The Single-Agent Bcl-2 Inhibitor ABT-199 (GDC-0199) In Patients With Relapsed/Refractory (R/R) Non-Hodgkin Lymphoma (NHL): Responses Observed In All Mantle Cell Lymphoma (MCL) Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1789-1789 ◽  
Author(s):  
Matthew S. Davids ◽  
John F. Seymour ◽  
John F. Gerecitano ◽  
Brad S. Kahl ◽  
John M. Pagel ◽  
...  
Keyword(s):  
Medical Research ◽  
Dose Escalation ◽  
Research Funding ◽  
Progressive Disease ◽  
Cell Transplant ◽  
Upper Respiratory Tract ◽  
Bulky Disease ◽  
Anti Tumor Activity ◽  
Eliza Hall Institute ◽  
Hall Institute

Abstract Introduction New treatment options are needed for patients (pts) with R/R NHL, particularly in MCL where there are no curative options. Dysregulation of the anti-apoptotic protein Bcl-2 is a hallmark of NHL pathogenesis and contributes to chemotherapy resistance. ABT-199 is a selective, potent, orally bioavailable small molecule Bcl-2 inhibitor that is a promising agent for the treatment of pts with NHL. Methods The primary objectives of this phase I, dose-escalation study were to evaluate the safety and pharmacokinetics (PK), and to determine a maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ABT-199. Secondary objectives were to assess the efficacy of ABT-199 and to explore biomarkers for response. Adult pts requiring therapy, with ECOG performance status ≤1 and adequate marrow function (ANC ≥1.0 x 109/L, Plt ≥50 x 109/L) received ABT-199 on Week 1 Day -7 (W1D-7), followed by continuous, once-daily dosing from W1D1 until progressive disease or unacceptable toxicity. A 2 to 3 week lead-in period with stepwise escalation starting with lower doses to final cohort doses of 200, 300, 400, 600, and 900 mg was implemented. Evaluations include adverse events (AE; NCI-CTCAE-V4), PK parameters and disease responses (IWG 2007 criteria). Results As of July 4, 2013, 32 pts were enrolled, 11 (34%) with follicular (FL), 8 (25%) with MCL, 8 (25%) with diffuse large B-cell (DLBCL), 1 (3%) with marginal zone (MZL), 3 (9%) with Waldenström macroglobulinemia (WM), and 1 (3%) multiple myeloma (MM). The median age was 68 (range 35-85), 63% were male with a median of 3.5 prior therapies (range 1-7), and the median time on study was 6.0 months (range 0.5-15.0). 44% of the pts had bulky disease ≥5 cm, including ≥10 cm in 16%. 22 pts have discontinued (D/C) drug: 18 due to progressive disease, 2 due to AEs, and 2 who proceeded to stem cell transplant in ongoing response. The most common AEs of any grade (G) occurring in ≥20% of pts were nausea (41%), diarrhea (31%), vomiting (22%), fatigue (22%), and upper respiratory tract infection (22%). G 3/4 AEs occurring in >3 pts were anemia (15%), neutropenia (13%), and thrombocytopenia (13%). G 3/4 thrombocytopenia was not dose-dependent or dose-limiting. Two of 10 pts in cohort 5 experienced a DLT (G3 febrile neutropenia and G4 neutropenia) at the target dose of 600 mg. G3 laboratory tumor lysis syndrome was seen after the initial dose in 1 pt with bulky MCL (elevations in phosphate and potassium only) and 1 pt with DLBCL (elevations in phosphate and uric acid only). After a single dose with food, ABT-199 had Tmax and T1/2 of approximately 8 and 15 hours, respectively. Food increased ABT-199 bioavailability by 3-4 fold. Preliminary efficacy data are summarized in the table. Conclusions ABT-199 showed anti-tumor activity as monotherapy for several NHL subtypes, with an overall response rate of 53% in this R/R population. Anti-tumor activity was seen in all MCL and WM pts treated across the range of ABT-199 cohort doses, and responses in DLBCL and FL pts were observed at doses ≥600 mg. Dose escalation is continuing to determine the MTD and RP2D. Biomarker studies are also underway in various NHL subtypes to explore a potential correlation with response. Disclosures: Seymour: Genentech: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Gerecitano:AbbVie: Research Funding; Genentech: Research Funding. Kahl:AbbVie, Inc.: Research Funding; Genentech: Consultancy, Research Funding. Wierda:AbbVie, Inc.: Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau. Anderson:Genentech: Research Funding; AbbVie, Inc.: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employee, which recieves commercial income related to ABT-199, Employee, which recieves commercial income related to ABT-199 Other. Rudersdorf:AbbVie, Inc.: Employment, Stock Other. Gressick:AbbVie, Inc: Employment, Stock Other. Montalvo:AbbVie, Inc.: Employment, Stock Other. Yang:AbbVie, Inc.: Employment, Stock Other. Busman:AbbVie, Inc.: Employment, Stock Other. Dunbar:AbbVie, Inc.: Employment, Stock Other. Cerri:AbbVie, Inc.: Employment, Stock Other. Enschede:AbbVie, Inc.: Employment, Stock Other. Humerickhouse:AbbVie, Inc.: Employment, Stock Other. Roberts:AbbVie, Inc.: Research Funding; Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employee, recieves commercial income related to ABT-199, Employee, recieves commercial income related to ABT-199 Other, Employment.

scholarly journals Deep Profiling of Chronic Lymphocytic Leukaemia (CLL) and Healthy Immune Cells By Mass Cytometry Resolves Impacts of Venetoclax Pressure

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3710-3710
Author(s):  
Charis E Teh ◽  
Tania Tan ◽  
Marie Trussart ◽  
Mengxiao Luo ◽  
Rachel Thijssen ◽  
...  
Keyword(s):  
T Cells ◽  
Medical Research ◽  
Dose Escalation ◽  
Immune Cells ◽  
Research Funding ◽  
Short Term ◽  
Survival Pathways ◽  
Eliza Hall Institute ◽  
Hall Institute

Abstract Introduction The BCL-2 inhibitor, venetoclax, is an effective treatment for chronic lymphocytic leukaemia (CLL). Most CLL patients (pts) treated with venetoclax respond, however in the relapsed/refractory (r/r) setting 30-50% patients progress after 2-3 years despite continuous treatment. Although the molecular drivers of relapse are becoming clearer, precisely how the pressure exerted by venetoclax is manifest at the cellular level to engender resistance remains unclear. In this study, we performed mass cytometric (CyTOF) profiling of CLL samples taken from pts during venetoclax dose escalation and employed in vivo modelling to determine the impact of short-term treatment upon survival pathways, proliferation and homing characteristics in both leukemic and normal immune cells. Methods We conducted serial analysis of peripheral blood (PB) samples from 20 pts with r/r CLL (median 2 lines therapy, range 1-5) at baseline and during venetoclax dose escalation (weekly increases of 20, 50, 100, 200, 400 mg) using deep profiling by CyTOF. We measured changes in 43 regulators of immune cells, cell death, proliferation, cell signalling and cancer-related pathways at the single-cell resolution. The data were normalized using CytofRUV, then analyzed using high-dimensional FlowSOM clustering, tSNE/UMAP visualization tools and conventional cytometric analysis. In order to distinguish cell intrinsic and extrinsic impacts, we assayed venetoclax pressure on immune cells with in vivo models using wild-type, Bak -/-Bax Δcd23 and Vav-BCL-2 transgenic mice and haematopoietic chimeras. Results CyTOF analysis of CLL patients demonstrated inter-patient and intra-patient heterogeneity in leukemic cell populations. After six weeks of short-term venetoclax therapy, all pts showed steep decreases in CLL burden in the PB. In the remaining CLL cells, there was a striking dose-dependent increase in amounts of BCL-2, but not MCL-1 and BCL-XL protein expression. The BCL-2 +++ CLL cells remaining after venetoclax therapy were enriched for the proliferative CXCR4 high CD5 low CLL cells. As PB CLL cells are reduced upon venetoclax treatment, there were proportional increases in healthy PB T cells in CLL patients. Compared to baseline samples, all T cell subpopulations were maintained and targets of immune checkpoint inhibitors, such as PD-1, remained unchanged after venetoclax therapy. We then modelled venetoclax responses in vivo by treating mice with 100 mg/kg venetoclax daily for 7 days and assessed the sensitivity of various immune cell subsets, their proliferation and expression of cell survival proteins. Immature lymphocytes were relatively insensitive to venetoclax, while mature naïve populations were depleted. In accord with the CLL patient data, the remaining mature B and T cells expressed very high levels of BCL-2 and were highly proliferative. Lymphocytes lacking the apoptotic effectors BAX and BAK from Bak-/-BaxΔcd23 micedid not exhibit these changes. By contrast, transgenic mice with overexpression of BCL-2 (vav-bcl-2 mice) did not rescue cells from the impacts of venetoclax. These data reveal direct and consistent impacts of venetoclax pressure in normal and leukemic cells at the single cell level. Conclusions Collectively, our findings reveal that short-term treatment with venetoclax exerts pressure on both CLL and healthy immune cells (Figure). Striking changes in the wiring of survival pathways in CLL cells occurred shortly after venetoclax treatment, suggesting that therapies targeting orthogonal survival pathways should be considered shortly after dose-escalation. Furthermore, the limited changes in healthy T cells opens a window for targeting these cells by adjunct immune checkpoint inhibitors to achieve deeper responses. Figure 1 Figure 1. Disclosures Teh: The Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: Employee of the Walter and Eliza Hall Institute and eligilble for payments in relation to venetoclax. Tan: The Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: Employee of the Walter and Eliza Hall Institute and eligilble for payments in relation to venetoclax. Trussart: The Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: Employee of the Walter and Eliza Hall Institute and eligilble for payments in relation to venetoclax. Luo: The Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: Employee of the Walter and Eliza Hall Institute and eligilble for payments in relation to venetoclax. Thijssen: The Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: Employee of the Walter and Eliza Hall Institute and eligilble for payments in relation to venetoclax. Roberts: Janssen: Research Funding; Abbvie: Research Funding; The Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: Employee of the Walter and Eliza Hall Institute and eligilble for payments in relation to venetoclax; Servier: Research Funding. Huang: The Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: Employee of the Walter and Eliza Hall Institute and eligilble for payments in relation to venetoclax. Speed: The Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: Employee of the Walter and Eliza Hall Institute and eligilble for payments in relation to venetoclax. Anderson: The Walter and Eliza Hall Institute: Honoraria, Patents & Royalties: Employee of the Walter and Eliza Hall Institute and eligilble for payments in relation to venetoclax, Speakers Bureau. Gray: The Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: Employee of the Walter and Eliza Hall Institute and eligilble for payments in relation to venetoclax.

scholarly journals Sequential Blinatumomab with Reduced Intensity Chemotherapy in the Treatment of Older Adults with Newly Diagnosed Ph Negative B-Precursor Acute Lymphoblastic Leukemia - Interim Analysis of the Australasian Leukemia and Lymphoma Group ALL08 Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1234-1234
Author(s):  
Shaun Fleming ◽  
John Reynolds ◽  
Ashish Bajel ◽  
Nicola Venn ◽  
John Kwan ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Progressive Disease ◽  
Lymphoblastic Leukemia ◽  
Cell Transplant ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Major Toxicity ◽  
Eliza Hall Institute ◽  
Hall Institute

Abstract The advent of pediatric inspired regimens has improved the outcome for younger adults with Acute Lymphoblastic Leukemia (ALL), however this comes at a considerable toxicity burden limiting its applicability in older adults. The advent of novel immunotherapies, such as Blinatumomab, an anti-CD19 targeting Bi-specific T-cell engager, has improved outcomes for adults with relapsed refractory and minimal residual disease (MRD) positive B-precursor (BCP) ALL. The Australasian Leukemia and Lymphoma Group (ALLG) undertook a phase 2 proof-of-concept study to explore the combination of Blinatumomab with reduced intensity chemotherapy in adults with newly diagnosed Ph- BCP ALL. Patients received an initial pre-phase of corticosteroids (Prednisolone 100mg/d, 5 days) followed by a low intensity chemotherapy debulking (Cyclophosphamide 150mg/m 2 BD D1-3, Vincristine 2mg IV D1, 11 and Dexamethasone 10mg/m 2 D1-4, D11-14). Following this patients received Blinatumomab at 9mcg/d days 1-7 and 28mcg/d days 8-28. A B cycle of Hyper-CVAD (Cytarabine 3g/m 2 BD for 4 doses and Methotrexate 1g/m 2 D1 with Methylprednisolone 50mg BD D1-3). Patients then received 3 alternating cycles of Blinatumomab (28mcg/d for 28 days) and B-cycles of Hyper-CVAD followed by 2-years of POMP maintenance in subjects not proceeding to allogeneic stem cell transplant (alloHSCT) which was at investigator discretion. MRD assessments by ASO-PCR were performed after the first B cycle, second B cycle and prior to maintenance therapy with an MRD response being a level of 10 -4 or less. This analysis is from a pre-specified interim analysis with a data cutoff of 29 th June 2021. 30 patients were enrolled with a median age of 51.7(range, 39.5 - 66.5 years) with 70% male subjects. ECOG performance score was 0 in 14 subjects, 1 in 12 and 2 in 4. High risk disease was identified in 5 subjects (1 t(4;11), 2 hypodiploid, 1 t(1;19) and 1 Ph-like). All patients attained a CR, with 28 at end of 1B and a further 2 at end of 2B. Of 26 patients evaluable for MRD, 70% had achieved an MRD response after cycle 1B and 83% at the end of cycle 2B. 15 patients have ceased study therapy; 6 patients died with progressive disease, 4 subjects exited to allogeneic stem cell transplant, 1 patient was withdrawn due to progressive disease, 1 had intolerable toxicity (peripheral neuropathy) and 1 at investigator discretion. There were no treatment related deaths. 15 remain on protocol in maintenance with the remainder having completed therapy. At data cut-off the median event free survival (EFS) was not reached (95% CI 8.3 months - NA) with an estimated 24 month EFS of 61.8% (95% CI 36.3 - 84.2%) (figure 1A), and similarly the median overall survival (OS) S was not reached (95% CI 21.0 months - NA) with an estimated 24 month OS of 68.6% (95% CI 41.5 - 85.1%)(figure 1B). This predicted EFS was greater than the pre-specified stopping rule of a 24-month EFS of 50%. 2 episodes of cytokine release syndrome (CRS) were recorded (1 grade 2, 1 grade 3) with the major toxicity being infective (53 episodes of sepsis, infection or febrile neutropenia) predominately related to chemotherapy cycles. 7 episodes of neurological toxicity were demonstrated (1 myelopathy and 4 peripheral neuropathy occurring during chemotherapy and 2 encephalopathy occurring during Blinatumomab administration). Overall, the combination of Blinatumomab with chemotherapy was tolerable and appeared efficacious with a high rate of remission and deep MRD responses observed. Responses appeared durable despite a low rate of alloHSCTin first remission. The major toxicity was infective and occurred in the context of chemotherapy cycles. Future developments from this protocol will emphasise further reduction in cytotoxic chemotherapy through incorporation of further novel agents to minimise this toxicity. Figure 1 Figure 1. Disclosures Fleming: Servier: Honoraria; Pfizer: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau. Reynolds: Abbvie: Research Funding; Novartis AG: Current equity holder in publicly-traded company; Alcon: Current equity holder in publicly-traded company. Bajel: Abbvie, Amgen, Novartis, Pfizer: Honoraria; Amgen: Speakers Bureau. Yeung: BMS: Honoraria, Research Funding; Pfizer: Honoraria; Amgen: Honoraria; Novartis: Honoraria, Research Funding. Verner: Janssen-Cilag Pty Ltd: Research Funding. Wei: Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Honoraria; Novartis, Abbvie, Celgene/BMS: Speakers Bureau; Servier: Consultancy; Abbvie, Amgen, AstraZeneca, Celgene/BMS, Novartis, Servier and F. Hoffmann-La Roche: Research Funding; Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees; Former employee of Walter and Eliza Hall Institute: Patents & Royalties: Prof. Andrew Wei is a former employee of the Walter and Eliza Hall Institute and is eligible for a fraction of the royalty stream related to Venetoclax. Greenwood: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Blinatumomab - usage in front-line therapy for Acute Lymphoblastic Leukaemia

scholarly journals High Major Response Rate, Including Very Good Partial Responses (VGPR), in Patients (pts) with Waldenstrom Macroglobulinemia (WM) Treated with the Highly Specific BTK Inhibitor Bgb-3111: Expansion Phase Results from an Ongoing Phase I Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1216-1216 ◽  
Author(s):  
Constantine S. Tam ◽  
Judith Trotman ◽  
Stephen Opat ◽  
Paula Marlton ◽  
Gavin Cull ◽  
...  
Keyword(s):  
Medical Research ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Phase 1 ◽  
Advisory Committees ◽  
Major Response ◽  
Btk Inhibitor ◽  
Eliza Hall Institute ◽  
Hall Institute

Abstract Introduction: The BTK inhibitor ibrutinib (IB) is highly active in WM, achieving major responses (CR+VGPR+PR) in approximately 70% of pts. However, VGPR is infrequent, with rates ≤15% in reported series (Treon NEJM 2015, Dimopoulos EHA 2016). BGB-3111 is a potent, highly-specific and irreversible BTK inhibitor, with greater selectivity than IB for BTK vs. other TEC- and HER-family kinases, and superior bioavailability. We previously reported that the recommended phase 2 dose of BGB-3111 is 320mg daily (in single or split dose) in pts with advanced B cell malignancies. This achieves plasma levels equivalent to 6-10 fold that of IB, and >90% continuous inhibition of BTK in lymph node biopsies. We specifically investigated the safety and efficacy of BGB-3111 in pts with WM in an expansion cohort of the initial Phase 1 trial. Reported here are updated results of this study, including data from WM specific expansion cohorts. Aims: To define the safety profile, and clinical activity of BGB-3111 in pts with WM. Methods: These results are from a pre-specified a component of a Phase 1 study (Part 1: dose escalation [DEsc] in pts with R/R B cell malignancies, Part 2: disease-specific dose expansion cohorts [EC] at the recommended Phase 2 dose that included patients with relapsed / refractory or previously untreated WM). Adverse events (AEs) were reported per CTCAE v4.03. Responses were determined according to the modified Sixth International Workshop on WM (IWWM) criteria. The data cut-off is 10 June 2016. Results: As of 10 June 2016, 31 pts with WM have been enrolled; 6 pts in DEsc (40mg [n=2], 80mg [n=2], 160mg QD [n=1], and 320mg QD [n=1]), and 25 in the WM EC (160mg BID [n=18], 320mg QD [n=7]). Three pts in DEsc were increased to 160mg QD after analysis of DEsc data, as allowed by protocol. Twenty-four pts are included in this analysis; 5 pts were excluded because of short (<60 day) follow-up for safety and efficacy, and 2 pts accrued at a single site were excluded because of insufficient documentation at baseline. Patient demographics, disease characteristics, and prior treatment history are summarized in Table 1. BGB-3111 was well tolerated with 71% reporting no drug related AE >Gr 1 severity within the first 12 weeks of therapy. The most frequent AEs (>20%) of any attribution (all Gr 1/2) were upper respiratory infection (25%), diarrhea (25%), and nausea (21%). There were 2 SAEs assessed as possibly related to BGB-3111 (Gr 2 atrial fibrillation, Gr 3 cryptococcal meningitis); in both cases, BGB-3111 was temporarily held but safely resumed. In total, 2 pts developed AF (one Gr 1, one Gr 2). No serious hemorrhage (≥Gr 3 or CNS hemorrhage of any grade) was reported. After a median follow-up of 7.6 months (2-21 months), the response rate was 92% (22/24). The major response rate was 83% (20/24), with VGPR (>90% reduction in IgM and reduction in extramedullary disease) in 33% (8/24) and PR (50-90% reduction in IgM and reduction in extramedullary disease) in 50% (12/24) pts. Pts with WM refractory to their last therapy were equally responsive: major response 77% [10/13], VGPR 31% [4/13], PR 46% [6/13]. Median time to initial response and major response were 29 days and 34 days, respectively. IgM decreased from a median of 29.9g/l at baseline to 3.0g/l; hemoglobin increased from a median of 10.1 g/dl at baseline to 13.5g/l. Two of 3 pts who had a dose increase after reaching a stable IgM plateau had further falls in IgM levels after dose escalation. Kinetics of IgM and hemoglobin response are presented in Figure 1. Lymphadenopathy was present in 8 pts at baseline; serial CT demonstrated reduction or resolution in all 8 pts (27%-100% reduction in SPD). Only one patient discontinued BGB-3111, due to exacerbation of pre-existing bronchiectasis while in VGPR. There have been no cases of disease progression. Analysis of response by genomic characteristics (including MYD88 and CXCR4 mutational status) is ongoing. Conclusions: BGB-3111 is well-tolerated and highly active in WM. The depth and quality of responses, as reflected by the VGPR rate of 33%, warrant a randomized comparison against ibrutinib in pts with WM. Table 1. Table 1. Figure 1. Figure 1. Disclosures Tam: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; janssen: Honoraria, Research Funding. Opat:Roche: Consultancy, Honoraria, Other: Provision of subsidised drugs, Research Funding. Simpson:Amgen Pharmaceuticals: Research Funding; Celgene, Roche, Janssen: Honoraria. Anderson:Walter and Eliza Hall Institute of Medical Research: Other: Walter and Eliza Hall Institute of Medical Research receives milestone payments for the development of venetoclax. Kirschbaum:Beigene: Employment. Wang:Beigene: Employment. Xue:Beigene: Employment. Yang:BeiGene: Employment. Hedrick:Beigene: Employment. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Roberts:AbbVie: Research Funding; Servier: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax.

Navitoclax (ABT-263) Plus Fludarabine/Cyclophosphamide/Rituximab (FCR) or Bendamustine/Rituximab (BR): A Phase 1 Study In Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2455-2455 ◽  
Author(s):  
Thomas J. Kipps ◽  
William G. Wierda ◽  
Jeffrey A. Jones ◽  
Lode J. Swinnen ◽  
Jianning Yang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Cell Transplant ◽  
Phase 2 ◽  
Anti Tumor Activity

Abstract Abstract 2455 Background: Navitoclax (ABT-263), a novel, orally bioavailable, small molecule, binds with high affinity (Ki ≤1nM) to Bcl-2, Bcl-xL, and Bcl-w, promoting apoptosis. In vitro, navitoclax shows potent targeted cytotoxicity (EC50 ≤ 1μM) against T and B lymphoid malignancies that over-express Bcl-2. A phase 1 trial demonstrated oral navitoclax monotherapy to be well-tolerated and to have anti-tumor activity in patients (pts) with chronic lymphocytic leukemia (CLL). However, thrombocytopenia (TCP) was the dose-limiting toxicity (DLT). Phase 3 studies showed improved outcomes in CLL pts with the fludarabine/cyclophosphamide/rituximab (FCR) combination, and a phase 2 trial showed bendamustine/rituximab (BR) to be effective for pts with relapsed or refractory CLL. Navitoclax enhanced R (monotherapy and in combination with chemotherapy) efficacy in preclinical models of B-cell lymphoma. Methods: This is an ongoing, international, phase 1 dose-escalation study to evaluate the safety and pharmacokinetics (PK) of oral navitoclax in combination with FCR (Arm A) or BR (Arm B) in pts with relapsed/refractory CLL. Secondary objectives are efficacy endpoints (PFS, ORR, TTP, OS, duration of response). Eligible pts had measurable disease, ECOG performance score ≤1, ANC ≥100/μL, platelets ≥100,000/mm3, and hemoglobin ≥9.0 g/dL. Preliminary results are reported. After obtaining informed consent, pts were assigned to Arm A or Arm B based on physician preference, each consisting of 28-day dose-escalation cycles with once-daily, pre-infusion, navitoclax treatment on Days 3–5 of Cycle 1 and Days 1–3 of subsequent cycles. In both arms, R was 375 mg/m2 on Day 1 of Cycle 1; and 500 mg/m2 on Day 2 of Cycle 2 and on Day 1 of subsequent cycles. In Arm A, F 25 mg/m2 and C 175 mg/m2 were dosed on Days 2–4 in Cycles 1 and 2, and on Days 1–3 in subsequent cycles. In Arm B, B was dosed at 70 mg/m2 on Days 2 and 3 of Cycles 1 and 2, and on Days 1 and 2 in subsequent cycles. Navitoclax starting dose was 110 mg daily. Dose escalation to the next cohort (200 mg) was according to a continuous reassessment model. Tumor responses were evaluated using NCI-WG 1996 criteria. Pts could continue on navitoclax therapy for 1 yr in the absence of progressive disease or significant toxicity. Results: As of July 2010, 7 pts enrolled in the initially prioritized Arm B (BR+navitoclax); all completed the first cohort of 110 mg (median age 60 yr [range 55–72]). Study sites are currently enrolling pts in Arm A (FCR+navitoclax); 2 pts have enrolled to date. The median number of prior therapies was 2 (range 1–7). One pt had a DLT of elevated AST (Arm B, 110 mg cohort) and 1 pt had a DLT of neutropenic fever (Arm A, 110 mg cohort). In Arm B, neither TCP nor neutropenia have been DLTs. For the 7 pts with navitoclax-related AEs, the most common were diarrhea (3 pts), nausea (5 pts), and fatigue (3 pts). Seven pts remain on study; 2 pts discontinued due to disease progression and 2 withdrew per physician preference. In Arm B, preliminary antitumor best responses were assessable in 4 pts who received 2 cycles; 1 CRi in a pt with del17p- (based on lymph node [LN] response and no morphologic evidence of CLL in the bone marrow), 2 unconfirmed CRs (based on LN response and no bone marrow at this time), and 1 PR in a pt with del17p- (this pt subsequently received an allogeneic stem cell transplant). Preliminary PK results for the Arm B 110 mg cohort indicated that navitoclax PK was similar in Cycle 1 (navitoclax+BR) and Cycle 2 (navitoclax alone), and appeared comparable to PK in the navitoclax monotherapy study. Conclusions: Early results show that the combination of navitoclax with BR is well-tolerated, without DLTs of TCP or neutropenia, and show evidence of anti-tumor activity. Data are limited in the FCR portion of the study. The maximum tolerated dose of navitoclax has not been reached. Accrual is ongoing and following completion of the dose-escalation components of this study, expanded cohorts of pts will be assessed using the recommended phase 2 dose of navitoclax to further assess the tolerability and dose, and to continue to explore for efficacy signals in combinations. Preliminary data in combination with BR are encouraging. Disclosures: Kipps: Abbott Laboratories: Research Funding; Genentech/Roche: Research Funding. Wierda: Abbott: Research Funding; Genentech: Honoraria, Speakers Bureau. Jones: Glaxo Smith-Kline: Consultancy; Abbott: Research Funding. Swinnen: Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yang: Abbott: Employment. Cui: Abbott: Employment. Busman: Abbott: Employment. Krivoshik: Abbott: Employment. Enschede: Abbott: Employment. Humerickhouse: Abbott: Employment.

Navitoclax (ABT-263) Plus Fludarabine/Cyclophosphamide/Rituximab (FCR) or Bendamustine/Rituximab (BR): A Phase 1 Study in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3904-3904 ◽  
Author(s):  
Thomas J. Kipps ◽  
Lode J. Swinnen ◽  
William G. Wierda ◽  
Jeffrey Alan Jones ◽  
Steven E. Coutre ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Febrile Neutropenia ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Progressive Disease ◽  
Phase 1 ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Anti Tumor Activity

Abstract Abstract 3904 Background: Navitoclax (ABT-263), a novel, orally bioavailable, small molecule, binds with high affinity (Ki ≤1nM) to Bcl-2, Bcl-xL, and Bcl-w, promoting apoptosis. In vitro, navitoclax shows potent targeted cytotoxicity (EC50≤1 μM) against T and B lymphoid malignancies that overexpress Bcl-2. In preclinical models of B-cell lymphoma, navitoclax enhanced efficacy of rituximab (R) when used alone or in combination with chemotherapy. Based on phase 1 trial data, oral navitoclax monotherapy was well-tolerated and had anti-tumor activity in patients (pts) with chronic lymphocytic leukemia (CLL). Thrombocytopenia was the dose-limiting toxicity (DLT). We examined whether navitoclax could be used safely in combination with fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR) for treatment of pts with CLL. Methods: This ongoing, phase 1 dose-escalation study is evaluating the safety and pharmacokinetics (PK) of oral navitoclax used in combination with FCR (Arm A) or BR (Arm B) for treatment of pts with relapsed/refractory CLL. Secondary objectives are efficacy endpoints (PFS, ORR, TTP, OS, duration of response). Eligible pts had measurable disease, ECOG performance score ≤1, ANC ≥1000/μL, platelets ≥100,000/mm3, and hemoglobin ≥9.0 g/dL. Preliminary results are reported. Enrolled pts (6 pts/cohort) were assigned to Arm A or Arm B based on physician preference. In both arms, R was 375 mg/m2 on Day 1 of Cycle 1; and 500 mg/m2 on Day 2 of Cycle 2 and on Day 1 of subsequent 28-day cycles. In Arm A, F 25 mg/m2 and C 175 mg/m2 were dosed on Days 2–4 in Cycles 1 and 2, and on Days 1–3 in subsequent cycles. In Arm B, B was dosed at 70 mg/m2 on Days 2 and 3 of Cycles 1 and 2, and on Days 1 and 2 in subsequent cycles. Oral navitoclax was administered once daily (starting dose of 110 mg) pre-chemotherapy on Days 3–5 of Cycle 1 and Days 1–3 of subsequent cycles. Dose escalation decisions were made independently in each arm via a continuous reassessment method, and the objective was to identify a dose of navitoclax in combination with chemotherapy in which <33% of subjects experienced DLTs. Tumor responses were evaluated using NCI-WG 1996 criteria. Adverse events (AE) were graded by NCI CTCAE V3. Pts continued on navitoclax monotherapy up to the recommended phase 2 dose of 250 mg daily for 1 year or until progressive disease or intolerable toxicity. Results: As of July 2011, 28 pts (median age 59 yr [39–80]) have enrolled; 5 in Arm A (FCR+navitoclax; 110 mg) and 23 in Arm B (BR+navitoclax; 110–250 mg). The median number of prior therapies was 2 (range 1–13). In Arm A, 1 pt had a DLT of febrile neutropenia (110 mg). In Arm B, 5 pts had DLT; 1 had elevated ALT and AST (110 mg), 1 had grade 4 febrile neutropenia (200 mg), and 3 had grade 4 thrombocytopenia (250 mg). Overall, the most common (>20%) navitoclax-related AEs of any grade were nausea (73%), fatigue (50%), neutropenia (50%), cough (39%), vomiting (35%), chills (31%), diarrhea (31%), constipation (27%), headache (27%), anemia (23%), and thrombocytopenia (23%). The most common (>19%) grade 3/4 navitoclax-related AE was neutropenia (35%) and thrombocytopenia (19%); but only 2 of the latter pts had hemorrhagic events (Grade 1 epistaxis) unlikely related to navitoclax. Of the 28 pts evaluated for safety, 6 remain active and 22 discontinued (DC); 1 due to AE, 1 due to AE and progressive disease (PD), 3 due to PD, 6 withdrew consent, 3 due to physician discretion, 4 completed therapy, 2 proceeded to transplant, and 2 due to toxicity. Preliminary best anti-tumor responses were assessed in 20 pts. Of the 16 pts assessed in Arm B (BR), 6 achieved complete responses (CR), 7 partial responses (PR), 2 stable disease (SD) and 1 with PD. The ORR was 81% (13/16). In this arm, 3/5 pts with 17p deletion achieved PR. Of the 4 pts assessed in Arm A (FCR), 2 achieved PR, 1 SD and 1 with PD. Preliminary PK results suggest that there is no apparent PK interaction between navitoclax and bendamustine. Conclusions: The combination of navitoclax with BR appears well-tolerated and to have anti-tumor activity. The maximum tolerated dose of navitoclax has been reached at 250 mg for Arm B, but not for Arm A where escalation continues. To date, we have not observed unacceptable myelotoxicity when this bcl-2 antagonist was used in combination with standard cytotoxic chemo-immunotherapy regimens for treatment of pts with CLL. Disclosures: Kipps: Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbott Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Consultancy, Research Funding; Amgen: Research Funding. Off Label Use: R05429083 is a novel humanized antibody direct against the standard region of CD44. R05429083 is currently intensive pre-clinical studies and fist dosing of cancer patients has started in Europe in 2011. Swinnen:Abbott Laboratories: Research Funding. Yang:Abbott Laboratories: Employment. Cui:Abbott Laboratories: Employment, Stock Holder at Abbott Laboratories. Busman:Abbott Laboratories: Employment, Owns Abbott Laboratories Stock. Enschede:Abbott Laboratories: Employment, Owns Abbott Laboratories Stock. Humerickhouse:Abbott Laboratories: Employment, Owns Abbott Laboratories Stock.

The BCL-2-Specific BH3-Mimetic ABT-199 (GDC-0199) Is Active and Well-Tolerated in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Interim Results of a Phase I First-in-Human Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3923-3923 ◽  
Author(s):  
John F. Seymour ◽  
Matthew S. Davids ◽  
Mary Ann Anderson ◽  
Thomas J. Kipps ◽  
William G. Wierda ◽  
...  
Keyword(s):  
Phase I ◽  
Medical Research ◽  
Research Funding ◽  
Board Member ◽  
Cell Lymphoma ◽  
Advisory Board ◽  
Tumor Lysis ◽  
Eliza Hall Institute ◽  
Hall Institute ◽  
Bh3 Mimetic

Abstract Abstract 3923 Background: BCL-2 is highly expressed in indolent non-Hodgkin lymphomas (NHL), mantle cell lymphoma (MCL) and other selected aggressive lymphomas, and is a promising target for therapeutic intervention. The first-generation BCL-2 inhibitor navitoclax showed some activity in indolent lymphoma, but its co-inhibition of BCL-xL resulted in dose-limiting thrombocytopenia, precluding the full exploration of the potential of BCL-2 inhibition with this drug in NHL. ABT-199 is an orally bioavailable, second-generation BH3-mimetic that inhibits BCL-2 (Ki<0.10 nM), but has 500-fold less activity for BCL-xL (Ki=48 nM). ABT-199 demonstrated antitumor activity against a variety of human cell lines and xenograft models that include B cell NHL, follicular lymphomas (FL), diffuse large B-cell Lymphoma (DLBCL) and MCL. Methods: This is a phase-I dose-escalation trial using a modified Fibonacci design in patients with relapsed/refractory NHL. The primary objectives of this study are to determine the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of ABT-199; to recommend a phase-2 dose; and to assess efficacy and biomarkers in patients with relapsed/refractory NHL. Adult patients requiring therapy, with ECOG performance status £1, and adequate marrow function received ABT-199 on Week 1 Day −7 (W1D-7), followed by continuous once-daily dosing from W1D1, until progressive disease (PD) or unacceptable toxicity. Due to concerns of potential tumor lysis, a strategy of commencing with a 2 to 3 week lead-in period with step-wise increases to the target cohort dose is being evaluated. In the first four cohorts, the starting dose increased from 50 to 200 mg (50, 100, 200, and 200 mg, respectively), with target cohort doses of 200 mg [n=3], 300 mg [n=3], 400 mg [n=4], and 600 mg [n=7]. Evaluations include: adverse events (AE; NCI-CTCAE-V4) and tumor response (IWG 2007 criteria). Results: To date, 17 patients (median age, 71 [35–85]) have been treated with ABT-199. Median prior therapies were 3 (range, 1–7) and 6 patients had bulky adenopathy (>5cm). Most common AEs (experienced by >2 patients) were nausea (41%), diarrhea (24%), dyspepsia (24%), fatigue (24%), extremity pain (24%); and anemia, constipation, upper respiratory tract infection and cough (18% each). Grade 3 or 4 AEs occurring in >1 patient were anemia (18%) and neutropenia (12%). Treatment-related thrombocytopenia has not been reported and no dose-limiting toxicities (DLTs) have been identified to date. After a single dose administration with a high-fat meal, ABT-199 reached Cmax at approximately 7 hrs with a terminal half-life of about 15 hrs. Food increased ABT-199 exposure by approximately 3-fold. With a median follow-up of 2.8 months (range, 1.2 to 10.8), 14 patients remain on study and 3 have discontinued due to PD. In patients who have completed at least a W6 assessment, reductions of >50% in target lesions have been observed in 8/15 patients (53%); 6/6 patients with MCL, 1/2 patients with WM and 1/2 patients with DLBCL. Additionally, 5 FL patients have been evaluated (3 with rituxan-refractory disease) with a median time on study of 6.4 months (range, 3.5 to 10.8). 4/5 FL patients had nodal disease reductions ranging from 18% to 40%. Conclusions: ABT-199 shows single agent anti-tumor activity in patients with NHL; particularly in MCL. Activity is also observed in DLBCL and WM. To date, no DLTs have been identified and tumor lysis syndrome related to ABT-199 has not been reported. Dose escalation is continuing to identify the optimal dosing regimen and MTD of ABT-199 in NHL. Updated results will be presented. Disclosures: Seymour: Roche: Advisory Board member Other, Consultancy; Genentech: Advisory Board member, Advisory Board member Other, Consultancy. Anderson:Abbott: Research Funding; Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment, receives commercial income related to ABT-199, receives commercial income related to ABT-199 Other. Kipps:Abbott: Consultancy, Research Funding. Wierda:Abbott: Research Funding; Genentech: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; AmGen: Research Funding; Merck: Consultancy; Celgene: Consultancy; Pharmacyclics: Consultancy; Genzyme: Consultancy. Kahl:Abbott: Research Funding; Genentech: Consultancy, Research Funding. Miller:Abbott: Research Funding; Genentech: Research Funding. Darden:Abbott: Employment, owner of Abbott stock Other. Nolan:Abbott: Employment, own Abbott stock Other. Gressick:Abbott: Employment, stock owner Other. Xiong:Abbott: Employment, own Abbott stock Other. Huang:Genentech: Research Funding; Abbott: Research Funding; Walter and Eliza Hall Institiute of Medical Research: Employment, receives commercial income related to ABT-199, receives commercial income related to ABT-199 Other. Chyla:Abbott: Employment, Stock owner Other. Busman:Abbott: Employment, Stock owner Other. Graham:Abbott: Employment, Stock owner Other. Cerri:Abbott: Employment, Stock owner Other. Enschede:Abbott: Employment, own Abbott stocks Other. Humerickhouse:Abbott: Employment, own Abbott stocks Other. Roberts:Abbott: Research Funding; Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment, Receives commercial income related to ABT-199, Receives commercial income related to ABT-199 Other.

Multicenter Phase 1b Dose-Escalation Study of Ibrutinib and Lenalidomide Combined with Dose-Adjusted EPOCH-R in Patients with Relapsed/Refractory DLBCL

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1527-1527 ◽  
Author(s):  
Wyndham H. Wilson ◽  
Leslie L. Popplewell ◽  
Tycel Phillips ◽  
Amy S. Kimball ◽  
Saurabh Chhabra ◽  
...  
Keyword(s):  
B Cell ◽  
Dose Level ◽  
Dose Escalation ◽  
Progressive Disease ◽  
B Cell Lymphoma ◽  
Fixed Dose ◽  
Combination Regimen ◽  
Cell Transplant ◽  
Bulky Disease ◽  
Grade 3

Abstract Introduction Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have a poor outcome and few achieve durable remission. DA-EPOCH-R (dose-adjusted cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone with rituximab) is a regimen recommended by the NCCN guidelines for untreated and R/R DLBCL. The immunomodulator, lenalidomide, and the Bruton's tyrosine kinase inhibitor, ibrutinib, have both shown single-agent efficacy in non-germinal center B-cell-like (non-GCB) DLBCL, which is enriched for the activated B-cell [ABC] subtype, and are synergistic in vitro against ABC DLBCL. This nonrandomized, multicenter, open-label study is designed to evaluate the efficacy of ibrutinib in combination with lenalidomide and DA-EPOCH-R in subjects with R/R DLBCL. Part 1 of the study is designed to determine the maximum tolerated dose (MTD) of ibrutinib and lenalidomide with DA-EPOCH-R in R/R DLBCL. In Part 2, the efficacy of this combination will be evaluated in R/R ABC DLBCL. Here, we report the results of Part 1. Methods For Part 1, patients aged ≥18 years with pathologically confirmed R/R DLBCL were enrolled. The dose-escalation phase was conducted using a standard 3+3 design. Ibrutinib was administered at a fixed dose of 560 mg (Days 1-7) and lenalidomide was dose-escalated at doses of 0, 15, 20 and 25 mg (Dose Levels 1-4, respectively) and administered on Days 1-7 of each 21-day cycle. DA-EPOCH-R was given at standard doses. Treatment was continued in 21-day cycles for up to 6 cycles. The dose-limiting toxicity (DLT) assessment period was defined as the first 22 days of dosing (Day 1 of Cycle 1 through Day 1 of Cycle 2 [predose]). The primary endpoints were the MTD and safety and tolerability of the combination regimen; the secondary endpoint was overall response rate (ORR). Results Fifteen patients (13 male) were enrolled in Part 1. Median age was 58 years (range, 38-89) with 4 (27%) patients aged ≥65 years. Median time from initial diagnosis to first dose was 17.4 months (range, 7.4-65.5). Seven (47%) patients each had GCB and non-GCB DLBCL (subtype not reported for 1 patient). At baseline, 13 (87%) patients had stage III/IV disease; 8 (53%) had bulky disease ≥5 cm (2 >10 cm), and 10 (67%) were refractory to their last treatment. Patients had received a median of 3 prior regimens (range, 1-5). Dose escalation was completed through Dose Level 4. One DLT of diffuse alveolar damage was seen at the highest dose of lenalidomide tested. The MTD was not reached. Subjects in Part 2 will be treated with ibrutinib (560 mg) and lenalidomide (25 mg) on Days 1-7 combined with standard DA-EPOCH-R. Grade ≥3 adverse events (AEs) occurred in 14 (93%) patients. The most common grade ≥3 AEs (occurring in >20% of patients) were anemia (60%), febrile neutropenia (47%), leukopenia (40%), neutropenia (40%), thrombocytopenia (40%), hypokalemia (40%), and hypotension (33%). Serious AEs (SAEs) occurred in 14 patients (93%) including 2 cases (13%) of grade 2 atrial fibrillation. In 10 response evaluable patients (with at least one post-baseline radiological assessment), 2 patients had complete response (CR), 3 had partial response (PR), 2 patients had best response of stable disease, and 3 had progressive disease; 4 (67%) of 6 response evaluable non-GCB patients achieved objective response (CR/PR). Three patients continue treatment, 2 patients completed the protocol-specified treatment, and 10 patients discontinued treatment. Reasons for treatment discontinuation included AEs (n=3), progressive disease (n=3), stem cell transplant after achieving CR/PR (n=2), disease worsening (n=1), and death (n=1). Enrollment into Part 2 of the study has been initiated at Dose Level 4. Conclusions The Part 2 dose was established as 560 mg ibrutinib and 25 mg lenalidomide combined with standard DA-EPOCH-R. Ibrutinib in combination with lenalidomide and DA-EPOCH-R showed acceptable safety and tolerability and promising anti-tumor activity in patients with R/R DLBCL. The efficacy of this combination regimen will be further evaluated in Part 2 of this trial. Disclosures Off Label Use: yes; ibrutinib and lenalidomide in relapsed/refractory DLBCL. Phillips:Incyte: Other: Travel, Accommodations, Expenses. Ping:Pharmacyclics LLC, an AbbVie Company: Employment. Neuenburg:Pharmacyclics LLC, an AbbVie Company: Employment. Cavazos:Pharmacyclics LLC, an AbbVie Company: Employment. Staudt:NIH: Patents & Royalties; Pharmacyclics LLC, an AbbVie Company: Patents & Royalties, Research Funding.

scholarly journals Determination of Recommended Phase 2 Dose of ABT-199 (GDC-0199) Combined with Rituximab (R) in Patients with Relapsed / Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 325-325 ◽  
Author(s):  
Andrew W. Roberts ◽  
Shuo Ma ◽  
Danielle M. Brander ◽  
Thomas J. Kipps ◽  
Jacqueline C. Barrientos ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dose Escalation ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Phase 2 ◽  
Institutional Funding ◽  
Eliza Hall Institute ◽  
Hall Institute

Abstract Introduction: ABT-199 is a selective, orally bioavailable BCL-2 inhibitor that rapidly induces responses in ~80% of patients (pts) with relapsed/refractory (R/R) CLL or small lymphocytic lymphoma (SLL) as a single agent (Seymour, EHA 2014). Rituximab (R) has only modest and short-lived activity as a single-agent in CLL; it can enhance the activity of other agents with minimal additional toxicity. ABT-199 and R demonstrate synergy in preclinical models of CD20-positive lymphoid malignancies, and the combination has the potential to improve efficacy. Methods: Primary objectives of this phase 1b, open-label, dose-escalation, multicenter study were to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RPTD) of ABT-199 + R in pts with R/R CLL/SLL and evaluate the safety profile; secondary objectives examine the pharmacokinetics (PK) and efficacy of the combination. Eligible pts began treatment with 20 or 50 mg ABT-199 (modified to 20 mg during the study) daily, with weekly increases in a ramp-up phase to a final cohort dose of 200 - 600 mg. After completion of the ramp-up phase, R was added starting at 375 mg/m2 and then 500 mg/m2 monthly for a total of 6 doses. ABT-199 was continued daily until progressive disease (PD) or unacceptable toxicity. Adverse events (AEs) were graded according to NCI-CTCAE v4.0. The MTD was determined using the Continual Reassessment Method. Responses were assessed using established criteria for CLL/SLL, including CT scan at month 3 and CT scan and bone marrow (BM) biopsy at the end of combination therapy. MRD was assessed using four color flow cytometry in peripheral blood (PB) and/or BM aspirate ≥2 months after response criteria were first met, and in PB every 12 weeks until MRD negativity was achieved. Results: As of July 6, 2014, 49 pts enrolled in 5 dose escalation cohorts (n = 41) and a safety expansion cohort (n = 8), with a median time on study of 201 days (1 – 624). Median age was 68 years (range 50–88) and 30 (61%) were male. The median number of prior therapies was 3 (1–10). Thirteen (27%) had fludarabine-refractory disease and 9 (18%) R-refractory. Nine (18%) had del (17p) and 19/27 (70%) with available data had unmutated IGVH. Thirteen pts have discontinued therapy: 6 due to PD; 3 after attaining complete remission; 2 due to AEs and 2 withdrew consent. Preliminary PK data suggest a negligible effect of R on ABT-199 exposure. The most common overall treatment-emergent AEs (>25% pts) were neutropenia (47%), nausea (41%), diarrhea (37%), pyrexia (31%), headache (31%), fatigue, upper respiratory tract infection, and cough (each 29%). The most common overall grade 3/4 AEs were neutropenia (47%), thrombocytopenia (16%), and anemia (14%). Treatment-emergent SAEs occurred in 20 (41%) pts; the most common were pyrexia (6%), and febrile neutropenia, infusion-related reaction, TLS, and Richter's Transformation (each 4%). Six pts experienced a DLT: 1 febrile neutropenia (200mg), 1 each thrombocytopenia, hematophagocytic syndrome, neutropenia (300mg), 1 neutropenia (600mg), and 1 pt experienced a fatal event of hyperkalemia in the setting of TLS after the first dose (50mg). That event led to a modified dosing scheme; no TLS was observed in the 32 subsequent pts using the revised ramp up dosing scheme. No MTD was identified. Of 34 pts who were evaluable for response in dose escalation cohorts, the overall response rate (ORR) was 88%, with 11 (32%) achieving a CR/CRi and 20 (56%) achieving a partial response (PR). MRD was quantified by local laboratory in 19 pts. Thirteen pts (7 in CR (6 at 10-4 and 1 at 10-3 sensitivity) and 6 in PR (10-4 sensitivity)) were MRD negative in bone marrow while one was MRD negative in peripheral blood (10-4 sensitivity). The RPTD of ABT-199 is 400 mg daily based on safety data; key safety and efficacy data for the dose selection are summarized in the table. Conclusions: The combination of ABT-199 and R is well-tolerated and achieves an overall response rate of 86% with 31% CRs in pts with CLL/SLL. Efficacy was observed across all dose cohorts. The RPTD of ABT-199 is 400mg daily, supported by a trend of lower rates of neutropenia and GI toxicity events in the absence of a clear difference in efficacy, compared to the higher doses. A phase 3 trial comparing ABT-199 and R versus bendamustine and R in pts with previously treated CLL is underway. Figure 1 Figure 1. Disclosures Roberts: Walter and Eliza Hall Institute of Medical Research : Employment, Research Funding; AbbVie: Research Funding; Genentech: Research Funding. Ma:Genentech: Consultancy; AbbVie: Research Funding. Kipps:AbbVie: Consultancy, Research Funding. Barrientos:Gilead: institutional funding Other; Pharmacyclics: Consultancy, institutional funding, institutional funding Other; AbbVie: institutional funding, institutional funding Other; Celgene: Consultancy. Davids:Genentech: Consultancy; Infinity Pharmaceuticals: Consultancy. Anderson:Walter and Eliza Hall Institute of Medical Research: Employment, milestone payments related to ABT-199 Other; AbbVie: Research Funding; Genentech: Research Funding. Tam:Roche: Honoraria. Mason-Bright:AbbVie : Employment. Rudersdorf:AbbVie: Employment. Gressick:AbbVie: Employment. Yang:AbbVie, Inc: Employment. Munasinghe:AbbVie: Employment. Zhu:AbbVie, Inc: Employment. Cerri:AbbVie: Employment. Enschede:AbbVie, Inc: Employment. Humerickhouse:AbbVie, Inc: Employment. Seymour:AbbVie: Research Funding; Genentech: Consultancy, Research Funding; Roche: Consultancy.

scholarly journals Combined BCL-2 and HDAC Targeting Has Potent and TP53 Independent Activity in AML

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1426-1426
Author(s):  
Jessica M Salmon ◽  
Giovanna Pomilio ◽  
Donia M Moujalled ◽  
Sarah Macraild ◽  
Charis E Teh ◽  
...  
Keyword(s):  
Medical Research ◽  
Advisory Committee ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Research Funding ◽  
Deacetylase Inhibitor ◽  
Institutional Funding ◽  
Eliza Hall Institute ◽  
Hall Institute

Abstract Background: Acute myeloid leukaemia (AML) arises from the transformation of hematopoietic stem and progenitor cells. Targeting BCL-2 with the BH3-mimetic venetoclax (VEN) has emerged as a highly efficacious treatment option for elderly patients with AML, in combination with either low-dose ara-C (LDAC) (Wei, ASH 2017) or hypomethylating agents (HMA) (Di Nardo, Lancet Oncol 2018). Long-term survival outcomes, however, remain poor among patients with adverse risk karyotype, who often harbour mutations in the TP53 gene. Identification of more effective treatment options with TP53 independent activity represents an area of high unmet therapeutic need in AML. Methods: Panobinostat (histone deacetylase inhibitor; HDACi) was obtained from Novartis, S55746 (BCL-2 inhibitor) was obtained from Servier, and venetoclax (BCL-2 inhibitor) was obtained from Selleck Chemicals. Primary AML samples were obtained from patients providing informed consent. For in vivo experiments, NOD/Rag-/-/Il2rgtm1Wjl Tg(IL3, CSF2, KITLG) (NRG-SG3) mice were used. Dosing for S55746 was 100mg/kg daily Mon-Fri and panobinostat 10mg/kg on Mon/ Wed/ Fri. Results: A panel of 22 drugs were screened for enhanced anti-leukaemic activity in combination with BH3-mimetics targeting either BCL-2 or MCL1 against 45 primary AML patient samples. This revealed the histone deacetylase inhibitor (HDACi) panobinostat to have substantially enhanced efficacy: LC50 at 48h was reduced by >2 logs when combined with VEN to target BCL-2 in 13/21 (62%) or S55746 in 19/24 (79%) cases. Targeted exome sequencing revealed adverse-risk AML, including TP53 mutant cases, to be sensitive to this combination. Studies performed in factor dependent myeloid (FDM) cells, derived from gene knockout mice, demonstrated cell death from panobinostat to be Bax/Bak dependent. CRISPR/Cas9 BIM (MV4;11) and TP53 (OCI-AML3) deleted AML cell lines confirmed panobinostat-VEN activity to be independent of these pathways. Comparison of panobinostat in combination with BCL-2 targeting showed the combination to be less affected by p53 deficiency than cytotoxic (idarubicin, ara-C) + BCL2 inhibitor combinations. Patient-derived xenograft (PDX) models confirmed that this combination was tolerable and able to rapidly suppress bone marrow AML in vivo. Exploratory CyTOF and Western blot studies in MV4;11 cells showed that panobinostat +/- BCL-2 targeting markedly suppressed levels of MYC, pSTAT5 and pERK. Conclusions: Combined targeting of HDAC and BCL-2 represents a promising, chemotherapy-free, treatment option for patients with AML, including sub-groups with adverse risk genomic characteristics. The combination may have particular relevance for patients with adverse risk AML, including cases defective in functioning TP53. Figure. Figure. Disclosures Teh: The Walter and Eliza Hall Institute of Medical Research: Other: Institutional funding for venetoclax including milestone and royalty payments.. Kraus-Berthier:servier: Employment. Kloos:Servier: Employment; Novartis: Other: Partnership. Schoumacher:Servier: Employment. Gray:The Walter and Eliza Hall Institute of Medical Research: Other: Institutional funding for venetoclax including milestone and royalty payments.. Wei:Celgene: Honoraria, Other: Advisory committee, Research Funding; Novartis: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau; Amgen: Honoraria, Other: Advisory committee, Research Funding; Pfizer: Honoraria, Other: Advisory committee; Servier: Consultancy, Honoraria, Other: Advisory committee, Research Funding; Abbvie: Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

Clinicopathological Features and Outcomes of Progression for Chronic Lymphocytic Leukaemia (CLL) Treated with the BCL2 Inhibitor Venetoclax

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3223-3223 ◽  
Author(s):  
Thomas E Lew ◽  
Mary Ann Anderson ◽  
Constantine S. Tam ◽  
David C.S. Huang ◽  
Surender Juneja ◽  
...  
Keyword(s):  
Risk Factors ◽  
Medical Research ◽  
Board Of Directors ◽  
Research Funding ◽  
Univariate Analysis ◽  
Complex Karyotype ◽  
Advisory Committees ◽  
Risk Of Progression ◽  
Eliza Hall Institute ◽  
Hall Institute

Abstract Background: The natural history of CLL/small lymphocytic lymphoma (SLL) treated with chemo-immunotherapy included enrichment for del(17p) with each progression and evolution to Richter transformation (RT) in some patients (pts) with refractory disease.In early phase clinical trials, the BCL2 inhibitor venetoclax achieves objective responses in ~80% of pts with heavily pre-treated relapsed/refractory CLL/SLL, irrespective of disease bulk, chemo-refractoriness or del(17p)/TP53 aberrations. However, the nature of progressions during ongoing therapy has not yet been well characterised. We report the clinicopathological features, outcomes and dominant predictors of progression on venetoclax for CLL/SLL. Methods: We retrospectively reviewed data from 67 pts treated with venetoclax for relapsed/refractory CLL/SLL at two institutions in Australia between June 2011 and March 2016. Pts were enrolled in 1 of 3 ongoing trials: Phase 1 venetoclax monotherapy (NCT01328626), Phase 1b venetoclax + rituximab (NCT01682616), or Phase 2 venetoclax monotherapy in del(17p) CLL (NCT01889186). Pts received 150Ð1200mg/day of venetoclax ± 6 doses of rituximab (n=16).Forty-nine received the approved dose of 400mg/day or higher.Pts were investigated for RT at progression with PET scans and biopsies. There was no mandated systematic screening for RT at trial entry. Univariate Kaplan Meier, Cox proportional hazards multivariate and Classification and Regression Tree (CART) analyses were used to identify risk factors for progression. Results: Median age was 68 (range 20Ð87) years; pts had received a median 3 (1Ð12) prior therapies. CLL/SLL was fludarabine refractory (F-refr; defined as no response or progression within 6 months) in 51%. With median follow up of 23 (2Ð46) months, 25 pts (37%) had progressed; 17 (68%) with RT (14 DLBCL, 3 Hodgkin-like) and 8 (32%) with CLL/SLL. Median time-to-progression (TTP) was 8 (1Ð23) months for RT and 23 (7Ð38) months for CLL/SLL (p = 0.0033). PET scans were performed in 12/17 cases of RT. High FDG-avidity disease (SUVmax > 10) was multifocal in 9 cases (median 4 sites (2 Ð 10)),unifocal in 2 and negative in 1pt with histologically confirmed DLBCL RT. All 13 cases of DLBCL RT tested for BCL2 protein expression by IHC were positive. TTP was closely related to best iwCLL response (median: not reached, 25 and 6 months for CR, PR and SD, respectively; p<0.0001). Univariate analysis examined putative factors associated with modulation of risk of progression in pts treated at _400mg/day (n=49) including: age, number of prior therapies, disease bulk (>5 cm), presence of del(17p), presence of del(17p) and/or TP53 mutation, del(11q), and concurrent rituximab therapy. None were statistically significant (p>0.1). F-refr disease and complex karyotype (defined as ³3 cytogenetic abnormalities on conventional karyotype) were associated with risk of progression by univariate analysis (HR 6.1, p=0.0052;and HR 6.6, p=0.0045, respectively; see Figure). A limited power multivariate and CART analysis supported independence between these variables. Median overall survival after progression was 11.4 months (32% at 2-years). Salvage chemotherapy was used in 16/17 pts with RT, followed byautograftsor allografts in 2 cases each. Seven pts with RT remain alive (response to salvage: 5 CR, 2 PR), including all 3 pts with Hodgkin-like RT (22, 23 and 43 months post progression). Three pts with DLBCL RT who responded to salvage (2 CR, 1 PR) subsequently progressed with CLL/SLL and remain alive on BTK inhibitors (BTKIs) at 30, 34 and 38 months. Six of 8 pts with progressive CLL/SLL onvenetoclaxwere treated withibrutinib(5 PR, 1 SD) and 3 remain alive on therapy at last follow up (6, 6 and 9 months). Conclusions: F-refractoriness and complex karyotype are the dominant risk factors for progression onvenetoclax, which may presentearly as RT, as might be expected in heavily pretreated patients with these risk factors, or later as CLL/SLL, with PET features being discriminatory. A minority of pts with RT progression can attain durable disease control with multimodality therapy and progressive CLL/SLL can respond to BTKIs, even if after RT. Patients with CLL/SLL that isF-refr or has complex karyotype should have clinically occult RTexcluded before treatment with venetoclax monotherapy. Disclosures Anderson: Walter and Eliza Hall Institute of Medical Research: Other: Walter and Eliza Hall Institute of Medical Research receives milestone payments for the development of venetoclax. Tam:janssen: Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Huang:Walter and Eliza Hall Institute of Medical Research: Other: Walter and Eliza Hall Institute of Medical Research receives milestone payments for the development of venetoclax. Seymour:Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Roberts:Walter and Eliza Hall Institute of Medical Research: Employment.

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