Clinical Trials /

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

NCT04447027

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 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 greater than or equal to 18 years of age - ECOG performance status of less than or equal to 2 (or less than or equal to 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 (21-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

Related Conditions:
  • Mature T-Cell and NK-Cell Neoplasm
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Phase 1 Study of 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

Clinical Trial IDs

  • ORG STUDY ID: 200127
  • SECONDARY ID: 20-C-0127
  • NCT ID: NCT04447027

Conditions

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

Interventions

DrugSynonymsArms
Romidepsin1- Experimental Treatment: Dose Escalation
Lenalidomide1- Experimental Treatment: Dose Escalation
5-azacitidine1- Experimental Treatment: Dose Escalation
Dexamethasone1- Experimental Treatment: Dose Escalation

Purpose

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 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 greater than or equal to 18 years of age - ECOG performance status of less than or equal to 2 (or less than or equal to 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 (21-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

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 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 greater than or equal to 18 years of age

        -  ECOG performance status of less than or equal to 2 (or less than or equal to 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 (21-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
    

Trial Arms

NameTypeDescriptionInterventions
1- Experimental Treatment: Dose EscalationExperimentalLenalidomide 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 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
  • Romidepsin
  • Lenalidomide
  • 5-azacitidine
  • Dexamethasone
2 - Experimental Treatment: Dose ExpansionExperimentalLenalidomide by oral intake at MTD on days -7 to 10 of each 21-day cycle (max 6 cycles) with 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
  • Romidepsin
  • Lenalidomide
  • 5-azacitidine
  • Dexamethasone

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 NK neoplasm per
             2016 WHO classification excluding chronic lymphoproliferative disorder of NK cells and
             aggressive NK-cell leukemia.

          -  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

          -  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 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 greater than or equal to18 years

        NOTE: Because no dosing or adverse event data are currently available on the use of
        lenalidomide combination with romidepsin and CC-486 (5-azacitidine) in patients <18 years
        of age, children are excluded from this study, but may be eligible for future pediatric
        trials

          -  ECOG performance status less than or equal to 2, or less than or equal to 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 greater than or equal to 1,000/mcL

               -  Platelets greater than or equal to 75,000/mcL

               -  Total bilirubin less than or equal to 1.5 X institutional upper limit of normal
                  (ULN)

               -  AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional ULN

               -  Creatinine clearance greater than or equal to 60 mL/min/1.73 m^2 calculated by
                  eGFR in the clinical lab

          -  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[registered
             trademark] program and be willing and able to comply with the requirements of the
             REMS[registered trademark] 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 28 days after completion of treatment.
             Females of reproductive potential must adhere to the scheduled pregnancy testing as
             required in the Revlimid REMS[registered trademark] 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 lenalidomide, romidepsin, and 5-azacitidine at any time
             point during prior treatments. Patients who have received one or two of the three
             drugs (alone or in combination) remain eligible.

          -  Patients with previous malignant disease other than the target malignancy within the
             last 5 years with the exception of basal or squamous cell carcinoma of the skin or
             cervical carcinoma in situ

          -  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 (greater than or equal
             to 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 greater than or equal to
             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 greater than or equal to 480 ms

          -  Patients taking drugs leading to significant QT prolongation

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD)
Time Frame:21 days
Safety Issue:
Description:Frequency (number and percentage) of treatment emergent adverse events

Secondary Outcome Measures

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

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Histone Deacytelase Inhibitors (HDACi)
  • Immunomodulatory Drugs (IMiDs)
  • TCM
  • ALCL

Last Updated

June 24, 2020