Solid TumorPhase 1/2SMARTPLUS-106NCT04122625
Study to Assess Safety and Efficacy of the Second Mitochondrial-derived Activator of Caspases (SMAC) Mimetic Debio 1143
A Phase 1/2 study testing Debio 1143 and Nivolumab in people with Solid Tumor, run by Debiopharm International SA at 17 sites in 3 countries.
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Solid Tumor
- What is being tested?
- Debio 1143 and Nivolumab
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 46 participants
- Where
- 17 sitesin 3 countries
- Study dates
- 26 Apr 2019to 6 Apr 2022
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
17 sites in 3 countries.
17 sites in 3 countries
United States11 sites
St. Luke's University Health Network
Bethlehem, Pennsylvania, 18015
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215
Dana-Farber/Partners Cancer Care
Boston, Massachusetts, 02215
Rush University Medical Center
Chicago, Illinois, 60612
UC Health, LLC.
Cincinnati, Ohio, 45229
University of Florida
Gainesville, Florida, 32611
Methodist Hospital, Houston Methodist Cancer Center
Houston, Texas, 77030
Georgetown University - Lombardi Comprehensive Cancer Center
Northwest, Washington, 20007
Washington University
St Louis, Missouri, 63110
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, 33612-9497
Montefiore Medical Center PRIME
The Bronx, New York, 10461
France3 sites
Centre Leon Berard
Lyon, 69008
Institut Universitaire du Cancer de Toulouse Oncopole
Toulouse, 31100
Institut Gustave Roussy
Villejuif, 94800
Spain3 sites
Hospital Vall d'Hebron
Barcelona, 08035
START Madrid, Fundacion Jimenez Diaz
Madrid, 28040
START Madrid, H.U. Sanchinarro
Madrid, 28050
About this study
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
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).
- Conditions
- Solid Tumor
- Being tested
- Debio 1143, Nivolumab
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Debio 1143Drug
Administered as capsules.
NivolumabDrug
Administered as IV infusion.
| Study group | Role | What they receive |
|---|---|---|
| Part A - Debio 1143 150 mg + Nivolumab | Experimental | 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. Receives: Drug: Debio 1143; Drug: Nivolumab |
| Part A - Debio 1143 200 mg + Nivolumab | Experimental | 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. Receives: Drug: Debio 1143; Drug: Nivolumab |
| Part B - Cohort 1 (SCLC): Debio 1143 200 mg + Nivolumab | Experimental | 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. Receives: Drug: Debio 1143; Drug: Nivolumab |
| Part B - Cohort 2 (SCCHN): Debio 1143 200 mg + Nivolumab | Experimental | 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. Receives: Drug: Debio 1143; Drug: Nivolumab |
| Part B - Cohort 3 (GI Cancers): Debio 1143 200 mg + Nivolumab | Experimental | 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. Receives: Drug: Debio 1143; Drug: Nivolumab |
| Part B - Cohort 4 (Gynecologic Cancers): Debio 1143 200 mg + Nivolumab | Experimental | 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. Receives: Drug: Debio 1143; Drug: Nivolumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 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.
Measured: 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 outcomes (25)
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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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.
Measured: 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)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Oct 2019
- Study start26 Apr 2019
- Primary completion6 Apr 2022
- Study completion6 Apr 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Solid TumorStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 46 participants (actual)
Sponsor and investigators
- Lead sponsor
- Debiopharm International SA
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04122625
- Sponsor's protocol ID
- Debio 1143-106
- Other IDs
- 2018-003546-16, 2018
- Acronym
- SMARTPLUS-106
- Status last verified
- May 2023
- First submitted
- 30 Aug 2019
- Last updated
- 12 Jun 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 12 Jun 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04122625
- Acronym / sponsor ID
- SMARTPLUS-106 / Debio 1143-106
- Conditions
- Solid Tumor
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 46 participants (actual)
- Lead sponsor
- Debiopharm International SAIndustry (pharma, biotech, devices)
- Study start
- 26 Apr 2019 (actual)
- Primary completion
- 6 Apr 2022 (actual)
- Study completion
- 6 Apr 2022 (actual)
- First posted
- 10 Oct 2019 (actual)
- Results
- Posted 12 Jun 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Part A - Debio 1143 150 mg + Nivolumab | Experimental | Drug: Debio 1143, Drug: NivolumabParticipants 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. |
| Part A - Debio 1143 200 mg + Nivolumab | Experimental | Drug: Debio 1143, Drug: NivolumabParticipants 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. |
| Part B - Cohort 1 (SCLC): Debio 1143 200 mg + Nivolumab | Experimental | Drug: Debio 1143, Drug: NivolumabParticipants 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. |
| Part B - Cohort 2 (SCCHN): Debio 1143 200 mg + Nivolumab | Experimental | Drug: Debio 1143, Drug: NivolumabParticipants 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. |
| Part B - Cohort 3 (GI Cancers): Debio 1143 200 mg + Nivolumab | Experimental | Drug: Debio 1143, Drug: NivolumabParticipants 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. |
| Part B - Cohort 4 (Gynecologic Cancers): Debio 1143 200 mg + Nivolumab | Experimental | Drug: Debio 1143, Drug: NivolumabParticipants 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (3 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Debio 1143Administered as capsules. | Drug | Part A - Debio 1143 150 mg + Nivolumab, Part A - Debio 1143 200 mg + Nivolumab, Part B - Cohort 1 (SCLC): Debio 1143 200 mg + Nivolumab, Part B - Cohort 2 (SCCHN): Debio 1143 200 mg + Nivolumab, Part B - Cohort 3 (GI Cancers): Debio 1143 200 mg + Nivolumab, Part B - Cohort 4 (Gynecologic Cancers): Debio 1143 200 mg + Nivolumab |
| NivolumabAdministered as IV infusion. | Drug | Part A - Debio 1143 150 mg + Nivolumab, Part A - Debio 1143 200 mg + Nivolumab, Part B - Cohort 1 (SCLC): Debio 1143 200 mg + Nivolumab, Part B - Cohort 2 (SCCHN): Debio 1143 200 mg + Nivolumab, Part B - Cohort 3 (GI Cancers): Debio 1143 200 mg + Nivolumab, Part B - Cohort 4 (Gynecologic Cancers): Debio 1143 200 mg + Nivolumab |
Primary outcome
Part A: Number of Participants With Dose-limiting Toxicities (DLTs)
Time frame: Part A: Cycle 1 (28 days)
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 B: Confirmed Objective Response Rate (ORR)
Time frame: 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)
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.
25 secondary outcomes
Parts A and B: Number of Participants With Treatment-emergent Adverse Events (TEAEs) Including Laboratory Abnormalities Reported as TEAEs, and Serious Adverse Events (SAEs)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: 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
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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
Time frame: Months 6 and 12
Parts A and B: Overall Survival (OS)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: 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)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Jun 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
17 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Debio 1143 and Nivolumab in people with Solid Tumor, run by Debiopharm International SA at 17 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Jun 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 17 sites in United States, France, Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 12 Jun 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Part A: Number of Participants With Dose-limiting Toxicities (DLTs) (time frame: Part A: Cycle 1 (28 days)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Jun 2023.