Jason Gotlib
An Open-Label, Dose Escalation, Phase 1 Study of MLN4924, a Novel Inhibitor of Nedd8-Activating Enzyme, in Adult Patients with Acute Myelogenous Leukemia and High-Grade Myelodysplastic Syndrome
Contact Information
Stanford University School of Medicine 300 Pasteur Drive Stanford, CA 94305Brief
Brief Summary: The purpose of this study is to determine the safety profile, establish the maximum tolerated dose (MTD), and inform the recommended phase 2 dose of MLN4924 administered intravenously (IV) in patients with Acute Myelogenous Leukemia (AML) and high grade Myelodysplastic Syndrome (MDS). We will also evaluate disease response that may be observed with MLN4924. We will also describe the pharmacokinetics (PK) of IV-administered MLN4924 in plasma and the pharmacodynamic effects of MLN4924 in peripheral blood and bone marrow.
Recruiting Status:
RecruitingStanford Recruiting Status:
RecruitingCondition(s):
Intervention(s):
- Drug: MLN4924
Phase:
Phase 1Eligibility
Ages Eligible for Study:
18 years to Any AgeGenders Eligible for Study:
Male and FemaleHealth of Volunteers:
People with the conditions listed in this trial can participate as controls.Key Inclusion Criteria:
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Male or female patients 18 years or older
2. Have the following diagnosis:
a) AML (as defined in the World Health Organization [WHO] criteria(7)) including leukemia secondary to prior chemotherapy or resulting from an antecedent hematologic disorder, who have failed to achieve CR or who have relapsed after prior therapy and are not candidates for potentially curative treatment. Patients with APL are not eligible. Patients with AML who are over age 60 and have not received prior therapy are also eligible, if they are not candidates for standard induction chemotherapy, or
b) High-grade MDS, defined as > 10% blasts on bone marrow examination
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (refer to Section 14.1)
4. Female patients who:
- Are postmenopausal for at least 1 year before the screening visit, OR
- Are surgically sterile, OR
- If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study drug, or agree to completely abstain from heterosexual intercourse
Male patients, even if surgically sterilized (ie, status postvasectomy), who:
- Agree to practice effective barrier contraception during the entire study treatment period and through 30 days after the last dose of study drug, or
- Agree to completely abstain from heterosexual intercourse
5. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
6. Suitable venous access for the study-required blood sampling including PK and pharmacodynamic sampling and blood transfusion support
7. Clinical laboratory values as specified below within 3 days before the first dose of study drug:
- Total bilirubin must be <= 1.5 ? the upper limit of the normal range (ULN).
- ALT and AST must be <= 2.5 ? ULN.
- Calculated creatinine clearance > 50 mL/minute (refer to Section 14.4).
- 8. Patients who are on hydroxyurea may be included in the study and may continue on hydroxyurea while participating in this study.
Key Exclusion Criteria:
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Female patients who are lactating or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug
2. Any serious medical or psychiatric illness that could, in the investigator?s opinion, potentially interfere with the completion of treatment according to this protocol
3. Treatment with any investigational products within 14 days before the first dose of study drug
4. Systemic antineoplastic therapy or radiotherapy within 14 days before the first dose of study drug, except for hydroxyurea
5. Major surgery within 14 days before the first dose of study drug
6. Life-threatening illness unrelated to cancer
7. Clinically uncontrolled central nervous system (CNS) involvement. Patients who have a history of CNS involvement, but no evidence of active CNS disease are not excluded.
8. A prothrombin time (PT) or aPTT above the ULN that is not a result of anticoagulation therapy, or a history of a coagulopathy or bleeding disorder
9. Known human immunodeficiency virus (HIV) positive
10. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection
11. Evidence of current uncontrolled CV conditions, including cardiac arrhythmias, congestive heart failure (CHF), angina, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
12. Diarrhea > Grade 1, based on the NCI CTCAE categorization despite use of optimal antidiarrheals
13. Use of moderate and strong CYP3A inhibitors and CYP3A inducers (see Section 14.2) within 14 days before the first dose of MLN4924
14. Ongoing anticoagulant therapy (eg, aspirin, coumadin, heparin) that cannot be held to permit bone marrow biopsy
Additional Study Details
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 and High-Grade Myelodysplastic SyndromeAnticipated start date:
7/1/2009Lead Sponsor:
Millennium PharmaceuticalsInvestigator(s):
Study Type:
InterventionalPurpose:
TreatmentAllocation:
Non-randomizedMasking:
OpenControl:
noneAssignment:
Single GroupEndpoints:
Safety/EfficacyPrimary Outcomes:
- Adverse events (AEs), serious adverse events (SAEs), assessments of clinical laboratory values, and vital sign measurements
Secondary Outcomes:
- Pharmacodynamic effects such as pIκBα stabilization in tumor cells
- Measures of disease response (CR or PR; including response rate, duration of response, and progression free survival) based on the investigator?s assessment using the Revised Recommendations of the International Working Group (IWG) for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia
- NAEα, NAEβ and indicators of NF-κB pathway activity in baseline leukemic blast specimens
- Cytogenetic abnormalities in leukemic blasts
- Polymorphic variants in drug metabolizing enzymes, ubiquitin pathway components or molecules prognostic or predictive of leukemia outcome, if applicable
- PK parameters including but not limited to Cmax and AUC0-tlast on Day 1
Total Number to be Enrolled:
38Total Number to be Enrolled at Stanford:
10More Information
Secondary ID(s):
- C15003
- HEM0011
- NCT00911066
Locations & Contacts
Stanford Locations & Contacts:
Stanford University School of Medicine 300 Pasteur Drive Stanford, CA 94305Non-Stanford Locations:
The Stanford website does not have any locations outside of Stanford listed for this trial. You may want to check clinicaltrials.gov for posible additional locations.
This listing was last updated:
7/6/2009PLEASE NOTE:
Study Coordinators and Research Nurses cannot give medical advice over the phone. Telephone numbers are provided for obtaining additional information on specific clinical research trials only. If you have specific questions which require clinical expertise, please call your primary care physician. If you do not have a primary care physician please feel free to call the SHC Physician Referral Service at (800) 756-9000 or send an email.
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