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

• Sponsor: PharmaMar (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03070964
• Collaborator: (none)
• Enrollment: 14
• Locations: 17
• Arm: 1
• Actual Duration (Months): 20.2
• Patients Per Site: 0.8
• Patients Per Site Per Month: 0

Study Details

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).

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Drug: plitidepsin	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Plitidepsin in Patients With Relapsed or Refractory Angioimmunoblastic T-cell Lymphoma
• Actual Study Start Date: Oct 25, 2016
• Actual Primary Completion Date: Jul 1, 2018
• Actual Study Completion Date: Jul 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Plitidepsin	Drug: plitidepsin; Other Names: APLD Aplidine

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

Eligibility Criteria

Criteria

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

8. 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.

9. Platelet count ≥ 75 × 109/L.

10. Hemoglobin ≥ 9 g/dL. Patients may receive red blood cells (RBC) and/or erythropoietin (EPO) and/or platelet transfusions in accordance with institutional guidelines.

11. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × the upper limit of normal (ULN).

12. Total bilirubin ≤ 1.5 × ULN.

13. Alkaline phosphatase (ALP) ≤ 3.0 × ULN (< 5 × ULN if isolated ALP increase, i.e., without ALT/AST or bilirubin increase).

14. Calculated creatinine clearance (CrCL) ≥ 30 mL/minute (Cockcroft-Gault formula).

15. Creatine phosphokinase (CPK) ≤ 2.5 × ULN.

16. Albumin ≥ 2.5 g/dL.

17. 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:

3. History or presence of angina, myocardial infarction, clinically relevant valvular heart disease, uncontrolled hypertension, or congestive heart failure within the previous 12 months.

4. 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.

5. Active uncontrolled infection. Active hepatitis B or C virus (HBV or HCV), or human immunodeficiency virus (HIV)infection.

6. Morphological or cytological features of myelodysplasia and/or post chemotherapy aplasia on bone marrow (BM) assessment.

7. 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).

8. Limitation of the patient's ability to comply with the treatment or follow-up requirements.

9. 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.

10. Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study.

11. Central nervous system (CNS) involvement.

12. 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.

13. 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.

14. Major upper gastrointestinal bleeding episode occurring during the previous year before screening.

15. Known hypersensitivity to any of plitidepsin's formulation components

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University Medical School	Chicago	Illinois	United States	60611
2	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
3	Faculty Hospital Ostrava	Ostrava		Czechia	708 52
4	Fakultni Nemocnice Praha	Praha		Czechia	100 34
5	Ospedale Clinico Aviano	Aviano	Pordenone	Italy	33081
6	Instituto di Ematologia "Seragnoli"	Bologna		Italy	40138
7	Spedali Civili di Brescia	Brescia		Italy	25123
8	Azienda Ospedaliera Universitaria Careggi	Firenze		Italy	50134
9	Hospital Clínic i Provincial de Barcelona	Barcelona		Spain	08036
10	Hospital Universitari Vall d'Hebron	Barcelona		Spain	119 - 129
11	Centro Oncológico MD Anderson International España	Madrid		Spain	28033
12	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
13	Hospital Universitario La Paz	Madrid		Spain	28046
14	Hospital Universitari Son Espases	Palma de Mallorca		Spain	07010
15	Hospital Universitario de Salamanca	Salamanca		Spain	37007
16	Hospital Universitario Marqués de Valdecilla	Santander		Spain	39008
17	Hospital Virgen del Rocío	Sevilla		Spain	41013

Sponsors and Collaborators

• PharmaMar

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - May 7, 2018
• Statistical Analysis Plan - Oct 13, 2016

More Information

Publications

None provided.

• Responsible Party: PharmaMar
• ClinicalTrials.gov Identifier: NCT03070964
• Other Study ID Numbers: APL-B-021-13
• First Posted: Mar 6, 2017
• Last Update Posted: Oct 14, 2020
• Last Verified: Sep 1, 2020

• Additional relevant MeSH terms: Lymphoma; Lymphoma, T-Cell; Immunoblastic Lymphadenopathy

Study Results

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

Arm/Group Title	Plitidepsin
Arm/Group Description	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.
Period Title: Overall Study
STARTED	14
COMPLETED	0
NOT COMPLETED	14

Baseline Characteristics

Arm/Group Title	Plitidepsin
Arm/Group Description	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.
Overall Participants	14
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	9 64.3%
>=65 years	5 35.7%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61
Sex: Female, Male (Count of Participants)
Female	6 42.9%
Male	8 57.1%
Race/Ethnicity, Customized (Count of Participants)
White	13 92.9%
Hispanolatin	1 7.1%
ECOG PS (Count of Participants)
PS 0	8 57.1%
PS 1	5 35.7%
PS 2	1 7.1%
Ann Arbor stage (Count of Participants)
III	1 7.1%
III-A	3 21.4%
III-B	3 21.4%
IV-A	3 21.4%
IV-B	4 28.6%
Extranodal disease at diagnosis (Count of Participants)
Yes	5 35.7%
No	9 64.3%
Bulky lesion at diagnosis (Count of Participants)
Yes	1 7.1%
No	13 92.9%
International Prognostic Index score at diagnosis (Count of Participants)
Low risk (0-1 risk factors)	2 14.3%
Low-intermediate risk (2 risk factors)	2 14.3%
High-intermediate risk (3 risk factors)	2 14.3%
High risk (4-5 risk factors)	4 28.6%
NA	4 28.6%
Prognostic index for peripheral T-cell lymphoma at diagnosis (Count of Participants)
Group 1 (no adverse factors)	1 7.1%
Group 2 (1 risk factor)	1 7.1%
Group 4 (3-4 risk factors)	2 14.3%
NA	10 71.4%
Prognostic index for angioimmunoblastic T-cell lymphoma score at diagnosis (Count of Participants)
Low-risk group	3 21.4%
High-risk group	3 21.4%
NA	8 57.1%
International prognostic index score at current disease (Count of Participants)
Low risk (0-1 risk factors)	3 21.4%
Low-intermediate risk (2 risk factors)	3 21.4%
High-intermediate risk (3 risk factors)	4 28.6%
High risk (4-5 risk factors)	4 28.6%
Prognostic index for peripheral T-cell lymphoma at current disease (Count of Participants)
Group 1 (no adverse factors)	2 14.3%
Group 2 (1 risk factor)	3 21.4%
Group 3 (2 risk factors)	1 7.1%
Group 4 (3-4 risk factors)	1 7.1%
NA	7 50%
Prognostic index for angioimmunoblastic T-cell lymphoma score at current disease (Count of Participants)
Low-risk group	5 35.7%
High-risk group	4 28.6%
NA	5 35.7%
Prior anticancer therapy lines (Count of Participants)
1 line	2 14.3%
2 lines	5 35.7%
3 lines	5 35.7%
4 lines	1 7.1%
5 lines	1 7.1%
Best response to last prior therapy (Count of Participants)
CR	4 28.6%
PR	4 28.6%
SD	1 7.1%
PD	3 21.4%
UK	2 14.3%
Prior stem cell transplantation (Count of Participants)
NO	8 57.1%
Allogenic stem cell transplantation	1 7.1%
Autologous stem cell transplantation	5 35.7%
Weight (Kg) [Median (Full Range) ]
Median (Full Range) [Kg]	72.5
Height (cm) [Median (Full Range) ]
Median (Full Range) [cm]	166.5
Body Surface Area (m^2) [Median (Full Range) ]
Median (Full Range) [m^2]	1.8
Time from diagnosis to first plitidepsin infusion (months) [Median (Full Range) ]
Median (Full Range) [months]	24.1
Time from last progressive disease to infusion (weeks) [Median (Full Range) ]
Median (Full Range) [weeks]	6.9
Prior anticancer therapy lines (therapy lines) [Median (Full Range) ]
Median (Full Range) [therapy lines]	2.5
Time to progressions to last anticancer therapy (months) [Median (Full Range) ]
Median (Full Range) [months]	4.6

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate by the Lugano Classification Per Independent Review Assessment
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Plitidepsin
Arm/Group Description	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.
Measure Participants	12
Count of Participants [Participants]	NA NaN

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

A patient was never treated with plitidepsin. A patient due to lack of AITL diagnosis confirmation

Arm/Group Title	Plitidepsin
Arm/Group Description	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.
Measure Participants	12
CR	1 7.1%
PR	1 7.1%
SD	1 7.1%
PD	7 50%
NE	2 14.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Plitidepsin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Exact binomial estimator
	Estimated Value	16.7
	Confidence Interval	(2-Sided) 95%; 2.1 to 48.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Participants were assessed through study completion, approximately 2 years
Adverse Event Reporting Description	One patient was never treated with plitidepsin and was excluded from the analysis of safety.
Arm/Group Title	Plitidepsin
Arm/Group Description	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.
All Cause Mortality
	Plitidepsin
	Affected / at Risk (%)	# Events
Total	7/13 (53.8%)
Serious Adverse Events
	Plitidepsin
	Affected / at Risk (%)	# Events
Total	9/13 (69.2%)
Blood and lymphatic system disorders
Febrile neutropenia	1/13 (7.7%)	1
Cardiac disorders
Cardiac arrest	1/13 (7.7%)	1
Cardiac failure	1/13 (7.7%)	1
General disorders
Pyrexia	1/13 (7.7%)	1
Immune system disorders
Anaphylactic reaction	1/13 (7.7%)	1
Infections and infestations
Pneumonia	1/13 (7.7%)	2
Rhinovirus infection	1/13 (7.7%)	1
Septic shock	1/13 (7.7%)	1
Skin infection	1/13 (7.7%)	1
Investigations
Alanine aminotransferase increased	1/13 (7.7%)	1
Aspartate aminotransferase increased	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/13 (7.7%)	1
Pulmonary embolism	1/13 (7.7%)	1
Skin and subcutaneous tissue disorders
Rash	1/13 (7.7%)	1
Vascular disorders
Peripheral embolism	1/13 (7.7%)	2
Other (Not Including Serious) Adverse Events
	Plitidepsin
	Affected / at Risk (%)	# Events
Total	13/13 (100%)
Gastrointestinal disorders
Abdominal pain	2/13 (15.4%)	2
Abdominal pain upper	1/13 (7.7%)	1
Diarrhoea	5/13 (38.5%)	7
Dysphagia	1/13 (7.7%)	1
Epigastric discomfort	1/13 (7.7%)	1
Flatulence	1/13 (7.7%)	1
Gastric mucosa erythema	1/13 (7.7%)	1
Melaena	1/13 (7.7%)	1
Nausea	6/13 (46.2%)	7
Rectal haemorrhage	1/13 (7.7%)	1
Vomiting	3/13 (23.1%)	4
General disorders
Asthenia/Fatigue	4/13 (30.8%)	6
Chills	1/13 (7.7%)	2
Malaise	1/13 (7.7%)	1
Oedema peripheral	3/13 (23.1%)	3
Pyrexia	6/13 (46.2%)	17
Infections and infestations
Candida infection	1/13 (7.7%)	1
Cytomegalovirus infection	1/13 (7.7%)	1
Herpes zoster	2/13 (15.4%)	2
Influenza	1/13 (7.7%)	1
Nasopharyngitis	2/13 (15.4%)	2
Pharyngitis	1/13 (7.7%)	1
Respiratory tract infection	2/13 (15.4%)	2
Rhinovirus infection	1/13 (7.7%)	1
Upper respiratory tract infection	1/13 (7.7%)	1
Injury, poisoning and procedural complications
Limb injury	1/13 (7.7%)	1
Investigations
Alanine aminotransferase increased	4/13 (30.8%)	15
Aspartate aminotransferase increased	1/13 (7.7%)	2
Blood creatine phosphokinase increased	1/13 (7.7%)	2
Electrocardiogram QT prolonged	1/13 (7.7%)	6
Weight decreased	1/13 (7.7%)	1
Anaemia	3/13 (23.1%)	13
Eosinophilia	1/13 (7.7%)	1
Lymphadenopathy	1/13 (7.7%)	1
Neutropenia	2/13 (15.4%)	2
Thrombocytopenia	2/13 (15.4%)	2
Metabolism and nutrition disorders
Decreased appetite	1/13 (7.7%)	1
Hypokalaemia	2/13 (15.4%)	2
Hypomagnesaemia	2/13 (15.4%)	3
Hyponatraemia	1/13 (7.7%)	1
Musculoskeletal and connective tissue disorders
Joint swelling	1/13 (7.7%)	1
Musculoskeletal pain	2/13 (15.4%)	2
Myalgia	1/13 (7.7%)	3
Myopathy	1/13 (7.7%)	1
Nervous system disorders
Dizziness	2/13 (15.4%)	2
Dysaesthesia	1/13 (7.7%)	1
Headache	1/13 (7.7%)	1
Neuropathy peripheral	1/13 (7.7%)	1
Paraesthesia	2/13 (15.4%)	2
Transient ischaemic attack	1/13 (7.7%)	1
Psychiatric disorders
Insomnia	1/13 (7.7%)	1
Renal and urinary disorders
Renal failure	1/13 (7.7%)	1
Renal impairment	2/13 (15.4%)	2
Respiratory, thoracic and mediastinal disorders
Cough	3/13 (23.1%)	3
Dyspnoea	2/13 (15.4%)	3
Nasal congestion	1/13 (7.7%)	1
Oropharyngeal pain	1/13 (7.7%)	1
Rhinorrhoea	1/13 (7.7%)	1
Skin and subcutaneous tissue disorders
Night sweats	1/13 (7.7%)	1
Pruritus	4/13 (30.8%)	5
Rash	3/13 (23.1%)	8
Rash macular	1/13 (7.7%)	1
Vascular disorders
Subclavian vein thrombosis	1/13 (7.7%)	1

Limitations/Caveats

On 14May18, Sponsor informed to the sites and IPs its decision to close the recruitment. Study was terminated before reaching the target enrollment due to slow patient accrual and the negative opinion of the EMA-refusal of the mark. auth. plitidepsin

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 from the time submitted to the sponsor for review.