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

Solid Tumor Clinical Trial

— SMARTPLUS-106  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04122625
• Other study ID #: Debio 1143-106
• Secondary ID: 2018-003546-16
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: April 26, 2019
• Est. completion date: April 6, 2022

Study information

• Verified date: May 2023
• Source: Debiopharm International SA
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 46
• Est. completion date: April 6, 2022
• Est. primary completion date: April 6, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Solid Tumor

Intervention

Drug:
• Debio 1143
Administered as capsules.
• Nivolumab
Administered as IV infusion.

Locations

Country	Name	City	State
France	Centre Leon Berard	Lyon
France	Institut Universitaire du Cancer de Toulouse Oncopole	Toulouse
France	Institut Gustave Roussy	Villejuif
Spain	Hospital Vall d'Hebron	Barcelona
Spain	START Madrid, Fundacion Jimenez Diaz	Madrid
Spain	START Madrid, H.U. Sanchinarro	Madrid
United States	St. Luke's University Health Network	Bethlehem	Pennsylvania
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Dana-Farber/Partners Cancer Care	Boston	Massachusetts
United States	Montefiore Medical Center PRIME	Bronx	New York
United States	Rush University Medical Center	Chicago	Illinois
United States	UC Health, LLC.	Cincinnati	Ohio
United States	University of Florida	Gainesville	Florida
United States	Methodist Hospital, Houston Methodist Cancer Center	Houston	Texas
United States	Georgetown University - Lombardi Comprehensive Cancer Center	Northwest	Washington
United States	Washington University	Saint Louis	Missouri
United States	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Debiopharm International SA

Countries where clinical trial is conducted

United States,  France,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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)
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)