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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

Information source: Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Relapsed Acute Leukemia; Refractory Acute Leukemia; High-Risk Myelodysplasia

Intervention: PD 0332991 (Drug)

Phase: Phase 1

Status: Terminated

Sponsored by: Sidney Kimmel Comprehensive Cancer Center

Official(s) and/or principal investigator(s):
Judith Karp, MD, Study Chair, Affiliation: Sidney Kimmel Comprehensive Cancer Center


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


- 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

Clinical Details

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

Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: The Toxicities of Administration of PD 0332991 in Combination With Cytarabine and Mitoxantrone.

Secondary outcome: To Determine the Maximal Tolerated Dose (MTD) of PD 0332991 in Timed Sequential Combination With Ara-C and Mitoxantrone


Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.


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


- 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

Locations and Contacts

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21287, United States

Weill Cornell Medical Center, New York, New York 10065, United States

Additional Information

Starting date: September 2012
Last updated: August 30, 2013

Page last updated: August 23, 2015

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