Copanlisib + Ibrutinib for Central Nervous System Lymphoma

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

18 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drugs Copanlisib and Ibrutinib for treating central nervous system lymphoma?

Research shows that Ibrutinib, a drug that can cross the blood-brain barrier, has been effective in treating central nervous system lymphomas, with studies reporting good response rates and improved survival compared to traditional chemotherapy. Additionally, Ibrutinib has shown promise in maintaining remission in patients with primary central nervous system lymphoma. ^{1 2 3 4 5}

What safety data exists for Ibrutinib in treating central nervous system lymphoma?

Ibrutinib, used alone or with other treatments, has shown good tolerance in patients with central nervous system lymphoma, but there is a risk of increased aspergillosis (a fungal infection) due to its effect on the immune system. It has been used successfully in elderly patients and those with relapsed conditions, with some experiencing rapid symptom recovery and sustained remission. ^{1 4 6 7 8}

How is the drug combination of Copanlisib and Ibrutinib unique for treating central nervous system lymphoma?

The combination of Copanlisib and Ibrutinib is unique because Ibrutinib is a Bruton's tyrosine kinase inhibitor that can cross the blood-brain barrier, offering a targeted approach for central nervous system lymphoma, which is a rare and aggressive cancer with limited standard treatment options. This combination may provide a novel therapeutic strategy, especially for patients who are not suitable for traditional chemotherapy. ^{1 2 3 4 9}

What is the purpose of this trial?

This trial is testing the safety of using two drugs, copanlisib and ibrutinib, together. The study focuses on patients with a type of brain and spinal cord cancer called PCNSL. These drugs work by blocking proteins that cancer cells need to grow.

Research Team

Christian Grommes, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

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.

- International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper limit of normal

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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 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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Successful Consolidation/Maintenance Therapy with Single Agent Ibrutinib for Primary CNS Lymphoma after Initial Induction Therapy. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Ibrutinib for central nervous system lymphoma: the Australasian Lymphoma Alliance/MD Anderson Cancer Center experience. [2021]

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

Ibrutinib improves survival compared with chemotherapy in mantle cell lymphoma with central nervous system relapse. [2023]

4. China pubmed.ncbi.nlm.nih.gov

Bruton's tyrosine kinase inhibitors in primary central nervous system lymphoma-evaluation of anti-tumor efficacy and brain distribution. [2022]

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

Spotlight on Ibrutinib in PCNSL: Adding Another Feather to Its Cap. [2021]

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

Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse. [2021]

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

Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma. [2022]

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

Rituximab-Lenalidomide-Ibrutinib Combination for Relapsed/Refractory Primary CNS Lymphoma: A Case Series of the LOC Network. [2021]

9. Poland 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. [2023]