Efficacy and Safety of Zolbetuximab with Nab-Paclitaxel and Gemcitabine in Claudin 18.2 Positive Metastatic Pancreatic Adenocarcinoma
- Trial ID
- 2024-510985-17-00
- Protocol
- 8951-CL-5201
Trial statistics
Diseases & Conditions
Objectives
The primary objectives of this study are to confirm the recommended phase 2 dose (**RP2D**) of **zolbetuximab** in combination with **Nab-Paclitaxel** and **Gemcitabine** for subjects with **Claudin 18.2 (CLDN18.2)** positive, metastatic pancreatic adenocarcinoma, and to assess whether this combination improves overall survival (**OS**) compared to Nab-Paclitaxel and Gemcitabine alone. Additionally, the study aims to evaluate the safety and tolerability of zolbetuximab in combination with Nab-Paclitaxel and Gemcitabine. These objectives are clinically relevant as they aim to establish an effective first-line treatment regimen for patients with this specific subtype of metastatic pancreatic adenocarcinoma, potentially improving survival outcomes and providing a new therapeutic option.
Secondary objectives include assessing whether treatment with zolbetuximab in combination with Nab-Paclitaxel and Gemcitabine improves progression-free survival (**PFS**) and objective response rate (**ORR**) compared to Nab-Paclitaxel and Gemcitabine in subjects with CLDN18.2 positive, metastatic pancreatic adenocarcinoma. These measures are important for understanding the efficacy of the treatment in delaying disease progression and achieving tumor response.
Participants
The clinical trial involves a total of **283 participants** diagnosed with **metastatic pancreatic adenocarcinoma** expressing Claudin 18.2. The study population includes both male and female adults, as defined by local regulations, with an **ECOG performance status** of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants were selected based on their histologically or cytologically confirmed diagnosis and the presence of measurable lesions. The trial includes individuals who have not previously received chemotherapy for their condition, although prior treatment with 5-FU or GEM as a radiation sensitizer is permissible under specific conditions. Participants are required to have a predicted life expectancy of at least 12 weeks and meet specific laboratory criteria. Both genders are included, with considerations for reproductive health, such as the use of contraception and restrictions on donating ova or sperm. The trial population is characterized by a diverse age range, and the inclusion of a vulnerable population is acknowledged. Lifestyle factors such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is a **Phase II**, open-label, randomized study designed to evaluate the efficacy and safety of **zolbetuximab** in combination with nab-paclitaxel and **gemcitabine** as a first-line treatment for subjects with **Claudin 18.2** positive, metastatic pancreatic adenocarcinoma. The trial aims to confirm the recommended phase 2 dose (RP2D) of zolbetuximab and assess whether this combination improves overall survival compared to nab-paclitaxel and gemcitabine alone. The study will also evaluate the safety and tolerability of the treatment regimen.
The trial is structured into two phases: a safety lead-in phase to confirm the RP2D and a randomization phase to compare the treatment arms. Participants will be randomly assigned to receive either the combination therapy or the standard treatment. The trial is expected to last until August 31, 2026, with participant recruitment having started on November 2, 2019. The study involves multiple visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as histologically confirmed pancreatic adenocarcinoma, measurable lesions, and specific laboratory test results. Participants must also have a predicted life expectancy of at least 12 weeks and an ECOG performance status of 0 or 1.
Following the screening, participants will undergo regular follow-up visits to monitor treatment response, safety, and tolerability. These visits will include assessments of adverse events, laboratory tests, vital signs, and performance status. The primary endpoints include confirming the RP2D and evaluating overall survival, while secondary endpoints focus on progression-free survival, overall response rate, and quality of life measures. The end-of-study visit will occur after the final treatment cycle, where comprehensive evaluations will be conducted to assess the long-term effects of the treatment.
Participant involvement is expected to last for the duration of the treatment period, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The trial is not a low-intervention study and is categorized under Phase II clinical trials. The investigational products, including zolbetuximab, are administered via intravenous infusion, with specific dosing regimens outlined for each participant based on the study protocol.
Treatment
The clinical trial involves the administration of **Zolbetuximab**, an experimental medication, which is provided in the form of a **powder for concentrate for solution for infusion**. The active substance, zolbetuximab, is a protein-based biologic developed by Astellas Pharma Global Development, Inc. The medication is administered via **intravenous use**. The maximum daily and total dose is 1000 mg/m², with a treatment period of up to 2 weeks. The trial aims to confirm the recommended phase 2 dose of zolbetuximab in combination with other treatments for subjects with CLDN18.2 positive, metastatic pancreatic adenocarcinoma.
In addition to zolbetuximab, the study includes the administration of **Gemcitabine**, a non-experimental treatment, which is a **solution for infusion**. Gemcitabine is a chemical-based medication used as a standard-of-care therapy. It is administered through **intravenous infusion** with a maximum daily and total dose of 1000 mg/m² over a treatment period of 2 weeks. This medication serves as a comparator treatment in the study to evaluate the efficacy of the experimental drug combination.
Another non-experimental treatment used in the study is **Paclitaxel**, provided as a **concentrate for solution for infusion**. Paclitaxel is also a chemical-based medication and is administered via **intravenous infusion**. The maximum daily and total dose for paclitaxel is 125 mg/m², with a treatment period of up to 2 weeks. This medication is part of the standard treatment regimen and is used in combination with gemcitabine to assess the overall survival improvement when combined with zolbetuximab.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The study is designed to assess the safety, tolerability, and efficacy of the combination of zolbetuximab with nab-paclitaxel and gemcitabine in the specified patient population.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include confirming the recommended phase 2 dose (RP2D) of **zolbetuximab** as assessed by dose-limiting toxicities (DLTs) during the Safety Lead-in Phase, and evaluating overall survival (OS), defined as the time from randomization until death from any cause. Safety and tolerability will also be measured through adverse events (AEs), laboratory test results, vital signs, electrocardiograms (ECGs), and Eastern Cooperative Oncology Group (ECOG) performance status.
Secondary endpoints will include progression-free survival (PFS), defined as the time from randomization until radiological progression of disease (PD) per RECIST 1.1 or death from any cause. The overall response rate (ORR) will be determined by the proportion of subjects achieving complete response (CR) or partial response (PR) as assessed by local investigator evaluation per RECIST 1.1. Additional secondary endpoints include pharmacokinetic parameters of **zolbetuximab**, Nab-Paclitaxel, and Gemcitabine, disease control rate (DCR), duration of response (DOR), and time to worsening of pancreatic pain and global health status/quality of life (GHS/QoL) as measured by QLQ-C30, QLQ-PAN26, and PGIS. Health-related quality of life (HRQoL) will be assessed using EORTC QLQ-C30, EORTC QLQ-PAN26, EQ-5D-5L, PGIS, and PGIC questionnaires. Serum CA19-9 change from baseline and the immunogenicity of **zolbetuximab** will be evaluated by the frequency of anti-drug antibody (ADA) positive subjects.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act Authorization for United States sites) must be obtained from the subject or legally authorized representative prior to any study related procedures (including withdrawal of prohibited medication, if applicable).
- Subject is considered an adult according to local regulation at the time of signing informed consent.
- Subject agrees not to participate in another interventional study while receiving study drug in present study.
- 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) as defined in the Protocol. OR ● WOCBP who agrees to follow the contraceptive guidance as defined in the Protocol 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 as detailed in the Protocol 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 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 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 5-FU or GEM administered as a radiation sensitizer during and up to 4 weeks after radiation therapy is allowed (if there is lingering toxicity, then the sponsor should be consulted). • 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 measureable 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 IHC testing. Physical or Laboratory Findings
- Subject has ECOG performance status of 0 or 1
- Subject has predicted life expectancy ≥ 12 weeks in the opinion of the investigator.
- Subject must meet all of the following criteria based on the laboratory tests 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 109 /L •Platelets ≥ 100 x 109 /L •Albumin ≥ 2.5 g/dL •Total bilirubin ≤ 1.5 x upper limit of normal (ULN) •Aspartate aminotransferase and alanine aminotransferase ≤ 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 and partial thromboplastin time ≤ 1.5 x ULN (except for subjects receiving anticoagulation therapy)
Exclusion Criteria
- 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 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 3 per CTCAE v 4.03.
- 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 randomizatio
- 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 are eligible.)
- Subject has a history of central nervous system metastases and/or carcinomatous meningitis from pancreatic adenocarcinoma
- Subject has known peripheral sensory neuropathy ≥ Grade 2 per CTCAE v.4.03 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 per investigator's judgment.
- Subject has another malignancy for which treatment is required per investigator's clinical judgment
- 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 in the opinion of the investigator.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 02 Nov 2019 | 60 |
 Ireland | Not Recruiting | 02 Nov 2019 | 5 |
 Italy | Not Recruiting | 02 Nov 2019 | 21 |
 Spain | Not Recruiting | 02 Nov 2019 | 27 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
GEMCITABINE | Test | — | INTRAVENOUS INFUSION | 1000 | 2 | SUB07892MIG |
PACLITAXEL | Test | — | INTRAVENOUS INFUSION | 125 | 2 | SUB09583MIG |
ASP8951 | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1000 | 2 | PRD11142563 |