Clinical trial NCT04946890: A Study of MRX2843 in Subjects With Relapsed/Refractory Acute Myeloid Leukemia
Official title: Phase I/II Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Effectiveness of MRX2843 Tablets in Patients With Relapsed/Refractory Acute Myeloid Leukemia
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Leukemia Leukemia
Keywords: MRX2843
Lead sponsor: Betta Pharmaceuticals Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2021-07-01
Enrollment: 104
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Patients will receive oral MRX2843 for 28 days to study the side effects, tolerability and best dose for treating relapsed or refractory acute myeloid leukemia With FLT3 Mutations.

Detailed description: It is open-label, dose escalation study designed to characterize the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of orally administered MRX2843 as a single agent given daily for 28 days.

The study includes two parts, Phase I and Phase II, and is carried out in three phases. The Phase I clinical study is divided into two phases: the dose escalation study (Ia) and the expanded enrollment study (Ib). The third phase is the phase II research phase, which is designed based on phase I clinical results.

Phase Ia：Cohorts of 3 patients receive MRX2843 until dose limiting toxicity is noted (DLT). At that point cohorts will expand to 6 patients until MTD is determined.

Phase Ib/ II：According to the relevant data on safety and effectiveness, expand the enrollment of FLT3 mutation relapsed/refractory AML patients at the appropriate dose

Eligibility criteria: Inclusion Criteria:

1. Males and females age ≥ 18 years;
2. Expected survival period ≥ 12 weeks;
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2;
4. Histopathologically documented primary or secondary AML, as defined by WHO criteria, confirmed by pathology review at treating institution, meeting at least one of the following: i. After complete remission, leukemia cells reappear in peripheral blood, or the ratio of bone marrow immature cells to bone marrow cells\> 5%, or leukemia cell infiltration outside the bone marrow; ii. After standard protocol (including cytarabine and a kind of Anthracycline or anthraquinone drugs) for refractory AML patients who have not achieved complete remission after two courses of treatment;
5. During the dose escalation phase, there is no need to test for FLT3 mutation status; for the expansion of the enrollment and phase II study phase, the FLT3 mutation status test results within the past 6 months will be accepted; if not, the central laboratory or research center needs to test and confirm the test Patients with FLT3 mutation status in bone marrow or whole blood. The test results show that the subject has any of the following FLT3 mutation types, and can be included in the group: FLT3 internal tandem repeat (ITD), FLT3 tyrosine kinase domain (TKD);
6. Laboratory inspection must meet the following standards:

   1. Blood routine: Under normal circumstances, the white blood cell count (WBC) ≤20×109/L; or the patient's white blood cell count (WBC)\>20×109/L before using hydroxyurea or cytarabine, use for a period of time and stop the drug After 3 days, check the white blood cell count (WBC) ≤20×109/L;
   2. Blood coagulation function: the international standardized ratio of prothrombin time and partial thromboplastin time ≤ 1.5 times the upper limit of normal (ULN);
   3. Liver: If there is no clear liver metastasis, serum total bilirubin ≤1.5 ULN, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 ULN; if there is clear Gilbert syndrome (Unconjugated hyperbilirubinemia), total bilirubin ≤ 3.0 ULN;
   4. Kidney: Serum creatinine (Scr) ≤1.5×ULN, or creatinine clearance (Ccr) ≥50 mL/min (calculated according to Cockcroft-Gault formula);
7. Normal or abnormal ocular retinal examination has no clinical significance;

Exclusion Criteria:

1. Previously received medications targeting MerTK and/or FLT3
2. Histologic diagnosis of acute promyelocytic leukemia;
3. Have had other malignant tumors in the past 5 years ;
4. Persistent clinically significant toxicity from prior chemotherapy that is Grade 2 or higher;
5. The tumor involves the central nervous system and/or the testis;
6. Active, uncontrolled infection;
7. Radiation therapy within 4 weeks prior to study;
8. Received systemic glucocorticoids within 14 days before the first dose ；
9. Left ventricular ejection fraction ≤1 × ULN,or﹤50%. Clinically significant ECG QTc prolongation (Male: \>450ms, Female: \>470ms).Significant cardiac disease；
10. Human immunodeficiency virus positivity;
11. Active hepatitis B or C or other active liver disease;
12. Women who are pregnant, lactating;
13. Have a history or family history of known or suspected retinitis pigmentosa;
14. Inability to swallow drugs orally, and conditions that seriously affect the absorption or pharmacokinetic parameters of the test drug;
15. History of type 1 diabetes;
16. Any situation that is unstable or may endanger the safety of patients and their compliance with research;
17. Medical condition, serious intercurrent illness, or other extenuating circumstance that, in the judgment of the Principal Investigator, could jeopardize patient safety or interfere with the objectives of the study.

Primary outcomes:
measure: Safety
timeFrame: 28 Days
measure: RP2D
timeFrame: 28 Days
Secondary outcomes:
measure: Maximum serum concentration (Cmax)
timeFrame: 28 Days
measure: Area under the plasma concentration-time curve (AUC) from time zero to the time point of t (AUC0-tn)
timeFrame: 28 Days
measure: Area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC0-inf)
timeFrame: 28 Days
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax)
timeFrame: 28 Days
measure: Apparent volume of distribution at equilibrium after oral administration（Vss/F）
timeFrame: 28 Days
measure: Plasma Decay Half-Life (t1/2z)
timeFrame: 28 Days
measure: Apparent Oral Clearance (CLz/F)
timeFrame: 28 Days
measure: Average plasma or serum concentration(Cav)
timeFrame: 28 Days
measure: changes in FLT3 mutation status in plasma
timeFrame: 28 Days
measure: Rate of Complete Remission (CR)
timeFrame: 28 Days
measure: Rate of partial remission (PR)
timeFrame: 28 Days
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Junmin Li，Ph.D
state: Shanghai
Study officials:
References: