Pharmacokinetic and Safety Study of MRX-2843 in Adolescents and Adults With Relapsed/Refractory AML, ALL, or MPAL

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Brief Title

Pharmacokinetic and Safety Study of MRX-2843 in Adolescents and Adults With Relapsed/Refractory AML, ALL, or MPAL

Official Title

An Open Label Evaluation Phase 1 Trial of the Safety and Pharmacokinetics of MRX-2843 in Adolescents and Adults With Relapsed/Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Mixed Phenotype Acute Leukemia

Brief Summary

      This is a Phase I, open-label, non-randomized, dose escalation study in adolescents and
      adults with relapsed/refractory acute myeloid leukemia, acute lymphoblastic leukemia, or
      mixed phenotype acute leukemia. Patients will receive continuous oral MRX-2843 in 28 day
      cycles at predefined dose cohorts.
    

Detailed Description

      This is a Phase I, open-label, non-randomized, dose escalation study in up to 50 adolescent
      or adult patients with relapsed/refractory acute myeloid leukemia, acute lymphoblastic
      leukemia, or mixed phenotype acute leukemia. Patients will receive a single dose of MRX-2843
      followed by continuous oral MRX-2843 in 28 day cycles at predefined dose cohorts.

      A dose expansion arm of approximately 12 patients (with 6 patients being FLT3 ITD+ and 6
      patients being Mer+/FLT3 WT) will be accrued to further evaluate patients at the RP2D.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Percentage of subjects with Dose Limiting Toxicities (DLTs)

Secondary Outcome

 Determine Maximum Tolerated Dose (MTD) in mg of MRX-2843

Condition

Acute Myeloid Leukemia

Intervention

MRX-2843

Study Arms / Comparison Groups

 Dose Escalation - Level 1
Description:  MRX-2843 capsules, QD - 28 day cycles

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

50

Start Date

May 10, 2021

Completion Date

January 31, 2024

Primary Completion Date

January 31, 2024

Eligibility Criteria

        Inclusion Criteria:

          -  Patient is a male or female at least 12 years of age.

          -  Patient must weigh at least 40 Kg.

          -  Patient has histologically or cytologically confirmed diagnosis of AML as defined by
             the World Health Organization (WHO) criteria (2017), ALL, or MPAL and is in second or
             later relapse or is refractory to at least one induction regimen.

          -  The effects of MRX-2843 on developing human fetus are unknown. For this reason, women
             of child-bearing potential and men must agree to remain abstinent, or agree to
             practice double barrier forms of birth control in which 2 of the following precautions
             are used during the study and for 4 months after last dose of study drug(s):
             vasectomy, tubal ligation (or other transcervical sterilization procedures), vaginal
             diaphragm, intrauterine device, birth control pills, birth control implant, or condom
             or sponge with spermicide.

          -  Female patients of childbearing potential must be nonpregnant, nonlactating, and have
             a negative pregnancy test result at Screening and a negative pregnancy test on Day 1
             of Cycles 1-4.

          -  Patient is able to provide written, informed consent or assent for patients < 18 years
             of age is provided along with parent/guardian consent before initiation of any study
             related procedures, and patient is able, in the opinion of the investigator, to comply
             with all the requirements of the study.

          -  Patient is able to swallow oral medication.

          -  Patient has white blood cell (WBC) lower than 25,000/mm3 at Screening prior to
             initiation of MRX-2843. Patients who are otherwise medically eligible for enrollment
             but have WBC above 25,000/mm3 are allowed concurrent treatment with hydroxyurea to
             stabilize the WBC. In these situations, hydroxyurea will be discontinued once WBC is
             below 10,000/mm3 and at least 1 day prior to start of study treatment. Treatment with
             hydroxyurea will be allowed during Cycle 1 if deemed needed by the Investigator.

          -  The Patient has laboratory values at Screening:

               1. Bilirubin ≤ 1.5 the upper limit of normal (ULN). For patients with documented
                  Gilbert's disease, bilirubin ≤ 3.0 mg/dL

               2. Creatinine clearance (CrCl) ≥ 60 mL/min. For creatinine clearance estimation, the
                  Cockcroft and Gault equation should be used:

                  Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72) (For
                  females: Multiply above result by 0.85)

               3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × ULN

          -  Patient has Eastern Cooperative Oncology Group (ECOG) performance status 0-2 or
             Lansky/Karnofsky ≥ 50.

          -  For the FLT3ITD expansion cohort at RP2D, the FLT3ITD+ patients should have previously
             been treated with at least one FLT3 inhibitor prior to enrollment.

        Exclusion Criteria:

          -  To be eligible for this study, each of the following criteria must be satisfied with a
             "NO" answer:

        All Subjects:

          -  Patient has diagnosis of acute promyelocytic leukemia (or AML M3).

          -  Patients with known active CNS leukemia.

          -  Patient has any surgical or medical condition (active or chronic) that may interfere
             with drug absorption, distribution, metabolism, or excretion of the study drug, or any
             other condition that may place the patient at risk.

          -  Patient has a history of other malignancies that have required systemic treatment
             within the last 2 years or are deemed by the investigator to have a potential to
             interfere with the safety and efficacy assessment of MRX2843. Patients with treated
             nonmelanoma skin cancer, in situ carcinoma or cervical intraepithelial neoplasia,
             regardless of the disease-free duration, are eligible for this study if definitive
             treatment for the condition has been completed.

          -  Patient has received radionuclide treatment within 6 weeks of the first dose of study
             treatment.

          -  Patient has received systemic antineoplastic therapy within 14 days of study treatment
             or 6 weeks for nitrosoureas or mitomycin C. (However, hydroxyurea can be given for the
             purposes of cytoreduction up to 1 day prior to enrollment, with the exceptions noted
             above in the inclusion criteria).

          -  Patient has not fully recovered from acute toxic effects due to all prior therapies,
             except alopecia and other non-clinically significant AEs prior to enrollment.

          -  Patient has active clinically significant GvHD.

          -  Patient has received calcineurin inhibitors within four weeks of study treatment.

          -  Patient is known to have human immunodeficiency virus infection (HIV).

          -  Patient has used a small molecular kinase inhibitor or any investigational drug or
             product within 28 days or 5 half lives, whichever is longer, before study drug dosing.

          -  Patient has a diagnosis of active hepatitis B or C.

          -  Patient has an active uncontrolled infection.

          -  Patient has a history of Type 1 Diabetes (T1D) or is considered at high risk for T1D,
             where high risk is defined as

               1. Patient has 1 first-degree relative (FDR; defined as parents, offspring or
                  siblings) with T1D AND A1C value > 6.5% or

               2. Patient has 2+FDR with T1D

          -  Patient has known or suspected history of retinitis pigmentosa or known or suspected
             familial history of retinitis pigmentosa.

          -  Patient requires concomitant treatment, in therapeutic doses, with anticoagulants such
             as warfarin or coumadin-related agents, thrombin or FXa inhibitors, and antiplatelet
             agents (e.g., clopidogrel). Low dose aspirin (≤ 81 mg/day), low-dose warfarin (≤1
             mg/day), and prophylactic Low Molecular Weight Heparin (LMWH) are permitted.

          -  Patient has congestive heart failure New York Heart Association (NYHA) class 3 or 4,
             or patient with a history of congestive heart failure NYHA class 3 or 4 in the past,
             unless a screening echocardiogram performed within 3 months prior to study entry
             results in a left ventricular ejection fraction that is ≥ 45%.

          -  Patient has QTcF > 480 ms.

          -  Patient has had major surgery within 4 weeks of the first dose of study drug.

          -  The patient is unable or unwilling to abide by the study protocol or cooperate fully
             with the investigator or designee.
      

Gender

All

Ages

12 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Melinda Pauley, MD, 919-270-4667, [email protected]



Administrative Informations


NCT ID

NCT04872478

Organization ID

2843-1003


Responsible Party

Sponsor

Study Sponsor

Meryx, Inc.


Study Sponsor

Melinda Pauley, MD, Principal Investigator, Emory University, Children's Healthcare of Atlanta


Verification Date

May 2021