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.
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
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
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
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
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
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