This is a two-phase, multicenter, open phase I clinical study, with phase Ia as dose escalation phase and phase Ib as dose expansion phase, to evaluate the safety tolerability and pharmacokinetic characteristics of BEBT-607 tablets in patients with advanced or metastatic solid tumors associated with KRAS G12C mutation. To evaluate the efficacy of BEBT-607 tablets in the treatment of patients with advanced or metastatic solid tumors with KRAS G12C mutation, and to determine the recommended dose (RP2D) for Phase II clinical trials of BEBT-607 tablets in patients with advanced or metastatic solid tumors with KRAS G12C mutation.
Phase Ⅰa: The dose escalation plan is to carry out about 6 dose levels. The initial dose of BEBT-607 tablets is set at 100mg/ day, and the subsequent dose groups are first increased by 100%. If a case of drug-related grade 2 non-hematological toxicity or grade 3 hematological toxicity is found and does not reach DLT, the subsequent dose groups are increased by 50%. If one case of dose limiting toxicity(DLT) is found and does not reach maximum tolerated dose(MTD ), the subsequent dose group is increased by 33%(Doses are rounded to multiples of 100mg).The single dose is 1/2 of the total daily dose, and the single administration phase is administered once a day, and the continuous administration phase is administered twice a day (only once on the 28th day of the first cycle). Phase Ⅰb: According to the pharmacokinetics, safety and preliminary efficacy results of phase Ⅰa dose escalation phase, one to three cohorts with target dose or tumor species are selected for dose extension trial, and a maximum of 30 subjects are enrolled in each cohort. The subjects receive BEBT-607 tablets twice a day, orally before breakfast and before dinner, respectively. There is a treatment cycle every 28 days (On days 1 and 28 of the first cycle, the drug is administered only once before breakfast). The study process for each subject consisted of three phases: screening, treatment, and follow-up. During treatment, participants are required to undergo safety checks every four weeks from the first dose, tumor assessments every eight weeks, safety follow-up at the end of treatment 28 days after the last dose, efficacy follow-up every eight weeks, and survival follow-up every three months. Participants will need to understand the requirements and risks of the trial, sign an informed consent form, accept the dosing regimen required by the trial protocol, and follow the investigator's guidance.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
126
PhaseⅠa:100mg,200mg,300mg,400mg,600mg or 800mg/day,50mg,100mg,150mg,200mg,300mg or 400mg each time, once a day in the single administration phase and twice a day in the continuous administration phase (only once on the 28th day of the first cycle) for 28 days,28 days is as a treatment cycle. PhaseⅠb:300mg,400mg or 600mg/day, 150mg,200mg or 300mg each time,twice a day (only once on day 1 and day 28 of the first cycle), continuous administration for 28 days,28 days is as a treatment cycle.
Xiangya Hospital of Central South University
Changsha, Hunan, China
RECRUITINGMTD
Maximum tolerated dose
Time frame: Phase Ⅰa:Day 2 after the single dose phase, day 1, day 15, and day 28 of the first cycle of the continuous dose phase,assessed up to 4 weeks.
DLT
Dose-limiting toxicity
Time frame: Phase Ⅰa:Day 2 after the single dose phase, day 1, day 15, and day 28 of the first cycle of the continuous dose phase,assessed up to 4 weeks.
RDE
Expand the recommended dose
Time frame: Phase Ⅰa:Day 2 after the single dose phase, day 1, day 15, and day 28 of the first cycle of the continuous dose phase,assessed up to 4 weeks.
AE
Adverse event
Time frame: Phase Ⅰa:From the first administration of the study drug to 28 days after the last administration of the study drug.
ORR
Objective response rate
Time frame: Phase Ⅰb:Every 8 weeks,assessed up to 20 months.
PR2D
Recommended Phase II Dose
Time frame: Phase Ⅰb:Every 8 weeks,assessed up to 20 months.
PFS
Progression-free survival
Time frame: From date of administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
ORR
Objective response rate
Time frame: Phase Ⅰa:Every 4 weeks,assessed up to 4 weeks.
DOR
Duration of response
Time frame: Phase Ⅰa:Every 4 weeks,PhaseⅠb:Every 8 weeks,assessed up to 24 months.
DCR
Disease control rate
Time frame: Phase Ⅰa:Every 4 weeks,PhaseⅠb:Every 8 weeks,assessed up to 24 months.
AE
Adverse event
Time frame: Phase Ⅰb:From the first administration of the study drug to 28 days after the last administration of the study drug.
AUC0-t
Area under the plasma concentration time curve from 0 hour to last time of quantifiable concentration after administration
Time frame: Phase Ⅰa:Day 1 and Day 28 of cycle 1 before administration and within 48 hours after administration (each cycle is 28 days).Phase Ⅰb:Day 1 and Day 28 of cycle 1 before administration and within 24 hours after administration (each cycle is 28 days).
Cmax
Peak Plasma Concentration
Time frame: Phase Ⅰa:Day 1 and Day 28 of cycle 1 before administration and within 48 hours after administration (each cycle is 28 days).Phase Ⅰb:Day 1 and Day 28 of cycle 1 before administration and within 24 hours after administration (each cycle is 28 days).
Tmax
Time of peak Plasma Concentration
Time frame: Phase Ⅰa:Day 1 and Day 28 of cycle 1 before administration and within 48 hours after administration (each cycle is 28 days).Phase Ⅰb:Day 1 and Day 28 of cycle 1 before administration and within 24 hours after administration (each cycle is 28 days).
Vss
Apparent volume of distribution
Time frame: Day 1 and Day 28 of cycle 1 before administration and within 48 hours after administration,Day 15 and Day 27 of cycle 1 before administration (each cycle is 28 days).
t1/2
Half-life of plasma drug concentrations
Time frame: Phase Ⅰa:Day 1 and Day 28 of cycle 1 before administration and within 48 hours after administration (each cycle is 28 days).Phase Ⅰb:Day 1 and Day 28 of cycle 1 before administration and within 24 hours after administration (each cycle is 28 days).
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