Acalabrutinib + Chemotherapy for Waldenstrom's Macroglobulinemia

(BRAWM Trial)

Recruiting at 8 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

63 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a combination of two established drugs and one new drug in untreated patients with a specific type of blood cancer. The treatment works by killing cancer cells, boosting the immune system, and blocking growth signals.

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.

What data supports the effectiveness of the drug combination Acalabrutinib, Bendamustine, and Rituximab for treating Waldenstrom's Macroglobulinemia?

Research shows that Bendamustine and Rituximab together are effective for treating Waldenstrom's Macroglobulinemia, with high response rates and good survival outcomes. Acalabrutinib, used alone, has also shown activity and safety in treating this condition. ^{1 2 3 4 5}

Is the combination of Acalabrutinib and chemotherapy safe for treating Waldenstrom's Macroglobulinemia?

Acalabrutinib, a targeted cancer drug, has been shown to have a tolerable safety profile in treating B-cell cancers, with most side effects being mild, like headaches and diarrhea. Bendamustine, another drug used in combination therapies, was well tolerated in studies, with no unexpected toxicities. Overall, these treatments have been generally safe in clinical trials for similar conditions. ^{1 3 5 6 7}

What makes the drug Acalabrutinib + Chemotherapy unique for treating Waldenstrom's Macroglobulinemia?

Acalabrutinib combined with Bendamustine and Rituximab offers a novel approach for treating Waldenstrom's Macroglobulinemia by targeting specific pathways in cancer cells, potentially providing a more effective treatment option compared to traditional therapies. This combination leverages the unique mechanisms of each drug, such as Acalabrutinib's ability to inhibit Bruton's tyrosine kinase (a protein involved in cancer cell growth), which may enhance the overall treatment efficacy. ^{8 9 10 11 12}

Research Team

Neil L Berinstein, MD

Principal Investigator

Sunnybrook Research Institute

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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 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]

References

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

Acalabrutinib monotherapy in patients with Waldenström macroglobulinemia: a single-arm, multicentre, phase 2 study. [2021]

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

Bendamustine plus rituximab for the treatment of Waldenström Macroglobulinemia: Patient outcomes and impact of bendamustine dosing. [2023]

3. Germany pubmed.ncbi.nlm.nih.gov

Bendamustine and rituximab (BR) versus dexamethasone, rituximab, and cyclophosphamide (DRC) in patients with Waldenström macroglobulinemia. [2018]

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

Bendamustine and rituximab combination is safe and effective as salvage regimen in Waldenström macroglobulinemia. [2022]

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

Bendamustine therapy in patients with relapsed or refractory Waldenström's macroglobulinemia. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

BeEAM Conditioning including High-Dose Bendamustine before Autologous Stem Cell Transplantation Is Safe and Effective in Patients with Waldenstrom's Macroglobulinemia. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

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

8. Germany pubmed.ncbi.nlm.nih.gov

Oral vinorelbine in combination with trastuzumab as a first-line therapy of metastatic or locally advanced HER2-positive breast cancer. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Margetuximab for the treatment of HER2-positive metastatic breast cancer. [2021]

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

Vinorelbine in breast cancer. [2019]

11. Japan pubmed.ncbi.nlm.nih.gov

Efficacy and toxicity of vinorelbine with doxorubicin/cyclophosphamide combination chemotherapy in a phase I-II study for advanced or recurrent breast cancer patients. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Vinorelbine-based salvage therapy in HER2-positive metastatic breast cancer patients progressing during trastuzumab-containing regimens: a retrospective study. [2021]