Study Of Venetoclax Research Articles

Abstract 5184: Biomarker results from PEVENAZA, a randomized phase 2 study of venetoclax and azacitidine +/- pevonedistat in newly diagnosed AML patients unfit for intensive chemotherapy: Increased efficacy in a subset of patients with IDH1/2 mutations and other observations

Abstract Background: Many newly diagnosed patients with AML are ineligible for intensive chemotherapy due to pre-existing comorbidities and older age. VIALE-A, a phase-3 trial with venetoclax (ven) and azacitidine (aza) established this combination as a new standard of care (SOC) for this patient population. The addition of pevonedistat (pevo) to this combination was evaluated in the same patient population in the current trial (NCT04266795). Here we present results of biomarker analyses from baseline and on-treatment bone marrow samples. Methods: Molecular mutational analysis was performed using a next generation sequencing (NGS) panel on baseline bone marrow samples. Combining this data with cytogenetics allowed centralized assignment of risk category based on ELN2017 guidelines. Longitudinal bone marrow aspirate samples were also examined by multi-color flow cytometry for expression of select surface antigen expression and to identify AML leukemic stem cells (LSCs) from the blast population. Results: Eleven genes were selected for analyses based on prevalence and scientific interest, including DNMT3A, ASXL1, TET2, FLT3, and IDH1/2. In contrast to other genes and ELN risk categories, we observed a statistically significant increase (p-value 0.013) in CR+CRi rates for IDH1/2 mutant patients when treated with pevo + ven + aza (95%, n=21) compared to ven+aza control arm (62%, n=21). In addition, we evaluated the prevalence of CD33, CD123 and CLEC12a, targets of current AML developmental therapeutics, in both the blast and LSC populations at baseline. The median (n=120 pts) % blast cells expressing CD33, CD123, or CLEC12a were 89.8%, 63.2%, and 66.0%, respectively. The median (n=78 pts) % LSCs expressing CD33, CD123, or CLEC12a were 48.2%, 90.9%, and 32.0%, respectively. Importantly, we did not see any significant difference in median fluorescence intensity (MFI) or % expression in any of the three proteins after treatment with ven and aza (+/- pevo). Finally, no strong associations were observed between expression levels and either mutations or ELN risk categories. Conclusions: Analyses of biomarker samples as part of the PEVENAZA trial resulted in several insights for not only the pevonedistat program but also for other AML therapeutics in development. The observation that newly diagnosed patients with IDH1/2 mutations may benefit from the addition of pevo to ven+aza is certainly hypothesis-generating but would require further follow-up with higher patient numbers. In addition, baseline CD33, CD123, and CLEC12a expression levels were in line with published studies. Here we have also shown they remain similar after SOC treatment (ven+aza) supporting the development of agents that target these proteins in both first and second line settings for AML. Citation Format: Radha Ramesh, Xiang Fang, Shuli Li, Sharon Friedlander, Farhad Sedarati, Lionel Adès, Nicholas Short, Cristina Papayannidis, Tammie Yeh. Biomarker results from PEVENAZA, a randomized phase 2 study of venetoclax and azacitidine +/- pevonedistat in newly diagnosed AML patients unfit for intensive chemotherapy: Increased efficacy in a subset of patients with IDH1/2 mutations and other observations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5184.

Outcomes of Patients (pts) with Newly Diagnosed Acute Myeloid Leukemia (AML) and TP53 mutation/Loss Treated on the Phase 2 Study of Venetoclax (Ven) Added to Alternating Cladribine (Clad) Plus Low-Dose Cytarabine (LDAC) and Azacitidine (Aza): A Subgroup Analysis

Background: Despite the introduction of newer drugs and combination therapies, outcomes of patients with AML and TP53mutation (mut) and/or loss continue to remain poor, with a median survival of 6-12 months. The phase 2 study of venetoclax (Ven) added to Clad+ LDAC alternating with azacitidine (Aza) in pts with newly diagnosed (ND) AML demonstrated a composite complete remission (CRc) rate of 93% and median overall survival (OS) not reached (NR) at 22 months (mos) (Kadia et al, JCO, 2022) (NCT03586609) . The trial was amended to increase enrollment, including a prespecified cohort of pts with AML with TP53mut/loss. Methods: This is a subgroup analysis of pts with TP53mut/loss on the phase 2 clinical trial. The treatment protocol has been previously published. Pts with AML with TP53 mut (next generation sequencing, lower limit of detection: 2% variant allele frequency [VAF]) or loss by conventional cytogenetics/fluorescent in situ hybridization and/or array comparative genomic hybridization at AML diagnosis were included. CRc was defined as complete remission (CR) plus CR with incomplete count recovery (CRi). Relapse free survival (RFS) was calculated from response to relapse/death and OS from treatment initiation to death; neither censored for allogeneic hematopoietic stem cell transplantation (HSCT). Results: From Nov 2018-Apr 2023, 124 pts with ND AML were treated on this trial, 14 (11%) of whom had TP53mut/loss. The median age in this subgroup was 66 years (yrs) (range 48-75 yrs) and 8 pts (57%) were male. Two pts (14%) had secondary AML (one treated secondary, post HSCT) and another 2 pts (14%) had therapy-related AML. Twelve pts (86%) had a TP53 mut, 8 of whom had bi-allelic loss (two mut, 1 mut with chromosome 17 loss or 1 mut with VAF≥50%). Two pts (14%) had only TP53 deletion (ie. -17/del17p). CRc was attained in 8 pts (57%) [7 CR (50%) and 1 CRi (7%)] and another pt attained partial remission (PR) with 5% bone marrow blasts as best response. 5/8 pts (63%) pts with CRc attained measurable residual disease (MRD) negativity and 4/8 (50%) also had normalization of their TP53 abnormality . The median therapy cycle to best response was 1. Notably 3 pts (21%) had erythroid leukemia, one of whom attained an MRD+ CR. Nine pts had a complex karyotype, 4 (44%) of whom attained a CRc. 4/8 pts (50%) with bi-allelic TP53 loss attained a CRc (2 became MRD negative by flow cytometry and one cleared both TP53 mutations). Pts received a median of 1 cycle (range, 1-5) of therapy. At a median follow-up of 9 mos from study initiation, the median RFS in the responders was not reached (NR) and 1-yr RFS was 56%; median OS for the entire cohort was NR and 1-yr OS was 56%. The 1 yr-OS in responders was 75%. 4/8 pts with CRc and the pt with PR underwent HSCT at a median of 4.5 mos (range 3.9-5.9 mos) from study therapy initiation; all are alive and in remission at a median of 6 mos (range 1-12.3 mos) from HSCT. Conclusion: The phase 2 trial of Ven added to alternating Clad+LDAC and Aza showed promising remission rates of 57% in pts with ND AML having TP53 mut/loss and high rates of MRD negativity in responders; median RFS and OS was not reached at 9 mos follow-up. Five pts (36% overall, and 50% of the responders) could be consolidated with HSCT, with none of them relapsing after HSCT. The trial continues to accrue pts.

A Phase 1 Study of Venetoclax in Combination with a Pediatric-Inspired Regimen for the Treatment of Newly Diagnosed Adults with B-Cell Ph-like ALL

Background: Aberrant overexpression of pro-survival Bcl-2 family proteins is one mechanism by which leukemic cells circumvent apoptosis. BCL-2 overexpression is common in various subtypes of B-acute lymphocytic leukemia (ALL), including Philadelphia (Ph)-like ALL. Ph-like ALL is a chemotherapy-resistant disease associated with higher rates of induction failure and persistent measurable residual disease (MRD), and poor overall survival (OS) outcomes with frontline chemotherapy regimens, compared to other subtypes. Venetoclax (VEN) is a selective BCL2 inhibitor, and its addition to pediatric-type frontline regimens could improve response and long-term outcomes for B-ALL, including Ph-like subtype. Design: This is a phase 1 study with an expansion cohort investigating the safety of combining VEN with induction (IND) and consolidation (CON) cycles of the CALGB 10403 backbone regimen (NCT05157971). Post CONS therapy was per the treating physician discretion. The study enrolled newly diagnosed adults [18-54 years (yrs)] with Ph-negative B-ALL. To enrich the study for Ph-like ALL, we excluded patients (pts) with KMT2A-rearranged, TCF3::PBX1, and ETV6::RUNX1 subtypes at diagnosis. Identification of Ph-like ALL was performed using RNA-sequencing, conventional cytogenetics, fluorescence in situ hybridization, and whole genome array studies. Dose level (DL) 1 of VEN was 400 mg orally daily on days 1-14 of IND and CON, with a ramp-up dosing during IND [Day 1= 100 mg, Day 2= 200 mg, Days 3-14= 400 mg/day]. Results: We enrolled 14 pts as of July 1 st, 2023. The median age was 33 (20-53) yrs, of which 9 pts were males and 13 (93%) were Hispanics. Seven (50%) pts had Ph-like ALL (6 with CRLF2-alterations, 1 JAK2-fusion). Six pts were treated on the phase 1 part, and no dose limiting toxicity was observed during IND. Among 14 pts that completed IND, all achieved complete remission (CR), including 1 pt who required an extended IND phase, and 79% (n= 11) achieved MRD- (<0.01%) by multicolor flow (MCF) on day 28 of IND. Eleven pts completed CONS, and all achieved undetectable MRD CR or CR with incomplete count recovery (CRi) by MCF. Post CONS next-generation sequencing of MRD (clonoSEQ) was available for all 11 pts who completed CONS, and 7 (64%) were undetectable while 4 were detected at very low levels (range: 0.0007-0.0024%). Median time to neutrophil count ≥1000 and platelet count ≥100,000 were 19 (15-26) and 14 (2-27) days from starting IND, respectively. No pt died during IND or CONS cycles. Grade ≥3 adverse events at least possibly related to venetoclax and/or the C10403 regimen that occurred in ≥ 20% of evaluable pts during either IND or CONS cycles were leukopenia (100%), neutropenia (100%), lymphopenia (100%), anemia (70%), thrombocytopenia (50%), hyperbilirubinemia (30%) and hypertriglyceridemia (20%). Only 1 pt underwent consolidation with allogeneic stem cell transplant while in remission. With a median follow up for the entire cohort of 7.2 months (range: 1.9-16.1 months), only 1 pt with Ph-like ALL relapsed and he is currently alive. Conclusion: The addition of 14 days of VEN at 400 mg daily dose to a pediatric-inspired regimen during IND and CONS was safe in adults with newly diagnosed B-ALL and did not delay counts recovery. The addition of VEN led to a promising higher than expected MRD- CR rate in high-risk B-ALL, including for pts with Ph-like subtype. The study is actively enrolling on the expansion cohort, and BH3 profiling on pre-treatment and post relapse samples will be performed to determine BCL-2 dependency and correlates to early MRD- response.

A Phase I Study of Venetoclax in Combination with Inotuzumab Ozogamicin for Relapsed or Refractory ALL in Adults

Introduction Adults with acute lymphoblastic leukemia (ALL), especially those who are older and/or have unfavorable disease biology frequently relapse. Inotuzumab ozogamicin (INO), an anti-CD22 monoclonal antibody covalently linked to calicheamicin, is approved for treatment of relapsed or refractory (R/R) CD22+ ALL. Although INO induces measurable residual disease negative (MRD-neg) complete remission (CR) in >75% of patients (pts), the duration of response (DOR) is limited (<6 months). Pre-clinical work demonstrates that malignant lymphoblasts are BCL2-dependent (Del Gaizo Moore Blood 2008). Initial results of the BCL2 inhibitor venetoclax (VEN) combination therapies for ALL are promising (Jain ASH 2019, Pullarkat Cancer Discov 2021). Due to distinct mechanisms of activity, non-overlapping toxicity, and possible synergy (Kirchhoff Blood 2021), we hypothesized that INO and VEN can be safely and effectively combined. Study Design and Eligibility This is an investigator-sponsored phase I study (NCT05016947) with a 3+3 dose escalation design. The primary objective is to determine the maximum tolerated dose (MTD) of VEN plus INO at the FDA-approved doses in adults with R/R CD22+ ALL. Secondary objectives assess efficacy (hematologic response, MRD by multi-parametric flow cytometry [MFC] threshold <0.01%, and DOR). A 14 pt expansion cohort is planned. Dose-limiting toxicity (DLT) is defined as treatment-related CTCAE v5 non-heme toxicity grade 3+, sinusoidal obstructive syndrome (SOS) any grade, or liver toxicity during Induction (Ind) Cycle (C) 1 and/or failure of hematologic recovery (ANC ≥500, Plts ≥25 K/mL) by day 42 of Ind C1 in responding pts. Eligibility: ≥18 years (yrs); ALL (≥5% blasts) or LBL (marrow involvement not required); CD22 expression on ≥20% of blasts; R/R to one or more cycles of CC or in the case of Philadelphia-chromosome (Ph)-positive ALL, failed by two or more TKIs, or refractory to/ineligible for ponatinib; ≥60 days from bone marrow transplant (BMT), and off immune suppression ≥2 weeks; adequate liver and kidney function; no history of liver disease including SOS; blast count ≤25 K/mL prior to treatment; no symptomatic central nervous system (CNS) disease. Pts with prior INO or VEN treatment for R/R ALL are excluded. Regimen Pts are treated with a VEN Ramp-Up over 3 days (DL1: 100/200/200; DL2: 100/200/400) followed by Induction C1: IV INO days 1, 8, 15 (0.8/0.5/0.5 mg/m2) and VEN daily per DL days 1-21. DEX 10 mg/m2 IV/PO is administered during Ramp-Up and Ind C1 days 1-4 (7 days total). Pts with >5% blasts after C1 receive Ind C2 without DEX. Pts with <5% blasts after Ind (1 or 2 cycles) continue with up to four 28-day consolidation cycles (INO 0.5 mg/m2 days 1, 8, 15 plus VEN per DL days 1-21). Pts receive CNS prophylaxis with intrathecal chemotherapy. Results The 2-level dose-escalation phase has been completed; we enrolled 9 pts (5 female/4 male) with Ph-negative (n=7) or Ph-positive (n=2) ALL. The median age was 45 yrs (range 25 -74). Pts had received 1 (n=5) or 2 (n=4) prior lines of therapy. DL1 enrolled 3 pts without DLT. All DL1 pts achieved an MRD-neg CR and bridged to consolidation: 1 pt XRT to involved disease site (ankle) after 3 cycles and 2 pts to BMT after 2 cycles (Table). Three pts enrolled at DL2; no DLTs were observed. All achieved an MRD-neg CR. Two pts bridged to consolidation (donor lymphocyte infusion after 3 cycles, blinatumomab after 5 cycles) while 1 pt with KMT2A-r ALL experienced early relapse with lineage switch during second cycle. A confirmatory cohort of 3 pts enrolled at DL2 without DLT. All achieved a CR (n=2, MRD-neg; n=1, MRD-pos). The pt with MRD-pos CR as best response proceeded to blinatumomab as bridge to BMT after 2 cycles with 2 pts continuing treatment (currently cycle 2). Overall, CR was achieved in 100% (9/9) of pts with 7/8 (87%) achieving MRD-negativity. With median follow-up of 195 days (95% CI 80 - NR), 2 pts have relapsed 48 (on treatment) and 177 (after BMT) days from registration while other pts remain alive in CR. Non-heme grade 3-4 AEs include febrile neutropenia (2), DIC (1), tumor lysis syndrome (1), anxiety (1), hypertension (1), and hypotension (1). There have been no SOS. There were no delays in count recovery during C1, with median time from C1 to C2 being 30 days (range 27-42). Conclusion VEN 400mg x 21 days in combination with INO at standard doses was well tolerated and declared the recommended phase 2 dose (RP2D) with a CR rate of 100%.

P-313 ALLG MM25 (VIBER-M): a phase Ib/II study of venetoclax, iberdomide and dexamethasone for patients in first or second relapse of multiple myeloma with t(11;14)

P-313 ALLG MM25 (VIBER-M): a phase Ib/II study of venetoclax, iberdomide and dexamethasone for patients in first or second relapse of multiple myeloma with t(11;14)

Retrospective, real-life study of venetoclax plus azacitidine or low-dose cytarabine in French patients with acute myeloid leukemia ineligible for intensive chemotherapy.

Recently, the combination of venetoclax plus a hypomethylating agent (HMA; azacitidine ordecitabine) or low-dose cytarabine (LDAC) showed promise in Phase III trials in previously untreated AML. In France at the time of this study, venetoclax was not yet approved for AML and there were therefore no formal usage recommendations. Here we report the first study in a French cohort that assessed venetoclax in combination with existing treatments for AML under real-life conditions. This retrospective, real-life study collected data on venetoclax use and management in a French cohort with acute myeloid leukemia (AML) ineligible for intensive chemotherapy. Of 118 patients, 81 were in second line/beyond (71.6% also hypomethylating agent [HMA]; 23.5% lowdose cytarabine [LDAC]) and 37 in first line. For venetoclax initiation, 57.3% underwent ramp up and 74.6% were hospitalized. Median venetoclax duration was 2.5 months (range 0.03-16.2). With all treatment lines and regimens, most common grade 3/4 adverse events were hematologic (overall 96.4% of patients) and infections (57.1%). Dosage adjustments for drug interactions and safety varied between centers. In second-line/beyond, median progression-free survival was 4.0 months (95% confidence interval [CI] 2.7-12.8) with venetoclax-HMA and 3.4 months (1.3-8.9) with venetoclax-LDAC; overall response rate was 51.9% and 41.2%, respectively. Thus, we showed that venetoclax-based treatment yields promising findings in patients with AML, but to address treatment complexity, practice harmonization is needed.

A Prospective Phase 2 Study of Venetoclax and Low Dose Ara-C (VALDAC) to Target Rising Molecular Measurable Residual Disease and Early Relapse in Acute Myeloid Leukemia

Introduction The 2021 European LeukemiaNet (ELN) recognizes MRD relapse as ≥1 log rise confirmed on repeat testing (Heuser Blood 2021). Molecular MRD relapse (e.g. NPM1mut) precedes clinical relapse by ~3-4 months (Ivey NEJM 2016) and provides a window of opportunity for pre-emptive therapy to be delivered prior to clinical relapse. Venetoclax (VEN)-based low intensity therapy is associated with rapid achievement of clinical response in older patients (pts) with AML (DiNardo NEJM 2020 and Wei Blood 2020) but only has modest activity in relapsed/refractory AML. We hypothesized that VEN-based therapy initiated at the time of MRD relapse could be associated with improved clinical response and longer clinical benefit. We therefore conducted a prospective study to explore the efficacy of low dose ara-C (LDAC) + VEN in pts with AML and MRD relapse (ACTRN12619000746134). Methods This multicenter phase 2 study stratified pts into either oligoblastic relapse (marrow blasts 5-15%; Group A), or molecular MRD relapse (Group B). Pts received VEN 600 mg (days 1-28, without dose ramp-up for Group B) and LDAC 20 mg/m2 sc (days 1-10). Primary objectives were morphologic or MRD response (≥1 log reduction) in groups A and B, respectively. Key secondary objectives were realization of allogeneic hematopoietic cell transplantation (HCT), relapse-free (RFS) and overall survival (OS). The study was approved by Alfred Health ethics committee (196/19). NPM1mut and other fusions (per 100 ABL1) from bone marrow were analyzed by RT-qPCR, and IDH1/2mut by Bio-RadTM droplet digital PCR. Results A total of 48 pts were recruited (median age 67; range 18-80). Cytogenetic risk was intermediate in 91%, favorable in 4.5% and adverse in 4.5%. Most (94%) had received prior intensive chemotherapy and only 2 (4%) had received prior HCT in first remission. The median interval from AML diagnosis to study entry was 13.7 months (IQR 9, 23). At the time of study screening, 22 (46%) pts had oligoblastic disease and 26 (54%) MRD relapse. Oligoblastic relapse included pts with early progression not captured by interval MRD surveillance. Pts received a median of 3 cycles (range 1-21+) of VEN-LDAC (ongoing in 11). Reasons for treatment cessation in 37 pts were: HCT (n=19, 51%), treatment failure (n=11, 30%), adverse events (n=3), donor lymphocyte infusion (DLI, n=2) or death before response assessment (n=2). One patient (Group B, NPM1mut) was deemed not evaluable for response assessment after only receiving 9 days of therapy but included in the survival analysis. Among 22 pts with oligoblastic disease, CR/CRi was achieved in 17 (77%). Two additional pts achieved morphologic leukemia-free state and 1 had stable disease. MRD response (≥1 log reduction) among those with an evaluable marker (N=8; all NPM1 mutated) was achieved in 8/8 (100%), with MRD negative in 6/8 (75%) (Figure). Among 25 evaluable pts with MRD relapse, MRD response (≥1 log reduction) was observed in 68% and MRD negative in 52%. Of patients with NPM1mut AML treated at MRD relapse, 13/19 (68%) achieved an MRD response and 10/19 (53%) an MRD negative response (Figure). An MRD response was observed in 2/3 with IDH1/2mut, 1/2 with core-binding factor and 1/1 with KMT2A::MLLT3. Bridging to HCT or DLI (median time 4 months) was successful in 18/27 (67%) pts ≤70 years. With a median follow up time of 14.4 months, the median RFS was 21.5 months and not reached for OS. The estimated 18-month RFS was 63.3% (95% CI, 48.0-83.5) and OS 71.1% (95% CI, 56.5-89.4). Similar outcomes were observed for Groups A and B. Subsequent HCT (as a time-dependent covariate) was the only significant factor for RFS (HR 0.13, 95% CI 0.03-0.61) but not OS (HR 0.48, 95% CI 0.13-1.75) in a multivariate Cox regression model that included age, features at original diagnosis (NPM1, FLT3-ITD and ELN 2017 risk), time since AML diagnosis, and study cohort (A vs B). FLT3-ITD was detected in 3/7 (43%) of relapsed pts. Conclusions In this prospective study of pts with early relapsing AML (oligoblastic or MRD relapse), VEN in combination with LDAC induced a high rate of molecular MRD response, resulting in excellent RFS and OS outcomes. Follow-up is ongoing to determine the durability of response. This novel MRD-targeting approach is being further investigated in a multi-arm, precision-based platform trial ( INTERCEPT: Investigating Novel Therapy to Target Early Relapse and Clonal Evolution as Pre-emptive Therapy in AML; ACTRN12621001265864). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase 1 Study of Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide in Combination with Polatuzumab (ViPOR-P) in Relapsed/Refractory B-Cell Lymphoma: Preliminary Analysis of Safety and Efficacy

Background: Diffuse large B-cell lymphoma (DLBCL) is often curable with frontline chemotherapy; however, pts with relapsed/refractory (R/R) disease and those who fail CAR-T therapy have poor overall outcome. Oral small molecule targeted agents can disrupt key survival pathways in DLBCL, but fail to induce deep or durable responses as monotherapy. We have previously shown that ViPOR is safe and active in DLBCL, with preferential activity in non-GCB DLBCL and HGBCL-DH (Melani et al. Blood. 2020). Synergistic activity has also been demonstrated with MMAE, the chemotherapy payload of Polatuzumab (Pola), with ViPOR in pre-clinical DLBCL cell lines (unpublished data). We hypothesized that additional genotoxic stress with Pola will further leverage efficacy and time-limited, cyclic dosing will limit the hematologic toxicity of the regimen. Methods: R/R aggressive B-cell lymphoma pts with adequate organ function were eligible. In phase 1, a 3+3 design was used to determine the maximum tolerated dose (MTD) of 3 dose-levels (DLs) of Pola IV D2 and venetoclax (Ven) PO D2-14 (DL1: 1.4mg/kg + 600mg, DL2: 1.8mg/kg + 600mg, and DL3: 1.8mg/kg + 800mg) in combination with fixed-dose ibrutinib 560mg PO D1-14, prednisone 100mg PO D1-7, obinutuzumab 1000mg IV D1-2, and lenalidomide 15mg PO D1-14. An expansion cohort was included at the MTD for further analysis of safety and efficacy. ViPOR-P q21d x 6 cycles (C) was given without maintenance or planned consolidation. All pts received TLS, PCP, HSV, and G-CSF prophylaxis (ppx) with VTE ppx per investigator discretion. Baseline CT, PET, BM, and tumor biopsy were performed with CT scans after C2, 4, and 6 and PET after C6 or at time of suspected complete response (CR). Surveillance CT was performed q3m for 1y, q4m x 1y, q6m x 1y, then annually x 2y. Results: 15 pts were enrolled and treated in the dose-escalation cohort; 3 at DL1, 6 at DL2, and 6 at DL3. Lymphoma subtypes included DLBCL NOS (60%) and HGBCL-DH (40%). In 9 DLBCL NOS pts, 11% were GCB and 89% non-GCB subtype by IHC. Three (20%) pts had transformed disease. Median age was 51y (range 39-83), with stage III/IV disease in 80%, elevated LDH in 80%, and >2 extranodal sites of disease in 67%. Nine (60%) pts had high-intermediate/high-risk IPI. Median prior therapies were 2 (range 1-6), with prior BTKi in 27%, Pola in 7%, and CAR-T in 20%. Ten (67%) pts were primary refractory (i.e., <CR to frontline tx) and 8 (53%) of pts were refractory (i.e., <PR) to last tx. One dose-limiting toxicity (DLT) of prolonged G4 thrombocytopenia occurred at DL3, but no other DLTs were noted. Pola 1.8mg/kg and Ven 800mg were identified as the MTD and safe doses for use in the expansion cohort. Heme AEs were most common and included G3-4 (% cycles) thrombocytopenia (17%), anemia (7%), and neutropenia (5%). No cases of febrile neutropenia occurred across 58 cycles. The only non-heme G3-4 AE occurring in >10% pts was hypokalemia (29%), with all pts experiencing any grade hypokalemia requiring replacement. Other common non-heme AEs (% pts) included diarrhea (71%), increased LFTs (64%), nausea (50%), hypomagnesemia (43%), and rash (43%). VTE occurred in 7% with no a.fib or major bleeding observed. No events of TLS or treatment-related mortality occurred. Dose reductions and delays occurred in 3% and 5% of cycles, respectively. Of 12 pts off-tx, 7 completed all 6C, 3 experienced disease progression, and 1 each came off-tx per investigator discretion or unacceptable AE. Of 15 enrolled pts, 14 are evaluable for response with an overall response rate (ORR) and CR rate of 64% (9/14) and 36% (5/14), respectively (Fig 1A). With a median potential f/u of 7.4m, median TTR in responding pts was 1.35m, with 8 (89%) of 9 total responses ongoing (Fig 1B). One HGBCL-DH pt relapsed by imaging at 10.6m, 2 PR pts received consolidative XRT with allo-HSCT, and 2 PR pts remain on-tx. PFS and OS at 6m was 69.8% and 75%, respectively. Conclusion: ViPOR-P is safe without significant additional toxicity compared to ViPOR, and Pola 1.8mg/kg and Ven 800mg were taken forward in the ongoing expansion cohort. Most common G3-4 AEs were hematologic with no febrile neutropenia observed with the use of G-CSF ppx. Fixed-duration ViPOR-P x 6C without maintenance led to CR in 5 (42%) of 12 off-tx DLBCL pts with 80% CRs ongoing from 3.7-9.3m. A randomized phase 2 trial is planned to further elucidate the safety and efficacy of Pola in combination with ViPOR across R/R DLBCL and within pre-defined molecular and genetic subtypes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract P5-13-06: Exploratory biomarker analysis in VERONICA, a phase 2 study of venetoclax + fulvestrant versus fulvestrant in patients with estrogen receptor (ER)-positive HER2-negative metastatic breast cancer (mBC)

Abstract BACKGROUND: Venetoclax (VEN) is a potent and selective inhibitor of the anti-apoptotic protein, BCL2. Preclinical studies have implicated the BCL2 family members, BCLXL and MCL1, in VEN resistance, and clinical studies in hematological malignancies have demonstrated subgroups with high ratios of BCL2/BCLXL and BCL2/MCL1 have the greatest VEN antitumor activity. The randomized phase 2 VERONICA study (NCT03584009) evaluated VEN in combination with fulvestrant (F) vs F alone in ER-positive, HER2-negative MBC pts who experienced disease recurrence/progression during or after a CDK4/6 inhibitor. Previously reported results from VERONICA (Lindeman et al. ASCO 2021) did not show an improved clinical benefit rate or progression-free survival (PFS) with VEN+F vs F alone. Here we present exploratory biomarker analyses of the expression of BCL2 family members and genomic alterations in circulating tumor DNA (ctDNA) and association with clinical outcomes from VEN+F vs F. METHODS: Tumor specimens were obtained during screening from 103 patients enrolled in the study, and expression levels of BCL2, BCLXL and MCL1 were analyzed by IHC. Baseline plasma-derived ctDNA was evaluated using the FoundationOne® Liquid assay. Expression of BCL2, BCLXL, MCL1 and mutations in ctDNA were correlated with PFS from VEN+F vs F based on the primary analysis (cutoff: Aug 5, 2020). RESULTS: In the overall population, protein levels of BCL2, BCLXL and MCL1 were similar between the VEN+F vs F arms. Patients whose tumors were BCL2 3+ trended towards having the greatest difference in median (m) PFS (3.9 months [mo] in VEN+F vs 1.7 mo in F; hazard ratio [HR] 0.38 [95% CI 0.09, 1.62]) albeit in a small sample size (n=13). Similarly, subgroup analysis suggested a trend for increasing mPFS and improved HR in VEN+F vs F alone in patients with the lowest BCLXL expression. mPFS in patients with a BCL2/BCLXL ratio ≥1 was 3.7 mo for VEN+F vs 1.8 mo for F (HR 0.67 [95% CI 0.3-1.49]) whereas patients with a BCL2/BCLXL ratio &amp;lt;1 had no difference in mPFS between the arms (2.0 mo in both arms, HR 1.21 [95% CI 0.7-2.1]). In the ctDNA-evaluable population, ESR1 (42.6%), TP53 (41.5%) and PIK3CA (35%) were the most prevalent genomic alterations observed and well-controlled between arms. PFS was similar between the ESR1 wildtype (wt) and mutant (mut) subgroups. TP53 mut status was a poor prognostic factor in both treatment arms. The PIK3CA wt subgroup had increased mPFS with VEN+F vs F alone (HR 0.66 [95% 0.38-1.17]) compared to PIK3CA mut (HR 1.59 [95% 0.74-3.34]). Patients with PIK3CA wt and BCL2 high tumors had the largest difference in mPFS between VEN+F (3.7 mo) vs F alone (1.9 mo) (HR 0.58 [95%CI 0.28-1.19]), compared to PIK3CA wt-BCL2 low tumors (2.4 vs 1.9 mo; HR 0.67 [95%CI 0.26-1.72]). CONCLUSION: Our data suggest that a high ratio of BCL2 to BCLXL conferred a trend towards a greater benefit to VEN+F compared to F alone, consistent with other clinical studies evaluating VEN. These analyses highlight the need to profile BCL2 and its family members to identify the VEN-sensitive subgroups, especially in indications where high expression of BCLXL or MCL1 may be observed. The ctDNA profile of VERONICA patients indicate a heavily pretreated patient population. The benefit observed in PIK3CA wt patients from VEN+F suggest increased dependence on BCL2 in this subgroup, while PIK3CA mut tumors likely rely on PI3K/AKT/mTOR survival programs or other BCL2 family members to evade apoptosis. Exploratory biomarker analyses are ongoing to further understand the VERONICA patient population. Citation Format: Geoffrey J. Lindeman, Tharu M. Fernando, Rebecca Bowen, Ching-Wei Chang, Rupal Desai, Kushagra Gupta, Aulde Fléchais, Timothy R. Wilson, Aditya Bardia. Exploratory biomarker analysis in VERONICA, a phase 2 study of venetoclax + fulvestrant versus fulvestrant in patients with estrogen receptor (ER)-positive HER2-negative metastatic breast cancer (mBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-06.

A Phase I/II Study of Venetoclax in Combination with 5-Azacytidine in Treatment-Naïve and Relapsed/Refractory High-Risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)

A Phase I/II Study of Venetoclax in Combination with 5-Azacytidine in Treatment-Naïve and Relapsed/Refractory High-Risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)

Final Overall Survival Results from BELLINI, a Phase 3 Study of Venetoclax or Placebo in Combination with Bortezomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma

Final Overall Survival Results from BELLINI, a Phase 3 Study of Venetoclax or Placebo in Combination with Bortezomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma

A Prospective Phase 2 Study of Venetoclax and Low Dose Ara-C (VALDAC) to Target Rising Molecular Measurable Residual Disease and Early Relapse in Acute Myeloid Leukemia

A Prospective Phase 2 Study of Venetoclax and Low Dose Ara-C (VALDAC) to Target Rising Molecular Measurable Residual Disease and Early Relapse in Acute Myeloid Leukemia

Phase 1 Study of Venetoclax in Combination with Dexamethasone As Targeted Therapy for t(11;14) Relapsed/Refractory Multiple Myeloma

▪Background: Venetoclax (VEN) is a selective, small molecule inhibitor of anti-apoptosis protein BCL-2 that has antitumoral activity against multiple myeloma (MM) cell lines and primary samples, notably those with translocation t(11;14). Recent data suggest that dexamethasone (DEX) enhances the expression of BCL-2 and pro-apoptotic protein Bim, shifting its binding towards BCL-2 and sensitizing MM cells to VEN. Therefore, the combination of VEN with DEX may provide a novel therapeutic approach to improve clinical outcomes in patients with MM, including those with t(11;14) and also those who express higher levels of resistance factors (eg, MCL-1).Methods: This cohort is part of an ongoing, dose-escalation, open-label, phase 1 study (NCT01794520) and it is being conducted to evaluate safety profile, pharmacokinetics (PK) and preliminary efficacy of VEN in combination with DEX in patients with t(11;14)-positive MM. Eligible patients were adults (≥18 years of age) who had previous treatment with a proteasome inhibitor and an immunomodulatory drug, an Eastern Cooperative Oncology Group score ≤1, measurable disease, and adequate bone marrow function. Presence of t(11;14) was confirmed for all eligible patients by means of FISH performed at a central laboratory. Patients were given oral VEN 800 mg/day plus oral DEX 40 mg (20 mg for patients ≥75 years of age) on days 1, 8, and 15 of each 21-day cycle. Preliminary efficacy was assessed as the overall response rate (ORR), time to progression (TTP), and duration of response (DOR) of VEN combined with DEX based on the 2011 International Uniform Response Criteria for Multiple Myeloma.Results: Twenty patients with t(11;14) R/R MM were enrolled (17 [85%] male; median age, 63 years [range, 46-77 years]). International Staging System status was I in 9 patients (45%), II in 7 (35%), III in 3 (15%), and missing in 1 (5%).The median number of prior therapies was 3 (range, 1-7). Sixteen (80%) patients had received bortezomib (11 [55%] refractory), 18 (90%) had received lenalidomide (17 [85%] refractory), and 17 (85%) had prior autologous stem cell transplantation. In addition, 8 patients (40%) were refractory to pomalidomide, and 4 (20%) were refractory to carfilzomib. Common adverse events (AEs) in ≥20% of patients were nausea, diarrhea, or insomnia (35% each); hyperglycemia or hypophosphatemia (30% each); and thrombocytopenia, leukopenia, pyrexia, upper respiratory tract infection, cough, nasal congestion, increased lactate dehydrogenase, increased creatinine, or hypokalemia (20% each). Grade 3/4 AEs in ≥10% of patients were lymphopenia or hypophosphatemia (15% each), as well as hyperuricemia or laboratory tumor lysis syndrome (10% each). Serious AEs in ≥2 patients were 2 cases of laboratory tumor lysis syndrome (10%). No deaths have occurred. ORR (partial response or better) was observed in 65% of patients (13/20) and included 7 very good PRs and 6 PRs. Six discontinuations of study drug occurred, and all were due to disease progression. ORRs were 82% (9/11) and 71% (12/17) in patients refractory to bortezomib and to lenalidomide, respectively. The ORR was also comparable between patients who had 1-3 prior lines of therapy (64% [7/11]) and those who had ≥3 lines (78% [7/9]). The median time to first response was 1.4 months (95% CI, 1.3-2.0 months). As of May 15, 2017, the median time on study was 6 months (range, <1 to 9 months). For this data cut, the median TTP and DOR have not been reached yet, but the estimated 6-month TTP rate was 64% (95% CI, 39-81%).Conclusions: VEN plus DEX demonstrated a tolerable safety profile in patients with t(11;14) R/R MM. Similar to previously reported results with VEN monotherapy, this combination appears to be clinically active regimen in patients whose disease is positive for t(11;14), with 65% of patients achieving a response of PR or better. These early findings support the further investigation of VEN combined with DEX in this patient population. DisclosuresKaufman:Amgen, Novartis: Research Funding; Amgen, Roche, BMS, Seattle Genetics, Sutro Biopharma, Pharmacyclics: Consultancy. Gasparetto:Janssen, BMS, Celgene: Other: Travel, accommodations, or other expenses paid or reimbursed; Celgene: Research Funding; Janssen, BMS, Celgene: Consultancy; Janssen, BMS, Celgene, Takeda: Honoraria. Mikhael:Onyx, Celgene, Sanofi, AbbVie: Research Funding. Moreau:Millennium: Consultancy, Honoraria; Celgene, Janssen, Takeda, Novartis, Amgen, Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Celgene: Consultancy, Honoraria; Onyx Pharmaceutical: Consultancy, Honoraria. Touzeau:AbbVie: Research Funding. Vij:Takeda, Onyx: Research Funding; Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy. Facon:Amgen, Celgene: Speakers Bureau. Pegourie:Takeda, Novartis, Janssen, BMS: Consultancy. Benboubker:Takeda, Celgene, Janssen, Amgen: Consultancy. Boise:Abbvie: Consultancy; Eli Lilly and Company: Research Funding. Alzate:AbbVie: Employment, Equity Ownership. Dunbar:AbbVie: Employment, Equity Ownership. Jia:AbbVie: Employment, Equity Ownership. Freise:AbbVie: Employment, Equity Ownership. Verdugo:AbbVie: Employment, Equity Ownership. Ross:AbbVie: Employment, Equity Ownership. Maciag:AbbVie: Employment, Equity Ownership. Kumar:Celgene, Millennium/Takeda, Onyx, AbbVie, Janssen, Sanofi, Novartis, Amgen, Genentech, Merck, Oncopeptides, Roche, Skyline Diagnostics: Research Funding; Skyline: Honoraria; Celgene, Millennium, BMS, Onyx, Janssen, Noxxon, AbbVie, Amgen, Merck, Oncopeptides, Skyline Diagnostics, Takeda: Consultancy.

BCL2 Expression Identifies a Population with Unmet Medical Need in Previously Untreated (1L) Patients with DLBCL

▪Introduction.High BCL2 protein expression has been associated with inferior outcome in multiple studies in diffuse large B-cell lymphoma (DLBCL) (Gascoyne et al. 1997; Salles et al. 2011; Horn et al. 2013; Tsuyama et al. 2017). Patients with high levels of BCL2 expression may benefit from treatment with venetoclax, a first-in-class, highly selective BCL2 inhibitor with demonstrated activity in cell lines and xenograft models (Souers et al. 2013, Punnoose et al. 2016). The evaluation of BCL2 as a prognostic marker has been complicated by the variability in recognized immunohistochemistry (IHC) thresholds (de Jong et al. 2007; Tsuyama et al. 2017) and the impact of cell-of-origin (COO) (Iqbal et al. 2011). Using a BCL2 IHC scoring algorithm that was developed to identify cell lines that are sensitive to BCL2 inhibition, and that could potentially identify patients likely to benefit from venetoclax, we evaluated the prognostic capability of BCL2 IHC in three independent cohorts of 1L DLBCL patients. Cohorts included two Phase 3 studies (MAIN [NCT00486759] and GOYA [NCT01287741]), and a representative cohort from the British Columbia Cancer Agency (BCCA) registry-based population, in which subjects received chemoimmunotherapy (either rituximab or obinutuzumab, combined with cyclophosphamide, doxorubicin, vincristine and prednisone [CHOP]).Patients and Methods. Pretreatment tumor samples were tested for BCL2 IHC using an algorithm that assesses both the percent of tumor cells stained and the intensity of staining, similar to the BCL2 algorithm proposed by Tsuyama et al. (Table 1).Whole-tissue slides from184 patients from MAIN were tested at Genentech , whole tissue slides from 366 patients from GOYA were tested at Hematogenex (Ventana assay) and tissue microarray slides from 310 patients from BCCA were tested at Ventana (Ventana assay). The NanoString Lymphoma Subtyping gene expression assay was used for classification of COO into germinal center B-cell (GCB), activated B-cell (ABC) or unclassified subtypes in MAIN (n=159), GOYA (n=353) and BCCA (n=302). Multivariate Cox regression analysis of progression-free survival (PFS) was performed in each study with the International Prognostic Index (IPI; The International NHL Prognostic Factors Project 1993) and/or COO as covariates. Given the similar treatment effect, patient data from both treatment arms in each study were merged for this analysis.Results. Baseline characteristics were similar for the BCL2 IHC evaluable and intent-to-treat (ITT) populations of these three cohorts. Prevalence of BCL2 positive patients was 48% in MAIN, 49% in GOYA and 58% in the BCCA cohort. The prevalence of BCL2 positive samples within the ABC subtype was 64%, 75% and 60% in the MAIN, GOYA and BCCA cohorts, respectively, and 40%, 38% and 56% within the GCB subtype, respectively. In univariate analysis, BCL2 positivity was associated with shorter PFS in all three cohorts (Figure 1, A-C). In the MAIN study, the prognostic effect of BCL2 appeared to be in the GCB subgroup, not ABC, as previously reported (Punnoose et al. ASH 2015). In the two largest studies of GOYA and BCCA cohorts, the prognostic effect of BCL2 was similar in ABC and GCB (not shown), and was independent of IPI (Table 2).Conclusions. Using a newly developed BCL2 IHC scoring algorithm, we demonstrate that DLBCL patients positive for BCL2 have a consistently inferior prognosis compared with patients negative for BCL2. The prognostic value of BCL2 IHC is independent of IPI and COO in GOYA and BCCA. The Ventana assay is currently being used in a Phase 2 study of venetoclax in combination with R-CHOP to evaluate the correlation (if any) of BCL2 expression with venetoclax + R-CHOP treatment (CAVALLI - NCT02055820). [Display omitted] DisclosuresSzafer-Glusman:Genentech: Employment. Peale:Genentech / Roche: Employment, Equity Ownership. Lei:Roche: Employment. Ray:Genentech/Roche: Employment. Farazi:Genentech: Employment. Kornacker:Roche: Equity Ownership; F. Hoffmann-La Roche: Employment. Oestergaard:F. Hoffmann-La Roche Ltd: Employment. Liu:F. Hoffmann-La Roche: Employment. Punnoose:Genentech: Employment.

V2 Trial: A phase I study of venetoclax and CPX-351 for young patients with relapsed/refractory acute leukemia.

TPS7052 Background: Despite significant advances in therapy for acute myeloid leukemia (AML), 30-40% of young patients will relapse, after which prognosis is poor. In young patients, curative-intent salvage therapy involves intensive re-induction followed by hematopoietic stem cell transplant. Recently, the COG Phase II study of CPX-351 (liposomal cytarabine:daunorubicin, Vyxeos™) in pediatric patients with AML in first relapse (NCT02642965) demonstrated a CR/CRi rate of 81.3%. Separately, our first-in-pediatrics CPX-351 Phase I (NCT01943682) showed 48% in a heavily pre-treated pediatric cohort with multiply relapsed and refractory (R/R) AML. Our integrated pilot study of single cell RNA sequencing (scRNA-seq) done before, during, and after CPX-351 showed p53 targets over time with enrichment for genes regulating apoptosis (ex.: FAS, BAX), suggesting blasts may be primed for apoptosis following CPX-351. Venetoclax is a small molecule inhibitor of the anti-apoptotic protein BCL-2, a regulator of apoptotic balance in some leukemias. Based on our preclinical data, we developed a Phase I study to investigate venetoclax with CPX-351 for the treatment of young patients with R/R acute leukemias. Methods: The V2 Trial (NCT03826992) is a single-institution Phase I study to evaluate the safety and tolerability of venetoclax with CPX-351 in patients ages 1-39 years with R/R acute leukemias. Inclusion diagnoses include AML, mixed phenotype acute leukemia (MPAL), KMT2A-rearranged acute lymphoblastic leukemia (ALL), and T-ALL. Exclusion criteria include CNS status 3, bone marrow failure syndromes, and prior cardiotoxic exposures above acceptable risk thresholds. Subjects receive a single course of CPX-351 at the FDA approved adult dose on Days 1, 3, 5 with concurrent daily venetoclax. In the dose exploration phase, venetoclax dosing is 400 mg daily (or allometrically-scaled equivalent) for 21 (Dose Level 0) or 14 days (Dose Level -1) using a rolling 6 design. Primary endpoints are determination of the recommended phase 2 dose of venetoclax in combination with CPX-351 and description of toxicities. Secondary endpoints include estimations of CR/CRp/CRi +/- MRD negativity in the context of a phase I study and evaluation of therapy-related cardiac dysfunction. Correlative studies include analysis of venetoclax pharmacokinetics with concomitant CPX-351. At the initial dose level, DLT were encountered and the study is now continuing enrollment at Dose Level -1. Clinical trial information: NCT03826992.

Abstract OT-28-03: VICKI: A Phase Ib/II, randomized, placebo-controlled, study of venetoclax plus ado-trastuzumab emtansine (T-DM1) in patients (pts) with previously treated HER2-positive locally advanced (LA) or metastatic breast cancer (MBC)

Abstract Background ~15-20% of primary, invasive breast cancer (BC) overexpresses HER2 and, despite survival improvements, there remains an unmet need for further progress. The antibody-drug conjugate T-DM1 is approved for HER2-positive LA and/or MBC that has previously been treated with trastuzumab and a taxane (separately or in combination), and as adjuvant therapy for HER2-positive early BC, where there is residual invasive disease after neoadjuvant taxane and trastuzumab- or HER2-based treatment. Venetoclax (GDC-0199/ABT-199), an oral, selective small-molecule inhibitor of the antiapoptotic protein BCL-2, is approved for treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma, and acute myeloid leukemia. BCL-2 may play a key role in HER2-positive BC, and venetoclax has shown promising activity in estrogen receptor-positive, BCL-2-positive MBC. We describe VICKI (Venetoclax in Combination with Kadcyla), a Phase Ib/II, randomized, double-blind, placebo-controlled, study of venetoclax plus T-DM1 in previously treated HER2-positive LA/MBC (NCT04298918). Trial design The study comprises a Phase Ib stage (dose escalation and expansion cohorts) and a randomized Phase II stage. Phase II will be initiated following identification of the recommended Phase II dose of venetoclax in Phase Ib (400 mg or 800 mg). Pts will be randomized 1:1 to T-DM1 (intravenous 3.6 mg/kg q3w) plus venetoclax or placebo. Randomization will be stratified per BCL-2 status (BCL-2 high vs. low), visceral disease (Yes vs. No), and HER2 immunohistochemistry (IHC) 3+ status (Yes vs. No). Eligibility Adult pts with HER2-positive (IHC 3+ or IHC 2+/in situ hybridization-positive), previously treated, unresectable, histologically or cytologically confirmed invasive LA/MBC are eligible. Pts will have measurable disease per RECIST v1.1 and an Eastern Cooperative Oncology Group performance status of 0 or 1. Pts in Phase II will have BCL-2 expression status by IHC (≥50% of pts BCL-2 high) and will not have received prior treatment with T-DM1, venetoclax, or anti-HER2 drug conjugates. Aims The Phase II co-primary efficacy endpoints will be objective response rate (ORR) and progression-free survival (PFS) per RECIST v1.1 (both investigator-assessed). Secondary and exploratory efficacy endpoints will include duration of response, overall survival, clinical benefit rate, and patient-reported outcomes. Non-efficacy endpoints will be pharmacokinetics, immunogenicity, biomarkers, and safety. Statistical methods In Phase II, the primary efficacy populations will include all randomized pts according to their assigned treatment arm (intention-to-treat). A point estimate and 95% CI for ORR and the difference in ORR between treatment groups will be calculated using the normal approximation to the binomial distribution. PFS will be defined as time from randomization to the first occurrence of disease progression or death from any cause. Kaplan-Meier methodology will be used to estimate median PFS. An interim analysis is planned when ~56 PFS events have occurred. Primary efficacy analysis will occur when 161 pts have had a PFS event. Cox proportional-hazards models, stratified by the stratification factors, will be used to estimate the hazard ratio with 95% CI. Safety will be analyzed per treatment received in pts who received any study treatment (safety population). Accrual Target accrual is ~226-284 pts at 145 sites globally (Phase Ib dose escalation: 6-24 pts; Phase Ib expansion cohorts: ~20-40 pts; Phase II: 220 pts). Accrual is ongoing. Contact information For more information or to refer a patient, email global-roche-genentech-trials@gene.com or call 1-888-662-6728 (USA only). Citation Format: Geoffrey J Lindeman, Erika Hamilton, Ian Krop, Bora Lim, Shanu Modi, Cristina Saura, Rupal Desai, Bradford J Danner, Tharu M Fernando, Shengchun Kong, Fatema A Legrand, Federico Nasroulah. VICKI: A Phase Ib/II, randomized, placebo-controlled, study of venetoclax plus ado-trastuzumab emtansine (T-DM1) in patients (pts) with previously treated HER2-positive locally advanced (LA) or metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-28-03.

A phase 2 study of venetoclax plus R-CHOP as first-line treatment for patients with diffuse large B-cell lymphoma

AbstractThe phase 2 CAVALLI (NCT02055820) study assessed efficacy and safety of venetoclax, a selective B-cell lymphoma-2 (Bcl-2) inhibitor, with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in first-line (1L) diffuse large B-cell lymphoma (DLBCL), including patients demonstrating Bcl-2 protein overexpression by immunohistochemistry (Bcl-2 IHC+). Eligible patients were ≥18 years of age and had previously untreated DLBCL, Eastern Cooperative Oncology Group performance status ≤2, and International Prognostic Index 2 to 5. Venetoclax 800 mg (days 4-10, cycle 1; days 1-10, cycles 2-8) was administered with rituximab (8 cycles) and cyclophosphamide, doxorubicin, vincristine, and prednisone (6-8 cycles) in 21-day cycles. Primary end points were safety, tolerability, and complete response (CR) at end of treatment (EOT). Secondary end points were progression-free survival (PFS) and overall survival. Comparative analyses used covariate-adjusted R-CHOP controls from the GOYA/BO21005 study, an appropriate contemporary benchmark for safety and efficacy. Safety and efficacy analyses included 206 patients. CR rate at EOT was 69% in the overall population and was maintained across Bcl-2 IHC+ subgroups. With a median follow-up of 32.2 months, trends were observed for improved investigator-assessed PFS for venetoclax plus R-CHOP in the overall population (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.43-0.87) and Bcl-2 IHC+ subgroups (HR, 0.55; 95% CI, 0.34-0.89) vs R-CHOP. Despite a higher incidence of grade 3/4 hematologic adverse events (86%), related mortality was not increased (2%). Chemotherapy dose intensity was similar in CAVALLI vs GOYA. The addition of venetoclax to R-CHOP in 1L DLBCL demonstrates increased, but manageable, myelosuppression and the potential of improved efficacy, particularly in high-risk Bcl-2 IHC+ patient subgroups.

Initial Results of a Phase I/II Study of Venetoclax in Combination with Azacitidine in Treatment-Naive and Relapsed/Refractory High-Risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)

Introduction: Venetoclax (VEN) is an oral BCL2 inhibitor, that has been shown to overcome apoptotic stress in cells from patients (pts) with high-risk myelodysplastic syndrome (MDS). Pre-clinical evidence indicates that VEN plus azacytidine (Aza) combination results in synergistic effects in myeloid malignancies. The objective of this trial is to evaluate the safety, tolerability, and overall response rate (ORR) of VEN in combination with Aza in pts with treatment-naive high-risk MDS or chronic myelomonocytic leukemia (CMML) and pts that were relapsed/refractory (R/R) to prior hypomethylating agent (HMA) therapy. Methods: This is a single-arm phase I/II clinical trial for pts with treatment-naive high-risk MDS or CMML, or pts with R/R MDS or CMML post-HMA failure (NCT04160052). Pts with prior BCL2 inhibitor therapy or low-risk disease (IPSS low or Int-1) are excluded. Aza is administered at 75mg/m2 IV or SC for 5 days on days 1-5 of each treatment cycle. VEN is studied at 100 mg, 200 mg, or 400 mg daily, on days 1-7 or 1-14 of each cycle. The primary endpoint is to determine the maximum tolerated dose and dose-limiting toxicity (DLT) of VEN in combination with Aza, as well as to evaluate ORR, defined as achieving complete remission (CR), marrow complete remission (mCR), partial response (PR), or hematologic improvement (HI) lasting ≥4 weeks. Response is assessed based on the modified International Working Group 2006 criteria (Cheson et al Blood 2006). Overall survival (OS) is calculated from the start date of treatment to the date of death, or last follow-up. Progression-free survival (PFS) is calculated from the start date of treatment to the date of disease progression, or last follow-up. Duration of response is calculated from the date of response to the date of disease progression, or last follow-up. Safety profile events were recorded according to the CTCAE v5.0. Results: To date 9 pts were enrolled. Four pts received VEN at 100mg dose, 3 pts at 200mg dose, and 2 pts at 400mg dose on days 1-7. There has been no protocol defined DLTs. The median age was 66 years (range, 59-83), 89% were male, 67% with MDS, 67% with normal karyotype. Five pts (56%) were treatment-naive, and 4 (44%) with R/R disease. Of the treatment-naive cohort (N=5), 4/5 (80%) pts had normal karyotype and none had TP53 mutations. ORR rate in this treatment-naive cohort was 100%, all pts achieving mCR, of which 1 (20%) had neutrophil response. Of the R/R cohort (N=4), cytogenetics were normal in 2/4 (50%) and complex in 2/4 (50%), and 2/4 (50%) had TP53 mutations. ORR in this R/R cohort was 3/4 (75%), all achieving mCR. One pt (25%) had stable disease (Table 1 and Figure 1). With a median follow-up duration of 3.6 months (95% CI: 1.4-8.4), 3 (33%) had disease progression and 1 (11%) died. Pts received median 2 courses of therapy (range, 1-4). One pt went to transplant. Median progression-free survival (PFS) for the entire cohort was 4.6 months (95% CI: 3.4-NA) and median OS has not been reached (Figure 2). Median duration of response is 4.1 months (95% CI: 2.4-NA). Possibly/probably related grade 3/4 adverse events included neutropenia in 4/9 (44%), thrombocytopenia in 3/9 (33%), and anemia in 1/9 (11%) pts. There were no grade 5 events (Table 2). Conclusions: The administration of VEN with Aza appears safe and well tolerated in treatment-naive and R/R pts with high-risk MDS and CMML. The study continues to accrue. Disclosures Thompson: Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy; Janssen-Cilag: Honoraria. Alvarado:BerGenBio ASA: Research Funding; FibroGen: Research Funding; Sun Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Tolero Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding. Jabbour:Genentech: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding. Kantarjian:BioAscend: Honoraria; Delta Fly: Honoraria; Abbvie: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Janssen: Honoraria; Oxford Biomedical: Honoraria; Aptitute Health: Honoraria; Adaptive biotechnologies: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Ascentage: Research Funding. Garcia-Manero:Amphivena Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Onconova: Research Funding.

Proposed Scheme for Dosing Venetoclax in Pediatric Patients with Relapsed/Refractory Acute Myeloid Leukemia: Analysis of Developmental Pharmacokinetics and Exposure-Response Relationships

M. Badawi and S. Gopalakrishnan equally contributed to this work Introduction: Venetoclax is a selective BCL2 inhibitor approved for patients with CLL and patients with newly diagnosed AML who are ineligible for induction chemotherapy. Venetoclax is currently being evaluated in other hematologic and solid tumors in both adult and pediatric populations. In this analysis, we characterized the pharmacokinetics and exposure response relationships of venetoclax to guide dose selection of venetoclax in combination with high dose cytarabine (HDAC) in pediatric patients with relapsed or refractory AML. Methods: A population PK model describing venetoclax PK in pediatric patients was developed using data from 121 subjects across three venetoclax studies that tested venetoclax at 400-800 mg doses across different tumors. The model accounted for the CYP3A4 developmental changes in early years of life using a maturation function and allometric scaling was also incorporated in the model to account for growth and body size effect. Individual subject average venetoclax plasma concentration (Cavg) up to the event of interest, determined based on the population PK analysis using the post-hoc empirical Bayesian parameter estimates, was used as an exposure metric to explore exposure-efficacy and exposure-safety relationships. Data from subjects with AML (database version 23-Mar-2020) who received venetoclax in combination with either azacitidine, decitabine, or cytarabine were included in the exposure-efficacy and exposure-safety analyses. The population PK model was then used to simulate venetoclax exposures in pediatric subgroups to guide dose selection for future trials. Results: Population PK estimates (clearance, volume of distribution, rate of absorption and peripheral volume of distribution) were comparable to previously reported estimates. Additionally, weight was identified as a statistically significant covariate on clearance and volume of distribution. Exposure-response analyses showed a flat relationship between venetoclax exposures and efficacy in patients with AML who received venetoclax in combination with azacitidine, decitabine, or cytarabine. Moreover, venetoclax exposures did not correlate with incidence of neutropenia. Specifically, in AML patients who received venetoclax in combination with HDAC (&amp;gt;500-2000 mg/m2/day, n=15), higher venetoclax exposures were not associated with better clinical response. A 600 mg dose of venetoclax was selected based on high response rates observed in the clinic. Venetoclax doses for pediatric subgroups were selected based on weight (allometric scaling) for children aged ≥ 2 years old and based on weight and CYP3A ontogeny for children aged &amp;lt; 2 years old. Table 1 presents the selected doses for the pediatric age and weight groups. Simulations of exposures (steady state area under the curve [AUCss]) using the population PK model for the pediatric age and weight groups are represented in Figure 1. Reasonable overlap in exposures was observed across the pediatric groups. Conclusions: Exposure-efficacy and exposure-safety showed lack of superiority of higher exposures and hence, 600 mg QD venetoclax in combination with HDAC was selected for pediatric patients with relapsed or refractory AML in future trials. Simulations of exposures demonstrated that the selected age- and weight-based doses would achieve exposures in pediatric subgroups comparable to that expected in adults receiving a 600 mg dose of venetoclax. Disclosures Badawi: AbbVie Inc.: Current Employment, Other: may hold stock or other options. Gopalakrishnan:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Engelhardt:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Palenski:AbbVie: 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. Karol:AbbVie Inc.: Other: Unrelated to this study, St. Jude has received a charitable contribution from AbbVie, Inc. The charitable contribution is not being used for clinical or research activities, including any activities related to this study. . Rubnitz:AbbVie Inc.: Research Funding. Menon:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Salem:AbbVie Inc.: Current Employment, Other: may hold stock or other options.

Debulking Regimens Prior to Initiating Venetoclax Therapy in Untreated Patients with Chronic Lymphocytic Leukemia: Interim Results from a Phase 3b Study

Debulking Regimens Prior to Initiating Venetoclax Therapy in Untreated Patients with Chronic Lymphocytic Leukemia: Interim Results from a Phase 3b Study