Testing the Addition of an Anti-cancer Drug, Nedisertib, to the Usual Treatment (Mitoxantrone, Etoposide, and Cytarabine) for Relapsed or Refractory Acute Myeloid Leukemia
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|ClinicalTrials.gov Identifier: NCT03983824|
Recruitment Status : Not yet recruiting
First Posted : June 12, 2019
Last Update Posted : June 12, 2019
|Condition or disease||Intervention/treatment||Phase|
|Blasts 5 Percent or More of Bone Marrow Nucleated Cells Minimal Residual Disease Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia||Drug: Cytarabine Drug: Cytarabine Hydrochloride Drug: Etoposide Drug: Etoposide Phosphate Drug: Mitoxantrone Drug: Mitoxantrone Hydrochloride Drug: Nedisertib||Phase 1|
I. To assess the safety and tolerability and determine the recommended phase two dose (RP2D) of nedisertib (M3814) in combination with mitoxantrone, etoposide, and cytarabine (MEC) in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML).
I. To characterize the pharmacokinetic (PK) profile of MEC alone and of M3814 in combination with MEC.
II. To evaluate the preliminary efficacy of M3814 in combination with MEC in patients with R/R AML as measured by the response rate (complete remission [CR] plus CR with incomplete count recovery), duration of CR/CRi (DOR), event-free survival (EFS) and overall survival (OS).
I. To evaluate correlative biomarkers of M3814 target engagement and response. II. To correlate cytogenetic and molecular abnormalities with response. III. To evaluate the rates of early mortality and allogeneic hematopoietic cell transplantation.
IV. To perform molecular profiling assays on malignant and normal tissues, including, but not limited to, whole exome sequencing (WES) and messenger ribonucleic acid (RNA) sequencing (RNAseq), in order to:
IVa. Identify potential predictive and prognostic biomarkers beyond any genomic alteration by which treatment may be assigned.
IVb. Identify resistance mechanisms using genomic deoxyribonucleic acid (DNA)- and RNA-based assessment platforms.
V. To contribute genetic analysis data from de-identified biospecimens to Genomic Data Commons (GDC), a well annotated cancer molecular and clinical data repository, for current and future research; specimens will be annotated with key clinical data, including presentation, diagnosis, staging, summary treatment, and if possible, outcome.
OUTLINE: This is a dose-escalation study of nedisertib.
Patients receive nedisertib orally (PO) twice daily (BID) on days 2-21, mitoxantrone intravenously (IV) over 15 minutes, etoposide IV over 60 minutes and cytarabine IV over 60 minutes on days 1-5 in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, every 3 months for 1 year, then every 6 months thereafter.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||48 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 1 Study of M3814 in Combination With MEC in Patients With Relapsed or Refractory Acute Myeloid Leukemia|
|Estimated Study Start Date :||October 4, 2019|
|Estimated Primary Completion Date :||December 31, 2020|
|Estimated Study Completion Date :||December 31, 2020|
Experimental: Treatment (nedisertib, mitoxantrone, etoposide, cytarabine)
Patients receive nedisertib PO BID on days 2-21, mitoxantrone IV over 15 minutes, etoposide IV over 60 minutes and cytarabine IV over 60 minutes on days 1-5 in the absence of disease progression or unacceptable toxicity.
Drug: Cytarabine Hydrochloride
Drug: Etoposide Phosphate
Other Name: Etopophos
Drug: Mitoxantrone Hydrochloride
- Incidence of adverse events [ Time Frame: Up to 2 years ]Coded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.
- Pharmacokinetic (PK) profile of nedisertib (M3814) in combination with mitoxantrone, etoposide, and cytarabine (MEC) [ Time Frame: Days 1 and 5 ]Individual PK parameters will be estimated for maximum concentration (Cmax), area under the concentration-time curve (AUC), half-life (t1/2), apparent clearance (Cl/F), and apparent volume of distribution (V/F) using non-compartmental methods. The PK variables will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. PK parameters will be reported descriptively for exploratory comparison with historical data.
- Overall response rate [ Time Frame: Up to 2 years ]Defined as the proportion of subjects with complete remission (CR) plus CR with incomplete count recovery (CRi) using European Leukemia Net response criteria. The percent of CR will be calculated and associated exact 95% confidence intervals will be constructed.
- Duration of CR/CRi (DOR) [ Time Frame: From first documented CR/CRi response to relapse, assessed up to 2 years ]Summarized using Kaplan-Meier plots.
- Event-free survival (EFS) [ Time Frame: From study entry to treatment failure (lack of response, i.e., no CR or CRi), relapse from CR or CRi, or death from any cause, assessed up to 2 years ]Summarized using Kaplan-Meier plots.
- Overall survival (OS) [ Time Frame: From study entry to death from any cause, assessed up to 2 years ]Summarized using Kaplan-Meier plots.
- Rate of early mortality [ Time Frame: At 90 days ]Defined as the proportion of subjects with death from any cause at 90 days after starting study treatment.
- Rate of allogeneic hematopoietic cell transplantation (HCT) [ Time Frame: Up to 2 years ]Defined as the proportion of subjects proceeding to allogeneic HCT after starting study treatment.
- Pharmacodynamic effects of M3814 in combination with MEC [ Time Frame: Up to 2 years ]Studies with pharmacodynamic (biological endpoints, toxicity and efficacy) will be analyzed using nonparametric statistics.
- Effect of cytogenetic and molecular abnormalities [ Time Frame: Baseline ]Will assess the effect of cytogenetic and molecular abnormalities as potential predictive biomarkers of sensitivity to these regimens.
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): NCT03983824
|Principal Investigator:||Brian A Jonas||City of Hope Comprehensive Cancer Center LAO|