Romidepsin in Conditioning and Maintenance in Patients with T-cell Leukemia or Lymphoma Undergoing Donor Stem Cell Transplant

This phase I / II trial studies the side effects and best dose of romidepsin when given together with busulfan and fludarabine phosphate before donor stem cell transplant (SCT) (conditioning) and alone after SCT (maintenance) in treating patients with T-cell leukemia or lymphoma. Drugs used in chemotherapy, such as romidepsin, busulfan, and fludarabine phosphate, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving romidepsin together with busulfan and fludarabine phosphate may help prevent the patient's body from rejecting transplanted cells, and help kill any cancer cells that are in the body. Maintenance romidepsin may keep the cancer cells from coming back after the transplant.

Inclusion Criteria

• Diagnosis of either cutaneous T-cell lymphoma; T-prolymphocytic leukemia; T-large granulocytic leukemia; T-lymphoblastic leukemia/lymphoma; or peripheral T-cell lymphoma, natural killer/T-cell lymphoma for whom allogeneic stem cell transplantation is indicated
• An 10/10 or 8/8 human leukocyte antigen (HLA) matched (high resolution typing at A, B, C, DRB1, DQ1) sibling or unrelated donor
• Ejection fraction (EF) >= 50% on multi gated acquisition (MUGA) scan or echocardiogram
• Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and corrected diffusing capacity of the lungs for carbon monoxide (DLCO) >= 40%
• Estimated serum creatinine clearance >= 50 ml/min (using the Cockcroft-Gault formula) and/or serum creatinine =< 1.6 mg/dL; renal function will be calculated using ideal body weight (IBW), unless a patient weighs > 40% of their IBW, then adjusted body weight will be utilized
• Serum bilirubin =< 1.5 x upper limit of normal
• Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) =< 2 x upper limit of normal
• Able to sign informed consent
• Men and women of reproductive potential must agree to follow accepted birth control methods for the duration of the study; female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study; male subject agrees to use an acceptable method for contraception for the duration of the study

Exclusion Criteria

• Patient with active central nervous system (CNS) disease
• Pregnancy (positive beta human chorionic gonadotropin [HCG] test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization) or currently breast-feeding; pregnancy testing is not required for post-menopausal or surgically sterilized women
• Active hepatitis B, either active carrier (hepatitis B surface antigen positive [HBsAg +]) or viremic (hepatitis B virus [HBV] deoxyribonucleic acid [DNA] >=10,000 copies/mL, or >= 2,000 IU/mL)
• Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients with chronic hepatitis C or positive hepatitis C serology
• Human immunodeficiency virus (HIV) infection
• Active uncontrolled bacterial, viral or fungal infections
• Exposure to other investigational drugs within 4 weeks before enrollment
• Grade >= 3 non-hematologic toxicity from previous therapy that has not resolved to =< grade 1
• Radiation therapy to head and neck (excluding eyes), and internal organs of chest, abdomen or pelvis in the month prior to enrollment
• Prior whole brain irradiation
• Prior autologous stem cell transplant (SCT) in the prior 12 months
• Congenital QT syndrome, corrected QT (QTc) > 500 ms
• Myocardial infarction within 1 year of study entry; subjects with a history of myocardial infarction between 6 and 12 months prior to study entry who are asymptomatic and have had a negative cardiac risk assessment (treadmill stress test, nuclear medicine stress test, or stress echocardiogram) since the event may participate
• Other significant electrocardiogram (EKG) abnormalities including second (2nd) degree atrio-ventricular (AV) block type II, third (3rd) degree AV block, or bradycardia (ventricular rate less than 50 beats/min)
• Symptomatic coronary artery disease (CAD), e.g., angina Canadian class II-IV; in any patient in whom there is doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present
• An EKG recorded at screening showing evidence of cardiac ischemia (ST depression of >= 2 mm, measured from isoelectric line to the ST segment); if in any doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present
• Congestive heart failure (CHF) that meets New York Heart Association (NYHA) class II to IV definitions and/or ejection fraction < 40% by MUGA scan or < 50% by echocardiogram and/or magnetic resonance imaging (MRI)
• A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), torsade de pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD)
• Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or other causes
• Uncontrolled hypertension, i.e., blood pressure (BP) of >= 160/95; patients who have a history of hypertension controlled by medication must be on a stable dose and meet all other inclusion criteria; or
• Any cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable doses of beta-blockers)
• Patients taking drugs leading to significant QT prolongation where the interaction is too great to proceed with romidepsin
• Concomitant use of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors where the interaction is thought too great to proceed with romidepsin

PRIMARY OBJECTIVES:

I. To determine the most safe and efficacious dose of romidepsin in conditioning therapy, when combined with busulfan and fludarabine phosphate (fludarabine) for allogeneic stem cell transplantation for T cell leukemia/lymphoma in conjunction with post-transplant maintenance romidepsin.

SECONDARY OBJECTIVES:

I. To determine the safety and feasibility of maintenance romidepsin after allogeneic stem cell transplantation for T cell lymphoma/leukemias.

II. To determine the rates of overall survival (OS) and non-relapse mortality (NRM).

III. To determine the rates of acute graft-versus host disease (aGVHD) and chronic graft-versus-host disease (cGVHD).

IV. To determine the immunologic effects of romidepsin on GVHD, immune recovery, and the graft-versus-tumor effect through correlative studies.

OUTLINE: This is a phase I, dose-escalating study of romidepsin followed by a phase II study.

CONDITIONING: Patients receive busulfan intravenously (IV) over 3 hours on days -13 and -12. Patients also receive romidepsin IV over 4 hours followed by fludarabine phosphate IV over 1 hour and busulfan IV over 3 hours on days -6 to -3. Patients receiving a graft from a matched unrelated donor receive rabbit anti-thymocyte globulin IV over 4 hours on days -3 to -1.

GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously over 24 hours daily starting on day -2 until patients are able to take it orally (PO) and then PO daily for about 3 months. Patients also receive methotrexate IV over 15 minutes on days 1, 3, 6, and 11.

TRANSPLANT: Patients undergo bone marrow (BM) or peripheral blood stem cell (PBSC) transplant on day 0.

Beginning 28-100 days after transplant, patients receive maintenance romidepsin IV over 1 hour on day 1. Treatment repeats every 14 days for 1 year in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 year.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
Ohio State University Comprehensive Cancer Center

Principal Investigator
Jonathan E. Brammer

• Primary ID OSU-16242
• Secondary IDs NCI-2015-01555, 2017C0008
• Clinicaltrials.gov ID NCT02512497