A Study of Plitidepsin in Patients With Relapsed or Refractory Angioimmunoblastic T-cell Lymphoma

Inclusion Criteria:

1. Voluntary written informed consent of the patient (both to participate in the study and to provide biopsy samples) obtained before any study-specific procedure.
2. Age ≥ 18 years.
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2.
4. Life expectancy ≥ 3 months.
5. Histologically confirmed diagnosis of R/R AITL (eligibility needs to be confirmed by central pathological review).
6. At least a two-week washout period since the end of the last therapy (six weeks for a prior nitrosourea-containing regimen), recovery to grade ≤ 1 from any non-hematological adverse event (AE) derived from previous treatment (excluding alopecia).
7. Adequate bone marrow (BM), renal, hepatic, and metabolic function (assessed ≤ 14 days before inclusion in the study):

   1. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L. Screening of ANC should be independent of granulocytecolony stimulating factor (G-CSF) support for at least one week and of pegylated G-CSF for at least two weeks.
   2. Platelet count ≥ 75 × 109/L.
   3. Hemoglobin ≥ 9 g/dL. Patients may receive red blood cells (RBC) and/or erythropoietin (EPO) and/or platelet transfusions in accordance with institutional guidelines.
   4. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × the upper limit of normal (ULN).
   5. Total bilirubin ≤ 1.5 × ULN.
   6. Alkaline phosphatase (ALP) ≤ 3.0 × ULN (\< 5 × ULN if isolated ALP increase, i.e., without ALT/AST or bilirubin increase).
   7. Calculated creatinine clearance (CrCL) ≥ 30 mL/minute (Cockcroft-Gault formula).
   8. Creatine phosphokinase (CPK) ≤ 2.5 × ULN.
   9. Albumin ≥ 2.5 g/dL.
8. Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan within normal range (according to institutional standards).

Exclusion Criteria:

1. Prior treatment with plitidepsin.
2. Concomitant diseases/conditions:

   1. History or presence of angina, myocardial infarction, clinically relevant valvular heart disease, uncontrolled hypertension, or congestive heart failure within the previous 12 months.
   2. Symptomatic arrhythmia (excluding grade ≤ 2 anemia-related sinusal tachycardia) or any arrhythmia requiring ongoing treatment, and/or prolonged grade ≥ 2 QT-QTc, or presence of unstable atrial fibrillation. Patients with stable atrial fibrillation on treatment are allowed provided they do not meet any other cardiac or prohibited drug exclusion criterion.
   3. Active uncontrolled infection. Active hepatitis B or C virus (HBV or HCV), or human immunodeficiency virus (HIV)infection.
   4. Morphological or cytological features of myelodysplasia and/or post chemotherapy aplasia on bone marrow (BM) assessment.
   5. Myopathy \> grade 2 or any clinical situation that causes significant and persistent elevation of CPK (\> 2.5 × ULN in two different determinations performed one week apart).
   6. Limitation of the patient's ability to comply with the treatment or follow-up requirements.
   7. Diagnosis of another invasive malignancy unless free of disease for at least three years following therapy with curative intent. Patients with early-stage basal cell or squamous cell skin cancer, cervical intraepithelial neoplasia, cervical carcinoma in situ, or superficial bladder cancer, may be eligible to participate at the Investigator's discretion.
   8. Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study.
3. Central nervous system (CNS) involvement.
4. Women who are pregnant or breast feeding. Fertile patients (men and women) who are not using an effective method of contraception. All patients (men and women) must agree to use an effective contraceptive measure (if applicable) up to six months after treatment discontinuation.
5. Concomitant medications that include corticosteroids, chemotherapy, or other therapy that is or may be active against AITL, within the two weeks prior to treatment start. Concurrent corticosteroids are allowed, provided they are administered at an equivalent prednisone dose of ≤ 10 mg daily, as premedication for blood products only.
6. Major upper gastrointestinal bleeding episode occurring during the previous year before screening.
7. Known hypersensitivity to any of plitidepsin's formulation components