This study is testing the effectiveness of the study drug combination of acalabrutinib, umbralisib, and ublituximab in participants with Chronic Lymphocytic leukemia (CLL).

The names of the study drugs involved in this study are/is:

* Acalabrutinib (CALQUENCE®, ACP-196)
* Umbralisib (TGR-1202)
* Ublituximab (TG-1101)

BACKGROUND:

Irreversible inhibition of Bruton's tyrosine kinase (BTK) by ibrutinib represents an important therapeutic advance for the treatment of chronic lymphocytic leukemia (CLL). However, ibrutinib also irreversibly inhibits alternative kinase targets, which potentially compromises its therapeutic index. Acalabrutinib (ACP-196) is a more selective, irreversible BTK inhibitor that is specifically designed to improve on the safety and efficacy of first-generation BTK inhibitors.

METHODS:

In this uncontrolled, phase 1-2, multicenter study, we administered oral acalabrutinib to 61 patients who had relapsed CLL to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of acalabrutinib. Patients were treated with acalabrutinib at a dose of 100 to 400 mg once daily in the dose-escalation (phase 1) portion of the study and 100 mg twice daily in the expansion (phase 2) portion.

RESULTS:

The median age of the patients was 62 years, and patients had received a median of three previous therapies for CLL; 31% had chromosome 17p13.1 deletion, and 75% had unmutated immunoglobulin heavy-chain variable genes. No dose-limiting toxic effects occurred during the dose-escalation portion of the study. The most common adverse events observed were headache (in 43% of the patients), diarrhea (in 39%), and increased weight (in 26%). Most adverse events were of grade 1 or 2. At a median follow-up of 14.3 months, the overall response rate was 95%, including 85% with a partial response and 10% with a partial response with lymphocytosis; the remaining 5% of patients had stable disease. Among patients with chromosome 17p13.1 deletion, the overall response rate was 100%. No cases of Richter's transformation (CLL that has evolved into large-cell lymphoma) and only one case of CLL progression have occurred.

CONCLUSIONS:

In this study, the selective BTK inhibitor acalabrutinib had promising safety and efficacy profiles in patients with relapsed CLL, including those with chromosome 17p13.1 deletion. (Funded by the Acerta Pharma and others; ClinicalTrials.gov number, NCT02029443.).

To evaluate the safety and tolerability and determine the recommended phase 2/phase 3 dose of RAD regimen in PCNSL

Background: Diffuse large B-cell lymphoma (DLBCL) subtypes have differential response to BTK inhibitors (BTKi). Ibrutinib with R-CHOP improves survival in DLBCL subsets, but toxicity is limiting. Precise characterization of BTKi-responsive tumors enhances pt selection. Acalabrutinib (acala) is a BTKi with activity in DLBCL, but the molecular correlates of acala response are unknown. Circulating tumor DNA (ctDNA) is a prognostic biomarker in DLBCL including early changes during chemotherapy. PhasED-Seq is a novel ctDNA method that lowers the error profile of mutation detection by requiring the concordant detection of two separate mutations on an individual cell-free DNA molecule (Kurtz et al. Nat Biotechnol 2021). We employed a response-adapted study of acala for up to 14d prior to frontline therapy for aggressive B-cell lymphoma to determine the molecular profile of BTKi-responsive tumors. We report preliminary results including dynamic changes in ctDNA from this ongoing trial [NCT04002947]. Methods: Pts with untreated aggressive B-cell lymphoma and any HIV status are eligible if age ≥18, ≥stage 2, PS ≤2, and adequate organ function. Pts with PMBL, unmeasurable lesions, or active CNS disease are excluded. Screening includes labs, CT and FDG-PET, BM, and CSF with flow cytometry. Pts first receive acala 100mg twice daily x 14d. Pts with <25% reduction in bi-dimensional lesions by CT after acala receive DA-EPOCH-R or R-CHOP for 4-6 cycles every 21d. Pts with ≥25% reduction on CT after the window continue acala 100mg twice daily on days 1-10 of each cycle of R-chemo. Tumors undergo multi-platform profiling including whole exome, RNA sequencing, and assessment of DNA copy number. Streck tubes are collected at baseline, after 7d of acala, end of acala, end of C2, end of therapy, and during surveillance. ctDNA levels were quantified using PhasED-Seq (Foresight Diagnostics Inc.) to track phased variants. Results: 34 pts enrolled between August 2019 and July 2021 and completed the acala window. Median age was 64 (range 28-85) including 13 (38%) < 60y, 14 (41%) 61-69, and 7 (21%) ≥70y. Three (9%) pts had HIV and 17 (50%) were high-risk by IPI. The median diagnosis to treatment was 22.5d (4-53). IHC subtypes by Hans included 17 (50%) non-GCB, 16 (47%) GCB, and 1 (3%) T-cell/histiocyte-rich large B-cell lymphoma (TRLBCL). Four (12%) pts were high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 (HGBL-DH). Fifteen (44%) pts responded to acala during the window, while 19 (56%) pts had no response (Figure 1A). Acala responses were seen across DLBCL subtypes including 7 (47%) pts with non-GCB, 7 (47%) pts with GCB, and 1 (7%) pt with TRLBCL. Twenty pts had RNA sequencing to confirm cell-of-origin including 10 responders which included 7 (70%) GCB, 2 (20%) ABC, and 1 (10%) Unclassified. Notably, 13 (86%) BTKi-responsive tumors were CD10 negative and only 2 (18%) CD10+ tumors were BTKi-responsive. ctDNA dynamics strongly correlated with CT response as the log-fold change in ctDNA (hGE/mL) at the end of the window correlated with change on CT (r=0.75, p=0.0013). Remarkably, ctDNA dynamics after only 7d also correlated with change on CT (r=0.82, p=0.00006)(Figure 1B-C). Interestingly, one pt had improved symptoms and a 20-fold drop in ctDNA, but no corresponding CT changes suggesting that ctDNA changes may precede CT changes in some cases. Twenty-nine (85%) pts completed all planned cycles of therapy while 5 pts stopped chemotherapy early due to myelosuppression (n=3), CHF (n=1), and MI (n=1). Toxicity across 156 cycles was mostly hematologic. G3/G4 neutropenia occurred in 50% and 38% of cycles and febrile neutropenia in 10% of cycles. G3/G4 thrombocytopenia occurred in 22% and 12% of cycles. No increase in infections, atrial fibrillation, or bleeding were observed in pts treated with acala. All 27 pts who completed therapy achieved a CR. Two pts (1 acala responder) have relapsed from CR and 1 pt died of an MI. After a median follow-up of 9.2m the estimated 1-year PFS was 84.9% (95% CI.: 58-95). Conclusions: Acalabrutinib prior to frontline therapy has activity in GCB, non-GCB, and

HGBL-DH:

confirmed by gene expression profiling. CD10+ GCB tumors are mostly acala-resistant. Toxicity is mainly hematologic and manageable across age groups including pts with HIV. ctDNA correlates with CT change and may predict response to targeted agents as early as 7 days. Updated clinical results within genetic subtypes will be presented at the meeting. [Formula presented] Disclosures: Chabon: Foresight Diagnostics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Lurain: CTI Biopharma: Research Funding; EMD-Serrono: Research Funding; Merck: Research Funding; BMS-Celgene: Research Funding; Janssen: Research Funding. Bagaev: BostonGene Corp.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: BostonGene. Postovalova: BostonGene Corp.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: BostonGene. Meerson: BostonGene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: BostonGene. Kudryashova: BostonGene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: BostonGene. Kotlov: BostonGene Corp: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Fowler: BostonGene: Current Employment, Current holder of stock options in a privately-held company. Kurtz: Roche: Consultancy; Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Genentech: Consultancy. Alizadeh: CAPP Medical: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Forty Seven: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Foresight Diagnostics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Roche: Consultancy, Honoraria; Janssen Oncology: Honoraria; Celgene: Consultancy, Research Funding; Gilead: Consultancy; Bristol Myers Squibb: Research Funding; Cibermed: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company.

Background: Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) often have a poor prognosis despite therapies using second-line chemoimmunotherapy. Achievement of CR with second-line therapy is associated with improved long-term outcomes. Unfortunately, only 25-35% of patients achieve complete response (CR) with RICE chemotherapy alone. The addition of novel targeted agents such as Bruton Tyrosine Kinase inhibitors (BTKi) to second-line therapy may offer improved treatment responses given the importance of B-cell receptor (BCR) signaling in DLBCL. BTK has been shown to be essential for BCR-mediated activation of the NF- κB/Rel family of transcription factors and BCR signaling has been recognized as a key pathway in the pathogenesis of DLBCL. Moreover, NF-κB activity relies upon chronic active BCR signaling in activated B-cell-like DLBCL, which can be potentially blocked by kinase inhibitors targeting BTK. The goal of this study is to examine the feasibility and efficacy of adding the BTKi, acalabrutinib, to standard second-line therapy as a means to improve disease response. Establishing the feasibility of combining acalabrutinib with RICE chemotherapy in autologous hematopoietic cell transplantation (HCT) eligible and HCT ineligible patients with R/R DLBCL may provide the foundation for a larger study of efficacy and long-term outcomes of the combination therapy for patients with R/R DLBCL. Study Design and Methods: The primary objective of this phase 2 trial is to evaluate the tolerability, feasibility, and efficacy of combining acalabrutinib with RICE as second line therapy in R/R DLBCL patients. There are two study cohorts. Cohort A is open to R/R DLBCL patients who are eligible for autologous HCT. Cohort B is open to R/R DLBCL patients who are considered medically ineligible for autologous HCT. The primary endpoint for cohort A is to estimate the confirmed CR rate (RECIL 2017 criteria) prior to HCT in patients undergoing second-line therapy. The primary endpoint for cohort B is defined as the estimate of one-year progression-free survival in patients undergoing second-line induction and maintenance acalabrutinib therapy. Secondary endpoints include assessment of the proportion of patients completing 3 cycles of acalabrutinib with RICE and proceeding with HCT or 2 additional cycles of maintenance acalabrutinib for HCT ineligible patients, overall response rate, incidence of Grade 3/4 adverse events, and incidence of SAEs. Patients in cohort A receive 2 cycles of standard RICE salvage chemoimmunotherapy in combination with acalabrutinib, 100mg BID day 1-21 of a 21 day cycle. After 2 cycles of therapy, patients in cohort A undergo autologous stem cell mobilization and collection. Patients then receive a 3rd cycle of RICE in combination with acalabrutinib. PET-CT (PET3) is performed 14-21 days after day 1 of cycle 3 to assess response. Those patients with CR or partial response (PR) after PET3 proceed to autologous HCT with BEAM conditioning within 28-42 days of PET3. After adequate hematopoietic recovery, patients restart acalabrutinib 100mg BID as maintenance therapy for a period of 12 additional months. Patients in cohort B receive 3 cycles of RICE salvage chemoimmunotherapy in combination with acalabrutinib 100mg BID day 1-21 of a 21-day cycle followed by PET-CT (PET3) 14-21 days after start of Cycle 3. Patients without progressive disease at PET3 continue with acalabrutinib maintenance up to 12 additional cycles until disease progression or unacceptable toxicity. Patients demonstrating progressive disease are withdrawn from study treatment but their outcomes continue to be recorded and will be included in the final data analysis. Historical outcomes from completed, published prospective clinical trials using RICE chemoimmunotherapy serve as a reference for statistical calculations. This trial is currently ongoing and additional information can be found on clinicaltrials.gov NCT listing NCT03736616 Disclosures: Bensinger:

BMS:

Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau;

GSK:

Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Mawad: Abbvie: Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau. Glennie: Pharmacyclics: Speakers Bureau; Janssen: Speakers Bureau. Patel: Pharmacyclics: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Kite: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Consultancy; Genentech: Consultancy, Speakers Bureau; Celgene

/BMS:

Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy. OffLabel Disclosure: Acalabrutinib is used an investigational agent for DLBCL in this study.

BACKGROUND:

The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival, but without improvement to overall survival likely due to toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL.

METHODS:

Patients aged ≥65 years with previously untreated mantle cell lymphoma received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus 6 cycles of bendamustine (90 mg/m2; days 1 and 2) and rituximab (375 mg/m2; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. Primary endpoint was progression-free survival per independent review committee; overall response rate and overall survival were secondary endpoints.

RESULTS:

In total, 598 patients were randomized, with 299 in each arm. At a median follow-up of 44.9 months, median progression-free survival was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio, 0.73; 95% confidence interval, 0.57 to 0.94; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. Overall survival was not significantly different (hazard ratio, 0.86; 95% confidence interval, 0.65 to 1.13; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively.

CONCLUSIONS:

Combination of acalabrutinib with bendamustine-rituximab significantly improved progression-free survival. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Introduction: Bruton tyrosine kinase inhibitors (BTKi) are a mainstay of treatment for B‐cell malignancies; however, their use can be limited by adverse events (AEs), many of which are potentially caused by off‐target inhibition of other tyrosine kinases. The next‐generation BTKi zanubrutinib was designed to maximize tolerability by minimizing off‐target binding. Previous results from this ongoing phase 2 study (BGB‐3111‐215; NCT04116437) showed that zanubrutinib was well tolerated in pts intolerant of ibrutinib and/or acalabrutinib (Shadman et al. Lancet Haematol. 2023;10[1]:e35‐e45). Here, we report updated results of the tolerability and efficacy of zanubrutinib in pts intolerant of acalabrutinib (cohort 2). Methods: Eligible pts with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), or marginal zone lymphoma (MZL) who met protocol‐defined criteria for intolerance of acalabrutinib received zanubrutinib 160 mg twice daily or 320 mg once daily. Pts whose disease progressed with prior BTKi therapy were excluded. Safety and efficacy, including recurrence of acalabrutinib intolerance events, were evaluated. Investigators assessed responses every 3 cycles based on standard response criteria for each indication using parameters at study entry as baseline. Results: As of May 15, 2023, 27 pts received zanubrutinib in cohort 2 (CLL/SLL, 19; WM, 4; MCL, 2; MZL, 2). Median age was 73 y (range, 51‐87 y); median treatment duration was 11.4 mo (range, 0.5‐32.2 mo), with median follow‐up of 12.4 mo (range, 1.6‐32.2 mo). Median number of prior therapies was 2 (range, 1‐6); 13 pts (48%) received prior ibrutinib and acalabrutinib. Median cumulative exposure to acalabrutinib was 5.4 mo (range, 0.5‐33.7 mo). Seven pts discontinued zanubrutinib (AE, n=2; physician decision, n=2; withdrawal, n=2; progressive disease, n=1) and 20 pts remained on treatment. A total of 40 acalabrutinib intolerance events were reported in 27 pts, most commonly arthralgia (n=6 events), headache (n=5), myalgia (n=5), diarrhea (n=3), and rash (n=3). Twenty‐eight acalabrutinib intolerance events (70%) did not recur with zanubrutinib, corresponding to 17 pts (63%) not experiencing any recurrence of acalabrutinib intolerance events. Twelve events (30%) recurred (5 at a lower grade, 7 at the same grade, 0 at a higher grade; Figure 1) and 2 pts discontinued due to recurrence (myalgia and diarrhea; both recurred at the same grade); 1 pt discontinued due to investigator decision after the pt experienced a fall. Of 3 pts who experienced the same intolerance event with ibrutinib and acalabrutinib, 2 pts (1 experiencing atrial fibrillation and the other, pain in extremity) did not have a recurrence of these events with zanubrutinib, and 1 pt (experiencing diarrhea of grade 3 with ibrutinib and grade 2 with acalabrutinib) had a recurrence with zanubrutinib at a lower grade (grade 1). Although many pts entered the study with well‐controlled disease, 24 of 25 efficacy‐evaluable pts receiving zanubrutinib (96%) maintained or improved responses (at least stable disease) and 16 (64%) achieved a response better than stable disease compared with baseline. Conclusions: With a median zanubrutinib exposure that was 6 months longer than the reported cumulative acalabrutinib exposure before discontinuation (11.4 vs 5.4 mo, respectively), 17 pts (63%) did not experience any recurrence of their prior acalabrutinib intolerance events, and disease was controlled in 24 of 25 efficacy‐evaluable pts treated with zanubrutinib (96%). This suggests that pts who are intolerant of acalabrutinib can attain clinical benefit by switching to zanubrutinib. Enrollment and follow‐up are ongoing.

This phase II trial tests how well acalabrutinib works in treating patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and evaluates how treatment with acalabrutinib affects heart function. Acalabrutinib is in a class of medications called kinase inhibitors. It blocks a protein called BTK, which is present on B-cell (a type of white blood cells) cancers at abnormal levels. This may help keep cancer cells from growing and spreading. CLL/SLL patients treated with a different BTK inhibitor called ibrutinib often experience cardiac side effects, leading to discontinuation of life-saving therapy. Treatment with acalabrutinib after discontinuing, or even before starting, treatment with ibrutinib may reverse or prevent cardiac side effects and be an effective treatment option for patients with CLL/SLL.

Background: Bruton tyrosine kinase (BTK) inhibition has shown clinical benefit in FL. Acalabrutinib is a highly selective, potent, covalent inhibitor of BTK. We evaluated acalabrutinib ± R in a Phase 1b study of patients (pts) with treatment-naive (TN) or relapsed/refractory (R/R) FL. Methods: Pts with R/R FL (≥1 prior treatment) were randomized to acalabrutinib (mono) or acalabrutinib + R (combo); TN pts received the combo. In 28-day cycles, R (375 mg/m2 IV) was given weekly in Cycle 1 and on Day 1 of Cycles 2-6; acalabrutinib (100 mg PO bid [2 pts received 200 mg qd]) was given until progressive disease (PD) or intolerance. The primary endpoint was safety. Secondary endpoints included overall response rate (ORR), duration of response (DOR), pharmacokinetics (PK) and pharmacodynamics. Results: Thirteen TN and 27 R/R pts were treated. In all pts, the median age was 66 years (range 32-83), 98% of pts had ECOG PS ≤1, and 88% had stage III/IV disease. R/R pts received a median of 2 prior therapies (range 1-5). At a median follow-up of 22 and 7.6 months, 62% of TN and 26% of R/R pts, respectively, were still on treatment. Discontinuations were primarily due to PD (TN 15%; R/R 56%) and adverse events (AEs; TN 8%; R/R 11%). BTK occupancy and PK parameters were consistent with previous acalabrutinib studies. In all pts, common AEs (any grade) were fatigue (48%), headache (43%), diarrhea (40%), nausea (30%) and sinusitis (25%). Common Gr 3/4 AEs were hypertension (8%), increased alanine aminotransferase, increased aspartate aminotransferase, and cellulitis (all 5%), with no Gr 5 events. There were no cases of atrial fibrillation or Gr ≥3 hemorrhage. Efficacy outcomes are reported in the table. Conclusions: Acalabrutinib, alone and combined with R, was well-tolerated and yielded promising response rates in FL. These results support further evaluation of acalabrutinib in FL. (Table Presented).

This phase Ib/II trial studies the side effects and efficacy of maintenance acalabrutinib following cellular therapy in treating patients with large B-cell lymphoma at very high risk of the cancer coming back. Acalabrutinib is a small molecular inhibitor that may interfere with the ability of cancer cells to grow and spread.