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

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

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.

Study Overview

• Status: Completed
• Conditions: Ewing's Sarcoma; Primitive Neuroectodermal Tumor (PNET); Askin's Tumor of the Chest Wall; Extraosseous Ewing's Sarcoma (EOE)
• Intervention / Treatment: Drug: Zalypsis

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Lyon, France, 69373
    • Centre Leon Berard
• Italy
  • Bologna, Italy, 40136
    • Istituto Ortopedici Rizzoli
  • Milan, Italy, 20133
    • Istituto Nazionale dei Tumori
  • Rozzano, Italy, 20089
    • Istituto Clinico Humanitas
• United States
  • California
    • Santa Monica, California, United States, 90403
      • Sarcoma Oncology Center
  • Tennessee
    • Memphis, Tennessee, United States, 38105A
      • St. Jude Children 's Research Hospital
  • Washington
    • Seattle, Washington, United States
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.
13. Left ventricular ejection fraction (LVEF) within normal limits (LVEF of at least 50%).
14. 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).
8. 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.
9. 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.
10. Treatment with any investigational product within 30 days prior to inclusion in the study.
11. Known hypersensitivity to any component of Zalypsis®.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	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	At baseline and every other cycle (± 1 week) until evidence of PD, up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Tumor Response	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	At baseline and every other cycle (± 1 week) until evidence of PD, up to 2 years
Progression-free Survival	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	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 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	At 3 months
Overall Survival	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.	from the first day of treatment to the date of death, up to 2 years
Overall Survival Rate 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.	At 6 months
Overall Survival Rate 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.	At 12 months
PM00104 Plasma PK Parameters (Cmax) at First Infusion	Cmax Maximum plasma concentration, directly determined from the experimental data	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)
PM00104 Plasma PK Parameters (AUC) at First Infusion	AUC Area under the plasma concentration-time curve from time zero to infinity	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)
PM00104 Plasma PK Parameters (Cmax) at Second Infusion	Cmax Maximum plasma concentration, directly determined from the experimental data	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)
PM00104 Plasma PK Parameters (AUC) at Second Infusion	AUC Area under the plasma concentration-time curve from time zero to infinity	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)

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): April 1, 2012
• Study Completion (Actual): April 1, 2012

Study Registration Dates

• First Submitted: October 8, 2010
• First Submitted That Met QC Criteria: October 15, 2010
• First Posted (Estimate): October 18, 2010

Study Record Updates

• Last Update Posted (Actual): October 29, 2021
• Last Update Submitted That Met QC Criteria: September 30, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: PNET; EOE; EFT
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms; Sarcoma; Sarcoma, Ewing; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral
• Other Study ID Numbers: PM104-B-003-10