Acalabrutinib + Rituximab for Peripheral Neuropathy

Recruiting at 1 trial location

Overseen By Shayna R. Sarosiek, 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

Trial Summary

What is the purpose of this trial?

In this research study, is combining a new treatment acalabrutinib with a standard treatment, rituximab or other CD20 antibody, to determine whether this combination is safe and effective for participants with Immunoglobulin (Ig) M monoclonal gammopathy of undetermined significance ( IgM MGUS) or Waldenström macroglobulinemia WM related neuropathies. The names of the study drugs involved in this study are/is: * Acalabrutinib * Rituximab or similar CD20 antibody

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.

What data supports the effectiveness of the drugs Acalabrutinib and Rituximab for treating peripheral neuropathy?

Research shows that Rituximab, one of the drugs in the treatment, has been effective in improving symptoms in patients with certain types of peripheral neuropathy, particularly those associated with specific antibodies. It has shown benefits in reducing symptoms like sensory impairment and muscle weakness in patients with anti-MAG neuropathy. ^{1 2 3 4 5}

Is the combination of Acalabrutinib and Rituximab safe for treating peripheral neuropathy?

Rituximab has been studied for safety in patients with neuropathy related to anti-myelin-associated glycoprotein antibodies. It was generally well tolerated, with some patients showing improvement in their condition. However, larger controlled studies are needed to fully understand its safety profile. ^{1 2 6 7 8}

How does the drug Acalabrutinib + Rituximab differ from other treatments for peripheral neuropathy?

The combination of Acalabrutinib and Rituximab is unique because it combines a Bruton tyrosine kinase inhibitor (Acalabrutinib) with a monoclonal antibody (Rituximab) that targets B-cells, potentially offering a novel approach to treating peripheral neuropathy by addressing underlying immune-related mechanisms. ^{2 4 5 8 9}

Research Team

Shayna Sarosiek, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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 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]

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 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]

References

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

Predictors of response to rituximab in patients with neuropathy and anti-myelin associated glycoprotein immunoglobulin M. [2015]

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

Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein neuropathy. [2021]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Neurophysiological and clinical responses to rituximab in patients with anti-MAG polyneuropathy. [2015]

4. England pubmed.ncbi.nlm.nih.gov

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

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

Rituximab treatment of an IgM monoclonal autonomic and sensory neuropathy. [2015]

6. England pubmed.ncbi.nlm.nih.gov

Beneficial effects of Rituximab in patients with anti-MAG (myelin-associated glycoprotein) neuropathy: case reports. [2015]

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

Rituximab in the treatment of polyneuropathy associated with anti-MAG antibodies. [2015]

8. England pubmed.ncbi.nlm.nih.gov

Obinutuzumab, a new anti-CD20 antibody, and chlorambucil are active and effective in anti-myelin-associated glycoprotein antibody polyneuropathy. [2019]

9. Germany pubmed.ncbi.nlm.nih.gov

Rituximab in cryoglobulinemic peripheral neuropathy. [2021]