Thiotepa + Stem Cell Transplant for Lymphoma

(CNS-PHLAT Trial)

Overseen By Amanda F Cashen, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Washington University School of Medicine

Must not be taking: Investigational agents

Disqualifiers: Relapsed lymphoma, Primary CNS lymphoma, 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: Unknown

36 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

What data supports the effectiveness of the treatment Thiotepa + Stem Cell Transplant for Lymphoma?

Research shows that thiotepa-based conditioning regimens, when used in autologous stem cell transplants for lymphoma, have similar effectiveness and safety compared to traditional regimens like BEAM. This suggests that thiotepa can be a valuable alternative, especially for older patients or those with more prior treatments. ^{1 2 3 4 5}

Is the combination of Thiotepa and Stem Cell Transplant generally safe for humans?

Research shows that using thiotepa in combination with stem cell transplants for lymphoma has a safety profile similar to other common regimens, with no significant differences in survival or complications. However, some studies noted serious side effects like respiratory issues and infections, especially at higher doses or in heavily pretreated patients. ^{1 4 5 6 7}

What makes the Thiotepa + Stem Cell Transplant treatment unique for lymphoma?

The Thiotepa + Stem Cell Transplant treatment is unique because it uses thiotepa, a drug that can penetrate the central nervous system, making it potentially more effective for lymphomas that affect this area. This treatment is an alternative to the conventional BEAM regimen and has shown comparable efficacy and safety, with a possible advantage for older patients. ^{1 2 4 5 8}

What is the purpose of this trial?

A serious consequence of systemic diffuse large B-cell lymphoma (DLBCL) is secondary central nervous system (CNS) relapse, which occurs in approximately 5% of all patients. Many CNS relapses occur within the first year after completion of frontline treatment and are associated with significantly increased mortality; thus, it is important to tailor frontline treatment to provide prophylaxis against CNS relapse in those patients who are determined to be high-risk. Autologous stem cell transplantation (ASCT) is standard of care for patients with DLBCL who relapse one year or more after first remission, and it has been shown to improve progression-free survival for patients with primary CNS lymphoma. The four-drug BEAM regimen (carmustine, etoposide, cytarabine, and melphalan) is the preferred conditioning regimen for DLBCL patients undergoing ASCT; however, patients with primary CNS lymphoma receive thiotepa plus carmustine as their conditioning regimen due to its better CNS penetration. This study tests the hypothesis that consolidation thiotepa/carmustine ASCT in first complete remission will reduce the risk of CNS relapse in transplant-eligible patients with DLBCL with no prior CNS disease at high risk of secondary CNS recurrence.

Research Team

Amanda Cashen, MD

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for high-risk patients with Diffuse Large B-cell Lymphoma (DLBCL) who are in their first complete remission and eligible for a stem cell transplant. It's not suitable for those with prior central nervous system disease or other conditions that would exclude them from safely receiving the treatments being tested.

Inclusion Criteria

Agree to use adequate contraception if of childbearing potential

I have been diagnosed with a type of aggressive B-cell lymphoma.

I can take care of myself but might not be able to do heavy physical work.

Exclusion Criteria

History of allergic reactions to specific compounds

Pregnant and/or breastfeeding

I do not have another cancer that could affect this treatment's safety or results.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Chemotherapy

Participants receive anthracycline-based induction chemotherapy regimen per standard of care for 6 cycles

12-18 weeks

Conditioning and Transplantation

Participants undergo conditioning with thiotepa and carmustine followed by autologous stem cell transplantation (ASCT)

1-2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Autologous Stem Cell Transplant
• Carmustine
• Thiotepa

Trial Overview The study is testing if using Thiotepa and Carmustine as part of an autologous stem cell transplant can prevent brain relapse in DLBCL patients at high risk. This approach is compared to the standard BEAM regimen, which includes different chemotherapy drugs.

Participant Groups

Group I: Anthracycline-based induction chemotherapy + ASCT + Thiotepa + Carmustine Experimental Treatment 4 Interventions

* Patients should receive induction treatment with anthracycline-based chemotherapy regimen per standard of care (6 cycles). Management, dose delays, and dose modifications will be per standard of care and treating physician discretion; administration of anthracycline-based induction therapy is not dictated by the study. Patients who have a PR by PET criteria but whose residual abnormality on PET is unlikely to represent residual disease may proceed to ASCT. * After confirmation of complete response (CR) following induction therapy, patients will begin conditioning with thiotepa (days -5 and -4) and carmustine (day -6), followed by ASCT on day 0.

Autologous Stem Cell Transplant is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Autologous Stem Cell Transplant for:

• Multiple Myeloma
• Non-Hodgkin Lymphoma
• Hodgkin Lymphoma
• Leukemia

Approved in European Union as Autologous Stem Cell Transplant for:

• Multiple Myeloma
• Non-Hodgkin Lymphoma
• Hodgkin Lymphoma
• Leukemia

Approved in Canada as Autologous Stem Cell Transplant for:

• Multiple Myeloma
• Non-Hodgkin Lymphoma
• Hodgkin Lymphoma
• Leukemia

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Findings from Research

The TECAM conditioning regimen, which includes thiotepa and cyclophosphamide, showed comparable efficacy and safety to the conventional BEAM regimen in a study of 125 patients undergoing autologous stem cell transplantation for B-cell lymphomas, with 3-year progression-free survival rates of 49% for TECAM and 62% for BEAM.

TECAM was particularly effective for older patients, with 23% of TECAM recipients over 65 years old achieving similar outcomes to younger patients, suggesting it may be a suitable option for older individuals who have had more prior treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Replacing carmustine by thiotepa and cyclophosphamide for autologous stem cell transplantation in Hodgkin's and non-Hodgkin's B-cell lymphoma. Joffe, E., Rosenberg, D., Rozovski, U., et al.[2019]

In a retrospective study of 56 patients with primary central nervous system lymphoma (PCNSL) undergoing autologous stem cell transplant (ASCT), there was no significant difference in progression-free survival or overall survival between those receiving thiotepa-based conditioning and those receiving BEAM conditioning, despite the thiotepa group having higher-risk disease features.

The study found that the disease response status before transplant was a critical factor influencing outcomes, with patients in complete remission showing significantly better overall survival rates compared to those with partial response, highlighting the importance of pre-transplant disease status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of Autologous Stem Cell Transplant Consolidation in Primary Central Nervous System Lymphoma: A Mayo Clinic Experience. Khurana, A., Micallef, IN., LaPlant, BR., et al.[2021]

In a study involving 77 patients with Hodgkin's disease and non-Hodgkin's lymphoma, high-dose etoposide combined with either fractionated total body irradiation (TBI) or carmustine before autologous bone marrow transplantation showed promising results, with a 1-year survival rate of 85% for TBI patients and 79% for carmustine patients.

Despite the effectiveness, there was an 8% rate of toxic deaths, all occurring in the carmustine group, highlighting a safety concern associated with this treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Stanford experience with high-dose etoposide cytoreductive regimens and autologous bone marrow transplantation in Hodgkin's disease and non-Hodgkin's lymphoma: preliminary data. Horning, SJ., Chao, NJ., Negrin, RS., et al.[2020]

In a study of 108 relapsed/refractory lymphoma patients, both TECAM and BEAM conditioning regimens showed similar efficacy, with 2-year progression-free survival rates of 55.7% and 52.9%, respectively, indicating that TECAM is a viable option before autologous stem cell transplant.

While the overall survival rate was slightly lower for the TECAM group (55.9%) compared to the BEAM group (67%), the differences were not statistically significant, suggesting comparable safety and effectiveness between the two regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Retrospective Comparison of TECAM and BEAM Conditioning Regimens Before Autologous Hematopoietic Stem Cell Transplant in Lymphoma Patients: Efficacy and Toxicity. Patir, P., Soyer, N., Durusoy, IR., et al.[2019]

In a study involving 14,544 patients, thiotepa-based preparative regimens for autologous stem cell transplantation showed no significant differences in survival outcomes compared to the standard BEAM regimen for diffuse large B-cell lymphoma, follicular lymphoma, and Hodgkin lymphoma.

The rates of common complications, including infections and secondary malignancies, were similar between patients treated with thiotepa and those treated with BEAM, suggesting that thiotepa could be a safe and effective alternative for high-dose therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thiotepa-based high-dose therapy for autologous stem cell transplantation in lymphoma: a retrospective study from the EBMT. Sellner, L., Boumendil, A., Finel, H., et al.[2023]

In a study of 218 adult patients with primary CNS lymphoma undergoing autologous stem cell transplant (ASCT) with thiotepa/carmustine (TT-BCNU) conditioning, varying the thiotepa dose (10 mg/kg vs. 20 mg/kg) did not significantly affect outcomes such as non-relapse mortality, relapse rates, progression-free survival, or overall survival.

Both the 10 mg/kg and 20 mg/kg thiotepa groups showed similar efficacy and safety profiles, suggesting that higher thiotepa doses may not provide additional benefits in ASCT for PCNSL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of thiotepa dose-intensity in primary diffuse large B-cell lymphoma of the central nervous system undergoing autologous hematopoietic cell transplant with thiotepa/carmustine conditioning. Arshad, S., Fang, X., Ahn, KW., et al.[2023]

In a phase I study involving 40 patients with refractory solid tumors or non-Hodgkin's lymphoma, a combination of high-dose cyclophosphamide, thiotepa, and carmustine (BCNU) followed by autologous stem cell rescue resulted in a 63% overall response rate, indicating significant efficacy in reducing tumor burden.

However, the treatment was associated with serious safety concerns, including a 20% early death rate due to toxic effects like sepsis and respiratory failure, particularly at higher doses of BCNU, which limits its use in heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose tri-alkylator chemotherapy with autologous stem cell rescue in patients with refractory malignancies. Moormeier, JA., Williams, SF., Kaminer, LS., et al.[2019]

Thiotepa, used as high-dose chemotherapy before autologous hematopoietic stem cell transplantation (HSCT) in patients with malignant lymphoma, demonstrated a high safety profile with no unexpected adverse events and a 100% survival rate at day 100 post-transplantation in a study of 51 patients.

The most common side effect observed was febrile neutropenia, affecting 96.1% of patients, but this did not lead to any deaths or treatment modifications, indicating that thiotepa can be safely administered in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An expanded-access clinical study of thiotepa (DSP-1958) high-dose chemotherapy before autologous hematopoietic stem cell transplantation in patients with malignant lymphoma. Nishikori, M., Masaki, Y., Fujii, N., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Replacing carmustine by thiotepa and cyclophosphamide for autologous stem cell transplantation in Hodgkin's and non-Hodgkin's B-cell lymphoma. [2019]

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

Outcomes of Autologous Stem Cell Transplant Consolidation in Primary Central Nervous System Lymphoma: A Mayo Clinic Experience. [2021]

3. England pubmed.ncbi.nlm.nih.gov

The Stanford experience with high-dose etoposide cytoreductive regimens and autologous bone marrow transplantation in Hodgkin's disease and non-Hodgkin's lymphoma: preliminary data. [2020]

4. Turkey pubmed.ncbi.nlm.nih.gov

A Retrospective Comparison of TECAM and BEAM Conditioning Regimens Before Autologous Hematopoietic Stem Cell Transplant in Lymphoma Patients: Efficacy and Toxicity. [2019]

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

Thiotepa-based high-dose therapy for autologous stem cell transplantation in lymphoma: a retrospective study from the EBMT. [2023]

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

Impact of thiotepa dose-intensity in primary diffuse large B-cell lymphoma of the central nervous system undergoing autologous hematopoietic cell transplant with thiotepa/carmustine conditioning. [2023]

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

High-dose tri-alkylator chemotherapy with autologous stem cell rescue in patients with refractory malignancies. [2019]

8. Japan pubmed.ncbi.nlm.nih.gov

An expanded-access clinical study of thiotepa (DSP-1958) high-dose chemotherapy before autologous hematopoietic stem cell transplantation in patients with malignant lymphoma. [2022]