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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
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase I trial studies the best dose and side effects of nedisertib when given in combination with mitoxantrone, etoposide, and cytarabine in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory). Nedisertib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as mitoxantrone, etoposide, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nedisertib in combination with mitoxantrone, etoposide, and cytarabine may lower the chance of the acute myeloid leukemia growing or spreading.

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

Detailed Description:

PRIMARY OBJECTIVES:

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).

SECONDARY OBJECTIVES:

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).

EXPLORATORY OBJECTIVES:

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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


Arm Intervention/treatment
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
Given IV
Other Names:
  • .beta.-Cytosine arabinoside
  • 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-.beta.-D-Arabinofuranosylcytosine
  • 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-Beta-D-arabinofuranosylcytosine
  • 1.beta.-D-Arabinofuranosylcytosine
  • 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
  • 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
  • Alexan
  • Ara-C
  • ARA-cell
  • Arabine
  • Arabinofuranosylcytosine
  • Arabinosylcytosine
  • Aracytidine
  • Aracytin
  • Aracytine
  • Beta-cytosine Arabinoside
  • CHX-3311
  • Cytarabinum
  • Cytarbel
  • Cytosar
  • Cytosine Arabinoside
  • Cytosine-.beta.-arabinoside
  • Cytosine-beta-arabinoside
  • Erpalfa
  • Starasid
  • Tarabine PFS
  • U 19920
  • U-19920
  • Udicil
  • WR-28453

Drug: Cytarabine Hydrochloride
Given IV
Other Names:
  • Ara-C HCl
  • Arabinosylcytosine Hydrochloride
  • Aracytidine Hydrochloride
  • CHX-3311
  • Cytosar Hydrochloride
  • Cytosine Arabinosine Hydrochloride
  • U-19920A

Drug: Etoposide
Given IV
Other Names:
  • Demethyl Epipodophyllotoxin Ethylidine Glucoside
  • EPEG
  • Lastet
  • Toposar
  • Vepesid
  • VP 16
  • VP 16-213
  • VP-16
  • VP-16-213
  • VP16

Drug: Etoposide Phosphate
Given IV
Other Name: Etopophos

Drug: Mitoxantrone
Given IV
Other Names:
  • Dihydroxyanthracenedione
  • Mitozantrone

Drug: Mitoxantrone Hydrochloride
Given IV
Other Names:
  • CL 232315
  • DHAD
  • DHAQ
  • Dihydroxyanthracenedione Dihydrochloride
  • Mitoxantrone Dihydrochloride
  • Mitoxantroni Hydrochloridum
  • Mitozantrone Hydrochloride
  • Mitroxone
  • Neotalem
  • Novantrone
  • Onkotrone
  • Pralifan

Drug: Nedisertib
Given PO




Primary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 2 years ]
    Coded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. Overall survival (OS) [ Time Frame: From study entry to death from any cause, assessed up to 2 years ]
    Summarized using Kaplan-Meier plots.


Other Outcome Measures:
  1. 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.

  2. 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.

  3. 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.

  4. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • An established and confirmed diagnosis of AML by World Health Organization criteria, excluding acute promyelocytic leukemia (APL) (with promyelocytic leukemia -retinoic acid receptor alpha [PML-RARA])
  • Patients with R/R AML, defined as:

    • Relapsed: >= 5% bone marrow blasts by morphology or reappearance of minimal residual disease by flow cytometry, reappearance of peripheral blood blasts, or development of extramedullary leukemia after one or two prior lines of therapy. First or second relapse is eligible, and consolidation regimens, including autologous and allogeneic hematopoietic cell transplant, do not count as a separate prior line of therapy
    • Refractory: no CR or CRi after two courses of induction
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (or Karnofsky >= 60%)
  • Serum bilirubin =< 1.5 institutional upper limit of normal (ULN) (unless resulting from hemolysis, Gilbert's syndrome or liver infiltration with leukemia)
  • Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN (unless resulting from liver infiltration with leukemia)
  • Serum creatinine =< 1.5 x institutional ULN OR
  • Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2
  • Patients must be medically eligible to receive MEC, including acceptable pre-study cardiac function (left ventricular ejection fraction of >= 45%) and lifetime anthracycline exposure (=< 400 mg/m^2 doxorubicin equivalents)
  • Patients may have had prior allogeneic hematopoietic cell transplant at least 3 months prior to enrollment but should not have evidence of active graft versus host disease or require systemic immune suppression
  • Patients must be willing to submit the blood sampling and bone marrow sampling for the PK and pharmacodynamics analyses and exploratory biomarkers
  • Female patients with child bearing potential must have a negative serum pregnancy test within 72 hours prior to the first study drug administration and all patients must be willing to use effective methods of contraception during the treatment period and 3 months after study completion
  • Human immunodeficiency virus (HIV)-infected patients will be eligible for this trial if they are on effective antiretroviral regimens utilizing non-CYP-interacting agents, they have an undetectable viral load, they have a CD4 count > 350 cells/mm^3, and they have no history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections. If there is evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy, if indicated. If there is history of hepatitis C virus (HCV) infection, the patient must have been treated and have undetectable HCV viral load
  • Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients must not have had prior treatment with MEC
  • Patients must not have documented active central nervous system (CNS) involvement by leukemia. Patients with known brain metastases 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 adverse events (AEs)
  • Patients must not have received any other investigational or commercial agents or therapies administered with the intention to treat their leukemia within 14 days or 5 half-lives (whichever is shorter) of first receipt of study drug, with the exception of hydroxyurea used to control white blood cell counts
  • All non-hematologic AEs of prior chemotherapy, surgery, or radiotherapy, except alopecia, must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade =< 2 prior to starting therapy
  • Patients who cannot discontinue concomitant medications or herbal supplements that are strong inhibitors or strong inducers of cytochrome P450 (CYP) isoenzymes CYP3A4/5 and CYP2C19. Concomitant use of CYP3A4/5 substrates with a narrow therapeutic index are also excluded. Patients may confer with the study doctor to determine if alternative medications can be used. The following categories of medications and herbal supplements must be discontinued for at least the specified period of time before the patient can be treated:

    • Strong inducers of CYP3A4/5 and CYP2C19: >= 3 weeks prior to study treatment
    • Strong inhibitors of CYP3A4/5 and CYP2C19: >= 1 week prior to study treatment
    • Substrates of CYP3A4/5 with a narrow therapeutic index: >= 1 day prior to study treatment
  • Patients who cannot discontinue concomitant H2 blockers or proton-pump inhibitors (PPIs). Patients may confer with the study doctor to determine if such medications can be discontinued. These must be discontinued >= 5 days prior to study treatment. Patients do not need to discontinue calcium carbonate
  • Patients receiving sorivudine or any chemically related analogues (such as brivudine) are excluded
  • Patients who require oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes (including coumadin and warfarin), or who received such agents within 5 days of the first dose of M3814. Low and high-molecular weight heparins are permitted provided the platelets are maintained at greater than 30,000/mm^3
  • Patients who have received a live attenuated vaccine within 30 days of dosing with M3814
  • Patients must not have known significant cardiopulmonary disease defined as:

    • Unstable angina;
    • Congestive heart failure (New York Heart Association [NYHA] class III or IV;
    • Myocardial infarction (MI) within 6 months prior to first dose. Patients who had ischemic heart disease such as acute coronary syndrome (ACS), MI, and/or revascularization more than 6 months before screening and who are without cardiac symptoms or those with a prior non-ST elevation MI (NSTEM) due to demand-supply mismatch (NSTEM Type II) may enroll
  • Patients should not have severe and/or uncontrolled medical conditions or other conditions that, in the opinion of the investigator, could affect their participation in the study
  • Patients with psychiatric illness/social situations that would limit compliance with study requirements
  • Patients should not be pregnant or breastfeeding

Information from the National Library of Medicine

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


Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Brian A Jonas City of Hope Comprehensive Cancer Center LAO

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03983824     History of Changes
Other Study ID Numbers: NCI-2019-03607
NCI-2019-03607 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
PHI-103
10273 ( Other Identifier: City of Hope Comprehensive Cancer Center LAO )
P10273 ( Other Identifier: CTEP )
UM1CA186717 ( U.S. NIH Grant/Contract )
First Posted: June 12, 2019    Key Record Dates
Last Update Posted: June 12, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasm, Residual
Neoplasms by Histologic Type
Neoplasms
Neoplastic Processes
Pathologic Processes
Cytarabine
Etoposide
Podophyllotoxin
Mitoxantrone
Etoposide phosphate
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Keratolytic Agents