Acalabrutinib for Chronic Lymphocytic Leukemia

Not currently recruiting at 13 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Acerta Pharma BV

Must not be taking: Proton-pump inhibitors, Warfarin

Disqualifiers: Prior malignancy, Cardiovascular disease, CNS involvement, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Until disease progression

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests acalabrutinib, a new treatment for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). The goal is to assess the safety and effectiveness of acalabrutinib for individuals who have not responded well to other treatments or cannot tolerate their current medication. The study includes various groups: one for those who haven't received treatment yet, another for those who can't tolerate ibrutinib, and others for specific conditions like Richter's transformation. Individuals with CLL or SLL whose symptoms are not improving with current treatments might be suitable for this trial. As a Phase 1, Phase 2 trial, it focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take proton-pump inhibitors or certain blood thinners like warfarin within 7 days of starting the study drug. If you're on these medications, you may need to discuss alternatives with your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that acalabrutinib has been tested for safety in people with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). One study found that acalabrutinib is generally well-tolerated, with many participants not experiencing severe side effects. The most common mild side effects included headaches, diarrhea, and fatigue.

Another study compared acalabrutinib to ibrutinib and found that acalabrutinib caused fewer heart-related side effects, such as irregular heartbeat, than ibrutinib. While some participants experienced side effects, most were manageable.

The FDA has approved acalabrutinib for treating CLL and SLL, indicating its safety for these conditions. However, this approval does not specifically cover the new uses being tested in this trial.

It is important to remember that individuals react differently to treatments. In a trial, doctors will closely monitor participants for any side effects to ensure safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for CLL?

Acalabrutinib is unique because it targets Bruton's tyrosine kinase (BTK), a protein essential for the survival and proliferation of cancer cells in chronic lymphocytic leukemia (CLL). This specificity allows acalabrutinib to interfere with the underlying disease mechanism more precisely compared to traditional chemotherapy. Unlike other treatments like ibrutinib, acalabrutinib offers a more targeted action, potentially reducing side effects for patients who are intolerant to standard therapies. Researchers are excited because it provides a promising alternative for those who have relapsed or are refractory to existing treatments, offering hope for improved outcomes with fewer complications.

What evidence suggests that this trial's treatments could be effective for chronic lymphocytic leukemia?

Research has shown that acalabrutinib effectively treats chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). In this trial, participants will receive acalabrutinib in different cohorts based on their treatment history and condition. Some participants will be treatment-naive, while others may have relapsed or become refractory to previous treatments like ibrutinib. Studies have found that acalabrutinib is safe and effective both as an initial treatment and after other treatments for CLL/SLL. In patients whose CLL is difficult to treat or has returned, acalabrutinib has shown promising results, improving their health. Real-world evidence supports these findings, consistently demonstrating its effectiveness and safety for many CLL patients. Overall, acalabrutinib represents a promising treatment option for people with CLL or SLL. ^{1 2 6 7 8}

Who Is on the Research Team?

Acerta Clinical Trials

Principal Investigator

1-888-292-9613 [e-mail]

Are You a Good Fit for This Trial?

This trial is for adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who need treatment, have specific symptoms like anemia or large spleen, and haven't responded well to other therapies. It's also for those intolerant to a drug called ibrutinib. People can't join if they've had certain recent treatments, uncontrolled heart issues, active infections like HIV/HBV/HCV, severe bleeding disorders, major surgery within the last month, or are pregnant.

Inclusion Criteria

Active disease meeting ≥ 1 of the following International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for requiring treatment: Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin < 10 g/dL) and/or thrombocytopenia (platelets < 100,000/μL). Massive (i.e., ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly. Massive nodes (i.e., ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy. Progressive lymphocytosis with an increase of > 50% over a 2-month period or a lymphocyte doubling time (LDT) of < 6 months. The LDT may be obtained by linear regression extrapolation of absolute lymphocyte counts (ALC) obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In participants with initial blood lymphocyte counts of < 30 X 10^9/L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections) should be excluded. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy. Constitutional symptoms documented in the participant's chart with supportive objective measures, as appropriate, defined as ≥ 1 of the following disease-related symptoms or signs: i. Unintentional weight loss ≥ 10% within the previous 6 months before screening. ii. Fevers higher than 100.5°F or 38.0°C for 2 or more weeks before screening without evidence of infection. iii. Night sweats for > 1 month before screening without evidence of infection. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. Agreement to use highly effective methods of contraception during the study and for 2 days after the last dose of study drug if sexually active and able to bear or beget children (see Section 3.7.9 for list of highly effective methods of contraception). Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local participant privacy regulations).

I am 18 or older with CLL/SLL and cannot tolerate ibrutinib due to its side effects.

I am 18 or older with CLL/SLL and need treatment but can't or don't want to undergo chemoimmunotherapy.

Exclusion Criteria

Serum amylase > 1.5 x ULN or serum lipase > 1.5 x ULN.

I do not have active HIV, hepatitis B, or C, or any uncontrolled infection.

I do not have uncontrolled AIHA or ITP requiring high doses of steroids.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oral acalabrutinib in various dosing regimens until disease progression or intolerance

Until disease progression

Follow-up

Participants are monitored for safety and effectiveness after treatment

7 years 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib

Trial Overview The trial is testing Acalabrutinib's safety and effectiveness in treating CLL/SLL. Participants will take this new BTK inhibitor to see how it helps manage their leukemia compared to current standard treatments.

How Is the Trial Designed?

Group I: Treatment-naive Cohort Experimental Treatment 1 Intervention

Treatment-naïve participants with confirmed CLL or SLL, will receive oral acalabrutinib Dose 5 QD (Cohort 7, later will be switched to Dose 1 BID per protocol amendment 6) or Dose 1 BID (Cohort 11) until disease progression or until the investigator will consider the study treatment to be intolerable or no longer in the participant's best interest.

Group II: Richters Syndrome/Prolymphocytic Leukemia Transformation Cohort Experimental Treatment 1 Intervention

Participants with diffuse large B-cell lymphoma (DLBCL) Richter's transformation (RS) or prolymphocytic leukemia (PLL) transformation, will receive oral acalabrutinib Dose 5 BID (Cohort 9) until disease progression or until the investigator will consider the study treatment to be intolerable or no longer in the participant's best interest.

Group III: Relapsed/Refractory Cohort Experimental Treatment 1 Intervention

Phase 1 (dose-escalation) and Phase 2 (dose-expansion) will be conducted for participants with relapsed/refractory CLL or SLL. In Phase 1, participants will receive oral once daily (QD) acalabrutinib at Dose 1 (Cohort 1), Dose 2 (Cohort 2a), Dose 3 (Cohort 3), and Dose 4 (Cohort 4a), and twice daily (BID) acalabrutinib at Dose 1 (Cohort 2b) and Dose 5 (Cohort 4b) for 28 days (1 cycle). In Phase 2, participants will receive oral acalabrutinib at Dose 1 BID (Cohort 2b) or Dose 5 QD (Cohort 2c, later will be switched to Dose 1 BID per protocol amendment 6) until disease progression or until the investigator will consider the study treatment to be intolerable or no longer in the participant's best interest. Participants from Phase 1 will be continued to receive Dose 1 BID until disease progression or until the investigator will consider the study treatment to be intolerable or no longer in the participant's best interest.

Group IV: Ibrutinib-intolerant Cohort Experimental Treatment 1 Intervention

Participants with confirmed CLL or SLL and were not tolerating ibrutinib treatment, will receive oral acalabrutinib Dose 5 QD (Cohort 8a, later switched to Dose 1 BID per protocol amendment 4) or Dose 1 BID (Cohort 8b) until disease progression or until the investigator will consider the study treatment to be intolerable or no longer in the participant's best interest.

Group V: Ibrutinib Relapsed/Refractory Cohort Experimental Treatment 1 Intervention

Participants with confirmed CLL/SLL and had relapsed/refractory to ibrutinib treatment, will receive oral acalabrutinib Dose 5 QD (Cohort 10) until disease progression or until the investigator will consider the study treatment to be intolerable or no longer in the participant's best interest.

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

Who Is Running the Clinical Trial?

Acerta Pharma BV

Lead Sponsor

Trials

46

Recruited

5,900+

Published Research Related to This Trial

In a pivotal phase 3 study with 310 patients, acalabrutinib significantly improved progression-free survival (PFS) compared to standard treatments (Idelalisib plus rituximab or bendamustine plus rituximab), with a median PFS not reached for acalabrutinib versus 16.8 months for IdR/BR.

After approximately 4 years of follow-up, acalabrutinib demonstrated a favorable safety profile, with lower rates of treatment discontinuation due to adverse events compared to IdR/BR, while maintaining similar rates of serious infections and other significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib Versus Investigator's Choice in Relapsed/Refractory Chronic Lymphocytic Leukemia: Final ASCEND Trial Results. Ghia, P., Pluta, A., Wach, M., et al.[2022]

In a phase III study involving 310 patients with relapsed/refractory chronic lymphocytic leukemia (CLL), acalabrutinib monotherapy significantly improved progression-free survival (PFS) compared to investigator's choice treatments, with a median PFS not reached for acalabrutinib versus 16.5 months for the comparator group.

Acalabrutinib demonstrated a favorable safety profile, with serious adverse events occurring in 29% of patients, compared to 56% for idelalisib plus rituximab and 26% for bendamustine plus rituximab, indicating it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. Ghia, P., Pluta, A., Wach, M., et al.[2021]

Acalabrutinib demonstrated a high overall response rate of 97% in treatment-naive patients with chronic lymphocytic leukemia (CLL), with a median follow-up of 53 months, indicating its strong efficacy as a monotherapy.

The treatment was generally safe, with serious adverse events reported in 38% of patients, but only 6% discontinued due to adverse effects, suggesting that acalabrutinib can be a durable and manageable option for patients with CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib in treatment-naive chronic lymphocytic leukemia. Byrd, JC., Woyach, JA., Furman, RR., et al.[2022]

In a phase 3 study involving 535 patients with treatment-naive chronic lymphocytic leukaemia, acalabrutinib combined with obinutuzumab or as a monotherapy significantly improved progression-free survival compared to the standard treatment of obinutuzumab with chlorambucil, with median survival not reached for the acalabrutinib groups versus 22.6 months for the chlorambucil group.

The safety profile of acalabrutinib was favorable, with fewer infusion reactions and a lower incidence of grade 3 or higher adverse events compared to the obinutuzumab-chlorambucil group, indicating it is a viable chemotherapy-free treatment option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Sharman, JP., Egyed, M., Jurczak, W., et al.[2021]

Acalabrutinib, a selective Bruton tyrosine kinase inhibitor, showed improved safety outcomes compared to other targeted therapies for treatment-naïve chronic lymphocytic leukemia (CLL) patients, although it was associated with a higher risk of neutropenia and leukopenia in some cases.

The analysis indicated that acalabrutinib (with or without obinutuzumab) had similar efficacy in terms of progression-free survival compared to other treatments, suggesting it is a safe and effective option for CLL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Matching-adjusted indirect comparisons of safety and efficacy of acalabrutinib versus other targeted therapies in patients with treatment-naïve chronic lymphocytic leukemia. Davids, MS., Telford, C., Abhyankar, S., et al.[2021]

Acalabrutinib, a selective Bruton's tyrosine kinase inhibitor, was found to increase the risk of any-grade cardiac events in patients with chronic lymphocytic leukemia, with a risk ratio of 1.75.

There was a notable trend indicating a higher risk of any-grade atrial fibrillation associated with acalabrutinib, with a risk ratio of 2.56, although no significant increase in hypertension or high-grade cardiac events was observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib-Related Cardiac Toxicities in Patients with Chronic Lymphocytic Leukemia: A Meta-Analysis of Randomized Controlled Trials. Htut, TW., Han, MM., Thein, KZ.[2022]

Acalabrutinib has been approved in the EU for treating both treatment-naïve and relapsed/refractory chronic lymphocytic leukemia (CLL), showing significant improvements in progression-free survival compared to standard therapies in two phase III trials involving adult patients.

The safety profile of acalabrutinib is generally acceptable, with common side effects including headache, diarrhea, and infections, and the overall benefit-risk ratio is considered positive for its use in CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EMA Review of Acalabrutinib for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia. Delgado, J., Josephson, F., Camarero, J., et al.[2021]

Acalabrutinib, a selective BTK inhibitor, has been FDA approved for treating chronic lymphocytic leukemia (CLL) and shows improved efficacy and safety compared to standard treatments, including ibrutinib.

In multinational phase 1/2 and phase 3 studies, acalabrutinib demonstrated significant effectiveness in treatment-naïve and relapsed refractory CLL patients, with fewer treatment-limiting toxicities such as atrial fibrillation and bleeding.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib and Its Therapeutic Potential in the Treatment of Chronic Lymphocytic Leukemia: A Short Review on Emerging Data. Isaac, K., Mato, AR.[2020]

Citations

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Real-World Effectiveness and Safety Outcomes of ... Real-world effectiveness and safety outcomes of Acalabrutinib treatment by line of therapy in patients with chronic lymphocytic leukemia and/or small ...

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Real-world efficacy and safety outcomes of acalabrutinib in ... NAOS, one of the largest real-world cohorts of acalabrutinib-treated CLL patients in Europe, showed effectiveness and safety consistent with ...

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How Effective Is CALQUENCE® (acalabrutinib)? | CLL Based on clinical trials, the FDA has determined that CALQUENCE is safe and effective as a first-line CLL/SLL treatment (or second-line or beyond).

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Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic ... In this study, the selective BTK inhibitor acalabrutinib had promising safety and efficacy profiles in patients with relapsed CLL, including those with ...

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Real-World Effectiveness and Safety Outcomes of ... Real-World Effectiveness and Safety Outcomes of Acalabrutinib Treatment By Line of Therapy in Patients with Chronic Lymphocytic Leukemia and/or ...

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Treatment for CLL/SLL and R/R MCL | CALQUENCE ... Important Safety Information About CALQUENCE® (acalabrutinib). EXPAND ... This product information is intended for US residents only. CALQUENCE is a registered ...

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Real-world safety profile of therapy with ibrutinib or ... Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial

8. calquencehcp.com calquencehcp.com/cll.html

BTK Inhibitor for Adult Patients with CLL or SLL - Calquence CALQUENCE® (acalabrutinib) is a BTK inhibitor for the treatment of adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).