Clinical Trials /

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

NCT04122625

Description:

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).

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Ampulla of Vater Carcinoma
  • Cervical Carcinoma
  • Endometrial Carcinoma
  • Esophageal Carcinoma
  • Gastrointestinal Stromal Tumor
  • Head and Neck Squamous Cell Carcinoma
  • Malignant Esophagogastric Neoplasm
  • Malignant Gastric Neoplasm
  • Malignant Intestinal Neoplasm
  • Malignant Ovarian Epithelial Tumor
  • Malignant Small Intestinal Neoplasm
  • Malignant Solid Tumor
  • Primary Peritoneal Carcinoma
  • Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: Debio 1143-106
  • SECONDARY ID: 2018-003546-16
  • NCT ID: NCT04122625

Conditions

  • Solid Tumor

Interventions

DrugSynonymsArms
Debio 1143Debio 1143 + Nivolumab
NivolumabDebio 1143 + Nivolumab

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
Debio 1143 + NivolumabExperimentalPart A: Participants will receive Debio 1143 at a starting dose of 150 milligrams (mg) orally once daily on Days 1-10 and Days 15-24 every 4 weeks (q4w) along with nivolumab at a flat dose of 240 mg intravenously (IV) on Days 1 and 15 of a 28-day cycle, participants may be switched to 480 mg IV on Day 1 q4w, exclusively upon investigator request with the sponsor agreement. Part B: Participants will receive Debio 1143 at RP2D established in Part A in combination with nivolumab as per standard care.
  • Debio 1143
  • Nivolumab

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 (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 (including adjuvant or neoadjuvant regimens if relapse
             within six months prior to C1D1)

          -  Liver cirrhosis Child-Pugh score B or C
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part A: Recommended Phase 2 Dose (RP2D) of Debio1143
Time Frame:Up to 28 days (Cycle 1)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Part A and B: Number of Participants with Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Laboratory Abnormalities
Time Frame:Up to 17 months
Safety Issue:
Description:
Measure:Part A and B: Number of Participants with Change in Weight
Time Frame:Up to 17 months
Safety Issue:
Description:
Measure:Part A and B: Number of Participants with Change in Vital Signs
Time Frame:Up to 17 months
Safety Issue:
Description:
Measure:Part A and B: Number of Participants with Change in Temperature
Time Frame:Up to 17 months
Safety Issue:
Description:
Measure:Part A and B: Number of Participants with Change in Electrocardiogram (ECG)
Time Frame:Up to 17 months
Safety Issue:
Description:
Measure:Part A and B: Number of Participants with Change in Eastern Cooperative Oncology Group performance status (ECOG-PS)
Time Frame:Up to 17 months
Safety Issue:
Description:
Measure:Part A and B: Number of Participants Leading to Treatment Discontinuations and Treatment Modifications due to AEs and Laboratory Abnormalities
Time Frame:Up to 17 months
Safety Issue:
Description:
Measure:Part A: Confirmed Objective Response Rate (ORR)
Time Frame:From first occurrence of objective response until disease progression or death from any cause or end of study (Up to 17 months)
Safety Issue:
Description:
Measure:Part A and B: Unconfirmed Objective Response Rate (ORR)
Time Frame:From first occurrence of objective response until disease progression or death from any cause or end of study (Up to 17 months)
Safety Issue:
Description:
Measure:Part A and B: Disease Control Rate (DCR)
Time Frame:From the start of study treatment until disease progression/recurrence or analysis cut-off, whichever occurs first (Up to 17 months)
Safety Issue:
Description:
Measure:Part A and B: Time to Response (TTR)
Time Frame:From the date of first dose to the date of the first documented evidence of response (Up to 17 months)
Safety Issue:
Description:
Measure:Part A and B: Duration of Response (DOR)
Time Frame:From the time of documentation of response to disease progression or analysis cut-off date, which-ever occur first (Up to 17 months)
Safety Issue:
Description:
Measure:Part 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 17 months)
Safety Issue:
Description:
Measure:Part A and B: Percentage of Participants with PFS at Month 6, 12 and 18
Time Frame:Month 6, 12 and 18
Safety Issue:
Description:
Measure:Part A and B: Overall Survival (OS)
Time Frame:From the start of study treatment until death from any cause, whichever occurs first (Up to 17 months)
Safety Issue:
Description:
Measure:Part A and B: OS Rate at Month 12 and 18
Time Frame:Month 12 and 18
Safety Issue:
Description:
Measure:Part A and B: Area Under the Curve (AUC) of Debio 1143 and Debio 1143-MET1
Time Frame:Part A: Day 1, 3, 8, 15, 17, 22 Cycle 1 (each cycle is 28 days); Day 1, 3, 15, 17 Cycle 3; Day 1 Cycle 6. Part B: Day 1, 8, 15, 22 Cycle 1; Day 1, 15, Cycle 3; Day 1 Cycle 6; End of Treatment (Up to 17 months)
Safety Issue:
Description:
Measure:Part A and B: Maximum Observed Concentration (Cmax) of Debio 1143 and Debio 1143-MET1
Time Frame:Part A: Day 1, 3, 8, 15, 17, 22 Cycle 1 (each cycle is 28 days); Day 1, 3, 15, 17 Cycle 3; Day 1 Cycle 6. Part B: Day 1, 8, 15, 22 Cycle 1; Day 1, 15, Cycle 3; Day 1 Cycle 6; End of Treatment (Up to 17 months)
Safety Issue:
Description:
Measure:Part A and B: Trough Concentration (Cmin) of Debio 1143 and Debio 1143-MET1
Time Frame:Part A: Day 1, 3, 8, 15, 17, 22 Cycle 1 (each cycle is 28 days); Day 1, 3, 15, 17 Cycle 3; Day 1 Cycle 6. Part B: Day 1, 8, 15, 22 Cycle 1; Day 1, 15, Cycle 3; Day 1 Cycle 6; End of Treatment (Up to 17 months)
Safety Issue:
Description:
Measure:Part A and B: Serum Concentration of Nivolumab
Time Frame:Part A: Day 1, 3, 8, 15, 17, 22 Cycle 1 (each cycle is 28 days); Day 1, 3, 15, 17 Cycle 3; Day 1 Cycle 6. Part B: Day 1, 8, 15, 22 Cycle 1; Day 1, 15, Cycle 3; Day 1 Cycle 6; End of Treatment (Up to 17 months)
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Debiopharm International SA

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