Trial Summary
What is the purpose of this trial?This trial is testing Acalabrutinib, a drug used in other cancers, to see if it can help people with a type of brain cancer that hasn't responded to other treatments. The drug works by stopping the cancer cells from growing.
What safety data is available for Acalabrutinib in treating lymphoma?Acalabrutinib, also known as Calquence or ACP-196, has been evaluated for safety in several studies. It is generally well-tolerated, with most adverse events being mild to moderate, such as headache and diarrhea. Serious adverse events include infections, hypertension, bleeding events, and atrial fibrillation, but these are less common. A meta-analysis indicated a higher risk of any-grade cardiac events, including atrial fibrillation, but no significant increase in high-grade cardiac events. The overall safety profile is considered acceptable, with a low rate of treatment discontinuation due to adverse events.456810
What data supports the idea that Acalabrutinib for Lymphoma is an effective drug?The available research shows that Acalabrutinib is effective for treating certain types of lymphoma, like mantle cell lymphoma and marginal zone lymphoma. In patients with relapsed or refractory marginal zone lymphoma, 53% showed a positive response, with 13% achieving complete responses. Additionally, Acalabrutinib was found to be effective in chronic lymphocytic leukemia, a related condition, where it showed a longer time before the disease worsened compared to other treatments. This suggests that Acalabrutinib is a promising option for treating these types of lymphoma.345711
Do I need to stop taking my current medications to join the trial?The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you require treatment with strong CYP3A4 inhibitors/inducers or anticoagulation with warfarin or equivalent vitamin K antagonists. It's best to discuss your current medications with the trial team.
Is the drug Acalabrutinib a promising treatment for lymphoma?Yes, Acalabrutinib is a promising drug for treating lymphoma. It is a new type of medicine that targets specific cells involved in the disease, showing good results in improving patient outcomes. It has been approved for use in certain types of lymphoma and has shown to be effective in clinical trials, with a tolerable safety profile.12489
Eligibility Criteria
Adults with recurrent or refractory central nervous system lymphoma (CNSL) who have had at least one prior CNS-directed therapy can join this trial. They must be able to understand and sign consent, have a life expectancy over 3 months, an ECOG Performance Status of 0-1, and meet specific health criteria like adequate blood counts and organ function. Pregnant women, those unable to swallow pills or with certain infections or bleeding disorders cannot participate.Treatment Details
The trial is testing the safety and effectiveness of Acalabrutinib for people whose CNSL has come back after treatment or didn't respond to previous treatments. It's in phases 1/2 which means they're starting to see how well it works and what doses are safe.
2Treatment groups
Experimental Treatment
Group I: Acalabrutinib Dose ExpansionExperimental Treatment1 Intervention
Phase 2
Participants will receive Acalabrutinib at the pre-determined dosage established in Phase 1.
Group II: Acalabrutinib Dose EscalationExperimental Treatment1 Intervention
Phase 1 Dose escalation will occur using a 3+3 dose escalation approach, evaluating three separate dose levels.
* Acalabrutinib 200mg 2x daily
* Acalabrutinib 300mg 2x daily
* Acalabrutinib 400mg 2x daily
Acalabrutinib is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Calquence for:
- Mantle cell lymphoma
- Chronic lymphocytic leukemia
- Small lymphocytic lymphoma
🇪🇺 Approved in European Union as Calquence for:
- Chronic lymphocytic leukemia
- Small lymphocytic lymphoma
- Mantle cell lymphoma
Find a clinic near you
Research locations nearbySelect from list below to view details:
Dana Farber Cancer InstituteBoston, MA
Brigham and Women's HospitalBoston, MA
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Who is running the clinical trial?
Dana-Farber Cancer InstituteLead Sponsor
References
Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma. [2018]Acalabrutinib (ACP-196) is a second-generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK) with increased target selectivity and potency compared to ibrutinib. In this study, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy similar to human diffuse large B-cell lymphoma (DLBCL). First, we demonstrated that acalabrutinib potently inhibited BTK activity and downstream effectors in CLBL1, a canine B-cell lymphoma cell line, and primary canine lymphoma cells. Acalabrutinib also inhibited proliferation in CLBL1 cells. Twenty dogs were enrolled in the clinical trial and treated with acalabrutinib at dosages of 2.5 to 20mg/kg every 12 or 24 hours. Acalabrutinib was generally well tolerated, with adverse events consisting primarily of grade 1 or 2 anorexia, weight loss, vomiting, diarrhea and lethargy. Overall response rate (ORR) was 25% (5/20) with a median progression free survival (PFS) of 22.5 days. Clinical benefit was observed in 30% (6/20) of dogs. These findings suggest that acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients and support the use of canine lymphoma as a relevant model for human non-Hodgkin lymphoma (NHL).
Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. [2021]Acalabrutinib is a selective, covalent Bruton tyrosine-kinase inhibitor with activity in chronic lymphocytic leukaemia. We compare the efficacy of acalabrutinib with or without obinutuzumab against chlorambucil with obinutuzumab in patients with treatment-naive chronic lymphocytic leukaemia.
ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. [2021]Acalabrutinib, a highly selective, potent, Bruton tyrosine kinase inhibitor, was evaluated in this global, multicenter, randomized, open-label, phase III study in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).
Acalabrutinib: Managing Adverse Events and Improving Adherence in Patients With Mantle Cell Lymphoma. [2022]Acalabrutinib is a selective Bruton tyrosine kinase inhibitor approved for patients with relapsed or refractory mantle cell lymphoma, an aggressive B-cell malignancy. Treatment-related adverse events (AEs) can have a negative effect on treatment adherence.
EMA Review of Acalabrutinib for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia. [2021]On November 5, 2020, a marketing authorization valid through the European Union (EU) was issued for acalabrutinib monotherapy or acalabrutinib in combination with obinutuzumab (AcalaObi) in adult patients with treatment-naïve (TN) chronic lymphocytic leukemia (CLL) and also for acalabrutinib monotherapy in adult patients with relapsed or refractory (RR) CLL. Acalabrutinib inhibits the Bruton tyrosine kinase, which plays a significant role in the proliferation and survival of the disease. Acalabrutinib was evaluated in two phase III multicenter randomized trials. The first trial (ACE-CL-007) randomly allocated acalabrutinib versus AcalaObi versus chlorambucil plus obinutuzumab (ChlObi) to elderly/unfit patients with TN CLL. The progression-free survival (PFS), as assessed by an independent review committee, was superior for both the AcalaObi (hazard ratio [HR], 0.1; 95% confidence interval [CI], 0.06-0.17) and acalabrutinib (HR, 0.2; 95% CI, 0.13-0.3) arms compared with the ChlObi arm. The second trial (ACE-CL-309) randomly allocated acalabrutinib versus rituximab plus idelalisib or bendamustine to adult patients with RR CLL. Also in this trial, the PFS was significantly longer in the acalabrutinib arm (HR, 0.31; 95% CI, 0.20-0.49). Adverse events for patients receiving acalabrutinib varied across trials, but the most frequent were generally headache, diarrhea, neutropenia, nausea, and infections. The scientific review concluded that the benefit-risk ratio of acalabrutinib was positive for both indications. This article summarizes the scientific review of the application leading to regulatory approval in the EU. IMPLICATIONS FOR PRACTICE: Acalabrutinib was approved in the European Union for the treatment of adult patients with chronic lymphocytic leukemia who have not received treatment before and for those who have received therapy but whose disease did not respond or relapsed afterward. Acalabrutinib resulted in a clinically meaningful and significant lengthening of the time from treatment initiation to further disease relapse or patient's death compared with standard therapy. The overall safety profile was considered acceptable, and the benefit-risk ratio was determined to be positive.
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.
Matching-adjusted indirect comparisons of safety and efficacy of acalabrutinib versus other targeted therapies in patients with treatment-naïve chronic lymphocytic leukemia. [2021]Acalabrutinib is a highly selective, potent, next-generation, covalent Bruton tyrosine kinase inhibitor with minimal off-target activity. Matching-adjusted indirect comparisons (MAICs) were performed to estimate the safety and efficacy of acalabrutinib compared to other targeted therapies for treatment-naïve patients with chronic lymphocytic leukemia (CLL). Individual patient data for acalabrutinib (ELEVATE-TN trial) were matched to aggregate baseline characteristics for comparators. After matching, acalabrutinib (with or without obinutuzumab) showed improved safety outcomes, except for increased risk of neutropenia (p < 0.001) for acalabrutinib plus obinutuzumab versus ibrutinib and increased risk of leukopenia (p < 0.05) for acalabrutinib (with or without obinutuzumab) versus venetoclax plus obinutuzumab. There was no statistically significant difference in progression-free survival between acalabrutinib (with or without obinutuzumab) and any of the comparators. This MAIC demonstrated a favorable safety profile for acalabrutinib-based therapy compared with other targeted therapies in treatment-naïve patients with CLL, without compromising efficacy.
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: Nursing Considerations for Use in Patients With Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma. [2022]Acalabrutinib is a next-generation Bruton tyrosine kinase inhibitor (BTKi) that has moved to the forefront of treatment options for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Patients with CLL/SLL can experience adverse events and toxicities unique to BTKi therapy.
Acalabrutinib-Related Cardiac Toxicities in Patients with Chronic Lymphocytic Leukemia: A Meta-Analysis of Randomized Controlled Trials. [2022]Acalabrutinib, a second-generation and more selective Bruton's tyrosine kinase inhibitor, was developed to potentiate efficacy while minimizing ibrutinib-associated side effects. We undertook a systematic review and meta-analysis of randomized clinical trials to determine the risks of acalabrutinib-related cardiac toxicities in patients with chronic lymphocytic leukemia. Patients on acalabrutinib experienced higher risk of any-grade cardiac events (risk ratio, 1.75; p = 0.01) while there was a considerable trend toward statistical significance in the risk of any-grade atrial fibrillation (risk ratio, 2.56; p = 0.05). There was no significant increase in the risk of hypertension or high-grade cardiac events or atrial fibrillation in the acalabrutinib group.
A phase 2, multicentre, open-label trial (ACE-LY-003) of acalabrutinib in patients with relapsed or refractory marginal zone lymphoma. [2022]Acalabrutinib, a Bruton tyrosine kinase inhibitor, demonstrated greater selectivity and improved safety versus ibrutinib in a head-to-head trial in relapsed/refractory (R/R) chronic lymphocytic leukaemia. In the R/R marginal zone lymphoma (MZL) cohort (phase 2) of a phase 1b/2 trial (NCT02180711), 43 patients with MZL and at least one prior therapy received acalabrutinib 100 mg twice daily until disease progression or unacceptable toxicity [median age 69 years (range 42-84); median one (1-4) prior systemic regimens]. Median follow-up was 13.3 months (range 0.5-45.5). Among 40 patients evaluable for response, investigator-assessed overall response rate was 53% [95% confidence interval (CI) 36%-69%] with five (13%) complete responses. Tumour reduction occurred in 40 (93%) of the treated patients. Median time to response was 2.9 months (median duration of response not estimable). Estimated median progression-free survival (PFS) was 27.4 months (12-month PFS rate, 67%). Five patients died (disease progression, n = 4; septic shock, n = 1). Seventeen patients (40%) had grade 3 or higher adverse events (AEs), most commonly neutropenia (14%), anaemia, dyspnoea (7% each), fatigue and thrombocytopenia (5% each). Hypertension occurred in 5%; atrial fibrillation/flutter and major haemorrhage were not reported. AEs led to treatment discontinuation in three (7%) patients. Acalabrutinib was active and well tolerated in patients with R/R MZL.