Copanlisib + Ibrutinib for Central Nervous System Lymphoma

Not currently recruiting at 8 trial locations

Overseen By Ingo Mellinghoff, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Warfarin, Strong CYP3A4/5 inhibitors

Disqualifiers: Active malignancy, Cardiovascular disease, Diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety of using two drugs, copanlisib and ibrutinib, together to treat primary central nervous system lymphoma (PCNSL). It focuses on individuals whose cancer has returned or who cannot receive standard chemotherapy. Participants must have a PCNSL diagnosis and have experienced worsening conditions despite previous treatment. The study aims to determine if this new combination can be a safe and effective option for these patients. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Do I need to stop my current medications to join the trial?

Yes, you may need to stop certain medications before joining the trial. Specifically, you must stop using warfarin or other vitamin K antagonists 7 days before starting the trial drug, and strong CYP3A4/5 inhibitors and inducers 2 weeks prior. Additionally, enzyme-inducing antiepileptic drugs should be switched to non-inducing alternatives 2 weeks before starting the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of copanlisib and ibrutinib is under evaluation for safety in treating central nervous system lymphoma. Early results suggest patients can tolerate this combination, though some side effects occur.

Previous studies have found that copanlisib can cause high blood sugar and high blood pressure. Ibrutinib may lead to diarrhea, tiredness, and bleeding. These side effects were generally manageable and did not prevent the treatments from being used.

Ongoing studies aim to find the optimal dose that balances effectiveness and safety. As this is an early phase trial, researchers focus on ensuring the treatment is safe for humans. This involves careful monitoring and dose adjustments to reduce risks. Concerns or questions about the safety of joining this trial should be discussed with the research team. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining Copanlisib and Ibrutinib for treating central nervous system lymphoma because they work in a unique way compared to standard chemotherapy and radiation therapies. Copanlisib is a PI3K inhibitor, which targets a specific pathway crucial for cancer cell survival, while Ibrutinib is a BTK inhibitor, disrupting signals that help lymphoma grow. This duo targets cancer cells more precisely, potentially leading to fewer side effects and better outcomes. By focusing on these specific pathways, this treatment combo might offer a more effective approach for patients who have limited options with existing therapies.

What evidence suggests that the combination of copanlisib and ibrutinib could be effective for central nervous system lymphoma?

Research has shown that using copanlisib and ibrutinib together yields promising results for treating certain lymphomas. In some studies, many patients responded well to this treatment. For example, one study found that patients lived for an average of 7.7 months without their cancer worsening. Another report highlighted a patient with central nervous system lymphoma who tolerated ibrutinib well and went into remission. In this trial, participants will receive a combination of copanlisib and ibrutinib, which could effectively treat central nervous system lymphoma. ^{1 4 5 6 7}

Who Is on the Research Team?

Christian Grommes, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

Adults with primary central nervous system lymphoma (PCNSL) that's come back or hasn't responded to treatment, or those newly diagnosed but can't have standard chemo. They must be able to handle MRI/CT scans and lumbar punctures, have a life expectancy over 3 months, and good organ function. Contraception is required during the study.

Inclusion Criteria

- Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L

My kidney function, measured by creatinine, is within normal limits.

My kidneys are functioning well enough (creatinine clearance ≥ 30 mL/min).

Exclusion Criteria

I have been newly diagnosed with primary CNS lymphoma and can receive methotrexate chemotherapy.

I have previously been treated with a PI3K, AKT, or mTOR inhibitor, but ibrutinib is allowed.

My high blood pressure is not controlled, even with medication.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase Ib

Participants receive Ibrutinib and Copanlisib to determine the maximum tolerated dose using a '3+3' design

1 year

Weekly visits for drug administration and monitoring

Treatment Phase II

Participants receive sequential drug dosing with Ibrutinib and Copanlisib in 28-day cycles

1 year

Weekly visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Copanlisib
• Ibrutinib

Trial Overview The trial tests the safety of combining two drugs, copanlisib and ibrutinib, for treating PCNSL. Participants will receive both medications in an effort to determine how well they work together against this type of lymphoma.

How Is the Trial Designed?

Group I: Copanlisib in combination with Ibrutinib Experimental Treatment 2 Interventions

Participants will be assigned to the following dose levels: Dose level 1: Ibrutinib 560 mg daily + Copanlisib 60 mg weekly (3w on/1w off) Dose level 2: Ibrutinib 840 mg daily + Copanlisib 60 mg weekly (3w on/1w off) Dose level -1: Ibrutinib 560 mg daily + Copanlisib 45 mg weekly (3w on/1w off). Phase II: (Simon two-stage design: 14 patients will be treated at the MTD (including 6 patients from the phaseIb portion) If at least 11 patients respond then an additional 19 patients will be accrued to the second stage. Patients in the phase II portion of the trial will receive sequential drug dosing. Patient will be treated in 28-day cycles. During one cycle, only one drug will be administered with a ibrutinib/copanlisib ratio of 1:2. Patients will receive Ibrutinib at 840 mg daily during cycle 1 (day 1 through day 28) (28-day cycles), then copanlisib 60mg weekly on day 1, 8, and 15 during cycle 2 and 3. Patients will then repeat the sequence.

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Published Research Related to This Trial

Ibrutinib treatment showed a high overall response rate of 75% in patients with relapsed/refractory primary central nervous system lymphoma (PCNSL), with a median progression-free survival of 4 months, indicating its efficacy in this aggressive cancer type.

Genomic analysis revealed that patients with simpler genetic variants and lower tumor mutation burdens (TMB) responded better to ibrutinib, suggesting that genomic profiling could help predict treatment outcomes and tailor therapies for CNS lymphoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The outcome of ibrutinib-based regimens in relapsed/refractory central nervous system lymphoma and the potential impact of genomic variants. Wang, S., Zhu, Y., Qian, X., et al.[2023]

Ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase, shows a high rate of durable responses in patients with primary central nervous system lymphoma and secondary diffuse large B-cell lymphoma, indicating its efficacy in treating these challenging conditions.

Mutations in the CD79B protein and activation of the MTOR pathway were linked to reduced effectiveness of ibrutinib, but combining it with PIK3CA and PIK3CD inhibitors in preclinical studies demonstrated potential to overcome this resistance, suggesting new avenues for targeted therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spotlight on Ibrutinib in PCNSL: Adding Another Feather to Its Cap. Lakshmanan, A., Byrd, JC.[2021]

In a retrospective study of patients with primary central nervous system lymphoma (PCNSL), three patients showed good clinical responses to ibrutinib-based therapy, indicating its potential effectiveness in treating this aggressive cancer, especially in those unfit for traditional chemotherapy.

In vitro and pharmacokinetic studies revealed that ibrutinib demonstrated the strongest anti-tumoral effects compared to other BTK inhibitors, and both ibrutinib and tirabrutinib effectively penetrated the blood-brain barrier, making them promising candidates for targeted therapy in PCNSL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bruton's tyrosine kinase inhibitors in primary central nervous system lymphoma-evaluation of anti-tumor efficacy and brain distribution. Yu, H., Kong, H., Li, C., et al.[2022]

A 77-year-old patient with primary central nervous system lymphoma (PCNSL) showed good tolerance and sustained remission after receiving ibrutinib as a consolidation therapy following high-dose methotrexate and rituximab plus temozolomide.

This case suggests that ibrutinib, a Bruton's tyrosine kinase inhibitor that can cross the blood-brain barrier, may be an effective option for elderly patients with PCNSL, but further studies are needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Consolidation/Maintenance Therapy with Single Agent Ibrutinib for Primary CNS Lymphoma after Initial Induction Therapy. Du, S., Bota, D., Kong, XT.[2022]

In a phase Ib study involving 18 patients with primary CNS lymphoma (PCNSL), 94% experienced tumor reductions with ibrutinib monotherapy, highlighting its efficacy, especially in patients with specific mutations (CD79B and MYD88) that enhance B cell receptor signaling.

While ibrutinib showed promising results in reducing tumors and enhancing chemotherapy effectiveness, there was an increased risk of aspergillosis, a fungal infection, indicating a potential safety concern linked to impaired fungal immunity due to BTK inhibition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma. Lionakis, MS., Dunleavy, K., Roschewski, M., et al.[2022]

Ibrutinib, an oral Bruton tyrosine kinase inhibitor, demonstrated rapid and dramatic responses in 3 patients with symptomatic CNS relapse of mantle cell lymphoma, leading to almost immediate recovery from symptoms.

Pharmacokinetic analyses confirmed that ibrutinib effectively crosses the blood-brain barrier, with ongoing responses observed in patients from 2 months to 1 year after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse. Bernard, S., Goldwirt, L., Amorim, S., et al.[2021]

The combination of rituximab, lenalidomide, and ibrutinib (R2I) showed a high response rate in 14 patients with relapsed/refractory primary CNS lymphoma, with 4 achieving complete response and 4 achieving partial response within a median of 2.5 months.

R2I was generally well-tolerated, with manageable toxicity leading to discontinuation in only 3 patients, and no deaths related to toxicity, indicating its potential as a treatment option for patients who have failed conventional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab-Lenalidomide-Ibrutinib Combination for Relapsed/Refractory Primary CNS Lymphoma: A Case Series of the LOC Network. Houillier, C., Chabrot, CM., Moles-Moreau, MP., et al.[2021]

Ibrutinib showed promising efficacy in treating relapsed/refractory primary and secondary central nervous system lymphomas, with an objective response rate of 58% and a complete response rate of 55% among 33 patients studied.

The treatment resulted in a median progression-free survival of 3.1 months for primary CNS lymphoma and 10.2 months for secondary CNS lymphoma, with only one case of invasive fungal infection reported, indicating a favorable safety profile despite concurrent steroid use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib for central nervous system lymphoma: the Australasian Lymphoma Alliance/MD Anderson Cancer Center experience. Lewis, KL., Chin, CK., Manos, K., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03581942

Study Details | NCT03581942 | Copanlisib With Ibrutinib for ... The purpose of this study is to test the safety of combined use of the study drugs, copanlisib and ibrutinib, in people with PCNSL. Official Title. Phase IB/II ...

2. withpower.com withpower.com/trial/phase-2-lymphoma-7-2018-21eba

Copanlisib + Ibrutinib for Central Nervous System Lymphoma A 77-year-old patient with primary central nervous system lymphoma (PCNSL) showed good tolerance and sustained remission after receiving ibrutinib as a ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12126982/

Novel Therapies in Primary Central Nervous System Lymphoma In this review, we focus on the biology of PCNSL and novel chemotherapeutics, including targeted and immunotherapeutic agents as well as cellular therapies.

4. onclive.com onclive.com/view/copanlisib-plus-ibrutinib-produces-high-response-rate-in-relapsed-refractory-mcl-but-limited-by-additive-toxicity

Copanlisib Plus Ibrutinib Produces High Response Rate in ... Moreover, the median progression-free survival (PFS) with copanlisib plus ibrutinib was 7.7 months (95% CI, 2.7–not reached). “Our study ...

5. ashpublications.org ashpublications.org/bloodadvances/article/9/7/1485/535449/Phase-2-trial-of-ibrutinib-and-nivolumab-in

Phase 2 trial of ibrutinib and nivolumab in patients with ... Ibrutinib and nivolumab showed a response rate of 78% and the best complete response rate was 50% for relapsed/refractory CNS lymphomas.

6. clinicaltrial.be clinicaltrial.be/en/details/68123?per_page=20&only_recruiting=0&only_eligible=0&only_active=0

Copanlisib With Ibrutinib for Patients With Recurrent/ Re... Trial description. The purpose of this study is to test the safety of combined use of the study drugs, copanlisib and ibrutinib, in people with ...

7. cancer.gov cancer.gov/clinicaltrials/NCI-2018-02477

Copanlisib and Ibrutinib in Treating Patients with Recurrent ... This phase Ib/II trial studies the side effects and best dose of ibrutinib when given together with copanlisib, and to see how well they work in treating ...