This is a first-in-human Phase 1a/b, open-label, multicenter, dose escalation, optimization and expansion study of ISM5939 to evaluate the safety, tolerability, PK, PD, and preliminary antitumor activity of ISM5939 in patients with advanced or metastatic solid tumors. The study will be conducted in 3 parts sequentially: Part 1 dose escalation ISM5939 monotherapy, Part 2 dose optimization to determine RP2D of ISM5939 monotherapy, and Part 3 dose expansion in 3 cohorts after initial safety run-in of ISM5939 combination therapy.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
159
ISM5939 tablets will be administered orally once daily (QD).
Cisplatin will be administered intravenously in combination with ISM5939 on day 1 during each cycle.
Docetaxel will be administered intravenously in combination with ISM5939 on day 1 during each cycle.
Pembrolizumab will be administered intravenously in combination with ISM5939 on day 1 during each cycle.
Dose-limiting toxicities (DLTs) occurrence
DLT is defined as any of the adverse event which meets DLT criteria if assessed at least possibly related to study treatment and not clearly related to progressive disease or other extraneous cause and occurring during the DLT period.
Time frame: Day 1 up to Day 28 for Part 1 and Day 1 up to Day 21 for Part 3 safety run-in dose escalation period
Adverse events (AEs)
Incidence and severity of AEs will be evaluated based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 \[NCI CTCAE v5.0\]).
Time frame: Approximately 36 months
Recommended Phase 2 doses (RP2Ds)
The maximum tolerated dose (MTD) or RP2Ds in patients with advanced or metastatic solid tumors will be determined based on the available data of safety and tolerability, PK, PD and preliminary activity from all dosed patients.
Time frame: Approximately 36 months
Maximum concentration (Cmax)
Blood samples for Pharmacokinetics (PK) analysis will be assessed after dose of ISM5939.
Time frame: Approximately 36 months
Area under the concentration-time curve (AUC)
Blood samples for Pharmacokinetics (PK) analysis will be assessed after dose of ISM5939.
Time frame: Approximately 36 months
Terminal half-life (t1/2)
Blood samples for Pharmacokinetics (PK) analysis will be assessed after dose of ISM5939.
Time frame: Approximately 36 months
Objective response rate (ORR)
ORR is defined as the percentage of participants with Complete Response or Partial Response.
Time frame: Approximately 36 months
Duration of response (DOR)
DOR is defined as the time from the first tumor assessment when the Complete Response/Partial Response is met to the date of disease progression or death, which occurs first.
Time frame: Approximately 36 months
Disease control rate (DCR)
DCR is defined as the percentage of participants with Complete Response or Partial Response or Stable Disease (persisted for at least 6 weeks).
Time frame: Approximately 36 months
Best overall response (BOR)
BOR is defined as the best response from the initial oral dose of ISM5939 until disease progression, initiation of another anti-tumor treatment, or early withdrawal (whichever occurs first). Confirmation of CR and PR is required.
Time frame: Approximately 36 months
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