Acalabrutinib for Chronic Lymphocytic Leukemia and Heart Failure

Recruiting at 22 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: AstraZeneca

Must not be taking: Warfarin, Strong CYP3A inhibitors

Disqualifiers: Active CNS leukemia, Richter's transformation, others

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

Prior Safety Data This treatment has passed at least one previous human trial

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: 41

Duration: 32 weeks

60 Participants Needed

Trial Summary

What is the purpose of this trial?

This will be a global Phase IV, open-label, randomised study to evaluate the safety and tolerability of acalabrutinib (monotherapy, 100 mg orally \[po\], twice daily \[bd\]) compared to investigator's choice of treatment, in patients with CLL (TN or R/R) and moderate to severe cardiac impairment. All patients will have cardiac impairment as defined by LVEF of \< 50%. Randomisation will be stratified by LVEF \> 40% vs ≤ 40% to stratify for moderate and severe cardiac impairment, which for this study are defined as follows: Severe cardiac impairment: in those with LVEF ≤ 40% Moderate cardiac impairment: in those with LVEF \> 40% to \< 50%. The study is planned to take place in approximately 20 centres globally. The study will be conducted in centres that have established close collaboration between the Haematology and Cardiology divisions, preferably with a cardio-oncologist on the team. An IDMC will be responsible for making recommendations for study continuation.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot take strong CYP3A inhibitors or inducers close to starting the study. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug Acalabrutinib for treating chronic lymphocytic leukemia?

Acalabrutinib has been shown to significantly extend the time patients with chronic lymphocytic leukemia live without their disease getting worse compared to standard treatments. It was effective both for patients who had never been treated before and for those whose disease returned after previous treatments. ^{1 2 3 4 5}

Is acalabrutinib safe for humans?

Acalabrutinib has been shown to be generally safe for humans, with common side effects including headache, diarrhea, and infections. Some studies noted an increased risk of heart-related issues like atrial fibrillation, but serious heart problems were not significantly higher compared to other treatments. ^{1 2 3 4 6}

How is the drug Acalabrutinib unique for treating chronic lymphocytic leukemia?

Acalabrutinib is a highly selective Bruton tyrosine kinase inhibitor, which means it specifically targets a protein that helps cancer cells grow and survive, making it more effective and with fewer side effects compared to older treatments. It has shown superior progression-free survival rates in patients with chronic lymphocytic leukemia, both in those who have never been treated before and those whose disease has returned or not responded to previous treatments. ^{1 2 3 4 5}

Eligibility Criteria

This trial is for adults with Chronic Lymphocytic Leukemia (CLL) who also have heart failure, specifically those with a left ventricular ejection fraction (LVEF) less than 50%. Patients must be able to take oral medication twice daily and should not have other health conditions that would interfere with the study.

Inclusion Criteria

I agree to use effective birth control during and for 2 days after my last dose.

Meet the following laboratory parameters: Absolute neutrophil count (ANC) ≥ 500 cells/μL, Platelet count ≥ 30,000 cells/μL, Serum aspartate aminotransferase and ALT ≤ 3.0 × ULN, Total bilirubin ≤ 1.5 × ULN unless directly attributable to Gilbert's syndrome, Estimated creatinine clearance (eGFR using Cockcroft-Gault) ≥ 40 mL/min or serum creatinine ≤ 2 × ULN

I have had no more than 2 treatments for my CLL.

Exclusion Criteria

I have not had major surgery in the last 30 days.

Received any investigational drug within 30 days or 5 half-lives (whichever is shorter) before first dose of study treatment

I have not received a live virus vaccine in the last 28 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive either acalabrutinib or investigator's choice of treatment. Each treatment cycle is 28 days/4 weeks.

32 weeks

8 visits (in-person) every 4 weeks, then every 16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment discontinuation. Safety follow-up occurs within 45 days of the last dose.

4 years

Every 16 weeks until study termination

Long-term Follow-up

Participants are contacted every 16 weeks for survival status and information on any new anti-cancer therapy until WoC, death, or study termination.

4 years

Every 16 weeks

Treatment Details

Interventions

• Acalabrutinib

Trial Overview The trial is testing Acalabrutinib, taken orally twice a day, against treatments chosen by the investigator in patients with CLL and moderate to severe heart failure. The safety and tolerability of these treatments are being compared, with special attention to how they affect heart function.

Participant Groups

Group I: Treatment Arm B Experimental Treatment 1 Intervention

Patients in Arm B will receive investigator's choice of treatment its duration will be based on standard duration of therapy for that regimen or until disease progression/patient withdrawal/study termination, whichever occurs first.

Group II: Treatment Arm A (Acalabrutinib Monotherapy) Active Control 1 Intervention

All participants randomised to Arm A will receive treatment with the investigational product acalabrutinib.

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?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Fortrea

Industry Sponsor

Trials

22

Recruited

5,800+

eResearch Technology, Inc.

Industry Sponsor

Trials

5

Recruited

1,400+

CALYX Inc.

Collaborator

Trials

1

Recruited

60+

CISCRP Inc.

Collaborator

Trials

1

Recruited

60+

CISCRP

Industry Sponsor

Trials

4

Recruited

1,400+

Findings from Research

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 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]

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, 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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

EMA Review of Acalabrutinib for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Acalabrutinib-Related Cardiac Toxicities in Patients with Chronic Lymphocytic Leukemia: A Meta-Analysis of Randomized Controlled Trials. [2022]

3. United States 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. [2021]

4. United States 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. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Acalabrutinib Versus Investigator's Choice in Relapsed/Refractory Chronic Lymphocytic Leukemia: Final ASCEND Trial Results. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Acalabrutinib in treatment-naive chronic lymphocytic leukemia. [2022]