Acalabrutinib + Chemotherapy for Waldenstrom's Macroglobulinemia

(BRAWM Trial)

Not currently recruiting at 9 trial locations

Overseen By Neil L Berinstein, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Sunnybrook Health Sciences Centre

Must not be taking: Warfarin, Proton pump inhibitors

Disqualifiers: Cardiovascular disease, Hypertension, Autoimmune, 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

Compensation: Varies

Number of Visits: 12

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of treatments for Waldenstrom's Macroglobulinemia, a type of blood cancer. The researchers aim to determine the effectiveness of adding Acalabrutinib, an investigational oral drug, to standard chemotherapy drugs Bendamustine and Rituximab. Participants should have untreated Waldenstrom's Macroglobulinemia with symptoms affecting daily life. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important medical advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot be on warfarin or proton pump inhibitors. If you are on proton pump inhibitors, you can switch to H2-receptor antagonists or antacids 7 days before starting the trial.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that the combination of acalabrutinib, bendamustine, and rituximab is generally safe and well-tolerated. Earlier studies used this combination as an initial treatment for certain blood cancers in older adults, and patients managed the treatment well, with manageable side effects.

Additionally, the FDA has approved this combination for treating mantle cell lymphoma, indicating its safety. However, like any treatment, side effects may occur, so discussing these with a doctor is important. Overall, current evidence supports this treatment as a safe option for those considering joining the trial. ^{1 2 3 4}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for Waldenstrom's Macroglobulinemia, which typically involve chemotherapy and monoclonal antibodies like rituximab, this new approach combines acalabrutinib with chemotherapy. Acalabrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor, which works differently by specifically targeting and blocking signals that cancer cells need to grow and survive. Researchers are excited about acalabrutinib because it offers a more targeted attack on cancer cells, potentially leading to fewer side effects and improved effectiveness compared to traditional therapies. Additionally, the combination with bendamustine and rituximab could enhance the overall treatment response, providing a more powerful option for patients.

What evidence suggests that Acalabrutinib combined with chemotherapy could be an effective treatment for Waldenstrom's Macroglobulinemia?

Research shows that acalabrutinib holds promise for treating Waldenstrom's Macroglobulinemia. In studies, 93% of previously untreated patients responded positively. This trial will administer a combination of acalabrutinib, bendamustine, and rituximab. The combination of bendamustine and rituximab has a strong track record, with about 46% of patients responding well. This combination is effective as an initial treatment for this condition. Overall, these treatments offer a good chance of managing symptoms and improving outcomes for patients with Waldenstrom's Macroglobulinemia. ^{2 5 6 7 8}

Who Is on the Research Team?

Neil L Berinstein, MD

Principal Investigator

Sunnybrook Research Institute

Are You a Good Fit for This Trial?

This trial is for adults with untreated Waldenstrom's Macroglobulinemia, a type of lymphoma. Participants must have a life expectancy over 6 months, be willing to use effective birth control methods, and have adequate organ function. They should not have had previous systemic treatments for the disease (except certain allowed therapies) and must be able to comply with study requirements.

Inclusion Criteria

Ability to comply with protocol requirements

I haven't had any drug treatments for my condition, but treatments like plasmapheresis, specific radiation, or corticosteroids for symptoms are okay.

My lymphoma is causing symptoms or is about to cause symptoms.

Exclusion Criteria

Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

I have a history of active tuberculosis.

I have had treatment for Waldenstrom macroglobulinemia before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive bendamustine and rituximab for 6 cycles, and acalabrutinib for 1 year

12 months

6 cycles of 28 days each, with additional visits for acalabrutinib administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, with extended follow-up by telephone

Up to 6 years

Extended follow-up by telephone every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Bendamustine
• Rituximab

Trial Overview The trial tests Acalabrutinib in combination with standard-of-care Bendamustine and Rituximab in patients who haven't been treated before. It's an open-label phase II study where participants receive Bendamustine intravenously on two days per cycle, Rituximab either intravenously or subcutaneously once per cycle, and take Acalabrutinib orally twice daily for one year.

How Is the Trial Designed?

Group I: Single arm intervention Experimental Treatment 3 Interventions

100 mg Acalabrutinib (ACP-196) oral capsules twice daily for 1 year Bendamustine and rituximab will be given for 6 x 28-day cycles. Bendamustine will be given intravenously at 90 mg/m2 on days 1 and 2 of each cycle. Rituximab will be given on day 1 of each cycle (375 mg/m2 intravenously for the first cycle and 1400 mg subcutaneously OR 375 mg/m2 intravenously for subsequent cycles (as per institutional procedures).

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?

Sunnybrook Health Sciences Centre

Lead Sponsor

Trials

693

Recruited

1,569,000+

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

Published Research Related to This Trial

Acalabrutinib, a selective BTK inhibitor, has shown improved progression-free survival in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) compared to standard treatments, indicating its efficacy as a treatment option.

The safety profile of acalabrutinib is favorable, with most side effects being mild (grade 1/2), such as headache and diarrhea, and a low rate of treatment discontinuation due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib: A Selective Bruton Tyrosine Kinase Inhibitor for the Treatment of B-Cell Malignancies. Abbas, HA., Wierda, WG.[2023]

In a study of 160 patients with Waldenstrom macroglobulinemia, the bendamustine-rituximab (BR) regimen showed a trend towards longer progression-free survival (PFS) compared to dexamethasone, rituximab plus cyclophosphamide (DRC), with 2-year PFS rates of 88% for BR versus 61% for DRC, although the difference was not statistically significant (p=0.07).

Both treatment regimens had comparable overall response rates and grade ≥3 adverse events, indicating similar safety profiles, and the effectiveness of both regimens was not influenced by the presence of the MYD88L265P mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine and rituximab (BR) versus dexamethasone, rituximab, and cyclophosphamide (DRC) in patients with Waldenström macroglobulinemia. Paludo, J., Abeykoon, JP., Shreders, A., et al.[2018]

In a study of 77 women with HER2-positive, trastuzumab-resistant advanced breast cancer, vinorelbine-based therapy showed an overall response rate of 28% and a clinical benefit rate of 50%, indicating its potential effectiveness as a salvage treatment.

The median time to progression was 7.1 months and the median overall survival was 21 months after starting vinorelbine-based therapy, suggesting that it can provide meaningful clinical benefits in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vinorelbine-based salvage therapy in HER2-positive metastatic breast cancer patients progressing during trastuzumab-containing regimens: a retrospective study. Montemurro, F., Redana, S., Nolè, F., et al.[2021]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31866281/

a single-arm, multicentre, phase 2 study This study provides evidence that acalabrutinib is active as single-agent therapy with a manageable safety profile in patients with treatment-naive, or relapse ...

2. ashpublications.org ashpublications.org/ashclinicalnews/news/3900/Acalabrutinib-Induces-Durable-Response-in-Patients

Acalabrutinib Induces Durable Response in Patients With ... Acalabrutinib Induces Durable Response in Patients With Waldenström Macroglobulinemia Available ; 24-Month Rate ; Duration of response, 90%, 84%.

3. journals.lww.com journals.lww.com/hemasphere/fulltext/2022/06003/p1130__acalabrutinib_in_treatment_naive_or.1020.aspx

p1130: acalabrutinib in treatment-naive or relapsed ... Acalabrutinib is a highly effective treatment that achieved durable responses with a favorable safety profile in patients with TN or R/R WM.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11672393/

Optimal use of BTK inhibitors in Waldenström's ... The long-term results of the study confirmed the high response rates (overall response rate (ORR) of 90.5% and major response rate (MRR) of 79.4 ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2352302619302108

Acalabrutinib monotherapy in patients with Waldenström ... With a median follow-up of 27·4 months (IQR 26·0–29·7), 13 (93% [95% CI 66–100]) of 14 treatment naive patients achieved an overall response and 86 (93% [86–98]) ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04624906

Study Details | NCT04624906 | Bendamustine, Rituximab ... This is a multi-centre, open label, single-arm, phase II clinical trial in untreated patients with Waldenstrom's Macroglobulinemia.

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124091183

Indolent Lymphoma: Well Tolerated, Fixed Duration ... Bendamustine, rituximab and acalabrutinib front-line therapy for WM is safe and well tolerated in a relatively elderly population with a toxicity profile ...

8. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-acalabrutinib-bendamustine-and-rituximab-previously-untreated-mantle-cell-lymphoma

FDA approves acalabrutinib with bendamustine and ... FDA approves acalabrutinib with bendamustine and rituximab for previously untreated mantle cell lymphoma · Efficacy and Safety · Expedited ...