Venetoclax and Navitoclax in Pediatric Patients with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma
Authors: Rubnitz Jeffrey E. , Alexander Thomas B. , Laetsch Theodore W. , Khaw Seong Lin , Pullarkat Vinod A. , Opferman Joseph T. , Roberts Kathryn G , Rosenwinkel Lindsey , Tong Bo , Pesko John C. , Badawi Mohamed , Vishwamitra Deeksha , Kim Su Young , Mullighan Charles G , Lacayo Norman J. 
Published: November 2020

Background: Improved therapeutic strategies for patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) remain an unmet need. Venetoclax (Ven), a potent, highly selective, oral B-cell lymphoma 2 (BCL-2) inhibitor, and navitoclax (Nav), an oral BCL-2, BCL-XL, and BCL-W inhibitor, directly bind their BCL-2 family member targets to promote apoptosis. Ven and Nav have shown synergistic antileukemic effects in ALL preclinical models, suggesting dependence on BCL-2 family members. The addition of Ven to low-dose Nav may potentiate efficacy without the dose-limiting thrombocytopenia associated with Nav monotherapy (J Clin Oncol. 2012;30:488). Ven in combination with Nav and chemotherapy are under investigation in a Phase 1, multicenter, open-label, dose-escalation study in patients with R/R ALL and LL (NCT03181126). The results of a previous report on the overall study population (adult and pediatric patients) showed the triplet combination was well tolerated, with promising response rates observed (Jabbour, et al. EHA 2020. Abstract 2389). For the first time, reported here are safety, tolerability, pharmacokinetics, and antitumor activity of Ven with Nav and chemotherapy among the pediatric patients treated in that Phase 1 study.
Methods: Eligible pediatric patients (aged ≥4-&lt;18 years and weight ≥20 kg) with R/R ALL and LL were enrolled to receive 400 mg Ven (weight-adjusted equivalent) daily. Nav was administered daily at 3 dose levels (25, 50, 100 mg) for patients weighing ≥45 kg and 2 dose levels (25, 50 mg) for patients weighing &lt;45 kg. Dose escalation decisions were guided by Bayesian optimal interval design. Patients could receive chemotherapy (PEG-asparaginase, vincristine, and dexamethasone) at the investigator's discretion. Primary outcome measures included safety assessments and pharmacokinetics. Secondary outcome measures included efficacy assessments. Exploratory biomarker assessments included evaluation of minimal residual disease (MRD). A safety expansion cohort assessed a discontinuous dosing schedule, 21 days on and 7 days off, of Ven with 50 mg Nav (25 mg for patients weighing &lt;45 kg).
Results: As of June 23, 2020, 18 pediatric patients (pts) have enrolled (12 in dose-escalation; 6 in safety expansion); 13, 3, and 2 pts had B-ALL, T-ALL, and LL, respectively. Among pts in the dose-escalation phase, 6 received 25 mg Nav and 6 received 50 mg. Median age was 10 years (range, 6-16 years), 56% of pts were male, and the median number of prior therapies was 2 (range, 1-6). Median time on study was 10.4 months. All pediatric pts experienced treatment-emergent adverse events (TEAEs), and the most common were febrile neutropenia (50%), vomiting (44%), hyperglycemia (39%), and hypokalemia (39%). Grade 3/4 TEAEs occurred in 89% of pediatric pts, and the most common were febrile neutropenia (50%), neutropenia (33%), thrombocytopenia (33%), and anemia (28%). The only Grade 3/4 nonhematologic TEAEs related to Ven or Nav that occurred in &gt;1 pediatric pt were alanine aminotransferase increased (n=2) and vomiting (n=2). Of 8 dose-limiting toxicities (DLTs), 2 occurred in pediatric pts. The 2 DLTs included delayed count recovery (25 mg Nav) and sepsis (50 mg Nav, occurred after database lock). No pediatric pts experienced tumor lysis syndrome. No Grade 5 TEAEs occurred in pediatric pts; 8 pediatric pts (44%) died from disease progression.
Ten pediatric pts (56%) achieved complete response (CR)/CR incomplete recovery (CRi)/CR without platelet recovery (CRp); 7 pts (39%) achieved undetectable MRD. Median overall survival was 11.4 months (95% CI, 2.9 months-not estimable). Eight pts (44%) proceeded to transplantation (n=5) or CAR T-cell therapy (n=3; cells harvested before start of study; Figure). Weight-based dosing of Ven and Nav achieved comparable exposures in pediatric pts. Exploratory correlative biomarker analyses, including BH3 profiling and genomic analyses, are underway and will be presented.
Conclusion: In this Phase 1 study, Ven with Nav and chemotherapy was well tolerated and had promising efficacy in heavily pretreated pediatric patients with ALL and LL. Given that there were four DLTs with 100 mg Nav without evidence of increased efficacy, the recommended Phase 2 dose for adult and pediatric patients is 400 mg Ven with 50 mg Nav for patients weighing ≥45 kg and 25 mg Nav for patients weighing &lt;45 kg.
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Disclosures
Rubnitz: AbbVie Inc.: Research Funding. Alexander:Abbvie, Inc.: Other: Travel Support. Laetsch:Bayer: Consultancy, Research Funding; Cellectis: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Research Funding. Khaw:Amgen: Other: Travel Support, Research Funding; Novartis: Other: Travel Support; AbbVie, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Jazz Pharmaceuticals: Research Funding; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: recipient of a share in royalty payments . Pullarkat:Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Opferman:St. Jude Children's Research Hospital: Current Employment; AbbVie, Inc.: Research Funding; National Institutes of Health: Research Funding. Rosenwinkel:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Tong:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Pesko:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Badawi:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Vishwamitra:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Kim:AbbVie, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: may hold stock or other options. Mullighan:Illumina: Consultancy, Honoraria, Speakers Bureau; AbbVie, Inc.: Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau.

OffLabel Disclosure:
Yes, venetoclax is a BCL-2 inhibitor that is FDA approved for some indications. Venetoclax for treatment of acute lymphoblastic leukemia is not an approved indication.