| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory Angioimmunoblastic T cell Lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| A rare type of non-hodgkin lymphoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10002449 |
| E.1.2 | Term | Angioimmunoblastic T-cell lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10002449 |
| E.1.2 | Term | Angioimmunoblastic T-cell lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To find out if treating patients with relapsed or refractory angioimmunoblastic T cell Lymphoma (AITL) with oral azacitidine gives them a longer time before their disease worsens than treating with the current Standard of Care (SoC) treatments. To do this, azacitidine will be compared to the Investigator’s Choice of Treatment (bedamustine or gemcitabine). |
|
| E.2.2 | Secondary objectives of the trial |
To find out if treating patients with relapsed or refractory angioimmunoblastic T cell Lymphoma (AITL) with oral azacitidine gives them a longer survival time than treating with the current Standard of Care (SoC) treatments. To do this, azacitidine will be compared to the Investigator’s Choice of Treatment (bedamustine or gemcitabine).
Other secondary research questions are about how well the disease responds to treatment and how long it takes for this to happen, how many participants have a complete response/remission, how long the response lasts, quality of life for participants, and the safety of the drug. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is ≥ 18 years of age at the time of signing the informed consent form
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 including any one of:
• Angioimmunoblastic T cell lymphoma (AITL)
• Follicular T cell lymphoma
• Nodal peripheral T-cell lymphoma with TFH phenotype
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:
a. ANC ≥ 1,5 x 109/L (≥ 1 x 109/L if BM involvement by lymphoma)
b. Platelet ≥ 75 x 109/L (≥ 50 x 109/L if BM involvement by lymphoma)
c. 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:
a. Have two negative pregnancy tests as verified by the investigator prior to starting study treatment
b. Agrees to practice true abstinence or agree to the use of highly effective methods of contraception from 28 days prior to study treatment
11. Male patients must either practice true abstinence from heterosexual contact or agree to avoid fathering a child, to use highly effective methods of contraception
12. For EU countries, patient covered by a social security system |
|
| E.4 | Principal exclusion criteria |
1. Clinical evidence of central nervous system 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 (HCV) infection, or evidence of positive HTLV1 serology orof 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 myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) at Screening (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:
a. Basal or squamous cell carcinoma of the skin
b. Carcinoma in situ of the cervix
c. Carcinoma in situ of the breast
d. Incidental histologic finding of prostate cancer (T1a or T1b) using the tumor, nodes, metastasis [TNM] clinical staging system
e. Early-stage gastric cancer suitable for endoscopic mucosal resection or endoscopic submucosal dissection
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 investigator’s choice therapy (eg, prior exposure to
gemcitabine is an exclusion if gemcitabine is the planned 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 investigators’ discretion. 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. Patient deprived of his/her liberty by a judicial or administrative decision
17. Adult patient under legal protection |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival (PFS), using local assessment of progressive disease according to Lugano Response Criteria (2014). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Within one week before start of cycle 4 (all treatments), within one week before start of cycle 7 (oral azacitidine only), every 12 weeks in year 1 and 2, and every 24 weeks in year 3. |
|
| E.5.2 | Secondary end point(s) |
Key Secondary endpoint:
- Overall Survival (OS)
Other Secondary endpoints:
- PFS by the Independent Review Committee
- Overall response rate (ORR)
- Complete response rate (CRR)
- Duration of response
- Time to response
- PFS using local assessment of progressive disease
- Health related quality of life (HRQOL) endpoints EORTC QLQ-C30
- Safety |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of study will either be when 57 deaths have occurred (approximately 38.5 months after the first randomised patient) or two years after the last randomised patient. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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