AC676 for B-Cell Malignancies
Recruiting in Palo Alto (17 mi)
+8 other locations
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Accutar Biotechnology Inc
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial is testing a new oral drug, AC676, in patients with blood cancers that have returned or are resistant to treatment. The drug aims to stop cancer cells from growing by targeting and destroying a specific protein they need.
Is the drug AC676 a promising treatment for B-Cell Malignancies?Yes, AC676 is a promising drug for B-Cell Malignancies because it targets specific proteins involved in cancer cell growth, potentially improving survival and treatment effectiveness.2571011
What safety data is available for AC676 in treating B-cell malignancies?AC676, also known as acalabrutinib, has been evaluated for safety in several studies. It is a second-generation Bruton's tyrosine kinase (BTK) inhibitor used for treating B-cell malignancies like chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Acalabrutinib has shown an acceptable safety profile with most adverse events being of grade 1/2 severity, such as headache and diarrhea. Serious adverse events were reported in 38% of patients in one study, with grade ≥3 events including infection (15%), hypertension (11%), bleeding events (3%), and atrial fibrillation (2%). The drug is generally more tolerable than first-generation BTK inhibitors like ibrutinib, with a lower rate of discontinuation due to adverse events.412131415
What data supports the idea that AC676 for B-Cell Malignancies (also known as: AC676, AC676) is an effective treatment?The available research does not provide specific data on the effectiveness of AC676 for B-Cell Malignancies. However, it mentions other treatments like fludarabine, which has shown a response rate of over 50% in previously treated patients and over 70% in untreated patients. Additionally, rituximab, an anti-CD20 monoclonal antibody, has improved response rates in B-cell malignancies, although some patients develop resistance. Without specific data on AC676, it's unclear how it compares to these treatments.13689
Do I have to stop taking my current medications for the trial?The trial protocol does not specify if you must stop all current medications, but you cannot have taken certain cancer treatments recently. These include small molecule anti-cancer drugs within 5 half-lives or 2 days, systemic chemotherapy within 14 days, radiation therapy within 14 days, biologics within 28 days, radioimmunoconjugates or toxin conjugates within 12 weeks, CAR T cell therapy within 3 months, and stem cell transplants within 100 days. Check with the trial team for more details.
Eligibility Criteria
This trial is for adults with certain types of B-cell malignancies that have come back or didn't respond to treatment. They must have tried at least two treatments already, or be unable to use standard therapies. People can't join if they've had recent cancer treatments, stem cell transplants, CAR-T therapy (for DLBCL patients), active bleeding issues, or are within a specific timeframe after receiving other specific therapies.Participant Groups
The study tests AC676 in participants with relapsed/refractory B-cell malignancies. It aims to find the safest dose, understand side effects and how the body processes the drug (pharmacokinetics), and assess its effectiveness against these blood cancers.
1Treatment groups
Experimental Treatment
Group I: AC676 Dose EscalationExperimental Treatment1 Intervention
Participants will receive an assigned dose of AC676 in a 28-days cycle.
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Colorado Blood Cancer InstituteDenver, CO
Florida Cancer SpecialistsSarasota, FL
Oregon Health & Science UniversityPortland, OR
Swedish Cancer InstituteSeattle, WA
More Trial Locations
Loading ...
Who is running the clinical trial?
Accutar Biotechnology IncLead Sponsor
References
Current approaches to the chemotherapy of B-cell chronic lymphocytic leukemia: a review. [2019]Standard therapy has not substantially improved the outcome of patients with chronic lymphocytic leukemia (CLL). However, an increased understanding of the biology and immunology of CLL, and the availability of several new and active chemotherapy agents (eg, fludarabine, 2'-deoxycoformycin [DCF], 2-chlorodeoxyadenosine [CDA]) has stimulated enthusiasm for clinical trials. DCF induces CRs or PRs in 25% of heavily treated patients. Fludarabine has been associated with a response rate of greater than 50% in previously treated patients, and greater than 70% in untreated patients, with almost a third of these achieving a CR. Currently, phase I and II clinical trials are evaluating combinations of these drugs with each other or with conventional agents (eg, fludarabine/chlorambucil [CLB]/prednisone [P]; DCF/CLB/P; fludarabine/DCF; fludarabine/P) in previously treated patients. To facilitate comparison of these regimens, each study is adhering to the NCl-Working Group guidelines for eligibility and response criteria, and toxicity assessment. A collaborative phase III trial will then compare the most promising of these regimens with "standard" chemotherapy in previously untreated patients. The widespread availability of these clinical trials will allow clinicians ready access to the new treatments.
Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma. [2018]Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed biologically and prognostically distinct subgroups: germinal center B-cell-like (GCB), activated B-cell-like (ABC) and primary mediastinal (PM) DLBCL. The BCL6 gene is often translocated and/or mutated in DLBCL. Therefore, we examined the BCL6 molecular alterations in these DLBCL subgroups, and their impact on BCL6 expression and BCL6 target gene repression. BCL6 translocations at the major breakpoint region (MBR) were detected in 25 (18.8%) of 133 DLBCL cases, with a higher frequency in the PM (33%) and ABC (24%) subgroups than in the GCB (10%) subgroup. Translocations at the alternative breakpoint region (ABR) were detected in five (6.4%) of 78 DLBCL cases, with three cases in ABC and one case each in the GCB and the unclassifiable subgroups. The translocated cases involved IgH and non-IgH partners in about equal frequency and were not associated with different levels of BCL6 mRNA and protein expression. BCL6 mutations were detected in 61% of DLBCL cases, with a significantly higher frequency in the GCB and PM subgroups (>70%) than in the ABC subgroup (44%). Exon-1 mutations were mostly observed in the GCB subgroup. The repression of known BCL6 target genes correlated with the level of BCL6 mRNA and protein expression in GCB and ABC subgroups but not with BCL6 translocation and intronic mutations. No clear inverse correlation between BCL6 expression and p53 expression was observed. Patients with higher BCL6 mRNA or protein expression had a significantly better overall survival. The biological role of BCL6 in translocated cases where repression of known target genes is not demonstrated is intriguing and warrants further investigation.
Evolution of anti-CD20 monoclonal antibody therapeutics in oncology. [2023]Approval of an anti-CD20 chimeric monoclonal antibody, rituximab, has revolutionized cancer treatment and also validated CD20 targeting for providing benefit and improvement of overall response rate in B cell malignancies. Although many patients have benefited from the treatment of rituximab, there are still significant numbers of patients who are refractory or develop resistance to the treatment. Here we discuss pre-clinically well-defined potential mechanisms of action for rituximab and review the ways next generation anti-CD20 monoclonal antibodies can potentially exploit them to further enhance the treatment of B cell malignancies. Although the relative importance of each of these mechanism remains to be established in the clinic, well-designed clinical trials will help to define the efficacy and understanding of which effector activity of modified next generation anti-CD20 mAb will be important in the treatment of B-cell malignancies.
Acadesine for patients with relapsed/refractory chronic lymphocytic leukemia (CLL): a multicenter phase I/II study. [2021]Acadesine has shown in vitro to selectively induce apoptosis in B cells from chronic lymphocytic leukemia (CLL) patients. We conducted a phase I/II open-label clinical study, to determine the safety and tolerability of acadesine given intravenously as a 4-h infusion to CLL patients.
BCL6 expression correlates with the t(1;19) translocation in B-lymphoblastic leukemia. [2016]Study to date suggests that BCL6 protein expression in B-cell neoplasia predominates in germinal center-derived tumors, but less is known regarding its expression in B-lymphoblastic leukemia. Therefore, we designed a comprehensive study of BCL6 expression in B-lymphoblastic leukemia.
So FCR, so good. [2021]In this issue of Blood, Rossi et al show that certain predictive biomarkers are able to identify a subgroup of patients with chronic lymphocytic leukemia (CLL) who have an exceptionally good outcome following front-line therapy with the combination of fludarabine, cyclophosphamide, and rituximab (FCR).
Knockdown of B7-H6 inhibits tumor progression and enhances chemosensitivity in B-cell non-Hodgkin lymphoma. [2022]B7 homologue 6 (B7-H6) is a new member of the B7 family molecules and is selectively expressed on tumor cells, especially in hematologic malignancies. However, the role of B7-H6 in lymphoma progression and chemosensitivity remains unclear. We determined the effects of downregulating B7-H6 expression on tumorigenesis and chemosensitivity in B-cell lymphoma. Stable B7-H6 knockdown in CA46 cells was established with a lentiviral system. The expression of mRNA was measured by PCR while protein expression was detected by western blotting and flow cytometry. Cell viability, apoptosis and cell cycle distribution were analyzed using CCK-8, colony formation and flow cytometry assays, respectively. Cell migration and invasion were determined using the Transwell chamber assay. B7-H6 was widely expressed in B-cell lymphomas. Knockdown of B7-H6 inhibited cell proliferation, colony formation and migration and invasion of lymphoma cells. After B7-H6 silencing, CA46 cells were arrested in G0/G1 phase. Moreover, the silencing of B7-H6 increased cell apoptosis and sensitivity to vincristine and dexamethasone. Investigation of expression of downstream targets of STAT3 supported a theory in which B7-H6 knockdown may confer an antitumor effect via abrogation of the STAT3 pathway. This study demonstrates that B7-H6 plays an important role in the pathogenesis and chemosensitivity of lymphoma. B7-H6 is therefore a potential clinical biomarker and therapeutic target in B-cell lymphomas.
Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience. [2021]B-cell receptor kinase inhibitor (KI) therapy represents a paradigm shift in chronic lymphocytic leukemia (CLL) management, but data on practice patterns after KI discontinuation and optimal sequencing are limited. We conducted a multicenter, retrospective, comprehensive analysis on 178 patients with CLL (ibrutinib = 143; idelalisib = 35) who discontinued KI therapy. We examined responses, toxicity, post-KI therapies, and overall survival (OS). Patients had a median of 3 prior therapies (range 0-11); del17p (34%), p53 mutation (27%), del11q (33%), and complex karyotype (29%). Overall response rate (ORR) to first KI was 62% (complete response 14%). The most common reasons for KI discontinuation were toxicity (51%), CLL progression (29%), and Richter transformation (RT) (8%). Median progression-free survival (PFS) and OS from KI initiation were 10.5 and 29 months, respectively. Notably, initial KI choice did not impact PFS or OS; however, RT portended significantly inferior OS (P = .0007). One hundred fourteen patients received subsequent salvage therapy following KI discontinuation with an ORR to subsequent KI at 50% and a median PFS of 11.9 months. Median PFS in KI-intolerant patients treated with an alternate KI was not reached vs 7 months for patients with CLL progression. In summary, these data demonstrate that toxicity was the most common reason for KI discontinuation, that patients who discontinue KI due to toxicity can respond to an alternate KI, and that these responses may be durable. This trial was registered at www.clinicaltrials.gov as #NCT02717611 and #NCT02742090.
New Pharmacotherapies in Chronic Lymphocytic Leukemia. [2020]The authors present the clinical outcomes and therapeutic application of newly approved pharmacotherapies for chronic lymphocytic leukemia and highlight emerging investigational therapeutic options.
Silencing of HDAC6 as a therapeutic target in chronic lymphocytic leukemia. [2021]Although the treatment paradigm for chronic lymphocytic leukemia (CLL) is rapidly changing, the disease remains incurable, except with allogeneic bone marrow transplantation, and resistance, relapsed disease, and partial responses persist as significant challenges. Recent studies have uncovered roles for epigenetic modification in the regulation of mechanisms contributing to malignant progression of CLL B cells. However, the extent to which epigenetic modifiers can be targeted for therapeutic benefit in CLL patients remains poorly explored. We report for the first time that expression of epigenetic modifier histone deacetylase 6 (HDAC6) is upregulated in CLL patient samples, cell lines, and euTCL1 transgenic mouse models compared with HDAC6 in normal controls. Genetic silencing of HDAC6 conferred survival benefit in euTCL1 mice. Administration of isoform-specific HDAC6 inhibitor ACY738 in the euTCL1 aging and adoptive transfer models deterred proliferation of CLL B cells, delayed disease onset via disruption of B-cell receptor signaling, and sensitized CLL B cells to apoptosis. Furthermore, coadministration of ACY738 and ibrutinib displayed synergistic cell kill against CLL cell lines and improved overall survival compared with either single agent in vivo. These results demonstrate for the first time the therapeutic efficacy of selective HDAC6 inhibition in preclinical CLL models and suggest a rationale for the clinical development of HDAC6 inhibitors for CLL treatment, either alone or in combination with Bruton tyrosine kinase inhibition.
Cluster of Differentiation 96 in Children with Acute Leukemia: A Single Center Cohort Study. [2021]Cluster of differentiation 96 (CD96) is an important leukemic stem cells (LSCs) surface marker. We evaluated CD96 expression in children with acute leukemia (AL) and described its relation with treatment response. We conducted a prospective cohort study in Mansoura University Children's Hospital, Egypt during the period from 2014 to 2016. We studied 96 children with AL and 96 controls at clinical, laboratory and radiological levels. We assessed CD96% in LSCs using flow cytometry. AL group included 59 acute lymphoblastic leukemia (ALL) and 37 acute myeloid leukemia (AML) patients. ALL subgroup involved 44 B-ALL and 15 T-ALL patients while AML subgroup included 17 M2, 12 M4 and 8 M5 patients. CD96% was higher in AL group [57.63 (21.18-89.93)] than control [34.12 (16.15-39.51)] (P < 0.001). CD96% was higher in AML [68.25 (31.1-89.86)] than ALL [54.18 (21.18-89.93] (P < 0.001). CD96% in AML was M4 > M2 > M5 (P = 0.04) while within ALL subgroup, no significant difference was found between B-ALL and T-ALL (P = 0.807). CD96% in patients with non-complete remission was higher than those with complete remission (P = 0.004). CD96 is a reliable diagnostic marker for AL mainly AML and could be used as a prognostic marker for treatment response.
Acalabrutinib in treatment-naive chronic lymphocytic leukemia. [2022]Acalabrutinib has demonstrated significant efficacy and safety in relapsed chronic lymphocytic leukemia (CLL). Efficacy and safety of acalabrutinib monotherapy were evaluated in a treatment-naive CLL cohort of a single-arm phase 1/2 trial (ACE-CL-001). Adults were eligible for enrollment if chemotherapy was declined or deemed inappropriate due to comorbidities (N = 99). Patients had a median age of 64 years and 47% had Rai stage III/IV disease. Acalabrutinib was administered orally 200 mg once daily, or 100 mg twice daily until progression or intolerance. A total of 99 patients were treated; 57 (62%) had unmutated immunoglobulin heavy-chain variable gene, and 12 (18%) had TP53 aberrations. After median follow-up of 53 months, 85 patients remain on treatment; 14 discontinued treatment, mostly because of adverse events (AEs) (n = 6) or disease progression (n = 3). Overall response rate was 97% (90% partial response; 7% complete response), with similar outcomes among all prognostic subgroups. Because of improved trough BTK occupancy with twice-daily dosing, all patients were transitioned to 100 mg twice daily. Median duration of response (DOR) was not reached; 48-month DOR rate was 97% (95% confidence interval, 90-99). Serious AEs were reported in 38 patients (38%). AEs required discontinuation in 6 patients (6%) because of second primary cancers (n = 4) and infection (n = 2). Grade ≥3 events of special interest included infection (15%), hypertension (11%), bleeding events (3%), and atrial fibrillation (2%). Durable efficacy and long-term safety of acalabrutinib in this trial support its use in clinical management of symptomatic, untreated patients with CLL.
Acalabrutinib: A Selective Bruton Tyrosine Kinase Inhibitor for the Treatment of B-Cell Malignancies. [2023]Bruton tyrosine kinase (BTK) is a validated target for treatment of B-cell malignancies, and oral inhibitors of BTK have emerged as a standard of care for these diseases. Acalabrutinib is a second generation, highly selective, potent, covalent BTK inhibitor that exhibits minimal off-target activity in in vitro assays, providing the potential to improve tolerability over the first-in-class BTK inhibitor, ibrutinib. Acalabrutinib was approved for the treatment of relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) in the US in 2017 and 2019, respectively. Acalabrutinib is also undergoing trials for other B-cell malignancies, both as monotherapy and in combinations. In this review, we discuss results from clinical trials evaluating the efficacy and safety of acalabrutinib in patients with CLL, MCL, and Waldenstrom's macroglobulinemia. Recent phase 3 data showed that acalabrutinib improved progression-free survival (PFS) compared with rituximab plus idelalisib or rituximab plus bendamustine in patients with relapsed/refractory CLL, and acalabrutinib with or without obinutuzumab improved PFS compared with chlorambucil plus obinutuzumab in patients with treatment-naïve CLL. Overall, acalabrutinib had a tolerable safety profile, with most adverse events being grade 1/2 severity (most commonly headache and diarrhea) and a low rate of discontinuation due to adverse events.
Acalabrutinib and its use in the treatment of chronic lymphocytic leukemia. [2022]Bruton's tyrosine kinase inhibitors have changed the treatment landscape for chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and lymphoplasmacytic lymphoma dramatically. In 2019, acalabrutinib was approved by the US FDA for the treatment of treatment-naive and relapsed/refractory CLL and MCL. Acalabrutinib monotherapy was found to be effective and safe in CLL patients. In ASCEND and ELEVATE treatment-naive studies, acalabrutinib monotherapy and the combination with obinutuzumab demonstrated improved efficacy and an acceptable safety profile. The triple combination with venetoclax showed a high rate of molecular remission without an impaired safety profile. Adverse events, with an occurrence rate of >20%, were as follows: grade 1-2 myelosuppression, gastrointestinal toxicity, rash, constitutional symptoms; grade 3 or 4 toxicities were syncope, pneumonia, hypertension, atrial fibrillation, neutropenia and thrombocytopenia.
How We Manage Patients with Indolent B-Cell Malignancies on Bruton's Tyrosine Kinase Inhibitors: Practical Considerations for Nurses and Pharmacists. [2023]The most common forms of B-cell malignancy, non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), have seen a drastic shift in the treatment landscape over the last two decades with the introduction of targeted agents. Among them are Bruton's tyrosine kinase (BTK) inhibitors, which have demonstrated excellent efficacy in indolent B-cell NHLs and CLL. Although BTK inhibitors are generally thought to be more tolerable than chemoimmunotherapy, they are associated with a unique safety profile including varying rates of rash, diarrhea, musculoskeletal events, cardiovascular events, and bleeding. Ibrutinib was the first BTK inhibitor to gain a Health Canada indication, followed by second-generation BTK inhibitors acalabrutinib and zanubrutinib, which have better safety profiles compared to ibrutinib, likely due to their improved selectivity for BTK. As BTK inhibitors are oral agents given continuously until disease progression, long-term adverse event (AE) monitoring and management as well as polypharmacy considerations are important for maintaining patient quality of life. This paper intends to serve as a reference for Canadian nurses and pharmacists on dosing, co-administration, and AE management strategies when caring for patients with indolent B-cell NHL or CLL being treated with BTK inhibitors.