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

A Phase 1 Study of Romidepsin, CC-486 (5-azacitidine), Dexamethasone, and Lenalidomide (RAdR) for Relapsed/Refractory T-cell Malignancies

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 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.

Study Overview

• Status: Active, not recruiting
• Conditions: Cutaneous T-Cell Lymphoma; Peripheral T-Cell Lymphoma; Mature T-cell Malignancies; Relapsed/ Refractory T-cell Malignancies
• Intervention / Treatment: Drug: Romidepsin; Drug: Lenalidomide; Drug: CC-486 (5-azacitidine); Drug: Dexamethasone

Detailed Description

Background:

• Mature T-cell malignancies (TCM) are rare and heterogeneous group of leukemias and lymphomas accounting for 5 to 10% of all lymphomas in the US
• Patients with systemic TCM are most commonly treated with a CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone)-like regimens, that produce long-term progression-free survival in about 30% of these cases
• Patients with relapsed/refractory (R/R) TCM have very poor prognosis with median overall survival of less than 1 year. Treatment options for R/R TCM are very few and of limited efficacy, thus novel treatment strategies are urgently needed.
• Mutations in epigenetic regulators are common in aggressive TCMs and standard treatment with histone deacetylase inhibitors (HDACi) such as romidepsin show modest clinical activity with single agent the overall response (ORR) around 25%
• Combination of romidepsin and 5-azacitidine (hypomethylating agents) was synergistic in preclinical models, and has demonstrated high clinical activity with an ORR of 79%
• Many TCMs rely on The Ikaros-dependent NF-kB/IRF4 signaling pathway to maintain proliferation, which is why lenalidomide, which induces degradation of Ikaros and downregulates IRF4, has single agent activity in R/R TCM with ORR of 26% to 42%, depending on the subtype.
• Lenalidomide synergizes with romidepsin and enhances tumor cell death in TCM cell lines, predicting that the addition of lenalidomide to the established romidepsin/ CC-486 (5-azacitidine) combination will further improve efficacy.

Objectives:

-To determine the safety and toxicity profile and the maximum tolerated dose (MTD) of the four drug combination of CC-486 (5-azacitidine), romidepsin, lenalidomide and dexamethasone in patients with TCM

Eligibility:

• Refractory/relapsed TCM (excluding in Cutaneous T-Cell Lymphoma) defined as follows:

  • Patients with systemic disease
  • Have received at least one line of prior therapy
  • Must have received brentuximab vedotin if the disease is anaplastic large cell lymphoma or CD30-positive cutaneous T-cell lymphoma
• Age >= 18 years of age
• ECOG performance status of <= 2 (or <= 3 if decrease is due to the disease)
• Histologically or cytologically confirmed relapsed and/or refractory mature TCM
• Adequate organ and marrow function

Design:

• Open-label, single-center, uncontrolled Phase 1 study
• 3 + 3 design will be used to determine the MTD of dose-escalated lenalidomide with fixed dose of romidepsin and CC-486 (5-azacitidine)
• An expansion cohort of 9 patients will be evaluated at the MTD
• Maximum 6 cycles (28-day cycle) of combination therapy
• To explore all dose levels, including further evaluation in a dose expansion cohort, the accrual ceiling will be set at 30 patients

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Mark J Roschewski, M.D.; Phone Number: (240) 760-6183; Email: mark.roschewski@nih.gov
• Study Contact Backup: Name: NCI Medical Oncology Referral Office; Phone Number: (888) 624-1937; Email: ncimo_referrals@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:
• 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 NK neoplasm per 2016 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, NCI,
• Patients with ALCL or CD30 positive MF/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 RECIL 2017 or mSWAT criteria, or have an abnormal clonal T-cell population detectable by peripheral blood flow cytometry
• Age >18 years
• 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)
  • AST(SGOT)/ALT(SGPT) <= 2.5 X institutional 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 (HCG blood or urine) during screening.
• All study participants must be registered into the mandatory Revlimid REMS(R) program and be willing and able to comply with the requirements of the REMS(R) program.
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 6 months after completion of treatment for women, and for at least 3 months after completion of treatment for men. Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS(R) program.
• Ability of subject to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

• 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 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.
• 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 (for at least one month) and meet all other inclusion criteria.
• Triplicate average baseline 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.
• Concomitant use of rifampin and other strong CYP3A4 inhibitors and inducers within 2 weeks prior to starting protocol therapy.
• Other severe acute or chronic medical conditions including psychiatric conditions such as recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
• Pregnant or lactating women. Pregnant women are excluded from this study because lenalidomide is a Class X agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with lenalidomide, breastfeeding should be discontinued if the mother is treated with lenalidomide. These potential risks may also apply to other agents used in this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1- Experimental Treatment: Dose Escalation; 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/m2 by IV infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle, to determine MTD	Drug: Romidepsin; Romidepsin (12mg/ m2 ) will be administered on days 1 and 10 of each cycle through a peripheral or central intravenous catheter for 6 cycles.; Drug: Lenalidomide; 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.; Drug: CC-486 (5-azacitidine); CC-486 (5-azacitidine) with a dose of 300mg oral intake daily will be given on day 1 to day 10 for 6 cycles.; Drug: Dexamethasone; Dexamethasone, 40mg, PO, will be given on days 1 and 10 of each cycle.
Experimental: 2 - Experimental Treatment: Dose Expansion; Lenalidomide by oral intake at 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/m2 by IV infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle	Drug: Romidepsin; Romidepsin (12mg/ m2 ) will be administered on days 1 and 10 of each cycle through a peripheral or central intravenous catheter for 6 cycles.; Drug: Lenalidomide; 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.; Drug: CC-486 (5-azacitidine); CC-486 (5-azacitidine) with a dose of 300mg oral intake daily will be given on day 1 to day 10 for 6 cycles.; Drug: Dexamethasone; Dexamethasone, 40mg, PO, will be given on days 1 and 10 of each cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD)	Frequency (number and percentage) of treatment emergent adverse events	21 days
safety and tolerability	rate and severity of AEs will be summarized by grade and type of toxicity	6 cycles

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Repsonse Rate	The response rate will be determined and reported along with a 95% confidence interval	6 cycles
Progression-free survival	The response rate will be determined and reported along with a 95% confidence interval	every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually
Complete Response Rate	The response rate will be determined and reported along with a 95% confidence interval	6 cycles
Duration of response (DOR)	The response rate will be determined and reported along with a 95% confidence interval	every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually
Overall Survival (OS)	The response rate will be determined and reported along with a 95% confidence interval	every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Mark J Roschewski, M.D., National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): December 17, 2020
• Primary Completion (Estimated): November 15, 2024
• Study Completion (Estimated): May 15, 2025

Study Registration Dates

• First Submitted: June 24, 2020
• First Submitted That Met QC Criteria: June 24, 2020
• First Posted (Actual): June 25, 2020

Study Record Updates

• Last Update Posted (Actual): February 20, 2024
• Last Update Submitted That Met QC Criteria: February 16, 2024
• Last Verified: February 14, 2024

More Information

Terms related to this study

• Keywords: ALCL; Immunomodulatory Drugs (IMiDs); TCM; Histone Deacetylase Inhibitors (HDACi)
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Neoplasms; Lymphoma; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Lymphoma, T-Cell, Cutaneous; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antibiotics, Antineoplastic; Histone Deacetylase Inhibitors; Dexamethasone; Lenalidomide; Azacitidine; Romidepsin; Cc-486
• Other Study ID Numbers: 200127; 20-C-0127

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request. @@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.
• IPD Sharing Time Frame: Clinical data will be available during the study and indefinitely. @@@@@@Genomic data will be available once genomic data are uploaded per protocol GDS plan for as long as database is active
• IPD Sharing Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@Genomic data will be made available via dbGaP through requests to the data custodians.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No