A Study of Zolbetuximab (IMAB362) in Adults With Gastric Cancer

Phase 2Active Not RecruitingNCT03505320

Astellas Pharma Global Development, Inc.143 enrolled

Overview

Zolbetuximab is being studied as a treatment for people with cancer in and around the stomach or cancer where the food pipe (esophagus) joins the stomach (gastroesophageal junction cancer). Most people with this type of cancer have a protein called Claudin 18.2 in their tumor. Zolbetuximab is thought to work by attaching to Claudin 18.2 in their tumor. This switches on the body's immune system to attack the tumor. There is an unmet medical need to treat people with advanced cancer in and around the stomach or gastroesophageal junction cancer. This study will provide more information on zolbetuximab given by itself and in combination with other treatments in adults with advanced stomach or gastroesophageal junction cancer. The study is currently ongoing globally. People in this study will either be treated with zolbetuximab by itself, with zolbetuximab and chemotherapy, with zolbetuximab and a medicine called pembrolizumab, or zolbetuximab with chemotherapy and a medicine called nivolumab. This study is ongoing, but enrollment in any of the treatment options has been completed. In addition, at this stage of the study, treatment in some of these treatment options has completed. The main aim of this study is to check how well zolbetuximab controls tumors when given by itself. Adults with cancer in and around the stomach or gastroesophageal junction cancer can take part. Their cancer is locally advanced unresectable or metastatic and has the CLDN18.2 marker in a tumor sample. Locally advanced means the cancer has spread to nearby tissue. Unresectable means the cancer cannot be removed by surgery. Metastatic means the cancer has spread to other parts of the body. They may have been previously treated with standard therapies. People cannot take part if they need to take medicines to suppress their immune system, have blockages or bleeding in their gut, have specific uncontrollable cancers such as symptomatic or untreated cancers in the nervous system, have a specific heart condition or infections. There are different treatments in the study. People who take part will receive just 1 of the treatments. Treatment will be given in cycles. The treatment is given through a vein; this is called an infusion. Some people with advanced disease will have 1 infusion in 3 week (21-day) cycles. Some people will have several infusions in 6 week (42-day) cycles. Some people with cancer in and around the stomach or gastroesophageal junction who have surgery for their cancer will have a few infusions in 2-week (14-day) cycles. This will happen before and after they have surgery for their cancer. People may receive chemotherapy for up to 6 months. Some people enrolled to received zolbetuximab and pembrolizumab, may have received pembrolizumab for up to 2 years. People will visit the clinic on certain days during their treatment; there may be extra visits during the first cycle of treatment. The study doctors will check if people had any medical problems from zolbetuximab and the other study treatments. 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 at certain visits with 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. After the clinic visits end some people will have a telephone health check every 3 months. 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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Female subject eligible to participate if she is not pregnant and at least one of the following conditions applies: * Not a woman of child-bearing potential (WOCBP) OR * WOCBP who agrees to follow the contraceptive guidance throughout the treatment period and for at least 9 months after the final oxaliplatin administration and 6 months after the final administration of all other study drugs. * 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 agree not to donate ova starting at screening and throughout the study period, and for 9 months after the final oxaliplatin administration and 6 months after the final administration of all other study drugs. * A sexually active male subject with a female partner(s) who is 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. * Male subject must agree not to donate sperm starting at screening and throughout the study 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 confirmed gastric or GEJ adenocarcinoma. * Cohorts 1-4: Subject has radiographically-confirmed, locally advanced, unresectable or metastatic disease within 28 days prior to the first dose of study treatment. * Subject's tumor is positive for CLDN18.2 expression demonstrating moderate to strong membranous staining as determined by central IHC testing. * Subject agrees to not participate in another interventional study while on treatment. * Subject has ECOG performance status 0 to 1. * Subject has predicted life expectancy ≥ 12 weeks. * Subject must meet all of the following criteria based on the centrally or locally analyzed laboratory tests collected within 14 days prior to the first dose of study treatment. In case of multiple central laboratory data within this period, the most recent data should be used. * Hemoglobin (Hgb) ≥ 9 g/dL (transfusion is allowed, but post-transfusion Hgb \[24 hours or later following transfusion\] must be ≥ 9 g/dL) * Absolute neutrophil count (ANC) ≥ 1.5 × 109/L * Platelets ≥ 100 × 10\^9/L * Albumin ≥ 2.5 g/dL * Total bilirubin ≤ 1.5 × upper limit of normal (ULN) * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN in subjects without liver metastases (≤ 5 × ULN if liver metastases are present) * Cohorts 1-4: Estimated creatinine clearance ≥ 30 mL/min * Cohort 5: Serum creatinine ≤ 1.5 × ULN, or estimated creatinine clearance ≥ 50 mL/min for subjects with serum creatinine levels \> 1.5 × ULN * Prothrombin time/international normalized ratio and partial thromboplastin time ≤ 1.5 × ULN (except for subjects receiving anticoagulation therapy) Specific to Cohort 1A: * Subject has measurable disease according to RECIST 1.1 within 28 days prior to the first dose of study treatment per investigator assessment. For subjects with only 1 evaluable lesion and prior radiotherapy ≤ 3 months before enrollment, the lesion must either be outside the field of prior radiotherapy or must have documented progression following radiation therapy. * Subject has disease progression on or after at least 2 prior regimens for their advanced disease, including fluoropyrimidine and platinum-containing chemotherapy, and if appropriate, HER2/neu-targeted therapy and all associated side effects have resolved to grade 1 or less. * Subject must have an additional available tumor specimen collected within 3 months prior to the first dose of study treatment. * Subject must be an appropriate candidate for a tumor biopsy and is amenable to undergo a tumor biopsy during the screening period (if applicable) and treatment period as indicated in the Schedule of Assessments. Specific to Cohort 2: * Subject has measurable disease according to RECIST 1.1 within 28 days prior to the first dose of study treatment per investigator assessment. For subjects with only 1 evaluable lesion and prior radiotherapy ≤ 3 months before enrollment, the lesion must either be outside the field of prior radiotherapy or must have documented progression following radiation therapy. * Subject has not received prior systemic anti-cancer therapy for their advanced disease (subject may have received neoadjuvant and/or fluorouracil-containing adjuvant chemotherapy as long as it has been completed ≥ 6 months before the first dose of study treatment). * Subject has a gastric or GEJ tumor that is HER2-negative as determined by local or central testing. * Subject must have an additional available tumor specimen collected within 3 months prior to the first dose of study treatment. * Subject must be an appropriate candidate for a tumor biopsy and is amenable to undergo a tumor biopsy during the screening period (if applicable) and treatment period as indicated in the Schedule of Assessments. Specific to Cohort 3A: * Subject has radiologically evaluable disease (measurable and/or non-measurable) according to RECIST 1.1, per local assessment, ≤ 28 days prior to the first dose of study treatment. For subjects with only 1 evaluable lesion and prior radiotherapy ≤ 3 months before enrollment, the lesion must either be outside the field of prior radiotherapy or must have documented progression following radiation therapy. * Subject has disease progression on or after at least 2 prior regimens for their advanced disease, including fluoropyrimidine and platinum-containing chemotherapy, and if appropriate, HER2/neu-targeted therapy. * Subject has not received prior checkpoint inhibitor therapy. Specific to Cohort 4A and 4B: * Subject has radiologically evaluable disease. * Subject has not received prior systemic anti-cancer therapy for their advanced disease. * Subject has a gastric or GEJ tumor that is HER2-negative as determined by local or central testing. * Subject has not received prior checkpoint inhibitor therapy. Specific to Cohort 4B Only: * Subject must have an additional available tumor specimen collected within 3 months prior to the first dose of study treatment. * Subject must be an appropriate candidate for a tumor biopsy and is amenable to undergo a tumor biopsy during the screening period (if applicable) and treatment period. Specific to Cohort 5 Only: * Subject has new histologically confirmed primary gastric or GEJ adenocarcinoma that is amenable to curative resection. * Subject has locoregional, resectable gastric or GEJ adenocarcinoma. GEJ may include type I-III Siewert classification. Clinical stage will be determined by endoscopic ultrasound (EUS) and/or CT or MRI. Diagnostic laparoscopy may be used as per institutional guidelines and clinical practices. * Subject meets one of the following criteria of locoregional disease by clinical TNM staging: * GEJ: cT2,N0 (high risk-lesions: ≥ 3 cm, poorly differentiated), cT1b-cT2,N+ or cT3-cT4a,Any N. * Gastric: T2 to T4a, and/or N1-3,M0. * Subject's tumor expresses CLDN18.2 in ≥ 75% of tumor cells demonstrating moderate to strong membranous staining as determined by central IHC testing Exclusion Criteria: * Subject has had prior severe allergic reaction or intolerance to known ingredients of zolbetuximab or other monoclonal antibodies, including humanized or chimeric antibodies. * Subject has known immediate or delayed hypersensitivity or contraindication to any component of study treatment. * Subject has received other investigational agents or devices concurrently or within 28 days prior to first dose of study treatment. * Subject has received systemic immunosuppressive therapy, including systemic corticosteroids 14 days prior to first dose of study treatment. * Subject has a complete gastric outlet syndrome or a partial gastric outlet syndrome with persistent recurrent vomiting. * Subject has significant gastric bleeding and/or untreated gastric ulcers that would preclude the subject from participation. * Subject has history of central nervous system metastases and/or carcinomatous meningitis from gastric/GEJ cancer. * Subject has a known history of a positive test for human immunodeficiency virus (HIV) infection or known active hepatitis B (positive hepatitis B surface antigen \[HBsAg\]) or hepatitis C infection. * Subject has had within 6 months prior to first dose of study treatment any of the following: unstable angina, myocardial infarction, ventricular arrhythmia requiring intervention or hospitalization for heart failure. * Subject has active infection requiring systemic therapy that has not completely resolved within 7 days prior to the start of study treatment. * Subject has active autoimmune disease that has required systemic treatment within the past 3 months prior to the start of study treatment. * Subject has a clinically significant disease or co-morbidity that may adversely affect the safe delivery of treatment within this study or make the subject unsuitable for study participation. * Subject has psychiatric illness or social situations that would preclude study compliance. * Subject has had a major surgical procedure ≤ 28 days before start of study treatment. * Subject is without complete recovery from a major surgical procedure ≤ 14 days before start of study treatment * Subject has received radiotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma ≤ 14 days (Cohorts 1 and 3A) and ≤ 28 days (Cohorts 2 and 4A or 4B) prior to start of study treatment and has NOT recovered from any related toxicity. * Subject has another malignancy, for which treatment is required. * Cohort 2, 4 and 5 Only, subject has any of the following: * Prior severe allergic reaction or intolerance to any component of mFOLFOX6 or FLOT chemotherapeutics in this study * Known dihydropyrimidine dehydrogenase deficiency (DPD). * Known peripheral neuropathy \> Grade 1 (absence of deep tendon reflexes as the sole neurological abnormality does not render the subject ineligible). * Sinusoidal obstruction syndrome, formerly known as veno-occlusive disease, if present, should be stable or improving. * History of clinically significant ventricular arrhythmias. * QTc interval \> 450 msec for male subjects; QTc interval \> 470 msec for female subjects. * History or family history of congenital long QT syndrome. * Cardiac arrhythmias requiring anti-arrhythmic medications (Subjects with rate controlled atrial fibrillation for \> 1 month prior to first dose of study treatment are eligible). * Cohorts 3A, 4A and 4B Only, subject has any of the following: * Ongoing or previous autoimmune disease or interstitial lung disease, active diverticulitis or gastrointestinal ulcerative disease, or solid organ or stem cell transplant (for Cohort 4) or other uncontrolled or clinically significant medical disorders. * Type 1 diabetes mellitus, endocrinopathies stably maintained on appropriate replacement therapy or skin disorders (e.g., vitiligo, psoriasis, or alopecia) not requiring systemic treatment are allowed. * Known history of serious hypersensitivity reaction to a known ingredient of pembrolizumab or nivolumab. * Cohort 4B Only: Subjects has microsatellite instability-high or mismatch repair deficient tumors. * Cohort 5 Only, subject has either of the following: * Subject cannot undergo curative resection per the investigator's judgment * Subject meets the following criterion of locoregional disease by clinical TNM staging: cT1N0.

Outcomes

Primary Outcomes

Objective Response Rate (ORR) of zolbetuximab as a single agent by central review (Cohort 1)

The ORR is defined as the proportion of participants with complete or partial objective response based on Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 (assessed by an independent review committee (IRC)).

Time frame: Up to 3 months

Secondary Outcomes

Pharmacokinetics (PK) of zolbetuximab: Area Under the Concentration-time Curve from the Time of Dosing Extrapolated to Time Infinity (AUCinf) (Cohorts 1A, 2, 3A, 4 and 5)

AUCinf will be derived from the PK serum samples collected.

Time frame: Up to 16 months

PK of zolbetuximab: Area Under the Concentration-time Curve from the Time of Dosing Extrapolated to Time Infinity Percentage (AUCinf (%extrap)) (Cohorts 1A, 2, 3A, 4 and 5)

AUCinf (%extrap) will be derived from the PK serum samples collected.

Time frame: Up to 16 months

PK of zolbetuximab: Area Under the Concentration-time Curve from the Time of Dosing Until the Last Measurable Concentration (AUClast) (Cohorts 1A, 2, 3A, 4 and 5)

AUClast will be derived from the PK serum samples collected.

Time frame: Up to 16 months

PK of zolbetuximab: Area Under the Concentration-Time Curve from the Time of Dosing to the Start of the Next Dosing Interval (AUCtau) (Cohorts 1A, 2, 3A, 4 and 5)

AUCtau will be derived from the PK serum samples collected.

Time frame: Up to 16 months

PK of zolbetuximab: Maximum Concentration (Cmax) (Cohorts 1A, 2, 3A, 4 and 5)

Cmax will be derived from the PK serum samples collected.

Time frame: Up to 16 months

PK of zolbetuximab: Concentration Immediately Prior to Dosing (Ctrough) (Cohorts 1A, 2, 3A, 4 and 5)

Ctrough will be derived from the PK serum samples collected.

Time frame: Up to 16 months

PK of zolbetuximab: Time of Maximum Concentration (Tmax) (Cohorts 1A, 2, 3A, 4 and 5)

Tmax will be derived from the PK serum samples collected.

Time frame: Up to 16 months

PK of zolbetuximab: Terminal Elimination Half-life (T1/2) (Cohorts 1A, 2, 3A, 4 and 5)

T1/2 will be derived from the PK serum samples collected.

Time frame: Up to 16 months

PK of zolbetuximab: Time of the last measurable concentration (Tlast) (Cohorts 1A, 2, 3A, 4 and 5)

Tlast will be derived from the PK serum samples collected.

Time frame: Up to 16 months

PK of zolbetuximab: Clearance (CL) (Cohorts 1A, 2, 3A, 4 and 5)

CL will be derived from the PK serum samples collected.

Time frame: Up to 16 months

PK of zolbetuximab: Volume of Distribution During the Terminal Phase (Vz) (Cohorts 1A, 2, 3A, 4 and 5)

Vz will be derived from the PK serum samples collected.

Time frame: Up to 16 months

PK of oxaliplatin: AUCinf (Cohort 2)

AUCinf will be derived from the PK plasma samples collected.

Time frame: Up to 16 months

PK of oxaliplatin: AUCinf (%extrap) (Cohort 2)

AUCinf (%extrap) will be derived from the PK plasma samples collected.

Time frame: Up to 16 months

PK of oxaliplatin: AUClast (Cohort 2)

AUClast will be derived from the PK plasma samples collected.

Time frame: Up to 16 months

PK of oxaliplatin: Cmax (Cohort 2)

Cmax will be derived from the PK plasma samples collected.

Time frame: Up to 16 months

PK of oxaliplatin: Tmax (Cohort 2)

Tmax will be derived from the PK plasma samples collected.

Time frame: Up to 16 months

PK of oxaliplatin: T1/2 (Cohort 2)

T1/2 will be derived from the PK plasma samples collected.

Time frame: Up to 16 months

PK of oxaliplatin: Tlast (Cohort 2)

Tlast will be derived from the PK plasma samples collected.

Time frame: Up to 16 months

PK of oxaliplatin: CL (Cohort 2)

TL will be derived from the PK plasma samples collected.

Time frame: Up to 16 months

PK of oxaliplatin: Vz (Cohort 2)

Vz will be derived from the PK plasma samples collected.

Time frame: Up to 16 months

PK of fluorouracil bolus (5-FU): AUCinf (Cohort 2)

AUCinf will be derived from the PK plasma samples collected.

Time frame: Up to 16 months

PK of fluorouracil bolus (5-FU): AUCinf (%extrap) (Cohort 2)

AUCinf (%extrap) will be derived from the PK plasma samples collected.

Time frame: Up to 16 months

PK of fluorouracil bolus (5-FU): AUClast (Cohort 2)

AUClast will be derived from the PK plasma samples collected.

Time frame: Up to 16 months

PK of fluorouracil bolus (5-FU): Cmax (Cohort 2)

Cmax will be derived from the PK plasma samples collected.

Time frame: Up to 16 months

PK of fluorouracil bolus (5-FU): Tmax (Cohort 2)

Tmax will be derived from the PK plasma samples collected.

Time frame: Up to 16 months

PK of fluorouracil bolus (5-FU): T1/2 (Cohort 2)

T1/2 will be derived from the PK plasma samples collected.

Time frame: Up to 16 months

PK of fluorouracil bolus (5-FU): Tlast (Cohort 2)

Tlast will be derived from the PK plasma samples collected.

Time frame: Up to 16 months

PK of fluorouracil bolus (5-FU): CL (Cohort 2)

CL will be derived from the PK plasma samples collected.

Time frame: Up to 16 months

PK of fluorouracil bolus (5-FU): Vz (Cohort 2)

Vz will be derived from the PK plasma samples collected.

Time frame: Up to 16 months

Safety and tolerability assessed by adverse events (AEs) (Cohorts 1A, 2, 3A, 4 and 5)

An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Time frame: Up to 16 months

Number of participants with electrocardiogram (ECG) abnormalities and or adverse events (Cohorts 1A, 2, 3A, 4 and 5)

Number of participants with potentially clinically significant ECG values.

Time frame: Up to 14 months

Number of participants with vital signs abnormalities and or adverse events (Cohorts 1A, 2, 3A, 4 and 5)

Number of participants with potentially clinically significant vital sign values.

Time frame: Up to 14 months

Number of participants with European Cooperative Oncology Group (ECOG) performance status abnormalities and or adverse events (Cohorts 1A, 2, 3A, 4 and 5)

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.

Time frame: Up to 14 months

Number of participants with laboratory assessments abnormalities and or adverse events (Cohorts 1A, 2, 3A, 4 and 5)

Number of participants with potentially clinically significant laboratory values.

Time frame: Up to 14 months

Number of anti-drug antibody (ADA) Positive Participants (Cohorts 1A, 2, 3A, 4 and 5)

Immunogenicity will be measured by the number of participants that are ADA positive.

Time frame: Up to 16 months

Health Related Quality of Life (HRQoL) measured by the Quality of Life Questionnaire - Core Questionnaire (QLQ-C30) questionnaire (Cohorts 1A, 2, 3A, 4 and 5)

The EORTC-QLQ-C30 is a cancer-specific instrument consisting of 5 functional domain scales: physical, role, emotional, social and cognitive.

Time frame: Up to 16 months

HRQoL measured by the Oesophago-Gastric Module (EORTC QLQ-OG-25) questionnaire (Cohorts 1A, 2, 3A, 4 and 5)

The EORTC-QLQ-OG25 instrument evaluates GC- and GEJC-specific symptoms such as stomach discomfort, difficulties eating and swallowing and indigestion.

Time frame: Up to 16 months

HRQoL measured by the Global Pain (GP) questionnaire (Cohorts 1A, 2, 3A, 4 and 5)

The GP instrument is a single assessment of overall pain.

Time frame: Up to 16 months

HRQoL measured by the EuroQOL Five Dimensions Questionnaire 5L (EQ-5D-5L) questionnaire (Cohorts 1A, 2, 3A, 4 and 5)

The EQ-5D-5L is a standardized instrument developed by the EuroQol Group for use as a generic, preference-based measure of health outcomes. The EQ-5D-5L is a 5-item self-reported measure of functioning and wellbeing, which assesses 5 dimensions of health, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension comprises 5 levels (no problems, slight problems, moderate problems, severe problems, extreme problems). A unique EQ-5D-5L health state is defined by combining 1 level from each of the 5 dimensions. This questionnaire also 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.

Time frame: Up to 16 months

HRQoL measured by the Health Resource Utilization (HRU) questionnaire (Cohorts 1A, 2, 3A, 4 and 5)

Health resource utilization questionnaire to assess the number of office visits, hospital stays and other healthcare resource utilization that occur outside of the clinical trial.

Time frame: Up to 16 months

Disease Control Rate (DCR) of zolbetuximab as a single agent by investigator assessment (Cohort 1A)

The DCR is defined as the proportion of subjects with complete or partial objective response, or stable disease based on RECIST V1.1.

Time frame: Up to 3 months

DCR of zolbetuximab in combination with mFOLFOX6 by investigator assessment (Cohort 2)

The DCR is defined as the proportion of subjects with complete or partial objective response, or stable disease based on RECIST V1.1.

Time frame: Up to 13 months

DCR of zolbetuximab in combination with mFOLFOX6 (with nivolumab) by investigator assessment (Cohort 4)

DCR is defined as the proportion of subjects with complete or partial objective response, or stable disease based on RECIST V1.1.

Time frame: up to 13 months

DCR of zolbetuximab as a single agent by independent central reader (Cohort 1A)

The DCR is defined as the proportion of subjects with complete or partial objective response, or stable disease based on RECIST V1.1.

Time frame: Up to 3 months

DCR of zolbetuximab in combination with mFOLFOX6 by Independent central reader (Cohort 2)

The DCR is defined as the proportion of subjects with complete or partial objective response, or stable disease based on RECIST V1.1.

Time frame: Up to 13 months

Duration of Response (DOR) of zolbetuximab as a single agent by investigator assessment (Cohort 1A)