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

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

Study Overview

• Status: Terminated
• Conditions: Refractory Acute Leukemia; Relapsed Acute Leukemia; High-Risk Myelodysplasia
• Intervention / Treatment: Drug: PD 0332991

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: Pfizer; The Leukemia and Lymphoma Society
• Investigators: Study Chair: Judith Karp, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: September 11, 2012
• First Submitted That Met QC Criteria: October 3, 2012
• First Posted (Estimate): October 5, 2012

Study Record Updates

• Last Update Posted (Estimate): September 9, 2013
• Last Update Submitted That Met QC Criteria: August 30, 2013
• Last Verified: August 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic Syndromes; Leukemia; Preleukemia; Acute Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Palbociclib
• Other Study ID Numbers: J1275; NA_00076003 (Other Identifier: JHMIRB)