Study of Zalypsis® (PM00104) in Patients With Unresectable Locally Advanced and/or Metastatic Ewing Family of Tumors (EFT) Progressing After at Least One Prior Line of Chemotherapy

• Sponsor: PharmaMar (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01222767
• Collaborator: (none)
• Enrollment: 17
• Locations: 7
• Arm: 1
• Duration (Months): 16
• Patients Per Site: 2.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is a phase II Multicenter, Open-label, Clinical and Pharmacokinetic Study of Zalypsis® (PM00104) in Patients with Unresectable Locally Advanced and/or Metastatic Ewing Family of Tumors (EFT) Progressing After at Least One Prior Line of Chemotherapy to determine the antitumor activity of Zalypsis.

Condition or Disease	Intervention/Treatment	Phase
Ewing's Sarcoma; Primitive Neuroectodermal Tumor (PNET); Askin's Tumor of the Chest Wall; Extraosseous Ewing's Sarcoma (EOE)	Drug: Zalypsis	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Multicenter, Open-label, Clinical and Pharmacokinetic Study of Zalypsis® (PM00104) in Patients With Unresectable Locally Advanced and/or Metastatic Ewing Family of Tumors (EFT) Progressing After at Least One Prior Line of Chemotherapy
• Study Start Date: Dec 1, 2010
• Actual Primary Completion Date: Apr 1, 2012
• Actual Study Completion Date: Apr 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1	Drug: Zalypsis; Zalypsis is provided as a lyophilized powder for concentrate for solution for infusion in a strength of 2.5 mg/vial.; Other Names: PM00104

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR) [At baseline and every other cycle (± 1 week) until evidence of PD, up to 2 years]

   Overall response rate (ORR), defined as the percentage of patients with confirmed objective response (OR), either CR or PR according to the RECIST v.1.1. CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; RECIST, Response Evaluation Criteria in Solid Tumors

Secondary Outcome Measures

1. Best Tumor Response [At baseline and every other cycle (± 1 week) until evidence of PD, up to 2 years]

   Best tumor response was defined as the best response achieved during the study according to RECIST v1.1 CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; RECIST, Response Evaluation Criteria in Solid Tumors

2. Progression-free Survival [From the first day of study treatment to the day of negative assessment (progression or death), start of subsequent antitumor therapy, or last tumor evaluation, up to 2 years]

   Progression-free survival (PFS), defined as the time from the first day of study treatment to the day of negative assessment (progression or death), start of subsequent antitumor therapy, or last tumor evaluation. PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density

3. Progression-free Survival at 3 Months [At 3 months]

   Progression-free survival (PFS), defined as the time from the first day of study treatment to the day of negative assessment (progression or death), start of subsequent antitumor therapy, or last tumor evaluation. PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density

4. Overall Survival [from the first day of treatment to the date of death, up to 2 years]

   Overall survival (OS), defined as the time from the first day of treatment to the date of death (or the last day when the patient was known to be alive). Survival was to be followed for up to six months after the last treatment visit of the last patient, or 12 months after the last patient was included, whichever occurred first.

5. Overall Survival Rate at 6 Months [At 6 months]

   Overall survival (OS), defined as the time from the first day of treatment to the date of death (or the last day when the patient was known to be alive). Survival was to be followed for up to six months after the last treatment visit of the last patient, or 12 months after the last patient was included, whichever occurred first.

6. Overall Survival Rate at 12 Months [At 12 months]

   Overall survival (OS), defined as the time from the first day of treatment to the date of death (or the last day when the patient was known to be alive). Survival was to be followed for up to six months after the last treatment visit of the last patient, or 12 months after the last patient was included, whichever occurred first.

7. PM00104 Plasma PK Parameters (Cmax) at First Infusion [0 (Pre-infusion) and 5 min, 30 min, 2 hours, 6 hours, 24 hours, 48 hours and 168 hours after the end of first infusion (Day 1)]

   Cmax Maximum plasma concentration, directly determined from the experimental data

8. PM00104 Plasma PK Parameters (AUC) at First Infusion [0 (Pre-infusion) and 5 min, 30 min, 2 hours, 6 hours, 24 hours, 48 hours and 168 hours after the end of first infusion (Day 1)]

   AUC Area under the plasma concentration-time curve from time zero to infinity

9. PM00104 Plasma PK Parameters (Cmax) at Second Infusion [0 (Pre-infusion) and 5 min, 30 min, 2 hours, 6 hours, 24 hours, 48 hours and 168 hours after the end of second infusion (Day 8)]

   Cmax Maximum plasma concentration, directly determined from the experimental data

10. PM00104 Plasma PK Parameters (AUC) at Second Infusion [0 (Pre-infusion) and 5 min, 30 min, 2 hours, 6 hours, 24 hours, 48 hours and 168 hours after the end of second infusion (Day 8)]

    AUC Area under the plasma concentration-time curve from time zero to infinity

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Voluntary written informed consent, obtained from the patient or his/her representative before the beginning of any specific study procedures.

2. Age ≥ 16 years.

3. Histologically or cytologically confirmed EFT (Ewing Family of Tumors), with recurrent disease.

4. Documented failure to at least one prior chemotherapy regimen for their disease.

5. Radiographic documentation of disease progression at study entry.

6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≤ 2.

7. Life expectancy ≥ 3 months.

8. Complete recovery from the effects of drug-related adverse events (AEs) derived from previous treatments, excluding alopecia and grade 1 peripheral neuropathy, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v. 4.0.

9. At least one measurable lesion ("target lesion" according to the RECIST v.1.1), located in a non-irradiated area and adequately measured less than four weeks before study entry. Tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is clearly documented or biopsy proven.

10. Absolute neutrophil count (ANC) ≥ 1.5 x 109/l; platelet count ≥ 100 x 109/l, and hemoglobin ≥ 9 g/dl.

11. Adequate renal function: calculated creatinine clearance (using Cockcroft and Gault's formula) ≥ 30 ml/min.

12. Adequate hepatic function:

• Total bilirubin ≤ 1.5 x upper limit or normality (ULN), unless due to Gilbert's syndrome.

• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 3 x ULN (≤ 5 x ULN in case of hepatic metastases), and alkaline phosphatase (AP) ≤ 2.5 x ULN (≤ 5 x ULN in case of extensive bone involvement).

• Albumin ≥ 25 g/l.

1. Left ventricular ejection fraction (LVEF) within normal limits (LVEF of at least 50%).

2. Women of childbearing potential must have a negative serum pregnancy test before study entry. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for three months after discontinuation of treatment. Acceptable methods of contraception include complete abstinence, intrauterine device (IUD), oral contraceptive, subdermal implant and double barrier (condom with a contraceptive sponge or contraceptive suppository).

Exclusion Criteria:

1. Prior therapy with Zalypsis®.

2. Pregnant or lactating women or women of childbearing potential not using an appropriate contraceptive method.

3. Less than three weeks from prior radiation therapy, biological therapy or chemotherapy.

4. Less than six weeks from prior nitrosourea, mitomycin C, high-dose chemotherapy or radiotherapy involving the whole pelvis or over 50% of the spine, provided that acute effects of radiation treatment have resolved. Hormonal therapy and palliative radiation therapy (i.e., for control of pain from bone metastases) must be discontinued before study entry.

5. Patients with a prior invasive malignancy (except non-melanoma skin cancer and in situ cervix carcinoma) who have had any evidence of disease within the last five years or whose prior malignancy treatment contraindicates the current protocol therapy.

6. Evidence of progressive or symptomatic central nervous system (CNS) metastases or leptomeningeal metastases.

7. Other diseases or serious conditions:

• Increased cardiac risk, as defined by:

• Unstable angina or myocardial infarction within 12 months before inclusion in the study.

• New York Heart Association (NYHA) grade II or greater congestive heart failure.

• Symptomatic arrhythmia or any arrhythmia requiring ongoing treatment.

• Abnormal electrocardiogram (ECG), i.e., patients with the following are excluded: QT prolongation - QTc > 480 msec; signs of cardiac enlargement or hypertrophy; bundle branch block; partial blocks; signs of ischemia or necrosis, and Wolff Parkinson White patterns.

• History or presence of valvular heart disease.

• Uncontrolled arterial hypertension despite optimal medical therapy.

• Previous mediastinal radiotherapy.

• Previous treatment with doxorubicin at cumulative doses exceeding 400 mg/m2.

• History of significant neurological or psychiatric disorders.

• Active infection requiring systemic treatment.

• Significant non-neoplastic liver disease (e.g., cirrhosis).

• Known hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.

• Immunocompromised patients, including those known to be infected with the human immunodeficiency virus (HIV).

• Uncontrolled (i.e., requiring relevant changes in medication within the last month or hospital admission within the last three months) endocrine diseases (e.g., diabetes mellitus, hypo- or hyperthyroidism, adrenal disorder).

1. Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in the study. The Investigator should feel free to consult the Study Coordinator or the Sponsor(s) in case of uncertainty in this regard.

2. Limitation of the patient's ability to comply with the treatment or to follow-up at a participating center. Patients enrolled into this trial must be treated and followed at a participating center.

3. Treatment with any investigational product within 30 days prior to inclusion in the study.

4. Known hypersensitivity to any component of Zalypsis®.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sarcoma Oncology Center	Santa Monica	California	United States	90403
2	St. Jude Children 's Research Hospital	Memphis	Tennessee	United States	38105A
3	Seattle Cancer Care Alliance	Seattle	Washington	United States
4	Centre Léon Bérard	Lyon		France	69373
5	Istituto Ortopedici Rizzoli	Bologna		Italy	40136
6	Istituto Nazionale dei Tumori	Milan		Italy	20133
7	Istituto Clinico Humanitas	Rozzano		Italy	20089

Sponsors and Collaborators

• PharmaMar

Investigators

• Principal Investigator: Fariba Navid, MD, St. Jude Children 's Research Hospital
• Principal Investigator: Sant P Chawla, MD, Sarcoma Oncology Center
• Principal Investigator: Jean Yves Blay, MD, Centre Leon Berard
• Principal Investigator: Stefano Ferrari, MD, Istituto Ortopedici Rizzoli
• Principal Investigator: Armando Santoro, Prof., Istituto Clinico Humanitas
• Principal Investigator: Paolo Casali, MD, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
• Principal Investigator: Robin L. Jones, MD, Seattle Cancer Care Alliance

Study Documents (Full-Text)

• Study Protocol - Jul 30, 2010
• Statistical Analysis Plan - Feb 7, 2013

More Information

Publications

None provided.

• Responsible Party: PharmaMar
• ClinicalTrials.gov Identifier: NCT01222767
• Other Study ID Numbers: PM104-B-003-10
• First Posted: Oct 18, 2010
• Last Update Posted: Oct 29, 2021
• Last Verified: Jul 1, 2021

• Keywords provided by PharmaMar: EFT; PNET; EOE
• Additional relevant MeSH terms: Neoplasms; Sarcoma; Sarcoma, Ewing; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral

Study Results

Participant Flow

Recruitment Details	A total of 17 patients were included and 16 of them were treated with PM00104 at five investigational sites from the USA (n=3), France and Italy. The patients participated in this study between 22 December 2010 (first consent) and 21 May 2012 (last follow-up). First and last doses were administered on 4 January 2011 and 24 January 2012, respectively

Arm/Group Title	PM00104
Arm/Group Description	PM00104 was administered at a dose of 2 mg/m2 as a 1-hour i.v. infusion d1, d8 and d15 q4wk to patients with advanced and/or metastatic Ewing's sarcoma previously treated with at least one line of chemotherapy. A treatment cycle consisted of PM00104 administration on Days 1, 8 and 15, plus one week of follow-up. Study evaluations had to be completed during each cycle prior to subsequent PM00104 infusion. Treatment cycles were repeated every four weeks
Period Title: Overall Study
STARTED	17
Received Treatment	16
COMPLETED	0
NOT COMPLETED	17

Baseline Characteristics

Arm/Group Title	PM00104
Arm/Group Description	PM00104 was administered at a dose of 2 mg/m2 as a 1-hour i.v. infusion d1, d8 and d15 q4wk to patients with advanced and/or metastatic Ewing's sarcoma previously treated with at least one line of chemotherapy. A treatment cycle consisted of PM00104 administration on Days 1, 8 and 15, plus one week of follow-up. Study evaluations had to be completed during each cycle prior to subsequent PM00104 infusion. Treatment cycles were repeated every four weeks
Overall Participants	17
Age (Count of Participants)
<=18 years	4 23.5%
Between 18 and 65 years	13 76.5%
>=65 years	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	23
Sex: Female, Male (Count of Participants)
Female	5 29.4%
Male	12 70.6%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (Count of Participants)
United States	12 70.6%
Italy	3 17.6%
France	2 11.8%
ECOG PS (Count of Participants)
0	9 52.9%
1	7 41.2%
2	1 5.9%
Tumor diagnosis (Count of Participants)
Ewing's bone sarcoma	13 76.5%
Extraosseous sarcoma	4 23.5%
Primary location at diagnosis (Count of Participants)
Lower extremity	7 41.2%
Trunk/abdominal wall	7 41.2%
Upper extremity	1 5.9%
Unknown	2 11.8%
Metastatic disease (Count of Participants)
Count of Participants [Participants]	17 100%
Time from diagnosis to first infusion (months) [Median (Full Range) ]
Median (Full Range) [months]	43.3
Time from last disease progression to first infusion (months) [Median (Full Range) ]
Median (Full Range) [months]	0.3
Sites of disease at diagnosis (Count of Participants)
1	7 41.2%
2	6 35.3%
3	3 17.6%
>3	1 5.9%
Prior radiotherapy (Count of Participants)
Count of Participants [Participants]	14 82.4%
Prior Antitumor surgery (palliative or curative) (Count of Participants)
Count of Participants [Participants]	14 82.4%
Prior Systemic anticancer therapy (Count of Participants)
Count of Participants [Participants]	17 100%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR)
Description	Overall response rate (ORR), defined as the percentage of patients with confirmed objective response (OR), either CR or PR according to the RECIST v.1.1. CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; RECIST, Response Evaluation Criteria in Solid Tumors
Time Frame	At baseline and every other cycle (± 1 week) until evidence of PD, up to 2 years

Outcome Measure Data

Analysis Population Description

One patient never treated

Arm/Group Title	PM00104
Arm/Group Description	PM00104 was administered at a dose of 2 mg/m2 as a 1-hour i.v. infusion d1, d8 and d15 q4wk to patients with advanced and/or metastatic Ewing's sarcoma previously treated with at least one line of chemotherapy. A treatment cycle consisted of PM00104 administration on Days 1, 8 and 15, plus one week of follow-up. Study evaluations had to be completed during each cycle prior to subsequent PM00104 infusion. Treatment cycles were repeated every four weeks
Measure Participants	16
Count of Participants [Participants]	0 0%

2. Secondary Outcome

Title	Best Tumor Response
Description	Best tumor response was defined as the best response achieved during the study according to RECIST v1.1 CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; RECIST, Response Evaluation Criteria in Solid Tumors
Time Frame	At baseline and every other cycle (± 1 week) until evidence of PD, up to 2 years

Outcome Measure Data

Analysis Population Description

One patient never treated Two patients were non-evaluable for efficacy because they were withdrawn due to toxicity without any tumor assessment after the start of study treatment and were considered as "treatment failures"

Arm/Group Title	PM00104
Arm/Group Description	PM00104 was administered at a dose of 2 mg/m2 as a 1-hour i.v. infusion d1, d8 and d15 q4wk to patients with advanced and/or metastatic Ewing's sarcoma previously treated with at least one line of chemotherapy. A treatment cycle consisted of PM00104 administration on Days 1, 8 and 15, plus one week of follow-up. Study evaluations had to be completed during each cycle prior to subsequent PM00104 infusion. Treatment cycles were repeated every four weeks
Measure Participants	14
SD	4 23.5%
PD	10 58.8%

3. Secondary Outcome

Title	Progression-free Survival
Description	Progression-free survival (PFS), defined as the time from the first day of study treatment to the day of negative assessment (progression or death), start of subsequent antitumor therapy, or last tumor evaluation. PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density
Time Frame	From the first day of study treatment to the day of negative assessment (progression or death), start of subsequent antitumor therapy, or last tumor evaluation, up to 2 years

Outcome Measure Data

Analysis Population Description

One patient never treated

Arm/Group Title	PM00104
Arm/Group Description	PM00104 was administered at a dose of 2 mg/m2 as a 1-hour i.v. infusion d1, d8 and d15 q4wk to patients with advanced and/or metastatic Ewing's sarcoma previously treated with at least one line of chemotherapy. A treatment cycle consisted of PM00104 administration on Days 1, 8 and 15, plus one week of follow-up. Study evaluations had to be completed during each cycle prior to subsequent PM00104 infusion. Treatment cycles were repeated every four weeks
Measure Participants	16
Median (95% Confidence Interval) [months]	1.8

4. Secondary Outcome

Title	Progression-free Survival at 3 Months
Description	Progression-free survival (PFS), defined as the time from the first day of study treatment to the day of negative assessment (progression or death), start of subsequent antitumor therapy, or last tumor evaluation. PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density
Time Frame	At 3 months

Outcome Measure Data

Analysis Population Description

One patient never treated

Arm/Group Title	PM00104
Arm/Group Description	PM00104 was administered at a dose of 2 mg/m2 as a 1-hour i.v. infusion d1, d8 and d15 q4wk to patients with advanced and/or metastatic Ewing's sarcoma previously treated with at least one line of chemotherapy. A treatment cycle consisted of PM00104 administration on Days 1, 8 and 15, plus one week of follow-up. Study evaluations had to be completed during each cycle prior to subsequent PM00104 infusion. Treatment cycles were repeated every four weeks
Measure Participants	16
Number (95% Confidence Interval) [percentage of participants]	28.6 168.2%

5. Secondary Outcome

Title	Overall Survival
Description	Overall survival (OS), defined as the time from the first day of treatment to the date of death (or the last day when the patient was known to be alive). Survival was to be followed for up to six months after the last treatment visit of the last patient, or 12 months after the last patient was included, whichever occurred first.
Time Frame	from the first day of treatment to the date of death, up to 2 years

Outcome Measure Data

Analysis Population Description

One patient never treated

Arm/Group Title	PM00104
Arm/Group Description	PM00104 was administered at a dose of 2 mg/m2 as a 1-hour i.v. infusion d1, d8 and d15 q4wk to patients with advanced and/or metastatic Ewing's sarcoma previously treated with at least one line of chemotherapy. A treatment cycle consisted of PM00104 administration on Days 1, 8 and 15, plus one week of follow-up. Study evaluations had to be completed during each cycle prior to subsequent PM00104 infusion. Treatment cycles were repeated every four weeks
Measure Participants	16
Median (95% Confidence Interval) [months]	NA

6. Secondary Outcome

Title	Overall Survival Rate at 6 Months
Description	Overall survival (OS), defined as the time from the first day of treatment to the date of death (or the last day when the patient was known to be alive). Survival was to be followed for up to six months after the last treatment visit of the last patient, or 12 months after the last patient was included, whichever occurred first.
Time Frame	At 6 months

Outcome Measure Data

Analysis Population Description

One patient never treated

Arm/Group Title	PM00104
Arm/Group Description	PM00104 was administered at a dose of 2 mg/m2 as a 1-hour i.v. infusion d1, d8 and d15 q4wk to patients with advanced and/or metastatic Ewing's sarcoma previously treated with at least one line of chemotherapy. A treatment cycle consisted of PM00104 administration on Days 1, 8 and 15, plus one week of follow-up. Study evaluations had to be completed during each cycle prior to subsequent PM00104 infusion. Treatment cycles were repeated every four weeks
Measure Participants	16
Number (95% Confidence Interval) [percentage of participants]	62.5 367.6%

7. Secondary Outcome

Title	Overall Survival Rate at 12 Months
Description	Overall survival (OS), defined as the time from the first day of treatment to the date of death (or the last day when the patient was known to be alive). Survival was to be followed for up to six months after the last treatment visit of the last patient, or 12 months after the last patient was included, whichever occurred first.
Time Frame	At 12 months

Outcome Measure Data

Analysis Population Description

One patient never treated

Arm/Group Title	PM00104
Arm/Group Description	PM00104 was administered at a dose of 2 mg/m2 as a 1-hour i.v. infusion d1, d8 and d15 q4wk to patients with advanced and/or metastatic Ewing's sarcoma previously treated with at least one line of chemotherapy. A treatment cycle consisted of PM00104 administration on Days 1, 8 and 15, plus one week of follow-up. Study evaluations had to be completed during each cycle prior to subsequent PM00104 infusion. Treatment cycles were repeated every four weeks
Measure Participants	16
Number (95% Confidence Interval) [percentage of participants]	54.7 321.8%

8. Secondary Outcome

Title	PM00104 Plasma PK Parameters (Cmax) at First Infusion
Description	Cmax Maximum plasma concentration, directly determined from the experimental data
Time Frame	0 (Pre-infusion) and 5 min, 30 min, 2 hours, 6 hours, 24 hours, 48 hours and 168 hours after the end of first infusion (Day 1)

Outcome Measure Data

Analysis Population Description

Fourteen of the 16 patients treated in this study had plasma profiles

Arm/Group Title	PM00104
Arm/Group Description	PM00104 was administered at a dose of 2 mg/m2 as a 1-hour i.v. infusion d1, d8 and d15 q4wk to patients with advanced and/or metastatic Ewing's sarcoma previously treated with at least one line of chemotherapy. A treatment cycle consisted of PM00104 administration on Days 1, 8 and 15, plus one week of follow-up. Study evaluations had to be completed during each cycle prior to subsequent PM00104 infusion. Treatment cycles were repeated every four weeks
Measure Participants	14
Mean (Standard Deviation) [μg/l]	21.23 (8.35)

9. Secondary Outcome

Title	PM00104 Plasma PK Parameters (AUC) at First Infusion
Description	AUC Area under the plasma concentration-time curve from time zero to infinity
Time Frame	0 (Pre-infusion) and 5 min, 30 min, 2 hours, 6 hours, 24 hours, 48 hours and 168 hours after the end of first infusion (Day 1)

Outcome Measure Data

Analysis Population Description

Fourteen of the 16 patients treated in this study had plasma profiles

Arm/Group Title	PM00104
Arm/Group Description	PM00104 was administered at a dose of 2 mg/m2 as a 1-hour i.v. infusion d1, d8 and d15 q4wk to patients with advanced and/or metastatic Ewing's sarcoma previously treated with at least one line of chemotherapy. A treatment cycle consisted of PM00104 administration on Days 1, 8 and 15, plus one week of follow-up. Study evaluations had to be completed during each cycle prior to subsequent PM00104 infusion. Treatment cycles were repeated every four weeks
Measure Participants	14
Mean (Standard Deviation) [h*μg/l]	87.06 (75.49)

10. Secondary Outcome

Title	PM00104 Plasma PK Parameters (Cmax) at Second Infusion
Description	Cmax Maximum plasma concentration, directly determined from the experimental data
Time Frame	0 (Pre-infusion) and 5 min, 30 min, 2 hours, 6 hours, 24 hours, 48 hours and 168 hours after the end of second infusion (Day 8)

Outcome Measure Data

Analysis Population Description

Eleven of the 16 patients treated in this study had plasma profiles at second infusion

Arm/Group Title	PM00104
Arm/Group Description	PM00104 was administered at a dose of 2 mg/m2 as a 1-hour i.v. infusion d1, d8 and d15 q4wk to patients with advanced and/or metastatic Ewing's sarcoma previously treated with at least one line of chemotherapy. A treatment cycle consisted of PM00104 administration on Days 1, 8 and 15, plus one week of follow-up. Study evaluations had to be completed during each cycle prior to subsequent PM00104 infusion. Treatment cycles were repeated every four weeks
Measure Participants	11
Mean (Standard Deviation) [μg/l]	22.37 (8.77)

11. Secondary Outcome

Title	PM00104 Plasma PK Parameters (AUC) at Second Infusion
Description	AUC Area under the plasma concentration-time curve from time zero to infinity
Time Frame	0 (Pre-infusion) and 5 min, 30 min, 2 hours, 6 hours, 24 hours, 48 hours and 168 hours after the end of second infusion (Day 8)

Outcome Measure Data

Analysis Population Description

Eleven of the 16 patients treated in this study had plasma profiles at second infusion

Arm/Group Title	PM00104
Arm/Group Description	PM00104 was administered at a dose of 2 mg/m2 as a 1-hour i.v. infusion d1, d8 and d15 q4wk to patients with advanced and/or metastatic Ewing's sarcoma previously treated with at least one line of chemotherapy. A treatment cycle consisted of PM00104 administration on Days 1, 8 and 15, plus one week of follow-up. Study evaluations had to be completed during each cycle prior to subsequent PM00104 infusion. Treatment cycles were repeated every four weeks
Measure Participants	11
Mean (Standard Deviation) [h*μg/l]	69.76 (17.69)

Adverse Events

Time Frame	From first infusion to study termination, up to 2 years
Adverse Event Reporting Description	Sixteen of 17 patients included in this study were treated with PM00104 and were therefore evaluable for safety
Arm/Group Title	PM00104
Arm/Group Description	PM00104 was administered at a dose of 2 mg/m2 as a 1-hour i.v. infusion d1, d8 and d15 q4wk to patients with advanced and/or metastatic Ewing's sarcoma previously treated with at least one line of chemotherapy. A treatment cycle consisted of PM00104 administration on Days 1, 8 and 15, plus one week of follow-up. Study evaluations had to be completed during each cycle prior to subsequent PM00104 infusion. Treatment cycles were repeated every four weeks
All Cause Mortality
	PM00104
	Affected / at Risk (%)	# Events
Total	7/16 (43.8%)
Serious Adverse Events
	PM00104
	Affected / at Risk (%)	# Events
Total	2/16 (12.5%)
Infections and infestations
Acute sinusitis	1/16 (6.3%)	1
Bronchitis	1/16 (6.3%)	1
Pneumonia	1/16 (6.3%)	1
Metabolism and nutrition disorders
Dehydration	1/16 (6.3%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/16 (6.3%)	1
Other (Not Including Serious) Adverse Events
	PM00104
	Affected / at Risk (%)	# Events
Total	16/16 (100%)
Blood and lymphatic system disorders
Anaemia	2/16 (12.5%)	4
Neutropenia	7/16 (43.8%)	11
Thrombocytopenia	2/16 (12.5%)	2
Cardiac disorders
Palpitations	3/16 (18.8%)	3
Pericardial effusion	1/16 (6.3%)	1
Tachycardia	2/16 (12.5%)	2
Ear and labyrinth disorders
Ear congestion	1/16 (6.3%)	1
Tinnitus	1/16 (6.3%)	1
Eye disorders
Eye swelling	1/16 (6.3%)	1
Myopia	1/16 (6.3%)	1
Vision blurred	1/16 (6.3%)	1
Gastrointestinal disorders
Abdominal distension	2/16 (12.5%)	2
Abdominal pain	2/16 (12.5%)	2
Constipation	2/16 (12.5%)	3
Diarrhoea	1/16 (6.3%)	1
Dry mouth	1/16 (6.3%)	4
Gastrooesophageal reflux disease	2/16 (12.5%)	2
Nausea	4/16 (25%)	7
Stomach discomfort	1/16 (6.3%)	1
Stomatitis	1/16 (6.3%)	1
Vomiting	2/16 (12.5%)	2
General disorders
Chest pain	3/16 (18.8%)	3
Chills	1/16 (6.3%)	1
Fatigue	7/16 (43.8%)	10
Non-cardiac chest pain	1/16 (6.3%)	1
Oedema peripheral	1/16 (6.3%)	1
Pyrexia	6/16 (37.5%)	6
Infections and infestations
Nasopharyngitis	1/16 (6.3%)	1
Pneumonia	1/16 (6.3%)	1
Investigations
Breath sounds abnormal	1/16 (6.3%)	1
Metabolism and nutrition disorders
Anorexia	2/16 (12.5%)	2
Dehydration	1/16 (6.3%)	1
Hyperglycaemia	1/16 (6.3%)	1
Hypocalcaemia	1/16 (6.3%)	1
Hypokalaemia	1/16 (6.3%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/16 (6.3%)	1
Bone pain	2/16 (12.5%)	3
Musculoskeletal pain	3/16 (18.8%)	5
Myalgia	1/16 (6.3%)	2
Pain in extremity	1/16 (6.3%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain	2/16 (12.5%)	2
Nervous system disorders
Depressed level of consciousness	1/16 (6.3%)	1
Dizziness	2/16 (12.5%)	2
Dysgeusia	2/16 (12.5%)	3
Headache	2/16 (12.5%)	2
Peripheral sensory neuropathy	1/16 (6.3%)	1
Psychiatric disorders
Anxiety	2/16 (12.5%)	2
Insomnia	2/16 (12.5%)	2
Renal and urinary disorders
Urinary retention	1/16 (6.3%)	1
Respiratory, thoracic and mediastinal disorders
Cough	4/16 (25%)	10
Dry throat	1/16 (6.3%)	1
Dyspnoea	2/16 (12.5%)	4
Dyspnoea exertional	1/16 (6.3%)	1
Haemoptysis	1/16 (6.3%)	1
Hypoxia	1/16 (6.3%)	2
Oropharyngeal blistering	1/16 (6.3%)	1
Pleuritic pain	1/16 (6.3%)	1
Pneumothorax	1/16 (6.3%)	1
Throat irritation	1/16 (6.3%)	3
Skin and subcutaneous tissue disorders
Alopecia	2/16 (12.5%)	2
Hyperhidrosis	1/16 (6.3%)	1
Night sweats	1/16 (6.3%)	1
Pruritus	2/16 (12.5%)	2
Rash	1/16 (6.3%)	1
Vascular disorders
Pallor	1/16 (6.3%)	1
Superior vena caval occlusion	1/16 (6.3%)	2
Venous thrombosis	1/16 (6.3%)	1

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 from the time submitted to the sponsor for review.