Debio 1143 in Combination With Carboplatin and Paclitaxel in Patient With Advanced Solid Malignancies

Study Overview
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Brief Summary
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This is a two-part trial in patients with squamous non-small cell lung cancer (NSCLC), platinum (Pt)-refractory ovarian cancer, and basal-like/claudin low triple negative breast cancer (TNBC). The primary objective of Part A is to determine the maximum tolerated dose (MTD) of Debio 1143 when administered to these patients in combination with full doses of paclitaxel and carboplatin. The primary objective of Part B is to consolidate the safety profile of the recommended dose of Debio 1143 when administered to these patients in combination with full doses of paclitaxel and carboplatin.

Official Title
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A Phase I Study to Evaluate the Safety and Determine the Maximum Tolerated Dose (MTD) of Debio 1143 Combined With Carboplatin and Paclitaxel in Patients With Squamous Non-Small Cell Lung Cancer (NSCLC), Platinum-refractory Ovarian Cancer, and Basal-like/Claudin Low Triple Negative Breast Cancer (TNBC)

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: Part A: Debio 1143
* Drug: Paclitaxel
* Drug: Carboplatin
* Drug: Part B: Debio 1143


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meets protocol-specified criteria for qualification and contraception Is willing and able to remain confined in the study unit for the entire duration of each treatment period and comply with restrictions related to food, drink and medications Voluntarily consents to participate and provides written informed consent prior to any protocol-specific procedures Exclusion Criteria: Has history or current use of over-the-counter medications, dietary supplements, or drugs (including nicotine and alcohol) outside protocol-specified parameters Has signs, symptoms or history of any condition that, per protocol or in the opinion of the investigator, might compromise: the safety or well-being of the participant or study staff; the safety or well-being of the participant's offspring (such as through pregnancy or breast-feeding); or the analysis of results

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Debio 1143<br>Eligible participants receive Part A: Debio 1143 once daily for 5 consecutive days in each 21-day treatment cycle according to dose escalation rules (in combination with Paclitaxel and Carboplatin standard of care) | Drug: Part A: Debio 1143<br>* Adaptive doses of Debio1143 oral capsules, between 50 and 400 mg until the recommended dose (RD) is determined.<br>Drug: Paclitaxel<br>* Paclitaxel standard of care, intravenous (IV), once on day 1 or 2 of each 21-day treatment cycle, after pre-medication to prevent severe hypersensitivity reactions.<br>Drug: Carboplatin<br>* Carboplatin standard of care, intravenous (IV), once on day 1 or 2 of each 21-day treatment cycle.<br>|
| Experimental: Part B: Lung Cancer<br>Participants with Lung Cancer receive Part B: Debio 1143 once daily for 5 consecutive days in each 21-day treatment cycle (in combination with Paclitaxel and Carboplatin standard of care) | Drug: Paclitaxel<br>* Paclitaxel standard of care, intravenous (IV), once on day 1 or 2 of each 21-day treatment cycle, after pre-medication to prevent severe hypersensitivity reactions.<br>Drug: Carboplatin<br>* Carboplatin standard of care, intravenous (IV), once on day 1 or 2 of each 21-day treatment cycle.<br>Drug: Part B: Debio 1143<br>* RD of Debio1143 oral capsules, once daily for five consecutive days starting on day 1 or 2 of each 21-day treatment cycle.<br>|
| Experimental: Part B: Ovarian Cancer<br>Participants with Ovarian Cancer receive Part B: Debio 1143 once daily for 5 consecutive days in each 21-day treatment cycle (in combination with Paclitaxel and Carboplatin standard of care) | Drug: Paclitaxel<br>* Paclitaxel standard of care, intravenous (IV), once on day 1 or 2 of each 21-day treatment cycle, after pre-medication to prevent severe hypersensitivity reactions.<br>Drug: Carboplatin<br>* Carboplatin standard of care, intravenous (IV), once on day 1 or 2 of each 21-day treatment cycle.<br>Drug: Part B: Debio 1143<br>* RD of Debio1143 oral capsules, once daily for five consecutive days starting on day 1 or 2 of each 21-day treatment cycle.<br>|
| Experimental: Part B: Breast Cancer<br>Participants with Breast Cancer receive Part B: Debio 1143 once daily for 5 consecutive days in each 21-day treatment cycle (in combination with Paclitaxel and Carboplatin standard of care) | Drug: Paclitaxel<br>* Paclitaxel standard of care, intravenous (IV), once on day 1 or 2 of each 21-day treatment cycle, after pre-medication to prevent severe hypersensitivity reactions.<br>Drug: Carboplatin<br>* Carboplatin standard of care, intravenous (IV), once on day 1 or 2 of each 21-day treatment cycle.<br>Drug: Part B: Debio 1143<br>* RD of Debio1143 oral capsules, once daily for five consecutive days starting on day 1 or 2 of each 21-day treatment cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of participants with dose-limiting toxicities | Categories: each Debio 1143 dose level and overall | up to 18 weeks | 
| Part B: Percentage of participants with adverse events (AEs) and serious AEs (SAEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria |  | up to 18 weeks + 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Percentage of participants with AEs and serious adverse events (SAEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria | Categories: each Debio 1143 dose level and overall | up to 18 weeks + 28 days | 
| Part A: Number of participants with change in vital signs | Categories: each Debio 1143 dose level and overall | up to 18 weeks | 
| Part A: Number of participants with change in electrocardiogram (ECG) | Categories: each Debio 1143 dose level and overall | up to 18 weeks | 
| Part A: Number of participants with change in Eastern Cooperative Oncology Group (ECOG) performance status (PS) | Categories: each Debio 1143 dose level and overall | up to 18 weeks | 
| Part B: Number of participants with change in vital signs | Categories: each indication at the recommended dose (RD) | up to 18 weeks | 
| Part B: Number of participants with change in electrocardiogram (ECG) | Categories: each indication at the recommended dose (RD) | up to 18 weeks | 
| Part B: Number of participants with change in Eastern Cooperative Oncology Group (ECOG) performance status (PS) | Categories: each indication at the recommended dose (RD) | up to 18 weeks | 
| Part A: Percentage of participants with incidence of laboratory abnormalities according to NCI-CTCAE criteria | Categories: each Debio 1143 dose level and overall | up to 18 weeks | 
| Part B: Percentage of participants with incidence of laboratory abnormalities according to NCI-CTCAE criteria | Categories: each indication at the RD | up to 18 weeks | 
| Part A: Percentage of participants with treatment discontinuations due to AEs and SAEs | Categories: each Debio 1143 dose level and overall | up to 18 weeks + 28 days | 
| Part B: Percentage of participants with treatment discontinuations due to AEs and SAEs | Categories: each indication at the RD | up to 18 weeks + 28 days | 
| Part A: Number of participants with change in left ventricular ejection fraction (LVEF) | Categories: each Debio 1143 dose level and overall | up to 18 weeks | 
| Part B: Number of participants with change in left ventricular ejection fraction (LVEF) | Categories: each indication at the RD | up to 18 weeks | 
| Part A: Number of participants with tumour response: disease control, change in tumour size from baseline and overall response | Categories: each Debio 1143 dose level and overall | up to 18 weeks | 
| Part B: Number of participants with tumour response: disease control, change in tumour size from baseline and overall response | Categories: each indication at the RD | up to 18 weeks | 
| Part A: Percentage of participants with progression-free survival (PFS) at 6 months | Categories: each Debio 1143 dose level and overall | at 6 months | 
| Part B: Percentage of participants with progression-free survival (PFS) at 6 months | Categories: each indication at the RD | at 6 months | 
| Part A: Percentage of participants with survival at 1 year | Categories: each Debio 1143 dose level and overall | at 12 months | 
| Part B: Percentage of participants with survival at 1 year | Categories: each indication at the RD | at 12 months | 
| Part B: Maximum concentration (Cmax) in the pharmacokinetic (PK) subset | Categories: Debio 1143 alone; Debio 1143 when administered with paclitaxel and carboplatin; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143 | up to 18 weeks | 
| Part B: Lowest concentration before the next dose (Ctrough) of Debio 1143 in the PK subset | Categories: alone and in combination with chemotherapy | up to 18 weeks | 
| Part B: Time to maximum concentration (tmax) in the PK subset | Categories: Debio 1143 alone; Debio 1143 when administered with paclitaxel and carboplatin; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143 | up to 18 weeks | 
| Part B: Area under the concentration versus time curve from the beginning to a point in time (AUC0-t) in the PK subset | Categories: Debio 1143 alone; Debio 1143 when administered with paclitaxel and carboplatin; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143 | up to 18 weeks | 
| Part B: Area under the concentration versus time curve extrapolated to infinity (AUC∞) in the PK subset | Categories: Debio 1143 alone; Debio 1143 when administered with paclitaxel and carboplatin; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143 | up to 18 weeks | 
| Part B: Terminal rate constant (λz) in the PK subset | Categories: Debio 1143 alone; Debio 1143 when administered with paclitaxel and carboplatin; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143 | up to 18 weeks | 
| Part B: Apparent terminal half-life (t½) in the PK subset | Categories: Debio 1143 alone; Debio 1143 when administered with paclitaxel and carboplatin; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143 | up to 18 weeks | 
| Part B: Mean residence time (MRT) in the PK subset | Categories: Debio 1143 alone; Debio 1143 when administered with paclitaxel and carboplatin; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143 | up to 18 weeks | 
| Part B: Apparent clearance (CL/F) of Debio 1143 in the PK subset | Categories: alone and in combination with chemotherapy | up to 18 weeks | 
| Part B: Apparent volume of distribution during the terminal phase (Vz/F) of Debio 1143 in the PK subset | Categories: alone and in combination with chemotherapy | up to 18 weeks | 
| Part B: Total amount of Debio 1143 excreted in urine (Ae) in the PK subset | Categories: alone and in combination with chemotherapy | up to 18 weeks | 
| Part B: Total amount of Debio 1143 excreted in urine in the first 8 hours (Ae0-8) in the PK subset | Categories: alone and in combination with chemotherapy | up to 18 weeks | 
| Part B: Total amount of Debio 1143 excreted in urine between 8 and 24 hours (Ae8-24) in the PK subset | Categories: alone and in combination with chemotherapy | up to 18 weeks | 
| Part B: Renal clearance calculated as Ae/AUC∞ (CLR) of Debio 1143 in the PK subset | Categories: alone and in combination with chemotherapy | up to 18 weeks | 
| Part B: Fraction of the dose excreted in urine calculated as Ae/dose (fe) of Debio 1143 in the PK subset | Categories: alone and in combination with chemotherapy | up to 18 weeks | 
| Part B: Area under the concentration versus time curve in the first 12 hours (AUC0-12) in the PK subset | Categories: paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143 | up to 18 weeks | 
| Part B: Total body clearance (CL) in the PK subset | Categories: paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143 | up to 18 weeks | 
| Part B: Volume of distribution at steady-state (Vss) in the PK subset | Categories: paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143 | up to 18 weeks | 
| Part B: Mean Residence Area under the concentration versus time curve (MR,AUC) in the PK subset | Categories: paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143 | up to 18 weeks | 
| Part B: Mean Residence Maximum Concentration (MR,Cmax) in the PK subset | Categories: paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143 | up to 18 weeks | 
| Part B: Platinum Refraction (PtR) in ovarian cancer participants included in the PK subset | Categories: paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143 | up to 18 weeks | 
| Part B: Cmax in patients other than the PK subset | Categories: paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143 | up to 18 weeks | 
| Part B: Concentration observed at time n (Cn) following Debio 1143 administration in patients other than the PK subset | Categories: paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143 | up to 18 weeks |