Description:
This phase I trial studies the best dose and side effects of M3814 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). M3814 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 M3814 in combination with mitoxantrone, etoposide,
and cytarabine may lower the chance of the acute myeloid leukemia growing or spreading.
Title
- Brief Title: Testing the Addition of an Anti-cancer Drug, M3814, to the Usual Treatment (Mitoxantrone, Etoposide, and Cytarabine) for Relapsed or Refractory Acute Myeloid Leukemia
- Official Title: A Phase I Study of M3814 in Combination With MEC in Patients With Relapsed or Refractory Acute Myeloid Leukemia
Clinical Trial IDs
- ORG STUDY ID:
NCI-2019-03607
- SECONDARY ID:
NCI-2019-03607
- SECONDARY ID:
PHI-103
- SECONDARY ID:
10273
- SECONDARY ID:
10273
- SECONDARY ID:
UM1CA186717
- NCT ID:
NCT03983824
Conditions
- Recurrent Acute Myeloid Leukemia
- Refractory Acute Myeloid Leukemia
Interventions
Drug | Synonyms | Arms |
---|
Cytarabine | .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 | Treatment (M3814, mitoxantrone, etoposide, cytarabine) |
Etoposide Phosphate | Etopophos | Treatment (M3814, mitoxantrone, etoposide, cytarabine) |
Mitoxantrone Hydrochloride | CL 232315, DHAD, DHAQ, Dihydroxyanthracenedione Dihydrochloride, Mitoxantrone Dihydrochloride, Mitoxantroni Hydrochloridum, Mitozantrone Hydrochloride, Mitroxone, Neotalem, Novantrone, Onkotrone, Pralifan | Treatment (M3814, mitoxantrone, etoposide, cytarabine) |
Peposertib | 3-Pyridazinemethanol, alpha-(2-Chloro-4-fluoro-5-(7-(4-morpholinyl)-4-quinazolinyl)phenyl)-6-methoxy-, (alphaS)-, M 3814, M-3814, M3814, MSC 2490484A, MSC-2490484A, MSC2490484A, Nedisertib | Treatment (M3814, mitoxantrone, etoposide, cytarabine) |
Purpose
This phase I trial studies the best dose and side effects of M3814 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). M3814 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 M3814 in combination with mitoxantrone, etoposide,
and cytarabine may lower the chance of the acute myeloid leukemia growing or spreading.
Detailed Description
PRIMARY OBJECTIVE:
I. To assess the safety and tolerability and determine the recommended phase two dose (RP2D)
of 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 M3814.
Patients receive M3814 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.
Trial Arms
Name | Type | Description | Interventions |
---|
Treatment (M3814, mitoxantrone, etoposide, cytarabine) | Experimental | Patients receive M3814 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. | - Cytarabine
- Etoposide Phosphate
- Mitoxantrone Hydrochloride
- Peposertib
|
Eligibility 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, reappearance of peripheral
blood blasts, or development of extramedullary leukemia after achieving prior CR
or CRi. First or second relapse is eligible. First relapse is restricted to
participants with CR 1 duration of less than 9-12 months
- Refractory: no CR or CRi after two cycles of induction. Induction cycles include
regimens with the intent to achieve remission and can include high intensity
and/or low intensity regimens
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (or Karnofsky >=
60%)
- Serum bilirubin =< 1.5 institutional upper limit of normal (ULN) (For patients with
hemolysis, Gilbert's syndrome or liver infiltration with leukemia, serum bilirubin =<
3 x institutional ULN)
- Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT])
=< 3 x institutional ULN (For patients with liver infiltration with leukemia,
AST[SGOT]/ALT[SGPT] =< 5 x institutional ULN)
- Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 using the Chronic Kidney
Disease Epidemiology Collaboration (CKD-EPI) formula
- Patients must be medically eligible to receive MEC, including acceptable pre-study
cardiac function (left ventricular ejection fraction of >= 45%) and lifetime
anthracycline exposure (=< 360 mg/m^2 daunorubicin 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 any
mandatory 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.
Participants with impaired decision-making capacity (IDMC) who have a
legally-authorized representative (LAR) and/or family member available will also be
eligible
- All non-hematologic adverse events (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 =< 1 prior to starting
therapy
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
elimination half-lives (whichever is shorter) of first receipt of study drug, with the
exception of hydroxyurea and/or leukapheresis used to control white blood cell counts
- Patients who cannot discontinue concomitant medications or herbal supplements that are
strong inhibitors or strong inducers of cytochrome P450 (CYP) isoenzymes CYP3A4/5,
CYP2C9 and CYP2C19 during treatment with M3814. Concomitant use of CYP1A2, CYP2B6 and
CYP3A4/5 substrates with a narrow therapeutic index are also excluded during treatment
with M3814. 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 prior to
the first dose of M3814:
- Strong inducers of CYP3A4/5, CYP2C9 and CYP2C19: >= 3 weeks or 5 elimination
half-lives (whichever is shorter) prior to the first dose of M3814
- Strong inhibitors of CYP3A4/5, CYP2C9 and CYP2C19: >= 1 week or 5 elimination
half-lives (whichever is shorter) prior to the first dose of M3814
- Substrates of CYP1A2, CYP2B6 and CYP3A4/5 with a narrow therapeutic index: >= 1
day prior to the first dose of M3814
- Patients who cannot discontinue concomitant 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 or 5 elimination half-lives (whichever is
shorter) prior to the first dose of M3814. Patients do not need to discontinue calcium
carbonate or H2 blockers
- 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 with ongoing active infection or 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
- A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a
QTc interval > 480 milliseconds (ms) (CTCAE grade 1) using Fredericia's QT correction
formula
- A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family
history of Long QT syndrome)
- The use of concomitant medications that prolong the QT/corrected QT (QTc) interval
- Gastrointestinal disorders that may affect the M3814 absorption
- Patients will need to avoid any intake of grapefruit, grapefruit juice, Seville
oranges, Seville orange marmalade, or other products containing grapefruit or Seville
oranges within 7 days before the first administration of M3814 and throughout the
duration of M3814 treatment
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Incidence of adverse events |
Time Frame: | Up to 2 years |
Safety Issue: | |
Description: | Coded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5. |
Secondary Outcome Measures
Measure: | Pharmacokinetic (PK) profile of M3814 in combination with mitoxantrone, etoposide, and cytarabine (MEC) |
Time Frame: | Days 1 and 5 |
Safety Issue: | |
Description: | 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. |
Measure: | Overall response rate |
Time Frame: | Up to 2 years |
Safety Issue: | |
Description: | 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. |
Measure: | Duration of CR/CRi (DOR) |
Time Frame: | From first documented CR/CRi response to relapse, assessed up to 2 years |
Safety Issue: | |
Description: | Summarized using Kaplan-Meier plots. |
Measure: | 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 |
Safety Issue: | |
Description: | Summarized using Kaplan-Meier plots. |
Measure: | Overall survival (OS) |
Time Frame: | From study entry to death from any cause, assessed up to 2 years |
Safety Issue: | |
Description: | Summarized using Kaplan-Meier plots. |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | National Cancer Institute (NCI) |
Last Updated
August 24, 2021