PD0332991 (Palbociclib) in Patients With Advanced or Metastatic Liposarcoma
Condition: Sarcoma; Liposarcoma
MeSH terms: Liposarcoma
Intervention: Palbociclib 200mg; Palbociclib 125mg
Intervention description: Schedule 2/1: Palbociclib 200mg given once daily by mouth for 14 consecutive days, followed by 7 days of rest. A cycle will be defined as 21 days.; Schedule 3/1: Palbociclib 125mg given once daily by mouth for 21 consecutive days, followed by 7 days of rest. A cycle will be defined as 28 days. Following the positive results of the study, a new Expansion Cohort has been added to permit enrollment of up to 20 additional patients.
Expansion Cohort: Dosed as per Schedule 3/1. Capsules should be taken with food.
Intervention MeSH terms: Palbociclib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 90.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: soft tissue; Palbociclib (PD0332991); 10-094

Summary:

      The purpose of this study is to find out what effects, good and/or bad, Palbociclib (Ibrance)
      (formerly known as PD0332991) has on the patient and on the liposarcoma.

      Palbociclib is an investigational drug. An investigational drug is a medication that has not
      been approved for marketing by the Food and Drug Administration (FDA). Palbociclib blocks a
      protein called CDK4 which is part of a pathway in liposarcoma cells that is over-active. The
      investigators hope that blocking CDK4 will shut down this pathway in the liposarcoma cells
      and stop tumors from growing. Palbociclib is an oral medication.
    

Eligibility criteria:

        Inclusion Criteria:

          -  A diagnosis of liposarcoma confirmed at MSKCC. Because myxoid / round cell liposarcoma
             does not have significant CDK4 amplification, patients with this subtype are not
             eligible.

          -  Metastatic and/or locally advanced or locally recurrent disease that is not surgically
             resectable, with evidence of disease progression, either clinically or
             radiographically, as determined by the investigator

          -  All patients must have measurable disease as defined by RECIST 1.1. Measurable disease
             is defined as at least one lesion that can be accurately measured in at least one
             dimension (longest diameter to be recorded). Each lesion must be >10 mm when measured
             by CT, MRI or caliper measurement by clinical exam; or >20 mm when measured by chest
             x-ray. Lymph nodes must be > 15 mm in short axis when measured by CT or MRI.

          -  A minimum of 1 prior systemic regimen for recurrent/metastatic disease. Note: This
             requirement does not apply to patients enrolled in the Expansion Cohort. The last dose
             of systemic therapy (include targeted therapies) must have been given at least 2 weeks
             prior to initiation of therapy. Patients receiving BCNU or mitomycin C must have
             received their last dose of such therapy at least 6 weeks prior to initiation of
             therapy.

          -  Patients with brain metastasis that have been treated with definitive surgery or
             radiation and have been clinically stable for 3 months are eligible.

          -  Age > or = 18 years.

          -  ECOG performance status 0 or 1.

          -  Adequate organ and marrow function as defined below (ULN indicates institutional upper
             limit of normal):

        Absolute neutrophil count ≥ 1.5x109/L Hemoglobin ≥ 9.0 g/dL WBC ≥ 3.0x109/L Platelets ≥
        100x109/L Total bilirubin ≤ 1.5 x ULN except for patients with known Gilbert syndrome
        AST(SGOT)/ALT(SGPT) ≤ 3 x institutional ULN Serum creatinine ≤ 1.5 x ULN or Creatinine
        Clearance > 50 mL/min (calculated by Cockcroft-Gault method)QTc interval ≤ 470 msec

          -  Patients must not have current evidence of another malignancy that requires treatment.

          -  The effects of Palbociclib on the developing human fetus at the recommended
             therapeutic dose are unknown. Women of child-bearing potential and men must agree to
             use adequate contraception (hormonal or barrier method of birth control; abstinence).
             Women must not breast feed while on study.

          -  Ability to understand and the willingness to sign a written informed consent document.

          -  Ability to swallow intact Palbociclib capsules.

          -  Patients" tumors must express Rb, as assessed using an historical biopsy sample if
             available or a newly obtained tumor sample. Samples must demonstrate ≥1+ staining for
             Rb. Patients' tumors must also have evidence of CDK4 amplification by FISH. Note: This
             does not apply to patients enrolled in the Expansion Cohort.

        Exclusion Criteria:

          -  Patients who have not recovered from adverse events of prior therapy to ≤ NCI
             CTCAEv4.0 Grade 1.

          -  Patients receiving any other investigational agents.

          -  Patients who have received prior treatment with a selective CDK4 inhibitor

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to Palbociclib.

          -  Uncontrolled intercurrent illness including, but not limited to, known ongoing or
             active infection, including HIV, active hepatitis B or C, symptomatic congestive heart
             failure, unstable angina pectoris, cardiac arrhythmia (specifically, atrial
             fibrillation or ventricular dysrhythmias except ventricular premature contractions),
             or psychiatric illness/social situations that would limit compliance with study
             requirements.

          -  Pregnant women and women who are breast-feeding.

          -  Patients with a history of long-QT syndrome or documented family history of long-QT
             syndrome. Patients who must remain on drugs that prolong the QT interval.

          -  Palbociclib is a substrate of CYP3A. Caution should be exercised when dosing
             Palbociclib concurrently with CYP3A inducers or inhibitors. Furthermore, patients who
             are taking concurrent medications that are strong inducers/inhibitors or substrates of
             CYP3A4 should be switched to alternative medications to minimize any potential risk. A
             list of CYP3A4 substrates, inducers and/or inhibitors is provided in Appendix B. The
             following medications with strong potential for interaction are not allowed: indinavir
             nelfinavir ritonavir clarithromycin itraconazole ketoconazole nefazodone saquinavir
             telithromycin carbamazepine phenobarbital phenytoin pioglitazone rifabutin rifampin
             St. John's wort Troglitazone