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

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01701375
• Collaborator: The Leukemia and Lymphoma Society (Other), Pfizer (Industry)
• Enrollment: 2
• Locations: 2
• Arm: 1
• Duration (Months): 7
• Patient Per Site: 1
• Patients Per Site Per Month: 0.1

Study Details

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
• 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: Sep 1, 2012
• Actual Primary Completion Date: Apr 1, 2013
• Actual Study Completion Date: Apr 1, 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. [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 [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

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21287
2	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT01701375
• Other Study ID Numbers: J1275; NA_00076003
• First Posted: Oct 5, 2012
• Last Update Posted: Sep 9, 2013
• Last Verified: Aug 1, 2013

• Additional relevant MeSH terms: Leukemia; Preleukemia; Myelodysplastic Syndromes; Acute Disease; Palbociclib

Study Results

Participant Flow

Recruitment Details	2 subjects were accrued

Arm/Group Title	Arm 1
Arm/Group Description	PD 0332991 125 was 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
Period Title: Overall Study
STARTED	2
COMPLETED	2
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Arm 1
Arm/Group Description	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
Overall Participants	2
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	2 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.5 (27)
Sex: Female, Male (Count of Participants)
Female	1 50%
Male	1 50%
Region of Enrollment (participants) [Number]
United States	2 100%

Outcome Measures

1. Primary Outcome

Title	The Toxicities of Administration of PD 0332991 in Combination With Cytarabine and Mitoxantrone.
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1
Arm/Group Description	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
Measure Participants	2
Number [participants]	2 100%

2. Secondary Outcome

Title	To Determine the Maximal Tolerated Dose (MTD) of PD 0332991 in Timed Sequential Combination With Ara-C and Mitoxantrone
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Arm 1
Arm/Group Description	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
All Cause Mortality
	Arm 1
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Arm 1
	Affected / at Risk (%)	# Events
Total	1/2 (50%)
Blood and lymphatic system disorders
Bone marrow aplasia	1/2 (50%)	1
Metabolism and nutrition disorders
Hyperbilirubinemia	1/2 (50%)	1
Other (Not Including Serious) Adverse Events
	Arm 1
	Affected / at Risk (%)	# Events
Total	2/2 (100%)
Gastrointestinal disorders
mucositis	2/2 (100%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.