A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of LP-108, a BCL-2 Inhibitor, Combined With Azacitidine In Subjects With AML, MDS, CMML
Overview
- Phase
- Phase 1
- Intervention
- LP-108
- Conditions
- Acute Myeloid Leukemia
- Sponsor
- Guangzhou Lupeng Pharmaceutical Company LTD.
- Enrollment
- 198
- Locations
- 3
- Primary Endpoint
- Maximum Tolerated Dose(MTD)
- Status
- Recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
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.
Detailed Description
This Phase 1 study will look at different doses and different treatment schedules in order to better understand the effects of the combined regimens on the newly diagnosed or refractory/relapsed adult participants with AML ,MDS or CMML. The procedures include screening for eligibility, study treatments, and blood \& bone marrow tests. All the safety events will be record, pharmacokinetic parameters (Tmax, Cmax,T1/2, AUC et al.) will be calculated, response and survival will be assess during the study. Participants will be treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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 ≤
- •Estimated survival ≥ 12 weeks.
- •Baseline white blood cell count (WBC) ≤ 25 x 109/L.
- •Subject must has adequate organ function as defined below: Aspartate transaminase (AST) and alanine transaminase (ALT)≤3 x ULN; Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin); adequate renal function as demonstrated by a creatinine clearance ≤1.5 x ULN ; calculated by the Cockcroft Gault formula; APTT ≤ 1.5 x ULN, INR ≤ 1.5 x ULN.
- •Prior treatment-related toxicities must be grade 1 or baseline except for alopecia.
- •If subject is sexually active, he/she must agree to carry out birth control throughout the study and 90 days after the last dose of LP-
- •Subject must agree to have a negative serum β-HCG test result within 7 days prior to study drug.
- •Subject must voluntarily sign and date an informed consent.
Exclusion Criteria
- •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.
- •Subject has known and active CNS involvement.
- •Subject has myeloid sarcoma but no bone marrow involvement.
- •Subject has Acute unidentified leukemia.
- •Subject has treatment related MDS or AML.
- •Subject has AML/MDS/CMML with myelofibrosis ≥ grade
- •Subject has received allogeneic Hematopoietic Stem Cell Transplantation (HSCT) or autologous HSCT within 3 months prior to the first dose of study drug.
Arms & Interventions
Dose Escalation
LP-108: Cycle 0: ramp-up from Day 1, Cycle 1+: at escalating dose levels in participants with AML, MDS or CMML. Azacitidine: beginning on Day 1 through Day 7 of each Cycle (expect for Cycle 0). Strong/moderate CYP3A inhibitor and inducer are prohibited. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.
Intervention: LP-108
Dose Escalation
LP-108: Cycle 0: ramp-up from Day 1, Cycle 1+: at escalating dose levels in participants with AML, MDS or CMML. Azacitidine: beginning on Day 1 through Day 7 of each Cycle (expect for Cycle 0). Strong/moderate CYP3A inhibitor and inducer are prohibited. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.
Intervention: Azacitidine
Safety Expansion
LP-108: Cycle 0: ramp-up from Day 1, Cycle 1+: Participants with AML, MDS or CMML will be treated with LP-108 to enable selection of the recommended Phase 2 dose (RP2D). Azacitidine: beginning on Day 1 through Day 7 of each Cycle (expect for Cycle 0). Strong/moderate CYP3A inhibitor and inducer are prohibited. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.
Intervention: LP-108
Safety Expansion
LP-108: Cycle 0: ramp-up from Day 1, Cycle 1+: Participants with AML, MDS or CMML will be treated with LP-108 to enable selection of the recommended Phase 2 dose (RP2D). Azacitidine: beginning on Day 1 through Day 7 of each Cycle (expect for Cycle 0). Strong/moderate CYP3A inhibitor and inducer are prohibited. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.
Intervention: Azacitidine
Efficacy Expansion [AML]
LP-108: Cycle 0: ramp-up from Day 1, Cycle 1+: at RP2D level in participants with AML . Azacitidine: beginning on Day 1 through Day 7 of each Cycle (expect for Cycle 0). After the completion of Part 1, the Part 2 dose expansion phase will begin. Strong/moderate CYP3A inhibitor and inducer are prohibited. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.
Intervention: LP-108
Efficacy Expansion [AML]
LP-108: Cycle 0: ramp-up from Day 1, Cycle 1+: at RP2D level in participants with AML . Azacitidine: beginning on Day 1 through Day 7 of each Cycle (expect for Cycle 0). After the completion of Part 1, the Part 2 dose expansion phase will begin. Strong/moderate CYP3A inhibitor and inducer are prohibited. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.
Intervention: Azacitidine
Efficacy Expansion [MDS&CMML]
LP-108: Cycle 0: ramp-up, Cycle 1+: at RP2D level in participants with MDS or CMML. Azacitidine: beginning on Day 1 through Day 7 of each Cycle (expect for Cycle 0). Strong/moderate CYP3A inhibitor and inducer are prohibited. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.
Intervention: LP-108
Efficacy Expansion [MDS&CMML]
LP-108: Cycle 0: ramp-up, Cycle 1+: at RP2D level in participants with MDS or CMML. Azacitidine: beginning on Day 1 through Day 7 of each Cycle (expect for Cycle 0). Strong/moderate CYP3A inhibitor and inducer are prohibited. Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.
Intervention: Azacitidine
Outcomes
Primary Outcomes
Maximum Tolerated Dose(MTD)
Time Frame: Up to 42 days after initial dose of study drug at the designated cohort dose.
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.
Incidence of clinically significant changes in clinical laboratory results
Time Frame: From first dose of study drug to 28 days after last dose of study drug
Clinically significant changes in hematology, chemistry, coagulation and urinalysis tests results.
Cmax of LP-108
Time Frame: Up to 24 hours post dose
Maximum plasma concentration (Cmax) of LP-108.
Incidence of AEs
Time Frame: From first dose of study drug to 28 days after last dose of study drug
Type, frequency and severity of AEs, relationship of AEs to study treatment
Tmax of LP-108
Time Frame: Up to 24 hours post dose
Time to maximum plasma concentration (Tmax) of LP-108.
t1/2 of LP-108
Time Frame: Up to 24 hours post dose
The terminal elimination half-life (t1/2).
AUC0-t of LP-108
Time Frame: Up to 24 hours post dose
Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration of LP-108.
Recommended Phase 2 Dose(RP2D)
Time Frame: Up to 1.5 years
RP2D will be determined using available safety and pharmacokinetics data upon completion of the dose escalation phase.
CL/F of LP-108
Time Frame: Up to 24 hours post dose
Apparent clearance (CL/F) of LP-108.
Vd/F of LP-108
Time Frame: Up to 24 hours post dose
Apparent volume of distribution of LP-108.
Secondary Outcomes
- Time to Response(TTR)(Measured from the date of the first dose of study drug to the date of earliest response, and assessed up to 6 months.)
- Duration of Response(DOR)(Measured from the date of the first remission to the date of earliest disease progression or death, and assessed up to 24 months.)
- Progression-Free Survival(PFS) (only for MDS or CMML)(Measured from the date of first dose of study drug to the date of earliest disease progression or death or last visit, and assessed up to 24 months.)
- DOCR (only for CR/CRi participants)(Measured from the date of the first CR/CRi to the date of earliest disease progression or death, and assessed up to 24 months.)
- Objective Response Rate (ORR)(Measured from Cycle 1 Day 1 to 28 days after last dose of study drug, and assessed up to 24 months.)
- Event-free Survival (EFS)(Measured from the date of first dose to the date of earliest evidence of disease progression, initiation of new non-protocol-specified antitumor therapy without documented progression, death, and for up to 5 years after the last subject is enrolled.)
- OS(Measured from the date of date of first dose to the date of death or last visit, and for up to 5 years after the last subject is enrolled.)