Rituximab + Lenalidomide for Patients With Previously Untreated CLL: Phase II ● Patients with previously untreated CLL (n = 69) – Patients younger than 65 yrs of age: n = 40 – Patients 65 yrs of age or older: n = 29 ● Primary endpoint: CR in patients <65 yrs vs. > 65 yrs ● Secondary endpoints – Safety, ORR, PFS James DF, et al. ASH 2011. Abstract 291.
Rituximab + Lenalidomide in Previously Untreated CLL: Study Design ● Treatment protocol: 7 cycles – Cycle 1: lenalidomide on 21 of 35 days – Cycles 2-7: lenalidomide on 21 of 28 days Lenalidomide – Day 1: Starting dose: 2.5 mg/day Rituximab – 50 mg/m2 on Day 29 of C 1 – 325 mg/m2 on Day 31 of C 1 – Day 8: Escalated to 5 mg/day – 375 mg/m2 on Day 33 of C 1 – Day 1 cycle 3: increase to 10 mg/day – 375 mg/m2/wk x 4 for cycle 2 – 375 mg/m2 on Day 1 of C 3-7 Tumor lysis syndrome prophylaxis with allopurinol 300 mg/day and oral hydration Thromboprophylaxis (aspirin 81 mg/day) added after 2 cases of pulmonary embolism Methylprednisolone for tumor flare reaction and growth factor support as needed James DF, et al. ASH 2011. Abstract 291.
ML21445: Efficacy ● ● No correlation between treatment response and standard prognostic factors Pretreatment gene expression differed between responders and nonresponders – Up-regulation of transcripts relevant to pro-proliferative and antiapoptotic pathways, including Ras (K-Ras, N-Ras) and Rho – Up-regulation of genes related to protein metabolism – CD20 down-regulation detected by gene profiling (P = .018 vs responders) but not by flow cytometry (P = .19 vs responders) Foa R, et al. ASH 2011. Abstract 294.
Identifying High Risk for Progression in CLL Patients Receiving FCR ● CLL8 study: FC vs FCR as primary CLL therapy – Median 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 mutations ● MRD, IgVH unmutated status, shorter PFS Elevated β2-microglobulin or high WBC count not predictive of short PFS 1.. Hallek M, et al. Lancet. 2010;376:1164-1174. 2. Boettcher S, et al. ASH 2008. Abstract 326. 3. Stilgenbauer S, et al. ASH 2008. Abstract 781.
Identifying 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 progression – MRD levels > 10-2 or – MRD levels > 10-4 to < 10-2 plus either ● del(17p), TP53 mutation, or IgVH unmutated status Fink A, et al. ASH 2011. Abstract 977. 1.. Hallek M, et al. Lancet. 2010;376:1164-1174
Identifying High Risk for Progression in CLL Patients Receiving FCR: PFS and OS ● Survival outcomes significantly better in patients with CLL and low risk – – Median PFS in low-risk vs high-risk patients ● 69 vs 22 months ● HR: 6.4 (95% CI: 3.97-10.347; P < .0001) Median OS in low-risk vs high-risk patients ● Not reached vs 57 mos ● HR: 5.758 (95% CI: 2.799-11.844; P < .0001) Fink A, et al. ASH 2011. Abstract 977.
Summary ● ● ● ● Rituximab + 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 cohort Rituximab + chlorambucil induction therapy active, well tolerated in elderly patients with previously untreated CLL In patients with CLL receiving FCR, cytogenetic analysis plus MRD detection identifies patients at high risk of disease progression Lenalidomide + 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 disease
Rationale for Targeting PI3K-δ in CLL • PI3-kinase active in CLL vs normal B-cells • PI3K-δ inhibition in CLL cells promotes ↑ Apoptosis ↓ Proliferation ↓ Chemokines ↓ Microenvironment response Herman S et al: Blood 2010 Lanutti B, et al: Blood 2011
Where is GS-1101 Going in CLL? ● Completion of phase I or II studies in untreated and relapsed CLL – GS-1101 +combinations (Sharman et al. Abstract # 1787) ● Registration studies in CLL ● OHSU expects to have: – GS1101 (CAL-101) registration trial for relapsed CLL – Novel combinations with other kinase inhibitors
The Bruton’s Tyrosine Kinase (BTK) Inhibitor PCI-32765 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, MD2 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX2Division of Hematology and The Department of Pathology, The Ohio State University, Columbus, OH3Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY4Divisions of Hematology and Oncology and Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA5US Oncology, Springfield, OR6Sarah Cannon Research Institute, Nashville, TN7Medicine, Vermont Cancer Center, University of Vermont, Burlington, VT8Pharmacyclics, Inc, Sunnyvale, CA 1
Dasatinib in CLL at OHSU Can we predict who will respond to treatment? ● Dasatinib Clinical Trial (NCT01441882) – Relapsed/refractory of if age > 70, Tx naive – Test patient CLL samples in the lab – Only enroll patients on trial if the drug first demonstrates in vitro killing activity – Measure cell death signaling pathways – Examine signaling and gene expression in vivo while receiving treatment
Summary: Targeting BCR signaling in CLL ● ● ● ● ● Promising activity including in poor risk patients Most effective for nodal disease Often results in lymphocytosis as CLL cells are mobilized from the micro-environement Well tolerated, oral agents Studies to predict response and with novel combinations are ongoing
MCL: Poor Prognosis and Long–Term Outcome 18 months Patients at risk R-CHOP 58 CHOP 44 45 35 28 17 15 10 5 3 1 Progression-free survival after CHOP and R-CHOP There were no significant differences between the two treatment arms (P=0.31) Lenz G. et al. J Clin Oncol. 2005;23:1984-1992.
R-CHOP vs R-FC followed by maintenance with Rituximab vs. Interferon-alfa in elderly patients with Mantle cell lymphoma Hanneke C. Kluin-Nelemans for the European MCL Network University Medical Center Groningen The Netherlands
RCT for MCL Elderly European First MCL Network 8 countries, n = 560 (Jan 2004-Oct 2010) Newly diagnosed, >60-65 yr; performance 0-2, Stages II-IV, central PA review 8 x R-CHOP IFN-a maintenance (3 x 3 M IU/week) or Peg-IFN (1mg/kg week) PR, CR 6 x R-FC Rituximab maintenance (all 2 months)
Phase I/II Study of Vorinostat (SAHA), Cladribine (2-CdA), and Rituximab Shows Significant Activity in Previously Untreated Mantle Cell Lymphoma Stephen 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 PhD2 1. Knight Cancer Institute at Oregon Health & Science University, Portland, OR 2. Penn State Hershey Cancer Institute, Hershey, PA 3. Albert Einstein College of Medicine, Bronx, NY
Study 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 lymphomas1 – ● increases tumor suppressor gene expression when combined with a hypomethylating agent2-4 Cladribine and HDAC inhibition are synergistic as evidenced by increased in vitro apoptosis in primary CLL cells.5 1. Human Pathology 2007;38(12):1849-1857 2. 3. 4. 5. J Clin Oncol. 2011 Mar 20;29(9):1198203. Cancer Sci. 2010 (1):196-200 Blood. 2010 Aug 19;116(7):1025-34 Br J Haematol. 2009 Jan;144(1):41-52.
Summary: Mantle Cell Lymphoma ● ● • • Induction therapy with R-CHOP vs R-FC favors R-CHOP: more overall responses, less toxicity Rituximab maintenance doubles the remission duration in patients responding upon initial therapy Vorinostat , cladribine , and rituximab is safe and effective regimen for lymphoid malignancies • All previously untreated MCL patients responded • 75% CR PCI-32765 active and well tolerated in relapsed MCL
Tumor Microenvironment ● ● CLL cells – Migrate to stromal cell layer which is protective – Secrete CCL3 and CCL4 which attracts T cells Lymph Nodes – ● CD40L engaged with CD40 on T-cells More sensitive to chemotherapy if removed from protective niche
Nurse-like cells ● Marrow stromal cells and nurse like cells – Secrete CXCL 12 and CXCL 13 – Attract CLL cells (via chemokine receptors CXCR4 and CXCR5) * Nishio M et al. Blood 106:1012-20, 2005 ¶ Burkle A et al. Blood 110:3316-25, 2007 † Burger JA et al. Blood 96, 2655-63, 2000 ‡ Deaglio S et al. Blood 105(8):3042-50, 2005
● ● ● Distinct differences between node and peripheral blood Increased expression of CCL3 and CCL4 in lymph nodes Increased expression of MYC Y Herishanu et al., Blood. 2011 Jan 13;117(2):563-74 JA Burger et al. Blood. 113(13):3050-8, 2009
A 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. Miller11 1US 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, WA Reference: Sharman, ASH 2011, #1787
G Mono (N=55) G+R (N=19) 100 80 84% n=46 84% n=16 84% n=16 LNR OR 60 G+F (N=7) G+B (N=14) 71% n=5 71% n=5 LNR OR 79% n=11 79% n=11 G+R+B (N=14) 86% n=12 86% n=12 LNR OR 40 20 24% n=13 b 0 a ITT Responsea Rate 95% CI GS-1101 Combination Therapies Substantially Increased Overall Response Rate a b Decrease by 50% in the nodal SPD Response by IWCLL criteria [Hallek 2008] LNR OR