Ibrutinib + Rituximab for Follicular Lymphoma

Recruiting at 169 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Pharmacyclics LLC.

Disqualifiers: Transformed lymphoma, Prior treatment, CNS lymphoma, Cardiovascular disease, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: 4

Duration: 4 weeks

445 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug combination Ibrutinib and Rituximab for treating follicular lymphoma?

A phase 2 study showed that the combination of Ibrutinib and Rituximab was effective in treating follicular lymphoma, with an overall response rate of 85% in one group and 75% in another, and complete responses in 40% and 50% of patients, respectively. Additionally, the combination was found to be active and tolerable, with most patients experiencing manageable side effects. ^{1 2 3 4 5}

Is the combination of Ibrutinib and Rituximab safe for humans?

The combination of Ibrutinib and Rituximab has been studied for safety in various conditions, including follicular lymphoma and chronic lymphocytic leukemia. Common side effects include fatigue, diarrhea, and nausea, while more serious effects like bleeding and heart issues are less frequent. Overall, the treatment is considered tolerable, but certain adverse events require monitoring. ^{1 2 6 7 8}

How is the drug combination of Ibrutinib and Rituximab unique for treating follicular lymphoma?

The combination of Ibrutinib and Rituximab is unique for treating follicular lymphoma because it targets B-cell activity through two different mechanisms: Ibrutinib inhibits Bruton's tyrosine kinase, while Rituximab binds to the CD20 antigen on B cells, enhancing their clearance. This dual approach has shown high response rates and is active and tolerable as a first-line treatment. ^{1 2 9 10 11}

What is the purpose of this trial?

The purpose of this study is to evaluate whether the addition of ibrutinib will result in prolongation of progression-free survival (PFS) when compared with rituximab alone in treatment naïve participants with follicular lymphoma.

Eligibility Criteria

This trial is for adults aged 60 and older with untreated follicular lymphoma, who meet specific health criteria. They should have a certain level of physical fitness (ECOG score 0-2) and their liver and kidneys must work well. People with transformed lymphoma, brain or spinal cord lymphoma, serious heart conditions, or previous treatments for this cancer can't join.

Inclusion Criteria

My liver and kidney functions are within normal ranges.

My cancer can be measured by tests.

I am 70 or older, or I am 60-69 with one or more health conditions.

Exclusion Criteria

I have a serious heart condition that is currently causing symptoms.

I have received treatment for follicular lymphoma before.

My cancer affects my brain or spinal cord.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ibrutinib or placebo in combination with rituximab weekly for 4 weeks with maintenance

4 weeks

4 visits (in-person)

Follow-up

Participants are monitored for progression-free survival and other outcomes

2-5 years

Treatment Details

Interventions

• Ibrutinib
• Placebo to match Ibrutinib
• Rituximab

Trial Overview The study tests if adding Ibrutinib to Rituximab therapy extends the time patients live without their cancer getting worse compared to using Rituximab alone. Participants will either receive Ibrutinib plus Rituximab or a placebo (inactive substance) plus Rituximab.

Participant Groups

Group I: (Arm A) ibrutinib + rituximab Experimental Treatment 2 Interventions

Participants will receive 560mg of ibrutinib and rituximab 375mg/m\^2 weekly x4 with maintenance.

Group II: (Arm B) placebo + rituximab Placebo Group 2 Interventions

Participants will receive placebo and rituximab 375mg/m\^2 weekly x4 with maintenance.

Ibrutinib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in United States as Imbruvica for:

• Chronic lymphocytic leukemia/small lymphocytic lymphoma
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in Canada as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma

Approved in Japan as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia

Who Is Running the Clinical Trial?

Pharmacyclics LLC.

Lead Sponsor

Trials

114

Recruited

13,800+

Dr. Maky Zanganeh

Pharmacyclics LLC.

Chief Executive Officer

Degree from Louis Pasteur University in Strasbourg, France; MBA from Schiller International University in France

Dr. Ellie Im

Pharmacyclics LLC.

Chief Medical Officer

MD from an unspecified institution

Findings from Research

In a phase 2 study involving 80 adults with untreated follicular lymphoma, the combination of ibrutinib and rituximab showed a high overall response rate of 85% in the first treatment arm and 75% in the second arm, indicating strong efficacy.

The treatment was generally well-tolerated, with common side effects including fatigue, diarrhea, and nausea, while serious adverse events were rare, suggesting a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The combination of ibrutinib and rituximab demonstrates activity in first-line follicular lymphoma. Fowler, NH., Nastoupil, L., De Vos, S., et al.[2021]

In the HELIOS trial involving 578 subjects, the combination of bendamustine/rituximab and ibrutinib (BR-I) resulted in significantly higher systemic exposure to rituximab compared to bendamustine/rituximab with placebo (BR), particularly in the initial treatment cycles.

The study found no significant safety differences between the BR-I and BR groups, suggesting that the enhanced efficacy of BR-I may be achieved without compromising patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic Exposure of Rituximab Increased by Ibrutinib: Pharmacokinetic Results and Modeling Based on the HELIOS Trial. Lavezzi, SM., de Jong, J., Neyens, M., et al.[2021]

Ibrutinib is an effective oral treatment for patients with relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukaemia (CLL), showing a 68% overall response rate in MCL and significant improvements in progression-free survival and overall survival in CLL patients, including those with specific genetic mutations.

The drug has a good safety profile, with less than 10% of patients discontinuing treatment due to adverse effects, making it a promising option for patients with various B-cell malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Ibrutinib: A new drug of B-cell malignancies]. Thieblemont, C.[2021]

In the phase 3 HELIOS trial involving 578 patients with previously treated chronic lymphocytic leukemia (CLL), the combination of ibrutinib and bendamustine-rituximab (BR) significantly improved progression-free survival (PFS) compared to placebo+BR, with a median PFS not reached for ibrutinib+BR versus 14.3 months for placebo+BR.

The treatment with ibrutinib+BR also resulted in a higher rate of minimal residual disease (MRD)-negative responses (26.3% vs. 6.2% for placebo+BR), indicating a deeper response to therapy, while the safety profile remained consistent with earlier reports.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Fraser, G., Cramer, P., Demirkan, F., et al.[2023]

Ibrutinib is an effective treatment for chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL), showing better outcomes than traditional therapies like chlorambucil and ofatumumab in phase III trials involving elderly and previously-treated patients.

The drug has a good safety profile, although it can cause some adverse effects like bleeding and atrial fibrillation; it is recommended in treatment guidelines for patients with high-risk disease, including those with specific genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib: A Review in Chronic Lymphocytic Leukaemia. Deeks, ED.[2021]

The combination of rituximab and ibrutinib in a 57-year-old patient with mantle cell lymphoma led to a severe disseminated enterovirus infection, highlighting the significant risk of immunodeficiency and severe immune-related side effects from this treatment regimen.

High-dose intravenous immunoglobulins were effective in clearing the virus and restoring organ function, suggesting that this treatment should be considered for patients experiencing severe enterovirus infections while on rituximab and ibrutinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Life-threatening disseminated enterovirus infection during combined rituximab and ibrutinib maintenance treatment for mantle cell lymphoma: a case report. Higer, M., Cana, D., Podlech, J., et al.[2021]

In a study of 838 patients with untreated non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL), the combination of ibrutinib and R-CHOP did not improve event-free survival (EFS) for the overall population, but showed significant benefits for patients under 60 years old, improving EFS, progression-free survival (PFS), and overall survival (OS).

For patients aged 60 and older, the combination treatment worsened EFS, PFS, and OS, increased serious adverse events, and reduced the number of patients able to complete the full R-CHOP regimen, indicating that age significantly influences the safety and efficacy of ibrutinib in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase III Trial of Ibrutinib and Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Non-Germinal Center B-Cell Diffuse Large B-Cell Lymphoma. Younes, A., Sehn, LH., Johnson, P., et al.[2022]

In a phase 1b/2 study involving 61 patients with relapsed/refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), the combination of ibrutinib and durvalumab showed an overall response rate of 25%, with the highest response in non-GCB DLBCL patients (38%).

The treatment was generally well-tolerated, with common side effects including diarrhea, fatigue, and nausea, and a notable 20% of patients experienced immune-related adverse events, indicating that while the combination therapy is effective, it also carries additional risks compared to single-agent treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and activity of ibrutinib in combination with durvalumab in patients with relapsed or refractory follicular lymphoma or diffuse large B-cell lymphoma. Herrera, AF., Goy, A., Mehta, A., et al.[2021]

References

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

The combination of ibrutinib and rituximab demonstrates activity in first-line follicular lymphoma. [2021]

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

Systemic Exposure of Rituximab Increased by Ibrutinib: Pharmacokinetic Results and Modeling Based on the HELIOS Trial. [2021]

3. France pubmed.ncbi.nlm.nih.gov

[Ibrutinib: A new drug of B-cell malignancies]. [2021]

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

Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. [2023]

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

A phase 1/1b study of rituximab, bendamustine, and ibrutinib in patients with untreated and relapsed/refractory non-Hodgkin lymphoma. [2021]

6. France pubmed.ncbi.nlm.nih.gov

Ibrutinib (Imbruvica). Relapsed chronic lymphocytic leukaemia and mantle cell lymphoma: uncertain impact on survival. [2021]

7. Italy pubmed.ncbi.nlm.nih.gov

Incidence and management of toxicity associated with ibrutinib and idelalisib: a practical approach. [2021]

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

Ibrutinib: A Review in Chronic Lymphocytic Leukaemia. [2021]

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

Life-threatening disseminated enterovirus infection during combined rituximab and ibrutinib maintenance treatment for mantle cell lymphoma: a case report. [2021]

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

Randomized Phase III Trial of Ibrutinib and Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Non-Germinal Center B-Cell Diffuse Large B-Cell Lymphoma. [2022]

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

Safety and activity of ibrutinib in combination with durvalumab in patients with relapsed or refractory follicular lymphoma or diffuse large B-cell lymphoma. [2021]