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A Randomized, Phase IIB, Multicenter, Trial of Oral Azacytidine Plus Romidepsin Versus Investigator's Choice in Patients With Relapse or Refractory Peripheral T-cell Lymphoma (PTCL)

NCT04747236

Description:

The purpose of this study is to find out whether the combination treatment of romidepsin and oral azacytidine is safe and effective in patients with Peripheral T-Cell Lymphoma (PTCL). This study will compare the experimental combination treatment of romidepsin and oral azacytidine to single agent drugs already determined effective in patients with PTCL. For the purposes of this study, the single agent drugs already used to treat lymphoma are called investigator's choice (IC), meaning the investigator will choose which one of these drugs to administer. The IC drug options include romidepsin, belinostat, pralatrexate or gemcitabine given alone. Funding Source: FDA OOPD.

Related Conditions:
  • Adult T-Cell Leukemia/Lymphoma
  • Anaplastic Large Cell Lymphoma
  • Angioimmunoblastic T-Cell Lymphoma
  • Enteropathy-Associated T-Cell Lymphoma
  • Follicular T-Cell Lymphoma
  • Hepatosplenic T-Cell Lymphoma
  • Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma
  • Nasal Type Extranodal NK/T-Cell Lymphoma
  • Nodal Peripheral T-Cell Lymphoma with TFH Phenotype
  • Peripheral T-Cell Lymphoma
  • Primary Cutaneous Anaplastic Large Cell Lymphoma
  • Primary Cutaneous CD4-Positive Small/Medium T-Cell Lymphoproliferative Disorder
  • Primary Cutaneous T-Cell Non-Hodgkin Lymphoma
  • Subcutaneous Panniculitis-Like T-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Randomized, Phase IIB, Multicenter, Trial of Oral Azacytidine Plus Romidepsin Versus Investigator's Choice in Patients With Relapse or Refractory Peripheral T-cell Lymphoma (PTCL)
  • Official Title: A Randomized, Phase IIB, Multicenter, Trial of Oral Azacytidine Plus Romidepsin Versus Investigator's Choice in Patients With Relapse or Refractory Peripheral T-cell Lymphoma (PTCL)

Clinical Trial IDs

  • ORG STUDY ID: HSR200080
  • SECONDARY ID: FD-R-006814-01
  • NCT ID: NCT04747236

Conditions

  • PTCL

Interventions

DrugSynonymsArms
AzacytidineAZA and ROMI
RomidepsinAZA and ROMI
BelinostatInvestigator's Choice
PralatrexateInvestigator's Choice
GemcitabineInvestigator's Choice

Purpose

The purpose of this study is to find out whether the combination treatment of romidepsin and oral azacytidine is safe and effective in patients with Peripheral T-Cell Lymphoma (PTCL). This study will compare the experimental combination treatment of romidepsin and oral azacytidine to single agent drugs already determined effective in patients with PTCL. For the purposes of this study, the single agent drugs already used to treat lymphoma are called investigator's choice (IC), meaning the investigator will choose which one of these drugs to administer. The IC drug options include romidepsin, belinostat, pralatrexate or gemcitabine given alone. Funding Source: FDA OOPD.

Detailed Description

      Peripheral T-Cell Lymphoma (PTCL) is a rare and heterogeneous group of non-Hodgkin lymphoma
      (NHL) originating from mature (or post-thymic or 'peripheral') T- lymphocytes and NK cells.
      They are considered very aggressive and are often resistant to conventional chemotherapy.

      This study employs a stratified randomization with equal allocation within strata of patients
      to receive oral 5-azacytidine (AZA) plus romidepsin (ROMI) versus pre-specified investigator
      choice (ROMI, belinostat, pralatrexate or gemcitabine), for the treatment of relapsed or
      refractory (R/R) PTCL. The dose and schedule of AZA/ROMI has been determined from a phase I
      clinical trial of the combination. The primary objective of this study is to estimate the
      progression free survival (PFS) among patients receiving the combination compared to single
      agent of choice.
    

Trial Arms

NameTypeDescriptionInterventions
AZA and ROMIExperimentalOral Azacytidine (AZA) (300 mg daily on days 1-14) plus Romidepsin (ROMI) (14 mg/m2 as an intravenous infusion over 4 hours on days 8, 15 and 22 of a 35-day cycle.
  • Azacytidine
  • Romidepsin
Investigator's ChoiceActive ComparatorInvestigator's choice to include: ROMI, 14 mg/m2 IV infusion on days 1, 8, and 15 of a 28 day cycle, belinostat,1000 mg/m2 IV infusion on days 1-5 every 21 days, pralatrexate, 30 mg/m2 IV push once weekly for 6 weeks of a 7-week treatment cycle, or gemcitabine, 1000 mg/m2 IV infusion on days 1, 8, and 15 of a 28-day cycle.
  • Romidepsin
  • Belinostat
  • Pralatrexate
  • Gemcitabine

Eligibility Criteria

        Inclusion Criteria:

        In order to be eligible to participate in this study, an individual must meet all of the
        following criteria:

          1. Patients must have histologically confirmed relapsed or refractory peripheral T-cell
             lymphoma as defined by 2016 WHO criteria (Section 13.7), who have progressed following
             one line of prior systemic therapy. PTCL histologies include:

               -  Adult T-cell leukemia/lymphoma;

               -  Extranodal NK-/T-cell lymphoma, nasal type;

               -  Enteropathy-associated T-cell lymphoma;

               -  Monomorphic epitheliotropic intestinal T-cell lymphoma;

               -  Hepatosplenic T-cell lymphoma;

               -  Subcutaneous panniculitis-like T-cell lymphoma;

               -  Primary cutaneous anaplastic large cell lymphoma;

               -  Primary cutaneous T-cell lymphoma;

               -  Primary cutaneous CD8+ T-cell lymphoma;

               -  Transformed mycosis fungoides;

               -  Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder;

               -  Peripheral T-cell lymphoma, NOS;

               -  Angioimmunoblastic T-cell lymphoma;

               -  Follicular T-cell lymphoma;

               -  Nodal peripheral T-cell lymphoma with TFH phenotype;

               -  Anaplastic large-cell lymphoma ALK+; anaplastic large-cell lymphoma ALK- ; Breast
                  implant-associated anaplastic large-cell lymphoma.

          2. Patients are required to have no more than 3 lines of prior therapy (with
             cytoreductive therapy [ex ICE, DHAP, etc.] followed by autologous stem cell transplant
             counting as one line of therapy). Patients are eligible if they have relapsed after
             prior autologous or allogeneic stem cell transplant.

          3. Patients with anaplastic large cell lymphoma are required to have received brentuximab
             vedotin (Bv) prior to study enrollment.

          4. Measurable Disease as defined in Section 8.1.3.1.

          5. Age ≥18 years.

          6. ECOG performance status ≤2

          7. Patients must have adequate organ and marrow function as defined below:

             Absolute neutrophil count (ANC): ≥1000/mm3 (≥1000/dL); Platelets: > 75,000/mm3; Serum
             Creatinine:< 2 x ULN OR creatinine clearance >50 mL/min/for patients with creatinine
             levels above ULN; Bilirubin: ≤ 1.5 x ULN (except in patients with Gilbert's disease,
             where bilirubin to 4x ULN is allowed); AST and ALT: ≤ 2 x ULN OR ≤ 3 X ULN in presence
             of demonstrable liver involvement; Serum potassium: ≥ 3.8 mmol/L; Serum magnesium≥1.8
             mg/dL.

          8. Negative urine or serum pregnancy test for females of childbearing potential

          9. All females of childbearing potential and male subjects must agree to use an effective
             method of contraception (see section 5.4 for more details)

         10. Ability to understand and the willingness to sign a written informed consent document.

        Exclusion Criteria:

        An individual who meets any of the following criteria will be excluded from participation
        in this study:

          1. Prior Therapy: Prior exposure to any hypomethylating agent or any histone deacetylase
             inhibitor (ex: romidepsin, chidamide, belinostat, or vorinostat); exposure to
             chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who
             have not recovered from adverse events due to agents administered more than 2 weeks
             earlier.

          2. Systemic steroids that have not been stabilized to the equivalent of ≤10 mg/day
             prednisone prior to the start of the study drugs.

          3. No other concurrent investigational agents are allowed within 2 weeks of enrollment.

          4. Known central nervous system metastases, including lymphomatous meningitis

          5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements.

          6. Nursing women

          7. Other active concurrent malignancy (except non-melanoma skin cancer, carcinoma in situ
             of the cervix, or carcinoma in situ of the breast (DCIS or LCIS). If there is a
             history of prior malignancy, the patient must be disease-free for ≥ 3-years. Patients
             whose lymphoma has transformed from a less aggressive histology remain eligible.

          8. Patients known to be Human Immunodeficiency Virus (HIV)-positive.

          9. Patients with active Hepatitis A, hepatitis B, or hepatitis C infection.

         10. Concomitant use of CYP3A4 inhibitors (see Section 13.3)

         11. History of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis),
             celiac disease (ie, 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

         12. Abnormal coagulation parameters (PT >15 seconds, PTT>40 seconds, and/or INR >1.5)

         13. Known or suspected hypersensitivity to azacitidine or mannitol

         14. Any known cardiac abnormalities such as:

               -  Congenital long QT syndrome

               -  QTc interval ≥ 500 millisecond (using the Fridericia formula)

               -  Patients taking drugs leading to significant QT prolongation (See Section 13.2)

               -  Myocardial infarction within 6 months of C1D1. [Subjects with a history of
                  myocardial infarction between 6 and 12 months prior to C1D1 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 ECG abnormalities including 2nd degree atrio-ventricular (AV)
                  block type II, 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 (see
                  Section 13.4) 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 ECG 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 (see Section 13.5) and/or ejection fraction <40% by MUGA
                  scan or <50% by echocardiogram and/or MRI;

               -  A known history of sustained ventricular tachycardia (VT), ventricular
                  fibrillation (VF), Torsade de Pointes, or cardiac arrest;

               -  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; or

               -  Any cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable
                  doses of beta-blockers)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival
Time Frame:Day of randomization to day of progression or death, whichever comes first; or date of last disease assessment or date of transition to other treatment for those without an event, up to 72 weeks.
Safety Issue:
Description:Difference in progression free survival in subjects treated with AZA/ROMI versus pre-specified investigator choice.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:Day of randomization to day of death, whichever comes first; or date of last contact for those without an event, up to 72 weeks.
Safety Issue:
Description:Difference in overall survival in subjects treated with AZA/ROMI versus pre-specified investigator choice.
Measure:Complete response rate
Time Frame:Day of first objective response to 8 weeks following last dose of study treatment
Safety Issue:
Description:Difference in complete response (CR) rate in subjects treated with AZA/ROMI versus pre-specified investigator choice, based on the Revised Criteria for Response Assessment.
Measure:Overall response rate
Time Frame:Day of first objective response to 8 weeks following last dose of study treatment
Safety Issue:
Description:Difference in overall response (OR) rate in subjects treated with AZA/ROMI versus pre-specified investigator choice, based on the Revised Criteria for Response Assessment.
Measure:Duration of response rate
Time Frame:Day of first objective response to day of progression or death, whichever comes first; or date of last disease assessment or date of transition to other treatment for those without an event, up to 72 weeks.
Safety Issue:
Description:Difference in duration of response (DOR) rate in subjects treated with AZA/ROMI versus pre-specified investigator choice, based on the Revised Criteria for Response Assessment.
Measure:Time to progression
Time Frame:Day of randomization to day of progression, or date of last disease assessment or date of transition to other treatment for those without an event, up to 72 weeks.
Safety Issue:
Description:Difference in time to progression in subjects treated wtih AZA/ROMI versus pre-specified investigator choice.
Measure:Frequency of adverse events
Time Frame:From time of informed consent until 90 days after the last day of study treatment for all adverse events or anytime for serious adverse events considered related to the study intervention, through study completion, an average of 18 months.
Safety Issue:
Description:Frequency of adverse events in subjects treated wtih AZA/ROMI versus prespecified investigator choice assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Virginia

Last Updated

March 19, 2021