Acalabrutinib for Graft-versus-Host Disease

Recruiting at 5 trial locations

Overseen By Gaby Desatnik

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Fred Hutchinson Cancer Research Center

Must not be taking: Ibrutinib, Strong CYP3A4 inhibitors

Disqualifiers: Infection, Malignancy, Cardiovascular disease, 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: Unknown

Duration: 6-24 months

51 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well acalabrutinib works in treating patients with chronic graft versus host disease. Acalabrutinib may be an effective treatment for graft-versus-host disease caused by a stem cell transplant.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop all current medications, but you cannot change your immunosuppressive regimen within 2 weeks before joining, and you cannot take certain medications like ibrutinib, strong CYP3A4 inhibitors/inducers, or warfarin. It's best to discuss your current medications with the trial team.

Is acalabrutinib generally safe for humans?

Acalabrutinib has been studied in various conditions like chronic lymphocytic leukemia and mantle cell lymphoma, showing a generally acceptable safety profile. Common side effects include headache, diarrhea, and infections, while serious side effects like heart issues and bleeding are less common. Overall, the benefits of acalabrutinib were found to outweigh the risks in these studies. ^{1 2 3 4 5}

How is the drug Acalabrutinib different from other treatments for graft-versus-host disease?

Acalabrutinib is unique because it is a Bruton tyrosine kinase (BTK) inhibitor, which means it works by blocking a specific protein that helps certain immune cells function, potentially reducing the immune response that causes graft-versus-host disease. This mechanism is different from other treatments like steroids or Ruxolitinib, which target different pathways in the immune system. ^{6 7 8 9 10}

Research Team

Stephanie Lee, MD, MPH

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

This trial is for adults over 18 with moderate to severe chronic graft versus host disease (GVHD) after a stem cell transplant. They must understand the study, be able to swallow capsules, and have a performance status indicating they can carry out daily activities. Women who can bear children and men must use effective contraception. People with uncontrolled heart or blood conditions, recent major surgery, certain infections or cancers, or those on specific medications cannot join.

Inclusion Criteria

I am able to care for myself but may not be able to do active work.

Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information

I have been diagnosed with moderate to severe chronic GVHD.

Exclusion Criteria

I do not have any severe, untreated infections.

I am not currently in another clinical trial or taking non-FDA approved drugs.

I do not have active hepatitis B or C according to recent tests.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive acalabrutinib 100 mg orally twice daily on days 1-28. Treatment repeats every 28 days for up to 6 cycles with an option to continue for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

6-24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then periodically thereafter.

Up to 3 years

Treatment Details

Interventions

• Acalabrutinib

Trial Overview The trial is testing Acalabrutinib's effectiveness in treating chronic GVHD following stem cell transplantation. It's a phase II study where participants will also complete questionnaires about their health status.

Participant Groups

Group I: Treatment (acalabrutinib) Experimental Treatment 2 Interventions

Patients receive acalabrutinib 100 mg PO BID on days 1-28. Treatment repeats every 28 days for up to 6 cycles with an option to continue for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

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?

Fred Hutchinson Cancer Research Center

Lead Sponsor

Trials

444

Recruited

148,000+

Fred Hutchinson Cancer Center

Lead Sponsor

Trials

583

Recruited

1,341,000+

AstraZeneca

Industry 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

Findings from Research

In a phase 2 trial involving 124 patients with relapsed or refractory mantle cell lymphoma, acalabrutinib was associated with common treatment-related adverse events (AEs) like headache and diarrhea, but these did not lead to any treatment discontinuations.

Effective management strategies, including patient education and the use of over-the-counter medications for mild AEs, helped maintain treatment adherence and allowed for better tracking and management of nonadherence issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib: Managing Adverse Events and Improving Adherence in Patients With Mantle Cell Lymphoma. Badillo, M., Nava, D., Rosa, M., et al.[2022]

Acalabrutinib, a Bruton tyrosine kinase inhibitor, showed a 53% overall response rate in patients with relapsed/refractory marginal zone lymphoma, indicating its efficacy in this patient population.

The treatment was generally well tolerated, with a median progression-free survival of 27.4 months and a low incidence of severe adverse events, suggesting improved safety compared to other treatments like ibrutinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2, multicentre, open-label trial (ACE-LY-003) of acalabrutinib in patients with relapsed or refractory marginal zone lymphoma. Strati, P., Coleman, M., Champion, R., et al.[2022]

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 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]

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]

In a study of 53 pediatric patients with graft-versus-host disease (GVHD), ruxolitinib demonstrated a high overall response rate of 75.5%, with 80.6% efficacy in chronic GVHD (cGVHD) cases compared to 64.7% in acute GVHD (aGVHD).

Ruxolitinib treatment allowed 39% of patients to discontinue steroids and 22.2% to reduce their steroid dosage, although it was associated with a high incidence of adverse events (94.1%) in the aGVHD group, indicating a need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effectiveness of Ruxolitinib for Acute/Chronic Graft-versus-Host Disease in Children: A Retrospective Study. Yang, W., Zhu, G., Qin, M., et al.[2022]

In a study of 18 patients with severe steroid-refractory acute graft-versus-host disease (aGVHD), the combination of ruxolitinib and extracorporeal photopheresis (ECP) was well tolerated, with no severe cytopenia observed and a 56% overall survival rate over two years.

The treatment led to complete or partial responses in 44% and 11% of patients, respectively, and allowed for rapid tapering of steroids, reducing the risk of steroid-related side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib plus extracorporeal photopheresis (ECP) for steroid refractory acute graft-versus-host disease of lower GI-tract after allogeneic stem cell transplantation leads to increased regulatory T cell level. Modemann, F., Ayuk, F., Wolschke, C., et al.[2021]

Steroid refractory chronic graft-versus-host disease (cGVHD) has limited treatment options, primarily based on phase II trials and retrospective analyses, highlighting the need for more systematic evaluations of second-line therapies.

Current treatment modalities include a variety of agents such as steroids, calcineurin inhibitors, and newer options like tyrosine kinase inhibitors, but the effectiveness of these treatments often relies on a trial-and-error approach, emphasizing the need for valid biomarkers to predict patient responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Consensus Conference on Clinical Practice in Chronic GVHD: Second-Line Treatment of Chronic Graft-versus-Host Disease. Wolff, D., Schleuning, M., von Harsdorf, S., et al.[2015]

In a clinical trial involving 95 patients with steroid-resistant acute graft-versus-host disease (GVHD), the treatment with ABX-CBL showed similar overall improvement compared to antithymocyte globulin (ATG), with 56% improvement in the ABX-CBL group versus 57% in the ATG group.

However, patient survival at 18 months was lower for those treated with ABX-CBL (35%) compared to those receiving ATG (45%), indicating that ABX-CBL does not provide a significant benefit over ATG in treating this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2/3 multicenter randomized clinical trial of ABX-CBL versus ATG as secondary therapy for steroid-resistant acute graft-versus-host disease. Macmillan, ML., Couriel, D., Weisdorf, DJ., et al.[2021]

In a study of 57 patients undergoing alternative donor transplantation for acute leukemia, early application of ruxolitinib significantly reduced the incidence of acute graft-versus-host disease (aGVHD) compared to the control group (22% vs. 50%).

Ruxolitinib was well tolerated, with no significant differences in overall survival or disease-free survival between the ruxolitinib and control groups, indicating its safety and efficacy in preventing aGVHD without compromising other health outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib early administration reduces acute GVHD after alternative donor hematopoietic stem cell transplantation in acute leukemia. Zhang, B., Chen, L., Zhou, J., et al.[2021]

References

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

Acalabrutinib: Managing Adverse Events and Improving Adherence in Patients With Mantle Cell Lymphoma. [2022]

2. England pubmed.ncbi.nlm.nih.gov

A phase 2, multicentre, open-label trial (ACE-LY-003) of acalabrutinib in patients with relapsed or refractory marginal zone lymphoma. [2022]

3. 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]

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

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

5. England pubmed.ncbi.nlm.nih.gov

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

6. New Zealand pubmed.ncbi.nlm.nih.gov

The Effectiveness of Ruxolitinib for Acute/Chronic Graft-versus-Host Disease in Children: A Retrospective Study. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Ruxolitinib plus extracorporeal photopheresis (ECP) for steroid refractory acute graft-versus-host disease of lower GI-tract after allogeneic stem cell transplantation leads to increased regulatory T cell level. [2021]

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

Consensus Conference on Clinical Practice in Chronic GVHD: Second-Line Treatment of Chronic Graft-versus-Host Disease. [2015]

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

A phase 2/3 multicenter randomized clinical trial of ABX-CBL versus ATG as secondary therapy for steroid-resistant acute graft-versus-host disease. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Ruxolitinib early administration reduces acute GVHD after alternative donor hematopoietic stem cell transplantation in acute leukemia. [2021]