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)
Sponsor:
Collaborators:
The Leukemia and Lymphoma Society
Pfizer
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT01701375
First received: September 11, 2012
Last updated: August 30, 2013
Last verified: August 2013
  Purpose

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
Endpoint Classification: Safety/Efficacy Study
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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01701375

Locations
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
Pfizer
Investigators
Study Chair: Judith Karp, MD Sidney Kimmel Comprehensive Cancer Center
  More Information

No publications provided

Responsible Party: Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT01701375     History of Changes
Other Study ID Numbers: J1275, NA_00076003
Study First Received: September 11, 2012
Results First Received: June 14, 2013
Last Updated: August 30, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Acute Disease
Leukemia
Myelodysplastic Syndromes
Preleukemia
Bone Marrow Diseases
Disease Attributes
Hematologic Diseases
Neoplasms
Neoplasms by Histologic Type
Pathologic Processes
Precancerous Conditions
Cytarabine
Mitoxantrone
Analgesics
Anti-Infective Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antiviral Agents
Central Nervous System Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sensory System Agents
Therapeutic Uses
Topoisomerase II Inhibitors

ClinicalTrials.gov processed this record on October 29, 2014