Ibrutinib + Chemotherapy for CNS Lymphoma

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by Mark J Roschewski, M.D.

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: Strong CYP3A inhibitors

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

No Placebo Group

Breakthrough Therapy

Trial Summary

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.

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.

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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.

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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.

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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

I am 18 years old or older.

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

I am 18 years old or older.

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.

Trial 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

Participant Groups

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.

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, MD

National Institutes of Health Clinical Center Bethesda, MD

Who Is Running the Clinical Trial?

National Cancer Institute (NCI) Lead Sponsor

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] Prior studies have suggested that pre-irradiation methotrexate (MTX)-based chemotherapy improves duration of response and survival in primary central nervous system lymphoma (PCNSL). To circumvent the potential emergence of drug resistance, we combined high-dose MTX with agents highly active against systemic lymphoma. Patients received three week cycles of CHOD (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 [2 mg maximum] on day 1; dexamethasone 10 mg/m2 days 1-5), and MTX (3.5 gm/m2) with leucovorin rescue on day 8 (or on recovery from the CHOD nadir). Whole brain irradiation (WBRT) was planned after at least three cycles. Eighteen patients were treated. Complete responses were seen in eleven patients, and partial responses in three. Four progressed during therapy, three succumbing to progressive disease and one subsequently responding to WBRT. Response duration was 37.5 months in those responding to therapy. The time to progression for all eighteen patients was 19.5 months. Medial survival was 25.5 months. Disease-free survival was 50% at 38 months in MCHOD responders. Grade 3 or 4 myelotoxicity was seen in 19 of 50 cycles. There were three instances of neutropenic fever, three of azotemia, two of deep vein thrombosis, and one each of community-acquired pneumonia, intracranial hemorrhage, superior vena cava syndrome, and hepatotoxicity. Late radiation-related toxicities were seen in two patients. Pre-irradiation MCHOD has activity against PCNSL, but appears to be no better than MTX monotherapy and has greater toxicity.

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

Central nervous system involvement in diffuse large B-cell lymphoma. [2022] Malignant lymphoma with central nervous system (CNS) involvement has an extremely poor prognosis. We retrospectively studied the risk factors for CNS involvement in patients with diffuse large B-cell lymphoma (DLBCL) treated by cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or rituximab (R) -CHOP chemotherapy.

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

Ibrutinib in PCNSL: The Curious Cases of Clinical Responses and Aspergillosis. [2018] In this issue of Cancer Cell, Lionakis et al. demonstrate that the combination of temozolomide, etoposide, doxorubicin, dexamethasone, rituximab, and the Bruton tyrosine kinase (BTK) inhibitor ibrutinib induced frequent responses in patients with primary central nervous system lymphoma but was associated with significant toxicity, including pulmonary and cerebral aspergillosis infections.

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

Immunochemotherapy with rituximab and temozolomide for central nervous system lymphomas. [2018] Methotrexate-based and alkylator-based chemotherapy regimens are associated with renal and bone marrow toxicities, which limit their use in patients with central nervous system (CNS) lymphomas. The authors report their experience with an immunochemotherapy regimen consisting of rituximab and temozolomide in patients with primary or metastatic CNS lymphoma.

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

Treatment of primary CNS lymphoma. [2021] In this issue of Blood, Omuro et al report the results of a phase 2 study for patients with newly diagnosed primary central nervous system lymphoma (PCNSL) using induction immunochemotherapy (rituximab, high-dose methotrexate [MTX], vincristine, procarbazine) followed by a novel consolidation high-dose chemotherapy (thiotepa, busulfan, cyclophosphamide) and autologous stem cell transplantation (HDC-ASCT).

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] To investigate the clinical efficacy of high dose methotrexate (HD-MTX), temozolomide (TMZ), and rituximab (R) in the treatment of patients with primary central nervous system lymphoma (PCNSL).

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

Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse. [2021] The risk of central nervous system (CNS) dissemination in mantle cell lymphoma (MCL) is low and occurs late in the course of the disease. However, prognosis in such cases remains extremely poor despite high-dose antimetabolite chemotherapy. Among novel drugs used to treat relapsing MCL patients, ibrutinib, an oral inhibitor of Bruton tyrosine kinase, shows great promise. Here we report the clinical observation of 3 MCL patients with symptomatic CNS relapse treated with single-agent ibrutinib. All 3 patients had dramatic and rapid responses with almost immediate recovery from symptoms. We also confirmed that ibrutinib crosses the blood-brain barrier with parallel pharmacokinetic analyses in plasma and cerebrospinal fluid using a validated LC-MS/MS method. All responses were ongoing after 2 months to 1 year of follow-up.

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] Ibrutinib-based combination therapy with high-dose methotrexate (HD-MTX) has recently shown clinical activity against relapse/refractory (R/R) primary central nervous system lymphoma (PCNSL). Herein, we report our real-world experience of treating 11 newly diagnosed PCNSL patients with the ibrutinib/MTX combination. HD-MTX was given at 3.5 g/m2 every 2-week for eight doses. Ibrutinib was held upon HD-MTX infusion until clearance and was administered daily post-induction until disease progression, intolerable toxicity, or death. Nine out of 11 patients completed the induction phase and received ibrutinib as maintenance therapy. An objective response rate (ORR) of 82% (9/11) was observed including complete response (64%) and partial response (18%). The median progression-free survival (PFS) was 7.4 months while the median overall survival (OS) was not reached. The ibrutinib/MTX combination was well tolerated in these treatment-naïve PCNSL patients with an acceptable safety profile. Moreover, the longitudinal analysis of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) revealed that CSF ctDNA detection was closely associated with tumor response, and sustained tumor responses correlated with the clearance of ctDNA from the CSF. In sum, our data not only demonstrated the clinical benefit of the ibrutinib and HD-MTX combination regimen in treating newly diagnosed PCNSL patients in a real-world setting, but also highlighted the significance of liquid biopsy including CSF ctDNA in tracing tumor burden and assessing treatment response.

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

Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma. [2021] Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses (4 cycles; 1 cycle = 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX, and rituximab was tolerated with an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at www.clinicaltrials.gov as #NCT02315326.

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

Ibrutinib in primary central nervous system diffuse large B-cell lymphoma. [2021] The standard regimen for the treatment of newly diagnosed primary CNS lymphoma (PCNSL) remains regimens that contain high-dose methotrexate (MTX). While these regimens can provide control for some patients, there is a dearth of options for the treatment of patients with PCNSL who cannot tolerate MTX-containing regimens, or whose cancers are refractory to MTX. In this article, we review a promising new option; ibrutinib, a Bruton tyrosine kinase inhibitor, for patients with relapsed and refractory PCNSL.