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.

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®.