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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 46
- 试验地点
- 17
- 主要终点
- Part A: Number of Participants With Dose-limiting Toxicities (DLTs)
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Part A - Debio 1143 150 mg + Nivolumab
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.
干预措施: Debio 1143 (Drug)
Part A - Debio 1143 150 mg + Nivolumab
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.
干预措施: Nivolumab (Drug)
Part A - Debio 1143 200 mg + Nivolumab
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.
干预措施: Debio 1143 (Drug)
Part A - Debio 1143 200 mg + Nivolumab
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.
干预措施: Nivolumab (Drug)
Part B - Cohort 1 (SCLC): Debio 1143 200 mg + Nivolumab
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.
干预措施: Debio 1143 (Drug)
Part B - Cohort 1 (SCLC): Debio 1143 200 mg + Nivolumab
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.
干预措施: Nivolumab (Drug)
Part B - Cohort 2 (SCCHN): Debio 1143 200 mg + Nivolumab
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.
干预措施: Debio 1143 (Drug)
Part B - Cohort 2 (SCCHN): Debio 1143 200 mg + Nivolumab
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.
干预措施: Nivolumab (Drug)
Part B - Cohort 3 (GI Cancers): Debio 1143 200 mg + Nivolumab
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.
干预措施: Debio 1143 (Drug)
Part B - Cohort 3 (GI Cancers): Debio 1143 200 mg + Nivolumab
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.
干预措施: Nivolumab (Drug)
Part B - Cohort 4 (Gynecologic Cancers): Debio 1143 200 mg + Nivolumab
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.
干预措施: Debio 1143 (Drug)
Part B - Cohort 4 (Gynecologic Cancers): Debio 1143 200 mg + Nivolumab
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.
干预措施: Nivolumab (Drug)
结局指标
主要结局
Part A: Number of Participants With Dose-limiting Toxicities (DLTs)
时间窗: 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)
时间窗: 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.
次要结局
- 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(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(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(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 Treatment-emergent Adverse Events (TEAEs) Including Laboratory Abnormalities Reported as TEAEs, and Serious Adverse Events (SAEs)(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: Number of Participants With Shift From Baseline to Worst On-Treatment Value in Eastern Cooperative Oncology Group Performance Status (ECOG-PS)(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)(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)(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)(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)(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)(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(Months 6 and 12)
- Parts A and B: Overall Survival (OS)(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(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)(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))