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
Overview
- Phase
- Phase 1
- Intervention
- SH1573 Capsules
- Conditions
- Acute Myelogenous Leukemia
- Sponsor
- Nanjing Sanhome Pharmaceutical, Co., Ltd.
- Enrollment
- 41
- Locations
- 2
- Primary Endpoint
- Number of Participants With Adverse Events (AEs)
- Last Updated
- 5 years ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
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
- •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.
- •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.
Arms & Interventions
SH1573 Capsules
SH1573 capsules administered orally. Multiple doses will be administered by effiacy and safety to determine the RP2D.
Intervention: SH1573 Capsules
Outcomes
Primary Outcomes
Number of Participants With Adverse Events (AEs)
Time Frame: From the first dose of the study drug to 30 days after the last dose of study drug
The intensity of each AE was graded from 1 to 5 according to the NCI CTCAE Version 5.0.
Dose-limiting toxicity (DLT)
Time Frame: Up to 28 days after first dose of study drug
DLT is defined as an adverse event (AE) that meets protocol defined DLT criteria during cycle 1 （28 days every cycle）and is at least possibly related to study drug.
Rate of CR/CRh (complete remission with incomplete hematologic recovery)
Time Frame: From the first dose of study drug to the time of progressive disease, assessed up to 36 months
CR was defined as \< 5% blasts in the bone marrow and full recovery of peripheral blood counts (platelets \> 100 x 10\^9/L and ANC \> 1.0 x 10\^9/L); CRh was defined as \< 5% blasts in the bone marrow and partial recovery ofperipheral blood counts (platelets \> 50 x 10\^9/L and ANC \> 0.5 x 10\^9/L).
Secondary Outcomes
- Complete Response (CR) Rate(From the first dose of study drug to the time of progressive disease, assessed up to 36 months)
- Overall Response Rate (ORR)(From the first dose of study drug to the time of progressive disease, assessed up to 36 months.)
- Overall Survival(From the first dose of study drug to the end of study or death, assessed up to 36 months)
- Duration of Response(DOR)(From the first dose of study drug to the time of progressive disease, assessed up to 36 months)
- Maximum serum drug concentration(0, 1, 2, 4, 8, 12, 24, 48, 72 hours post-dose on single dose; 0 hour of cycle1 day 15; 0, 1, 2, 4, 8, 12, 24 hours post-dose on cycle 2 day 1; 0 hour of cycle 2 day 15 and cycle 3 day 1. Each cycle is 28 days.)
- Time to response (TTR)(From the first dose of study drug to the first response, assessed up to 36 months)
- Proportion of non-blood transfusion dependent subjects(From the first dose of study drug to last dose of study drug, assessed up to 36 months)
- Area under the concentration-time curve (AUC)(0, 1, 2, 4, 8, 12, 24, 48, 72 hours post-dose on single dose; 0 hour of cycle1 day 15; 0, 1, 2, 4, 8, 12, 24 hours post-dose on cycle 2 day 1; 0 hour of cycle 2 day 15 and cycle 3 day 1. Each cycle is 28 days.)
- α-Hydroxyglutaric acid (2-HG)(0, 24, 48 hours post-dose on single dose; Day1, Day15 pre-dose on cycle 1 and cycle 2; Day 1 pre-dose on cycle 3 and every 2 cycles afterwards. Each cycle is 28 days.)