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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

This study has been terminated.
(Material sponsor withdrew support)
The Leukemia and Lymphoma Society
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center Identifier:
First received: September 11, 2012
Last updated: August 30, 2013
Last verified: August 2013

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

Condition Intervention Phase
Relapsed Acute Leukemia
Refractory Acute Leukemia
High-Risk Myelodysplasia
Drug: PD 0332991
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I and Pharmacodynamic Trial of Timed Sequential Administration of the Cyclin Dependent Kinase 4/6 Inhibitor PD 0332991 Followed by Cytarabine Plus Mitoxantrone for Adults With Relapsed and Refractory Acute Leukemias and High-Risk Myelodysplasias

Resource links provided by NLM:

Further study details as provided by Sidney Kimmel Comprehensive Cancer Center:

Primary Outcome Measures:
  • The Toxicities of Administration of PD 0332991 in Combination With Cytarabine and Mitoxantrone. [ Time Frame: 42 days ]
    The number of participants experiencing toxicities of administration of PD 0332991 in combination with cytarabine and mitoxantrone will be measured according to NCI-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Secondary Outcome Measures:
  • To Determine the Maximal Tolerated Dose (MTD) of PD 0332991 in Timed Sequential Combination With Ara-C and Mitoxantrone [ Time Frame: 42 days ]
    Dose escalation decisions will be based on nonhematologic toxicities in Cycle 1 (28 days) and hematologic toxicities, in the case of an aplastic marrow through Day 56, For cytopenias including ANC < 500/mm3 or platelets < 50, 000/mm3 a bone marrow will be performed between days 42 and 49.. Dose limiting toxicity (DLT) will be measured according to NCI-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Enrollment: 2
Study Start Date: September 2012
Study Completion Date: April 2013
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1
  • PD 0332991 will be given orally days 1,2,3
  • Cytarabine (ara-C) will be given by continuous 72 hour intravenous infusion beginning on day 6
  • Mitoxantrone will be given over 2 hour infusion day 9, 12 hours after the completion of the ara-C infusion. The mitoxantrone dose may be reduced by 25-50% for patients who have received previous anthracyclines as determined by total previous anthracycline dose
Drug: PD 0332991
• PD 0332991 will be given orally days 1,2,3


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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
  Contacts and Locations
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Please refer to this study by its identifier: NCT01701375

United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States, 21287
United States, New York
Weill Cornell Medical Center
New York, New York, United States, 10065
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center
The Leukemia and Lymphoma Society
Study Chair: Judith Karp, MD Sidney Kimmel Comprehensive Cancer Center
  More Information

Responsible Party: Sidney Kimmel Comprehensive Cancer Center Identifier: NCT01701375     History of Changes
Other Study ID Numbers: J1275
NA_00076003 ( Other Identifier: JHMIRB )
Study First Received: September 11, 2012
Results First Received: June 14, 2013
Last Updated: August 30, 2013

Additional relevant MeSH terms:
Acute Disease
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Disease Attributes
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Protein Kinase Inhibitors processed this record on May 23, 2017