Clinical Trial of Aplidin® in Patients With Primary Myelofibrosis
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2 |
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Arm one
|
Drug: 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.
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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 Outcome Measures
- 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.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Diagnosis of Primary Myelofibrosis (PMF) or Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis(post-ET/PV MF) as per revised World Health Organization (WHO) criteria.
-
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.
-
At least 18 years of age, with life expectancy of ≥12 weeks.
-
Able to provide informed consent and being willing to sign an informed consent form (ICF).
-
Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
-
Evidence of acceptable organ function within seven days of initiating study drug
Exclusion Criteria:
-
Previous treatment with plitidepsin.
-
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.
-
Incomplete recovery from major surgery within four weeks of study entry.
-
Radiation therapy within four weeks of study entry.
-
Women of childbearing potential
-
Women who are pregnant or are currently breastfeeding.
-
Myopathy grade > 2
-
Known positive status for human immunodeficiency virus (HIV).
-
Active hepatitis B or C virus (HBV or HCV) infection
-
Diagnosis of another invasive malignancy
-
Any acute active infection.
-
Known hypersensitivity to the study drug or any of its formulation components (e.g., Cremophor®).
-
Treatment with any investigational product in the 30 days before inclusion in the study.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Mayo Clinic | Rochester | Minnesota | United States | 55905 |
2 | Azienda Ospedaliero Universitaria Careggi di Firenze | Firenze | Italy | 50134 |
Sponsors and Collaborators
- PharmaMar
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- APL-B-020-10
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail |
Arm/Group Title | Aplidin® |
---|---|
Arm/Group Description | 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. |
Period Title: Overall Study | |
STARTED | 12 |
COMPLETED | 0 |
NOT COMPLETED | 12 |
Baseline Characteristics
Arm/Group Title | Aplidin® |
---|---|
Arm/Group Description | 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. |
Overall Participants | 12 |
Age (Count of Participants) | |
<=18 years |
0
0%
|
Between 18 and 65 years |
3
25%
|
>=65 years |
9
75%
|
Sex: Female, Male (Count of Participants) | |
Female |
7
58.3%
|
Male |
5
41.7%
|
Region of Enrollment (participants) [Number] | |
United States |
10
83.3%
|
Italy |
2
16.7%
|
Outcome Measures
Title | Objective Response Rate (ORR) |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
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/Group Title | Arm One |
---|---|
Arm/Group Description | 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. |
Measure Participants | 11 |
Clinical improvement |
1
8.3%
|
Stable disease |
9
75%
|
Progressive disease |
1
8.3%
|
Title | Quality of Life (QoL) |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Aplidin® |
---|---|
Arm/Group Description | 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. |
Measure Participants | 12 |
Overall quality of life - Baseline |
5.7
|
Overall quality of life - Cycle 1 |
5.0
|
Overall quality of life - Cycle 2 |
5.4
|
Overall quality of life - Cycle 3 |
6.3
|
Overall quality of life - Cycle 4 |
7.5
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Arm One |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.2364 |
Comments | ||
Method | Repeated measures analysis | |
Comments |
Title | Progression-free Survival (PFS) |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
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/Group Title | Aplidin® |
---|---|
Arm/Group Description | 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. |
Measure Participants | 11 |
Median (95% Confidence Interval) [months] |
4.6
|
Adverse Events
Time Frame | ||
---|---|---|
Adverse Event Reporting Description | ||
Arm/Group Title | Aplidin® | |
Arm/Group Description | 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. | |
All Cause Mortality |
||
Aplidin® | ||
Affected / at Risk (%) | # Events | |
Total | 0/12 (0%) | |
Serious Adverse Events |
||
Aplidin® | ||
Affected / at Risk (%) | # Events | |
Total | 5/12 (41.7%) | |
Blood and lymphatic system disorders | ||
Anaemia | 1/12 (8.3%) | |
Cardiac disorders | ||
Acute myocardial infarction | 1/12 (8.3%) | |
Gastrointestinal disorders | ||
Abdominal pain upper | 1/12 (8.3%) | |
Gastrointestinal haemorrhage | 2/12 (16.7%) | |
Oesophageal varices haemorrhage | 1/12 (8.3%) | |
General disorders | ||
Chest pain | 1/12 (8.3%) | |
Infections and infestations | ||
Bronchopneumonia | 1/12 (8.3%) | |
Respiratory, thoracic and mediastinal disorders | ||
Pulmonary oedema | 1/12 (8.3%) | |
Vascular disorders | ||
Deep vein thrombosis | 1/12 (8.3%) | |
Other (Not Including Serious) Adverse Events |
||
Aplidin® | ||
Affected / at Risk (%) | # Events | |
Total | 12/12 (100%) | |
Blood and lymphatic system disorders | ||
Anaemia | 1/12 (8.3%) | |
Neutropenia | 1/12 (8.3%) | |
Thrombocytopenia | 1/12 (8.3%) | |
Cardiac disorders | ||
Aortic valve disease | 1/12 (8.3%) | |
Mitral valve incompetence | 1/12 (8.3%) | |
Palpitations | 1/12 (8.3%) | |
Sinus arrhythmia | 1/12 (8.3%) | |
Sinus bradycardia | 1/12 (8.3%) | |
Sinus tachycardia | 1/12 (8.3%) | |
Eye disorders | ||
Ocular hyperaemia | 1/12 (8.3%) | |
Gastrointestinal disorders | ||
Abdominal pain | 8/12 (66.7%) | |
Diarrhoea | 5/12 (41.7%) | |
Faeces discoloured | 1/12 (8.3%) | |
Nausea | 10/12 (83.3%) | |
Vomiting | 5/12 (41.7%) | |
General disorders | ||
Early satiety | 8/12 (66.7%) | |
Fatigue | 12/12 (100%) | |
Infusion related reaction | 1/12 (8.3%) | |
Oedema | 3/12 (25%) | |
Oedema peripheral | 1/12 (8.3%) | |
Pyrexia | 2/12 (16.7%) | |
Infections and infestations | ||
Bronchitis | 1/12 (8.3%) | |
Cellulitis | 1/12 (8.3%) | |
Investigations | ||
Blood creatine phosphokinase increased | 1/12 (8.3%) | |
Blood creatinine increased | 1/12 (8.3%) | |
Ejection fraction decreased | 1/12 (8.3%) | |
Electrocardiogram QT prolonged | 3/12 (25%) | |
Electrocardiogram T wave abnormal | 2/12 (16.7%) | |
Troponin T increased | 1/12 (8.3%) | |
Weight decreased | 7/12 (58.3%) | |
Metabolism and nutrition disorders | ||
Anorexia | 1/12 (8.3%) | |
Gout | 1/12 (8.3%) | |
Hyperuricaemia | 1/12 (8.3%) | |
Iron overload | 1/12 (8.3%) | |
Musculoskeletal and connective tissue disorders | ||
Arthralgia | 2/12 (16.7%) | |
Bone pain | 6/12 (50%) | |
Joint swelling | 1/12 (8.3%) | |
Muscular weakness | 5/12 (41.7%) | |
Myalgia | 1/12 (8.3%) | |
Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||
Tumour pain | 1/12 (8.3%) | |
Nervous system disorders | ||
Balance disorder | 1/12 (8.3%) | |
Dizziness | 1/12 (8.3%) | |
Dysgeusia | 1/12 (8.3%) | |
Peripheral sensory neuropathy | 2/12 (16.7%) | |
Psychiatric disorders | ||
Insomnia | 2/12 (16.7%) | |
Renal and urinary disorders | ||
Haematuria | 1/12 (8.3%) | |
Micturition urgency | 1/12 (8.3%) | |
Pollakiuria | 1/12 (8.3%) | |
Respiratory, thoracic and mediastinal disorders | ||
Cough | 1/12 (8.3%) | |
Dyspnoea | 1/12 (8.3%) | |
Emphysema | 1/12 (8.3%) | |
Skin and subcutaneous tissue disorders | ||
Alopecia | 1/12 (8.3%) | |
Erythema | 1/12 (8.3%) | |
Night sweats | 7/12 (58.3%) | |
Pruritus | 4/12 (33.3%) | |
Rash macular | 1/12 (8.3%) | |
Vascular disorders | ||
Deep vein thrombosis | 1/12 (8.3%) | |
Hypertension | 2/12 (16.7%) | |
Pallor | 1/12 (8.3%) |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
Name/Title | Clinical Development Department of PharmaMar´s Oncology,Business Unit., |
---|---|
Organization | Pharma Mar, S.A. |
Phone | +34 918466000 |
clinicaltrials@pharmamar.com |
- APL-B-020-10