TEDDI-R for Central Nervous System Lymphoma

Overseen By Mark J Roschewski, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Strong CYP3A inhibitors

Disqualifiers: HIV, Cardiovascular disease, Hepatitis, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks better treatments for secondary central nervous system lymphoma (sCNSL), a cancer that spreads to the brain and spinal cord. Researchers are testing a combination of drugs, including Doxil (a chemotherapy drug), to determine if they can effectively reach and treat this challenging area. Participants will receive various combinations of these drugs over several treatment cycles. The trial is open to adults with sCNSL that has not responded to prior treatments or who have not received treatment but have the disease affecting the brain, eyes, or spinal fluid. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot take certain medications like strong CYP3A inhibitors or inducers within 7 days before starting the study. It's important to discuss your current medications with the study team to avoid any potential interactions.

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

Research has shown that the TEDDI-R regimen, which includes temozolomide, etoposide, doxil, dexamethasone, rituximab, and ibrutinib, may effectively treat secondary central nervous system lymphoma (sCNSL). This combination specifically targets the central nervous system, crucial for treating this cancer type.

Studies indicate that patients generally tolerate these drugs well. For instance, research on ibrutinib, a key component of the regimen, has examined its side effects and interactions with other drugs, demonstrating its general safety. However, side effects can occur, ranging from mild to serious, depending on individual health and drug reactions.

The TEDD-R regimen (excluding ibrutinib) is also under study and has been used in other contexts, providing reassurance about its safety. Each drug in the regimen has been previously used in various cancer treatments, offering a solid understanding of their safety profiles.

This trial is in its second phase, indicating that the treatment has shown some safety in smaller groups. The current study aims to provide more information on the tolerability of these drugs when used together for sCNSL. Participants will receive close monitoring to address any side effects promptly. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine multiple drugs, including ibrutinib, to tackle central nervous system lymphoma in novel ways. Unlike standard treatments, which often involve just chemotherapy or radiation, these regimens incorporate a mix of drugs like temozolomide, etoposide, doxil, and rituximab, with the potential addition of ibrutinib. Ibrutinib is particularly interesting because it targets specific pathways in cancer cells that other treatments might miss, potentially leading to more effective outcomes. Additionally, the combination with drugs like cytarabine and isavuconazole, depending on patient response, offers a tailored approach that could improve treatment effectiveness and patient outcomes.

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

Studies have shown that the drug combination TEDDI-R, which includes temozolomide, etoposide, doxil, dexamethasone, ibrutinib, and rituximab, effectively treats aggressive B-cell lymphomas affecting the brain and spinal cord. Research indicates that this treatment targets the central nervous system more effectively than other options. Initial findings suggest that ibrutinib, a key component of TEDDI-R, has a high success rate in treating primary and secondary CNS lymphoma, although its effects may not last long. Meanwhile, the TEDD-R regimen, similar but without ibrutinib, also shows promise in treating CNS lymphoma. In this trial, participants will receive either the TEDDI-R or TEDD-R regimen, as these treatments are being tested for their potential to improve outcomes for patients with this challenging condition. ^{1 6 7 8 9}

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 aged 18+ with secondary central nervous system lymphoma (sCNSL) are eligible. They must have certain blood levels, organ function within specific ranges, and no recent chemotherapy or strong drug interactions. Women of childbearing age need a negative pregnancy test and must use effective birth control methods.

Inclusion Criteria

I can understand and am willing to sign the consent form.

My aggressive B-cell lymphoma has spread to my CNS, including possibly my eye, brain, or CSF.

- AST (SGOT) and ALT (SGPT): less than or equal to 3.0 (SqrRoot) institutional ULN (less than or equal to 5 x ULN for participants with liver involvement by lymphoma)

Exclusion Criteria

I do not have HIV.

I cannot swallow pills or have serious digestive system issues.

I do not have serious heart problems or recent heart attacks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Ibrutinib Monotherapy Window

Participants receive ibrutinib monotherapy in combination with isavuconazole for 14 days to establish efficacy of ibrutinib

2 weeks

Regular visits for monitoring

Treatment

Participants receive TEDDI-R or TEDD-R chemotherapy for up to 4 cycles based on response to the ibrutinib window

12 weeks

Regular visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Visits every 3-6 months, then yearly

What Are the Treatments Tested in This Trial?

Interventions

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

Trial Overview The TEDDI-R regimen is being tested for treating aggressive B-cell lymphomas that have spread to the CNS. The trial involves taking drugs orally or through catheters over cycles of 21 days, with up to four treatment cycles followed by regular check-ups.

How Is the Trial Designed?

Group I: 2 Experimental Treatment 6 Interventions

Temozolomide, etoposide, doxil, dexamethasone, and rituximab without ibrutinib (TEDD-R) or TEDD-R with ibrutinib Days 1-10 (TEDDI-R), concurrent with cytarabine and isavuconazole, based upon response to 14-day ibrutinib window

Group II: 1 Experimental Treatment 5 Interventions

Temozolomide, etoposide, doxil, dexamethasone, and rituximab without ibrutinib (TEDD-R) or TEDD-R with ibrutinib (TEDDI-R), concurrent with cytarabine and isavuconazole, based upon response to 14-day ibrutinib window

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

Approved in United States as Doxil for:

• Ovarian cancer
• AIDS-related Kaposi's sarcoma
• Multiple myeloma

Approved in European Union as Caelyx for:

• Ovarian cancer
• AIDS-related Kaposi's sarcoma
• Multiple myeloma
• Breast cancer

Approved in Canada as Doxorubicin liposomal for:

• Ovarian cancer
• AIDS-related Kaposi's sarcoma
• Multiple myeloma

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

A 62-year-old male with mantle cell lymphoma (MCL) and meningeal lymphomatosis achieved tumor clearance after just three doses of intrathecal rituximab (IT-R), highlighting its efficacy in treating central nervous system involvement in MCL.

Following IT-R, the patient underwent a comprehensive systemic therapy regimen and an autologous stem cell transplant, resulting in a sustained remission for 23 months, suggesting a potential effective treatment strategy for MCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid complete response using intrathecal rituximab in a patient with leptomeningeal lymphomatosis due to mantle cell lymphoma. Villela, L., García, M., Caballero, R., et al.[2021]

In a phase II trial involving 19 patients, the combination of temozolomide (TMZ) and pegylated liposomal doxorubicin showed an overall response rate of 36.8%, with three patients achieving a complete response and four a partial response, indicating promising efficacy in treating brain metastases from solid tumors.

The treatment was well tolerated, with manageable toxicities, and resulted in a median overall survival of 10.0 months and a median progression-free survival of 5.5 months, along with significant improvements in quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of temozolomide plus pegylated liposomal doxorubicin in the treatment of brain metastases from solid tumours. Caraglia, M., Addeo, R., Costanzo, R., et al.[2018]

Pegylated liposomal doxorubicin, used alone or with tamoxifen, showed moderate efficacy in treating recurrent high-grade glioma, with a 40% overall response rate and 15% progression-free survival at 6 months in trials involving 40 patients.

Both treatment regimens were well tolerated, with palmoplantar erythrodysesthesia as the main side effect, and no significant predictors of clinical response were identified, indicating the need for further research to understand treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pegylated liposomal doxorubicin-efficacy in patients with recurrent high-grade glioma. Hau, P., Fabel, K., Baumgart, U., et al.[2022]

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]

The combination of rituximab and temozolomide (TMZ) showed promising efficacy in two patients with recurrent and refractory primary central nervous system lymphoma (PCNSL), achieving complete and partial responses after treatment cycles.

This therapy was effective regardless of the patients' different tumor profiles, suggesting it could be a viable option for diverse cases of PCNSL, although further research in larger populations is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapy with rituximab and temozolomide for recurrent and refractory primary central nervous system lymphoma. Murakami, M., Fujimaki, T., Asano, S., et al.[2021]

Temozolomide is a chemotherapeutic agent that effectively crosses the blood-brain barrier and has shown a good safety profile in treating brain metastases from solid tumors, with clinical activity observed in heavily pretreated patients.

In a randomized phase II trial, temozolomide combined with radiation therapy resulted in a significantly higher objective response rate (96% vs. 67%) compared to radiation alone, particularly benefiting patients with newly diagnosed brain and lung metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide for treating brain metastases. Abrey, LE., Christodoulou, C.[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]

Citations

1. ashpublications.org ashpublications.org/blood/article/142/21/1771/497854/How-I-treat-secondary-CNS-involvement-by

How I treat secondary CNS involvement by aggressive ... In a response-adapted approach, temozolomide, etoposide, liposomal doxorubicin, dexamethasone, ibrutinib, and rituximab demonstrated encouraging ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10862244/

How I treat secondary CNS involvement by aggressive ... Presence of active CNS lymphoma before ASCT has been consistently associated with worse outcomes,,; however, the use of thiotepa-based regimens demonstrated ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03964090

Study Details | NCT03964090 | Temozolomide, Etoposide, ... We developed a novel regimen that combines ibrutinib with a chemoimmunotherapy platform maximized for CNS penetrance that includes temozolomide, etoposide, ...

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCT03964090

Temozolomide, Etoposide, Doxil, Dexamethasone, ... Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib, and Rituximab (TEDDI-R) in Aggressive B-cell Lymphomas With Secondary Involvement of the Central ...

5. haematologica.org haematologica.org/article/view/11560

Not all central nervous system lymphomas are created equal Secondary CNS lymphoma (SCNSL) is an infrequent but devastating complication associated with poor outcomes and restricted long-term survival.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03964090

Study Details | NCT03964090 | Temozolomide, Etoposide, ... We developed a novel regimen that combines ibrutinib with a chemoimmunotherapy platform maximized for CNS penetrance that includes temozolomide, etoposide, ...

7. aol.amegroups.org aol.amegroups.org/article/view/7647/html

Relapsed and refractory primary CNS lymphoma: treatment ... Up to 50% of patients will experience refractory or relapsed disease following first-line treatment with high dose methotrexate (HD-MTX) based regimens.

8. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2152265022001872

Prophylaxis and Management of Secondary CNS Lymphoma Another regimen under investigation is ibrutinib with TEDD-R chemotherapy (temozolomide, etoposide, liposomal doxorubicin, dexamethasone, and rituximab). In ...

9. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCT02203526

Ibrutinib, Temozolomide, Etoposide, Pegylated Liposomal ... This phase I trial studies the side effects and best dose of ibrutinib when given together with temozolomide, etoposide, pegylated liposomal doxorubicin ...