High-Risk Myelodysplasia, Refractory Acute Leukemia, Relapsed Acute Leukemia
Conditions
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
Interventions
DRUGPD 0332991
• PD 0332991 will be given orally days 1,2,3
Sponsors
The Leukemia and Lymphoma Society
Pfizer
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Toxicities of Administration of PD 0332991 in Combination With Cytarabine and Mitoxantrone. | 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
| Measure | Time frame | Description |
|---|---|---|
| To Determine the Maximal Tolerated Dose (MTD) of PD 0332991 in Timed Sequential Combination With Ara-C and Mitoxantrone | 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 |
Countries
United States
Participant flow
Recruitment details
2 subjects were accrued
Participants by arm
| Arm | Count |
|---|---|
| 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 | 2 |
| Total | 2 |
Baseline characteristics
| Characteristic | Arm 1 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Age Continuous | 45.5 years STANDARD_DEVIATION 27 |
| Region of Enrollment United States | 2 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 2 / 2 |
| serious Total, serious adverse events | 1 / 2 |
Outcome results
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
Time frame: 42 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 | The Toxicities of Administration of PD 0332991 in Combination With Cytarabine and Mitoxantrone. | 2 participants |
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
Time frame: 42 days