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Dose Escalation Study With Novel Bcl-2 Inhibitor ABT-199 Shows Antitumor Activity and Manageable Safety Profile in Relapsed/Refractory CLL and SLL


Dose Escalation Study With Novel Bcl-2 Inhibitor ABT-199 Shows Antitumor Activity and Manageable Safety Profile in Relapsed/Refractory CLL and SLL

• Multicenter, open-label, dose-escalation phase I study[1]
Summary of Key Conclusions
• ABT-199 antitumor activity seen in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL)
    o ORR 84%, including CR 23%
    o Similar efficacy in high-risk patients with del(17p) and fludarabine-refractory disease
    o No or low-level minimal residual disease (MRD) detected in patients who achieved CR
    o Observed reduction of nodal masses, bone marrow infiltration, and lymphocyte counts by ? 50%
• Known risk of tumor lysis syndrome managed with revised dosing scheme, prophylaxis, and monitoring
    o No new tumor lysis events on new dosing scheme
    o Expanded safety cohort enrolled in study
• Further study of ABT-199 planned
    o Phase II monotherapy in relapsed CLL patients with del(17p)
    o Combination studies with rituximab or obinutuzumab in relapsed CLL
• Overexpression of antiapoptotic proteins, such as Bcl-2, and deficiency of proapoptotic proteins often results in dysregulation of apoptotic pathway in CLL/SLL
    o Contributes to resistance to cytotoxic agents
    o Novel agents needed in relapsed/refractory CLL/SLL
• ABT-199: potent, oral, selective, high-affinity Bcl-2 inhibitor
    o Preliminary antitumor activity
    o Demonstrated rapid tumor lytic activity in small number of patients with refractory CLL[2]
• Current dose-escalation study investigating safety, maximum tolerated dose, pharmacokinetics, and preliminary efficacy of ABT-199 in relapsed/refractory CLL/SLL and non-Hodgkin’s lymphoma
    o Current analysis presents CLL/SLL study arm data
Summary of Study Design
• Dose-escalation study
    o Initial dosing scheme

  • 50-mg dose on Day -7 for pharmacokinetic monitoring
  • Continuous once-daily dosing Week 1
  • Step up dose 100-400 mg Week 2
  • Designated cohort dose 150-1200 mg Week 3 until progression or unacceptable toxicity
  • Revised dosing schema following incidence of tumor lysis syndrome and 1 patient death due to resulting ischemia in December 2012

    o Revised dosing scheme in safety expansion cohort (n = 11)

  •  Week 1, Day 1: 20-mg test dose
  •  In absence of signs of tumor lysis syndrome or changes in peripheral blood lymphocytes, 50-mg dose on Days 2-7
  •  Stepwise 100-, 200-, and 400-mg dosing Weeks 2-4

• Inclusion criteria
    o CLL or SLL relapsed or refractory to fludarabine or alkylator-based therapy
    o Measurable disease requiring treatment
    o ECOG performance status ? 1
    o Adequate bone marrow function defined as neutrophils ? 1000/mL and platelets ? 50,000/mL
    o Adequate renal (creatinine clearance > 50 mL/min) and hepatic function
• Exclusion criteria
    o Active infection
    o Prior autologous or allogeneic stem cell transplant
Baseline Characteristics
• N = 67 patients
    o CLL: n = 58
    o SLL: n = 9

Description of Current Analysis
• 67 patients enrolled; 43 active
• Median time of study: 10.9 months (range: 0.03-23.7)
• Discontinuations
    o PD: n = 14
    o Adverse events (AEs): n = 8
    o Transplant: n = 1
    o Other: n = 1
• Primary endpoints
    o Safety and pharmacokinetics
    o Determine maximum tolerated dose and recommended phase II dose
• Secondary endpoints
    o Preliminary efficacy

  •  ORR
  •  Duration of response
  •  Time to tumor progression
  •  PFS
  •  OS

    o Biomarkers and pharmacogenomics
• Responses confirmed through 2 computed tomography scans approximately 8 weeks apart
Main Findings
• Safety profile
    o Many low-grade AEs, especially gastrointestinal events and neutropenia

  • Neutropenia usually transient

    o Dose-escalation schedule revised in conjunction with initiation of tumor lysis syndrome (TLS) prophylaxis and monitoring after TLS developed in some patients

• Serious AEs likely treatment related

• Preliminary pharmacokinetics
    o After single dose with low-fat meal, time to peak concentration (Cmax): 6 hours
    o Terminal elimination half-life: approximately 17 hours
    o Drug exposure (Cmax and area under the concentration curve) approximately dose proportional between 150-mg and 800-mg doses at steady-state
• Preliminary evidence of antitumor activity
    o 88% of evaluable patients (n = 57) had ? 50% reduction in sum of product of diameters of nodal masses; median       time to 50% reduction 6 weeks
    o 89% of evaluable patients (n = 37) showed ? 50% reduction of bone marrow infiltrate by Week 24
    o 100% of evaluable patients (n = 38) showed ? 50% reduction of lymphocyte count; median time to 50% reduction 15       days (range: 1-170)
    o All effects seen across all dose cohorts
• ABT-199 response seen in 84% of evaluable patients (n = 56)
    o Efficacy similar in patients with high-risk CLL
    o MRD assessed in 9 patients with CR

  • No detectable MRD in 5 patients, including 3 fludarabine refractory and 1 fludarabine refractory and with del(17p)
  • Low-level MRD in 4 patients

1. Seymour JF, Davids MS, Pagel JM, et al. Bcl-2 inhibitor ABT-199 (GDC-0199) monotherapy shows anti-tumor activity including complete remissions in high-risk relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Program and abstracts of the 55th American Society of Hematology Annual Meeting and Exposition; December 7-10, 2013; New Orleans, Louisiana. Abstract 872.
2. Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19:202-208.

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