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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for primary central nervous system lymphoma (PCNSL), a rare and aggressive brain cancer. It combines the drug ibrutinib, which targets specific cancer cells, with a group of chemotherapy drugs (called TEDDI-R) to determine the safest and most effective dose. The trial focuses on patients whose PCNSL has returned or resisted previous treatments and who have had the condition confirmed through specific medical tests. Participants should be managing this challenging diagnosis and open to trying a different treatment approach. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment combination.

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.

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

Research has shown that the TEDDI-R treatment, which includes drugs like temozolomide, etoposide, doxil, dexamethasone, ibrutinib, and rituximab, is generally well-tolerated by patients. For instance, a study on a similar treatment called mini-TEDDI-R found that patients with CNS lymphoma experienced few serious side effects.

Evidence suggests that ibrutinib, a key component of TEDDI-R, has been tested in other CNS lymphoma studies and is usually considered safe. However, some patients might still experience side effects. In some studies, ibrutinib showed potential in treating CNS lymphoma, helping patients improve partially or completely.

Since this trial is in an early stage, it aims to find the safest dose of ibrutinib when used with TEDDI-R. Early-stage trials focus on safety, making these studies crucial for understanding any possible risks. Overall, combining ibrutinib with TEDDI-R looks promising, but researchers continue to ensure its safety for future patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the investigational treatments for CNS lymphoma because they incorporate ibrutinib, which offers a novel mechanism of action by targeting Bruton's tyrosine kinase (BTK). This approach is different from the standard chemotherapy and immunotherapy treatments like methotrexate and rituximab that are commonly used for CNS lymphoma. Ibrutinib's ability to inhibit BTK can potentially disrupt cancer cell survival pathways more effectively. Additionally, the trial explores combinations with drugs like isavuconazole, aiming to enhance treatment effectiveness and overcome resistance issues seen with existing therapies. This could mean more effective and rapid responses for patients battling this aggressive form of lymphoma.

What evidence suggests that this trial's treatments could be effective for CNS lymphoma?

Research shows that ibrutinib holds promise for treating central nervous system lymphoma, with studies indicating a 72% overall response rate, meaning many patients experience tumor shrinkage. In this trial, participants will receive different combinations of treatments. Some arms include Dexamethasone, which helps manage symptoms but doesn't significantly improve outcomes. Other arms involve Doxil, a type of doxorubicin, which doesn't reach the central nervous system well but still shows some effectiveness. Etoposide is included in certain arms and has successfully treated relapsed cases of this lymphoma. Rituximab, when combined with other treatments, improves response rates and survival chances. Temozolomide is also part of the study and has shown effectiveness in recurrent brain tumors, with some patients experiencing complete tumor disappearance. Together, these drugs aim to attack the cancer from different angles in the various treatment arms of this trial. ^{6 7 8 9 10}

Who Is on the Research Team?

Mark J Roschewski, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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 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 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]

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]

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 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]

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]

Citations

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The Diagnosis and Treatment of Primary CNS Lymphoma In this selected patient population, HD-ASCT was a highly effective treatment option with curative potential (overall response 80–96%, median overall survival ...

2. academic.oup.com academic.oup.com/neuro-oncology/article/25/Supplement_5/v222/7406212

Neuro-Oncology | Oxford Academic These results suggest that more frequent dexamethasone dosing is not associated with better clinical outcomes in the symptomatic management of PCNSL.

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Influence of preoperative corticosteroid treatment on rate of ... The aim of this study was thus to analyze the difference in the rate of diagnostic surgeries in PCNSL patients with and without preoperative CST.

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Primary central nervous system lymphomas: EHA–ESMO ... This EHA–ESMO Clinical Practice Guideline provides key recommendations for managing primary DLBCL of the CNS. •. The guideline covers clinical, ...

5. sciencedirect.com sciencedirect.com/science/article/pii/0090301986901655

Steroid-induced regression of primary malignant ... Successful treatment of primary central nervous system lymphoma with chemotherapy after osmotic blood-brain barrier opening ... dexamethasone. Suggestive ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S1040842824003408

Efficacy and safety of ibrutinib in central nervous system ... Unfortunately, despite management, over 50 % of patients relapse within five years, and high-dose chemotherapy along with hematopoietic stem cell ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39689737/

Efficacy and safety of ibrutinib in central nervous system ... Ibrutinib shows promising efficacy in improving partial and complete response rates in CNSL. The substantial heterogeneity observed ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8280788/

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9. clinicaltrials.gov clinicaltrials.gov/study/NCT03770416

Study Details | NCT03770416 | Nivolumab and Ibrutinib in ... This phase II trial studies the side effects and how well nivolumab and ibrutinib works in treating patients with central nervous system lymphoma that has ...

10. aacrjournals.org aacrjournals.org/clincancerres/article/30/18/4005/747460/A-Phase-II-Study-Assessing-Long-term-Response-to

A Phase II Study Assessing Long-term Response to Ibrutinib ... We previously reported the safety and short-term antitumor activity of ibrutinib in 20 patients with relapsed or refractory (r/r) primary ...