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

23 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the Romidepsin Combination Therapy for Lymphoma?

Research shows that a combination of fludarabine and busulfan is effective in patients undergoing stem cell transplantation for conditions like non-Hodgkin lymphoma, with a 5-year overall survival rate of 50.6% for reduced-intensity busulfan. This suggests potential effectiveness for similar regimens in lymphoma treatment. ^{1 2 3 4 5}

Is Romidepsin combination therapy for lymphoma safe in humans?

The combination of busulfan and fludarabine, used in stem cell transplantation, has been studied for safety in humans. Studies show that this combination is generally safe, with mild early toxicities and low treatment-related mortality rates. However, some patients may experience reversible liver issues. ^{1 4 6 7 8}

What makes the romidepsin combination treatment unique for lymphoma?

The romidepsin combination treatment for lymphoma is unique because it includes romidepsin, a histone deacetylase inhibitor, which is known for its ability to induce durable responses in T-cell lymphomas. This treatment is combined with busulfan, fludarabine, and stem cell transplant, offering a novel approach that leverages the specific action of romidepsin in targeting T-cell malignancies. ^{9 10 11 12 13}

What is the purpose of this trial?

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 can help to control leukemia or lymphoma. Researchers also want to learn the highest tolerable dose of romidepsin that can be given with this combination. The safety of this combination and the safety of giving romidepsin after a stem cell transplant will also be studied. This is an investigational study. Romidepsin is FDA approved and commercially available for the treatment of CTCL in patients who have received at least 1 systemic (affecting the whole body) therapy before. Busulfan and fludarabine are FDA approved and commercially available for use with a stem cell transplant. The use of the combination of romidepsin, busulfan, and fludarabine to treat the type of leukemia or lymphoma you have is considered investigational. Up to 30 participants will be enrolled in this study. All will take part at MD Anderson.

Research Team

Jonathan Brammer, MD

Principal Investigator

The Ohio State University Comprehensive Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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]

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 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 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 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]

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 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]

References

1. China 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]. [2014]

2. Germany 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. [2023]

3. China pubmed.ncbi.nlm.nih.gov

[The efficacy and safety of modified busulfan/fludarabine conditioning regimen in elderly or drug-intolerable patients with hematologic malignancies]. [2014]

4. United States 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. [2013]

5. United States 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. [2013]

6. Germany pubmed.ncbi.nlm.nih.gov

Evaluation of different pharmacokinetically guided IV busulfan exposure ranges on adult patient outcomes after hematopoietic stem cell transplantation. [2023]

7. England pubmed.ncbi.nlm.nih.gov

F-ara-A pharmacokinetics during reduced-intensity conditioning therapy with fludarabine and busulfan. [2013]

8. United States 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. [2021]

9. England 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. [2018]

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

Romidepsin (FK228) combined with cisplatin stimulates DNA damage-induced cell death in ovarian cancer. [2021]

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

A phase 1 study of bortezomib and romidepsin in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, indolent B-cell lymphoma, peripheral T-cell lymphoma, or cutaneous T-cell lymphoma. [2019]

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

Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. [2022]

13. England pubmed.ncbi.nlm.nih.gov

Complete remission with romidepsin in a patient with T-cell acute lymphoblastic leukemia refractory to induction hyper-CVAD. [2021]