Updated Safety and Efficacy Results from a Phase 2 Study of Acalabrutinib, Venetoclax and Obinutuzumab (AVO) for Frontline Treatment of Chronic Lymphocytic Leukemia (CLL)
Authors: Davids Matthew S. , Lampson Benjamin L. , Tyekucheva Svitlana , Crombie Jennifer L. , Ng Samuel , Kim Austin I. , Weinstock Matthew , Lowney Jessica , Pazienza Samantha , Montegaard Josie , Patterson Victoria , Jacobson Caron A. , LaCasce Ann S. , Armand Philippe , Arnason Jon E. , Fisher David C. , Brown Jennifer R. 
Published: November 2020

Background
Despite active frontline regimens including venetoclax (V) plus obinutuzumab (O) and continuous BTK inhibitors (BTKi), the outcomes for some CLL patients (pts) remain suboptimal. The ibrutinib (I) plus V doublet and IVO triplet are active (Jain et al., NEJM, 2019, Huber et al., EHA, 2020), but are associated with cardiac and infectious toxicities. We hypothesized that a time-limited triplet with a more specific BTKi acalabrutinib (A) with V and O (AVO) would be well-tolerated and active. We report updated data from a phase 2 trial of AVO in previously untreated CLL pts enriched for high risk disease.
Methods
This ongoing phase 2 investigator-initiated study (NCT03580928) initially enrolled unselected pts with previously untreated CLL. A recent protocol amendment restricted additional enrollment to pts with TP53 aberrant CLL. Additional eligibility: treatment required per iwCLL criteria, ECOG PS ≤ 2, CrCl ≥50ml/min, ANC ≥500/mm3, and platelets ≥30,000/mm3. A, V, and O are started sequentially, with a 28-day lead-in with A at 100 mg bid, then 2 cycles of AO (with O at standard dosing), then AO plus a 4-week V ramp-up beginning C4D1 with 20 mg, then 50 mg on C4D2, then weekly ramp-up to 400 mg qd. After 3 more AVO cycles (6 total cycles of O), AV continues from C8-C15; pts with bone marrow undetectable MRD (BM-uMRD) CR after C15 may discontinue therapy, while all others continue AV until completing C24, with the option to discontinue if BM-uMRD then. Response by 2018 iwCLL criteria, with central MRD testing by 8-color flow cytometry in peripheral blood (PB) and BM at 10-4. Primary endpoint: rate of BM-uMRD CR at C16D1. Non-heme AEs by CTCAE v5.0, and heme toxicity by iwCLL criteria.
Results
As of July 24, 2020, 44 pts were accrued. Median age: 63 yrs (range: 41-78), 68% male. Baseline prognostics: TP53 aberrant (either del(17p) and/or TP53 mutation) in 17 (39%) pts, del(11q) in 12 (27%) pts, complex karyotype (3 or more changes) in 9 (20%) pts, unmutated IGHV in 29 (66%) pts. With a median follow-up of 19 mo. (range 6-26), 43 pts remain on study (1 withdrew consent after 6 mo. due to GI symptoms). Of 36 pts with at least 16 mo. of follow-up, the overall response rate is 100% (43% CR/CRi, 57% PR [in most cases due to small residual lymph nodes]), with 31% BM-uMRD CR at C16 (primary endpoint). By ITT at C16, 84% PB-uMRD and 78% BM-uMRD. In the 10 pts with TP53-aberrant disease who have reached C16 to date, 4 had CR and 6 had PR, with 9/10 pts PB-uMRD and 7/10 pts BM-uMRD. Response and uMRD did not differ based on IGHV status. Eleven pts in BM-uMRD CR discontinued therapy as allowed per protocol after 15 cycles. Median time off therapy for these pts is 4 mos (range: 1-10). No pts have progressed to date.
The most frequent non-heme AEs have been headache (80%, 61% gr1, 16% gr2, 2% gr3), fatigue (77%, 75% gr 1+2, 2% gr3), bruising (57%, 55% gr1, 2% gr2), nausea (45%, all gr 1/2), hypocalcemia (34%, 32% gr 1+2, 2% gr3), rash 32% (30% gr1, 2% gr2), and diarrhea (27%, 18% gr1, 9% gr2). Gr 3/4 heme toxicities: neutropenia (34%), thrombocytopenia (23%), and anemia (4.5%). G-CSF was used in 5 pts (11%). Infusion-related reactions occurred in 11 pts (25%, 23% gr1+2, 2% gr3). One case of gr3 afib (2%) and no cases of major bleeding or febrile neutropenia were observed. 6 pts required dose reductions, including 4 who reduced both A and V, and 1 pt each who reduced A or V alone. SAEs: gr4 neutropenia (n=4), and 1 pt each with gr3 lung infection, cardiac troponin increase, thrombocytopenia, and hyperkalemia. Gr≥3 infection occurred in 1 pt (2.3%). Transient lab TLS occurred in 2 pts (4.5%), both gr3 just after starting O (prior to any V). 41/44 pts (93%) were medium or high risk for TLS at baseline, but only 3 pts (7%) were medium risk at V initiation on C4D1. Five low or medium risk pts were admitted at investigator discretion for V initiation.
Conclusion
The AVO triplet is highly active, with 78% achieving BM-uMRD after 15 months of time-limited therapy in a frontline CLL population that included nearly 40% pts with TP53 aberrant disease. No pts have progressed, with a median of 19 months follow-up. The safety profile is favorable, with a 2% rate of ≥Gr3 infection and afib, and no TLS due to V, which was given with a more convenient 4-week ramp-up. AVO is now being studied in a registrational phase 3 trial CL-311 (NCT03836261) with the potential to define a new standard frontline therapy option for CLL pts.

Disclosures
Davids: TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Sunesis: Consultancy; Research to Practice: Honoraria; Janssen: Consultancy; Merck: Consultancy; Surface Oncology: Research Funding; AbbVie: Consultancy; Celgene: Consultancy; MEI Pharma: Consultancy, Research Funding; Zentalis: Consultancy; Gilead Sciences: Consultancy; Novartis: Consultancy, Research Funding; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Eli Lilly: Consultancy; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Syros Pharmaceuticals: Consultancy; Bristol Myers Squibb: Research Funding. Crombie:Bayer: Research Funding; Abbvie: Research Funding. Montegaard:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: KOL lecture seires guest lecturer. LaCasce:Research to Practice: Speakers Bureau; BMS: Consultancy; UptoDate: Patents & Royalties. Armand:Adaptive: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Merck: Consultancy, Honoraria, Research Funding; Affimed: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; Genentech: Research Funding; IGM: Research Funding; Infinity: Consultancy; Otsuka: Research Funding; Pfizer: Consultancy; Roche: Research Funding; Sigma Tau: Research Funding; Tensha: Research Funding. Arnason:Regeneron: Consultancy; Juno: Consultancy. Fisher:Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Brown:BeiGene: Consultancy; Catapult: Consultancy; Dynamo Therapeutics: Consultancy; Eli Lilly and Company: Consultancy; Juno/Celgene: Consultancy; Kite: Consultancy; MEI Pharma: Consultancy; Nextcea: Consultancy; Novartis: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy; Rigel Pharmaceuticals: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Sun: Research Funding; Acerta: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Gilead: Consultancy, Research Funding; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Astra-Zeneca: Consultancy; Janssen: Honoraria; AbbVie: Consultancy.

OffLabel Disclosure:
Although acalabrutinib, venetoclax, and obinutuzumab are each approved for frontline CLL, the AVO combination is not approved and therefore considered off-label.