Ensayos clínicos

Inclusion Criteria:

• Written informed consent in accordance with national, local, and institutional guidelines obtained prior to any screening procedures.
• Must be willing and able to comply with the protocol.
• Patients ≥ 12 years of age (patients <18 years of age are permitted only in countries in which adolescents have been approved by the national/local regulatory/ethical authority).
• Patients with a body surface area (BSA) ≥ 1.2 m2 as calculated per Dubois 1916 or Mosteller 1987.
• Documented histologic evidence of DDLS at any time from initial diagnosis to randomization AND current evidence of DDLS requiring treatment (documented evidence of disease progression from the most recent treatment):
  • Documentation of histologic evidence of DDLS requires the following:
    • This information will be provided based on prior diagnostic testing and is required for randomization;
    • Tissue (fresh or archival) will be provided for confirmatory histology at a central laboratory but confirmatory results are not required prior to randomization;
    • If archival tissue > 12 months old, the quality of the sample for confirmatory histology must be confirmed by the site histopathologist prior to randomization.
• Must have measurable disease according to:
  • The bidimensional WHO Response Criteria (Miller 1981) (Phase 2 patients only);
  • RECIST v. 1.1 (Eisenhauer 2009)(Phase 3 patients only).
• Radiologic evidence of progressive disease (PD) within 6 months prior to randomization.  If the patient received other intervening therapy after PD is documented, further PD must be documented after the completion of the intervening therapy, with the exception of patients who discontinued most recent treatment after no more than 1 dose.
• Must have received at least 2 but no more than 5 prior systemic therapies for the treatment of liposarcoma.
• Patients should have recovered from all major surgery, radiation or other interventions ≥ 21 days prior to randomization. Patients must have recovered from any clinically significant therapy-related toxicity to ≤ Grade 1 per CTCAE v. 4.03. Minor procedures, such as biopsies, dental work, or placement of a port or intravenous line for infusion, are permitted.
• If patients received any previous systemic therapy, the last dose must have been ≥21 days prior to randomization (or ≥5 half-lives of that drug [whichever is shorter]), with all clinically significant therapy-related toxicities having resolved to ≤ Grade 1 CTCAE.
• ECOG performance status ≤1 (Oken 1982).
• Adequate laboratory functional values:
  • Adequate hematopoietic function:
    • Absolute neutrophil count (ANC) ≥1500/mm3;
    • Platelets ≥100,000/mm3;
    • Hemoglobin (Hb) ≥9 g/dL;
    • Transfusions, hematopoietic growth factors, and hematinics are NOT permitted during screening.
  •  Adequate hepatic function:
    • Bilirubin ≤1.5 x upper limit of normal (ULN) (except patients with Gilbert’s syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of ≤ x ULN);
    • Alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) <3.0 x ULN (except patients with liver involvement of their liposarcoma who must have an AST and ALT ≤5 x ULN);
    • Adequate renal function: Serum creatinine of ≤ 1.5 mg/dL or estimated creatinine clearance of ≥ 30 mL/min, calculated using the Cockcroft and Gault formula (140 –Age) • Mass (kg)/ (72 • creatinine mg/dL); multiply by 0.85 if female (Cockcroft 1976).
• Female patients of childbearing potential must have a negative serum pregnancy test at Screening. Female patients of childbearing potential and fertile male patients who are sexually active with a female of childbearing potential must agree to use highly effective contraception throughout the study and for 3 months following the last dose of study treatment. Highly effective methods of contraception are listed in Section 13.3.1.

Exclusion Criteria:

• Patients with liposarcoma of pure WDLS, myxoid/round cell or pleomorphic tumor histologic subtypes.
• Significant cardiovascular impairment, defined as:
  • Cardiac failure, New York Heart Association (NYHA) Class ≥ 3 according to the NYHA Functional Classification;
  • Unstable angina or myocardial infarction within 3 months of enrollment;
  • Serious and potentially life-threatening arrhythmia.
• Patients with known central nervous system metastases.
• Female patients who are pregnant or nursing.
• Prior malignancy that required treatment, or has shown evidence of recurrence (except for non-melanoma skin cancer or adequately treated cervical carcinoma in situ) during the 5 years prior to randomization. Cancer treated with curative intent > 5 years prior to randomization and without evidence of recurrence is allowed.
• Known active hepatitis B infection, as defined by seropositivity for hepatitis B surface antigen (HBs Ag); or known hepatitis C infection, as defined by seropositivity for hepatitis C antibody, with elevated liver aminotransferases (i.e., above the levels specified in inclusion criterion) or any other evidence of active hepatitis.
• Known human immunodeficiency virus (HIV) infection.
• Any medical condition, such as an uncontrolled infection or uncontrolled diabetes mellitus (Type 2), which in the opinion of the Investigator would make study involvement unreasonably hazardous.
• Psychiatric illness that would prevent the patient from giving informed consent or being compliant with the study procedures.
• Patients unable to swallow tablets, patients with malabsorption syndrome, or any other GI disease or GI dysfunction that could interfere with absorption of study treatment.
• Inability or unwillingness to take supportive medications such as anti-nausea and antianorexia agents as recommended by the NCCN CPGO for antiemesis and anorexia/cachexia (palliative care).
• Patients who had involuntary weight loss of ≥ 10% in the 3 months prior to randomization.
• Participation in an investigational anticancer study ≤ 21 days prior to randomization.
• A circulating lymphocyte count of >50,000/μL (for sites in France only).