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
| Status: | Recruiting |
|---|---|
| Conditions: | Other Indications, Blood Cancer |
| Therapuetic Areas: | Oncology, Other |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 10/3/2013 |
| Start Date: | September 2012 |
| End Date: | September 2016 |
| Contact: | Judith Karp, MD |
| Email: | jkarp2@jhmi.edu |
| Phone: | 410-502-7726 |
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
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
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
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Weill Medical College of Cornell University Founded in 1898, and affiliated with what is now...
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Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins The name Johns Hopkins has become synonymous...
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