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

Primary Purpose

Lymphoma

Status

Terminated

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

plitidepsin

About this trial

This is an interventional treatment trial for Lymphoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Voluntary written informed consent of the patient (both to participate in the study and to provide biopsy samples) obtained before any study-specific procedure.
Age ≥ 18 years.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2.
Life expectancy ≥ 3 months.
Histologically confirmed diagnosis of R/R AITL (eligibility needs to be confirmed by central pathological review).
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).
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.
Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan within normal range (according to institutional standards).

Exclusion Criteria:

Prior treatment with plitidepsin.
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.
Central nervous system (CNS) involvement.
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.
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.
Major upper gastrointestinal bleeding episode occurring during the previous year before screening.
Known hypersensitivity to any of plitidepsin's formulation components

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Plitidepsin

Arm Description

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Full Information

NCT ID

NCT03070964

First Posted

January 16, 2017

Last Updated

September 18, 2020

Sponsor

PharmaMar

1. Study Identification

Unique Protocol Identification Number

NCT03070964

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2020

Overall Recruitment Status

Terminated

Why Stopped

The main reason that motivated the study termination was the slow recruitment of the trial.

Study Start Date

October 25, 2016 (Actual)

Primary Completion Date

July 2018 (Actual)

Study Completion Date

July 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

PharmaMar

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief 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).

Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Lymphoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

14 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Plitidepsin

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

plitidepsin

Other Intervention Name(s)

APLD Aplidine

Primary Outcome Measure Information:

Title

Overall Response Rate by the Lugano Classification Per Independent Review Assessment

Description

Time Frame

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 Outcome Measure Information:

Title

Overall Response Rate by Investigator's Assessment - Per Protocol Patients Population

Description

Time Frame

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Voluntary written informed consent of the patient (both to participate in the study and to provide biopsy samples) obtained before any study-specific procedure. Age ≥ 18 years. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2. Life expectancy ≥ 3 months. Histologically confirmed diagnosis of R/R AITL (eligibility needs to be confirmed by central pathological review). 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). Adequate bone marrow (BM), renal, hepatic, and metabolic function (assessed ≤ 14 days before inclusion in the study): 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. Platelet count ≥ 75 × 109/L. Hemoglobin ≥ 9 g/dL. Patients may receive red blood cells (RBC) and/or erythropoietin (EPO) and/or platelet transfusions in accordance with institutional guidelines. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × the upper limit of normal (ULN). Total bilirubin ≤ 1.5 × ULN. Alkaline phosphatase (ALP) ≤ 3.0 × ULN (< 5 × ULN if isolated ALP increase, i.e., without ALT/AST or bilirubin increase). Calculated creatinine clearance (CrCL) ≥ 30 mL/minute (Cockcroft-Gault formula). Creatine phosphokinase (CPK) ≤ 2.5 × ULN. Albumin ≥ 2.5 g/dL. Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan within normal range (according to institutional standards). Exclusion Criteria: Prior treatment with plitidepsin. Concomitant diseases/conditions: History or presence of angina, myocardial infarction, clinically relevant valvular heart disease, uncontrolled hypertension, or congestive heart failure within the previous 12 months. 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. Active uncontrolled infection. Active hepatitis B or C virus (HBV or HCV), or human immunodeficiency virus (HIV)infection. Morphological or cytological features of myelodysplasia and/or post chemotherapy aplasia on bone marrow (BM) assessment. 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). Limitation of the patient's ability to comply with the treatment or follow-up requirements. 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. Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study. Central nervous system (CNS) involvement. 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. 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. Major upper gastrointestinal bleeding episode occurring during the previous year before screening. Known hypersensitivity to any of plitidepsin's formulation components

Facility Information:

Facility Name

Northwestern University Medical School

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60611

Country

United States

Facility Name

Fred Hutchinson Cancer Research Center

City

Seattle

State/Province

Washington

ZIP/Postal Code

98109

Country

United States

Facility Name

Faculty Hospital Ostrava

City

Ostrava

ZIP/Postal Code

708 52

Country

Czechia

Facility Name

Fakultni Nemocnice Praha

City

Praha

ZIP/Postal Code

100 34

Country

Czechia

Facility Name

Ospedale Clinico Aviano

City

Aviano

State/Province

Pordenone

ZIP/Postal Code

33081

Country

Italy

Facility Name

Instituto di Ematologia "Seragnoli"

City

Bologna

ZIP/Postal Code

40138

Country

Italy

Facility Name

Spedali Civili di Brescia

City

Brescia

ZIP/Postal Code

25123

Country

Italy

Facility Name

Azienda Ospedaliera Universitaria Careggi

City

Firenze

ZIP/Postal Code

50134

Country

Italy

Facility Name

Hospital Clínic i Provincial de Barcelona

City

Barcelona

ZIP/Postal Code

08036

Country

Spain

Facility Name

Hospital Universitari Vall d'Hebron

City

Barcelona

ZIP/Postal Code

119 - 129

Country

Spain

Facility Name

Centro Oncológico MD Anderson International España

City

Madrid

ZIP/Postal Code

28033

Country

Spain

Facility Name

Hospital Universitario 12 de Octubre

City

Madrid

ZIP/Postal Code

28041

Country

Spain

Facility Name

Hospital Universitario La Paz

City

Madrid

ZIP/Postal Code

28046

Country

Spain

Facility Name

Hospital Universitari Son Espases

City

Palma de Mallorca

ZIP/Postal Code

07010

Country

Spain

Facility Name

Hospital Universitario de Salamanca

City

Salamanca

ZIP/Postal Code

37007

Country

Spain

Facility Name

Hospital Universitario Marqués de Valdecilla

City

Santander

ZIP/Postal Code

39008

Country

Spain

Facility Name

Hospital Virgen del Rocío

City

Sevilla

ZIP/Postal Code

41013

Country

Spain

12. IPD Sharing Statement

Learn more about this trial

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

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

Lymphoma

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial