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About
This phase Ib trial studies side effects and best dose of pevonedistat when given together with ixazomib in treating patients with multiple myeloma that has come back or does not respond to treatment. Pevonedistat and ixazomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Full description
PRIMARY OBJECTIVES:
I. Determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of MLN4924 (pevonedistat) in combination with MLN9708 (ixazomib citrate [ixazomib]) in relapsed and/or refractory multiple myeloma (RRMM) patients after more than one previous line of treatment. (Dose-escalation phase) II. Describe the safety profile and tolerability of the combination of MLN9708 (ixazomib) and MLN4924 (pevonedistat) in the proteasome inhibitor (PI)-sensitive and PI-refractory populations. (Dose-expansion phase) III. Determine the anti-tumor activity and overall response rates (ORR) in patients with RRMM with the use of MLN9708 (ixazomib) and MLN4924 (pevonedistat) in combination. (Dose-expansion phase)
SECONDARY OBJECTIVE:
I. Attain pharmacokinetic (PK) characterization of MLN4924 (pevonedistat) in combination with MLN9708 (ixazomib) for the purpose of understanding concentration-effect relationships of both agents. (Dose-escalation phase)
EXPLORATORY OBJECTIVE:
I. To correlate and predict disease response using the following tests: NAD(P)H dehydrogenase (quinone) 1 (NQO1) and cystine/glutamate transporter (SLC7A11) (nuclear factor [erythroid-derived 2]-like 2 [NRF2] target genes): evaluated on whole blood as markers of MLN4924 (pevonedistat) activity.
OUTLINE: This is a dose-escalation study of pevonedistat.
Patients receive ixazomib citrate orally (PO) once daily (QD) on days 1, 8, and 15 of each cycle and pevonedistat intravenously (IV) over 60 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, then every 2-3 months for up to 2 years.
Enrollment
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Volunteers
Inclusion criteria
Patients must have RRMM with measurable disease, as defined by at least one of the following:
At least two prior lines of therapy and all patients should have at least been exposed to a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody.
Age >= 18 years
Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
Leukocytes >= 3,000/mcL
Absolute neutrophil count >= 1,000/mcL
Platelets >= 75,000/mcL
Bilirubin =< institutional upper limit of normal (ULN).
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN
Creatinine clearance (CrCl) by Cockcroft-Gault >= 30 mL/min
Known human immunodeficiency virus (HIV) positive patients who meet the following criteria will be considered eligible:
The effects of MLN4924 (pevonedistat) and MLN9708 (ixazomib) on the developing human fetus are unknown. For this reason and because NAE inhibitory agents are known to be teratogenic, women of child-bearing potential and men must meet the following criteria:
Female patients who are:
Male patients, even if surgically sterilized, who:
Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible
Exclusion criteria
Diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection
Patients who are receiving any other investigational agents, within 30 days of the start of this trial and throughout the duration of this trial
Patients with known central nervous system involvement should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other AEs
History of allergic reactions attributed to compounds of similar chemical or biologic composition to MLN4924 (pevonedistat) or MLN9708 (ixazomib) (including boron or boron-containing products)
Patients with uncontrolled intercurrent illness
Pregnant women are excluded from this study because MLN4924 (pevonedistat) is an NAE inhibitory agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with MLN4924 (pevonedistat), breastfeeding should be discontinued if the mother is treated with MLN4924 (pevonedistat). These potential risks may also apply to the use of MLN9708 (ixazomib) in this study
Major surgery within 14 days before the first dose of any study drug or a scheduled surgery during study period
Patients with uncontrolled coagulopathy or bleeding disorder
Known hepatic impairment as defined by known hepatic cirrhosis, hepatitis B surface antigen seropositive or known or suspected active hepatitis C infection
Known cardiopulmonary disease defined as:
Unstable angina;
Congestive heart failure (New York Heart Association [NYHA] class III or IV);
Myocardial infarction within 6 months prior to first dose (patients who had ischemic heart disease such as acute coronary syndrome [ACS], myocardial infarction, and/or revascularization greater than 6 months before screening and who are without cardiac symptoms may enroll);
Symptomatic cardiomyopathy
Clinically significant arrhythmia:
Clinically significant pulmonary hypertension requiring pharmacologic therapy
Uncontrolled high blood pressure (i.e., systolic blood pressure > 180 mmHg, diastolic blood pressure > 95 mmHg)
Prolonged rate corrected QT (QTc) interval >= 500 msec, calculated according to institutional guidelines
Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram
Known moderate to severe chronic obstructive pulmonary disease, interstitial lung disease, and pulmonary fibrosis
Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of MLN9708 (ixazomib), including difficulty swallowing
Peripheral neuropathy that is grade >= 3, or grade 2 with pain on clinical examination during the screening period
Patients that have previously been treated with MLN9708 (ixazomib)
Systemic treatment, within 14 days before the first dose of MLN9708 (ixazomib), with strong CYP3A inducers (rifampin, rifapentine, rifabutin, ritonavir, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort. Clinically significant metabolic enzyme inducers are not permitted during this study
Radiotherapy within 14 days before enrollment. If the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the MLN9708 (ixazomib)
Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s)
Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s)
Primary purpose
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8 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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