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

Refractory Acute Leukemia Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01701375
• Other study ID #: J1275
• Secondary ID: NA_00076003
• Status: Terminated
• Phase: Phase 1
• First received: September 11, 2012
• Last updated: August 30, 2013
• Start date: September 2012
• Est. completion date: April 2013

Study information

• Verified date: August 2013
• Source: Sidney Kimmel Comprehensive Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2
• Est. completion date: April 2013
• Est. primary completion date: April 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Acute Disease
• High-Risk Myelodysplasia
• Leukemia
• Myelodysplastic Syndromes
• Preleukemia
• Refractory Acute Leukemia
• Relapsed Acute Leukemia

Intervention

Drug:
• PD 0332991
• PD 0332991 will be given orally days 1,2,3

Locations

Country	Name	City	State
United States	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	Weill Cornell Medical Center	New York	New York

Sponsors (3)

Lead Sponsor	Collaborator
Sidney Kimmel Comprehensive Cancer Center	Pfizer, The Leukemia and Lymphoma Society

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The Toxicities of Administration of PD 0332991 in Combination With Cytarabine and Mitoxantrone.	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	42 days	Yes
Secondary	To Determine the Maximal Tolerated Dose (MTD) of PD 0332991 in Timed Sequential Combination With Ara-C and Mitoxantrone	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	42 days	Yes