A Multicenter, Open-Label Phase 1 Study of U3-1402 in Subjects With Metastatic or Unresectable Non-small Cell Lung Cancer
概览
- 阶段
- 1 期
- 干预措施
- HER3-DXd (FL-DP)
- 疾病 / 适应症
- Non-Small Cell Lung Cancer (NSCLC)
- 发起方
- Daiichi Sankyo
- 入组人数
- 312
- 试验地点
- 69
- 主要终点
- Dose-limiting toxicities (DLTs) during dose escalation
- 状态
- 进行中（未招募）
- 最后更新
- 上个月
概览
简要总结
This study was designed to evaluate safety and antitumor activity of HER3-DXd in two parts: Dose Escalation and Dose Expansion.
In Dose Escalation, HER3-DXd was evaluated in participants with metastatic or unresectable NSCLC with epidermal growth factor receptor (EGFR) activating mutation after disease progression during/after EGFR tyrosine kinase inhibitor (TKI) therapy.
In Dose Expansion, HER3-DXd will be evaluated in participants with metastatic or unresectable NSCLC with EGFR activating mutation or squamous or non-squamous NSCLC (ie, without EGFR-activating mutations) with disease progression during/after systemic treatment for locally advanced or metastatic disease.
In addition, HER3-DXd will be evaluated in participants with locally advanced or metastatic NSCLC whose tumors harbor a KRAS-G12C mutation after progression on the most recent line of therapy (Cohort 5).
详细描述
The primary objectives are: * For Dose Escalation, to assess the safety and tolerability of HER3-DXd in the study population and to determine the recommended dose for expansion (RDE) of HER3-DXd in the study population * For Dose Expansion, to investigate the antitumor activity of HER3-DXd * For Cohort 5, investigate the antitumor activity of HER3-DXd in participants with locally advanced or metastatic NSCLC whose tumors harbor a KRAS-G12C mutation after the failure of targeted therapy The number of treatment cycles is not fixed in this study. Participants will continue study treatment (for approximately 36 months) until they decide not to (withdraw consent), their disease gets worse \[progressive disease (PD)\], or side effects become unacceptable (unacceptable toxicity) or other stopping reasons have been met.
研究者
入排标准
入选标准
- •for both Dose Escalation and Dose Expansion:
- •Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation
- •Has at least one measurable lesion per RECIST version 1.1
- •Has Eastern Cooperative Oncology Group performance status of 0 or 1 at Screening
- •Inclusion Criteria for Dose Escalation only:
- •Has histologically or cytologically documented adenocarcinoma NSCLC
- •Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011)
- •Historical confirmation that the tumor harbors an epidermal growth factor receptor (EGFR) mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q)
- •Has experienced clinical benefit from an EGFR TKI, followed by systemic progression of disease \[Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1\] or World Health Organization (WHO)\] while on continuous treatment with an EGFR TKI
- •Is currently receiving and able to discontinue erlotinib, gefinitib, afatinib, or osimertinib
排除标准
- •for Dose Escalation and Dose Expansion:
- •Has any evidence of small cell histology, or combined small cell and non-small cell histology, in original tumor biopsy or in Screening biopsy performed after progression
- •Treatment with any of the following:
- •Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s) from a previous cancer treatment regimen or clinical study (other than EGFR TKI in Cohorts 1, 3a, 3b, and 4 only), within 14 days of the first dose of study treatment
- •Immune checkpoint inhibitor therapy within 21 days of the first dose of study treatment
- •Prior treatment with an anti-HER3 antibody (dose escalation only)
- •Prior treatment with a topoisomerase I inhibitor (dose escalation only)
- •Prior treatment with an antibody-drug conjugate (ADC) that consists of an exatecan derivative that is a topoisomerase I inhibitor (eg, DS-8201a) (dose escalation only)
- •Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study drug treatment
- •Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug treatment, or palliative radiation therapy within 2 weeks of the first dose of study drug treatment, or stereotactic radiotherapy within 1 week prior to the first dose of U3-1402
研究组 & 干预措施
Dose Escalation: Cohort 4, 6.4 mg/kg
Participants in Dose Escalation Cohort 3 will receive HER3-DXd intravenously (IV) once every three weeks at 6.4 mg/kg.
干预措施: HER3-DXd (FL-DP)
Dose Escalation: Cohort 1, 3.2 mg/kg
Participants in the Dose Escalation Cohort 1 will receive HER3-DXd intravenously (IV) once every three weeks at 3.2 mg/kg.
干预措施: HER3-DXd (FL-DP)
Dose Escalation: Cohort 2, 4.8 mg/kg
Participants in Dose Escalation Cohort 2 will receive HER3-DXd intravenously (IV) once every three weeks at 4.8 mg/kg.
干预措施: HER3-DXd (FL-DP)
Dose Escalation: Cohort 3, 5.6 mg/kg
Participants in Dose Escalation Cohort 3 will receive HER3-DXd intravenously (IV) once every three weeks at 5.6 mg/kg.
干预措施: HER3-DXd (FL-DP)
Dose Expansion: Cohort 1, EGFR mutant
Participants with adenocarcinoma NSCLC with EGFR mutations in the Dose Expansion Cohort 1 will receive HER3-DXd IV once every three weeks at the established recommended dose for expansion (RDE).
干预措施: HER3-DXd (CTM-1 Lyo-DP)
Dose Expansion: Cohort 2, EGFR wild-type
Participants with squamous or non-squamous NSCLC without EGFR-activating mutations in the Dose Expansion Cohort 2 will receive HER3-DXd IV once every three weeks at the established recommended dose for expansion (RDE).
干预措施: HER3-DXd (CTM-1 Lyo-DP)
Dose Expansion: Cohort 3a, EGFR mutant
Randomized participants with NSCLC and EGFR mutations in the Dose Expansion Cohort 3a will receive HER3-DXd IV once every three weeks at the established recommended dose for expansion (RDE) or, if applicable, adjusted RDE (aRDE).
干预措施: HER3-DXd (CTM-1 Lyo-DP)
Dose Expansion: Cohort 3b, EGFR mutant
Randomized participants with NSCLC and EGFR mutations in the Dose Expansion Cohort 3b will receive HER3-DXd IV once every three weeks following an up-titration regimen (Cycle 1, Day 1: 57% of RDE or aRDE; Cycle 2, Day 1: 86% of RDE or, if applicable aRDE; Cycle 3 and subsequent cycles, Day 1: 114% of RDE or aRDE).
干预措施: HER3-DXd (CTM-1 Lyo-DP)
Dose Expansion: Cohort 4, EGFR mutant
Participants with NSCLC (including any histology other than small-cell or combined small-cell and non-small cell) with an EGFR-activating mutation will receive HER3-DXd IV at 5.6 mg/kg every 3 weeks.
干预措施: HER3-DXd (CTM-3 Lyo-DP)
Dose Expansion: Cohort 5, KRAS-G12C mutant NSCLC
Participants with locally advanced or metastatic NSCLC whose tumors harbor a KRAS-G12C mutation and that have progressed on the most recent line of therapy will receive HER3-DXd IV at 5.6 mg/kg every 3 weeks.
干预措施: HER3-DXd (CTM-3 Lyo-DP)
结局指标
主要结局
Dose-limiting toxicities (DLTs) during dose escalation
时间窗: 21 days of Cycle 1
Summary of adverse events during dose escalation
时间窗: By the global end of trial date, approximately within 36 months
Overall response rate (ORR) assessed by Blinded Independent Central Review (BICR) Committee during dose expansion (Dose Expansion Cohorts 1, 2, 3a, 3b, and Cohort 5)
时间窗: Approximately within 36 months
ORR will be evaluated using RECIST v1.1.
Maximum serum concentration (Cmax) of HER3-DXd, total anti-HER3 antibody, and MAAA-1181a during dose expansion (Cohort 4)
时间窗: During the first 5 cycles (each cycle is 21 days), including an intensive sampling schedule: pre-dose, end of infusion (EOI), 2 hour (hr), 4 hr, 8 hr post infusion, Day 8, and Day 15.
Area under the serum concentration-time curve from time 0 extrapolated to infinity (AUCinf) and up to last quantifiable time (AUC[last]) of HER3-DXd, total anti-HER3 antibody, and MAAA-1181a during dose expansion (Cohort 4)
时间窗: During the first 5 cycles (each cycle is 21 days), including an intensive sampling schedule: pre-dose, end of infusion (EOI), 2 hour (hr), 4 hr, 8 hr post infusion, Day 8, and Day 15.
次要结局
- Maximum serum concentration (Cmax) of HER3-DXd, total anti-HER3 antibody, and MAAA-1181a during dose escalation(During the first 5 cycles (each cycle is 21 days), including an intensive sampling schedule: pre-dose, end of infusion (EOI), 2 hour (hr), 4 hr, 8 hr post infusion, Day 8, and Day 15.)
- Time of maximum concentration (Tmax) of HER3-DXd, total anti-HER3 antibody, and MAAA-1181a during dose escalation(During the first 5 cycles (each cycle is 21 days), including an intensive sampling schedule: pre-dose, end of infusion (EOI), 2 hour (hr), 4 hr, 8 hr post infusion, Day 8, and Day 15.)
- Area under the serum concentration-time curve from time 0 to 21 days (AUC[0-21]) and up to last quantifiable time (AUC[last]) of HER3-DXd, total anti-HER3 antibody, and MAAA-1181a during dose escalation(During the first 5 cycles (each cycle is 21 days), including an intensive sampling schedule: pre-dose, end of infusion (EOI), 2 hour (hr), 4 hr, 8 hr post infusion, Day 8, and Day 15.)
- Overall response rate (ORR) during dose escalation(Approximately within 36 months)
- Disease control rate (DCR) during dose escalation(Approximately within 36 months)
- Duration of response (DOR) during dose escalation(Approximately within 36 months)
- Time to response (TTR) during dose escalation(Approximately within 36 months)
- Progression free survival (PFS) during dose escalation(Approximately within 36 months)
- Overall Survival (OS) during dose escalation(Approximately within 36 months)
- Summary of adverse events during dose expansion (Dose Expansion Cohorts 1-4 and Cohort 5)(By the global end of trial date, approximately within 60 months)
- Maximum serum concentration (Cmax) of HER3-DXd, total anti-HER3 antibody, and MAAA-1181a during dose expansion (Dose Expansion Cohorts 1-3 and Cohort 5)(During the first 5 cycles (each cycle is 21 days), including an intensive sampling schedule: pre-dose, end of infusion (EOI), 2 hour (hr), 4 hr, 8 hr post infusion, Day 8, and Day 15.)
- Time of maximum concentration (Tmax) of HER3-DXd, total anti-HER3 antibody, and MAAA-1181a during dose expansion (Dose Expansion Cohorts 1-4 and Cohort 5)(During the first 5 cycles (each cycle is 21 days), including an intensive sampling schedule: pre-dose, end of infusion (EOI), 2 hour (hr), 4 hr, 8 hr post infusion, Day 8, and Day 15.)
- Area under the serum concentration-time curve from time 0 to 21 days (AUC[0-21]) and up to last quantifiable time (AUC[last]) of HER3-DXd, total anti-HER3 antibody, and MAAA-1181a during dose expansion (Dose Expansion Cohorts 1-3 and Cohort 5)(During the first 5 cycles (each cycle is 21 days), including an intensive sampling schedule: pre-dose, end of infusion (EOI), 2 hour (hr), 4 hr, 8 hr post infusion, Day 8, and Day 15.)
- Overall response rate (ORR) by Investigator during dose expansion (Dose Expansion Cohorts 1-4 and Cohort 5)(Approximately within 60 months)
- Disease control rate (DCR) during dose expansion (Dose Expansion Cohorts 1-4 and Cohort 5)(Approximately within 60 months)
- Duration of response (DOR) during dose expansion (Dose Expansion Cohorts 1-4 and Cohort 5)(Approximately within 60 months)
- Time to response (TTR) during dose expansion (Dose Expansion Cohorts 1-4 and Cohort 5)(Approximately within 60 months)
- Progression free survival (PFS) during dose expansion (Dose Expansion Cohorts 1-4 and Cohort 5)(Approximately within 60 months)
- Overall survival (OS) during dose expansion (Dose Expansion Cohorts 1-4 and Cohort 5)(Approximately within 60 months)
- Percentage of participants who are anti-drug antibody (ADA)-positive (baseline and post-baseline) and Percentage of participants who have treatment-emergent ADA during dose expansion (Cohort 4)(Approximately within 60 months)
- Mean Change from Baseline in the NSCLC-SAQ Total Score (Cohort 5)(Approximately within 60 months)
- Proportions of Deteriorated, Stable, or Improved Symptoms from NSCLC-SAQ (Cohort 5)(Approximately within 60 months)
- Proportions of Deteriorated, Stable, or Improved Symptoms from PRO-CTCAE (Cohort 5)(Approximately within 60 months)