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Purpose

The purpose of this study is to determine the Objective Response Rate (ORR) of zolbetuzimab as a single agent as assessed by an independent central reader. This study will also assess the ORR and Progression Free Survival (PFS) of zolbetuximab in combination with mFOLFOX6 (with or without Nivolumab) and in combination with pembrolizumab, assess the safety and tolerability, assess the effects on CLDN18.2 expression and assess the immunogenicity and immunomodulatory effects of zolbetuximab as a single agent and in combination with mFOLFOX6 (with or without Nivolumab) and in combination with pembrolizumab and in combination with fluorouracil, leucovorin or folinic acid, oxaliplatin and docetaxel (FLOT). This study will also evaluate the pharmacokinetics (PK) of zolbetuximab as a single agent and in combination with mFOLFOX6 (with or without Nivolumab) and in combination with pembrolizumab and in combination with fluorouracil, leucovorin or folinic acid, oxaliplatin and docetaxel (FLOT) and PK of oxaliplatin, fluorouracil (5-FU), and pembrolizumab in combination with zolbetuximab, evaluate health-Related Quality of Life (HRQoL), evaluate the Disease Control Rate (DCR), Duration of Response (DOR), PFS of zolbetuximab as a single agent, in combination with mFOLFOX6 (with or without Nivolumab) and in combination with pembrolizumab based on both investigator and independent central reader assessment, assess Overall Survival (OS) of zolbetuximab as a single agent and in combination with mFOLFOX6 and nivolumab and in combination with FLOT.

Conditions

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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.

Study Design

Phase
Phase 2
Study Type
Interventional
Allocation
Non-Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
Double (Participant, Investigator)
Masking Description
Participants will be enrolled to receive zolbetuximab as monotherapy or in combination with mFOLFOX6 (with or without Nivolumab) and in combination with pembrolizumab and in combination with FLOT in an unblinded fashion.

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
zolbetuximab (Cohort 1A) 		Participants will be treated with zolbetuximab on a 21-day cycle in which zolbetuximab will be administered as a single agent every 3 weeks until disease progression, toxicity requiring cessation, start of another anti-cancer treatment or other treatment discontinuation criteria are met.
  • Drug: zolbetuximab
    Zolbetuximab will be administered as a minimum 2-hour IV infusion.
    Other names:
    • IMAB362
Experimental
mFOLFOX6 plus zolbetuximab (Cohort 2) 		Participants will be treated with zolbetuximab and mFOLFOX6 on a 42-day cycle in which zolbetuximab is administered on days 1 and 22, and mFOLFOX6 is administered on days 1, 15 and 29; however, for the first cycle, zolbetuximab will be administered on day 3 (instead of day 1) to allow for pharmacokinetic collection. Participants will receive up to 12 mFOLFOX6 treatments (4 cycles). Beginning at cycle 5, participants may continue on 5-FU and leucovorin or folinic acid along with zolbetuximab for the remainder of the study per investigator's discretion. mFOLFOX6 treatment includes oxaliplatin: intravenous [IV] infusion, leucovorin: IV infusion, fluorouracil bolus: IV bolus, fluorouracil infusion: continuous IV infusion.
  • Drug: zolbetuximab
    Zolbetuximab will be administered as a minimum 2-hour IV infusion.
    Other names:
    • IMAB362
  • Drug: oxaliplatin
    Oxaliplatin will be administered as a 2-hour IV infusion.
  • Drug: leucovorin
    Leucovorin will be administered as a 2-hour IV infusion.
  • Drug: fluorouracil
    Fluorouracil will be administered as IV bolus over 5 to 15 minutes and continuous IV infusion over 46 to 48 hours or per institutional guidelines.
  • Drug: folinic acid
    Folnic acid will be administered as a 2-hour IV infusion.
Experimental
Pembrolizumab plus zolbetuximab (Cohort 3A) 		Participants will be treated with zolbetuximab and pembrolizumab on a 21-day cycle. Loading dose of zolbetuximab will be administered at cycle 1, day 1 followed by maintenance dose of zolbetuximab once every 3 weeks (Q3W). Pembrolizumab will be administered to 3 to 6 subjects at a intravenously on day 1 of every 21-day cycle and will be infused 1 hour after the zolbetuximab infusion is completed. Tolerability and safety of zolbetuximab in combination with pembrolizumab will be evaluated during the 3-week dose-limiting toxicity (DLT) assessment period. If this cycle 1 dose is not tolerable, a lower dose of zolbetuximab in combination with pembrolizumab will subsequently be evaluated.
  • Drug: zolbetuximab
    Zolbetuximab will be administered as a minimum 2-hour IV infusion.
    Other names:
    • IMAB362
  • Drug: Pembrolizumab
    Pembrolizumab will be administered intravenously over 30 minutes.
Experimental
Zolbetuximab in combination with mFOLFOX6 and nivolumab (Cohort 4A/4B) 		Participants will be treated with zolbetuximab and mFOLFOX6, nivolumab on a 42-day cycle. Cohort 4A: Loading dose of zolbetuximab in combination with nivolumab and mFOLFOX6 on cycle 1 day 1, followed by zolbetuximab in combination with nivolumab and mFOLFOX6 q2w [days 15 and 29] (1 cycle = 6 weeks). Tolerability and safety of zolbetuximab in combination with nivolumab, mFOLFOX6 will be evaluated during the 3-week DLT assessment period. If cycle 1 dose is not tolerable, a lower dose of dose zolbetuximab in combination with nivolumab and mFOLFOX6 will be subsequently evaluated. Cohort 4B: Subjects will be treated with the combination of zolbetuximab, mFOLFOX6 and nivolumab at the dose deemed tolerable in Cohort 4A. Subjects will receive up to 12 mFOLFOX6 treatments (4 cycles). For Cohorts 4A and 4B, beginning at cycle 5, subjects may continue on 5-FU and leucovorin or folinic acid along with zolbetuximab and nivolumab for the remainder of the study per investigator's discretion.
  • Drug: zolbetuximab
    Zolbetuximab will be administered as a minimum 2-hour IV infusion.
    Other names:
    • IMAB362
  • Drug: oxaliplatin
    Oxaliplatin will be administered as a 2-hour IV infusion.
  • Drug: leucovorin
    Leucovorin will be administered as a 2-hour IV infusion.
  • Drug: fluorouracil
    Fluorouracil will be administered as IV bolus over 5 to 15 minutes and continuous IV infusion over 46 to 48 hours or per institutional guidelines.
  • Drug: folinic acid
    Folnic acid will be administered as a 2-hour IV infusion.
  • Drug: nivolumab
    Nivolumab will be administered intravenously according to institutional standards.
Experimental
Zolbetuximab in combination with FLOT (Cohort 5) 		Participants will be treated with zolbetuximab & FLOT for a total of eight 2-week cycles. 4 cycles preoperatively & 4 cycles postoperatively 6-12 weeks after surgery. Preoperative: Participants will receive zolbetuximab loading dose on cycle 1 day 1, followed by FLOT on cycle 1 day 2. For cycles 2-4, participants may receive zolbetuximab maintenance dose in combination with FLOT, dosed on day 1 of each cycle. However, dosing may be split over 2 days with zolbetuximab administration on day 1 & FLOT on day 2. Post operative: Participants will receive zolbetuximab loading dose on cycle 5 day 1, followed by FLOT on cycle 5 day 2. For cycles 6-8, participants may receive zolbetuximab maintenance dose in combination with FLOT, dosed on day 1 of each cycle. However, dosing may be split over 2 days with zolbetuximab administration on day 1 and FLOT on day 2. For participants who experience a DLT during preoperative treatment on the loading dose, the postoperative loading dose may be lowered.
  • Drug: zolbetuximab
    Zolbetuximab will be administered as a minimum 2-hour IV infusion.
    Other names:
    • IMAB362
  • Drug: oxaliplatin
    Oxaliplatin will be administered as a 2-hour IV infusion.
  • Drug: leucovorin
    Leucovorin will be administered as a 2-hour IV infusion.
  • Drug: fluorouracil
    Fluorouracil will be administered as IV bolus over 5 to 15 minutes and continuous IV infusion over 46 to 48 hours or per institutional guidelines.
  • Drug: folinic acid
    Folnic acid will be administered as a 2-hour IV infusion.
  • Drug: Docetaxel
    Docetaxel will be administered as a 1-hour IV infusion.

Recruiting Locations

More Details

Status
Recruiting
Sponsor
Astellas Pharma Global Development, Inc.

Study Contact

Astellas Pharma Global Development
800-888-7704
astellas.registration@astellas.com

Detailed Description

This is a study to assess the antitumor activity of zolbetuximab, an Immunoglobulin (IgG1) chimeric monoclonal antibody directed against CLDN18.2, in subjects with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma and locoregional gastric or GEJ adenocarcinoma whose tumors are CLDN18.2 positive. For each cohort, the study consists of the following periods: pre-screening; screening; treatment; and follow-up for disease progression (or post-treatment follow-up for disease recurrence, which will be conducted for Cohort 5). In addition, there will be a survival follow-up period for Cohorts 1A, 4B, and 5 participants only. Tolerability of zolbetuximab in combination with pembrolizumab in Japanese participant(s) will be evaluated in Cohort 3A DLT assessment. Tolerability of zolbetuximab in combination with mFOLFOX6 and nivolumab in Japanese subject(s) will be evaluated in Cohort 4B, if Japanese subjects are not enrolled in the Cohort 4A DLT assessment.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.