A Study to Assess the Efficacy and Safety of 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

Study Overview
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Brief Summary
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The purpose of this study is to confirm the recommended phase 2 dose (RP2D) of zolbetuximab in combination with Nab-P + GEM, determine overall survival and assess the safety and tolerability of the combination treatment. This study will also evaluate tumor markers and pharmacokinetics (PK) of zolbetuximab, Nab-P and GEM, and health-related quality of life (HRQoL).

Detailed Description
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This study will have a safety lead in phase and a randomization phase.

Official Title
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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

Conditions
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Pancreatic Cancer, Metastatic Pancreatic Cancer, Metastatic Pancreatic Adenocarcinoma

Intervention / Treatment
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* Drug: zolbetuximab
* Drug: nab-paclitaxel
* Drug: gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 1. 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) 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 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 3. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: zolbetuximab +nab-paclitaxel + gemcitabine<br>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. | Drug: zolbetuximab<br>* Administered as an intravenous infusion.<br>* Other names: IMAB362;Drug: nab-paclitaxel<br>* Administered as an intravenous infusion<br>Drug: gemcitabine<br>* Administered as an intravenous infusion<br>|
| Active Comparator: nab-paclitaxel + gemcitabine<br>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. | Drug: nab-paclitaxel<br>* Administered as an intravenous infusion<br>Drug: gemcitabine<br>* Administered as an intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicities (DLT) - (safety lead in) | Incidence of dose limiting toxicities. | Up to 28 days | 
| Overall Survival (OS) | OS is defined as the time from the date of randomization until the date of death from any cause. | Up to 65 months | 
| Safety assessed by Adverse Events (AEs) | 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. | Up to 65 months | 
| Safety assessed by incidence of serious adverse events (SAE) | 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. | Up to 65 months | 
| Safety assessed by incidence of treatment emergent adverse events (TEAE) | 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. | Up to 65 months | 
| Number of participants with laboratory value abnormalities and/or adverse events (AEs) | Number of participants with potentially clinically significant laboratory values. | Up to 65 months | 
| Number of participants with vital sign abnormalities and /or adverse events (AEs) | Number of participants with potentially clinically significant vital sign values. | Up to 65 months | 
| Number of participants with electrocardiograms (ECG) abnormalities and or adverse events | 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. | Up to 65 months | 
| Number of participants with Eastern Cooperative Oncology Group (ECOG) performance status abnormalities and or adverse events | 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. | Up to 65 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is defined as the time from the date of randomization until the date of radiological progressive disease (PD) per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 by investigator evaluation or death from any cause, whichever is earliest. | Up to 65 months | 
| Objective Response Rate (ORR) | ORR is defined as the proportion of participants who have a best overall response of Complete Response (CR) or Partial Response (PR) as assessed by investigator evaluation per RECIST 1.1. | Up to 65 months | 
| Number of anti-drug antibody (ADA) Positive Participants | Immunogenicity will be measured by the number of participants that are ADA positive. | Up to 65 months | 
| Disease Control Rate (DCR) | DCR is defined as the proportion of participants who have best overall response of stable disease, complete response (CR) or partial response (PR) as assessed by investigator evaluation per RECIST 1.1 | Up to 65 months | 
| Duration Of Response (DOR) | DOR is defined as the time from the date of the first response (CR/PR) until the date of progressive disease as assessed by investigator evaluation per RECIST 1.1 or date of death from any cause, whichever is earliest. | Up to 65 months | 
| Change in CA (Cancer Antigen) 19-9 | Change from baseline in serum CA19-9 will be assessed. | Baseline up to 65 months | 
| PK of zolbetuximab: Concentration Immediately Prior to Dosing (Ctrough) | Ctrough will be derived from the PK serum samples collected. | Up to 65 months | 
| PK of Nab-P: Area Under the Concentration-time Curve from the Time of Dosing Extrapolated to Time Infinity (AUCinf) | AUCinf will be derived from the PK plasma samples collected. | 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) | AUClast will be derived from the PK plasma samples collected. | Up to 30 days | 
| PK of Nab-P: Maximum Concentration (Cmax) | Cmax will be derived from the PK plasma samples collected. | Up to 30 days | 
| PK of Nab-P: Time of Maximum Concentration (Tmax) | Tmax will be derived from the PK plasma samples collected. | Up to 30 days | 
| PK of Nab-P: Terminal Elimination Half-life (T1/2) | T1/2 will be derived from the PK plasma samples collected. | Up to 30 days | 
| PK of Nab-P: Clearance (CL) | CL will be derived from the PK plasma samples collected. | Up to 30 days | 
| PK of Nab-P: Volume of Distribution During the Terminal Phase (Vz) | Vz will be derived from the PK plasma samples collected. | Up to 30 days | 
| PK of gemcitabine: Area Under the Concentration-time Curve from the Time of Dosing Extrapolated to Time Infinity (AUCinf) | AUCinf will be derived from the PK plasma samples collected. | Up to 30 days | 
| PK of gemcitabine: Area Under the Concentration-time Curve from the Time of Dosing Until the Last Measurable Concentration (AUClast) | AUClast will be derived from the PK plasma samples collected. | Up to 30 days | 
| PK of gemcitabine: Maximum Concentration (Cmax) | Cmax will be derived from the PK plasma samples collected. | Up to 30 days | 
| PK of gemcitabine: Time of Maximum Concentration (Tmax) | Tmax will be derived from the PK plasma samples collected. | Up to 30 days | 
| PK of gemcitabine: Terminal Elimination Half-life (T1/2) | T1/2 will be derived from the PK plasma samples collected. | Up to 30 days | 
| PK of gemcitabine: Clearance (CL) | CL will be derived from the PK plasma samples collected. | Up to 30 days | 
| PK of gemcitabine: Volume of Distribution During the Terminal Phase (Vz) | Vz will be derived from the PK plasma samples collected. | 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) | The EORTC-QLQ-C30 is a 30-item cancer-specific instrument consisting of 5 functional scales (physical, role, emotional, social and cognitive), 9 symptom scales/items (fatigue, nausea/vomiting, general pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status scale. Participants rate items on a four-point scale, with 1 as not at all and 4 as very much. For functional scales, higher scores indicate better functioning, while for symptom scales/items, higher scores indicate worse symptoms. | 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) | EORTC-QLQ-PAN26 is a 26-item questionnaire that evaluates pancreatic cancer-specific symptoms such as pain, dietary changes, jaundice, altered bowel habits, and emotional problems. Participants rate items on a four-point scale, with 1 as not at all and 4 as very much. For symptom scales/items, higher scores indicate worse symptoms. | Up to 65 months | 
| Health Related Quality of Life (HRQoL) measured by the EuroQOL Five Dimensions Questionnaire 5L (EQ-5D-5L) | The EQ-5D-5L is a standardized instrument for use as a measure of health outcome consisting of 6 items that cover 5 main domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a general visual analog scale for health status. Each domain comprises 5 severity levels (no problems, slight problems, moderate problems, severe problems, extreme problems). The general visual analog scale records the respondent's self-rated health status on a vertical graduated (0 = the worst health a participant can imagine to 100 = the best health a participant can imagine) visual analogue scale. Responses to the 5 items will also be converted to a weighted health state index (utility score) based on values derived from general population samples. | Up to 65 months | 
| Health Related Quality of Life (HRQoL) measured by the Patient Global Impression of Change (PGIC) scale | The PGIC is a single-item questionnaire that asks participants to provide the overall self-assessment of change in their disease on a 7-point scale ranging from very much worse to very much better as compared to the participant starting the study treatment. Only PGIC questions assessing pain and overall status will be collected. | Up to 65 months | 
| Health Related Quality of Life (HRQoL) measured by the Patient Global Impression of Severity (PGIS) Scale | The PGIS is a single-item questionnaire that asks participants to provide the overall self-assessment of their disease severity on a 4-point scale for the past week, with 1 as None and 4 as Severe. Only PGIS questions assessing pain and overall status will be collected. | Up to 65 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic pancreatic cancer, IMAB362, nab-paclitaxel, gemcitabine, zolbetuximab, metastatic pancreatic adenocarcinoma, pancreatic cancer, CLDN 18.2