Clinical trial NCT04122625: Study to Assess Safety and Efficacy of the Second Mitochondrial-derived Activator of Caspases (SMAC) Mimetic Debio 1143
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Solid Tumor
Lead sponsor: Debiopharm International SA
Sponsor class: INDUSTRY
First posted: 2019-10-10
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief 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).


Eligibility criteria: 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

Primary outcomes:
measure: Part A: Number of Participants With Dose-limiting Toxicities (DLTs)
timeFrame: Part A: Cycle 1 (28 days)
measure: Part B: Confirmed Objective Response Rate (ORR)
timeFrame: 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:
measure: Parts A and B: Number of Participants With Treatment-emergent Adverse Events (TEAEs) Including Laboratory Abnormalities Reported as TEAEs, and Serious Adverse Events (SAEs)
timeFrame: 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)
measure: Parts A and B: Change From Baseline in Weight
timeFrame: From Baseline up to end of treatment (up to approximately 1.53 years in Part A and up to 1 year in Part B)
measure: Parts A and B: Number of Participants With Markedly Abnormal Change From Baseline in Vital Signs
timeFrame: From Baseline up to end of treatment (up to approximately 1.53 years in Part A and up to 1 year in Part B)
measure: Parts A and B: Number of Participants With Change From Baseline in Temperature Reported as TEAEs
timeFrame: From Baseline up to end of treatment (up to approximately 1.53 years in Part A and up to 1 year in Part B)
measure: Parts A and B: Number of Participants With Markedly Abnormal Change From Baseline in Electrocardiogram (ECG) Readings
timeFrame: From Baseline up to end of treatment (up to approximately 1.53 years in Part A and up to 1 year in Part B)
measure: 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)
timeFrame: From Baseline up to end of treatment (up to approximately 1.53 years in Part A and up to 1 year in Part B)
measure: Parts A and B: Number of Participants With TEAEs Including Laboratory Abnormalities Leading to Treatment Discontinuations and Dose Modifications
timeFrame: 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)
measure: Part A: Confirmed Objective Response Rate (ORR)
timeFrame: 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)
measure: Parts A and B: Unconfirmed Objective Response Rate (uORR)
timeFrame: 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)
measure: Parts A and B: Disease Control Rate (DCR)
timeFrame: 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)
measure: Parts A and B: Median Duration of Response (DOR)
timeFrame: 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)
measure: Parts A and B: Progression Free Survival (PFS)
timeFrame: 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)
measure: Parts A and B: PFS Rate at Months 6 and 12
timeFrame: Months 6 and 12
measure: Parts A and B: Overall Survival (OS)
timeFrame: 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)
measure: Parts A and B: OS Rate at Months 12 and 18
timeFrame: Months 12 and 18
measure: Part A: Area Under the Curve From Time 0 to 4 Hours (AUC0-4H) of Debio 1143 and Debio 1143-MET1
timeFrame: 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)
measure: Part B: AUC0-4H of Debio 1143 and Debio 1143-MET1
timeFrame: 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)
measure: Part A: Area Under the Curve From Time 0 to 8 Hours (AUC0-8H) of Debio 1143 and Debio 1143-MET1
timeFrame: 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)
measure: Part A: Maximum Observed Concentration (Cmax) of Debio 1143 and Debio 1143-MET1
timeFrame: 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)
measure: Part B: Cmax of Debio 1143 and Debio 1143-MET1
timeFrame: 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)
measure: Part A: Trough Concentration (Cmin) of Debio 1143 and Debio 1143-MET1
timeFrame: 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
measure: Part B: Trough Concentration (Cmin) of Debio 1143 and Debio 1143-MET1
timeFrame: Cycle 1: predose on Days 8 and 22; Cycle 3: predose on Day 1 (each cycle = 28 days)
measure: Part A: Serum Trough Concentration of Nivolumab
timeFrame: 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)
measure: Part B: Serum Trough Concentration of Nivolumab
timeFrame: 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)
measure: Parts A and B: Time to Response (TTR)
timeFrame: 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)
Other outcomes:
Locations:
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber/Partners Cancer Care
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Bronx
country: United States
facility: Montefiore Medical Center PRIME
state: New York
city: Cincinnati
country: United States
facility: UC Health, LLC.
state: Ohio
city: Bethlehem
country: United States
facility: St. Luke's University Health Network
state: Pennsylvania
city: Houston
country: United States
facility: Methodist Hospital, Houston Methodist Cancer Center
state: Texas
city: Northwest
country: United States
facility: Georgetown University - Lombardi Comprehensive Cancer Center
state: Washington
city: Lyon
country: France
facility: Centre Leon Berard
city: Toulouse
country: France
facility: Institut Universitaire du Cancer de Toulouse Oncopole
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Madrid
country: Spain
facility: START Madrid, Fundacion Jimenez Diaz
city: Madrid
country: Spain
facility: START Madrid, H.U. Sanchinarro
Study officials:
References: