Clinical Trials /

Efficacy and Safety of Oral Azacitidine Compared to Investigator's Choice Therapy in Patients With Relapsed or Refractory AITL

NCT03593018

Description:

This study evaluates the efficacy of Oral azacitidine versus single-agent Investigator's Choice Therapy in patients with Relapsed or Refractory Angioimmunoblastic T-cell Lymphoma.

Related Conditions:
  • Angioimmunoblastic T-Cell Lymphoma
  • Follicular T-Cell Lymphoma
  • Nodal Peripheral T-Cell Lymphoma with TFH Phenotype
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Efficacy and Safety of Oral Azacitidine Compared to Investigator's Choice Therapy in Patients With Relapsed or Refractory AITL
  • Official Title: Randomized Phase 3 Study Evaluating the Efficacy and the Safety of Oral Azacitidine (CC-486) Compared to Investigator's Choice Therapy in Patient With Relapsed or Refractory Angioimmunoblastic T Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: ORACLE
  • NCT ID: NCT03593018

Conditions

  • Relapsed Angioimmunoblastic T-Cell Lymphoma
  • Refractory Angioimmunoblastic T-cell Lymphoma

Interventions

DrugSynonymsArms
Oral azacitidineCC-486Oral Azacitidine
RomidepsinIstodaxInvestigator's choice therapy
BendamustineLevactInvestigator's choice therapy
GemcitabineGemzarInvestigator's choice therapy

Purpose

This study evaluates the efficacy of Oral azacitidine versus single-agent Investigator's Choice Therapy in patients with Relapsed or Refractory Angioimmunoblastic T-cell Lymphoma.

Detailed Description

      Compared to B-cell Non-Hodgin Lymphoma (NHL), Angioimmunoblastic T-cell Lymphoma (AITL) is
      more resistant to conventional chemotherapy and is generally associated with an inferior
      outcome. In case of relapsed of refractory disease, survival durations are in the range of
      only a few months.

      Several agents have been evaluated in this setting in recent years: romidepsin, bendamustine
      or belinostat. The response rate with these agents rarely exceeds 30% and responses are
      usually of limited duration.

      Azacitidine is a nucleoside metabolic inhibitor indicated for the treatment of patients with
      various myelodysplastic syndrome (MDS) subtypes. In this case, azacitidine significantly
      increase the survival time compared to standard of care option. This response to azacitidine
      could be correlated to the existence of recurrent mutations and those mutations have also
      been described in AITL.

      The present protocol will use Azacitidine according to the same schedule than in MDS that is
      continuous treatment until progression or unacceptable toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
Oral AzacitidineExperimentalOral azacitidine 300mg during 14 first days of 28-days cycle for European (EU) patients, Oral azacitidine 200mg during 14 first days of 28-days cycle for Asian patients (Treatment until progression, patient decision or toxicity)
  • Oral azacitidine
Investigator's choice therapyActive ComparatorRomidepsin 14mg/m² on days 1, 8 and 15 of a 28-days cycle (Treatment until progression, patient decision or toxicity) or Bendamustine 120mg/m² on days 1 and 2 of a 21-days cycle (during 6 cycles) or Gemcitabine 1200mg/m² on days 1, 8 and 15 of a 28-days cycle (during 6 cycles)
  • Romidepsin
  • Bendamustine
  • Gemcitabine

Eligibility Criteria

        Inclusion Criteria:

        Patients must satisfy all following criteria to be enrolled in the study::

          1. Patient is ≥ 18 years of age at the time of signing the informed consent form (ICF).

          2. Patient must understand and voluntarily sign an ICF prior to any study-specific
             assessments/procedures being conducted.

          3. Patient is willing and able to adhere to the study visit schedule and other protocol
             requirements

          4. Patient had local diagnosed peripheral T cell lymphoma (PTCL) with T-follicular helper
             (TFH) phenotype according to the criteria of the latest World Health Organization
             (WHO) classification based on a surgical lymph node biopsy including any one of

               -  Angioimmunoblastic T cell lymphoma (AITL)

               -  Follicular T cell lymphoma

               -  Nodal peripheral T-cell lymphoma with TFH phenotype There should be a documented
                  expression of minimum two TFH markers among this panel of markers : CD10, CXCL13,
                  PD1, ICOS and BCL6 by the tumoral cells by immunohistochemistry. Biopsy at
                  relapse or progression is not mandatory, but highly encouraged on a surgical or
                  needle core biopsy, and diagnostic tissue should be available for central
                  pathology review and for ancillary molecular studies.

             Local pathology report should be reviewed by the sponsor's medical monitor prior to
             enrollment.

          5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 3

          6. Relapsed (after partial or complete response) or refractory AITL after at least one
             line of systemic therapy (there is no mandatory resting period after the previous
             treatment as long as the biochemistry and hematology labs meet the inclusion criteria
             as below.)

          7. Meet the following lab criteria:

               -  Absolute Neutrophil Count (ANC) ≥ 1,5 x 109/L (≥ 1 x 109/L if bone marrow (BM)
                  involvement by lymphoma)

               -  Platelet ≥ 75 x 109/L (≥ 50 x 109/L if BM involvement by lymphoma)

               -  Hemoglobin ≥ 8 g/dL.

          8. Anticipated life expectancy at least 3 months

          9. At least one measurable lesion on CT that is greater than 1.5 cm in the longest
             diameter for nodal lesions and greater than 1.0 cm in the longest diameter for
             extranodal lesions. The lesion must be measurable in two perpendicular dimensions.
             Patients with only cutaneous disease will be excluded.

         10. Female patient of childbearing potential (FCBP) may participate, providing she meets
             the following conditions:

             Have two negative pregnancy tests as verified by the investigator prior to starting
             study treatment: serum pregnancy test at Screening and negative serum or urine
             pregnancy test (investigator's discretion) within 72 hours prior to starting treatment
             with study treatment (Cycle 1 Day 1). She must agree to ongoing pregnancy testing
             during the study (before beginning each subsequent cycle of treatment), and 28 days
             after the last study drug administration. This applies even if the patient practices
             complete abstinence from heterosexual contact.

             Agrees to practice true abstinence (which must be reviewed monthly and source
             documented) or agrees to the use of highly effective methods of contraception from 28
             days prior to starting study treatment, and must agree to continue using such
             precautions during study treatment (including dose interruptions) and for up to 90
             days after the last study drug administration. True abstinence is acceptable when this
             is in line with the preferred and usual lifestyle of the patient. Periodic abstinence
             (eg, calendar, ovulation, symptom-thermal, post ovulation methods) and withdrawal are
             not acceptable methods of contraception. Cessation of contraception after this point
             should be discussed with a responsible physician.

             Agrees to abstain from breastfeeding during study participation and for at least 90
             days after the last study drug administration.

             A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at
             some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has
             not been naturally postmenopausal (amenorrhea following cancer therapy does not rule
             out childbearing potential) for at least 24 consecutive months (i.e., has had menses
             at any time during the preceding 24 consecutive months).

         11. Male patient must either practice true abstinence from heterosexual contact (which
             must be reviewed on a monthly basis and source documented) or agrees to avoid
             fathering a child, to use highly effective methods of contraception, male condom plus
             spermicide during sexual contact with a pregnant female or a female of childbearing
             potential (even if he has undergone a successful vasectomy), from starting dose of
             drug (cycle 1 Day 1), including dose interruptions through 90 days after receipt of
             the last study drug administration. Furthermore, male patient must agree to not give
             semen or sperm during study drug therapy and for a period of 1 year after end of study
             drug therapy.

         12. For EU countries, patient covered by a social security system

        Exclusion Criteria:

        Presence of any of the following will exclude a patient from enrollment:

          1. Clinical evidence of central nervous system involvement by lymphoma. Patients with
             suspicion of central nervous system (CNS) involvement must undergo neurologic
             evaluation and CT/MRI of head and lumbar puncture to exclude CNS disease.

          2. Any significant medical conditions, laboratory abnormality or psychiatric illness
             likely to interfere with participation in this clinical study (according to the
             investigator's decision)

          3. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing
             signs/symptoms related to the infection without improvement despite appropriate
             antibiotics, antiviral therapy, and/or other treatment)

          4. Known Human Immunodeficiency Virus (HIV) or Hepatitis C Virus (HCV) infection, or
             evidence of active Hepatitis B (HB) Virus (HBV) infection defined as:

               -  HB s Ag positive

               -  HB s Ag negative, anti-HB s antibody positive and/or anti-HB c antibody positive
                  with detectable viral DNA

          5. Impaired renal function (MDRD formula or Cockcroft-Gault Creatinine Clearance < 30
             ml/min) or impaired liver function tests (Serum total bilirubin level > 2.0 mg/dl [34
             µmol/L] (except in case of Gilbert's Syndrome, or documented liver or pancreatic
             involvement by lymphoma), Serum transaminases (AST or ALT) > 3 upper normal limits)
             unless they are related to the lymphoma.

          6. Active malignancy other than the one treated in this research. Prior history of
             malignancies, other than low risk MDS or chronic myelomonocytic leukemia (CMML) (with
             less than 5% blasts in bone marrow), unless the patient has been free of the disease
             for ≥ 3 years. However, patients with the following history/concurrent conditions are
             allowed:

               1. Basal or squamous cell carcinoma of the skin

               2. Carcinoma in situ of the cervix

               3. Carcinoma in situ of the breast

               4. Incidental histologic finding of prostate cancer (T1a or T1b) using the
                  tumor-nodes-metastasis (TNM)] clinical staging system

          7. Treatment with any investigational drug within 5 half-lives before planned first cycle
             of study treatment and during the study. Ongoing medically significant adverse events
             from previous treatment, regardless of the time period.

          8. Prior exposure to azacitidine and/ or any other demethylating agent (eg, decitabine)

          9. Prior exposure to planned study treatment investigator's choice therapy (eg, prior
             exposure to gemcitabine is an exclusion if gemcitabine is the investigator's choice
             therapy prior to randomization)

         10. Concurrent use of corticosteroids unless the patient is on a stable or decreasing dose
             for ≥ 1 week prior to informed consent form signature

         11. Knowing or suspected hypersensitivity to active substance or to any of the excipients.

         12. Pregnant, planning to become pregnant, or lactating woman

         13. Candidate for hematopoietic stem cell transplantation

         14. History of active 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 oral azacitidine and/or predispose the
             patient to an increased risk of gastrointestinal toxicity per investigator's decision.
             Any condition causing inability to swallow tablets.

         15. Significant active cardiac disease within the previous 6 months, including:

               -  New York Heart Association (NYHA) class IV congestive heart failure

               -  Unstable angina or angina requiring surgical or medical intervention; and/or

               -  Myocardial infarction

         16. Person deprived of his/her liberty by a judicial or administrative decision

         17. Adult person under legal protection
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:18 months after first randomisation (when 18 events will occur)
Safety Issue:
Description:PFS using local assessment of progressive disease according to Lugano Response Criteria (2014)

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:40 months after first randomisation (when 57 deaths will occur) or 2 years after last randomisation
Safety Issue:
Description:
Measure:PFS by the Independent Review Committee (IRC)
Time Frame:40 months after first randomisation (when 57 deaths will occur) or 2 years after last randomisation
Safety Issue:
Description:
Measure:Overall response rate
Time Frame:40 months after first randomisation (when 57 deaths will occur) or 2 years after last randomisation
Safety Issue:
Description:Percentage of Complete Response (CR)+ Partial Response (PR) among all patients
Measure:Complete response rate (CRR)
Time Frame:40 months after first randomisation (when 57 deaths will occur) or 2 years after last randomisation
Safety Issue:
Description:Percentage of CR among all patients
Measure:Duration of response (DoR)
Time Frame:40 months after first randomisation (when 57 deaths will occur) or 2 years after last randomisation
Safety Issue:
Description:
Measure:Time to response (TtR)
Time Frame:40 months after first randomisation (when 57 deaths will occur) or 2 years after last randomisation
Safety Issue:
Description:
Measure:PFS 2 using local assessment of progressive disease
Time Frame:40 months after first randomisation (when 57 deaths will occur) or 2 years after last randomisation
Safety Issue:
Description:
Measure:Quality of Life Questionnaire (QLQ-C30)
Time Frame:2 years after last randomisation
Safety Issue:
Description:questionnaire at baseline and at least one follow-up
Measure:Number of Serious Adverse Events (SAE)
Time Frame:2 years after last randomisation
Safety Issue:
Description:Treatment discontinuation, adverse events, deaths

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:The Lymphoma Academic Research Organisation

Trial Keywords

  • oral azacitidine

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