A Phase 1 Trial of TST of PD 0332991 Followed by Cytarabine and Mitoxantrone for Adults With Relapsed and Refractory Acute Leukemias and High-Risk Myelodysplasia
Condition: Relapsed Acute Leukemia; Refractory Acute Leukemia; High-Risk Myelodysplasia
MeSH terms: Leukemia; Preleukemia; Myelodysplastic Syndromes; Acute Disease
Intervention: PD 0332991
Intervention description: • PD 0332991 will be given orally days 1,2,3
Intervention MeSH terms: Palbociclib
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      1.1 Primary Objectives

        -  To determine the feasibility, tolerability, and toxicities of administering the
           selective CDK 4/6 inhibitor PD 0332991 prior to the combination of ara-C and
           Mitoxantrone for adults with relapsed and refractory acute leukemias and high risk
           myelodysplasias (MDS), including primary refractory disease

        -  To determine the direct cytotoxic effects of single agent PD 0332991 on malignant blasts

        -  To determine the maximal tolerated dose (MTD) of PD 0332991 in timed sequential
           combination with ara-C and Mitoxantrone

        -  To determine if the timed sequential combination of PD 0332991 with ara-C and
           mitoxantrone can induce clinical responses in adults with relapsed or refractory acute
           leukemias and high-risk MDS

      1.2 Secondary Objectives:

        -  To determine the ability of PD 0332991 to directly induce apoptosis in malignant cell
           populations in vivo

        -  To obtain pharmacodynamic (PD) data regarding the ability of PD 0332991 to arrest
           malignant cells in the G 1 phase of cell cycle, followed by synchronized release of
           those cells into S phase upon discontinuation of PD 0332991 and resultant enhanced ara-C
           cytotoxicity
    

Eligibility criteria:

        Inclusion Criteria:

          -  Adults age ≥ 18 years

               -  Multilineage bone marrow failure

               -  Serum creatinine ≤ 2.0 mg/dl

               -  Hepatic enzymes (AST, ALT) ≤ 3x upper limit of normal (ULN)

               -  Bilirubin ≤ 2.0 mg/dl, unless due to Gilbert's disease, hemolysis or leukemic
                  infiltration

               -  Left ventricular ejection fraction ≥ 45%

               -  QTc ≤ 470 msec

               -  RB expression is required for the action of PD 0332991. Because rb deletions and
                  mutations are rare in acute leukemias and MDS, screening for RB expression will
                  not be required before enrollment. Pretreatment biopsies will be stored and
                  analyzed for RB expression if needed subsequently.

        Exclusion Criteria:

          -  • No more than 5 cytotoxic regimens

               -  Previous allogeneic or autologous stem cell transplantation permitted

               -  ≥ 3 weeks delay from prior cytotoxic chemotherapy or radiation therapy

               -  ≥ 2 week delay from prior biologic therapies including hematopoietic growth
                  factors and vidaza or decitabine

               -  If using Hydroxyurea, steroids, tyrosine kinase/src kinase inhibitors, arsenic,
                  interferon for count control, must be off therapy for ≥ 48 hours prior to
                  beginning PD 0332991

               -  No concomitant use of potent CYP450 3A4 inhibitors (e.g. triazole antifungal
                  agents) or inducers (e.g. omperazole, dilantin, dexamethasone) within 7 days
                  prior to beginning PD 0332991