCLL, chronic lymphocytic leukemia.Tumor lysis syndrome prophylaxis with allopurinol 300 mg/day and oral hydrationThromboprophylaxis (aspirin 81 mg/day) added after 2 cases of pulmonary embolismMethylprednisolone for tumor flare reaction and growth factor support as neededJames DF, et al. ASH Abstract 291.
6Rituximab + Lenalidomide for Patients With Previously Untreated CLL: Efficacy OutcomeYounger Than 65 Yrs (n = 40)65 Yrs or Older (n = 29)ORR, %CRCRiNodular PRPR952055787468PDMedian PFS, mosMedian follow-up191817CLL, chronic lymphocytic leukemia; CR, complete response; CRi, CR with incomplete hematopoietic recovery; ECOG, Eastern Cooperative Oncology Group; ORR, overall response rate; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.ORR associated with higher median lenalidomide dose in younger patients (P = .05)Greater exposure to lenalidomide in younger patients vs older patientsJames DF, et al. ASH Abstract 291.
7Rituximab + Lenalidomide for Patients With Previously Untreated CLL: Toxicity AEs, %Younger Than 65 Yrs (n = 40)65 Yrs or Older (n = 29)Any toxicityGrade 1/2Grade 3/433651769Nonhematologic toxicity63353845Tumor flare reactionNoYes1883*4159AE, adverse event; CLL, chronic lymphocytic leukemia.*P = .05 vs older patients.James DF, et al. ASH Abstract 291.
8ML21445: Rituximab + Chlorambucil Induction Therapy in Elderly Patients Patients with previously untreated CLL (N = 97)Ineligible for first-line R-FC8 cycles (q 28 days)Primary endpoint: ORR at end of inductionobservationChlorambucil 8 mg/m2/dayDays 1-7PR, CRRituximab375 mg/m2 Day 1 of cycle 3500 mg/m2 on Day 1 > C4R 375 mg/m28 wks for 12 dosesCLL, chronic lymphocytic leukemia; ORR, overall response rate; R-FC, rituximab/fludarabine/cyclophosphamide.Foa R, et al. ASH Abstract 294.
9ML21445: Responses Response Following Induction, % Patients (ITT) ORRAll patients81.2Binet stage A86.0Binet stage B80.0Binet stage C79.060-64 yrs of age84.065-69 yrs of age85.070-74 yrs of age or older75.075 yrs of age81.0Response Following Induction, %Patients (ITT)(N = 85)CR/CRi19PR60.0PD3.5CLL, chronic lymphocytic leukemia; CR, complete response; CRi, CR with incomplete bone marrow recovery; ITT, intent to treat; MRD, minimal residual disease; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease.*By flow cytometry.Foa R, et al. ASH Abstract 294.
10ML21445: EfficacyNo correlation between treatment response and standard prognostic factorsPretreatment gene expression differed between responders and nonrespondersUp-regulation of transcripts relevant to pro-proliferative and antiapoptotic pathways, including Ras (K-Ras, N-Ras) and RhoUp-regulation of genes related to protein metabolismCD20 down-regulation detected by gene profiling (P = .018 vs responders) but not by flow cytometry (P = .19 vs responders)CLL, chronic lymphocytic leukemia; IgVH, immunoglobulin heavy-chain variable region.Foa R, et al. ASH Abstract 294.
11ML21445: ToxicityChlorambucil dose reduction required in 7.8 % of cyclesGrade 3/4 Hematologic AEs during induction:Neutropenia: 19.6%Thrombocytopenia: (1.0%)Infections: (1.0%)Grade 3/4 neutropenia during maintenance:11.8% with rituximab vs 3.1% on observationAE, adverse event; CLL, chronic lymphocytic leukemia; SAE, serious adverse event.Foa R, et al. ASH Abstract 294.
12Identifying High Risk for Progression in CLL Patients Receiving FCR CLL8 study: FC vs FCR as primary CLL therapyMedian PFS: 57.9 mos FCR vs 32.9 mos FC (P < .0001)OS dependent on length (< vs ≥ 2 yrs) of PFS (P < .001)shortened PFS:del(17p) + TP53 mutationsMRD, IgVH unmutated status, shorter PFSElevated β2-microglobulin or high WBC count not predictive of short PFSCLL, chronic lymphocytic leukemia; FC, fludarabine, cyclophosphamide; FCR, fludarabine, cyclophosphamide, rituximab; IgVH, immunoglobulin heavy-chain variable region; MRD, minimal residual disease; OS, overall survival; PFS, progression-free survival; WBC, white blood cell.1.. Hallek M, et al. Lancet. 2010;376: Boettcher S, et al. ASH Abstract Stilgenbauer S, et al. ASH Abstract 781.
13Identifying High Risk for Progression in CLL Patients on FCR: Study Design Subset analysis of GCLL CLL8 randomized phase III trial (FC vs. FCR)FCR-treated patients from CLL8 with short PFS and MRD at final restaging (N = 143)Definition of high risk for early progressionMRD levels > 10-2 orMRD levels > 10-4 to < 10-2 plus eitherdel(17p), TP53 mutation, or IgVH unmutated statusCLL, chronic lymphocytic leukemia; FCR, fludarabine, cyclophosphamide, rituximab; GCLLSG, German CLL Study Group; HR, hazard ratio; IgVH, immunoglobulin heavy-chain variable region; MRD, minimal residual disease; OS, overall survival; PFS, progression-free survival.Fink A, et al. ASH Abstract 977.1.. Hallek M, et al. Lancet. 2010;376:
14Identifying High Risk for Progression in CLL Patients Receiving FCR: PFS and OS Survival outcomes significantly better in patients with CLL and low riskMedian PFS in low-risk vs high-risk patients69 vs 22 monthsHR: 6.4 (95% CI: ; P < .0001)Median OS in low-risk vs high-risk patientsNot reached vs 57 mosHR: (95% CI: ; P < .0001)CI, confidence interval; CLL, chronic lymphocytic leukemia; FCR, fludarabine, cyclophosphamide, rituximab; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.Fink A, et al. ASH Abstract 977.
16Lenalidomide + Rituximab Combination Therapy in Relapsed/Refractory CLL Patients with relapsed/refractory CLL (N = 59)Treatment protocol: 28-day cyclesRituximab 375 mg/m2Cycle 1: Days 1, 8, 15, 22Cycle 2: no administrationCycles 3-12: Day 1Lenalidomide 10 mg/day starting Day 9Allopurinol 300 mg orally Days 1-14 for tumor lysis prophylaxisPrimary endpoint: ORRITT analysisAssessed at end of cycles 3, 6, then Q 6 monthsCLL, chronic lymphocytic leukemia; ITT, intent to treat; ORR, overall response rate.Badoux XC, et al. ASH Abstract 980.
17Lenalidomide + Rituximab Combination in Relapsed/Refractory CLL: Efficacy Lenalidomide/rituximab responses not correlated with disease biologyRai stage, bulky disease, cytogenetics by FISH: correlation insignificantFludarabine refractory patients do worseLower ORR (P < .05)Shorter PFS (P = .019)ATM, ataxia telangiectasia mutated gene; CLL, chronic lymphocytic leukemia; FISH, fluorescence in situ hybridization; ORR, overall response rate; PFS, progression-free survival.Badoux XC, et al. ASH Abstract 980.
18Lenalidomide + Rituximab Combination in Relapsed/Refractory CLL: Toxicity Grade 3/4 AEs, n (%)Patients (N = 59)Neutropenia43 (73)Thrombocytopenia20 (35)Anemia9 (15)Any infection14 (24)Pneumonia/bronchitis6 (10)Febrile neutropeniaHypercalcemia*1 (2)Gastrointestinal3 (5)Tumor lysisVTEPainWeaknessArrhythmiaFrequent grade 1/2 AEsFatigue (37%)Diarrhea (36%)Tumor flare (27%)Sensory neuropathy (24%)Rash (22%)4 patients experienced secondary malignancies on treatmentMyelodysplastic syndrome: n = 1Squamous cell carcinoma: n = 1Melanoma in situ: n = 1Head/neck cancer recurrence: n = 1AE, adverse event; CLL, chronic lymphocytic leukemia; VTE, venous thromboembolism.Badoux XC, et al. ASH Abstract 980.
19SummaryRituximab + lenalidomide active, well tolerated in both younger and older patients (younger than 65 or 65 yrs or older) with previously untreated CLL but produced higher ORR and CR in the younger cohortRituximab + chlorambucil induction therapy active, well tolerated in elderly patients with previously untreated CLLIn patients with CLL receiving FCR, cytogenetic analysis plus MRD detection identifies patients at high risk of disease progressionLenalidomide + rituximab combination is active as salvage therapy for patients with relapsed/refractory CLL and has a manageable AE profile; response rates were lower among patients with fludarabine-refractory diseaseCLL, chronic lymphocytic leukemia; CR, complete response; FCR, fludarabine, cyclophosphamide, rituximab; MRD, minimal residual disease; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; R-FC, rituximab/fludarabine/cyclophosphamide; SLL, small lymphocytic lymphoma.
20CLL is a Complex Disease Diagram courtesy of Jan Burger
21Therapeutic targeting of the BCR Signaling Pathway Stevenson et al. Blood
22Rationale for Targeting PI3K-δ in CLL PI3-kinase active in CLL vs normal B-cellsPI3K-δ inhibition in CLL cells promotes↑ Apoptosis↓ Proliferation↓ Chemokines↓ MicroenvironmentresponseHerman S et al: Blood 2010Lanutti B, et al: Blood 2011
24CAL-101 (GS-1101) Response in CLL Coutre S, et al: ASCO 2011
25Patient B.C. Diagnosed with CLL in 2002 70 year old man with relapsed bulky CLLSince 2005:8 treatment regimens2010 progressive disease
26Refractory CLL-after 1cycle of CAL-101Refractory CLL-pre treatment
27GS-1101 Progression Free Survival Coutre S, et al: ASCO 2011
28GS-1101 Grade 3-4 ToxicityCoutre S, et al: ASCO 2011
29Where is GS-1101 Going in CLL? Completion of phase I or II studies in untreated and relapsed CLLGS combinations (Sharman et al. Abstract # 1787)Registration studies in CLLOHSU expects to have:GS1101 (CAL-101) registration trial for relapsed CLLNovel combinations with other kinase inhibitors
30The Bruton’s Tyrosine Kinase (BTK) Inhibitor PCI Induces Durable Responses in Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Follow-up of a Phase Ib/II Study(abstract # 983)Susan O'Brien, MD1, Jan A. Burger, MD, PhD1, Kristie A. Blum, MD2, Richard R. Furman, MD3, Steven E. Coutre, MD4, Jeff Sharman, MD5, Ian W. Flinn, MD, PhD6, Barbara Grant, MD7, Nyla A. Heerema, PhD2, Amy J. Johnson, PhD2, Tasheda Navarro8, Eric Holmgren, PhD8, Eric Hedrick, MD8 and John C. Byrd, MD21Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 2Division of Hematology and The Department of Pathology, The Ohio State University, Columbus, OH 3Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY 4Divisions of Hematology and Oncology and Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA 5US Oncology, Springfield, OR 6Sarah Cannon Research Institute, Nashville, TN 7Medicine, Vermont Cancer Center, University of Vermont, Burlington, VT 8Pharmacyclics, Inc, Sunnyvale, CA
38Common AEs (All Grades) Events occurring in > 15% of Patients (n=61)
39Grade 3/4 Infectious and Hematologic Toxicity Grade 3/4 Hematology toxicity 1420 mg/d(n=27)840 mg/d(n=34)NeutropeniaAnemiaThrombocytopeniaGrade 3 Grade 44% %7% %0% %12% %9% %9% %Grade 3/4 Infectious toxicity420 mg/d(n=27)840 mg/d(n=34)Patients with any Grade 3/4 (%, %)5/2 (19%, 7%)9/1 (26%, 3%)1 Reported as AEs
40Dasatinib in CLL Inhibits SRC, LYN, BTK Results published on 15 relpased/refractory patientsORR 20%Nodal response 66%Can we do better?Amrein et al. Clinical Cancer Research 2011
41Dasatinib in CLL at OHSU Can we predict who will respond to treatment? Dasatinib Clinical Trial (NCT )Relapsed/refractory of if age > 70, Tx naiveTest patient CLL samples in the labOnly enroll patients on trial if the drug first demonstrates in vitro killing activityMeasure cell death signaling pathwaysExamine signaling and gene expression in vivo while receiving treatment
42C-F: Response to treatment C-F pretreatment scanC-F after 6 months of dasatinib
43CF Response to treatment Lymphocyte Count93 % changefrom baseline
44Summary: Targeting BCR signaling in CLL Promising activity including in poor risk patientsMost effective for nodal diseaseOften results in lymphocytosis as CLL cells are mobilized from the micro-environementWell tolerated, oral agentsStudies to predict response and with novel combinations are ongoing
45Mantle Cell Lymphoma Role of Rituximab R-Cladribine Based Treatment Kluin-Nelemans, et al. ASH Abstract 439R-Cladribine Based TreatmentSpurgeon, et al. ASH Abstract 441PCI in Mantle Cell LymphomaWang, et al. ASH Abstract 442
46MCL: Poor Prognosis and Long–Term Outcome 18 monthsMCL: Poor Prognosis and Long-Term OutcomeThe German Low Grade Lymphoma Study Group initiated a randomized trial (128 patients) comparing R-CHOP with CHOP as first-line therapy.1R-CHOP was superior to CHOP in terms of:Overall response rate 94% vs 75%; P=.0054)Complete response rate (34% vs. 7%; P=.00024)Time to treatment failure (median 21 vs 14 months; P=.0131).1However, induction therapy with R-CHOP did not translate into prolonged PFS vs CHOP (P=0.31).1In addition, there were no significant differences observed for overall survival.Along with R-HyperCVAD, R-CHOP is considered a standard of care for the initial treatment of MCL patients.2R-CHOP is listed in NCCN guidelines as a treatment option for front-line MCL. R-EPOCH and R-HyperCVAD are also listed in NCCN guidelines for initial treatment of MCL.2ReferencesLenz G, et al. J Clin Oncol. 2005:23;National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Non-Hodgkin’s Lymphomas. VPatients at riskR-CHOPCHOPProgression-free survival after CHOP and R-CHOPThere were no significant differences between the two treatment arms (P=0.31)Lenz G. et al. J Clin Oncol. 2005;23:
47Possible Improved Survival in Elderly Patients Receiving Rituximab Percentage SurvivingGriffiths, R, et. al. Blood 2011 Nov 3;118(18):
48R-Maintenance SAKK GLSG Modified R-HyperCVAD NO BENEFIT after R inductionGLSGPFS BENEFIT after R-FCM inductionModified R-HyperCVAD2 years of R-MaintenancePFS = 37 monthsMedian OS = 70 months1. Ghielmini M, et al. J Clin Oncol. 2005, 2. Forstpointner, R, et al. Blood 2006) , 3. (Kenkre, V, et al. Leuk Lymphoma 2011)
49R-CHOP vs R-FC followed by maintenance with Rituximab vs R-CHOP vs R-FC followed by maintenance with Rituximab vs. Interferon-alfa in elderly patients with Mantle cell lymphomaHanneke C. Kluin-Nelemansfor the European MCL NetworkUniversity Medical Center GroningenThe Netherlands
50First RCT for MCL Elderly 8 countries, n = 560 (Jan 2004-Oct 2010) European MCL NetworkFirst RCT for MCL Elderly 8 countries, n = 560 (Jan 2004-Oct 2010)Newly diagnosed, >60-65 yr; performance 0-2, Stages II-IV, central PA review8 x R-CHOP6 x R-FCPR, CRIFN-a maintenance(3 x 3 M IU/week)or Peg-IFN(1mg/kg week)Rituximabmaintenance(all 2 months)
58R-cladribine based Therapies for MCL Median PFS 37.5 monthsMedian OS 85 monthsSpurgeon et. al, Leukemia & Lymphoma, 2011
59R-cladribine based Therapies for MCL Spurgeon et. al, Leukemia & Lymphoma, 2011
60Phase I/II Study of Vorinostat (SAHA), Cladribine (2-CdA), and Rituximab Shows Significant Activity in Previously Untreated Mantle Cell LymphomaStephen E. Spurgeon,MD1, David F. Claxton, MD2,W. Christopher Ehmann, MD2, Samir S. Parekh, MD,3 Violetta Leshchenko, PhD3, Motomi Mori, PhD2, Sara Shimko, BA,2 August Stewart, BA,2 Elliot M. Epner, MD PhD2Knight Cancer Institute at Oregon Health & Science University, Portland, ORPenn State Hershey Cancer Institute, Hershey, PAAlbert Einstein College of Medicine, Bronx, NY
61Study Rationale Cladribine has cytotoxic and epigenetic properties Vorinostat (SAHA):inhibits class I and II histone de-acetylases (HDAC)has shown clinical activity in B-cell lymphomas1increases tumor suppressor gene expression when combined with a hypomethylating agent2-4Cladribine and HDAC inhibition are synergistic as evidenced by increased in vitro apoptosis in primary CLL cells.5Human Pathology 2007;38(12):J Clin Oncol Mar 20;29(9):Cancer Sci (1):Blood Aug 19;116(7):Br J Haematol Jan;144(1):41-52.
62Inclusion Criteria Treatment Population Phase I: relapsed CD20+ NHL, CLLPhase II: Two cohortsRelapsed CD20+ NHL, CLLPreviously untreated MCL
63Primary Study Objectives Phase I● Safety and toxicityPhase II● Response rates● Tolerability and toxicity
64Secondary Objectives Progression free survival Overall survival DNA methylation, histone deacetylation, and changes in target gene expression
65Phase II dosing Phase I Responses were seen in MCL and SLL No MTD reachedResponses were seen in MCL and SLLPhase II vorinostat dose 400 mg/day, days 1-14cycle > 1 Rituximab once per cycle
66Phase II: Response in Relapsed Cohort (n =17) PopulationTotalITT Overall Response (%)MCL102 (20%)2 CRMZL32 (66%)1 CR, 1 PRFL11 PR (100%)Relapsed CLLNHL Response by Modified Cheson CriteriaCLL Response by IWCLL Criteria
67Phase II: Previously Untreated Mantle Cell Cohort ( n=21) Median Age (range) ( 42-87)CharacteristicNumber of Patients (%)Age > 60Stage IVBlastic HistologyMIPI*lowintermediatehighB2 M > 3.0 g/dl14 (70%)20 (95%)4 (19%)11 (52%)6 (29%)* Mantle Cell International Prognostic Index
69Phase II Toxicity: Most Prevalent Adverse Events Frequency (158 treatment cycles)HematologicNeutropeniaThrombocytopeniaAnemiaGr Gr. 450 (32%) (11%)32 (20%) (5%)8 (5%)Non HematologicFatigueInfectionGrade 5 Pulmonary Hemorrhage6 (4%)3 (2%)1 (1%)For both relapsed and untreated cohorts
74Summary: Mantle Cell Lymphoma Induction therapy with R-CHOP vs R-FC favors R-CHOP: more overall responses, less toxicityRituximab maintenance doubles the remission duration in patients responding upon initial therapyVorinostat , cladribine , and rituximab is safe and effective regimen for lymphoid malignanciesAll previously untreated MCL patients responded75% CRPCI active and well tolerated in relapsed MCL
76Tumor Microenvironment CLL cellsMigrate to stromal cell layer which is protectiveSecrete CCL3 and CCL4 which attracts T cellsLymph NodesCD40L engaged with CD40 on T-cellsMore sensitive to chemotherapy if removed from protective nicheCCL3/4 function: potent T cell chemokines that are secreted by normal B cells during GC reaction to attract T cells
77Nurse-like cells Marrow stromal cells and nurse like cells Secrete CXCL 12 and CXCL 13Attract CLL cells (via chemokine receptors CXCR4 and CXCR5)* Nishio M et al. Blood 106: , 2005¶ Burkle A et al. Blood 110: , 2007† Burger JA et al. Blood 96, , 2000‡ Deaglio S et al. Blood 105(8): , 2005
78Distinct differences between node and peripheral blood Increased expression of CCL3 and CCL4 in lymph nodesIncreased expression of MYCY Herishanu et al., Blood Jan 13;117(2):563-74JA Burger et al. Blood. 113(13):3050-8, 2009
79CCL3 and CCL4 levels affect prognosis Sivina M et al, Blood 117:1662-9, 2011
80A Phase 1 Study of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3K) Inhibitor, GS-1101 (CAL-101), in Combination with Rituximab and/or Bendamustine in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)Jeff Sharman1, Sven de Vos2, John P. Leonard3, Richard R. Furman3, Steven E. Coutre4, Ian W. Flinn5, Marshall T. Schreeder6, Jacqueline Barrientos7, Nina D. Wagner-Johnston8, Thomas E. Boyd9, Nathan Fowler10, Leanne M. Holes11, Harriet (Sissy) Peterman11, Brian J. Lannutti11, Dave M. Johnson11, Thomas M. Jahn11, Langdon L. Miller111US Oncology Research and Willamette Valley Cancer Institute and Research Center, Springfield, OR; 2University of California Los Angeles, Los Angeles, CA; 3Weill Cornell Medical College, New York, NY; 4Stanford University Cancer Center, Stanford, CA; 5Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN; 6Clearview Cancer Institute, Huntsville, AL; 7Long Island Jewish Medical Center, New Hyde Park, NY; 8Washington University, St. Louis, MO; 9US Oncology Research and Yakima Valley Memorial Hospital, Yakima, WA; 10University of Texas, MD Anderson Cancer and Research Center, Houston, TX; 11Gilead Sciences, Inc., Seattle, WAReference: Sharman, ASH 2011, #1787
81In Previously Treated CLL, GS-1101 (CAL-101) Has Been Evaluated as Monotherapy and in Combination TherapyPhase 1bMonotherapyStudyPhase 1bCombination StudyGS to 350 mgBIDGS or 150 mgBIDGS mgBIDGS or 150 mgBIDGS mgBID++++Rituximab 375 mg/m2 weeklyC1 and C2Fludarabine 40 mg/m2 P.O.Days 1 – 5C1 – C6Bendamustine 70 or 90 mg/m2Days 1 and 2C1 – C6Rituximab 375 mg/m2 D1C1 – C6+Bendamustine 70 or 90 mg/m2Days 1 and 2C1 – C6Switching gears now and taking a closer look at the GS-1101 experience in patients with previously treated CLL.Treatment parameters were the same as in patients with iNHLa single-agent dose-ranging study with doses from 50 mg to 350 mg BID and- a combination with either rituximab or bendamustine at the same doses for pts with iNHL.Here also, benefitting pts could roll over to an extension study in order to receive single-agent GS-1101 at the highest dose previously tolerated.Designs: Phase 1-2 dose-ranging trialsEndpoints: Recommended dosing regimen, safety, antitumor activityFollow-up: After 48 weeks, patients who continue to benefit can continue GS single-agent therapy on an extension study81
82ITT Responsea Rate 95% CI GS-1101 Combination Therapies Substantially Increased Overall Response RateITT Responsea Rate 95% CIG Mono(N=55)G+R(N=19)G+F(N=7)G+B(N=14)G+R+B(N=14)LNRORLNRORLNRORLNROROverall Response(OR)bLymph NodeResponse(LNR)aAlthough lymph node response were comparable in different treatment groups,combining GS-1101 withrituximabOr bendamustine significantly improved the overall responsea Decrease by 50% in the nodal SPDb Response by IWCLL criteria [Hallek 2008]82
83GS-1101 combination therapy: Median PFS not yet reached Both GS-1101 Monotherapy and Combination Therapy were Associated with Durable Tumor ControlGS-1101 Mono(N=55)G+RG+F(N=19)(N=7)G+BG+R+B(N=14)% Progression-freeCycles (4 weeks)This is relevant in a greater scheme:The Kaplan-Meyer plots here document the PFS for the different treatment groups.The solid curve represents the actual PFSThe dotted curve the hypothetical data, if the early and transient lymphocytosis would have been interpreted as progressionSince addition of bendamustine to GS-1101 basically abolishes the ALC elevation, the difference between the curves is less significant.GS-1101 monotherapy:Median PFS >12 monthsGS-1101 combination therapy:Median PFS not yet reached83
84Adverse Event Profiles Have Been Generally Consistent with the Known Safety Profiles of Each Agent Grade 3 Adverse Events(Regardless of Cause)% (n)MonoCombinationGS-1101(N=63)GS R (N=19)GS B (N=20)GS BR (N=13)AllComb.(N=52)Anemia10% (6)5% (1)10% (2)̶6% (3)Neutropenia11% (7)32% (6)25% (5)23% (3)27% (14)Febrile neutropenia2% (1)4% (2)Thrombocytopenia8% (5)15% (3)8% (1)10% (5)ALT/AST elevated22% (14)21% (4)30% (6)*19% (10)*Cardiac arrestColitisFatigue6% (4)Pneumonia/Pneumonitis13% (8)11% (2)35% (7)17% (9)Rash3% (2)8% (4)Sepsis* Only 1 pt experienced repeated ALT/AST elevations upon GS-1101 re-exposurePatients had a median age of with some pts in their late 30s or 40sThe majority of pts in all treatment groups had bulky disease,……and refractory disease was present in the majority of pts in the single-agent group……as well as in the group receiving combination treatment with bendamustineThe amount of prior therapies was high especially in the single-treatment group, with a range up to 15 prior therapiesAs seen with iNHL virtually all the pts have had prior therapies containing rituximaband many have had previous treatments with bendamustine84