A Phase 2, Open-Label, Randomized Study to Assess the Efficacy and Safety of Zolbetuximab (IMAB362) in Combination With Nab-Paclitaxel and Gemcitabine (Nab-P + GEM) as First Line Treatment in Subjects With Claudin 18.2 (CLDN18.2) Positive, Metastatic Pancreatic Adenocarcinoma
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 393
- 试验地点
- 150
- 主要终点
- Overall Survival (OS)
研究概览
简要总结
Zolbetuximab is being studied as a treatment for people with pancreatic cancer. Most people with pancreatic cancer have a protein called Claudin 18.2 (CLDN18.2) in their tumor. Zolbetuximab is thought to work by attaching to CLDN 18.2 in their tumor. This switches on the body's immune system to attack the tumor. Zolbetuximab is a potential treatment for people with pancreatic cancer.
There is an unmet medical need to treat people with pancreatic cancer. This study will help find the dose of zolbetuximab to be used with chemotherapy and provide more information on this treatment in adults with metastatic pancreatic cancer. The study is currently ongoing globally. People in this study will be treated with either zolbetuximab and chemotherapy or chemotherapy by itself.
The study's main aims are to find a suitable dose of zolbetuximab to be used with chemotherapy in the second part of this study, to check if zolbetuximab and chemotherapy compared to chemotherapy by itself can improve the survival of people with pancreatic cancer, and to check the safety of zolbetuximab when given with chemotherapy and how well people cope with medical problems during the study.
Adults with metastatic pancreatic cancer can take part. Their cancer is metastatic, has the CLDN18.2 marker in a tumor sample and has not previously been treated with chemotherapy. Metastatic means the cancer has spread to other parts of the body. People cannot take part are if they have recently had radiotherapy and have not recovered, need to take medicines to suppress their immune system, have history of nervous system metastases from their pancreatic cancer, or they have other active cancers that need treatment. People who have a specific heart condition or infections also cannot take part.
This study will be in 2 parts. Part 1 is called the Safety Lead-in Phase. Groups of people will receive 1 of 2 different doses of zolbetuximab: a lower dose or a higher dose, both together with chemotherapy. A medical expert panel will check the results and decide the dose to use in Part 2.
Part 2 is called the Randomization Phase. People will be put in 1 of 2 groups by chance and will be given different treatments either zolbetuximab and chemotherapy or chemotherapy by itself. The chance of receiving zolbetuximab and chemotherapy is twice as high as receiving chemotherapy by itself. In both parts of the study, zolbetuximab and chemotherapy or chemotherapy by itself will be given through a vein. This is called an infusion. Each treatment cycle is 4 weeks (28 days) long and people will have either 2 infusions of zolbetuximab and 3 infusions of chemotherapy or 3 infusions of chemotherapy by itself during each treatment cycle. People will visit the clinic on certain days during their treatment. The study doctors will check for any medical problems from zolbetuximab. Also, people in the study will have a health check including blood tests. On some visits they will also have scans to check for any changes in their cancer. Tumor samples will be taken before treatment if a previous sample is not available. People will have the option of giving a tumor sample after treatment has finished. People will visit the clinic after they stop treatment. They will be asked about any medical problems and will have a health check including blood tests. The number of visits and checks done at each visit will depend on the health of each person and whether they completed their treatment or not.
Astellas is terminating the zolbetuximab pancreatic development program from Dec 2025 (following the final OS analysis in Oct 2025). Active subjects may remain on treatment if the investigator determines they are receiving benefit from it. The Survival follow-up period is no longer required.
详细描述
This study will have a safety lead in phase and a randomization phase.
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
- •A female subject is eligible to participate if she is not pregnant or lactating and at least 1 of the following conditions applies:
- •Not a woman of childbearing potential (WOCBP) OR
- •WOCBP who agrees to follow the contraceptive guidance throughout the treatment period and for at least 6 months after the final study drug administration.
- •Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 6 months after the final study drug administration.
- •Female subject must not donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
- •A male subject with female partner(s) of child-bearing potential must agree to use contraception during the treatment period and for at least 6 months after the final study drug administration.
- •A male subject must not donate sperm during the treatment period and for at least 6 months after the final study drug administration.
- •Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for 6 months after the final study drug administration.
- •Subject agrees not to participate in other interventional studies while receiving study drug in present study.
- •Subject has histologically or cytologically confirmed adenocarcinoma of pancreas.
- •Subjects must have metastatic pancreatic adenocarcinoma that has not been previously treated with chemotherapy.
- •Prior treatment with fluorouracil (5-FU) or GEM administered as a radiation sensitizer during and up to 4 weeks after radiation therapy is allowed
- •If a subject received adjuvant therapy, tumor recurrence or disease progression must have occurred at least 6 months after completing the last dose of the adjuvant therapy.
- •Subjects whose disease progressed on prior treatment with Nab-P and GEM are not eligible.
- •Subject has a measurable lesion(s) on at least 1 metastatic site based on RECIST 1.1 within 28 days prior to randomization. For subjects with only 1 measurable lesion and prior radiotherapy, the lesion must be outside the field of prior radiotherapy or must have documented progression following radiation therapy.
- •Subject's tumor sample has CLDN18.2 expression in ≥ 75% of tumor cells demonstrating moderate to strong membranous staining as determined by central immunohistochemistry (IHC) testing
- •Subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •Subject has predicted life expectancy ≥ 12 weeks.
- •Subject must meet all of the following criteria based on the laboratory tests that will be collected within 14 days prior to randomization. In case of multiple laboratory data within this period, the most recent data should be used.
- •Hemoglobin ≥ 9 g/dl (no transfusion within 14 days of start of study treatment)
- •Absolute neutrophil count ≥ 1.5 x 10^9/L
- •Platelets ≥ 100 x 10^9/L
- •Albumin ≥ 2.5 g/dL
- •Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN without liver metastases (≤ 5 x ULN if liver metastases are present)
- •Estimated creatinine clearance ≥ 30 mL/min
- •Prothrombin time/international normalized ratio (INR) and partial thromboplastin time ≤ 1.5 x ULN (except for subjects receiving anticoagulation therapy)
排除标准
- •Subject has received other investigational treatment within 28 days prior to randomization.
- •Subject has received radiotherapy for metastatic pancreatic adenocarcinoma ≤ 14 days prior to randomization and has not recovered from any related toxicity.
- •Subject has received systemic immunosuppressive therapy, including systemic corticosteroids within 14 days prior to randomization. Subject using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone or up to 10 mg per day of prednisone), receiving a single dose of systemic corticosteroids or receiving systemic corticosteroids as premedication for radiologic imaging contrast use are allowed.
- •Subject has prior severe allergic reaction or intolerance to known ingredients of zolbetuximab or other monoclonal antibody, including humanized or chimeric antibodies.
- •Subject has known immediate or delayed hypersensitivity, intolerance or contraindication to any component of study treatment.
- •Subject has a known history of a positive test for human immunodeficiency virus infection or known active hepatitis B (positive HBs antigen [Ag]) or hepatitis C infection. NOTE: Screening for these infections should be conducted per local requirements.
- •For subjects who are negative for HBs Ag, but hepatitis B core antibody positive, a hepatitis B virus DNA test will be performed and if positive, the subject will be excluded.
- •Subjects with positive hepatitis C serology but negative hepatitis C virus RNA test results are eligible.
- •Subjects treated for hepatitis C with undetectable viral load results are eligible.
- •Subject has a history of interstitial pneumonia or pulmonary fibrosis.
- •Subject has pleural effusion or ascites ≥ Grade
- •Subject has an active autoimmune disease that has required systemic treatment in the past 3 months prior to randomization.
- •Subject has active infection requiring systemic therapy that has not completely resolved per investigator judgment within 7 days prior to randomization.
- •Subject has significant cardiovascular disease, including:
- •Congestive heart failure (defined as New York Heart Association Class III or IV), myocardial infarction, unstable angina, coronary angioplasty, coronary stenting, coronary artery bypass graft, cerebrovascular accident or hypertensive crisis within 6 months prior to randomization;
- •History of clinically significant ventricular arrhythmias (i.e., sustained ventricular tachycardia, ventricular fibrillation or Torsades de Pointes);
- •QTc interval > 450 msec for male subjects; QTc interval > 470 msec for female subjects;
- •Cardiac arrhythmias requiring anti-arrhythmic medications (Subjects with rate controlled atrial fibrillation for > 1 month prior to randomization.)
- •Subject has a history of central nervous system metastases and/or carcinomatous meningitis from pancreatic adenocarcinoma.
- •Subject has known peripheral sensory neuropathy ≥ Grade 2 unless the absence of deep tendon reflexes is the sole neurological abnormality.
- •Subject has had a major surgical procedure ≤ 28 days prior to randomization.
- •Subject without complete recovery from a major surgical procedure ≤ 14 days prior to randomization.
- •Psychiatric illness or social situations that would preclude study compliance.
- •Subject has another malignancy for which treatment is required.
- •Subject has any concurrent disease, infection or co-morbid condition that interferes with the ability of the subject to participate in the study, which places the subject at undue risk or complicates the interpretation of data.
研究组 & 干预措施
zolbetuximab +nab-paclitaxel + gemcitabine
Participants will be treated with zolbetuximab in combination with nab-paclitaxel and gemcitabine for the phase 1 portion of the study to establish the recommended dose of zolbetuximab for the phase 2 portion. In the phase 2 portion, the participants will be treated with zolbetuximab at dose determined by the phase 1 portion of the study in combination with nab-paclitaxel and gemcitabine. Participants will be treated on continuous cycles until they no longer derive clinical benefit in the judgment of the treating physician, have unacceptable toxicity, undergo hematopoietic stem cell transplantation (HSCT), or meet one of the discontinuation criteria; whichever occurs first.
干预措施: gemcitabine (Drug)
zolbetuximab +nab-paclitaxel + gemcitabine
Participants will be treated with zolbetuximab in combination with nab-paclitaxel and gemcitabine for the phase 1 portion of the study to establish the recommended dose of zolbetuximab for the phase 2 portion. In the phase 2 portion, the participants will be treated with zolbetuximab at dose determined by the phase 1 portion of the study in combination with nab-paclitaxel and gemcitabine. Participants will be treated on continuous cycles until they no longer derive clinical benefit in the judgment of the treating physician, have unacceptable toxicity, undergo hematopoietic stem cell transplantation (HSCT), or meet one of the discontinuation criteria; whichever occurs first.
干预措施: nab-paclitaxel (Drug)
nab-paclitaxel + gemcitabine
Participants will be treated with nab-paclitaxel and gemcitabine. Participants will be treated on continuous cycles until they no longer derive clinical benefit in the judgment of the treating physician, have unacceptable toxicity, undergo hematopoietic stem cell transplantation (HSCT), or meet one of the discontinuation criteria; whichever occurs first.
干预措施: nab-paclitaxel (Drug)
zolbetuximab +nab-paclitaxel + gemcitabine
Participants will be treated with zolbetuximab in combination with nab-paclitaxel and gemcitabine for the phase 1 portion of the study to establish the recommended dose of zolbetuximab for the phase 2 portion. In the phase 2 portion, the participants will be treated with zolbetuximab at dose determined by the phase 1 portion of the study in combination with nab-paclitaxel and gemcitabine. Participants will be treated on continuous cycles until they no longer derive clinical benefit in the judgment of the treating physician, have unacceptable toxicity, undergo hematopoietic stem cell transplantation (HSCT), or meet one of the discontinuation criteria; whichever occurs first.
干预措施: zolbetuximab (Drug)
nab-paclitaxel + gemcitabine
Participants will be treated with nab-paclitaxel and gemcitabine. Participants will be treated on continuous cycles until they no longer derive clinical benefit in the judgment of the treating physician, have unacceptable toxicity, undergo hematopoietic stem cell transplantation (HSCT), or meet one of the discontinuation criteria; whichever occurs first.
干预措施: gemcitabine (Drug)
结局指标
主要结局
Overall Survival (OS)
时间窗: Up to 65 months
OS is defined as the time from the date of randomization until the date of death from any cause.
Safety assessed by incidence of treatment emergent adverse events (TEAE)
时间窗: Up to 65 months
Treatment Emergent Adverse Event (TEAE) is defined as any AE which starts, or worsens, after the first dose of study drug through 30 days after the last dose of study drug.
Number of participants with vital sign abnormalities and /or adverse events (AEs)
时间窗: Up to 65 months
Number of participants with potentially clinically significant vital sign values.
Number of participants with electrocardiograms (ECG) abnormalities and or adverse events
时间窗: Up to 65 months
12-lead ECGs will be recorded. Prior to the ECG, participants should rest in supine position for 10 minutes. ECGs will be read and assessed locally.
Dose Limiting Toxicities (DLT) - (safety lead in)
时间窗: Up to 28 days
Incidence of dose limiting toxicities.
Safety assessed by incidence of serious adverse events (SAE)
时间窗: Up to 65 months
Adverse Event (AE) is considered "serious" if the investigator or sponsor view any of the following outcomes: Death, life-threatening, persistent or significant disability/incapacity, congenital anomaly or birth defect, hospitalization, or medically important event.
Number of participants with laboratory value abnormalities and/or adverse events (AEs)
时间窗: Up to 65 months
Number of participants with potentially clinically significant laboratory values.
Safety assessed by Adverse Events (AEs)
时间窗: Up to 65 months
An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product.
Number of participants with Eastern Cooperative Oncology Group (ECOG) performance status abnormalities and or adverse events
时间窗: Up to 65 months
Number of participants with potentially clinically significant ECOG performance status values. ECOG grades 0-5, where 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair and 5 = Dead.
次要结局
- Number of anti-drug antibody (ADA) Positive Participants(Up to 65 months)
- Change in CA (Cancer Antigen) 19-9(Baseline up to 65 months)
- PK of zolbetuximab: Concentration Immediately Prior to Dosing (Ctrough)(Up to 65 months)
- PK of Nab-P: Area Under the Concentration-time Curve from the Time of Dosing Extrapolated to Time Infinity (AUCinf)(Up to 30 days)
- PK of Nab-P: Area Under the Concentration-time Curve from the Time of Dosing Until the Last Measurable Concentration (AUClast)(Up to 30 days)
- PK of Nab-P: Maximum Concentration (Cmax)(Up to 30 days)
- PK of Nab-P: Time of Maximum Concentration (Tmax)(Up to 30 days)
- Progression Free Survival (PFS)(Up to 65 months)
- PK of gemcitabine: Volume of Distribution During the Terminal Phase (Vz)(Up to 30 days)
- Disease Control Rate (DCR)(Up to 65 months)
- Objective Response Rate (ORR)(Up to 65 months)
- PK of Nab-P: Terminal Elimination Half-life (T1/2)(Up to 30 days)
- PK of Nab-P: Clearance (CL)(Up to 30 days)
- PK of Nab-P: Volume of Distribution During the Terminal Phase (Vz)(Up to 30 days)
- PK of gemcitabine: Area Under the Concentration-time Curve from the Time of Dosing Extrapolated to Time Infinity (AUCinf)(Up to 30 days)
- PK of gemcitabine: Area Under the Concentration-time Curve from the Time of Dosing Until the Last Measurable Concentration (AUClast)(Up to 30 days)
- PK of gemcitabine: Maximum Concentration (Cmax)(Up to 30 days)
- PK of gemcitabine: Time of Maximum Concentration (Tmax)(Up to 30 days)
- PK of gemcitabine: Terminal Elimination Half-life (T1/2)(Up to 30 days)
- PK of gemcitabine: Clearance (CL)(Up to 30 days)
- Health Related Quality of Life (HRQoL) measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core Questionnaire (EORTC-QLQ-C30)(Up to 65 months)
- Health Related Quality of Life (HRQoL) measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Pancreatic Cancer Module (EORTC-QLQ-PAN-26)(Up to 65 months)
- Health Related Quality of Life (HRQoL) measured by the EuroQOL Five Dimensions Questionnaire 5L (EQ-5D-5L)(Up to 65 months)
- Health Related Quality of Life (HRQoL) measured by the Patient Global Impression of Change (PGIC) scale(Up to 65 months)
- Health Related Quality of Life (HRQoL) measured by the Patient Global Impression of Severity (PGIS) Scale(Up to 65 months)
- Time to Improvement of pancreatic pain as measured by Quality-of-Life Questionnaire - Core Questionnaire (QLQ-C30)(Up to 65 months)
- Time to worsening of global health status (GHS)/quality of life (QoL) as measured by QLQ-C30(Up to 65 months)
- Time to Improvement of pancreatic pain as measured by Quality of Life Questionnaire - Pancreatic Cancer Module 26 (QLQ-PAN26)(Up to 65 months)
- Time to worsening of GHS/QoL as measured by QLQ-PAN26(Up to 65 months)
- Time to Improvement of pancreatic pain as measured by PGIS(Up to 65 months)
- Time to worsening of GHS/QoL as measured by PGIS(Up to 65 months)
- Duration Of Response (DOR)(Up to 65 months)