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A Phase 1 Study of M3814 in Combination With MEC in Patients With Relapsed or Refractory Acute Myeloid Leukemia


Brief Summary
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
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.



Inclusion and Exclusion 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

  • - 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
  • 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
  • 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


Please contact the trial administrator to learn more about where you can participate in this trial. Please use the contact form on the right side.

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