Romidepsin Combination Therapy for Lymphoma

Overseen By The Ohio State University Comprehensive Cancer Center

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Ohio State University Comprehensive Cancer Center

Must not be taking: QT prolonging drugs, CYP3A4 inhibitors

Disqualifiers: Active CNS disease, Hepatitis B, HIV, others

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

Compensation: Varies

Number of Visits: 8

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments to determine if it can better control certain types of leukemia and lymphoma. It uses romidepsin (also known as Istodax, a type of cancer therapy) with fludarabine and busulfan before and after a stem cell transplant. The trial aims to find the optimal dose of romidepsin and ensure the treatment's safety. Individuals with specific types of lymphoma or leukemia who are scheduled for a stem cell transplant might be suitable candidates. Participants must have a matched donor and meet certain health criteria to join.

As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that you cannot take drugs that significantly prolong the QT interval or strong CYP3A4 inhibitors while participating in the study.

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

A previous study found that patients tolerated the combination of romidepsin, busulfan, and fludarabine well. The FDA has already approved romidepsin for treating certain cancers, establishing its safety record for those uses. However, its combination with busulfan and fludarabine remains under investigation for this specific purpose.

Research has shown that this combination can cause expected side effects, but no new or unexpected serious problems have been reported so far. This suggests a safety level consistent with current medical standards. As this is an early-phase study, it aims to determine the best dose and confirm safety, making careful monitoring essential.

In summary, current evidence suggests that while the combination treatment is generally well-tolerated, it remains under close study to ensure its safety for treating leukemia or lymphoma. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Romidepsin combination therapy is unique because it integrates a novel approach by combining the histone deacetylase inhibitor, romidepsin, with traditional chemotherapy agents like busulfan and fludarabine, followed by a stem cell transplant. Unlike standard treatments for lymphoma, which often rely solely on chemotherapy or antibody therapies, this regimen aims to enhance the effectiveness of the stem cell transplant by modulating gene expression through romidepsin. Additionally, the use of romidepsin for maintenance therapy could potentially prolong remission by continuing to suppress cancer cell activity after the initial treatment. Researchers are excited about this treatment's potential to improve outcomes for patients who may not respond well to existing therapies.

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

In this trial, participants will receive a combination of romidepsin, fludarabine, and busulfan before a stem cell transplant to evaluate its effectiveness in treating certain blood cancers like lymphoma. Research has shown that using romidepsin with fludarabine and busulfan may improve treatment outcomes, as lab studies found that romidepsin increases the effectiveness of fludarabine and busulfan. Additionally, early results suggest that using romidepsin after a stem cell transplant could reduce the risk of cancer returning. Specifically, one study indicated a 20% reduction in relapse within a year. Romidepsin is already approved for treating another type of cancer, highlighting its potential as a reliable treatment option. ^{1 2 3 4 6}

Who Is on the Research Team?

Jonathan Brammer, MD

Principal Investigator

The Ohio State University Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults aged 18-70 with certain types of leukemia or lymphoma, such as Cutaneous T-Cell Lymphoma and Peripheral T-Cell Lymphoma, who need a stem cell transplant. Participants must have a matched donor, good heart and lung function, adequate kidney function, normal liver tests, and agree to use birth control.

Inclusion Criteria

EF >/= 50% on MUGA scan or Echocardiogram

FEV1, FVC and corrected DLCO >/= 40%

Able to sign informed consent

Exclusion Criteria

I have not had radiation therapy in the last month.

I have not had a heart attack in the last year.

I have been diagnosed with congestive heart failure.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning and Transplant

Participants receive busulfan, fludarabine, and romidepsin before undergoing stem cell transplant

16 days

Inpatient stay from Day -7 to Day 0

Romidepsin Maintenance Therapy

Participants receive romidepsin maintenance therapy starting between Day +28 and Day +100

Up to 48 weeks

Bi-weekly visits for romidepsin administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Visits at ½, 1, 3, 6, and 12 months post-transplant

What Are the Treatments Tested in This Trial?

Interventions

• Busulfan
• Fludarabine
• Romidepsin
• Stem Cell Transplant

Trial Overview The study aims to find the safest high dose of romidepsin when used with fludarabine and busulfan before and after stem cell transplantation in controlling leukemia or lymphoma. All participants will receive this combination at MD Anderson Cancer Center.

How Is the Trial Designed?

Group I: Romidepsin + Busulfan + Fludarabine + Stem Cell Transplant Experimental Treatment 5 Interventions

Part 1: Busulfan administered at the dose calculated to achieve a total (including first two doses delivered on Day -13 and -12) systemic exposure of 20,000 ± 12% µMol-min based on the pharmacokinetic studies. Fludarabine 40 mg/m2 by vein on Days -6 to -3. Romidepsin dosed per actual body weight/actual body surface area. Romidepsin administered on Day -6, -5, -4, and -3 at escalating doses of 1 mg/m2, 2 mg/m2, and 3 mg/m2 by vein to determine the optimal dose. Participants receiving a graft from a matched unrelated donor receive rabbit Thymoglobulin; 0.5 mg/kg on Day -3, 1.5 mg/kg on Day -2 and 2.0 mg/kg on Day -1. Stem cell infusion on Day 0. Romidepsin Maintenance Therapy - Part 2: Starting between Day +28 and Day +100, if participant is eligible based on disease status, they will continue to receive Romidepsin 8 mg/m2 by vein over 1 hour on Day 1 of each 2-week cycle.

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

Approved in United States as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Malignant lymphoma
• Bone marrow transplantation conditioning

Approved in European Union as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Canada as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Japan as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Who Is Running the Clinical Trial?

Ohio State University Comprehensive Cancer Center

Lead Sponsor

Trials

350

Recruited

295,000+

Celgene Corporation

Industry Sponsor

Trials

446

Recruited

58,500+

Mark Alles

Celgene Corporation

Chief Executive Officer since 2016

Bachelor's degree from Lock Haven University of Pennsylvania

Sol J. Barer

Celgene Corporation

Chief Medical Officer since 2006

PhD in Organic and Physical Chemistry from Rutgers University

Published Research Related to This Trial

The combination of intravenous busulfan and fludarabine as a conditioning therapy for allogeneic hematopoietic stem cell transplantation (HSCT) in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) demonstrated a high complete remission rate of 85% in patients with active disease.

This regimen showed low regimen-related (1%) and treatment-related (3%) mortality rates, indicating improved safety, while achieving a 1-year overall survival rate of 65% and event-free survival rate of 52% for all patients, suggesting it is an effective and reduced-toxicity option for these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. de Lima, M., Couriel, D., Thall, PF., et al.[2021]

In a study involving 16 patients with hematological malignancies, the pharmacokinetics of fludarabine were assessed before and after administration of busulfan, showing no significant changes in key parameters such as clearance and half-life.

The results suggest that there is unlikely to be a clinically relevant drug interaction between busulfan and fludarabine, supporting their combined use in conditioning regimens for stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

F-ara-A pharmacokinetics during reduced-intensity conditioning therapy with fludarabine and busulfan. Bonin, M., Pursche, S., Bergeman, T., et al.[2013]

In a study involving 179 patients undergoing allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia, the addition of 400 cGy of total body irradiation (TBI) to a regimen of fludarabine and busulfan significantly reduced relapse rates (hazard ratio 0.29) without increasing nonrelapse mortality.

The inclusion of TBI also improved overall survival (hazard ratio 0.50) and disease-free survival (hazard ratio 0.43), demonstrating that enhancing regimen intensity can lead to better outcomes in AML treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The addition of 400 cGY total body irradiation to a regimen incorporating once-daily intravenous busulfan, fludarabine, and antithymocyte globulin reduces relapse without affecting nonrelapse mortality in acute myelogenous leukemia. Russell, JA., Irish, W., Balogh, A., et al.[2013]

In a study of 62 patients undergoing reduced-intensity conditioning for stem cell transplantation, therapeutic dose monitoring of oral busulfan did not significantly impact post-transplant outcomes compared to standard dosing.

The presence of chronic graft-versus-host disease was identified as a strong predictor of overall survival and leukemia-free survival, highlighting its importance in patient outcomes after transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-intensity conditioning allogeneic blood stem cell transplantation with fludarabine and oral busulfan with or without pharmacokinetically targeted busulfan dosing in patients with myeloid leukemia ineligible for conventional conditioning. Martino, R., Pérez-Simón, JA., Moreno, E., et al.[2013]

In a study involving 37 patients with untreated peripheral T-cell lymphoma, romidepsin was found to be safely combined with CHOP therapy, with a recommended dose of 12 mg/m² established for further testing.

While the combination showed promise, it also resulted in significant side effects, including high rates of neutropenia and thrombocytopenia, indicating the need for careful monitoring and further randomized trials to assess its efficacy compared to CHOP alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of romidepsin with cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated patients with peripheral T-cell lymphoma: a non-randomised, phase 1b/2 study. Dupuis, J., Morschhauser, F., Ghesquières, H., et al.[2018]

In a study of 32 patients with acute myeloid leukemia in first complete remission, the busulfan/fludarabine (Bu/Flu) conditioning regimen resulted in significantly lower transplant-related toxicity compared to the busulfan/cyclophosphamide (Bu/Cy) regimen, with a lower incidence of severe side effects (68.8% vs. 25.0%).

Both regimens showed similar efficacy in terms of overall survival and event-free survival rates, indicating that Bu/Flu is a safer option without compromising treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A comparison of toxicity and efficacy between busulfan plus fludarabine and busulfan plus cyclophosphamide for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia]. Liu, H., Fan, ZP., Jiang, QL., et al.[2014]

In a study of 70 patients undergoing allogeneic hematopoietic stem cell transplantation, targeting a higher busulfan area under the curve (AUC) of ≥19.7 mg*h/L did not improve overall survival (OS) or relapse-free survival (RFS) compared to a lower AUC of <19.7 mg*h/L.

There were no significant differences in non-relapsed mortality or the incidence of acute and chronic graft-versus-host disease between the two dosing groups, indicating that increasing busulfan intensity may not enhance safety or efficacy in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of different pharmacokinetically guided IV busulfan exposure ranges on adult patient outcomes after hematopoietic stem cell transplantation. Mori, S., Guo, M., Rivera-Robles, N., et al.[2023]

In a study of 415 adult patients with relapsed and refractory non-Hodgkin lymphoma, those receiving the reduced-intensity conditioning regimen (Flu/Bu2) had a significantly better 5-year overall survival rate of 50.6% compared to 32.2% for those receiving the myeloablative regimen (Flu/Bu4).

The higher nonrelapse mortality (NRM) rate in the Flu/Bu4 group (31.9%) compared to the Flu/Bu2 group (15.7%) contributed to the poorer overall survival, indicating that the choice of conditioning regimen is critical for patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine plus reduced-intensity busulfan versus fludarabine plus myeloablative busulfan in patients with non-Hodgkin lymphoma undergoing allogeneic hematopoietic cell transplantation. Kamijo, K., Shimomura, Y., Shinohara, A., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02512497

Romidepsin Maintenance After Allogeneic Stem Cell ... The goal of this clinical research study is to learn if giving romidepsin before and after a stem cell transplant in combination with fludarabine and busulfan ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4961533/

Romidepsin enhances the cytotoxicity of fludarabine ... In the present study, we examined the efficacy of Rom in combination with Flu, Clo and Bu and determined the possibility of using this combination as part of ...

3. astctjournal.org astctjournal.org/article/S1083-8791(17)31130-8/fulltext

Romidepsin (Rom) in Combination with Fludarabine (Flu) ... 343 - Romidepsin (Rom) in Combination with Fludarabine (Flu) and Busulfan (Bu) Conditioning Followed by Rom Maintenance in Patients with T-Cell Malignancies ...

4. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/184/502890/Post-Allograft-Romidepsin-Maintenance-Mitigates

Post-Allograft Romidepsin Maintenance Mitigates Relapse ... An efficacy endpoint of 20% reduction in relapse risk at 1-year in the whole cohort or any individual disease cohort was set based upon ...

5. researchgate.net researchgate.net/publication/323490903_Romidepsin_Rom_in_Combination_with_Fludarabine_Flu_and_Busulfan_Bu_Conditioning_Followed_by_Rom_Maintenance_in_Patients_with_T-Cell_Malignancies_Receiving_Allogeneic_Stem_Cell_Transplant_Allo-SCT_Earl

Romidepsin (Rom) in Combination with Fludarabine (Flu) ... Romidepsin (Rom) in Combination with Fludarabine (Flu) and Busulfan (Bu) Conditioning Followed by Rom Maintenance in Patients with T-Cell ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0006497123047882

Post-Allograft Romidepsin Maintenance Mitigates Relapse ... BuFluRom with m-rom is effective at decreasing relapse in patients with T-cell malignancies, with 1-year CI relapse below expected relapse rates.