A Phase 1 Study of SH1573 Capsules in Subjects With Refractory or Relapsed Acute Myelogenous Leukemia

A Phase 1, Multicenter, Safety, Pharmacokinetic, and Clinical Activity Study of SH1573 Capsules in Subjects With Refractory or Relapsed Acute Myelogenous Leukemia With an IDH2 Mutation

An open label single-arm clinical trial to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of SH1573 in subjects with advanced relapsed, refractory acute myelogenous leukemia that harbor an IDH2 mutation.

SH1573 is an IDH2 mutation inhibitor.

This is a phase 1, open-label, multicenter, single-arm study to evaluate safety, tolerability, PK, PD, and preliminary efficacy of SH1573 capsules in treatment of subjects with advanced relapsed, refractory acute myeloid leukemias (AML) that harbor an IDH2 mutation.

The study consists of 2 parts: a dose-escalation part (Phase Ia) and a dose-expansion part (Phase Ib). The dose-escalation part will determine the MTD/R2PD. The dose-expansion part will administer the MTD/RP2D to subjects with mIDH2-positive AML.

Inclusion Criteria:

• 1.Subjects aged ≥18 years.
• 2.Refractory or relapsed AML, or Untreated AML with age ≥70 years if not candidates for standard therapy.
• 3.Subjects must have documented IDH2 mutaion by central testing.
• 4.ECOG performance score of 0 to 2.
• 5.Platelet count ≥ 20,000/μL (transfusions allowed) unless due to underlying malignancy.
• 6.AST, ALT ≤ 3.0 x ULN unless due to underlying malignancy, and Serum total bilirubin ≤ 1.5 x ULN unless due to Gilbert's disease, a gene mutation in UGT1A1, or leukemic organ involvement; Serum creatinine ≤1.5 x ULN or creatinine clearance > 40 mL/min based on the Cockroft-Gault formula.
• 7.Female subjects with reproductive potential must have a negative serum pregnancy test within 72 hours prior to the start of therapy. Females of child-bearing potential and male patients should be willing to use barrier contraception during the study and until 6 months after completion of studyusing adequate contraceptive measures throughout the study.
• 8.Never participate in other clinical trial in 1 month.
• 9.Patients must sign and date written informed consent prior to admission to the study.

Exclusion Criteria:

• 1.Acute promyelocytic leukemia (APL).

• 2.Secondary AML followed by chronic myeloid leukemia (CML).

• 3.Subjects who previously received IDH2 mutation inhibitor.

• 4. Subjects who received systemic anticancer therapy or radiotherapy <14 days prior to their first day of study drug administration. (Hydroxyurea is allowed for the control of peripheral leukemic blasts)

• 5.Subjects who received an non-cytotoxic targeted drug <14 days or 5 half-lives prior to their first day of study drug administration.

• 6.Subjects who have undergone hematopoietic stem cell transplant (HSCT) within 60 days of the first dose,or subjects on immunosuppressive therapy post HSCT at the time of screening, or with clinically significant graft-versus-host disease (GVHD).

• 7.Subjects with any clinically relevant toxic effects of any prior treatment of cancer. (Subjects with residual Grade 1 toxicity are allowed with approval of the Medical Monitor.)

• 8.Subjects with clinical symptoms suggesting active central nervous system (CNS) leukemia or known CNS leukemia.

• 9.Subjects with uncontrolled severe infection that required anti-infective therapy.

• 10.Subjects with immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation.

• 11.Any of the following cardiac criteria:

  1. Active cardiac disease in 6 month before the first dose, such as New York Heart Association (NYHA) Class III or IV congestive heart failure, acute coronary syndrome or stroke.
  2. Left ventricular ejection fraction (LVEF) ≤ 40%.
  3. Mean resting corrected QT interval (QTcF) > 470(female) or 450(male) msec.
  4. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome.
  5. Subjects taking medications that are known to prolong the QT interval unless discontinue at least 5 half-lives before the first dose of study drug.

• 12. History of any other malignant tumor unless disease free survival ≥ 1 year (except clinically cured cervical carcinoma in situ, basal cells or squamous epithelial skin cancer).

• 13.Active infection with HIV, syphilis, hepatitis B or C.

• 14.Subjects with known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally.

• 15.Subjects with uncontrolled hypertension (systolic blood pressure >180 mmHg or diastolic blood pressure > 100 mmHg) .

• 16.Subjects taking the sensitive cytochrome P450 (CYP) substrate medications that have a narrow therapeutic range are excluded from the study unless they can be transferred to other medications within ≥5 half-lives prior to dosing: paclitaxel (CYP2C8) warfarin, phenytoin (CYP2C9), S-mephenytoin (CYP2C19); Subjects taking breast cancer resistant protein (BCRP) transporter, OATP1B1 or OATP1B3 sensitive substrates should be excluded from the study unless they can be transferred to other medications within ≥ 5 half-lives prior to dosing.

• 17.Any disease or conditionins would compromise the safety of the patient or interfere with study assessments in the opinion of the Investigator.

• 18.female with breastfeeding.

• 19.History of hypersensitivity to any active or inactive ingredient of SH1573.

• 20.Subjects with any other conditions deemed by the Investigator to be likely to interfere with a subject's ability to sign informed consent, cooperate, or participate in the study participate in the study.