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

Randomized Phase 3 Study Evaluation 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

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.

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