Clinical trial NCT01701375: 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
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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Relapsed Acute Leukemia
Refractory Acute Leukemia
High-Risk Myelodysplasia
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
Collaborators: name: The Leukemia and Lymphoma Society
name: Pfizer
First posted: 2012-10-05
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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


Eligibility 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

Primary outcomes:
measure: The Toxicities of Administration of PD 0332991 in Combination With Cytarabine and Mitoxantrone.
timeFrame: 42 days
Secondary outcomes:
measure: To Determine the Maximal Tolerated Dose (MTD) of PD 0332991 in Timed Sequential Combination With Ara-C and Mitoxantrone
timeFrame: 42 days
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: New York
country: United States
facility: Weill Cornell Medical Center
state: New York
Study officials:
affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
name: Judith Karp, MD
role: STUDY_CHAIR
References: