Clinical Trial of Aplidin® in Patients With Primary Myelofibrosis

• Sponsor: PharmaMar (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01149681
• Collaborator: (none)
• Enrollment: 12
• Locations: 2
• Arm: 1
• Duration (Months): 7.1
• Patients Per Site: 6
• Patients Per Site Per Month: 0.8

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
Myelofibrosis	Drug: APLIDIN (plitidepsin)	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

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-label, Phase II Clinical Trial of Aplidin® (Plitidepsin) in Patients With Primary Myelofibrosis (PMF) and Post Polycythemia Vera/Essential Thrombocythemia (Post-PV/ET) Myelofibrosis
• Study Start Date: Jul 1, 2010
• Actual Primary Completion Date: Feb 1, 2011
• Actual Study Completion Date: Feb 1, 2011

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

1. 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

1. 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

1. 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

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

1. Incomplete recovery from major surgery within four weeks of study entry.

2. Radiation therapy within four weeks of study entry.

3. Women of childbearing potential

4. Women who are pregnant or are currently breastfeeding.

5. Myopathy grade > 2

6. Known positive status for human immunodeficiency virus (HIV).

7. Active hepatitis B or C virus (HBV or HCV) infection

8. Diagnosis of another invasive malignancy

9. Any acute active infection.

10. Known hypersensitivity to the study drug or any of its formulation components (e.g., Cremophor®).

11. 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.

• Responsible Party: PharmaMar
• ClinicalTrials.gov Identifier: NCT01149681
• Other Study ID Numbers: APL-B-020-10
• First Posted: Jun 23, 2010
• Last Update Posted: Oct 12, 2020
• Last Verified: Sep 1, 2020

• Keywords provided by PharmaMar: Aplidin; Plitidepsin; Myelofibrosis; Pharma Mar
• Additional relevant MeSH terms: Primary Myelofibrosis

Study Results

Participant Flow

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

1. Primary Outcome

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%

2. Secondary Outcome

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

3. Other Pre-specified Outcome

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

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

[Not Specified]

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.