This is an open-label, single-arm, Phase 1b/2 study designed to evaluate the safety, tolerability, and preliminary efficacy of milademetan in combination with atezolizumab in patients with advanced solid tumors with confirmed homozygous CDKN2A loss and WT TP53 who have progressed on or are refractory to prior PD-1/PD-L1 inhibitor therapy and who, in the opinion of the Investigator, are unlikely to tolerate or derive clinically meaningful benefit from other therapy. This study will determine the recommended dose of milademetan when given in combination with atezolizumab (the combination RP2D) using a dose de-escalation safety assessment cohort (Phase 1b). Following identification of the combination RP2D, the safety profile and preliminary anti-tumor activity of the combination RP2D will be evaluated in a larger population in a dose expansion cohort (Phase 2).
Up to 30 patients will be enrolled, 3 to 18 patients in the safety assessment cohort and 12 to 27 patients in the dose expansion cohort.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
260 mg once daily orally on 3 consecutive day sets with a minimum of 14 days and a maximum of 21 days between the first day of each 3- day dosing set.
1680mg administered every 4 weeks
The number of participants with treatment related AEs meeting DLT-defined criteria assessed by CTCAE v5.0 when receiving milademetan in combination with atezolizumab in patients with advanced solid tumors with HZ CDKN2A loss and WT TP53
Time frame: 4 months
The appropriate dose of milademetan in combination with atezolizumab based on the number of participants with DLT-defined adverse events assessed by CTCAE v5.0 criteria
Time frame: 4 months
Treatment emergent AE of the identified RP2D of milademetan in combination with atezolizumab in patients with advanced solid tumors with HZ CDKN2A loss and WT TP53
Time frame: 24 months
Objective response rate (ORR)
ORR, defined as the percentage of patients who achieve a confirmed CR or PR
Time frame: 24 months
Duration of response (DOR)
DOR, defined as the time from the date of first response (CR or PR) to the date of radiologically demonstrated disease progression, or death due to any cause
Time frame: 24 months
Disease control rate (DCR)
DCR, defined as the percentage of patients who achieve CR, PR, or SD for ≥ 16 weeks
Time frame: 24 months
Progression Free Survival (PFS)
PFS, defined as the time from the date of first dose to the earliest date of the first objective documentation of radiographic disease progression, or death due to any cause
Time frame: 24 months
Growth Modulation Index (GMI)
GMI: The GMI will be determined using the ratio of time to progression (TTP) with nth line of therapy (TTPn; here defined milademetan plus atezolizumab) to the most recent prior line of therapy (TTPn-1)
Time frame: 24 months
Pharmacokinetics Cmax
PK: maximum plasma concentration (Cmax) of milademetan
Time frame: Initiation of study treatment through milademetan dose 13, an average of 3 months
Pharmacokinetics AUC
PK: area under the plasma concentration-time curve (AUC)
Time frame: Initiation of study treatment through milademetan dose 13, an average of 3 months
Pharmacokinetics Tmax
PK: Time to reach maximum plasma concentration of milademetan
Time frame: Initiation of study treatment through milademetan dose 13, an average of 3 months
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