MLN4924 for the Treatment of Acute Myelogenous Leukemia, Myelodysplastic Syndrome, and Acute Lymphoblastic Leukemia

Sponsor

Millennium Pharmaceuticals, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT00911066

Collaborator

(none)

Enrollment

Locations

Arms

Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

An open-label, multicenter, phase 1, dose escalation study of MLN4924 in adult patients with acute myelogenous leukemia (AML), high-grade myelodysplastic syndrome (MDS). The patient population will consist of adults previously diagnosed with AML including high-grade MDS for which standard curative, life-prolonging treatment does not exist or is no longer effective.

Condition or Disease	Intervention/Treatment	Phase
Acute Myelogenous Leukemia Acute Lymphoblastic Leukemia Myelodysplastic Syndrome	Drug: MLN4924 Drug: Azacitidine	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

72 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Open-Label, Dose Escalation, Phase 1 Study of MLN4924, a Novel Inhibitor of Nedd8-Activating Enzyme, in Adult Patients With Acute Myelogenous Leukemia,Myelodysplastic Syndrome, and Acute Lymphoblastic Leukemia

Study Start Date :

Jun 1, 2009

Actual Primary Completion Date :

Aug 1, 2013

Actual Study Completion Date :

Oct 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MLN4924	Drug: MLN4924 MLN4924 intravenous (IV) on a 21-day cycle on one of the following schedules: Days 1, 3, and 5, followed by a rest period of 16 days (Schedule A) Days 1, 4, 8, and 11, followed by a rest period of 10 days (Schedule B) Continuous weekly dosing on Days 1, 8, and 15 (Schedule C) Days 1, 4, 11, 15 for Cycle 1 only; Days 1, 4, 8, 11 for all subsequent cycles (Schedule D) Dosing on Days 1, 3, and 5 in patients with high-grade MDS or AML (Schedule E)
Experimental: Azacitidine	Drug: Azacitidine Azacitidine will be administered (IV or subcutaneous (SC)) on Days 8 to 12 and Days 15 and 16 in Cycle 1, and on Days 1 to 5 and Days 8 to 9 (Schedule D)

Arm

Intervention/Treatment

Experimental: MLN4924

Drug: MLN4924

MLN4924 intravenous (IV) on a 21-day cycle on one of the following schedules: Days 1, 3, and 5, followed by a rest period of 16 days (Schedule A) Days 1, 4, 8, and 11, followed by a rest period of 10 days (Schedule B) Continuous weekly dosing on Days 1, 8, and 15 (Schedule C) Days 1, 4, 11, 15 for Cycle 1 only; Days 1, 4, 8, 11 for all subsequent cycles (Schedule D) Dosing on Days 1, 3, and 5 in patients with high-grade MDS or AML (Schedule E)

Experimental: Azacitidine

Drug: Azacitidine

Azacitidine will be administered (IV or subcutaneous (SC)) on Days 8 to 12 and Days 15 and 16 in Cycle 1, and on Days 1 to 5 and Days 8 to 9 (Schedule D)

Outcome Measures

Primary Outcome Measures

Adverse events, serious adverse events, assessments of clinical laboratory values, and vital sign measurements [12 months]

Secondary Outcome Measures

Pharmacokinetic parameters [12 months]
Pharmacodynamic effects [12 months]
Assess disease response [12 months]
Heart corrected QT intervals [During screening and during Cycle 1, Days 1 and 15]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age greater than or equal to 18 years
Have the following diagnosis:
AML or ALL (for the dose escalation phase only)including leukemia secondary to prior chemotherapy or resulting from an antecedent hematologic disorder, who have failed to achieve complete response (CR) or who have relapsed after prior therapy and are not candidates for potentially curative treatment.
Acute Promyelocytic Leukemia (APL) patients are not eligible
AML or ALL patients who are over age 60 and have not received prior therapy are also eligible if they are not candidates for standard induction chemotherapy
High-grade MDS, defined as > 10% blasts on bone marrow examination
Low-grade MDS, defined as < 10% blasts on bone marrow examination (Schedule B expansion cohort only)
Patients who are willing to refrain from donating blood for at least 90 days after their final dose of MLN4924 and (for male patients) willing to refrain from donating semen for at least 4 months after their final dose of MLN4924
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
Female patients who are postmenopausal, surgically sterile, or agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse
Male patients who agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse
Voluntary written consent
Suitable venous access
Adequate clinical laboratory values during the screening period as specified in the protocol
Patients who are on hydroxyurea may be included in the study and may continue on hydroxyurea while participating in this study.

Exclusion Criteria:

Female patients who are lactating or have a positive serum pregnancy test during the screening period
Any serious medical or psychiatric illness
Treatment with any investigational products
Systemic antineoplastic therapy or radiotherapy within 14 days before the first dose of study drug, except for hydroxyurea
Major surgery within 14 days before the first dose of study drug
Life-threatening illness unrelated to cancer
Clinically uncontrolled central nervous system (CNS) involvement
Known human immunodeficiency virus (HIV) positive
Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection
Evidence of uncontrolled cardiovascular conditions as specified in the protocol
Diarrhea > Grade 1, based on the NCI CTCAE categorization
Systemic treatment with prohibited medications
Ongoing anticoagulant therapy (eg, aspirin, Coumadin, heparin) that cannot be held to permit bone marrow sampling
Use of acetaminophen, acetaminophen-containing products, and statins are not permitted on the day before dosing, day of dosing, and day after dosing with MLN4924

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University Medical Center	Stanford	California	United States	94305
2	Robert H. Lurie Comprehensive Cancer Center Northwestern University	Chicago	Illinois	United States	60657
3	Johns Hopkins Kimmel Cancer Center	Baltimore	Maryland	United States	21287
4	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
5	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
6	Institute for Drug Development	San Antonio	Texas	United States	78229