A Phase Ib Multicenter, Open-label Study to Evaluate the Safety and Tolerability of Trastuzumab Deruxtecan (T-DXd) and Immunotherapy Agents With and Without Chemotherapy Agents in First-line Treatment of Patients With Advanced or Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) and Human Epidermal Growth Factor Receptor 2 (HER2) Overexpression (OE) (DESTINY-Lung03)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- AstraZeneca
- 入组人数
- 304
- 试验地点
- 92
- 主要终点
- Frequency of AEs and SAEs
研究概览
简要总结
DESTINY-Lung03 will investigate the safety and tolerability of trastuzumab deruxtecan in combination with Immunotherapy Agents with and without chemotherapy in patients with HER2 over-expressing non-small cell lung cancer. The efficacy will be also analyzed as a secondary endpoint.
详细描述
Part 1 is a dose escalation study by design, allowing the assessment of safety, tolerability, and recommended dose levels of the combination of T-DXd and durvalumab plus cisplatin, carboplatin, or pemetrexed. No more patients will be enrolled in this part of the study. Part 2, expansions in the treatment-naïve setting on any recommended dose level, will not be initiated.
The evaluation of T-DXd combination treatment with immunotherapy continues in Part 3, Part 4, and Part 5. In Part 3, T-DXd is assessed in combination with volrustomig, with carboplatin (Arm 3B) or without carboplatin (Arm 3A). Part 4 examines T-DXd with rilvegostomig, either with carboplatin (Arm 4B) or without carboplatin (Arm 4A). In Part 5, T-DXd is evaluated with volrustomig, given with or without a priming dose followed by a fixed dose in Arm 5A. There is also an optional Arm 5B at the Sponsor's discretion. These parts focus on further dose optimization for first-line HER2-overexpressing NSCLC.
For Part 3, patients will be randomized to Arms 3A and 3B, beginning with the cohorts receiving the volrustomig starting dose (SD). A total of 6 DLT-evaluable patients will be enrolled to the SD cohorts in each arm. If the combination of T-DXd with volrustomig at the starting dose is deemed safe, a dose escalation (E1) cohort will be opened for 6 DLT-evaluable patients. Once all open dose confirmation cohorts have 6 DLT-evaluable patients, the SRC will convene to select the volrustomig RP2D to be used in the dose-expansion (DE) cohorts of each arm (n=34). Part 3 is now permanently closed to recruitment; no further patients will be enrolled.
In Part 4, once a total of 6 DLT-evaluable patients/arm have been enrolled into Arm 4A and Arm 4B safety-run in (SR) cohorts and deemed safe, an additional 34 patients per arm will be enrolled in Arms 4A and 4B in dose expansion cohorts.
Part 5 involves additional dosing regimens of T-DXd in combination with volrustomig. The objective of Part 5 is to evaluate the safety and efficacy of priming and flat dosing regimens in 2 different cohorts of up to 30 patients per arm.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •Histologically documented unresectable locally advanced/metastatic non-squamous NSCLC
- •Part 1: Progression after 1 or 2 lines of systemic therapy for recurrent or metastatic setting.
- •Part 3, Part 4 and Part 5: Patients must have tumors that do not harbor known genomic alterations or actionable driver kinases, for which approved therapies are available are allowed.
- •Part 3, Part 4 and Part 5: Patient must be treatment-naïve for advanced or metastatic NSCLC. Patients who have received prior adjuvant, or neoadjuvant chemotherapy, or definitive chemoradiation for advanced disease are eligible, provided that progression has occurred > 6 months from end of last therapy
- •HER2overexpression status as determined by central review of tumor tissue
- •WHO / ECOG performance status of 0 or 1
- •Measurable target disease assessed by the investigator using RECIST 1.1
- •Has protocol defined adequate organ and bone marrow function
- •Part 3, Part 4 and Part 5: Minimum body weight of 35 kg.
排除标准
- •HER2 mutation if previously known
- •Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
- •Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder and prior pneumonectomy
- •Active primary immunodeficiency known HIV infection, or active chronic and resolved hepatitis B (positive hepatitis B virus surface antigen [HBsAg+ve] or hepatitis B virus core antibody (anti-HBc +ve) regardless of HBV DNA level)) or hepatitis C infection. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Patients should be tested for HIV prior to treatment assignment if required by local regulations or IRB/EC
- •Active infection including tuberculosis and uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
- •Spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms
- •Medical history of myocardial infarction within 6 months before treatment assignment, symptomatic CHF (New York Heart Association Class II to IV), clinically important cardiac arrhythmias, or a recent (< 6 months) cardiovascular event including stroke
- •For Part 3, Part 4 and Part 5: Cardiomyopathy of any etiology, symptomatic CHF (as defined by New York Heart Association Class > II), unstable angina pectoris, history of MI within the past 12 months, or cardiac arrhythmia are to be excluded. Patients with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before treatment assignment to rule out acute cardiopulmonary events.
- •Ascites or pericardial effusion that requires drainage, peritoneal shunt, Pleuroperitoneal shunt or CART (Concentrated Ascites Reinfusion Therapy)
- •For Part 3, Part 4 and Part 5: Active non-infectious skin disease (including any grade rash, urticarial, dermatitis, ulceration, or psoriasis) requiring systemic treatment, active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment.
- •Unresolved toxicities not yet resolved to Grade ≤ 1 or baseline from previous anticancer therapy OR prior discontinuation of any planned study therapy due to toxicity.
- •must not have any medical contraindication to platinum-based chemotherapy.
- •Part 3, Part 4 and Part 5 patients must not have had prior exposure to anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-TIGIT or any other experimental immunotherapy in any setting.
- •For Part 3, Part 4 and Part 5: History of substance abuse or any other medical or psychological conditions that may, in the opinion of the Investigator, interfere with the subject's participation in the clinical study or evaluation of the clinical study results
- •For Part 3, Part 4 and Part 5: History of thromboembolic events within 3 months before the first dose of IP (limited to pulmonary embolism, deep vein thrombosis, or cerebral venous sinus thrombosis).
研究组 & 干预措施
Arm 1B: T-DXd, Durvalumab and Carboplatin
T-DXd, Durvalumab and Carboplatin
干预措施: T-DXd (Drug)
Arm 1A: T-DXd, Durvalumab and Cisplatin
T-DXd, Durvalumab and Cisplatin
干预措施: T-DXd (Drug)
Arm 1A: T-DXd, Durvalumab and Cisplatin
T-DXd, Durvalumab and Cisplatin
干预措施: Durvalumab (Biological)
Arm 4B T-DXd and Rilvegostomig with Carboplatin
Drug: T-DXd, Rilvegostomig and Carboplatin T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Rilvegostomig Rilvegostomig: administered as an IV infusion Other Name: Rilvegostomig, AZD2936 Drug: Carboplatin Carboplatin: administered as an IV infusion
干预措施: Carboplatin (Drug)
Arm 4B T-DXd and Rilvegostomig with Carboplatin
Drug: T-DXd, Rilvegostomig and Carboplatin T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Rilvegostomig Rilvegostomig: administered as an IV infusion Other Name: Rilvegostomig, AZD2936 Drug: Carboplatin Carboplatin: administered as an IV infusion
干预措施: Rilvegostomig (Drug)
Arm 1A: T-DXd, Durvalumab and Cisplatin
T-DXd, Durvalumab and Cisplatin
干预措施: Cisplatin (Drug)
Arm 1C: T-DXd, Durvalumab and Pemetrexed
T-DXd, Durvalumab and Pemetrexed (Arm not initiated)
干预措施: Durvalumab (Biological)
Arm 1B: T-DXd, Durvalumab and Carboplatin
T-DXd, Durvalumab and Carboplatin
干预措施: Durvalumab (Biological)
Arm 1D: T-DXd
T-DXd
干预措施: T-DXd (Drug)
Arm 3A: T-DXd and Volrustomig
Drug: T-DXd and Volrustomig T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion Other Name: Volrustomig
干预措施: Volrustomig (Drug)
Arm 3B: T-DXd, Volrustomig and Carboplatin
Drug: T-DXd, Volrustomig and Carboplatin T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion Other Name: Volrustomig Drug: Carboplatin Carboplatin: administered as an IV infusion
干预措施: Volrustomig (Drug)
Arm 5A: T-DXd and Volrustomig
Drug: T-DXd and volrustomig T-DXd: administered as an IV infusion Other Name: DS-8201a, trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion (priming dose in first cycle, fixed dose in subsequent cycles) Other Name: volrustomig
干预措施: Volrustomig (Drug)
Arm 5B: T-DXd and Volrustomig
Drug: T-DXd and volrustomig T-DXd: administered as an IV infusion Other Name: DS-8201a, trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion (fixed dose from first cycle onward) Other Name: volrustomig
干预措施: T-DXd (Drug)
Arm 4A: T-DXd and Rilvegostomig
T-DXd and Rilvegostomig Drug: T-DXd, Rilvegostomig T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Rilvegostomig Rilvegostomig: administered as an IV infusion Other Name: Rilvegostomig, AZD2936
干预措施: T-DXd (Drug)
Arm 1C: T-DXd, Durvalumab and Pemetrexed
T-DXd, Durvalumab and Pemetrexed (Arm not initiated)
干预措施: T-DXd (Drug)
Arm 1C: T-DXd, Durvalumab and Pemetrexed
T-DXd, Durvalumab and Pemetrexed (Arm not initiated)
干预措施: Pemetrexed (Drug)
Arm 1B: T-DXd, Durvalumab and Carboplatin
T-DXd, Durvalumab and Carboplatin
干预措施: Carboplatin (Drug)
Arm 3A: T-DXd and Volrustomig
Drug: T-DXd and Volrustomig T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion Other Name: Volrustomig
干预措施: T-DXd (Drug)
Arm 3B: T-DXd, Volrustomig and Carboplatin
Drug: T-DXd, Volrustomig and Carboplatin T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion Other Name: Volrustomig Drug: Carboplatin Carboplatin: administered as an IV infusion
干预措施: Carboplatin (Drug)
Arm 3B: T-DXd, Volrustomig and Carboplatin
Drug: T-DXd, Volrustomig and Carboplatin T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion Other Name: Volrustomig Drug: Carboplatin Carboplatin: administered as an IV infusion
干预措施: T-DXd (Drug)
Arm 5A: T-DXd and Volrustomig
Drug: T-DXd and volrustomig T-DXd: administered as an IV infusion Other Name: DS-8201a, trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion (priming dose in first cycle, fixed dose in subsequent cycles) Other Name: volrustomig
干预措施: T-DXd (Drug)
Arm 4A: T-DXd and Rilvegostomig
T-DXd and Rilvegostomig Drug: T-DXd, Rilvegostomig T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Rilvegostomig Rilvegostomig: administered as an IV infusion Other Name: Rilvegostomig, AZD2936
干预措施: Rilvegostomig (Drug)
Arm 4B T-DXd and Rilvegostomig with Carboplatin
Drug: T-DXd, Rilvegostomig and Carboplatin T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Rilvegostomig Rilvegostomig: administered as an IV infusion Other Name: Rilvegostomig, AZD2936 Drug: Carboplatin Carboplatin: administered as an IV infusion
干预措施: T-DXd (Drug)
Arm 5B: T-DXd and Volrustomig
Drug: T-DXd and volrustomig T-DXd: administered as an IV infusion Other Name: DS-8201a, trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion (fixed dose from first cycle onward) Other Name: volrustomig
干预措施: Volrustomig (Drug)
结局指标
主要结局
Frequency of AEs and SAEs
时间窗: Safety and tolerability (and to determine RP2D) will be assessed for approximately 20 months from informed consent
Occurrence of AEs and SAEs graded according to NCI CTCAE v5.0
次要结局
- Pharmacokinetics (PK) assessed by the serum concentration of T-DXd, total anti-HER2 antibody, and MAAA-1181 in all arms(An average of approximately 20 months)
- Pharmacokinetics (PK) assessed by the serum concentration of durvalumab in study arms including T-DXd in combination with durvalumab(An average of approximately 20 months)
- Pharmacokinetics (PK) assessed by the serum concentration of rilvegostomig in study arms including T-DXd in combination with rilvegostomig(An average of approximately 20 months)
- The immunogenicity of T-DXd, durvalumab, volrustomig and rilvegostomig assessed by the presence of ADAs for T-DXd, durvalumab, volrustomig, or rilvegostomig(An average of approximately 20 months)
- Duration of Response (DoR)(An average of approximately 20 months)
- Disease Control Rate (DCR)(An average of approximately 12 months)
- Confirmed Objective Response Rate (ORR)(An average of approximately 12 months)
- Progression-free survival (PFS)(An average of approximately 20 months)
- Overall survival (OS)(An average of approximately 20 months)
- Pharmacokinetics (PK) assessed by the serum concentration of volrustomig in study arms including T-DXd in combination with volrustomig(An average of approximately 20 months)