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
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
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
- 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
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).
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
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
6. Evidence of progressive or symptomatic central nervous system (CNS) metastases or
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
- 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
- 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
11. Known hypersensitivity to any component of Zalypsis®.