Pevonedistat and Belinostat in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT03772925|
Recruitment Status : Recruiting
First Posted : December 12, 2018
Last Update Posted : July 2, 2019
|Condition or disease||Intervention/treatment||Phase|
|Recurrent Acute Myeloid Leukemia Recurrent Myelodysplastic Syndrome Refractory Acute Myeloid Leukemia Refractory Myelodysplastic Syndrome||Drug: Belinostat Drug: Pevonedistat||Phase 1|
I. To identify the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) for a regimen combining MLN4924 (pevonedistat) with belinostat in patients with refractory/relapsed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).
I. To describe the toxicities of this regimen. II. To observe and record anti-tumor activity. III. If responses are observed, to determine what relationship, if any, exists between such responses and TP53/FLT3 mutational status.
IV. To describe pharmacokinetic (PK) interactions, if any, between MLN4924 (pevonedistat) and belinostat.
V. To test the feasibility of performing correlative studies involving nuclear RelA, p-ATR, p-Chk1, Cdt-1, gammaH2A.X, p-BRCA1, p-FANCD2, Ac-H3K56, Ac-H4K16, BCL-2, BIM, BCL-xL, or MC-1.
OUTLINE: This is a dose-escalation study.
Patients receive belinostat intravenously (IV) once daily (QD) over 30 minutes on days 1-5 and pevonedistat IV QD over 60 minutes on days 1, 3, and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 days and then every 2 months for 2 years.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||45 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 1 Study of MLN4924 (Pevonedistat) and Belinostat in Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome|
|Actual Study Start Date :||February 28, 2019|
|Estimated Primary Completion Date :||July 1, 2021|
|Estimated Study Completion Date :||July 1, 2021|
Experimental: Treatment (belinostat, pevonedistat)
Patients receive belinostat IV QD over 30 minutes on days 1-5 and pevonedistat IV QD over 60 minutes on days 1, 3, and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
- Recommended phase 2 dose (RP2D) for the combination of MLN4924 (pevonedistat) and belinostat [ Time Frame: Up to the end of cycle 1 ]Patients' treatment dosing level, dose modification, dose-limiting toxicities (DLTs), and evaluability for DLTs will be listed and summarized by basic descriptive statistics (such as frequency and proportion). RP2D is defined as =< 1 out of 6 at highest dose level below the maximally administered dose.
- Incidence of adverse events (AEs) [ Time Frame: Up to 30 days post-treatment ]Graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. AEs and serious adverse events (SAEs), dosing levels, treatment received, best clinical response, and demographics will be listed. Basic descriptive statistics will be used to summarize toxicities related to the study drugs by grade, and all toxicities, whether related or unrelated to the study drugs.
- Treatment response rate [ Time Frame: Up to 2 years ]Classified according to International Working Group (IWG) and European Leukemia Net (ELN) criteria for response assessment in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). For the response rate calculations, all study reports will contain at least a section with all enrolled patients. Other sections of the reports may detail the response rate for evaluable patients only. All response rate analyses based on a subset of patients will be accompanied by explanations of which patients were excluded and the reasons; 95% confidence limits will be given.
- Duration of response [ Time Frame: From documentation of tumor response to disease progression or death, whichever occurs first, assessed up to 2 years ]If there are at least 3 responses, duration of response will be summarized by the first, second, and third quantiles and illustrated by a Kaplan-Meier plot.
- Time to response [ Time Frame: From registration to the time of documentation of tumor response, assessed up to 2 years ]If there are at least 3 responses, time to response will be summarized by the first, second, and third quantiles and illustrated by a Kaplan-Meier plot.
- TP53 and FLT3 mutational status [ Time Frame: Up to 2 years ]Assessed by next generation sequencing (NGS) and compared to best clinical response classified according to IWG and ELN criteria for response assessment in AML and MDS. A Chi-square test and a Fisher exact test will be used to determine whether there is a significant association between clinical responses and TP53/FLT3 mutational status. An ordinal regression (where best clinical responses are considered as an ordinal outcome variable) and a logistic regression (where best responses are dichotomized as yes or no responses) will be used to test the association between responses and TP53/FLT3 mutational status, with adjustment of potential factors (e.g., dose level, age, sex, etc.).
- Change in MLN4924 (pevonedistat) and belinostat plasma concentrations [ Time Frame: Baseline up to cycle 1 day 1 ]Pharmacokinetic parameters in MLN4924 (pevonedistat) and in belinostat will be calculated using standard non-compartmental methods and summarized as geometric mean and geometric coefficient of variation.
- Change in candidate biomarker levels in bone marrow and/or blood samples [ Time Frame: Baseline up to 24 hours post-treatment with the first doses of study drugs ]Various paired t-tests will be used to determine if there is a significant change in each of the candidate biomarker between the pre- and 24-hour post-treatment assessments, in bone marrow samples and/or blood samples.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03772925
|United States, Virginia|
|Virginia Commonwealth University/Massey Cancer Center||Recruiting|
|Richmond, Virginia, United States, 23298|
|Contact: Site Public Contact 804-628-1939 firstname.lastname@example.org|
|Principal Investigator: Steven Grant|
|Principal Investigator:||Danielle A Shafer||University Health Network Princess Margaret Cancer Center LAO|