Ixazomib and Pevonedistat in Treating Patients With Multiple Myeloma That Has Come Back or Does Not Respond to Treatment
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|ClinicalTrials.gov Identifier: NCT03770260|
Recruitment Status : Not yet recruiting
First Posted : December 10, 2018
Last Update Posted : February 15, 2019
|Condition or disease||Intervention/treatment||Phase|
|Recurrent Plasma Cell Myeloma Refractory Plasma Cell Myeloma||Drug: Ixazomib Citrate Drug: Pevonedistat||Phase 1|
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)
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) II. Define the changes in correlative pharmacodynamics measures, namely regulated in development and deoxyribonucleic acid (DNA) damage response 1 (REDD1) and neural precursor cell expressed, developmentally down-regulated 8 (NEDD8). (Dose-escalation phase) III. Assess bone marrow-based measures of neddylation. (Dose-expansion phase)
I. To correlate and predict disease response using the following tests: NEDD8: evaluated on blood and bone marrow samples; REDD1: evaluated on blood and bone marrow samples; and 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, and pevonedistat intravenously (IV) over 60 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, participants are followed up at 30 days, then every 2-3 months for up to 2 years.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||54 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||MLN9708 (Ixazomib) and MLN4924 (Pevonedistat) in Relapsed/Refractory Multiple Myeloma Patients: A Phase 1b Trial|
|Estimated Study Start Date :||June 7, 2019|
|Estimated Primary Completion Date :||September 30, 2021|
|Estimated Study Completion Date :||September 30, 2021|
Experimental: Treatment (ixazomib citrate, pevonedistat)
Patients receive ixazomib citrate PO QD on days 1, 8, and 15, and pevonedistat IV over 60 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Ixazomib Citrate
- Incidence of adverse events [ Time Frame: Up to 30 days ]Descriptive statistics will be provided for selected safety data by dose and time as appropriate.
- Maximum tolerated dose of pevonedistat and ixazomib citrate [ Time Frame: Up to course 1 ]
- Overall response rates [ Time Frame: Up to 2 years ]will be tabulated by dose cohort and overall for the IMWG categories of stringent complete response, complete response, very good partial response, partial response (PR), stable disease, progressive disease, and relapse and the European Group for Blood and Marrow Transplantation (EBMT) category of minimal response. A two-sided 95% exact binominal confidence intervals (CI) will be calculated for each category. The myeloma response rate (responses >= PR) will also be tabulated by dose cohort and overall. The myeloma response rate and each of the best overall response categories will be compared between dose cohorts with Chi-square test.
- Pharmacokinetics (PK) characterization of pevonedistat in combination with ixazomib citrate [ Time Frame: Cycle 1, day 1 pre-dose at 0.5, 1, 2, 2.5, 5, 8, and 21 hours ]Descriptive statistics will be provided for selected PK data by dose and time as appropriate. Pevonedistat concentrations in these samples will be quantitatively measured using a liquid chromatography/tandem mass spectrometry (liquid Chromatography with tandem mass spectrometry [LC/MS/MS]) method in place at Covance under contract with Takeda. For pevonedistat, the individual PK parameters from a single dose will be estimated for maximum concentration (Cmax), area under the curve (AUC), half-life (t1/2), apparent CL/F, and apparent volume of distribution (V/F) using non-compartmental or compartmental PK methods with the software WinNonlin. Advanced population PK methods may be employed to assess the link between drug exposure and biological effects and efficacy.
- Correlative pharmacodynamic measures (REDD1, NEDD8, NRF2 target genes) in both proteasome inhibitor (PI)-sensitive and PI-refractory patients [ Time Frame: Baseline up to course 1 ]Descriptive statistics will be provided for selected pharmacodynamic data by dose and time as appropriate. Changes in pharmacodynamic markers will be tabulated and descriptive statistics (e.g., geometric means and CV) calculated for each dose level. Exploratory correlative studies with pharmacodynamic (biological endpoints, toxicity, and efficacy) will be analyzed using Pearson or Spearman's correlation coefficient and tested with Wald's test. Significance for comparisons will be at the P<0.05 level.
- Biomarker analysis of NQO1 and SLC7A11 [ Time Frame: Up to 2 years ]Descriptive statistics will first be used to summarize their gene expression in whole blood by Reverse transcription-polymerase chain reaction (RT-PCR). Biomarker data will also be displayed graphically, where appropriate. Depending on whether data is normally distributed, Person or Spearman's correlation coefficient will be used to measure the correlations of NQO1 and SLC7A11 with the dosage of pevonedistat, and then tested with Wald's test. General Linear Model (GLM) will be used to compare each of the biomarkers (NQO1 and SLC7A11) between different dose levels of pevonedistat with and without adjusting for other factors. Logistics regression model will be further employed to test the adjusted effect of each biomarkers (NQO1 and SLC7A11) on the response rate after adjusting for dosage of pevonedistat as well as other factors.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03770260
|Principal Investigator:||Sagar Lonial||JHU Sidney Kimmel Comprehensive Cancer Center LAO|