Ibrutinib + Chemotherapy for CNS Lymphoma

Recruiting at 1 trial location

Overseen By Kimberly A Johnson, R.N.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Strong CYP3A inhibitors

Disqualifiers: HIV, Hepatitis B/C, Cardiovascular, others

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

Compensation: Varies

Number of Visits: 3

93 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does mention that you should not have taken certain treatments like chemotherapy or radiation therapy for at least 2 weeks before starting the trial. Additionally, you cannot use strong CYP3A inhibitors or inducers within 7 days before the trial.

What data supports the effectiveness of the drug combination Ibrutinib + Chemotherapy for CNS Lymphoma?

Research shows that a combination of drugs including ibrutinib, temozolomide, etoposide, doxorubicin, dexamethasone, and rituximab can lead to frequent positive responses in patients with primary central nervous system lymphoma, although it may also cause significant side effects. ^{1 2 3 4 5}

What safety data exists for the combination of Ibrutinib and chemotherapy in treating CNS lymphoma?

The combination of Ibrutinib with chemotherapy for CNS lymphoma has been associated with significant safety concerns, including serious infections like pulmonary and cerebral aspergillosis. Additionally, other chemotherapy regimens for CNS lymphoma have shown toxicities affecting the kidneys and bone marrow, and some patients experienced severe side effects like neutropenic fever (a dangerous drop in white blood cells leading to fever), deep vein thrombosis (blood clots), and liver toxicity. ^{1 3 4 6 7}

What makes the drug combination of Ibrutinib and chemotherapy unique for treating CNS lymphoma?

This treatment combines Ibrutinib, a drug that blocks a specific protein (Bruton tyrosine kinase) involved in cancer cell growth, with chemotherapy drugs to target CNS lymphoma. It has shown promising results in patients who cannot tolerate standard treatments, offering a new option for those with relapsed or hard-to-treat cases, although it may come with significant side effects. ^{3 7 8 9 10}

What is the purpose of this trial?

BACKGROUND: * Primary CNS lymphoma (PCNSL) is a rare subtype of diffuse large B-cell lymphoma. * The outcome for patients with this diagnosis is significantly worse than for that of systemic DLBCL. Most treatment approaches in the past have included high dose methotrexate and radiation treatment. * Most PCNSLs appear to be of activated B-cell (ABC) origin. * Ibrutinib is an inhibitor of Bruton s tyrosine kinase (BTK) and effective for systemic DLBCL of ABC origin. * We propose doing a study in which ibrutinib is combined with a novel chemotherapy platform called dose adjusted temozolomide, etoposide, doxil, dexamethasone, ibrutinib, rituximab (TEDDI-R). OBJECTIVE: - Identify the maximum tolerated dose (MTD) of ibrutinib or the dose that achieves adequate CSF concentrations, whichever comes first, when ibrutinib is given with TEDDI-R. ELIGIBILITY: * Relapsed/refractory PCNSL. * Age greater than or equal to 18 years. * No pregnant or breast-feeding women. * Adequate organ function (defined in protocol). STUDY DESIGN: * This is a phase 1 study of 40 patients. * The study will have two components. 1. Phase 1: MTD of ibrutinib will be identified or the dose at which ibrutinib achieves a concentration of less than or equal to 100 nM in the CSF, when given in combination with TEDDI-R immuno-chemotherapy, whichever comes first. 2. Expansion cohort: Safety and tolerability of the regimen in relapsed/refractory or previously untreated PCNSL (DLBCL type) will be assessed at the final ibrutinib dose with TEDDI-R in 10 patients. Secondary objectives will be PFS and OS.

Research Team

Mark J Roschewski, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults diagnosed with primary central nervous system diffuse large B-cell lymphoma that has returned or resisted treatment. They must be at least 18 years old, not pregnant or breastfeeding, and have recovered from previous treatments. Participants need to have good organ function and cannot have used certain drugs recently.

Inclusion Criteria

My lymphoma is in the brain or spinal cord and has not responded to treatment.

I stopped taking ibrutinib at least 7 days before major surgery or 3 days before minor surgery.

I have recovered from previous treatment side effects.

Exclusion Criteria

I have not had a stroke or brain bleed in the last 6 months.

I haven't taken strong CYP3A affecting drugs in the last 7 days.

I do not have any uncontrolled illnesses.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1: Dose Escalation

MTD of ibrutinib will be identified or the dose at which ibrutinib achieves a concentration of less than or equal to 100 nM in the CSF, when given in combination with TEDDI-R immuno-chemotherapy, whichever comes first.

Varies per patient

Expansion Cohort

Safety and tolerability of the regimen in relapsed/refractory or previously untreated PCNSL (DLBCL type) will be assessed at the final ibrutinib dose with TEDDI-R.

Varies per patient

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Every 3 months for 1 year, every 4 months year 2, every 6 months year 3 then yearly

Treatment Details

Interventions

• Dexamethasone
• Doxil
• Etoposide
• Ibrutinib
• Rituximab
• Temozolomide

Trial Overview The trial is testing the combination of Ibrutinib with a novel immuno-chemotherapy regimen (TEDDI-R) for brain lymphoma. The first phase determines the highest dose patients can tolerate or the dose needed to reach effective levels in spinal fluid without severe side effects.

Participant Groups

Group I: Arm 4 (Dose Expansion; Amendment 06/04/21) Experimental Treatment 6 Interventions

TEDDI-R, cytarabine or methotrexate, isavuconazole, ibrutinib for 10 days

Group II: Arm 3 (Dose Expansion; prior to Amendment 06/04/2021) Experimental Treatment 4 Interventions

TEDDI-R with cytarabine and isavuconazole

Group III: Arm 2 (Dose Escalation; prior to Amendment 06/04/2021) Experimental Treatment 4 Interventions

TEDDI-R with cytarabine, and isavuconazole

Group IV: Arm 1-B (original study design-prior to Amendment G) Experimental Treatment 3 Interventions

TEDDI-R with cytarabine

Group V: Arm 1-A (original study design - prior to Amendment G) Experimental Treatment 7 Interventions

TEDD-R (cycle 1) with ibrutinib; TEDDI-R with cytarabine (cycles 2-6)

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

Approved in European Union as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases
• Immune system disorders

Approved in United States as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders
• Neoplastic diseases
• Nervous system disorders

Approved in Canada as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases

Approved in Japan as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 18 patients with primary central nervous system lymphoma (PCNSL), the combination of high-dose methotrexate (MTX) and CHOD chemotherapy resulted in complete responses in 11 patients and partial responses in 3, with a median survival of 25.5 months.

Despite showing some activity against PCNSL, the pre-irradiation MCHOD regimen did not demonstrate superior efficacy compared to MTX alone and was associated with higher toxicity, including significant myelotoxicity and other serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapy of primary central nervous system lymphoma with pre-irradiation methotrexate, cyclophosphamide, doxorubicin, vincristine, and dexamethasone (MCHOD). Glass, J., Shustik, C., Hochberg, FH., et al.[2019]

In a study of 375 patients with diffuse large B-cell lymphoma (DLBCL), only 3.5% showed central nervous system (CNS) involvement, indicating that while CNS involvement is rare, it remains a significant concern in DLBCL.

Key predictors for CNS involvement included elevated serum lactate dehydrogenase (LDH) levels and high International Prognostic Index (IPI) scores, but the use of rituximab did not reduce the incidence of CNS involvement, suggesting that additional strategies may be needed to address this risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Central nervous system involvement in diffuse large B-cell lymphoma. Yamamoto, W., Tomita, N., Watanabe, R., et al.[2022]

A combination treatment of temozolomide, etoposide, doxorubicin, dexamethasone, rituximab, and the BTK inhibitor ibrutinib showed promising responses in patients with primary central nervous system lymphoma.

However, this treatment regimen was linked to significant toxicity, including serious infections like pulmonary and cerebral aspergillosis, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib in PCNSL: The Curious Cases of Clinical Responses and Aspergillosis. Grommes, C., Younes, A.[2018]

In a study of seven patients with CNS lymphoma, the combination of rituximab and temozolomide was well tolerated, with no toxicity reported from rituximab and manageable side effects from temozolomide, indicating a safer alternative to traditional chemotherapy regimens.

The treatment showed promising efficacy, with five patients achieving a complete response and two achieving a partial response, although the median survival was 8 months, suggesting that this regimen could be beneficial for elderly patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunochemotherapy with rituximab and temozolomide for central nervous system lymphomas. Wong, ET., Tishler, R., Barron, L., et al.[2018]

A phase 2 study demonstrated that a combination of induction immunochemotherapy and high-dose consolidation chemotherapy followed by autologous stem cell transplantation is being tested for newly diagnosed primary central nervous system lymphoma (PCNSL).

The treatment regimen includes rituximab, high-dose methotrexate, vincristine, procarbazine, thiotepa, busulfan, and cyclophosphamide, aiming to improve outcomes for patients with this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of primary CNS lymphoma. Schmitz, N.[2021]

The combination treatment of high dose methotrexate (HD-MTX), temozolomide (TMZ), and rituximab (R) significantly improved progression-free survival (PFS) and overall survival (OS) in patients with primary central nervous system lymphoma (PCNSL), with median PFS of 56.7 months compared to 7.3 months for those receiving only HD-MTX and TMZ.

The treatment was generally well-tolerated, with only mild side effects such as grade 1-2 nausea and vomiting reported during the induction phase, and no severe grade 3/4 toxicities observed during consolidation treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of High Dose Methotrexate, Temozolomide and Rituximab in the Treatment of Patients with Primary Central Nervous System Lymphoma]. Pang, DW., Chen, FL., Guo, HG., et al.[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 real-world study of 11 newly diagnosed patients with primary central nervous system lymphoma (PCNSL), the combination of ibrutinib and high-dose methotrexate (HD-MTX) showed an impressive objective response rate of 82%, with 64% achieving complete response.

The treatment was well tolerated, and the analysis of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) indicated that ctDNA levels could be used to monitor tumor response, suggesting a promising role for liquid biopsies in assessing treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcomes of newly diagnosed primary CNS lymphoma treated with ibrutinib-based combination therapy: A real-world experience of off-label ibrutinib use. Chen, F., Pang, D., Guo, H., et al.[2021]

In a phase 1b clinical trial involving 15 patients with recurrent CNS lymphoma, the combination of ibrutinib, high-dose methotrexate (HD-MTX), and rituximab was well-tolerated, showing no severe toxicity and allowing 11 out of 15 patients to continue with maintenance therapy after initial treatment.

The treatment resulted in clinical responses in 80% of patients, with sustained tumor responses linked to the clearance of circulating tumor DNA (ctDNA) from cerebrospinal fluid, indicating a potential mechanism for monitoring treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma. Grommes, C., Tang, SS., Wolfe, J., et al.[2021]

Ibrutinib, a Bruton tyrosine kinase inhibitor, presents a promising treatment option for patients with relapsed and refractory primary CNS lymphoma (PCNSL) who cannot tolerate or respond to high-dose methotrexate regimens.

This review highlights the need for alternative therapies in PCNSL, as current treatments primarily rely on high-dose methotrexate, which may not be suitable for all patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib in primary central nervous system diffuse large B-cell lymphoma. T Low, J., B Peters, K.[2021]

References

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

Therapy of primary central nervous system lymphoma with pre-irradiation methotrexate, cyclophosphamide, doxorubicin, vincristine, and dexamethasone (MCHOD). [2019]

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

Central nervous system involvement in diffuse large B-cell lymphoma. [2022]

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

Ibrutinib in PCNSL: The Curious Cases of Clinical Responses and Aspergillosis. [2018]

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

Immunochemotherapy with rituximab and temozolomide for central nervous system lymphomas. [2018]

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

Treatment of primary CNS lymphoma. [2021]

6. China pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of High Dose Methotrexate, Temozolomide and Rituximab in the Treatment of Patients with Primary Central Nervous System Lymphoma]. [2021]

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

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

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

Clinical outcomes of newly diagnosed primary CNS lymphoma treated with ibrutinib-based combination therapy: A real-world experience of off-label ibrutinib use. [2021]

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

Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Ibrutinib in primary central nervous system diffuse large B-cell lymphoma. [2021]