Study of Lunresertib Alone or in Combination With RP-3500 or Debio 0123 in Patients With Advanced Solid Tumors

Study arms

• Experimental
  Phase 1: Lunresertib Single-Agent, Dose Escalation and Food-effect Study

  Patients receive lunresertib orally until disease progression, unacceptable toxicity, or investigator/patient decision. Dose escalation will proceed until a maximum tolerated dose is identified.

  Drug: Lunresertib

• Experimental
  Phase 1: Lunresertib in combination with RP-3500, Dose Escalation Study

  Patients receive lunresertib with RP-3500 orally until disease progression, unacceptable toxicity, or investigator/patient decision. Dose escalation will proceed until a maximum tolerated dose is identified.

  Drug: Lunresertib · Drug: RP-3500

• Experimental
  Phase 1: Lunresertib in combination with Debio 0123, Dose Escalation Study

  Patients receive lunresertib with Debio 0123 orally until disease progression, unacceptable toxicity, or investigator/patient decision. Dose escalation will proceed until a maximum tolerated dose is identified.

  Drug: Lunresertib · Drug: Debio0123

Interventions

• DrugLunresertib

  Oral PKMYT1 Inhibitor

• DrugRP-3500

  Oral ATR Inhibitor

• DrugDebio0123

  Oral WEE1 Inhibitor

Primary outcomes

1. 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

   Time frame: Up to 90 days after last administration of study intervention

2. 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

   Time frame: Up to 90 days after last administration of study intervention

3. 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

   Time frame: Up to 90 days after last administration of study intervention

4. 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.

   Time frame: Time 0 (time of dosing) to 72 hours post-dose for each treatment condition

5. The effect of food on the PK of tablet formulation of lunresertib when administered in fed conditions compared to administration under fasted conditions

   Assessed by the plasma concentrations of lunresertib with calculation of the ratio of PK parameters (e.g., Cmax and AUC) between the tablet formulation under fasted and fed state.

   Time frame: Time 0 (time of dosing) to 72 hours post-dose for each treatment condition

6. To assess the safety and tolerability of lunresertib tablets in combination with RP-3500, confirm the MTD of lunresertib tablets in combination with RP-3500, and determine a RP2D and preferred schedule

   Assessed by DLTs, TEAEs, safety laboratory assessments, the incidence of DLTs and the incidence and severity of cumulative safety data

   Time frame: Up to 90 days after last administration of study intervention

Secondary outcomes

1. 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

   Time frame: Up to 90 days after last administration of study intervention

2. 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

   Time frame: Up to 90 days after last administration of study intervention

3. 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

   Time frame: Up to 90 days after last administration of study intervention

4. 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).

   Time frame: Through Study Completion, an average of 1 year

5. To assess the safety and anti-tumor effects of lunresertib capsule + RP-3500

   As measure by TEAEs, safety laboratory assessments, Best percent change in tumor size from baseline, ORR, overall response rate, DOR, CBR, tumor marker response, PFS

   Time frame: Through Study Completion, an average of 1 year

6. To further characterize the PK of lunresertib tablets and assess preliminary anti-tumor

   Measured by Plasma concentrations of lunresertib with calculation of Cmax, Tmax, AUC, elimination t1/2, and other PK parameters as appropriate, Best percent change in tumor size from baseline, ORR, overall response rate, DOR, CBR, tumor marker response, PFS

   Time frame: Through Study Completion, an average of 1 year

Individual participant data

Plan to share: No