Clinical Trial of PM00104 (Zalypsis®) in Patients With Advanced and/or Metastatic Endometrial or Cervical Cancer Previously Treated With One Line of Systemic Chemotherapy
Condition: Uterine Cervical Cancer; Endometrial Cancer
MeSH terms: Uterine Cervical Neoplasms; Endometrial Neoplasms
Intervention: Zalypsis ( PM00104)
Intervention description: Zalypsis (PM00104) (2.5 mg/vial) is provided as a powder for concentrate for solution for infusion
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 19.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Zalypsis; Cancer; Endometrial; Uterine Cervical; PharmaMar

Summary:

      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.
    

Eligibility criteria:

        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.