Lymphoma
Conditions
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.
Interventions
DRUGplitidepsin
Sponsors
PharmaMar
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate by the Lugano Classification Per Independent Review Assessment | 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) | 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
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate by Investigator's Assessment - Per Protocol Patients Population | 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 | 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. |
Countries
Czechia, Italy, Spain, United States
Participant flow
Recruitment details
The first IC was signed on 25Oct2016 and the first study treatment administration was on 9Nov2016. The cutoff date was 2Jul2018 (date of last follow-up, clinical cutoff). At cutoff date, 14 patients had been included, of whom 13 were treated and evaluable for safety, and 12 were evaluable for the primary efficacy endpoint
Participants by arm
| Arm | Count |
|---|---|
| Plitidepsin Plitidepsin was administered i.v. as a 1-hour infusion (fixed rate) via central or peripheral venous catheter. Patients received plitidepsin at a starting dose of 3.2 mg/m2 on Day 1, 8 and 15 every four weeks (q4wk). A 1-day window is allowed for plitidepsin administration. A cycle is defined as a fourweek period. A 1-day window was allowed for plitidepsin administration. | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Never treated | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Progressive disease | 8 |
| Overall Study | Treatment-unrelated adverse event | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Plitidepsin |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Age, Continuous | 61 years |
| Ann Arbor stage III | 1 Participants |
| Ann Arbor stage III-A | 3 Participants |
| Ann Arbor stage III-B | 3 Participants |
| Ann Arbor stage IV-A | 3 Participants |
| Ann Arbor stage IV-B | 4 Participants |
| Best response to last prior therapy CR | 4 Participants |
| Best response to last prior therapy PD | 3 Participants |
| Best response to last prior therapy PR | 4 Participants |
| Best response to last prior therapy SD | 1 Participants |
| Best response to last prior therapy UK | 2 Participants |
| Body Surface Area | 1.8 m^2 |
| Bulky lesion at diagnosis No | 13 Participants |
| Bulky lesion at diagnosis Yes | 1 Participants |
| ECOG PS PS 0 | 8 Participants |
| ECOG PS PS 1 | 5 Participants |
| ECOG PS PS 2 | 1 Participants |
| Extranodal disease at diagnosis No | 9 Participants |
| Extranodal disease at diagnosis Yes | 5 Participants |
| Height | 166.5 cm |
| International prognostic index score at current disease High-intermediate risk (3 risk factors) | 4 Participants |
| International prognostic index score at current disease High risk (4-5 risk factors) | 4 Participants |
| International prognostic index score at current disease Low-intermediate risk (2 risk factors) | 3 Participants |
| International prognostic index score at current disease Low risk (0-1 risk factors) | 3 Participants |
| International Prognostic Index score at diagnosis High-intermediate risk (3 risk factors) | 2 Participants |
| International Prognostic Index score at diagnosis High risk (4-5 risk factors) | 4 Participants |
| International Prognostic Index score at diagnosis Low-intermediate risk (2 risk factors) | 2 Participants |
| International Prognostic Index score at diagnosis Low risk (0-1 risk factors) | 2 Participants |
| International Prognostic Index score at diagnosis NA | 4 Participants |
| Prior anticancer therapy lines 1 line | 2 Participants |
| Prior anticancer therapy lines 2 lines | 5 Participants |
| Prior anticancer therapy lines 3 lines | 5 Participants |
| Prior anticancer therapy lines 4 lines | 1 Participants |
| Prior anticancer therapy lines 5 lines | 1 Participants |
| Prior anticancer therapy lines | 2.5 therapy lines |
| Prior stem cell transplantation Allogenic stem cell transplantation | 1 Participants |
| Prior stem cell transplantation Autologous stem cell transplantation | 5 Participants |
| Prior stem cell transplantation NO | 8 Participants |
| Prognostic index for angioimmunoblastic T-cell lymphoma score at current disease High-risk group | 4 Participants |
| Prognostic index for angioimmunoblastic T-cell lymphoma score at current disease Low-risk group | 5 Participants |
| Prognostic index for angioimmunoblastic T-cell lymphoma score at current disease NA | 5 Participants |
| Prognostic index for angioimmunoblastic T-cell lymphoma score at diagnosis High-risk group | 3 Participants |
| Prognostic index for angioimmunoblastic T-cell lymphoma score at diagnosis Low-risk group | 3 Participants |
| Prognostic index for angioimmunoblastic T-cell lymphoma score at diagnosis NA | 8 Participants |
| Prognostic index for peripheral T-cell lymphoma at current disease Group 1 (no adverse factors) | 2 Participants |
| Prognostic index for peripheral T-cell lymphoma at current disease Group 2 (1 risk factor) | 3 Participants |
| Prognostic index for peripheral T-cell lymphoma at current disease Group 3 (2 risk factors) | 1 Participants |
| Prognostic index for peripheral T-cell lymphoma at current disease Group 4 (3-4 risk factors) | 1 Participants |
| Prognostic index for peripheral T-cell lymphoma at current disease NA | 7 Participants |
| Prognostic index for peripheral T-cell lymphoma at diagnosis Group 1 (no adverse factors) | 1 Participants |
| Prognostic index for peripheral T-cell lymphoma at diagnosis Group 2 (1 risk factor) | 1 Participants |
| Prognostic index for peripheral T-cell lymphoma at diagnosis Group 4 (3-4 risk factors) | 2 Participants |
| Prognostic index for peripheral T-cell lymphoma at diagnosis NA | 10 Participants |
| Race/Ethnicity, Customized Hispanolatin | 1 Participants |
| Race/Ethnicity, Customized White | 13 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 8 Participants |
| Time from diagnosis to first plitidepsin infusion | 24.1 months |
| Time from last progressive disease to infusion | 6.9 weeks |
| Time to progressions to last anticancer therapy | 4.6 months |
| Weight | 72.5 Kg |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 13 |
| other Total, other adverse events | 13 / 13 |
| serious Total, serious adverse events | 9 / 13 |
Outcome results
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.
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)
Population: Justification: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Plitidepsin | Overall Response Rate by the Lugano Classification Per Independent Review Assessment | NA Participants |
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.
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
Population: A patient was never treated with plitidepsin. A patient due to lack of AITL diagnosis confirmation
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Plitidepsin | Overall Response Rate by Investigator's Assessment - Per Protocol Patients Population | CR | 1 Participants |
| Plitidepsin | Overall Response Rate by Investigator's Assessment - Per Protocol Patients Population | PR | 1 Participants |
| Plitidepsin | Overall Response Rate by Investigator's Assessment - Per Protocol Patients Population | SD | 1 Participants |
| Plitidepsin | Overall Response Rate by Investigator's Assessment - Per Protocol Patients Population | PD | 7 Participants |
| Plitidepsin | Overall Response Rate by Investigator's Assessment - Per Protocol Patients Population | NE | 2 Participants |
95% CI: [2.1, 48.4]