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

48 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Secondary central nervous system lymphoma (sCNSL) is cancer that has spread to the central nervous system. Most drugs used to treat it do not cross the blood-brain barrier. This makes it hard to treat. Researchers hope that a new combination of drugs may be able to help. Objective: To find a better way to treat sCNSL. Eligibility: People ages 18 and older with sCNSL Design: Participants will be screened with: * Medical history * Physical exam * Blood, urine, and heart tests * Eye exam * Tissue or tumor biopsy * Collection of cerebrospinal fluid * CT, PET, and MRI scans: Participants will like in a machine that takes pictures of the body. * Bone marrow aspirations or biopsies: A needle will be inserted into the participant s hipbone. The needle will remove a small amount of marrow. Participants will take the study drugs in 21-day cycles. They will take some drugs by mouth. They will take others through a catheter: A small tube will be inserted into a vein in the arm, neck, or chest. They may have drugs given through a catheter placed through the brain or injected into the spinal canal. Participants will have regular visits during the study. These will include repeats of the screening test. They may also provide a saliva sample or have a cheek swab. Participants will have up to 4 treatment cycles. Participants will have a follow-up visit 30 days after their last treatment dose. Then they will have visits every 3-6 months for 3 years and then yearly....

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.

What data supports the effectiveness of the drug TEDDI-R for Central Nervous System Lymphoma?

Research shows that a combination of rituximab and temozolomide has been effective in treating central nervous system lymphomas, with patients experiencing complete and partial responses. This suggests that these components of the TEDDI-R treatment may contribute to its effectiveness. ^{1 2 3 4 5}

Is the TEDDI-R treatment generally safe for humans?

The combination of temozolomide and Caelyx (pegylated liposomal doxorubicin) has been found to be generally well tolerated in patients with recurrent glioblastoma multiforme, with some experiencing manageable side effects like neutropenia (low white blood cell count), thrombocytopenia (low platelet count), rash, and nausea. Temozolomide alone has a good safety profile and is generally well tolerated in patients with brain metastases from solid tumors. ^{4 6 7 8 9}

What makes the TEDDI-R drug unique for treating central nervous system lymphoma?

The TEDDI-R drug combines multiple agents, including Doxil, Etoposide, Ibrutinib, Rituximab, and Temozolomide, which together target cancer cells in different ways, potentially offering a more comprehensive approach than treatments using fewer drugs. This combination may be particularly effective for central nervous system lymphoma, where standard treatments are limited. ^{1 3 10 11 12}

Research Team

Mark J Roschewski, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

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 am 18 years old or older.

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

- 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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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 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]

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]

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]

References

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

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

2. Korea (South) pubmed.ncbi.nlm.nih.gov

Combination therapy with rituximab and temozolomide for recurrent and refractory primary central nervous system lymphoma. [2021]

3. 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]

4. Germany pubmed.ncbi.nlm.nih.gov

Phase II study of temozolomide plus pegylated liposomal doxorubicin in the treatment of brain metastases from solid tumours. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Long-term outcomes of rituximab, temozolomide and high-dose methotrexate without consolidation therapy for lymphoma involving the CNS. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Phase 2 study of temozolomide and Caelyx in patients with recurrent glioblastoma multiforme. [2022]

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

Pegylated liposomal doxorubicin-efficacy in patients with recurrent high-grade glioma. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Improved effects of honokiol on temozolomide-induced autophagy and apoptosis of drug-sensitive and -tolerant glioma cells. [2022]

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

Temozolomide for treating brain metastases. [2019]

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

Rapid complete response using intrathecal rituximab in a patient with leptomeningeal lymphomatosis due to mantle cell lymphoma. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Immunochemotherapy using rituximab (RTX) and high-dose methotrexate (HD-MTX): an evaluation of the addition of RTX to HD-MTX in recurrent primary central nervous system lymphoma (PCNSL). [2022]

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

Fotemustine, teniposide and dexamethasone versus high-dose methotrexate plus cytarabine in newly diagnosed primary CNS lymphoma: a randomised phase 2 trial. [2018]