A Phase 1b/2, Safety Lead-in and Dose-Expansion, Open Label, Multicenter Trial Investigating the Safety, Tolerability, and Preliminary Activity of Ivosidenib in Combination With Durvalumab and Gemcitabine/Cisplatin as First-line Therapy in Participants With Locally Advanced, Unresectable or Metastatic Cholangiocarcinoma With an IDH1 Mutation
概览
- 阶段
- 1 期
- 干预措施
- Ivosidenib
- 疾病 / 适应症
- Locally Advanced, Unresectable or Metastatic Cholangiocarcinoma With an IDH1 Mutation
- 发起方
- Institut de Recherches Internationales Servier
- 入组人数
- 52
- 试验地点
- 65
- 主要终点
- Safety Lead-in Phase: Number of Dose-limiting toxicities (DLTs)
- 状态
- 招募中
- 最后更新
- 3个月前
概览
简要总结
The objective of this study is to investigate the safety, tolerability and preliminary activity of ivosidenib in combination with durvalumab and gemcitabine/cisplatin as first-line therapy in participants with locally advanced, unresectable or metastatic cholangiocarcinoma with an IDH1 mutation. The study will begin with a safety lead-in phase (Phase 1b study) to determine the recommended combination dose (RDC) and then will transition to an expansion phase (Phase 2 study) to assess the clinical activity of ivosidenib in combination with durvalumab and gemcitabine/cisplatin at the RCD. During the treatment period participants will have study visits on days 1, 8, and 15 of Cycle 1, on days 1 and 8 of Cycle 2 to 8, and on day 1 of each additional cycle. Cycles 1 through 8 are 21 day cycles, and each following cycle is 28 days. Approximately 30 days and 90 days after treatment has ended, safety follow-up visits will occur and then participants will be followed for survival every 3 months. Study visits may include blood tests, ECG, vital signs, and a physical examination.
研究者
入排标准
入选标准
- •Have a histopathological confirmed diagnosis consistent with locally advanced unresectable or metastatic cholangiocarcinoma.
- •Have documented IDH1 gene-mutated cholangiocarcinoma based on local or central laboratory testing (R132C/L/G/H/S mutation variants tested).
- •Have at least one evaluable and measurable lesion as defined by RECIST v1.
- •Have adequate bone marrow function as evidenced by:
- •Absolute neutrophil count ≥ 1,500/mm3 or 1.5 ×109/L
- •Hemoglobin ≥ 9 g/dL
- •Platelet count ≥ 100,000/mm3 or 100 × 109/L
- •Have adequate hepatic function as evidenced by:
- •Serum bilirubin ≤ 2.0 × the upper limit of normal (ULN); this will not apply to patients with confirmed Gilbert's syndrome. Any clinically significant biliary obstruction should be resolved before randomization
- •Aspartate aminotransferase (AST), and alanine aminotransferase (ALT) ≤ 2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤ 5.0 × ULN
排除标准
- •Received treatment for locally advanced, unresectable or metastatic disease with the following exceptions:
- •Treatment with up to one cycle of durvalumab plus gemcitabine/cisplatin treatment is permitted before study participation. Note: For the Safety Lead-In Phase, participants who received one prior cycle of durvalumab plus gemcitabine/cisplatin and required dose modifications for treatment-related toxicity are excluded.
- •Patients who developed recurrent disease \> 6 months after surgery with curative intent, and, if given, \> 6 months after the completion of adjuvant (chemotherapy and/or radiation).
- •Prior exposure to immune-mediated therapy, including, but not limited to, anti-PD-1or other anti-PD-L1, and anti-PD-L2, anti-CTLA-4 antibodies, excluding therapeutic anticancer vaccines.
- •Unresolved Grade ≥2 adverse events from a previous anticancer therapy, with the exception of alopecia and vitiligo and the laboratory values listed in the inclusion criteria.
- •Patients with Grade ≥2 neuropathy to be evaluated on a case-by-case basis after consultation with the medical monitor
- •Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with ivosidenib may be included only after consultation with the medical monitor
- •Participation in another interventional study at the same time or within 14 days prior to the first study medication (triple combination treatment) administration. For patients having participated to another prior interventional study, the first dose of ivosidenib should occur after a period greater than or equal to 5 half-lives or 28 days, whichever is shorter of the last dose of the prior investigational product.
- •Active or prior documented autoimmune or inflammatory disorders including:
- •inflammatory bowel disease (e.g., colitis or Crohn's disease)
研究组 & 干预措施
Safety Lead-In Phase
干预措施: Ivosidenib
Safety Lead-In Phase
干预措施: Durvalumab (for the first 8, 21-day, cycles)
Safety Lead-In Phase
干预措施: Gemcitabine (for the first 8, 21-day, cycles)
Safety Lead-In Phase
干预措施: Cisplatin (for the first 8, 21-day, cycles)
Safety Lead-In Phase
干预措施: Durvalumab (starting from cycle 9)
Expansion Phase
干预措施: Durvalumab (for the first 8, 21-day, cycles)
Expansion Phase
干预措施: Gemcitabine (for the first 8, 21-day, cycles)
Expansion Phase
干预措施: Cisplatin (for the first 8, 21-day, cycles)
Expansion Phase
干预措施: Durvalumab (starting from cycle 9)
Expansion Phase
干预措施: Ivosidenib Recommended Combination Dose (RCD)
结局指标
主要结局
Safety Lead-in Phase: Number of Dose-limiting toxicities (DLTs)
时间窗: Through Cycle 1 (Cycle 1 is 21 days)
Safety Lead-in Phase: Number of adverse events (AEs), adverse events of special interest (AESIs), and serious adverse events (SAEs)
时间窗: Through 90 days after the end of treatment (Approximately 5 years)
Expansion Phase: Objective response rate (ORR)
时间窗: Through the end of the study (Approximately 5 years)
Confirmed complete response (CR) or confirmed partial response (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
次要结局
- Safety Lead-in Phase: Ivosidenib Area under the concentration-versus-time curve (AUC) from time 0 to time of last measurable concentration (AUC0-t)(Through the end of treatment (Approximately 5 years))
- Safety Lead-in Phase: Ivosidenib AUC over 1 dosing interval at steady state (AUCtau,ss)(Through the end of treatment (Approximately 5 years))
- Safety Lead-in Phase: Ivosidenib time to maximum concentration (Tmax)(Through the end of treatment (Approximately 5 years))
- Safety Lead-in Phase: Ivosidenib maximum concentration (Cmax)(Through the end of treatment (Approximately 5 years))
- Safety Lead-in Phase: Ivosidenib trough concentration (Ctrough)(Through the end of treatment (Approximately 5 years))
- Safety Lead-in Phase: Ivosidenib apparent volume of distribution (Vd/F)(Through the end of treatment (Approximately 5 years))
- Safety Lead-in Phase: Ivosidenib apparent clearance (CL/F)(Through the end of treatment (Approximately 5 years))
- Expansion Phase: Overall survival (OS)(Through the end of the study (Approximately 5 years))
- Expansion Phase: Duration of response (DOR)(Through the end of the study (Approximately 5 years))
- Expansion Phase: Disease control(Through the end of the study (Approximately 5 years))
- Expansion Phase: Progression-free survival (PFS)(Through the end of the study (Approximately 5 years))
- Expansion Phase: Time to response (TTR)(Through the end of the study (Approximately 5 years))
- Expansion Phase: Ivosidenib Area under the concentration-versus-time curve (AUC) from time 0 to time of last measurable concentration (AUC0-t)(Through the end of treatment (Approximately 5 years))
- Expansion Phase: Ivosidenib AUC over 1 dosing interval at steady state (AUCtau,ss)(Through the end of treatment (Approximately 5 years))
- Expansion Phase: Ivosidenib time to maximum concentration (Tmax)(Through the end of treatment (Approximately 5 years))
- Safety Lead-in Phase: Plasma 2-hydroxygluturate (2-HG) concentrations(Through the end of treatment (Approximately 5 years))
- Expansion Phase: Ivosidenib trough concentration (Ctrough)(Through the end of treatment (Approximately 5 years))
- Expansion Phase: Ivosidenib apparent volume of distribution (Vd/F)(Through the end of treatment (Approximately 5 years))
- Expansion Phase: Ivosidenib apparent clearance (CL/F)(Through the end of treatment (Approximately 5 years))
- Expansion Phase: Plasma 2-hydroxygluturate (2-HG) concentrations(Through the end of treatment (Approximately 5 years))
- Expansion Phase: Number of AEs, AESIs, and SAEs(Through 90 days after the end of treatment (Approximately 5 years))
- Expansion Phase: Ivosidenib maximum concentration (Cmax)(Through the end of treatment (Approximately 5 years))