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

Prospective, multicenter, phase II clinical trial to determine the efficacy of plitidepsin in patients with relapsed/refractory (R/R) angioimmunoblastic Tcell lymphoma (AITL).This is an international, multicenter study (with approximately 17 investigative sites).

Prospective, multicenter, phase II clinical trial to determine the efficacy of plitidepsin in patients with relapsed/refractory (R/R) AITL. The primary endpoint will be overall response rate (ORR) according to the Lugano classification response criteria per independent review.

Medical specialists (radiologists and hematologists) who are directly involved in the care of patients with AITL (but are not participating in this trial as investigators) will review all efficacy data (including radiological assessments, bone marrow biopsies) and will assign the best response and the date of objective response or progression/censoring according to their independent evaluation.

Central pathological review of each patient's original diagnosis report(s) will be required before inclusion.

Two futility analyses of the primary endpoint (ORR according to the Lugano classification criteria and per Independent Review Committee (IRC)) are planned around six months after approximately 25% and 50% of eligible patients (i.e., 15 and 30 patients respectively with AITL confirmed by central pathological review) have been treated. Two or less responders out of 15 patients or seven or less responders out of 30 patients, according to boundaries and sample size assumptions, will mean that the alternative hypothesis could be rejected, and thus recruitment might be stopped at the time of the first or second futility analysis, respectively. Otherwise, accrual will continue to 60 patients with AITL confirmed by central pathological review. This decision will be taken at the time by an Independent Data Monitoring Committee (IDMC). The IDMC, which will include specialists in peripheral T-cell lymphomas (PTCL) supported by a medical statistician, will review data provided by the Investigators, the IRC efficacy assessments and safety information and will advise whether the study should continue. Recruitment can continue during the review period.

If there are 19 or more responders of 60 patients, the efficacy of plitidepsin will be considered as clinically relevant in AITL patients.

Central pathological review will be conducted by experienced pathologists appointed by the Sponsor and available to the investigative sites for consultation about AITL diagnosis confirmation. Central pathological review is required for (a) local histopathology reports prior to patient treatment, and (b) tumor samples before each futility analysis and at the end of the study.

The central laboratory pathologists will be responsible for (a) approving patient inclusion on the basis of investigative site pathology reports provided during screening, (b) analyzing tumor biopsies (initial diagnosis and/or relapses) to confirm the AITL diagnosis, and (c) analyzing blood samples to identify plasma biomarkers and extract DNA.

Tumor samples (initial diagnosis and relapses) are required for central review to confirm AITL diagnosis but not to approve inclusion. Archived tissue samples of representative tumors must be sent for central review and biomarker analysis. If the diagnosis biopsy is not available (because the patient was diagnosed at another site, for example), the most recent representative biopsy (relapse and/or progression) will be used. Submitting both, however, is strongly recommended. Tumor blocks will be returned to the centers.

Eligibility Criteria:
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