Alvocidib, Cytarabine, and Mitoxantrone in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00407966
• Collaborator: (none)
• Enrollment: 45
• Location: 1
• Arm: 1
• Duration (Months): 37
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

This phase II trial is studying the side effects and how well giving alvocidib together with cytarabine and mitoxantrone works in treating patients with newly diagnosed acute myeloid leukemia. Drugs used in chemotherapy, such as alvocidib, cytarabine, and mitoxantrone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

Condition or Disease	Intervention/Treatment	Phase
Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia	Drug: alvocidib; Drug: cytarabine; Drug: mitoxantrone hydrochloride	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the efficacy and toxicities of flavopiridol (alvocidib) followed by ara-C and mitoxantrone in adults with newly diagnosed acute myelogenous leukemia (AML) with poor-risk features.

2. To determine the disease free and overall survival of patients exhibiting a response to treatment with flavopiridol followed by ara-C and mitoxantrone.

OUTLINE:

Patients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9. Beginning 35-63 days after completion of course 1, patients achieving complete or partial remission may receive a second course of treatment as above.

Patients age 50 and over with "core binding factor" acute myeloid leukemia (AML) (e.g., t[8;21], inv[16], or t[16;16]) achieving a complete remission after course 1 of treatment may receive 3-4 courses of consolidation therapy comprising high-dose cytarabine at the discretion of the investigator.

After completion of study treatment, patients are followed periodically.

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Alvocidib (NSC 649890, Flavopiridol) in Timed Sequential Combination With Cytosine Arabinoside (Ara-C) and Mitoxantrone for Adults With Newly Diagnosed, Previously Untreated, Poor-Risk Acute Myelogenous Leukemias
• Study Start Date: Oct 1, 2006
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Nov 1, 2009

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (alvocidib, cytarabine, mitoxantrone hydrochloride) Patients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9. Beginning 35-63 days after completion of course 1, patients achieving complete or partial remission may receive a second course of treatment as above. Patients age 50 and over with "core binding factor" acute myeloid leukemia (AML) (e.g., t[8;21], inv[16], or t[16;16]) achieving a complete remission after course 1 of treatment may receive 3-4 courses of consolidation therapy comprising high-dose cytarabine at the discretion of the investigator.

Drug: alvocidib; Given IV; Other Names: FLAVO flavopiridol HMR 1275 L-868275 ; Drug: cytarabine; Given IV; Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside ; Drug: mitoxantrone hydrochloride; Given IV; Other Names: CL 232315 DHAD DHAQ Novantrone

Outcome Measures

Primary Outcome Measures

1. Complete Response [6 months]

   Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, an Absolute Neutrophil Count of at least 1000/mililiter and a platelet count of 100,000 mililiter, absence of blast in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease. A complete remission must be confirmed 4 to 6 weeks after the initial documentation. If possible, at least one bone marrow biopsy should be performed to confirm the complete remission.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adults with established, pathologically confirmed diagnoses of newly diagnosed, poor-risk Acute Myeloid Leukemia(AML) including de novo and secondary Acute Myeloid Leukemias but excluding newly diagnosed acute progranulocytic leukemia (APL, M3) will be considered eligible for study

• ECOG performance status 0-2

• Patient must be able to give informed consent

• Serum creatinine =< 2.0

• ALT, AST =< 5 x upper limit of normal

• Bilirubin =< 2.0 mg/dl

• Left ventricular ejection fraction >= 45%

• Newly diagnosed AML, subtypes M0,1,2,4-7 but excluding M3 (APL) with poor-risk features, including:

• Age > 50 years, or age > 18 years with one or more of the following criteria:

• Antecedent hematologic disorder including myelodysplasia (MDS)-related AML (MDS/AML) and prior myeloproliferative disorder (MPD)

• Treatment-related AML

• AML with trilineage dysplasia (AML-TLD)

• Adverse cytogenetics (defined as -5/-5q; -7/-7q; abnormal 3q, 9q, 11q, 20q, 21q or 17p; t(6;9); t(9;22); trisomy 8; trisomy 13, complex karyotypes (>= 3 unrelated abnormalities)

Exclusion Criteria:

• Patients who have received hydroxyurea alone or have received non-cytotoxic therapies previously for MDS or MPD (e.g., thalidomide or lenalidomide, interferon, cytokines, low-dose 5-azacytidine, low-dose cytoxan) will be eligible for this trial

• Any previous treatment with flavopiridol

• Concomitant chemotherapy, radiation therapy, or immunotherapy

• Hyperleukocytosis with >= 50,000 blasts/uL; leukapheresis or hydroxyurea may be used immediately prior to study drug administration for cytoreduction; must be stopped 24 hours before first dose of Flavopiridol

• Acute Progranulocytic Leukemia (APL, M3)

• Active CNS leukemia

• Active, uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible

• Presence of other life-threatening illness

• Patients with mental deficits and/or psychiatric history that preclude them form giving informed consent or from following protocol

• Pregnant and nursing patients are excluded

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Judith Karp, Johns Hopkins University/Sidney Kimmel Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00407966
• Other Study ID Numbers: NCI-2012-02986; NCI-2012-02986; U01CA070095; P30CA006973; J0669; 7845
• First Posted: Dec 5, 2006
• Last Update Posted: Aug 4, 2015
• Last Verified: Dec 1, 2012

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Monocytic, Acute; Leukemia, Myelomonocytic, Acute; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute; Leukemia, Basophilic, Acute; Leukemia, Eosinophilic, Acute; Hypereosinophilic Syndrome; Cytarabine; Mitoxantrone; Alvocidib

Study Results

Participant Flow

Recruitment Details	From December 2006 through June 2008

Arm/Group Title	Arm A
Arm/Group Description	Flavopiridol, ara-C, mitoxantrone
Period Title: Overall Study
STARTED	45
CR	30
COMPLETED	45
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Arm A
Arm/Group Description	Flavopiridol, ara-C, mitoxantrone
Overall Participants	45
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	32 71.1%
>=65 years	13 28.9%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61 (50)
Sex: Female, Male (Count of Participants)
Female	22 48.9%
Male	23 51.1%
Region of Enrollment (participants) [Number]
United States	45 100%

Outcome Measures

1. Primary Outcome

Title	Complete Response
Description	Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, an Absolute Neutrophil Count of at least 1000/mililiter and a platelet count of 100,000 mililiter, absence of blast in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease. A complete remission must be confirmed 4 to 6 weeks after the initial documentation. If possible, at least one bone marrow biopsy should be performed to confirm the complete remission.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Total number of participants entered between December 2006 and June 2008

Arm/Group Title	Arm A
Arm/Group Description	Flavopiridol, ara-C, mitoxantrone
Measure Participants	45
Number [participants]	45 100%

Adverse Events

Time Frame	Adverse events were collected from the time of treatmetn through recovery of blood counts and response assessment
Arm/Group Title	Arm A
Arm/Group Description	Flavopiridol, ara-C, mitoxantrone
All Cause Mortality
	Arm A
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Arm A
	Affected / at Risk (%)	# Events
Total	19/45 (42.2%)
Cardiac disorders
cardiac dysfunction	7/45 (15.6%)	7
Investigations
Desseminated Intravascular Coagulopathy	3/45 (6.7%)	3
Metabolism and nutrition disorders
Tumor lysis syndrome	19/45 (42.2%)	19
Other (Not Including Serious) Adverse Events
	Arm A
	Affected / at Risk (%)	# Events
Total	25/45 (55.6%)
Gastrointestinal disorders
oral mucositis	14/45 (31.1%)	14
Diarrhea	11/45 (24.4%)	11
GI Mucositis	5/45 (11.1%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.