ALBERT

Description: Backgound Venetoclax (V) plus obinutuzumab (O) regimen is active as frontline CLL treatment; a little over half of patients (pts) will achieve undetectable minimal residual disease in the bone marrow (BM-uMRD) with one year of time-limited therapy (Fischer et al. NEJM 2019). Novel strategies may further augment the efficacy of VO. Ibrutinib was previously combined with VO, but relatively high rates of infusion reactions and neutropenia were observed, as were the characteristic toxicities of ibrutinib including diarrhea and bruising (Rogers et al. Blood 2018). Acalabrutinib (A), a more selective BTK inhibitor, is well-tolerated and active as monotherapy or with O, and we previously found that it sensitizes CLL cells to V (Deng et al. Leukemia 2017). We hypothesized that a time-limited triplet combination of A, V, and O (AVO) could achieve a high rate of BM-uMRD with good tolerability. For the first time we now report on the safety and preliminary efficacy data of AVO in previously untreated CLL pts. Methods This ongoing open-label, single arm, phase 2 investigator-initiated study (NCT03580928) enrolled pts with previously untreated CLL without restriction by prognostic marker status. Eligibility: requiring treatment by iwCLL criteria, ECOG PS ≤ 2, creatinine clearance ≥50ml/min, absolute neutrophil count ≥500/mm3, and platelets ≥30,000/mm3. A, V, and O are started sequentially (see figure), with one 28-day cycle lead-in with A at 100 mg bid, then 2 cycles of AO (with O at standard dosing), then V ramp-up beginning at C4, followed by 3 more cycles of triplet AVO therapy. After 6 months of O, the AV doublet continues through C15; pts with BM-uMRD-negative CR after C15 may discontinue therapy, while all others continue AV until completing C24, with the option to discontinue therapy if in BM-uMRD CR at that time. Response is assessed by 2018 iwCLL criteria, including bone marrow biopsy with MRD testing in the BM and peripheral blood (PB) by 8-color flow cytometry at a sensitivity of at least 10-4. The primary endpoint is the rate of BM-uMRD CR after 15 cycles. Non-hematologic adverse events (AEs) are assessed by CTCAE v5.0, with hematologic toxicity determined by iwCLL criteria. Results The data cut for this interim analysis was July 11, 2019. The study is fully accrued at 37 pts. Median age: 63 years (range: 41-78), 73% male. Baseline prognostic features: unmutated IGHV in 23 (62%) pts, TP53 aberrant disease (defined as either del(17p) and/or TP53 mutation) in 10 (27%) pts, del(11q) in 10 (27%) pts, and complex karyotype in 7 (19%) pts. Thirty-six pts remain on study drugs with a median time on therapy of 8 months (range: 2-11). One pt withdrew consent after 6 cycles due to gastrointestinal symptoms. The overall response rate for the 24 pts who have completed re-staging at C8 is 100%, 18 (75%) PR and 5 (25%) CR. At C8 restaging, 65% of pts were PB-uMRD, 50% of pts were BM-uMRD, and 3 pts (13%) had BM-uMRD CRs. In 8 pts with TP53-aberrant disease who have reached C8, 6 had PR and 2 had CR, with 3 pts BM-uMRD. The most frequent AEs have been fatigue (81% total, 78% gr 1+2, 3% gr ≥3) and headache (76% total, 73% gr 1+2, 3% gr ≥3). Bruising was reported by 16 pts (43%, all gr 1+2). The most frequent gr 3/4 AE has been neutropenia (68% total, 32% gr ≥3). Infusion-related reactions were seen in 8 pts (22%, 19% gr 1+2, 3% gr ≥3). Laboratory tumor lysis syndrome (TLS) occurred in 2 pts (5%), both gr 3 immediately after starting O and prior to any V; both pts continued O. Out of 32 pts, 31 (97%) were medium-to-high risk for TLS on C1D1 but only 3 (9%) were medium-to-high risk at V initiation on C4D1, with 4 medium-to-low risk pts electively admitted for V initiation. One case of gr 3 atrial fibrillation and no cases of hemorrhage or febrile neutropenia were observed. Conclusion Our preliminary data suggest that even at an early response evaluation after 8 cycles of therapy (including only 4 months of V), AVO as frontline CLL therapy leads to a high proportion of pts achieving BM-uMRD and CR, including pts with TP53-aberrant disease. The AE profile is favorable, with a low rate of infusion reactions and no significant cardiac or bleeding toxicities. Updated data will be presented at the meeting for this ongoing study. Based on our initial results we have opened an expansion cohort to further characterize the efficacy and safety of AVO. AVO will also be studied head-to-head against chemoimmunotherapy and the AV doublet in the phase 3 trial CL-311 (NCT03836261), which is currently enrolling. Figure Disclosures Montegaard: Pharmacyclics: Consultancy; Janssen: Consultancy. Jacobson:Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel Expenses; Pfizer: Consultancy, Research Funding; Humanigen: Consultancy, Other: Travel Expenses; Bayer: Consultancy, Other: Travel Expenses; Precision Biosciences: Consultancy, Other: Travel Expenses; Celgene: Consultancy, Other: Travel Expenses. Jacobsen:Astra-Zeneca: Consultancy; Novartis: Research Funding; F. Hoffmann-LaRoche: Research Funding; Takeda: Honoraria; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Acerta: Consultancy. LaCasce:Seattle Genetics: Consultancy, Research Funding; BMS: Consultancy; Research to Practice: Speakers Bureau; Humanigen: Consultancy. Arnason:Regeneron Pharmaceuticals, Inc.: Consultancy; Celgene/Juno: Consultancy. Armand:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Otsuka: Research Funding; Sigma Tau: Research Funding; Infinity: Consultancy; Genentech: Research Funding; Pfizer: Consultancy; ADC Therapeutics: Consultancy; Tensha: Research Funding. Brown:BeiGene: Consultancy; AbbVie: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Juno/Celgene: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy, Research Funding; Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy. Davids:AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding; Research to Practice: Honoraria. OffLabel Disclosure: Acalabrutinib, venetoclax, obinutuzumab - combination therapy for previously untreated CLL

Description: Introduction: Duvelisib (DUV), an oral inhibitor of PI3K-δ/γ, and venetoclax (VEN), an oral inhibitor of BCL-2, are both approved for relapsed/refractory (R/R) CLL. We previously found that PI3K-δ inhibition sensitizes CLL cells to ex vivo BCL-2 inhibition (Davids et al., Blood, 2012). We hypothesized that DUV plus VEN would lead to deep remissions that allow for an all oral, time-limited therapy. Here, we report for the first time on a phase I study of DUV plus VEN for patients (pts) with R/R CLL/SLL. Methods: This is an investigator-initiated phase I trial with primary endpoints: DLTs, MTD, and RP2D of VEN plus DUV in pts with R/R CLL/SLL. Secondary endpoints: PK, preliminary efficacy. Pts are treated as per Figure 1, with a 7-day lead-in of DUV 25 mg BID. On day 8, DUV was continued and VEN initiated at 10 mg QD, with weekly ramp-up to 20/50/100 (dose level 1), 200 mg (dose level 2), and 400 mg (dose level 3). The last 3 pts initiated VEN at 20 mg. A 3+3 design was used, and the DLT observation period was the first cycle. Eligibility criteria: ≥1 prior therapy, requiring therapy by 2008 iwCLL criteria, ECOG PS ≤2, adequate hematologic and organ function, no prior VEN or DUV. CTCAE v5 and 2008 iwCLL were used to evaluate toxicity and efficacy. PK testing was performed at each VEN dose escalation and just prior to cycle 2. MRD was assessed by 8-color flow at a sensitivity of 10-4 (Mayo Laboratories) in the peripheral blood (PB) and bone marrow (BM). Results: As of July 12, 2019, 12 pts were evaluable. Median age 69 yrs (range 50 to 78). Del(17p): 3/12 (25%), del(11q): 1/12 (8%), unmutated IGHV: 12/12 (100%), mutation in NOTCH1: 7/12 (58%) and TP53: 5/12 (42%) pts. Median prior treatments: 3 (range 1-6), including 2 pts relapsed after alloHCT. Ten pts had prior BTKi, including 3 who progressed on therapy. No DLTs were observed, and the RP2D of VEN in combination with DUV was the approved dose of 400 mg. Most pts had baseline cytopenias, with a median ANC of 3 (range 1.19-7.78), Hgb 7 (range 7.6-13.5), PLT 43 (range 21-221). Heme toxicities were common and included: neutropenia (100%, 83% ≥ gr3), anemia (100%, 33% ≥ gr3), and thrombocytopenia (75%, 8% ≥ gr3). Nine pts required G-CSF support. All grade non-heme tox in 〉25% of pts: fatigue (92%, all gr1/2), hyperglycemia (100%, 25% gr1, 58% gr2, 17% gr3), hypocalcemia (100%, 50% ≥ gr3), hypophosphatemia (67%, 25% ≥ gr3), elevated alk phos (58%, all gr1/2), elevated AST (58%, all gr1/2), hypokalemia (50%, 17% ≥ gr3), hypomagnesemia (50%, all gr1/2), rash (50%, 8% ≥ gr3), diarrhea (42%, 8% ≥ gr3), and hyponatremia (42%, 8% ≥ gr3). SAEs: gr3 amylase/lipase, and gr3 febrile neutropenia (n=1 each). No laboratory or clinical tumor lysis syndrome (TLS) was observed per Cairo-Bishop criteria. One pt with medium TLS risk who initiated VEN at 20 mg had an increase in LDH prompting a brief VEN hold; a second pt with medium TLS risk had an early rise in K rapidly responsive to intervention and later LDH increase prompting a brief VEN hold. Five patients required DUV holds for asymptomatic elevation in amylase and/or lipase (n=4), rash (n=2), bronchitis (n=1), or diarrhea (n=1). Four pts required steroids for toxicity management. PK analyses demonstrated that VEN exposure increased with increasing doses in the presence of DUV. After receiving 25 mg DUV BID, 4h VEN plasma concentrations following 200 mg and 400 mg VEN were 1,803±819 ng/mL and 2,363±1134 ng/mL, respectively. These VEN concentrations are similar to values in the literature, suggesting no significant drug/drug interaction. At data cutoff, median number of treatment cycles was 6 (range 1-9), and the first 9 pts were evaluable for response (6 had 2 response assessments). Eight of the 9 pts achieved response, with 3 CRs and 5 PRs. Two pts had undetectable MRD (uMRD) in PB and BM (including 1 pt with CR and 1 pt with minimal nodes with SD). One pt with a CR was PB-uMRD only. Three pts have discontinued (1 electively moved to alloHCT, 2 with PD (including 1 ibrutinib progressor who developed Richter's Syndrome (RS)). Conclusions: DUV plus VEN is feasible in pts with R/R CLL/SLL, with no DLTs observed, and a RP2D of VEN 400 mg with DUV 25 mg BID. Although high rates of neutropenia were observed, infections were infrequent. Early efficacy data for this 1-year time-limited, all oral regimen are promising, with CRs and uMRD already observed despite short follow-up. Updated results will be presented at the meeting, and a phase II trial, which includes a cohort for RS, will further evaluate efficacy. Disclosures Montegaard: Pharmacyclics: Consultancy; Janssen: Consultancy. Soumerai:AbbVie: Consultancy; Verastem: Consultancy; BostonGene: Research Funding; Genentech/Roche: Research Funding; TG therapeutics: Research Funding; BeiGene: Research Funding. Arnason:Regeneron Pharmaceuticals, Inc.: Consultancy; Celgene/Juno: Consultancy. Brown:Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; AbbVie: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Juno/Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy. Davids:Research to Practice: Honoraria; AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding. OffLabel Disclosure: Duvelisib and venetoclax are approved for the treatment of CLL, but not in combination

Description: 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.

Description: Introduction: The MURANO study demonstrated that venetoclax (VEN) plus rituximab is an effective regimen for pts with relapsed/refractory (R/R) CLL, but included 2 years of treatment and an infusional component (Seymour et al., NEJM, 2018). Duvelisib (DUV) is an oral inhibitor of PI3K-δ/γ approved for R/R CLL/SLL after two prior therapies. We hypothesized that DUV + VEN would lead to deep remissions that allow for oral, time-limited therapy. DUV + VEN is also promising for Richter's Syndrome (RS), as this combination was synergistic in preclinical models (Iannello et al., ASH, 2019). Here we report the safety and preliminary efficacy of DUV + VEN in pts with R/R CLL/SLL and RS. Methods: This is an ongoing investigator-initiated phase I/II trial (NCT03534323) with primary endpoints: DLTs, MTD, and RP2D (phase I) and CR rate (phase II). Secondary endpoints: PK, preliminary efficacy. Pts are treated with a 7-day lead in of DUV 25 mg BID. In the phase I trial, on day 8, DUV was continued and VEN initiated at 10 mg or 20 mg (inpt) with weekly ramp-up to 20/50/100 (dose level (DL)1), 200 mg (DL2), and 400 mg (DL3) using a 3+3 design. In phase II VEN is started at 10 mg (outpt) or 20 mg (inpt) on day 8 and ramped up to 400 mg on a weekly basis. Pts with RS have the option of an accelerated VEN ramp-up to 400 mg over 5 days (inpt). Pts are treated with DUV + VEN for 12 cycles. If undetectable for minimal residual disease (uMRD), pts can discontinue therapy and reinitiate VEN with recurrence. Pts with persistent MRD after 12 cycles continue VEN. Eligibility criteria for CLL pts: ≥1 prior therapy, requiring therapy by 2008 iwCLL criteria, ECOG PS ≤2, adequate hematologic/organ function, no prior VEN/DUV. For RS, no prior therapy and prior VEN 〉 1 yr ago was allowed. CTCAE v5 and 2008 iwCLL were used to evaluate toxicity and efficacy. MRD was assessed by 8-color flow at 10-4 in the peripheral blood (PB) and bone marrow (BM) (Mayo Laboratories). Results: As of July 19, 2020, 22 pts were treated (phase I (n=12), phase II (CLL n=7, RS n=3)). Median age: 69 yrs (range 50-78). Del(17p): 7/22 (32%), TP53 mutation: 10/22 (45%), del(11q): 2/22 (9%), unmutated IGHV: 20/22 (91%), mutation in NOTCH1: 10/22 (45%). Median prior treatments was 3 (range 1-6), including 2 pts who relapsed after alloSCT. 15/22 (68%) pts had prior BTKi, including 7 progressors. No DLTs occurred in phase I, and PK data showed only modest increase in VEN exposure in the presence of DUV. The RP2D of VEN in combination with DUV was the approved dose of 400 mg. Heme toxicities and all grade non-heme toxicities in 〉25% of pts are shown in Table 1. SAEs included: gr3 febrile neutropenia and lung infection (n=2), gr3 amylase/lipase, gastritis, arthralgia (n=1), gr2 colitis (n=1), and g5 hepatic failure (n=1). All SAEs were reversible with the exception of the gr5 hepatic failure in a pt with RS involvement of the liver. Eleven pts held, 9 pts dose-reduced, and 6 pts discontinued DUV for toxicity. No laboratory or clinical tumor lysis syndrome (TLS) was observed per Cairo-Bishop criteria. VEN was briefly held during ramp-up in 2 pts for elevated LDH and K, then later in 2 pts for neutropenia and thrombocytopenia. At data cutoff, the median number of cycles was 7.5 (range 1-22) and 21 pts were evaluable after at least cycle 4 restaging (CLL n=18, RS n=3). The ORR for CLL/SLL pts was 94% (17/18), with 56% CR (primary endpt) and 39% PR. 61% (11/18) pts had uMRD in the PB, first occurring after cycle 3 (n=4), cycle 6 (n=5), or cycle 10 or 12 (n=1 each). 56% (10/18) pts have thus far achieved BM-uMRD and 4 pts have not yet reached the point of evaluation. 58% (7/12) pts who have to date completed 1 year of DUV + VEN had CR with uMRD in the PB and BM and discontinued therapy, including 2 pts with del(17p). All 4 CLL pts who had progressed on BTKi have responded thus far. Three CLL pts have come off study. One pt with minimal nodal disease achieved uMRD in PB and BM and proceeded to alloSCT. Two pts at DL1 came off study for PD (1 CLL and 1 RS). Of the 3 pts with RS, 1 had disease reduction but was in SD after 3 cycles and started new therapy, and 2 pts had early PD and came off study. 3 pts have died, all with RS. Conclusions: DUV + VEN has a manageable safety profile to date and is active for pts with R/R CLL/SLL, including those who have relapsed after BTKi. High rates of CR and uMRD for this 1-year MRD-guided, time-limited, all oral regimen have already been observed despite short follow-up. Updated results of this actively accruing study will be presented at the meeting. Disclosures Crombie: Bayer: Research Funding; Abbvie: Research Funding. Francoeur:Verastem: Current Employment, Other. 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. Soumerai:BostonGene: Research Funding; Verastem: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; TG Therapeutics: Research Funding; GlaxoSmithKine: Research Funding; Genentech/Roche: Research Funding; Beigene: Consultancy, Research Funding. Arnason:Regeneron: Consultancy; Juno: Consultancy. Brown:Janssen, Teva: Speakers Bureau; Abbvie, Acerta, AstraZeneca, Beigene, Invectys, Juno/Celgene, Kite, Morphosys, Novartis, Octapharma, Pharmacyclics, Sunesis, TG Therapeutics, Verastem: Consultancy; Gilead, Loxo, Sun, Verastem: Research Funding. Davids:Eli Lilly: Consultancy; Verastem: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy; Ascentage Pharma: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Surface Oncology: Research Funding; Novartis: Consultancy, Research Funding; Gilead Sciences: Consultancy; Zentalis: Consultancy; Sunesis: Consultancy; Syros Pharmaceuticals: Consultancy; Research to Practice: Honoraria; Merck: Consultancy; Bristol Myers Squibb: Research Funding; Janssen: Consultancy; MEI Pharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene: Consultancy. OffLabel Disclosure: Duvelisib and venetoclax are not approved in combination for CLL.