Promising Results in Leukemia From a BCL-2 Inhibitor

The beta cell lymphoma-2 (BCL-2) protein family—key regulators of apoptosis in human cells—includes both proapoptotic and antiapoptotic/prosurvival proteins. Cancer cells use prosurvival proteins to evade apoptosis, and inhibitors of these proteins have been in development for some time now. ABT-199, the result of a collaboration between AbbVie and Genentech, is a selective, potent, orally available BCL-2 inhibitor (Figure).¹ ABT-199 is being developed for the treatment of acute myelogenous leukemia and chronic lymphocytic leukemia (CLL).

The following posters presented at the meeting provided the current status of this promising drug moiety.

1. ABT-199 in the treatment of diffuse B-cell and follicular lymphoma.²

The objectives of this phase 1 dose-escalation study included evaluation of safety, pharmacokinetics (PK), and preliminary efficacy in patients with relapsed/refractory non-Hodgkin’s lymphoma (NHL). ABT-199 was administered on week 1, day 1, followed by continuous, once-daily dosing from week 1, day 7, until the disease progressed or unacceptable toxicity was observed. A 2- to 3-week lead-in period with stepwise dose titration was implemented. As of April 2014, 20% or more of 62 patients presented with all-grade adverse events (AEs) of nausea, vomiting, anemia, and fatigue, while 5% or more presented with grade 3/4 AEs of anemia, neutropenia, and thrombocytopenia. A case study presented showed anti tumor activity of ABT-199 in a stage 2 mantle cell lymphoma patient who had previously undergone 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, Oncovin, and prednisone) and 2 cycles of R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) and IFRT (involved-field radiation therapy). A 6-week treatment with ABT-199 showed complete clinical resolution of node after 6 weeks. The overall response rate was 48% in the evaluated NHL patients. The authors are in the process of conducting biomarker studies with ABT-199.

2. Interim results from a phase 1b trial of ABT-199 plus rituximab in CLL.³

The objective of this trial was to assess the safety, pharmacokinetics (PK), and preliminary efficacy of ABT-199 with rituximab in patients with relapsed/refractory (R/R) CLL, and to determine a recommended phase 2 dose. The most common treatment-emergent AEs, observed in more than 25% patients, were neutropenia (43%), nausea (38%), and diarrhea (30%). The most common grade 3/4 AEs were neutropenia (43%), thrombocytopenia (16%), and anemia (11%). Two dose-limiting toxicities were observed with ABT-199 + rituximab: thrombocytopenia and hemophagocytic syndrome. The addition of rituximab to ABT-199 identified no new toxicities. The combination was active in R/R CLL with a substantial complete response (CR) rate. Best CR of 89% was observed in R/R patients and 39% achieved CR/CR with inadequate recovery (CRi). Absence of minimal residual disease was observed in 6 of 8 patients tested who had achieved CR/CRi, along with 5 patients who had a partial response. A fatal episode of tumor lysis syndrome (TLS) occurred during the ABT-199 lead-in period, but dosing modifications and increased monitoring prevented the occurrence of any further TLS events. Rituximab did not seem to influence ABT-199 exposure.

A phase 3 trial is ongoing in previously treated CLL patients, to evaluate ABT-199 plus rituximab versus bendamustine plus rituximab.⁴

3. Phase 1 study of ABT-199 in CLL and SLL patients: determine safety, PK, efficiency.⁵

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The primary objectives of this phase 1 study were to evaluate the safety and PK and to determine the maximum tolerated dose and a recommended phase 2 dose of ABT-199 in patients with CLL and small lymphocytic leukemia (SLL). A secondary objective was to assess preliminary efficacy. Following early events of TLS, a weekly ramp-up period to the final cohort dose (150-1200 mg) was implemented. Patients are currently being enrolled in the safety expansion (SE) cohort. Most common AEs observed were diarrhea (37%), nausea (36%), neutropenia (35%), upper respiratory tract infection (29%), and fatigue (27%). Grade 3/4 AEs (≥3 patients) were neutropenia (32%), anemia (8%), TLS (8% including 1 G5), and febrile neutropenia, thrombocytopenia, hyperglycemia, and hypokalemia (6% each). Twenty-eight patients discontinued the study: 18 for disease progression, 8 for AEs, and 2 for other reasons. ABT-199 monotherapy was active in patients with R/R CLL with a 77% RR. Patients with high-risk CLL showed similar efficacy, with OR above 75%. ABT-199 monotherapy and combination therapy in CLL are currently enrolling. This includes a phase 3 trial evaluating the combination of ABT-199 and rituximab compared with bendamustine/rituximab in patients with relapsed CLL4 and combination studies with bendamustine/rituximab and obinutuzumab in patients with relapsed CLL. References

1. 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(2):202-208.

2. Davids MS, Seymour JF, Gerecitano JF, et al. Phase I study of ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL): responses observed in diffuse large B-cell (DLBCL) and follicular lymphoma (FL) Promising Results in Leukemia From a BCL-2 Inhibitor at higher cohort doses. J Clin Oncol. 2014;32(5s suppl 1): Abstract 8522.

3. Ma S, Seymour JF, Lanasa MC, et al. ABT-199 (GDC-0199) combined with rituximab (R) in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): interim results of a phase 1b study. J Clin Oncol. 2014;32(5 suppl 1): Abstract 7013.

4. A study of GDC-0199 (ABT-199) plus MabThera/Rituxan (Rituximab) compared with bendamustine plus MabThera/Rituxan (Rituximab) in patients with relapsed or resistant chronic lymphocytic leukemia. ClinicalTrials.gov website. http://clinicaltrials.gov/ct2/show/NCT02005471. Accessed July 10, 2014.

5. Seymour JF, Davids MS, Pagel JM, et al. ABT-199 (GDC-0199) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL): high completeresponse rate and durable disease control. J Clin Oncol. 2014;32(5s suppl 1): Abstract 7015.

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