This is a Phase 1, open-label, multicenter, dose-escalation \& expansion study to evaluate the safety,tolerability and pharmacokinetics (PK) of LP-108, a BCL-2 inhibitor, combined with azacitidine, to determine the dose limiting toxicity (DLT) and the recommended Phase 2 dose (RP2D), and to assess the preliminary efficacy of this combination.
Subject must has a diagnosis of one of the following: relapsed or refractory (R/R) or untreated ineligible for treatment with a standard induction chemotherapy acute myeloid leukemia (AML) ; R/R myelodysplastic syndrome(MDS) or untreated MDS with excess blasts defined as ≥ 5% blasts in either bone marrow or blood or with high risk (high and very high-risk groups according to IPSS-R) ;CMML-1 or 2 by WHO, no requirements for prior therapy.
ECOG performance status ≤ 2.
Estimated survival ≥ 12 weeks.
Baseline white blood cell count (WBC) ≤ 25 x 109/L.
Subject is allergic to LP-108, Azacitidine or excipients, or with poor tolerance to Azacitidine.
Subject has received prior therapy with a BH3 mimetic.
Subject has acute promyelocytic leukemia.
Subject has t(9;22) karyotype abnormality or positive BCR/ABL1 fusion gene.
Parallel
LP-108
DrugOral administration for 21 or 28 days on a 28-day cycle
Azacitidine
DrugSubcutaneous administration for 7 days on a 28-day cycle at the dose of 75mg/m2 2-2.5h hours after LP-108.
Maximum Tolerated Dose(MTD)
Standard phase I 3+3 design. The first 3 subjects will be assigned to dose level 1 cohort. If none of the first three subjects experiences DLT, escalation to dose level 2 cohort is permitted. If one of the first three subjects' experiences DLT, a total of six subjects will be required in that dose cohort, and escalation will only be permitted if five of six subjects do not experience DLT. If more than one DLT is observed in the dose level 2 cohort, this will be determined to be the maximally administered dose, and three more subjects will be enrolled in the dose level 1 cohort if only three were previously treated at that dose. Escalation from dose level 2 to level 3 cohort will be with the same method as before. The MTD will be the cohort in which ≤1/6 subjects have dose limiting toxicity at the dose prior to the maximally administered dose. If the dose level 3 cohort has ≤1/6 subjects with a DLT, the MTD will not have been reached.
Recommended Phase 2 Dose(RP2D)
RP2D will be determined using available safety and pharmacokinetics data upon completion of the dose escalation phase.
Incidence of AEs
Type, frequency and severity of AEs, relationship of AEs to study treatment
Incidence of clinically significant changes in clinical laboratory results
Clinically significant changes in hematology, chemistry, coagulation and urinalysis tests results.
Objective Response Rate (ORR)
Response criteria follows the 2017 European Leukemia Net (ELN) recommendations for AML( CR, CRi, PR) , the International Working Group (IWG) response criteria for MDS(CR, PR, marrow CR, HI), the international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults(CR, PR, Marrow response, Clinical benefit).
Progression-Free Survival(PFS) (only for MDS or CMML)
PFS is defined as the number of days from the date of the first dose of study drug to the date of earliest disease progression or death.
Time to Response(TTR)
TTR is defined as the number of days from the date of the first dose of study drug to the date of earliest response.
Duration of Response(DOR)
DOR is defined as the number of days from the date of the first remission to the date of earliest disease progression or death.
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