An Open-Label, Dose Escalation, Phase 1 Study of MLN4924, A Novel Inhibitor of Nedd8-Activating Enzyme, in Adult Patients with Lymphoma or Multiple Myeloma
The goal of this clinical research study is learn the highest safe dose of MLN4924 that can be given to patients with lymphoma or MM. How much MLN4924 is absorbed into the bloodstream and eliminated from the body, how it affects genes and proteins that are involved in cancer, how it affects its targets in tumor cells, and how it affects tumor growth will also be studied. This is the first study using MLN4924 in humans.
Disease Group: Lymphoma,Myeloma
Treatment Agent: MLN4924
Treatment Location: Both at MD Anderson & outside MD Anderson at one or more Collaborating Sites or Institutions
Estimatated Length of Stay in Houston: The maximum duration of therapy, however, will be 12 months unless it is ;determined that a patient would derive;benefit from continued therapy beyond 12 months. It is anticipated that this ;study will last;for approximately 30 months.
Sponsor: Millennium Pharmaceuticals, Inc.
Return Visit: Schedule A -Days 1, 2, 5, 8, 9, 10, 12, 15 & 21 Schedule B - 1, 2, 4, 8, 11, 12, 15 & 21 Schedule C - 1, 2, 4, 5, 8, 9, 15 & 21 Sch D - 1, 2, 3, 4, 8, 15 & 21 Dosing Days Schedule A - 1, 2, 8 & 9 Schedule B - 1, 4, 8 & 11 Sch C - 1 & 8 Sch D - 1, 8 & 15
Home Care: None
Primary Objectives To determine the safety profile, maximum tolerated dose (MTD), and inform the phase 2 dose of MLN4924 administered as an IV infusion in patients with lymphoma or multiple myeloma To describe the PK and pharmacodynamics of MLN4924 in blood To investigate the pharmacodynamic effects of MLN4924 on skin and tumor Secondary Objectives To evaluate disease response that may be observed with MLN4924 To evaluate the relationship of exposure to MLN4924 and inhibition of Nedd8-Activating Enzyme (NAE) pathway activity in blood, skin, and tumor tissue To assess relationships between polymorphic variations in CYP and transporter protein genes and exposure to MLN4924 To assess banked tumor specimens for candidate biomarkers of response to treatment with MLN4924 including, but not limited to, NAE pathway expression and NFêB levels or activity
IRB Review and Approval Date: 08/26/2008
Recruitment Status: Not Accepting
Projected Accrual: 111
1) Male or female patients 18 years or older.
2) Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2
3) Patients must have a confirmed diagnosis of lymphoma (Waldenstrom's macroglobulinemia is permitted) or multiple myeloma that is relapsed and/or refractory after at least two prior standard chemotherapeutic regimens and for whom no curative option exists
4) Expected survival longer than 6 weeks from enrollment in the study.
5) Tumor that is evaluable by radiography, serum or urine electrophoresis (for patients with multiple myeloma), or clinical evaluations.
6) Suitable venous access for the conduct of blood sampling for MLN4924 PK and pharmacodynamic evaluations.
7) Male patients must use an appropriate method of barrier contraception (eg, condoms), inform any sexual partners that they must also use a reliable method of contraception (ie, a hormonal contraceptive, an intrauterine device, diaphragm with spermicide, or abstinence), and refrain from blood and semen donation during the study and for 90 days after the last dose of study treatment.
8) Female patients must be postmenopausal, surgically sterilized, or willing to use reliable methods of birth control (ie, a hormonal contraceptive, an intrauterine device, diaphragm with spermicide, or abstinence) and refrain from blood donation during the study and for 90 days after the last dose of study treatment. Female patients must have a negative pregnancy test prior to receiving MLN4924.
9) 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.
1) Pregnant or lactating.
2) Major surgery within 14 days prior to the first dose of study treatment.
3) Serious infection within 14 days prior to the first dose of study treatment.
4) Receiving systemic antibiotic therapy within 14 days prior to the first dose of study treatment. Patients may be included in the study if they are on prophylactic antibiotics that are not moderate or strong inhibitors or inducers of CYP3A
5) Life-threatening illness unrelated to cancer.
6) Diarrhea that is greater than Grade 1 in severity.
7) Systemic antineoplastic therapy within 21 days preceding first dose of study treatment, or rituximab therapy within 2 months preceding first dose of study treatment (unless there was evidence of PD since their last dose of rituximab).
8) Treatment with corticosteroids within 7 days preceding first dose of study treatment.
9) Radiotherapy within 14 days preceding first dose of study treatment.
10) Prior treatment with radiation therapy involving >/= 25% of the hematopoietically active bone marrow. Patients who have received total body irradiation whose blood counts are adequate may be included in the study.
11) CYP3A inducers within 14 days before the first dose of MLN4924. Moderate and strong CYP3A inhibitors and CYP3A inducers are not permitted during the study.
12) Patients requiring Coumadin who can not be switched to a low molecular weight heparin should not be considered for this study.
13) Clinically significant central nervous system (CNS) metastases.
14) Absolute neutrophil count (ANC) <1,000/mm^3; platelet count <75,000/mm^3.
15) Patients with a prothrombin time (PT) or aPTT >1.5 x the upper limit of the normal range (ULN), or with a history of a coagulopathy or bleeding disorder.
16) Calculated creatinine clearance </= 50 mL/minute
17) Bilirubin >1.0 times the ULN (unless due to Gilbert’s disease); aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase (ALP) >2.5 times the ULN.
18) Uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure (CHF), angina, or myocardial infarction within the past 6 months.
19) Abnormalities on 12-lead ECG including, but not limited to, changes in rhythm and intervals that in the opinion of the investigator are considered to be clinically significant.
20) Known human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection.
21) Treatment with any investigational products within 28 days preceding the first dose of study treatment.
22) B-type natriuretic peptide (BNP) > 1.5 × ULN
23) Left ventricular ejection fraction (LVEF) < 45 percent or pulmonary artery systolic pressure (PASP) > 1.5 × ULN as assessed by echocardiogram with Doppler