Clinical Trial of PM00104 (Zalypsis®) in Patients With Advanced and/or Metastatic Endometrial or Cervical Cancer Previously Treated With One Line of Systemic Chemotherapy

Phase II Clinical and Pharmacokinetic Trial of PM00104 (Zalypsis®) in Patients With Advanced and/or Metastatic Endometrial or Cervical Cancer Previously Treated With One Line of Systemic Chemotherapy

This study is a phase II clinical and pharmacokinetic trial of PM00104 (Zalypsis®) in patients with advanced and/or metastatic endometrial or cervical cancer previously treated with one line of systemic chemotherapy to evaluate the antitumor activity and to determine the safety profile, the pharmacokinetic profile and the pharmacogenomic profile.

Inclusion Criteria:

1. Voluntary written informed consent, obtained from the patient before the beginning of any specific study procedures.

2. Group 1 (endometrial cancer):

   • Histologically confirmed advanced and/or metastatic endometrial cancer (any grade, including endometrioid, clear cell, serous and mixed types) with documented disease progression as per RECIST at study entry.
   • Patients must have failed one prior systemic chemotherapy line for advanced/metastatic disease (excluding chemosensitizing chemotherapy); prior hormone therapy and biological therapy are allowed.

3. Group 2 (cervical cancer):

   • Histologically confirmed advanced and/or metastatic cervical cancer with documented disease progression as per RECIST at study entry.
   • Patients must have failed one prior systemic chemotherapy line for advanced/metastatic disease (excluding chemosensitizing chemotherapy); prior hormone therapy and biological therapy are allowed.

4. Complete recovery from the effects of prior radiotherapy and from any 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 (NCICTCAE, v.3.0).

5. At least one measurable lesion ("target lesion" according to the RECIST), 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 "nontarget" lesions unless progression is clearly documented or biopsy proven.

6. Age ≥ 18 years.

7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 1.

8. Life expectancy ≥ 3 months.

9. Appropriate bone marrow reserve, renal and hepatic functions:

   • Platelet count ≥ 100 x 109/l, hemoglobin ≥ 9 g/dl and absolute neutrophil count (ANC) ≥ 1.5 x 109/l.
   • Alkaline phosphatase (AP) ≤ 2.5 x upper limit of normality (ULN) (≤ 5 x ULN in case of extensive bone metastases).
   • Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN in case of hepatic metastases).
   • Total bilirubin ≤ 1.5 x ULN, unless due to Gilbert's syndrome.
   • Renal function: patients with calculated creatinine clearance (using Cockcroft and Gault formula) ≥ 30 ml/min.
   • Albumin ≥ 2.5 g/dl.

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

11. Women of childbearing potential must have a negative serum pregnancy test before study entry. In case of childbearing potential, the patients and their partners must agree to use a medically acceptable method of contraception.

Exclusion Criteria:

1. Prior therapy with PM00104.

2. Uterine sarcomas, adenosarcoma, and malignant Mullerian tumors.

3. Cervical neuroendocrine or small cell carcinomas, nonepithelial cervical neoplasms such as sarcomas.

4. Patients who have isolated recurrences (vaginal, pelvic or paraaortic) potentially curative with radiation therapy or surgery.

5. Pregnant or lactating women, or in case of childbearing potential, women not using an appropriate contraceptive method.

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

   • 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.

7. Group 1 (endometrial cancer): more than one line of prior systemic chemotherapy for advanced/metastatic disease (excluding chemosensitizing chemotherapy), but not less than three weeks before.

8. Group 2 (cervical cancer): more than one line of prior systemic chemotherapy for advanced/metastatic disease (excluding chemosensitizing chemotherapy, but not less than three weeks before.

9. Patients with a prior invasive malignancy (except nonmelanoma skin cancer) who have had any evidence of disease within the last five years or whose prior malignancy treatment contraindicates the current protocol therapy.

10. Patients with serious non-healing wound, ulcer, or bone fracture.

    • This includes history of: abdominal fistula, gastrointestinal perforation or intra-abdominal abscess for which an interval of three to six months must pass before study entry.
    • In addition, the patient must have undergone correction (or spontaneous healing) of the perforation/fistula and/or the underlying process causing the fistula/perforation.
    • Patients with granulating incisions healing by secondary intention with no evidence of fascial dehiscence or infection are eligible but require weekly wound examinations.

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

12. 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, active chronic hepatitis).

    • 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).

13. 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 for uncertainty in this regard.

14. 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.

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

16. Known hypersensitivity to any component of PM00104.