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

Lymphoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03070964
• Other study ID #: APL-B-021-13
• Status: Terminated
• Phase: Phase 2
• Start date: October 25, 2016
• Est. completion date: July 2018

Study information

• Verified date: September 2020
• Source: PharmaMar
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 14
• Est. completion date: July 2018
• Est. primary completion date: July 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, T-Cell

Intervention

Drug:
• plitidepsin

Locations

Country	Name	City	State
Czechia	Faculty Hospital Ostrava	Ostrava
Czechia	Fakultni Nemocnice Praha	Praha
Italy	Ospedale Clinico Aviano	Aviano	Pordenone
Italy	Instituto di Ematologia "Seragnoli"	Bologna
Italy	Spedali Civili di Brescia	Brescia
Italy	Azienda Ospedaliera Universitaria Careggi	Firenze
Spain	Hospital Clínic i Provincial de Barcelona	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Centro Oncológico MD Anderson International España	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitari Son Espases	Palma de Mallorca
Spain	Hospital Universitario de Salamanca	Salamanca
Spain	Hospital Universitario Marqués de Valdecilla	Santander
Spain	Hospital Virgen del Rocío	Sevilla
United States	Northwestern University Medical School	Chicago	Illinois
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
PharmaMar

Countries where clinical trial is conducted

United States,  Czechia,  Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Response Rate by the Lugano Classification Per Independent Review Assessment	The study protocol established that the analysis of the primary endpoint should have been done once a total of 60 patients have received plitidepsin, with two futility analyses planned after the inclusion of approximately 15 and 30 patients, respectively. However, only a total of 14 patients were included, of whom 13 were treated, and 12 were evaluable for the primary efficacy endpoint (ORR per IRC in the "Per Protocol Patients" population). As a result of slow patient accrual, the study was closed before reaching the target enrollment of 15 patients for the first futility analysis, and the primary endpoint (ORR according to the Lugano classification criteria and per IRC) was not assessed.	Change from Baseline to assessments at: 1/2 weeks after cycle 3 and 4-8 weeks after cycle 6 (1cycle =28days), follow-up every 4 months +/- 2 weeks until progression disease or end of study (expected: 42 months)
Secondary	Overall Response Rate by Investigator's Assessment - Per Protocol Patients Population	CI, confidence interval; CR, complete response; NE, not evaluable; ORR, overall response rate; PD, disease progression; PR, partial response; SD, stable disease.; Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.	From the date when the remission criteria are fulfilled to the first date when progressive disease, recurrence or death (due to any cause)is documented, expected at a maximum of 42 months