The primary purpose of this study is to assess the safety and tolerability of lunresertib alone and in combination with RP-3500 or in combination with Debio 0123 in patients with eligible advanced solid tumors, determine the maximum tolerated dose (MTD) and assess preliminary anti-tumor activity.
Male or female and ≥12 years-of-age at the time of informed consent.
Lansky performance status ≥50% for patients ≤16 years of age, or ECOG score of 0, 1, (or 2 for module 1) for patients >16 years of age.
Locally advanced or metastatic resistant or refractory solid tumors.
Patients <18 years of age must weigh at least 40 kg.
Chemotherapy or small molecule antineoplastic agent given within 21 days or <5 half-lives, whichever is shorter, prior to first dose of study drug.
History or current condition, therapy, or laboratory abnormality that might confound the study results or interfere with the patient's participation for the full duration of the study treatment.
Patients who are pregnant or breastfeeding.
Life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction or other reasons which, in the investigator's opinion, could compromise the participating patient's safety.
Single group
Lunresertib
DrugOral PKMYT1 Inhibitor
RP-3500
DrugOral ATR Inhibitor
Debio0123
DrugOral WEE1 Inhibitor
Safety and Tolerability of lunresertib either in monotherapy or in combination with RP-3500 or with Debio 0123 in patients with eligible advanced solid tumors
Assessed by treatment-emergent adverse events (TEAEs), physical examinations (PEs), safety laboratory assessments, electrocardiograms (ECGs), and vital sign measurements
To define the MTD of lunresertib monotherapy, and determine a recommended Phase 2 dose (RP2D) and preferred schedule
Assessed by the incidence of Dose-limiting toxicities (DLTs) and the incidence and severity of cumulative safety data
To define the MTD of lunresertib in combination with RP-3500 or in combination with Debio 0123, and determine a recommended Phase 2 dose (RP2D) and preferred schedule
Assessed by the incidence of dose-limiting toxicities (DLTs) and the incidence and severity of cumulative safety data
The relative bioavailability of lunresertib capsule formulation as compared to lunresertib tablet formulation in the fasted state
Assessed by the plasma concentrations of lunresertib with calculation of pharmacokinetic (PK) parameters including maximum observed plasma concentration (Cmax), time to maximum observed plasma concentration (Tmax), area under the plasma concentration-time curve (AUC) , for both formulations in the fasted state.
The plasma concentrations of lunresertib monotherapy (capsule formulation) in the fasted and fed states
Assessed by the plasma concentrations of lunresertib with calculation of maximum observed plasma concentration (Cmax), time to maximum observed plasma concentration (Tmax), minimum observed plasma concentration (Cmin), area under the plasma concentration-time curve (AUC), elimination half-life (t1/2), and other parameters as appropriate
To assess the relationship between pharmacodynamic biomarkers and PK of lunresertib at different dose levels and/or schedules
Assessed by evaluation of biomarkers in pre- and on-treatment biopsies, and circulating tumor DNA (ctDNA) dynamics during treatment
The plasma concentrations of lunresertib and RP-3500 when dosed in combination
Assessed by the plasma concentrations of lunresertib and RP-3500 with calculation of maximum observed plasma concentration (Cmax), time to maximum observed plasma concentration (Tmax), minimum observed plasma concentration (Cmin), area under the plasma concentration-time curve (AUC), elimination half-life (t1/2), and other parameters as appropriate for each analyte
To assess preliminary anti-tumor activity achieved with lunresertib monotherapy, lunresertib in combination with RP-3500 or lunresertib in combination with Debio 0123
Measured by best percent change in tumor size from baseline, objective response rate (ORR), overall response rate, tumor marker response, duration of response (DOR), clinical benefit rate (CBR), progression-free survival (PFS).
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