Clinical Trials /

Efficacy and Safety of Oral Azacitidine (CC-486) Compared to Investigator's Choice Therapy in Patients With Relapsed or Refractory Angioimmunoblastic T Cell Lymphoma

NCT03703375

Description:

This study is a multicentric, open-label, randomized phase 3 trial. The study will be conducted in select countries in Europe and South Korea sponsored by LYSARC and in Japan sponsored by Celgene. There will be a combined enrollment target of 86 randomized patients, with approximately 14 randomized patients from Japan. The enrollment to the randomized study will start at European sites in parallel to a safety run-in part in Japan. A safety run-in will be conducted to confirm the tolerability of oral azacitidine at doses of 100 mg and 200 mg QD in Asian patients. Once oral azacitidine at 200 mg QD is confirmed as tolerable, Asian patients from Japan and South Korea will start to be randomized into the main study. Additional patients (non-randomized) are anticipated to enroll to the safety run-in.

Related Conditions:
  • Angioimmunoblastic T-Cell Lymphoma
  • Follicular T-Cell Lymphoma
  • Peripheral T-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: OA-CL-LYM-LYSARC-13134C
  • SECONDARY ID: U1111-1220-8294
  • SECONDARY ID: 2017-003909-17
  • NCT ID: NCT03703375

Conditions

  • Lymphoma, T-Cell

Interventions

DrugSynonymsArms
AzacitidineCC-486Administration of Oral Azacitidine (CC-486)
RomidepsinInvestigator's choice therapy - Romidepsin
GemcitabineInvestigator's choice therapy - Gemcitabine

Purpose

This study is a multicentric, open-label, randomized phase 3 trial. The study will be conducted in select countries in Europe and South Korea sponsored by LYSARC and in Japan sponsored by Celgene. There will be a combined enrollment target of 86 randomized patients, with approximately 14 randomized patients from Japan. The enrollment to the randomized study will start at European sites in parallel to a safety run-in part in Japan. A safety run-in will be conducted to confirm the tolerability of oral azacitidine at doses of 100 mg and 200 mg QD in Asian patients. Once oral azacitidine at 200 mg QD is confirmed as tolerable, Asian patients from Japan and South Korea will start to be randomized into the main study. Additional patients (non-randomized) are anticipated to enroll to the safety run-in.

Trial Arms

NameTypeDescriptionInterventions
Administration of Oral Azacitidine (CC-486)ExperimentalOral azacytidine 300 mg during 14 first days of 28-days cycle for European (EU) patients, Oral azacytidine 200 mg during 14 first days of 28-days cycle for Asian patients (Treatment until progression, patient decision or toxicity)
  • Azacitidine
Investigator's choice therapy - RomidepsinActive ComparatorRomidepsin 14mg/m2 on days 1, 8 and 15 of a 28-days cycle (Treatment until progression, patient decision or toxicity)
  • Romidepsin
Investigator's choice therapy - GemcitabineActive ComparatorGemcitabine 1000mg/m2 on days 1, 8 and 15 of a 28-days cycle (during 6 cycles)
  • Gemcitabine

Eligibility Criteria

        Inclusion Criteria:

          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 WHO classification based on a
             surgical lymph node biopsy or needle core 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. 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:

               -  ANC ≥ 1,5 x 109/L (≥ 1 x 109/L if 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 6
             months 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, symptomthermal, 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 6
             months 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 IP
             (cycle 1 Day 1), including dose interruptions through 6 months 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:

          1. Clinical evidence of central nervous system(CNS) involvement by lymphoma. Patients
             with suspicion of 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 Virus (HBV) infection defined as:

               -  HBs Ag positive

               -  HBs Ag negative, anti-HBs antibody positive and/or anti-HBc antibody positive
                  with detectable viral DNA

          5. Impaired renal function (calculated MDRD 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 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 randomization
Safety Issue:
Description:Is the time from randomization into the study to the first observation of documented disease progression or death due to any cause.

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:40 months after first randomization
Safety Issue:
Description:Is the time from the date of randomization to the date of death from any cause. Alive patients will be censored at their last contact.
Measure:Progression Free Survival (PFS) by Independent Review Committee (IRC)
Time Frame:40 months after first randomization
Safety Issue:
Description:Is the time from randomization into the study to the first observation of documented disease progression or death due to any cause.
Measure:Overall Response Rate (ORR)
Time Frame:40 months after first randomization
Safety Issue:
Description:Is the percentage of Complete Response (CR) + Partial Response (PR) among all patients.
Measure:Complete Response Rate (CRR)
Time Frame:40 months after first randomization
Safety Issue:
Description:Is the percentage of Complete Response (CR) among all patients.
Measure:Duration of Response
Time Frame:40 months after first randomization
Safety Issue:
Description:Is the time from attainment of CR or PR to the date of first documented disease progression, relapse (local assessment) or death from any cause.
Measure:Time to Response
Time Frame:40 months after first randomization
Safety Issue:
Description:Is the time from randomization to the date of attainment of CR or PR until end of treatment.
Measure:PFS2 using local assessment of progressive disease
Time Frame:40 months after first randomization
Safety Issue:
Description:Is the time from randomization to objective tumor progression on next-line treatment or death from any cause.
Measure:EORTC QLQ-C30
Time Frame:2 years after last randomization
Safety Issue:
Description:The QLQC30 is composed of both multi-item scales and single item measures. These include five functional scales (physical, role, emotional, cognitive and social), three symptom scales (fatigue, nausea/vomiting, and pain), a global health status/QOL scale, and six single items (dyspnoea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties).
Measure:Adverse Events (AEs)
Time Frame:2 years after last randomization
Safety Issue:
Description:Number of subjects with Adverse Event

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Celgene

Trial Keywords

  • CC-486
  • Azacitidine
  • Angioimmunoblastic
  • T Cell Lymphoma
  • Lymphoma

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