Thiotepa + Stem Cell Transplant for Lymphoma

(CNS-PHLAT Trial)

Recruiting at 1 trial location

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach to reduce the risk of cancer returning in the central nervous system for patients with diffuse large B-cell lymphoma (DLBCL). It combines an autologous stem cell transplant with two drugs, thiotepa and carmustine, to determine if they can better prevent cancer spread to the brain and spinal cord. The trial seeks patients recently diagnosed with DLBCL who are at high risk of their cancer returning in the central nervous system, based on criteria such as involvement of specific organs like the kidneys or skin. 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 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.

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

A previous study used thiotepa and carmustine together to treat certain types of brain and lymph node cancers. These drugs have known side effects. Thiotepa can increase cancer risk, harm unborn babies if given to pregnant women, and damage genes.

Carmustine carries its own risks, including lung problems. Repeat treatments should occur only after blood cells return to safe levels. Both drugs have long been used in cancer treatments, demonstrating tolerance, but they do have serious potential side effects.

These drugs are common in cancer treatment, and their side effects are well-documented. Prospective trial participants should discuss these risks with their doctor to understand personal implications. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatment involving Thiotepa, Carmustine, and Autologous Stem Cell Transplant (ASCT) for lymphoma because it offers a new approach to tackling the disease. Unlike standard chemotherapy treatments, this approach uses a combination of high-dose chemotherapy agents, Thiotepa and Carmustine, followed by the patient's own stem cells to help rebuild the immune system. This method aims to enhance the effectiveness of the treatment by intensively targeting cancer cells while minimizing long-term damage to the patient's body. Additionally, the use of the patient's own stem cells helps in faster recovery and reducing the risk of complications compared to traditional transplants. This approach could potentially improve outcomes for patients who have not responded well to conventional therapies.

What evidence suggests that thiotepa and carmustine with ASCT could be effective for reducing CNS relapse in high-risk DLBCL patients?

In this trial, participants will receive a combination of thiotepa, carmustine, and an autologous stem cell transplant (ASCT) as part of their treatment regimen. Research has shown that using thiotepa with ASCT may effectively treat high-risk diffuse large B-cell lymphoma (DLBCL). Thiotepa reaches the central nervous system (CNS) more effectively than other treatments, helping prevent cancer recurrence there. In one study, thiotepa with carmustine resulted in about 75% of patients being free from disease progression after three years. Carmustine is commonly used in lymphoma treatments and is effective with a relatively low risk of death from non-cancer causes. ASCT has improved long-term survival in lymphoma patients; one study found that 65% of patients were alive and 84% were free of disease after treatment. ^{6 7 8 9 10}

Who Is on the Research Team?

Amanda Cashen, MD

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

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

Currently receiving any other investigational agents

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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. Between the end of induction Cycle #2 and the end of induction Cycle #4, a PET/CT scan should be performed to assess response. If there are no signs of progressive disease and the treating physician recommends patient is eligible for ASCT, patients should be consented with the treatment consent. Treatment with thiotepa and carmustine may not take place prior to this second patient consent. Within 3 weeks after the end of the final cycle of induction, a PET-/CT scan should be performed to assessconfirm treatment response and eligibility for ASCT. * After signing the treatment consent and confirming 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+

Published Research Related to This Trial

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 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 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]

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 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]

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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5607634/

A review of autologous stem cell transplantation in ... After a 5-year follow-up, overall survival (OS) was 53% in the HDT/ASCT group compared to 32% in the ST group (P value = 0.038) [3]. Several investigators have ...

2. ashpublications.org ashpublications.org/bloodadvances/article/9/13/3281/536427/Autologous-stem-cell-transplantation-for-relapsed

Autologous stem cell transplantation for relapsed/refractory ... After a median follow-up of 74 months from infusion, 65% were alive and 84% free of disease.

3. nature.com nature.com/articles/s41408-023-00868-w

Real-world data of long-term survival in patients with T-cell ... This study retrospectively analyzed data from 598 patients who underwent transplantation for T-cell lymphomas from 2010 to 2020. In total, 317 ...

4. astctjournal.org astctjournal.org/article/S2666-6367(22)01838-3/fulltext

Outcomes of Older Adults with Non-Hodgkin Lymphoma ... Nonrelapse mortality after autologous stem cell transplantation (ASCT) in older patients with lymphoma was low and has improved over time.

5. chi.scholasticahq.com chi.scholasticahq.com/article/115919-outcomes-of-autologous-stem-cell-transplantation-in-patients-with-primary-refractory-diffuse-large-b-cell-lymphoma-who-demonstrate-chemosensitivity-to

Outcomes of Autologous stem cell transplantation in ... Rituximab with anthracycline-based combination frontline chemoimmunotherapy can cure 50–60% of patients with diffuse large B-cell lymphoma ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2011/017422s038lbl.pdf

BICNU (carmustine) injection label - accessdata.fda.gov Therefore, the risks and benefits of BiCNU therapy must be carefully considered, due to the extremely high risk of pulmonary toxicity. (See ADVERSE. REACTIONS: ...

7. pubchem.ncbi.nlm.nih.gov pubchem.ncbi.nlm.nih.gov/compound/Carmustine

Carmustine | C5H9Cl2N3O2 | CID 2578 - PubChem - NIH Bischloroethyl Nitrosourea (BCNU) (Carmustine) can cause cancer according to an independent committee of scientific and health experts. It can cause ...

8. mayoclinic.org mayoclinic.org/drugs-supplements/carmustine-intravenous-route/description/drg-20067151

Carmustine (intravenous route) - Side effects & uses Safety and efficacy have not been established. Geriatric. No information is available on the relationship of age to the effects of carmustine ...

9. bccancer.bc.ca bccancer.bc.ca/drug-database-site/Drug%20Index/Carmustine%20monograph.pdf

DRUG NAME: Carmustine However, repeat courses of carmustine should not be administered until leukocyte and platelet counts have returned to acceptable levels.

10. go.drugbank.com go.drugbank.com/drugs/DB00262

Carmustine: Uses, Interactions, Mechanism of Action Carmustine is an alkylating agent used in the treatment of various malignancies, including brain tumours and multiple myeloma, among others.