Study of Oral Debio 0123 in Combination With Carboplatin in Participants With Advanced Solid Tumors

Study Overview
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Brief Summary
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This study has two parts: Dose Escalation and Dose Expansion. The primary objective of the study, in the Dose Escalation Part is to determine the recommended phase 2 dose (RP2D) of Debio 0123 when administered in combination with carboplatin in participants with advanced solid tumors that recurred or progressed after prior cisplatin or carboplatin containing therapy and for which no standard therapy of proven benefit is available. The primary objective of the study, in the Dose Expansion Part is to characterize the safety and tolerability of Debio 0123 when administered in combination with carboplatin at the RP2D determined during the dose escalation part of the study and to evaluate the preliminary antitumor activity of Debio 0123 when administered in combination with carboplatin.

Official Title
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A Phase 1 Study of Oral Debio 0123 in Combination With Carboplatin in Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: Debio 0123
* Drug: Carboplatin
* Drug: Debio 0123
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Dose Escalation: Histologically or cytologically confirmed locally advanced or metastatic solid and nonbleeding tumors that had recurred or progressed following standard therapy, has not responded to standard therapy or for which no standard therapy of proven benefit is available Able and willing to undergo tumor biopsy Prior platinum-based therapy (carboplatin or cisplatin). Life expectancy of at least 3 months ECOG PS 0-1 Dose Expansion: Histologically or cytologically confirmed, recurrent solid tumors of selected types. Participants must have progressed after at least 1 prior platinum-based line of therapy for advanced/metastatic disease. Participants must be platinum resistant (defined as progression within 6 months of completion of their most recent platinum-based chemotherapy). Prior poly (ADP-ribose) polymerase (PARP) inhibitor therapy is allowed. Platinum-based therapy does not need to be the last treatment prior to study entry. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Documented progressive or recurrent disease according to RECIST 1.1 since the last anti-cancer therapy and prior to study entry Able and willing to undergo tumor biopsy ECOG PS 0-1 Life expectancy of at least 3 months Exclusion Criteria: Dose Escalation and Dose Expansion: History of other malignancies requiring active treatment in the last 6 months Brain tumors and/or symptomatic brain metastases Receiving other investigating agents Presence of significant cardiovascular disease or other co-morbidities such as symptomatic ascites Prior exposure to any WEE1 inhibitor

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation: Group A: Debio 0123<br>Participants will receive Debio 0123 as monotherapy (Day -3), orally, daily for 3 days during Cycle 1 then in combination with carboplatin intravenous infusion from Cycle 2 onwards. Depending on pharmacokinetics (PK) and safety results from previous cohorts, the Debio 0123 dosing regimen may be modified for subsequent cohorts. | Drug: Debio 0123<br>* Debio 0123 will be given as an oral capsule for 3 days during each 21-day cycle, except Cycle 1 which is of 24 days.<br>Drug: Carboplatin<br>* Carboplatin will be given as an IV infusion in combination with Debio 0123 on Day 1 from Cycle 2 onwards in Group A.<br>|
| Experimental: Dose Escalation: Group B: Debio 0123<br>Participants will receive Debio 0123, orally, daily, for 6 days during each cycle in combination with carboplatin IV infusion. | Drug: Debio 0123<br>* Debio 0123 will be given as an oral capsule for 3 or 6 days during each 21-day cycle.<br>Drug: Carboplatin<br>* Carboplatin will be given as an IV infusion in combination with Debio 0123 on Day 1 from Cycle 1 onwards.<br>|
| Experimental: Dose Expansion: Debio 0123<br>Participants with platinum-resistant selected solid tumors will receive Debio 0123, orally, daily, depending on the RP2D determined in the previous part, for 3 or 6 days during each cycle in combination with carboplatin IV infusion. | Drug: Debio 0123<br>* Debio 0123 will be given as an oral capsule for 3 or 6 days during each 21-day cycle.<br>Drug: Carboplatin<br>* Carboplatin will be given as an IV infusion in combination with Debio 0123 on Day 1 from Cycle 1 onwards.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation: Recommended Phase 2 Dose (RP2D) of Debio 0123 When Administered in Combination with Carboplatin |  | 2 Cycles i.e., 45 days (Cycle 1 = 24 days; Cycle 2 onwards = 21 day-cycles) | 
| Dose Expansion: Percentage of Participants with Treatment-Emergent Serious Adverse Events (SAEs) |  | Up to 46 months | 
| Dose Expansion: Percentage of Participants with Treatment Discontinuations and Treatment Modifications Due to Adverse Events (AEs) and Laboratory Abnormalities |  | Up to 46 months | 
| Dose Expansion: Overall Response Rate (ORR) |  | From the start of study treatment until disease progression/recurrence is documented or analysis cut-off, whichever occurs first (up to 46 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation: Percentage of Participants with Dose Limiting Toxicities (DLTs) of Debio 0123 When Administered in Combination with Carboplatin |  | 2 Cycles i.e., 45 days (Cycle 1 = 24 days; Cycle 2 onwards = 21 day-cycles) | 
| Dose Escalation: Percentage of Participants with Treatment-Emergent SAEs |  | Up to 46 months | 
| Dose Escalation: Percentage of Participants with TEAEs and Laboratory Abnormalities |  | Up to 46 months | 
| Dose Escalation: Percentage of Participants with Treatment Discontinuations and Treatment Modifications Due to Adverse Events (AEs) and Laboratory Abnormalities |  | Up to 46 months | 
| Dose Escalation: Number of Participants with Changes in Vital Signs |  | Day 1 of each cycle (up to 46 months) [Group A: Cycle 1 = 24 days, Cycle 2 onwards and all cycles in Group B = 21-day cycles] | 
| Dose Escalation: Number of Participants with Changes in ECG |  | Up to 46 months | 
| Number of Participants with Change in Eastern Cooperative Oncology Group Performance Status (ECOG PS) |  | Day 1 of each cycle (up to 46 months) [Group A: Cycle 1 = 24 days, Cycle 2 onwards and all cycles in Group B = 21-day cycles] | 
| Dose Escalation: Group A: Plasma Concentration of Debio 0123 | The pharmacokinetics (PK) of Debio 0123 will be evaluated in plasma. | Day -3 to predose Day 1; postdose at multiple time points from Day 3 to Day 21 in Cycle 1 (Cycle 1 = 24 days), Day 1 on Cycle 2 (Cycle 2 onwards = 21 day-cycles) and subsequent cycles (Up to 46 months) | 
| Dose Escalation: Group A: Concentration of Debio 0123 in Urine | The PK of Debio 0123 will be evaluated in urine. | Day -3 to Day 21 Cycle 1 (Cycle 1 = 24 days) | 
| Dose Escalation: Group A: Area Under the Concentration Curve Over the Time 0 to Infinity (AUC∞) of Free Platinum in Plasma Ultrafiltrate of Carboplatin in Combination |  | Day 1 to Day 21 Cycle 2 (Cycle 2 onwards = 21 day-cycles) and subsequent cycles (Up to 46 months) | 
| Dose Escalation: Group B: Plasma Concentration of Debio 0123 | The PK of Debio 0123 will be evaluated in plasma. | Cycle 1 to Cycle 3: Days 1 and 10 (cycle length = 21 days) | 
| Dose Escalation: Group B: Concentration of Free Platinum in Plasma of Carboplatin |  | Cycle 1 Day 1 (cycle length = 21 days) | 
| Dose Escalation: Correlation Between Plasma Concentration of Debio 0123 and Changes in QT Interval Corrected Using Fridericia's Formula (QTcF) |  | Up to 46 months | 
| Dose Escalation: Tumor Response |  | From the start of study treatment until disease progression/recurrence is documented or analysis cut-off, whichever occurs first (Up to 46 months) | 
| Dose Escalation: Progression Free-Survival (PFS) |  | From the start of study treatment until disease progression or death from any cause, whichever occurs first (Up to 46 months) | 
| Dose Escalation: Overall Survival (OS) |  | From the start of study treatment until death from any cause (Up to 46 months) | 
| Dose Expansion: Best Overall Response (BOR) |  | From the start of study treatment until disease progression/recurrence is documented or analysis cut-off, whichever occurs first (Up to 46 months) | 
| Dose Expansion: Disease Control Rate |  | From the start of study treatment until disease progression/recurrence is documented or analysis cut-off, whichever occurs first (Up to 46 months) | 
| Dose Expansion: Number of Participants with Best Change in Tumor Size |  | From the start of study treatment until disease progression/recurrence is documented or analysis cut-off, whichever occurs first (Up to 46 months) | 
| Dose Expansion: Duration of Response (DOR) |  | Up to disease progression (Up to 46 months) | 
| Dose Expansion: Time to Progression (TTP) |  | Time from treatment initiation until objective tumor progression (Up to 46 months) | 
| Dose Expansion: Plasma Concentration of Debio 0123 |  | Cycle 1 and Cycle 2: Days 1, 3, 8 and 15 (cycle length = 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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WEE1-inhibitor