Peripheral T-Cell Lymphoma (PTCL) is a rare and heterogeneous group of non-Hodgkin lymphoma
(NHL) originating from mature (or post-thymic or 'peripheral') T- lymphocytes and NK cells.
They are considered very aggressive and are often resistant to conventional chemotherapy.
This study employs a stratified randomization with equal allocation within strata of patients
to receive oral 5-azacytidine (AZA) plus romidepsin (ROMI) versus pre-specified investigator
choice (ROMI, belinostat, pralatrexate or gemcitabine), for the treatment of relapsed or
refractory (R/R) PTCL. The dose and schedule of AZA/ROMI has been determined from a phase I
clinical trial of the combination. The primary objective of this study is to estimate the
progression free survival (PFS) among patients receiving the combination compared to single
agent of choice.
In order to be eligible to participate in this study, an individual must meet all of the
1. Patients must have histologically confirmed relapsed or refractory peripheral T-cell
lymphoma as defined by 2016 WHO criteria (Section 13.7), who have progressed following
one line of prior systemic therapy. PTCL histologies include:
- Adult T-cell leukemia/lymphoma;
- Extranodal NK-/T-cell lymphoma, nasal type;
- Enteropathy-associated T-cell lymphoma;
- Monomorphic epitheliotropic intestinal T-cell lymphoma;
- Hepatosplenic T-cell lymphoma;
- Subcutaneous panniculitis-like T-cell lymphoma;
- Primary cutaneous anaplastic large cell lymphoma;
- Primary cutaneous T-cell lymphoma;
- Primary cutaneous CD8+ T-cell lymphoma;
- Transformed mycosis fungoides;
- Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder;
- Peripheral T-cell lymphoma, NOS;
- Angioimmunoblastic T-cell lymphoma;
- Follicular T-cell lymphoma;
- Nodal peripheral T-cell lymphoma with TFH phenotype;
- Anaplastic large-cell lymphoma ALK+; anaplastic large-cell lymphoma ALK- ; Breast
implant-associated anaplastic large-cell lymphoma.
2. Patients are required to have no more than 3 lines of prior therapy (with
cytoreductive therapy [ex ICE, DHAP, etc.] followed by autologous stem cell transplant
counting as one line of therapy). Patients are eligible if they have relapsed after
prior autologous or allogeneic stem cell transplant.
3. Patients with anaplastic large cell lymphoma are required to have received brentuximab
vedotin (Bv) prior to study enrollment.
4. Measurable Disease as defined in Section 188.8.131.52.
5. Age ≥18 years.
6. ECOG performance status ≤2
7. Patients must have adequate organ and marrow function as defined below:
Absolute neutrophil count (ANC): ≥1000/mm3 (≥1000/dL); Platelets: > 75,000/mm3; Serum
Creatinine:< 2 x ULN OR creatinine clearance >50 mL/min/for patients with creatinine
levels above ULN; Bilirubin: ≤ 1.5 x ULN (except in patients with Gilbert's disease,
where bilirubin to 4x ULN is allowed); AST and ALT: ≤ 2 x ULN OR ≤ 3 X ULN in presence
of demonstrable liver involvement; Serum potassium: ≥ 3.8 mmol/L; Serum magnesium≥1.8
8. Negative urine or serum pregnancy test for females of childbearing potential
9. All females of childbearing potential and male subjects must agree to use an effective
method of contraception (see section 5.4 for more details)
10. Ability to understand and the willingness to sign a written informed consent document.
An individual who meets any of the following criteria will be excluded from participation
in this study:
1. Prior Therapy: Prior exposure to any hypomethylating agent or any histone deacetylase
inhibitor (ex: romidepsin, chidamide, belinostat, or vorinostat); exposure to
chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who
have not recovered from adverse events due to agents administered more than 2 weeks
2. Systemic steroids that have not been stabilized to the equivalent of ≤10 mg/day
prednisone prior to the start of the study drugs.
3. No other concurrent investigational agents are allowed within 2 weeks of enrollment.
4. Known central nervous system metastases, including lymphomatous meningitis
5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
6. Nursing women
7. Other active concurrent malignancy (except non-melanoma skin cancer, carcinoma in situ
of the cervix, or carcinoma in situ of the breast (DCIS or LCIS). If there is a
history of prior malignancy, the patient must be disease-free for ≥ 3-years. Patients
whose lymphoma has transformed from a less aggressive histology remain eligible.
8. Patients known to be Human Immunodeficiency Virus (HIV)-positive.
9. Patients with active Hepatitis A, hepatitis B, or hepatitis C infection.
10. Concomitant use of CYP3A4 inhibitors (see Section 13.3)
11. History of 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 study drug and/or predispose the subject
to an increased risk of gastrointestinal toxicity
12. Abnormal coagulation parameters (PT >15 seconds, PTT>40 seconds, and/or INR >1.5)
13. Known or suspected hypersensitivity to azacitidine or mannitol
14. Any known cardiac abnormalities such as:
- Congenital long QT syndrome
- QTc interval ≥ 500 millisecond (using the Fridericia formula)
- Patients taking drugs leading to significant QT prolongation (See Section 13.2)
- Myocardial infarction within 6 months of C1D1. [Subjects with a history of
myocardial infarction between 6 and 12 months prior to C1D1 who are asymptomatic
and have had a negative cardiac risk assessment (treadmill stress test, nuclear
medicine stress test, or stress echocardiogram) since the event, may
- Other significant ECG abnormalities including 2nd degree atrio-ventricular (AV)
block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50
- Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II-IV (see
Section 13.4) In any patient in whom there is doubt, the patient should have a
stress imaging study and, if abnormal, angiography to define whether or not CAD
- An ECG recorded at screening showing evidence of cardiac ischemia (ST depression
of ≥2 mm, measured from isoelectric line to the ST segment). If in any doubt, the
patient should have a stress imaging study and, if abnormal, angiography to
define whether or not CAD is present;
- Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class
II to IV definitions (see Section 13.5) and/or ejection fraction <40% by MUGA
scan or <50% by echocardiogram and/or MRI;
- A known history of sustained ventricular tachycardia (VT), ventricular
fibrillation (VF), Torsade de Pointes, or cardiac arrest;
- Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or
- Uncontrolled hypertension, i.e., blood pressure (BP) of ≥160/95; patients who
have a history of hypertension controlled by medication must be on a stable dose
(for at least one month) and meet all other inclusion criteria; or
- Any cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable
doses of beta-blockers)