Acalabrutinib + Rituximab for Peripheral Neuropathy

Recruiting at 1 trial location

Overseen By Andrew Branagan, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Shayna Sarosiek, MD

Must not be taking: CYP3A inhibitors, Proton pump inhibitors

Disqualifiers: CLL, MCL, MZL, 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: 1

Duration: 48 cycles (approximately 4 years)

33 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining the new treatment, acalabrutinib (a Bruton tyrosine kinase inhibitor), with the standard treatment, rituximab (a monoclonal antibody), is safe and effective for individuals with certain nerve problems related to IgM MGUS or Waldenström macroglobulinemia. Participants will receive both treatments to assess their impact on symptoms like numbness or tingling. Suitable candidates for this trial include those diagnosed with IgM MGUS or Waldenström macroglobulinemia who are experiencing sensory nerve issues. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group of people.

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 certain medications that affect liver enzymes or use proton pump inhibitors. It's best to discuss your current medications with the study team to see if they are allowed.

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

Research has shown that the combination of acalabrutinib and rituximab has been studied before. One study with patients who have mantle cell lymphoma found this combination generally well-tolerated, with most side effects being mild to moderate. Common side effects included headaches, diarrhea, and fatigue.

Another study with patients who have anti-MAG IgM peripheral neuropathy also demonstrated promising safety results. Many patients responded well to the treatment, and the available data reported no severe side effects.

Both acalabrutinib and rituximab are approved for treating other conditions, indicating their well-known safety profiles. However, researchers continue to study their combined effects. Participants should consider these findings when deciding whether to join a trial. ^{1 2 3 4 5}

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

Researchers are excited about using acalabrutinib and rituximab for treating peripheral neuropathy because these drugs offer a novel approach compared to traditional treatments. Most standard treatments for peripheral neuropathy focus on managing symptoms rather than altering disease progression. Acalabrutinib targets Bruton's tyrosine kinase, a key player in immune cell signaling, which may help reduce inflammation and nerve damage at the source. Rituximab, on the other hand, targets and reduces B-cells, potentially addressing underlying immune-related causes of neuropathy. This combination could offer more direct disease modification rather than just symptom management, making it a potentially game-changing option for people with this condition.

What evidence suggests that the combination of acalabrutinib and rituximab could be effective for IgM MGUS or WM related neuropathies?

Research has shown that using acalabrutinib with rituximab, the combination tested in this trial, may help treat certain nerve damage related to IgM MGUS or WM. In one study, 86% of patients experienced improved blood conditions, and 57% showed better physical abilities, as measured by the I-RODS tool. These results suggest the treatment is effective and generally well-tolerated. Early findings also indicate it might alleviate nerve damage linked to IgM-related conditions, potentially reducing symptoms and enhancing quality of life. ^{1 2 6 7 8}

Who Is on the Research Team?

Shayna Sarosiek, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for people with IgM MGUS or Waldenström macroglobulinemia who have peripheral neuropathy. They must have good organ function, agree to use effective contraception, and be able to follow the study plan. Excluded are those with high serum IgM levels, prior chemotherapy/BTK inhibitors (except certain treatments over 90 days ago), other active cancers within 2 years (with some exceptions), uncontrolled diseases like heart failure or infections, and inability to take oral medication.

Inclusion Criteria

You have a specific type of protein in your blood called IgM monoclonal paraprotein.

I am using effective birth control or abstaining from sex.

My organs and bone marrow are functioning well.

Exclusion Criteria

I have not had major surgery in the last 4 weeks.

I do not have an active Hepatitis B or C infection.

My liver is severely impaired (Child-Pugh class C).

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive acalabrutinib and rituximab (or biosimilar) for up to 48 cycles, with acalabrutinib administered twice daily and rituximab on specific days of cycles 1 and 4.

48 cycles (approximately 4 years)

Study visits every cycle for cycles 1-6, then every 3 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment completion for up to 2 years.

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Rituximab

Trial Overview The trial tests a combination of acalabrutinib (a new treatment) and rituximab (or similar CD20 antibody) against neuropathies related to IgM MGUS or Waldenström macroglobulinemia. It aims to find out if this drug duo is safe and more effective compared to current standard therapies.

How Is the Trial Designed?

Group I: ACALABRUTINIB + RITUXIMAB/BIOSIMILAR Experimental Treatment 2 Interventions

Acalabrutinib and rituximab (or biosimilar) with be contained in the treatment regimen. Acalabrutinib will be administered twice daily, with 28 consecutive days defined as a treatment cycle. Acalabrutinib will be administered for 48 cycles or until disease progression or unacceptable toxicity. Rituximab will be administered on Days 1, 8, 15, and 22 of Cycles 1 and 4. Participants will have study visits every cycle for cycles 1-6, then every 3 cycles, with the next visit at Cycle 9, then C12, C15, etc. Participants will continue acalabrutinib until disease progression or intolerable adverse effect develops. They will be followed for up to 2 years after completion of 48 cycles of treatment or until death

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?

Shayna Sarosiek, MD

Lead Sponsor

Trials

2

Recruited

70+

Jorge J. Castillo, MD

Lead Sponsor

Trials

2

Recruited

40+

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

Rituximab, a monoclonal antibody targeting CD-20, has shown effectiveness in treating autonomic and painful sensory neuropathy linked to IgM monoclonal gammopathy, as demonstrated in a case report.

The treatment led to a reduction in total IgM levels and significant improvement in the patient's symptoms, suggesting that rituximab is a promising and well-tolerated option for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab treatment of an IgM monoclonal autonomic and sensory neuropathy. Goldfarb, AR., Weimer, LH., Brannagan, TH.[2015]

Rituximab infusions showed remarkable improvement in three patients suffering from anti-myelin-associated glycoprotein (MAG) neuropathy, a condition known for its treatment resistance.

Due to the limited evidence and the need for further research, Rituximab should only be used in patients with significant neurological deficits until its safety and efficacy are confirmed in larger studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beneficial effects of Rituximab in patients with anti-MAG (myelin-associated glycoprotein) neuropathy: case reports. Souayah, N., Noopur, R., Tick-Chong, PS.[2015]

In a study of 13 patients with polyneuropathy linked to anti-MAG antibodies, rituximab treatment led to a significant reduction in anti-MAG IgM titers and clinical improvement in sensory scores for 62% of participants after one year.

The results indicate that rituximab may be effective in treating anti-MAG associated neuropathy, especially in patients with moderately elevated antibody levels, suggesting that reducing antibody levels below a certain threshold is important for achieving clinical benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of response to rituximab in patients with neuropathy and anti-myelin associated glycoprotein immunoglobulin M. Benedetti, L., Briani, C., Grandis, M., et al.[2015]

Obinutuzumab, a novel anti-CD20 monoclonal antibody, showed significant efficacy in treating two patients with anti-MAG antibody polyneuropathy, leading to improved mobility and decreased anti-MAG antibody levels after treatment.

Both patients had concurrent chronic lymphocytic leukemia (CLL), suggesting that CLL may influence the response to obinutuzumab, warranting further investigation in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab, a new anti-CD20 antibody, and chlorambucil are active and effective in anti-myelin-associated glycoprotein antibody polyneuropathy. Briani, C., Visentin, A., Salvalaggio, A., et al.[2019]

In a study of 54 patients with IgM anti-MAG demyelinating neuropathy, rituximab did not show a significant improvement in the primary outcome measure, the INCAT sensory score, after 12 months compared to placebo.

However, secondary analyses indicated some improvements in patient-reported outcomes, suggesting that while rituximab may not be effective for the primary measure, it could have benefits in other areas of patient experience.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein neuropathy. Léger, JM., Viala, K., Nicolas, G., et al.[2021]

Rituximab treatment in 7 patients with anti-MAG polyneuropathy led to a significant reduction in CD20 B-lymphocytes and anti-MAG antibody titers, indicating its immunomodulatory effects.

While rituximab did not improve electrophysiological data, it resulted in significant improvements in small fiber sensory functions, such as pinprick sensation and two-point discrimination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurophysiological and clinical responses to rituximab in patients with anti-MAG polyneuropathy. Zara, G., Zambello, R., Ermani, M.[2015]

Rituximab, a chimeric anti-CD20 monoclonal antibody, has shown promise in treating treatment-resistant peripheral neuropathy associated with IgM gammopathy, offering a favorable side-effect profile compared to traditional treatments.

While large controlled studies are still needed, rituximab is administered at 375 mg/m² intravenously over four weekly doses, potentially providing a new therapeutic option for patients suffering from this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab in the treatment of peripheral neuropathy associated with monoclonal gammopathy. Zivković, SA.[2015]

In a study of nine patients with anti-MAG-associated IgM polyneuropathy, rituximab treatment led to a significant reduction in B-cells and IgM levels, with decreases ranging from 35% to 82%.

Clinical improvements were noted in six out of nine patients, with some experiencing enhanced motor nerve conduction velocity, indicating that rituximab may be a promising treatment option for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab in the treatment of polyneuropathy associated with anti-MAG antibodies. Renaud, S., Gregor, M., Fuhr, P., et al.[2015]

In a study of 13 patients with type II mixed cryoglobulinemia and polyneuropathy, treatment with rituximab led to significant improvements in sensory symptoms and clinical neuropathy scores over at least 12 months.

Rituximab was found to be effective and safe, with negligible side effects, while not significantly affecting the viral load, indicating its potential as a targeted therapy for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab in cryoglobulinemic peripheral neuropathy. Cavallo, R., Roccatello, D., Menegatti, E., et al.[2021]

Citations

1. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/213/500198/Prospective-Study-of-Acalabrutinib-with-Rituximab

Prospective Study of Acalabrutinib with Rituximab in Patients ... Hematologic responses occurred in 86% of patients and 57% had an improvement in the I-RODS score. Treatment is well tolerated. Additional data ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497123048176

Prospective Study of Acalabrutinib with Rituximab in ... Median improvement was 0.5 points (range -4 to 11). One patient was removed from the trial after 28 days due to grade 3 elevation in ALT. Two ...

3. onclive.com onclive.com/view/dr-castillo-on-acalabrutinib-plus-rituximab-in-patients-with-anti-mag-igm-peripheral-neuropathy

Dr Castillo on Acalabrutinib Plus Rituximab in Patients With ... Results showed that the combination of acalabrutinib and rituximab demonstrated early activity in patients with IgM-related anti-MAG peripheral ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04765111

Acalabrutinib and Rituximab for the Treatment of ... This phase II trial studies the side effects of acalabrutinib and rituximab and its effect in treating patients with previously untreated mantle cell lymphoma.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11399641/

Acalabrutinib plus venetoclax and rituximab in treatment-naive ... Overall response rate (ORR) was 100% (95% CI, 83.9-100.0) with 71.4% complete response. With median follow-up of 27.8 months, median progression-free survival ( ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12332063/

Frontline acalabrutinib, lenalidomide and rituximab for ... After a median follow-up of 43 months, median PFS and OS were not reached, 2-year PFS rate was 79% and 2-year OS rate was 92%. Here we show that ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12225732/

Acalabrutinib Plus Bendamustine-Rituximab in Untreated ... The addition of acalabrutinib to bendamustine plus rituximab significantly improved progression-free survival (PFS) compared with placebo and bendamustine plus ...

8. ema.europa.eu ema.europa.eu/en/documents/variation-report/calquence-h-c-005299-ii-0028-epar-assessment-report-variation_en.pdf

Calquence- INN; Acalabrutinib - European Medicines Agency The AMPLIFY study (also referred to as ACE-CL-311) was designed to assess the efficacy and safety of a fixed-duration therapy of acalabrutinib ...