Updated Results from a Phase I/II Study of Duvelisib and Venetoclax in Patients with Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) or Richter's Syndrome (RS)

Background While venetoclax (VEN) in combination with rituximab is an effective combination for patients (pts) with R/R CLL, it requires 2 years (yrs) of treatment (tx) and intravenous infusions. Duvelisib (DUV) is an oral PI3K-δ/γ inhibitor (PI3Ki) approved for R/R CLL/SLL after 2 prior therapies, and preclinical data support the potential for synergy both in CLL (Patel et al., 2017) and in RS PDX models (Iannello et al., 2019). This ongoing phase I/II study is investigating an all-oral, MRD-guided, time-limited regimen of DUV + VEN. Here, we report updated outcomes, now with nearly 2 yrs median follow-up.

Methods In this ongoing investigator-sponsored trial (NCT03534323), primary endpoints were DLTs, MTD, RP2D (phase 1) and best CR rate (phase 2). Key eligibility criteria for CLL pts: requiring tx by iwCLL criteria, ≥1 prior tx but no prior DUV or VEN, ECOG PS ≤2. For RS pts there was no restriction on # of prior tx, though no VEN was allowed within 1 yr. Pts receive a maximum of 12 cycles of combination DUV + VEN. Tx begins with a 7-day lead-in of DUV 25mg BID, and VEN initiation occurs on day 8. In phase 1, VEN was started at 10mg or 20mg inpatient (inpt) with weekly ramp-up outpatient (outpt) to 50mg, and then to a maximum dose of 100mg, 200mg, or 400mg using a 3+3 design. In phase 2, VEN is initiated at 10mg (outpt) or 20mg (inpt) with weekly ramp-up to 400mg daily. Pts with RS can undergo accelerated VEN ramp-up to 400mg over 5 days (inpt). After 12 cycles, pts with undetectable bone marrow MRD (BM-uMRD) can discontinue tx, with an option to reinitiate VEN at progression, and pts with detectable MRD continue VEN. Assessments: toxicities by CTCAE v5, efficacy by 2008 iwCLL criteria, MRD by central 8-color flow (10^-4 sensitivity). Research funding and DUV were provided by Secura Bio.

Results As of July 13, 2022, 43 pts were enrolled (n=35 CLL and n=8 RS). Median age: 69 yrs (range 50-79); 70% male. 70% unmutated IGHV. In all patients, 42% were TP53-aberrant (del(17p) or TP53 mut); 9% del(11q); 33% complex karyotype (≥ 3 abnormalities); 23% NOTCH1 mut. Median prior tx: 2 (range 1-6). 42% with prior BTKi tx (all ibrutinib).

The RP2D of VEN in combination with DUV was 400mg daily. In the total population of 43 pts, all-grade all-causality heme tox included: neutropenia (64%; 57% Gr3/4), thrombocytopenia (43%; 19% Gr3/4), anemia (33%, 5% Gr3). Notable non-heme tox ≥ 20% included: diarrhea (40%; 7% Gr 3), nausea (40%, 2% Gr3), fatigue (40%, all Gr1/2), hypertension (36%, 7% Gr3), increased alkaline phosphatase (36%, all Gr1/2), headache (26%, all Gr1/2), increased AST/ALT (24%; 7% Gr3), and cough (26%, all Gr1/2). Other notable SAEs ≥ 5%: increased bilirubin (12%, 5% Gr3/4), severe infection (9% Gr3, 1 pt with Gr5 COVID-19 pneumonia). 3 pts had laboratory evidence of tumor lysis syndrome (TLS); 1 pt had clinical TLS with acute kidney injury after the 20 mg VEN dose during ramp-up that fully resolved, and the pt successfully resumed VEN monotherapy. One pt developed a Gr4 gastric perforation while on high-dose steroids to manage diarrhea and discontinued study tx. One pt with RS had Gr5 hepatic failure in the setting of biopsy-proven RS liver involvement.

The median number of cycles was 13 (range 1-44). The best ORR in the pts with CLL (n=35) was 69% (43% CR/CRi, 26% PR; Figure 1A). 31% of pts with CLL achieved PB-uMRD and 31% BM-uMRD (Figure 1A). 9/35 pts (26%) achieved CR/CRi with BM-uMRD after 1 year of DUV+VEN and electively discontinued therapy in remission, including 4 pts with del(17p). In the pts with RS (n=8), 3 achieved a CR and 1 achieved a PR. In the 16 CLL pts with TP53-aberrancy, the best ORR was 50% (CR 44%, PR 6%). In 15 CLL pts with prior BTKi tx, the best ORR was 53% (CR/CRi 40%, PR 13%). Eleven pts remain on tx. Reasons for tx discontinuation include: achievement of BM-uMRD (n=12 CLL), electively moving on to allogeneic transplant (n=2 CLL, n=1 RS), PD (n=3 CLL, n=6 RS), unacceptable tox (n=4 CLL, n=1 RS), death due to COVID-19 pneumonia (n=1 CLL).

The 2-year PFS for pts with CLL was 78% (95% CI: 63-96; Figure 1B) and the 2-year OS was 90% (95% CI: 80-100).

Conclusion A time-limited, all oral regimen DUV + VEN is active in R/R CLL and RS, including in high-risk pts post-BTKi. Immune-mediated and infectious toxicities were observed, but were manageable for most patients. Our data support continued exploration of DUV + VEN in pts with R/R CLL and RS.

Crombie:Incyte: Consultancy; Kite: Consultancy; Karyopharm: Consultancy; Bayer: Research Funding; Abbvie: Research Funding; Roche: Research Funding; Merck: Research Funding. Montegaard:Pharmacyclics: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy. Soumerai:TG Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; Bristol Myers Squibb: Consultancy; Verastem: Consultancy; Biogen: Consultancy; Roche: Consultancy; MEI: Research Funding; Moderna: Research Funding; GlaxoSmithKline: Research Funding; Genentech/Roche: Consultancy, Research Funding; Boston Gene: Research Funding; Beigene: Consultancy, Research Funding; Adaptive Biotechnologies: Research Funding. Alencar:BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo Oncology: Research Funding; SeaGen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; OncLive: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Brown:Beigene: Consultancy; Bristol-Myers Squibb/Juno/Celgene: Consultancy; Catapult: Consultancy; Novartis: Consultancy; Sun: Research Funding; Verastem/SecuraBio: Research Funding; MEI Pharma: Consultancy; Loxo/Lilly: Research Funding; Invectys: Other: served on the data safety monitoring committee; TG Therapeutics: Research Funding; Gilead: Research Funding; Rigel: Consultancy; Pfizer: Consultancy; Morphosys AG: Consultancy; Janssen: Consultancy; Genentech/Roche: Consultancy; Acerta/Astra-Zeneca: Consultancy; Abbvie: Consultancy. Davids:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ascentage Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eli Lilly and Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy; Novartis: Research Funding; Ono Pharmaceuticals: Consultancy; Research to Practice: Honoraria; Takeda: Consultancy; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding.

Duvelisib and venetoclax were investigated in combination.