Clinical trial NCT04447027: Romidepsin, CC-486 (5-azacitidine), Dexamethasone, and Lenalidomide (RAdR) for Relapsed/Refractory T-cell Malignancies
Official title: A Phase 1 Study of Romidepsin, CC-486 (5-azacitidine), Dexamethasone, and Lenalidomide (RAdR) for Relapsed/Refractory T-cell Malignancies
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Cutaneous T-Cell Lymphoma
Mature T-cell Malignancies
Peripheral T-Cell Lymphoma
Relapsed/ Refractory T-cell Malignancies
Keywords: Immunomodulatory Drugs (IMiDs)
TCM
ALCL
Histone Deacetylase Inhibitors (HDACi)
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2020-06-25
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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 nuclear factor κB (NF-κB)/interferon regulatory factor 4 (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 overall response rate (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 cluster of differentiation 30 (CD30)-positive cutaneous T-cell lymphoma
* Age \>= 18 years of age
* Eastern Cooperative Oncology Group 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 maximum tolerated dose (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

Eligibility criteria: * 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 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.
* 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 Risk Evaluation and Mitigation Strategy (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 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.
* 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 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.
* Concomitant use of rifampin and other strong cytochrome P450 3A4 (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.

Primary outcomes:
measure: Maximum Tolerated Dose (MTD)
timeFrame: 21 days
measure: Rate and Severity of Serious and/or Non-serious Adverse Events (AE's) by Grade and Type of Toxicity
timeFrame: 6 cycles (each cycle is 28 days)
measure: Number of Treatment Emergent Grades 3, 4 and/or 5 Adverse Events Possibly Related to Drug Grouped by Severity
timeFrame: 6 cycles (each cycle is 28 days)
measure: 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
timeFrame: 6 cycles (each cycle is 28 days)
measure: 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
timeFrame: 6 cycles (each cycle is 28 days)
measure: 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
timeFrame: 6 cycles (each cycle is 28 days)
Secondary outcomes:
measure: Overall Response Rate (Complete Response + Partial Response)
timeFrame: 6 cycles (each cycle is 28 days)
measure: Progression-free Survival (PFS) in Months Reported Along With a 95% Confidence Interval
timeFrame: up to a median of 13.1 months
measure: Complete Response Rate (CRR)
timeFrame: 6 cycles (each cycle is 28 days)
measure: Duration of Response (DOR) in Months Reported Along With a 95% Confidence Interval
timeFrame: up to a median of 11.7 months
measure: Overall Survival (OS)
timeFrame: up to a median of 8.7 months
Other outcomes:
measure: Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).
timeFrame: up to 3.5 years
measure: Number of Participants With a Dose-limiting Toxicity (DLT)
timeFrame: Day -7 until end of cycle 1 (normally day 22)
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Mark J Roschewski, M.D.
role: PRINCIPAL_INVESTIGATOR
References: