93 Participants Needed

Ibrutinib + Chemotherapy for CNS Lymphoma

Recruiting at 1 trial location
AN
MJ
KA
Overseen ByKimberly A Johnson, R.N.
Age: 18+
Sex: Any
Trial Phase: Phase 1
Sponsor: National Cancer Institute (NCI)
No Placebo GroupAll trial participants will receive the active study treatment (no placebo)

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.12345

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.13467

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.378910

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

MJ

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.
See 20 more

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.
See 20 more

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
5Treatment groups
Experimental Treatment
Group I: Arm 4 (Dose Expansion; Amendment 06/04/21)Experimental Treatment6 Interventions
TEDDI-R, cytarabine or methotrexate, isavuconazole, ibrutinib for 10 days
Group II: Arm 3 (Dose Expansion; prior to Amendment 06/04/2021)Experimental Treatment4 Interventions
TEDDI-R with cytarabine and isavuconazole
Group III: Arm 2 (Dose Escalation; prior to Amendment 06/04/2021)Experimental Treatment4 Interventions
TEDDI-R with cytarabine, and isavuconazole
Group IV: Arm 1-B (original study design-prior to Amendment G)Experimental Treatment3 Interventions
TEDDI-R with cytarabine
Group V: Arm 1-A (original study design - prior to Amendment G)Experimental Treatment7 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:

๐Ÿ‡ช๐Ÿ‡บ
Approved in European Union as Dexamethasone for:
  • Inflammation
  • Allergic reactions
  • Respiratory diseases
  • Skin conditions
  • Eye diseases
  • Immune system disorders
๐Ÿ‡บ๐Ÿ‡ธ
Approved in United States as Dexamethasone for:
  • Inflammatory conditions
  • Allergic states
  • Respiratory diseases
  • Blood disorders
  • Neoplastic diseases
  • Nervous system disorders
๐Ÿ‡จ๐Ÿ‡ฆ
Approved in Canada as Dexamethasone for:
  • Inflammation
  • Allergic reactions
  • Respiratory diseases
  • Skin conditions
  • Eye diseases
๐Ÿ‡ฏ๐Ÿ‡ต
Approved in Japan as Dexamethasone for:
  • Inflammatory conditions
  • Allergic states
  • Respiratory diseases
  • Blood disorders

Find a Clinic Near You

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

References

Therapy of primary central nervous system lymphoma with pre-irradiation methotrexate, cyclophosphamide, doxorubicin, vincristine, and dexamethasone (MCHOD). [2019]
Central nervous system involvement in diffuse large B-cell lymphoma. [2022]
Ibrutinib in PCNSL: The Curious Cases of Clinical Responses and Aspergillosis. [2018]
Immunochemotherapy with rituximab and temozolomide for central nervous system lymphomas. [2018]
Treatment of primary CNS lymphoma. [2021]
[Clinical Efficacy of High Dose Methotrexate, Temozolomide and Rituximab in the Treatment of Patients with Primary Central Nervous System Lymphoma]. [2021]
Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse. [2021]
Clinical outcomes of newly diagnosed primary CNS lymphoma treated with ibrutinib-based combination therapy: A real-world experience of off-label ibrutinib use. [2021]
Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma. [2021]
Ibrutinib in primary central nervous system diffuse large B-cell lymphoma. [2021]
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