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

• ClinicalTrials.gov Identifier: NCT01701375
• Recruitment Status: Terminated
• First Posted: October 5, 2012
• Results First Posted: September 9, 2013
• Last Update Posted: September 9, 2013
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: The Leukemia and Lymphoma Society; Pfizer
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Description

Brief 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

Condition or disease	Intervention/treatment	Phase
Relapsed Acute Leukemia; Refractory Acute Leukemia; High-Risk Myelodysplasia	Drug: PD 0332991	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 2 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (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
• Study Start Date: September 2012
• Actual Primary Completion Date: April 2013
• Actual Study Completion Date: April 2013

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. The Toxicities of Administration of PD 0332991 in Combination With Cytarabine and Mitoxantrone. [ Time Frame: 42 days ]
   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 :

1. To Determine the Maximal Tolerated Dose (MTD) of PD 0332991 in Timed Sequential Combination With Ara-C and Mitoxantrone [ Time Frame: 42 days ]
   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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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

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 at Johns Hopkins

The Leukemia and Lymphoma Society

Pfizer

Investigators

• Study Chair: Judith Karp, MD; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

More Information

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT01701375
• Other Study ID Numbers: J1275; NA_00076003 ( Other Identifier: JHMIRB )
• First Posted: October 5, 2012
• Results First Posted: September 9, 2013
• Last Update Posted: September 9, 2013
• Last Verified: August 2013

Additional relevant MeSH terms:

Leukemia; Preleukemia; Myelodysplastic Syndromes; Acute Disease; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Pathologic Processes; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Palbociclib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action