Study to Assess Safety and Efficacy of the Second Mitochondrial-derived Activator of Caspases (SMAC) Mimetic Debio 1143

Study Overview
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Brief Summary
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Part A (dose-optimization)- to determine the recommended phase 2 dose (RP2D) taking into account dose-limiting toxicity (DLT/s) in Cycle 1, overall safety/tolerability and pharmacokinetic (PK), by optimizing doses of Debio 1143 when combined with the standard dose of nivolumab, as well as treatment compliance in participants with advanced solid malignancies who failed prior systemic standard treatments. Part B (basket trial)- to evaluate the preliminary anti-tumor activity of Debio 1143 at the RP2D in combination with nivolumab at the standard dose, overall and in each participant cohort (Cohort 1: small cell lung cancer [SCLC]; Cohort 2: squamous cell carcinoma of the head and neck [SCCHN]; Cohort 3: gastrointestinal (GI) cancers with known microsatellite instability-high/mismatch repair deficiency (MSI-H/MMRd) or other deoxyribonucleic acid (DNA) damage repair (DDR) abnormalities, including homologous recombination deficiency (HRD); Cohort 4: platinum-resistant epithelial ovarian cancer [EOC], endometrial cancer, primary peritoneal cancer (PPC) or cervical cancer, with known MSIH/MMRd, hereditary/somatic mutations of the breast cancer 1 (BRCA1) and BRCA2 genes or other DNA DDR abnormalities (incl. HRD).

Official Title
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A Dose-optimization, Exploratory Phase Ib/II Study to Assess Safety and Efficacy of the Second Mitochondrial-derived Activator of Caspases (SMAC) Mimetic Debio 1143, When Given in Combination With the Anti-PD-1 Antibody Nivolumab in Patients With Specific Solid Tumors Who Have Progressed During or Immediately After Anti-PD-1/PD-L1 Treatment

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: Debio 1143
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have received at least one prior line of standard systemic chemotherapy in the advanced/unresectable cancer setting (standard adjuvant/neoadjuvant treatment is acceptable if relapse occurred within six months of treatment end) Have progressed or relapsed during or after a prior anti-programmed cell death-1 (PD-1)/ programmed cell death-ligand 1 (PD-L1)-based treatment, given either as a single agent or in combination with standard/approved chemotherapy, tyrosine kinase inhibitors (TKIs), radiotherapy (RT) or other monoclonal antibodies (mAbs) that are not known to modulate/inhibit immune checkpoints (CPIs) Measurable disease (Part B only) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) or Gynecologic Cancer Intergroup (GCIG) criteria in Cohort #4 of Part B (if applicable) and documented PD during or after prior PD-1/PD-L1 based therapy Exclusion Criteria: Thoracic or head and neck radiation >30 gray (Gy) within the 3 months prior to Cycle 1 Day 1 (C1D1) Have received, in total, more than 3 (i.e., Cohorts 1 & 2) or 4 (i.e., Cohorts 3 & 4) lines of prior systemic treatments in Part B (including adjuvant or neoadjuvant regimens if relapse within six months prior to C1D1) Liver cirrhosis Child-Pugh score B or C

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: Part A - Debio 1143 150 mg + Nivolumab<br>Participants received Debio 1143, 150 milligrams (mg) capsules, orally once on Days 1 to 10 and Days 15 to 24 of each 28-day treatment cycle along with nivolumab 240 mg, intravenous (IV) infusion on Days 1 and 15 of each 28-day treatment cycle allowed for a maximum of 26 cycles. | Drug: Debio 1143<br>* Administered as capsules.<br>Drug: Nivolumab<br>* Administered as IV infusion.<br>|
| Experimental: Part A - Debio 1143 200 mg + Nivolumab<br>Participants received Debio 1143, 200 mg capsules, orally once on Days 1 to 10 and Days 15 to 24 of each 28-day treatment cycle along with nivolumab 240 mg, IV infusion on Days 1 and 15 of each 28-day treatment cycle allowed for a maximum of 26 cycles. | Drug: Debio 1143<br>* Administered as capsules.<br>Drug: Nivolumab<br>* Administered as IV infusion.<br>|
| Experimental: Part B - Cohort 1 (SCLC): Debio 1143 200 mg + Nivolumab<br>Participants with small-cell lung cancer (SCLC) received Debio 1143, 200 mg capsules, orally once on Days 1 to 28 in each 28-day treatment cycle along with nivolumab 240 mg, IV infusion on Days 1 and 15 of each 28-day treatment cycle allowed for a maximum of 26 cycles. | Drug: Debio 1143<br>* Administered as capsules.<br>Drug: Nivolumab<br>* Administered as IV infusion.<br>|
| Experimental: Part B - Cohort 2 (SCCHN): Debio 1143 200 mg + Nivolumab<br>Participants with squamous cell carcinoma of the head and neck (SCCHN) received Debio 1143, 200 mg capsules, orally once on Days 1 to 28 in each 28-day treatment cycle along with nivolumab 240 mg, IV infusion on Days 1 and 15 of each 28-day treatment cycle allowed for a maximum of 26 cycles. | Drug: Debio 1143<br>* Administered as capsules.<br>Drug: Nivolumab<br>* Administered as IV infusion.<br>|
| Experimental: Part B - Cohort 3 (GI Cancers): Debio 1143 200 mg + Nivolumab<br>Participants with gastrointestinal (GI) cancers received Debio 1143, 200 mg capsules, orally once on Days 1 to 28 in each 28-day treatment cycle along with nivolumab 240 mg, IV infusion on Days 1 and 15 of each 28-day treatment cycle allowed for a maximum of 26 cycles. | Drug: Debio 1143<br>* Administered as capsules.<br>Drug: Nivolumab<br>* Administered as IV infusion.<br>|
| Experimental: Part B - Cohort 4 (Gynecologic Cancers): Debio 1143 200 mg + Nivolumab<br>Participants with gynecologic cancers received Debio 1143, 200 mg capsules, orally once on Days 1 to 28 in each 28-day treatment cycle along with nivolumab 240 mg, IV infusion on Days 1 and 15 of each 28-day treatment cycle allowed for a maximum of 26 cycles. | Drug: Debio 1143<br>* Administered as capsules.<br>Drug: Nivolumab<br>* Administered as IV infusion.<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 (DLTs) | DLT: any of following treatment-emergent adverse events (TEAEs) as per NCI CTCAE Grade V5.0 Criteria (Grades 1=mild, 2=moderate, 3=severe and 4 or 5= life-threatening/fatal outcomes) which are possibly, probably or definitely related to combination treatment and occurring in Cycle 1 (1 Cycle=28 days): Any Grade 4 or 5 hematologic toxicity, clinical or laboratory non-hematologic toxicity; febrile neutropenia any grade, Grade 3 thrombocytopenia if associated with bleeding or requiring platelet transfusion; Grade 2; Grade 3 and any other Grade 3 non-hematologic, treatment-related clinical toxicity lasting ≥3 days; delay of >2 weeks due to drug-related toxicity in initiating Cycle 2; unable to complete at least 70% of the scheduled treatment (>six Debio 1143 skipped doses in Cycle 1) due to treatment-related toxicity; required dose reduction in Cycle 1 or on Cycle 2 Day 1 or requirement for treatment withdrawal due to treatment-related toxicity (even if not meeting other DLT criteria). | Part A: Cycle 1 (28 days) | 
| Part B: Confirmed Objective Response Rate (ORR) | ORR was determined per response evaluation criteria in solid tumors (RECIST) v1.1 and/or gynecologic cancer intergroup (GCIG) criteria (for Cohort 4). ORR was calculated as the percentage of participants with a confirmed objective response. A confirmed objective response is a confirmed best overall response of partial response (PR) or complete response (CR) recorded after the start of study treatment until disease progression/recurrence was documented, a new systemic anti-cancer therapy was started or analysis cut-off, whichever occurred first. CR is defined by the disappearance of all target lesions and reduction of any pathological lymph nodes in short axis to <10 millimeters (mm). PR is defined by at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameter. | Part B: From the start of study treatment until disease progression/recurrence was documented, a new systemic anti-cancer therapy was started or analysis cut-off, whichever occurred first (up to approximately 2.05 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts A and B: Number of Participants With Treatment-emergent Adverse Events (TEAEs) Including Laboratory Abnormalities Reported as TEAEs, and Serious Adverse Events (SAEs) | An adverse event (AE) is any untoward medical occurrence in a clinical trial participant administered a medicinal product that does not necessarily have a causal relationship with this treatment. A TEAE is any new, related or non-related, undesirable medical occurrence or change of an existing condition in a participant that occurs during the treatment-emergent period, starting or worsening on or after the first study drug administration and up to 5 months after last nivolumab infusion, or the earliest date of new anticancer therapy - 1 day, whichever occurs first. An SAE is defined as any untoward medical occurrence that at any dose results in death; is life-threatening (i.e., puts the participant at immediate risk of death); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect, or is otherwise medically significant. | From the first study drug administration and up to 5 months after last nivolumab infusion, or the earliest date of new anticancer therapy -1 day, whichever occurs first (up to approximately 2.08 years in Part A and 2.05 years in Part B) | 
| Parts A and B: Change From Baseline in Weight |  | From Baseline up to end of treatment (up to approximately 1.53 years in Part A and up to 1 year in Part B) | 
| Parts A and B: Number of Participants With Markedly Abnormal Change From Baseline in Vital Signs | Vital sign parameters assessed comprise of systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate. Markedly abnormal criteria for vital signs include SBP [millimeters of mercury (mmHg)]: ≤ 90 mmHg OR change from baseline ≤ -20 mmHg, ≥ 140 mmHg OR change from baseline ≥ 20 mmHg; DBP (mmHg): ≤ 60 mmHg OR change from baseline ≤ -20 mmHg, ≥ 90 mmHg OR change from baseline ≥ 20 mmHg; Heart rate [beats per minute (bpm)]: ≤ 50 bpm OR change from baseline ≤ -20 bpm, ≥ 100 bpm OR change from baseline ≥ 20 bpm. | From Baseline up to end of treatment (up to approximately 1.53 years in Part A and up to 1 year in Part B) | 
| Parts A and B: Number of Participants With Change From Baseline in Temperature Reported as TEAEs | Change from baseline in temperature reported as TEAEs included pyrexia. A TEAE is any new, related or non-related, undesirable medical occurrence or change of an existing condition in a participant that occurs during the treatment-emergent period, starting or worsening on or after the first study drug administration and up to 5 months after last nivolumab infusion, or the earliest date of new anticancer therapy - 1 day, whichever occurs first. | From Baseline up to end of treatment (up to approximately 1.53 years in Part A and up to 1 year in Part B) | 
| Parts A and B: Number of Participants With Markedly Abnormal Change From Baseline in Electrocardiogram (ECG) Readings | ECG parameters comprised of PR Interval [millisecond (msec)], QRS Interval (msec), QT Interval (msec), QTcB Interval (msec), QTcF Interval (msec), heart rate (HR) (bpm), RR interval (msec), derived HR (msec), calculated as 60000/RR interval [for data checking only: should be within 5% of HR]. Marked abnormal criteria for ECG parameters included absolute values QRS interval: < 50 msec, > 110 msec; absolute values for QT interval, QTcB interval: >450 msec, > 480 msec, > 500 msec, QTcF: > 480 msec, > 500 msec; change from baseline values for QTcB interval, and QTcF: >30 msec increase from baseline, >60 msec increase from baseline. Data for highest on-treatment change from baseline as per the markedly abnormal criteria for ECG parameters are reported. On-treatment is the period of time between the first and last administration of any study drug. Participants with at least one markedly abnormal change from baseline value in the above categories are reported. | From Baseline up to end of treatment (up to approximately 1.53 years in Part A and up to 1 year in Part B) | 
| Parts A and B: Number of Participants With Shift From Baseline to Worst On-Treatment Value in Eastern Cooperative Oncology Group Performance Status (ECOG-PS) | The ECOG-PS was used to assess the effect of disease progression on participants' daily activities. ECOG-PS is graded as follows: Grade 0 - fully active, able to carry on all pre-disease performance without restriction; Grade 1 - restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; Grade 2 - ambulatory and capable of all self-care, but unable to carry out any work activities, up and about more than 50% of waking hours; Grade 3 - capable of only limited self-care, confined to bed or chair for more than 50% of waking hours; Grade 4 - completely disabled, cannot carry on any self-care, totally confined to bed or chair; Grade 5 - dead. Shift values from baseline grade to worst on-treatment grade and missing values were reported. | From Baseline up to end of treatment (up to approximately 1.53 years in Part A and up to 1 year in Part B) | 
| Parts A and B: Number of Participants With TEAEs Including Laboratory Abnormalities Leading to Treatment Discontinuations and Dose Modifications |  | From the first study drug administration and up to 5 months after last nivolumab infusion, or the earliest date of new anticancer therapy -1 day, whichever occurs first (up to approximately 2.08 years in Part A and 2.05 years in Part B) | 
| Part A: Confirmed Objective Response Rate (ORR) | ORR was determined per RECIST v1.1. ORR was calculated as the percentage of participants with a confirmed objective response. A confirmed objective response is a confirmed best overall response of PR or CR recorded after the start of study treatment until disease progression/recurrence was documented, a new systemic anti-cancer therapy was started or analysis cut-off, whichever occurred first. CR is defined by the disappearance of all target lesions and reduction of any pathological lymph nodes in short axis to <10 mm. PR is defined by at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameter. | Part A: From the start of study treatment until disease progression/recurrence was documented, a new systemic anti-cancer therapy was started or analysis cut-off, whichever occurred first (up to approximately 2.08 years) | 
| Parts A and B: Unconfirmed Objective Response Rate (uORR) | uORR was calculated as the percentage of participants with unconfirmed objective response per RECIST v1.1. Unconfirmed objective response is an unconfirmed best overall response of PR or CR. Objective response was derived as any PR or CR recorded after the start of study treatment until disease progression/recurrence was documented, a new systemic anti-cancer therapy was started or analysis cut-off, whichever occurred first. CR is defined by the disappearance of all target lesions and reduction of any pathological lymph nodes in short axis to <10 mm. PR is defined by at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameter. | From the start of study treatment until disease progression/recurrence was documented, a new systemic anti-cancer therapy was started or analysis cut-off, whichever occurred first (up to approximately 2.08 years in Part A and 2.05 years in Part B) | 
| Parts A and B: Disease Control Rate (DCR) | DCR was calculated as the percentage of participants with disease control. Disease control was derived as any CR, PR, or stable disease reported during the study. CR is defined by the disappearance of all target lesions and reduction of any pathological lymph nodes in short axis to <10 mm. PR is defined by at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameter. | From the start of study treatment until disease progression/recurrence was documented, a new systemic anti-cancer therapy was started or analysis cut-off, whichever occurred first (up to approximately 2.08 years in Part A and 2.05 years in Part B) | 
| Parts A and B: Median Duration of Response (DOR) | DOR is defined as the time, in months, between date of the initial response (PR or CR) or date of first reduction of 50% in carbohydrate antigen 125 (CA-125), and date of the first documented disease progression or death due to any cause, whichever occurs first. CR is defined by the disappearance of all target lesions and reduction of any pathological lymph nodes in short axis to <10 mm. PR is defined by at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameter. Data is reported as Kaplan-Meier product-limit estimates. | From the start of study treatment until disease progression/recurrence was documented, a new systemic anti-cancer therapy was started or analysis cut-off, whichever occurred first (up to approximately 2.08 years in Part A and 2.05 years in Part B) | 
| Parts A and B: Progression Free Survival (PFS) | PFS duration is defined as the time, in months, elapsed between treatment initiation and tumor progression or death from any cause, whichever occurs first. | From the start of study treatment until disease progression/recurrence or death from any cause, whichever occurs first (up to approximately 2.08 years in Part A and 2.05 years in Part B) | 
| Parts A and B: PFS Rate at Months 6 and 12 | PFS is defined as duration elapsed between treatment initiation and tumor progression or death from any cause, whichever occurs first. Data for PFS rate is reported as Kaplan-Meier product-limit estimates and includes Brookmeyer-Crowley confidence intervals. | Months 6 and 12 | 
| Parts A and B: Overall Survival (OS) | OS is defined as the time elapsed, in months, between treatment initiation and death from any cause. | From the start of study treatment until death from any cause, whichever occurs first (up to approximately 2.08 years in Part A and 2.05 years in Part B) | 
| Parts A and B: OS Rate at Months 12 and 18 | OS is defined as the time elapsed, in months, between treatment initiation and death from any cause. Data for OS rate is reported as Kaplan-Meier product-limit estimates and includes Brookmeyer-Crowley confidence intervals. | Months 12 and 18 | 
| Part A: Area Under the Curve From Time 0 to 4 Hours (AUC0-4H) of Debio 1143 and Debio 1143-MET1 |  | Cycle 1: predose, 0.5, 1.5, 4 hours post-dose on Days 1 and 15, predose, 1.5, 4 hours post-dose on Days 8 and 22; Cycle 3: predose, 0.5, 1.5, 4 hours post-dose on Day 1 and predose, 1.5, 4 hours post-dose on Day 15 (each cycle=28 days) | 
| Part B: AUC0-4H of Debio 1143 and Debio 1143-MET1 |  | Cycle 1: predose, 1.5, 4 hours post-dose on Days 1 and 22; Cycle 3: predose, 1.5, 4 hours post-dose on Day 1 (each cycle = 28 days) | 
| Part A: Area Under the Curve From Time 0 to 8 Hours (AUC0-8H) of Debio 1143 and Debio 1143-MET1 |  | Cycle 1: predose, 0.5, 1.5, 4, 8 hours post-dose on Days 1 and 15, and predose, 1.5, 4, 8 hours post-dose on Day 8; Cycle 3: predose, 0.5, 1.5, 4, 8 hours post-dose on Day 1 and predose, 1.5, 4, 8 hours post-dose on Day 15 (each cycle = 28 days) | 
| Part A: Maximum Observed Concentration (Cmax) of Debio 1143 and Debio 1143-MET1 |  | Cycle 1: Predose,0.5,1.5,4,8 hours post-dose (Days 1 and 15), predose,1.5,4,8 hours post-dose (Day 8), predose,1.5,4 hours post-dose (Day 22); Cycle 3: predose,0.5,1.5,4,8 hours post-dose (Day 1), predose,1.5,4,8 hours post-dose (Day 15) (Cycle=28 days) | 
| Part B: Cmax of Debio 1143 and Debio 1143-MET1 |  | Cycle 1: predose, 1.5, 4 hours post-dose on Days 1 and 22; Cycle 3: predose, 1.5, 4 hours post-dose on Day 1 (each cycle = 28 days) | 
| Part A: Trough Concentration (Cmin) of Debio 1143 and Debio 1143-MET1 |  | Cycle 1: predose on Days 3, 8, 15, 17 and 22; Cycle 3: predose on Days 1, 3, 15, 17; Cycle 6: predose on Day 1 | 
| Part B: Trough Concentration (Cmin) of Debio 1143 and Debio 1143-MET1 |  | Cycle 1: predose on Days 8 and 22; Cycle 3: predose on Day 1 (each cycle = 28 days) | 
| Part A: Serum Trough Concentration of Nivolumab |  | Cycle 1: predose, 1.5, 8 hours post-dose on Day 15; Cycle 3: predose, 0.5, 1.5, 8 hours post-dose on Day 1 and predose, 1.5 hours post-dose on Day 15 (each cycle = 28 days) | 
| Part B: Serum Trough Concentration of Nivolumab |  | Cycle 1: predose, 1.5 hours post-dose on Day 15; Cycle 3: predose, 1.5 hours post-dose on Days 1 and Day 15; Cycle 6: predose on Day 1 (each cycle = 28 days) | 
| Parts A and B: Time to Response (TTR) | The average of the time taken in days for PR is reported. PR is defined by at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameter. | From the start of study treatment until disease progression/recurrence was documented, a new systemic anti-cancer therapy was started or analysis cut-off, whichever occurred first (up to approximately 2.08 years in Part A and 2.05 years in Part B) |