Romidepsin, CC-486 (5-azacitidine), Dexamethasone, and Lenalidomide (RAdR) for Relapsed/Refractory T-cell Malignancies

NCT04447027 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 20012720-C-0127
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Mature T-cell malignancies (TCMs) are a rare group of cancers that usually do not have effective treatments or cures. Because of this, participants with TCMs often relapse and have a poor overall prognosis. This trial is testing if combining several drugs against TCMs can be a more effective. Primary Objective: To test if the combination of romidepsin, CC-486 (5-azacitidine), dexamethasone, and lenalidomide (RAdR) can be given safely to participants with relapsed or treatment refractory TCM. Other (Secondary) Objective: Measure the activity of this combination treatment. Eligibility: People age 18 and older who have a failed or relapsed after standard treatments for mature TCMs. Design: Participants will be screened for eligibility by performing the following tests or procedures: Physical exam Medical history Medicine review Blood and urine tests Symptom review Bone marrow examination Total Body imaging scans or x-rays Tumor biopsy Participants will have blood tests during treatment to make sure their blood cell counts are okay. Romidepsin is infused through an intravenous (IV) placed in one of the veins usually in the arm. Lenalidomide, dexamethasone, and CC-486 (5-azacitidine) are pills or capsules taken by mouth. Participants are asked to keep a diary of when they take their pills to make sure they are taking these medicines properly. Participants will have tumor imaging scans after every 2nd cycle (or 6 weeks) to check if the treatment is working. If the doctors are concerned the cancer has spread to the brain and/or spine, they will have scans of the area(s) and a sampling of the fluid around the brain/spine which is obtained through a small needle inserted into the lower part of the back for a short time to collect the fluid. This procedure is called a spinal tap or lumbar puncture. Participants who have tumor in their skin will have repeat exams of their skin and sometimes photographs taken of these areas to see if the treatment is working. Participants will also be asked to give blood, saliva, and sometimes have optional biopsies of their tumor where these tests are done for research purposes. After they have completed the protocol treatment (6 cycles), they will be asked to return to clinic 30 days after treatment has ended, then every other month (or 60 days) for the first 6 months, then every 3 months (90 days) for 2 years, and then every 6 months for years 2 to 4 after completing treatment. After 4.5 years, they will be seen once a year.

Conditions

Mature T-cell Malignancies; Peripheral T-Cell Lymphoma; Cutaneous T-Cell Lymphoma; Relapsed/ Refractory T-cell Malignancies

Keywords

Immunomodulatory Drugs (IMiDs); TCM; ALCL; Histone Deacetylase Inhibitors (HDACi)

Outcome Measures

Primary Outcomes (6)

• Maximum Tolerated Dose (MTD)

  The MTD is the dose level at which no more than 1 of up to 6 participants experience dose-limiting toxicity (DLT) during the DLT evaluation window(s), or the dose below that at which at least 2 (of ≤6) participants have DLT. A DLT is defined as any treatment-emergent and related severe (grade ≥3) toxicity related to lenalidomide, romidepsin and/or CC-486 (5-azacitidine) and occurring during the maximum tolerated dose (MTD) observation time, defined as day -7 until end of cycle 1 (normally day 22).

  21 days

• Rate and Severity of Serious and/or Non-serious Adverse Events (AE's) by Grade and Type of Toxicity

  Rate and severity of AEs will be summarized by grade and type of toxicity. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event.

  6 cycles (each cycle is 28 days)

• Number of Treatment Emergent Grades 3, 4 and/or 5 Adverse Events Possibly Related to Drug Grouped by Severity

  Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event.

  6 cycles (each cycle is 28 days)

• Arm 1, Cohort 1, Dose Level -1, 1, and 2 Treatment Emergent Serious Grades 3, 4, and/or 5 Adverse Events Possibly Related to Drug Grouped by Relationship to the Study Drug and/or Combination

  Treatment emergent grades 3, 4, and/or 5 adverse events possibly related grouped by relationship to the study drug (e.g., lenalidomide, romidepsin, CC-486 (5-azacitidine) in any combinations) assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 3 is severe. Grade 4 is life threatening. Grade 5 is death related to adverse event.

  6 cycles (each cycle is 28 days)

• Arm 1, Cohort 1, Dose Level 3, and Arm 1, Cohort 1, Dose Level 4 Treatment Emergent Serious Grades 3, 4, and/or 5 Adverse Events Possibly Related to Drug Grouped by Relationship to the Study Drug and/or Combination

  Treatment emergent grades 3, 4, and/or 5 adverse events possibly related grouped by relationship to the study drug (e.g., lenalidomide, romidepsin, CC-486 (5-azacitidine) in any combinations) assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 3 is severe. Grade 4 is life threatening. Grade 5 is death related to adverse event.

  6 cycles (each cycle is 28 days)

• Arm 2, Cohort 2, Dose Level 2 and 4; and Arm 3, Cohort 2, Dose Level 4 Treatment Emergent Serious Grades 3, 4, and/or 5 Adverse Events Possibly Related to Drug Grouped by Relationship to the Study Drug and/or Combination

  Treatment emergent grades 3, 4, and/or 5 adverse events possibly related grouped by relationship to the study drug (e.g., lenalidomide, romidepsin, CC-486 (5-azacitidine) in any combinations) assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 3 is severe. Grade 4 is life threatening. Grade 5 is death related to adverse event.

  6 cycles (each cycle is 28 days)

Secondary Outcomes (5)

• Overall Response Rate (Complete Response + Partial Response)

  6 cycles (each cycle is 28 days)

• Progression-free Survival (PFS) in Months Reported Along With a 95% Confidence Interval

  up to a median of 13.1 months

• Complete Response Rate (CRR)

  6 cycles (each cycle is 28 days)

• Duration of Response (DOR) in Months Reported Along With a 95% Confidence Interval

  up to a median of 11.7 months

• Overall Survival (OS)

  up to a median of 8.7 months

Other Outcomes (2)

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).

  up to 3.5 years

• Number of Participants With a Dose-limiting Toxicity (DLT)

  Day -7 until end of cycle 1 (normally day 22)

Study Arms (2)

1- Experimental Treatment: Dose Escalation

EXPERIMENTAL

Lenalidomide by oral intake at escalating doses of 5, 10, 15, or 20 mg/day on days -7 to 10 of each 21-day cycle (max 6 cycles) with CC-486 (5-azacitidine) at 300mg/day by oral intake on days 1-10, romidepsin at 12mg/m\^2 by intravenous (IV) infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle, to determine maximum tolerated dose (MTD).

Drug: Romidepsin; Drug: Lenalidomide; Drug: CC-486 (5-azacitidine); Drug: Dexamethasone; Diagnostic Test: EKG; Procedure: Bone Marrow Aspiration/Biopsy; Diagnostic Test: MRI; Procedure: Lumbar Puncture; Diagnostic Test: TTE

2 - Experimental Treatment: Dose Expansion

EXPERIMENTAL

Lenalidomide by oral intake at maximum tolerated dose (MTD) on days -7 to 10 of each 21-day cycle (max 6 cycles) with CC-486 (5-azacitidine) at 300mg/day by oral intake on days 1-10, romidepsin at 12mg/m\^2 by intravenous (IV) infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle

Drug: Romidepsin; Drug: Lenalidomide; Drug: CC-486 (5-azacitidine); Drug: Dexamethasone; Diagnostic Test: EKG; Procedure: Bone Marrow Aspiration/Biopsy; Diagnostic Test: MRI; Procedure: Lumbar Puncture; Diagnostic Test: TTE

Interventions

Lenalidomide DRUG

Lenalidomide will be administered by oral intake in a dose-escalation with a starting dose of 5mg daily, a second dose level of 10mg daily, a third dose level at 15mg daily, and a fourth dose level at 20mg daily on days -7 to day 10 of first cycle. After the second cycle, lenalidomide will be given from day 1 to day 10 in each cycle for up to 6 cycles.

Also known as: REVLIMID

1- Experimental Treatment: Dose Escalation; 2 - Experimental Treatment: Dose Expansion

Dexamethasone DRUG

Dexamethasone, 40mg, by mouth (PO), will be given on days 1 and 10 of each cycle.

Also known as: azacitidine tablets

1- Experimental Treatment: Dose Escalation; 2 - Experimental Treatment: Dose Expansion

EKG DIAGNOSTIC_TEST

Screening

Also known as: Electrocardiogram

1- Experimental Treatment: Dose Escalation; 2 - Experimental Treatment: Dose Expansion

Bone Marrow Aspiration/Biopsy PROCEDURE

Baseline, end of treatment and disease progression, and Day 30 (+7).

Also known as: BM Aspiration/Bx

1- Experimental Treatment: Dose Escalation; 2 - Experimental Treatment: Dose Expansion

MRI DIAGNOSTIC_TEST

Baseline, every 2 cycles, end of treatment and disease progression, and follow-up.

Also known as: Magnetic resonance imaging

1- Experimental Treatment: Dose Escalation; 2 - Experimental Treatment: Dose Expansion

Lumbar Puncture PROCEDURE

Baseline, every 2 cycles, end of treatment and disease progression, and follow-up.

Also known as: LP

1- Experimental Treatment: Dose Escalation; 2 - Experimental Treatment: Dose Expansion

TTE DIAGNOSTIC_TEST

Screening

Also known as: Transthoracic echocardiogram

1- Experimental Treatment: Dose Escalation; 2 - Experimental Treatment: Dose Expansion

Romidepsin DRUG

Romidepsin (12mg/ m\^2) will be administered on days 1 and 10 of each cycle through a peripheral or central intravenous catheter for 6 cycles.

Also known as: Istodax

1- Experimental Treatment: Dose Escalation; 2 - Experimental Treatment: Dose Expansion

CC-486 (5-azacitidine) DRUG

CC-486 (5-azacitidine) with a dose of 300mg oral intake daily will be given on day 1 to day 10 for 6 cycles.

Also known as: ONUREG

1- Experimental Treatment: Dose Escalation; 2 - Experimental Treatment: Dose Expansion

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have relapsed after or progressed during at least one line of prior systemic therapy (which may include allogeneic stem cell transplantation) for mature T or NK/T neoplasm, i.e. have relapsed and/or refractory mature T and natural killer (NK) neoplasm per 2016 World Health Organization (WHO) classification excluding chronic lymphoproliferative disorder of NK cells, aggressive NK-cell leukemia, and Cutaneous T-Cell Lymphoma.
• T or NK/T neoplasm from initial diagnosis or recurrence must be histologically or cytologically proven and diagnosis be confirmed by the Laboratory of Pathology, National Cancer Institute (NCI),
• Patients with anaplastic large cell lymphoma (ALCL) or cluster of differentiation (CD30) positive mycosis fungoides (MF) or Sézary syndrome (SS) must have relapsed after or become intolerant to prior anti-CD30 targeting therapy treatment with brentuximab vedotin
• For patients without circulating leukemia/lymphoma cells detectable by flow cytometry, a formalin fixed tissue block or 15 slides of tumor sample (archival or fresh) must be available at enrollment for performance of correlative studies. NOTE: Patients without circulating malignant cells must be willing to have a tumor biopsy if prior tissue or adequate archival tissue is not available (i.e., post-enrollment and prior to treatment).
• Disease must be measurable with at least one measurable lesion by response evaluation criteria in lymphoma (RECIL) 2017 or Modified Severity-Weighted Assessment Tool (mSWAT) criteria, or have an abnormal clonal T-cell population detectable by peripheral blood flow cytometry
• Age \>18 years
• Eastern Cooperative Oncology Group (ECOG) performance status \<=2, or \<= 3 if the decreased performance status is deemed to be due to disease and not residual toxicity from prior therapy or other causes.
• Adequate organ and marrow function as defined below:
• Absolute neutrophil count \>= 1,000/mcL
• Platelets \>= 75,000/mcL
• Total bilirubin \<= 1.5 X institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) \<= 2.5 X institutional upper limit of normal (ULN)
• Serum Creatinine \<= 1.5 mg/dL OR
• Creatinine Clearance \>= 60 mL/min/1.73 m\^2 as calculated by direct measurement of 24-hour urine for creatinine clearance
• Negative serum or urine pregnancy test at screening for women of childbearing potential (WOCBP) NOTE: WOCBP is defined as any female who has experienced menarche and who has not undergone successful surgical sterilization or who is not postmenopausal. WOCBP must have a negative pregnancy test (hemoglobin (HCG) blood or urine) during screening.

You may not qualify if:

• Patients who are receiving any other investigational agents.
• Anti-cancer treatment within 2 weeks prior to enrollment. (4 weeks for monoclonal antibodies and 6 weeks for nitrosoureas or mitomycin C).
• Patients who have received two of the following drugs at any point: lenalidomide, romidepsin, and 5-azacitidine. Patients who have received only one of the three drugs remain eligible.
• Patients with a diagnosis of cutaneous T-cell lymphoma (CTCL) are excluded from participation in the expansion cohort.
• Other malignancy that requires ongoing systemic hormonal therapy, chemotherapy, or immunotherapy.
• History of allergic reactions or known or suspected hypersensitivity attributed to compounds of similar chemical or biologic composition to lenalidomide, romidepsin and 5-azacitidine
• Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring systemic therapy, or psychiatric illness/social situations that would limit compliance with study requirements.
• Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• History of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), celiac disease (i.e., sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption, distribution, metabolism or excretion of the study drug and/or predispose the subject to an increased risk of gastrointestinal toxicity.
• Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (\< 6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure (\>= New York Heart Association Classification Class II), congenital long QT syndrome, or other serious cardiac arrhythmia including 2nd degree atrio ventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min).
• Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or other causes.
• Triplicate average baseline QT corrected for heart rate by Fridericia's (QTcF) interval \>= 480 ms
• Patients taking drugs leading to significant QT prolongation Note: A 5 half-life washout period must have elapsed following the use of these drugs prior to administration of romidepsin.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Gordon MJ, Miljkovic MD, Milhon P, Lakhotia R, Melani C, Johnson K, Bryant BR, Pittaluga S, Jaffe ES, Conlon KC, Staudt LM, Wilson W, Roschewski M, Ng SY. A phase 1 trial of romidepsin, azacitidine, dexamethasone and lenalidomide in relapsed or refractory T-cell lymphoma. Blood Adv. 2026 Feb 12:bloodadvances.2025019186. doi: 10.1182/bloodadvances.2025019186. Online ahead of print.

  PMID: 41779512 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Lymphoma, T-Cell, Cutaneous; Lymphoma, T-Cell, Peripheral

Interventions

romidepsin; Lenalidomide; cc-486; Dexamethasone; Azacitidine; Electrocardiography; Biopsy; Magnetic Resonance Imaging; Spinal Puncture; Echocardiography

Condition Hierarchy (Ancestors)

Lymphoma, T-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Aza Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Heart Function Tests; Diagnostic Techniques, Cardiovascular; Diagnostic Techniques and Procedures; Diagnosis; Electrodiagnosis; Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Tomography; Diagnostic Imaging; Diagnostic Techniques, Neurological; Punctures; Therapeutics; Cardiac Imaging Techniques; Ultrasonography

Results Point of Contact

• Title: Dr. Max Gordon
• Organization: National Cancer Institute

max.gordon@nih.gov

240-858-7151

Study Officials

• Max Gordon, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 24, 2020
• First Posted: June 25, 2020
• Study Start: December 17, 2020
• Primary Completion: July 1, 2024
• Study Completion: December 17, 2025
• Last Updated: January 30, 2026
• Results First Posted: June 12, 2025

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data will be available during the study and indefinitely. Genomic data will be available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active
• Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data will be made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.

Locations

US (1)