Myelofibrosis
Conditions
Keywords
Aplidin, Plitidepsin, Myelofibrosis, Pharma Mar
Brief summary
This is an open-label, Phase II Clinical Trial of Aplidin® (plitidepsin) in Patients with Primary Myelofibrosis and post polycythemia vera/essential thrombocythemia (Post-PV/ET) Myelofibrosis.
Detailed description
This trial tries to assess response rate (ORR) of plitidepsin in patients with: primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), or post-essential thrombocythemia myelofibrosis (post-ET MF). Besides, the study results will allow to evaluate the effect of plitidepsin on bone marrow (BM) or peripheral blood histology and to determine the quality of life (QoL) and symptoms or participant patients.
Interventions
Aplidin® (plitidepsin) lyophilized powder and solvent for concentrate for solution for infusion. (2 mg plitidepsin vial and 4 ml ampoule). Plitidepsin will be administered at 5 mg/m2 intravenously diluted to a total volume of 250 ml in 0.9% saline or 5% dextrose solution on Day 1 and 15 every four weeks for a maximum period of 6 cycles.
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. Diagnosis of Primary Myelofibrosis (PMF) or Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis(post-ET/PV MF) as per revised World Health Organization (WHO) criteria. 2. High-risk or intermediate-2 risk Myelofibrosis (MF) as defined by the International Prognostic Scoring System (IPSS); or intermediate-I risk MF associated with symptomatic splenomegaly/hepatomegaly and/or unresponsive to available therapy. 3. At least 18 years of age, with life expectancy of ≥12 weeks. 4. Able to provide informed consent and being willing to sign an informed consent form (ICF). 5. Eastern Cooperative Oncology Group (ECOG) performance status ≤2. 6. Evidence of acceptable organ function within seven days of initiating study drug
Exclusion criteria
1. Previous treatment with plitidepsin. 2. Any of the following therapies within two weeks prior to initiation of study drug: * chemotherapy (e.g., hydroxyurea), * immunomodulatory drug therapy (e.g., thalidomide), * immunosuppressive therapy, * corticosteroids \>10 mg/day prednisone or equivalent, or * erythropoietin. 3. Incomplete recovery from major surgery within four weeks of study entry. 4. Radiation therapy within four weeks of study entry. 5. Women of childbearing potential 6. Women who are pregnant or are currently breastfeeding. 7. Myopathy grade \> 2 8. Known positive status for human immunodeficiency virus (HIV). 9. Active hepatitis B or C virus (HBV or HCV) infection 10. Diagnosis of another invasive malignancy 11. Any acute active infection. 12. Known hypersensitivity to the study drug or any of its formulation components (e.g., Cremophor®). 13. Treatment with any investigational product in the 30 days before inclusion in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | All patients were followed up to progressive disease, start of a new anti-cancer therapy, death or one year after the last treatment visit of the last patient, whichever occured first | Objective response rate (ORR) of plitidepsin in patients with: primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis. ORR according to the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) response criteria (Tefferi et al., 2006) in the evaluable population: defined as a confirmed disease response, on two consecutive evaluations performed at least eight weeks apart. Overall response (OR) = Complete Response (CR) + Partial response (PR) + Clinical improvement (CI). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Quality of Life (QoL) | All patients were followed up to progressive disease, start of a new anti-cancer therapy, death or one year after the last treatment visit of the last patient, whichever occured first | Quality of life (QoL) and symptoms assessment according to the Myelofibrosis Symptom Assessment Form (MFSAF), after treatment with plitidepsin. For full details please refer to Mesa RA, Schwager S, Radia D, Cheville A, Hussein K, Niblack J, et al. The Myelofibrosis Symptom Assessment Form (MFSAF): an evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis. Leuk Res 2009;33(9):1199-203. Scale measures: 0 to 10 (0 if absent) ranking being 1 the most favorable and 10 least favorable. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | All patients were followed up to progressive disease or death, whichever occured first, up to 30 days after their last dose | Progression free survival (PFS) is defined as the time from start of treatment to the date of documented progressive disease (PD) by IWG-MRT criteria or death (regardless of the cause of death), whichever comes first. Patients who progress or die will be considered to have had an event, except if this event occurs after the start of subsequent antitumor therapy, in which case the patient will be censored at the time of last disease assessment prior to or on the first day of the first subsequent antitumor therapy. If the patient is lost for the assessment of progression during the follow-up period, or has more than one missing follow-up between the date of last tumor assessment and the date of progression, death or further antitumor therapy, the PFS will be censored at the date of last valid disease assessment before the missing evaluations. |
Countries
Italy, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Aplidin® APLIDIN (plitidepsin): Aplidin® (plitidepsin) lyophilized powder and solvent for concentrate for solution for infusion. (2 mg plitidepsin vial and 4 ml ampoule).
Plitidepsin will be administered at 5 mg/m2 intravenously diluted to a total volume of 250 ml in 0.9% saline or 5% dextrose solution on Day 1 and 15 every four weeks for a maximum period of 6 cycles. | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | adverse events nonrelated study drug | 2 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Progressive disease | 1 |
| Overall Study | Withdrawal by Subject | 7 |
Baseline characteristics
| Characteristic | Aplidin® |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 9 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Region of Enrollment Italy | 2 participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 12 |
| other Total, other adverse events | 12 / 12 |
| serious Total, serious adverse events | 5 / 12 |
Outcome results
Primary
Objective Response Rate (ORR)
Objective response rate (ORR) of plitidepsin in patients with: primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis. ORR according to the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) response criteria (Tefferi et al., 2006) in the evaluable population: defined as a confirmed disease response, on two consecutive evaluations performed at least eight weeks apart. Overall response (OR) = Complete Response (CR) + Partial response (PR) + Clinical improvement (CI).
Time frame: All patients were followed up to progressive disease, start of a new anti-cancer therapy, death or one year after the last treatment visit of the last patient, whichever occured first
Population: 1 of the 12 patients treated was excluded. This patient received 1 complete infusion of plitidepsin in Cycle 1, and had the second infusion interrupted due to plitidepsin-related grade 3 chest and epigastric pain (reported as SAEs). Although the episode resolved a day later, she refused to continue treatment and had no disease evaluations done
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm One | Objective Response Rate (ORR) | Clinical improvement | 1 Participants |
| Arm One | Objective Response Rate (ORR) | Stable disease | 9 Participants |
| Arm One | Objective Response Rate (ORR) | Progressive disease | 1 Participants |
Secondary
Quality of Life (QoL)
Quality of life (QoL) and symptoms assessment according to the Myelofibrosis Symptom Assessment Form (MFSAF), after treatment with plitidepsin. For full details please refer to Mesa RA, Schwager S, Radia D, Cheville A, Hussein K, Niblack J, et al. The Myelofibrosis Symptom Assessment Form (MFSAF): an evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis. Leuk Res 2009;33(9):1199-203. Scale measures: 0 to 10 (0 if absent) ranking being 1 the most favorable and 10 least favorable.
Time frame: All patients were followed up to progressive disease, start of a new anti-cancer therapy, death or one year after the last treatment visit of the last patient, whichever occured first
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Arm One | Quality of Life (QoL) | Overall quality of life - Baseline | 5.7 score on a scale |
| Arm One | Quality of Life (QoL) | Overall quality of life - Cycle 1 | 5.0 score on a scale |
| Arm One | Quality of Life (QoL) | Overall quality of life - Cycle 2 | 5.4 score on a scale |
| Arm One | Quality of Life (QoL) | Overall quality of life - Cycle 3 | 6.3 score on a scale |
| Arm One | Quality of Life (QoL) | Overall quality of life - Cycle 4 | 7.5 score on a scale |
p-value: 0.2364Repeated measures analysis
Other Pre-specified
Progression-free Survival (PFS)
Progression free survival (PFS) is defined as the time from start of treatment to the date of documented progressive disease (PD) by IWG-MRT criteria or death (regardless of the cause of death), whichever comes first. Patients who progress or die will be considered to have had an event, except if this event occurs after the start of subsequent antitumor therapy, in which case the patient will be censored at the time of last disease assessment prior to or on the first day of the first subsequent antitumor therapy. If the patient is lost for the assessment of progression during the follow-up period, or has more than one missing follow-up between the date of last tumor assessment and the date of progression, death or further antitumor therapy, the PFS will be censored at the date of last valid disease assessment before the missing evaluations.
Time frame: All patients were followed up to progressive disease or death, whichever occured first, up to 30 days after their last dose
Population: 1 of the 12 patients treated was excluded. This patient received 1 complete infusion of plitidepsin in Cycle 1, and had the second infusion interrupted due to plitidepsin-related grade 3 chest and epigastric pain (reported as SAEs). Although the episode resolved a day later, she refused to continue treatment and had no disease evaluations done
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm One | Progression-free Survival (PFS) | 4.6 months |