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A Study to Assess the Antitumor Activity, Safety, Pharmacokinetics and Biomarkers of Zolbetuximab (IMAB362) in Participants With Claudin (CLDN) 18.2 Positive, Metastatic or Advanced Unresectable Gastric and Gastroesophageal Junction (GEJ) Adenocarcinoma and Locoregional Gastric or GEJ Adenocarcinoma (ILUSTRO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03505320
Recruitment Status : Recruiting
First Posted : April 23, 2018
Last Update Posted : May 9, 2024
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Pharmacokinetics of Zolbetuximab Gastric Cancer Gastro-esophageal Junction (GEJ) Cancer Pharmacokinetics of Oxaliplatin Pharmacokinetics of Fluorouracil Bolus (5-FU) Drug: zolbetuximab Drug: oxaliplatin Drug: leucovorin Drug: fluorouracil Drug: Pembrolizumab Drug: folinic acid Drug: nivolumab Drug: Docetaxel Phase 2

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

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.
Study Design
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Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 143 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
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.
Primary Purpose: Treatment
Official Title: A Phase 2 Study of Zolbetuximab (IMAB362) as Monotherapy and in Combination With Chemotherapy and/or Immunotherapy in Subjects With Metastatic or Locally Advanced Unresectable Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma and Locoregional Gastric or GEJ Adenocarcinoma Whose Are Claudin (CLDN) 18.2 Positive
Actual Study Start Date : June 29, 2018
Estimated Primary Completion Date : April 30, 2025
Estimated Study Completion Date : December 31, 2026

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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.


Outcome Measures
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Primary Outcome Measures :
  1. Objective Response Rate (ORR) of zolbetuximab as a single agent by central review (Cohort 1) [ Time Frame: Up to 3 months ]
    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)).


Secondary Outcome Measures :
  1. 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) [ Time Frame: Up to 16 months ]
    AUCinf will be derived from the PK serum samples collected.

  2. 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) [ Time Frame: Up to 16 months ]
    AUCinf (%extrap) will be derived from the PK serum samples collected.

  3. 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) [ Time Frame: Up to 16 months ]
    AUClast will be derived from the PK serum samples collected.

  4. 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) [ Time Frame: Up to 16 months ]
    AUCtau will be derived from the PK serum samples collected.

  5. PK of zolbetuximab: Maximum Concentration (Cmax) (Cohorts 1A, 2, 3A, 4 and 5) [ Time Frame: Up to 16 months ]
    Cmax will be derived from the PK serum samples collected.

  6. PK of zolbetuximab: Concentration Immediately Prior to Dosing (Ctrough) (Cohorts 1A, 2, 3A, 4 and 5) [ Time Frame: Up to 16 months ]
    Ctrough will be derived from the PK serum samples collected.

  7. PK of zolbetuximab: Time of Maximum Concentration (Tmax) (Cohorts 1A, 2, 3A, 4 and 5) [ Time Frame: Up to 16 months ]
    Tmax will be derived from the PK serum samples collected.

  8. PK of zolbetuximab: Terminal Elimination Half-life (T1/2) (Cohorts 1A, 2, 3A, 4 and 5) [ Time Frame: Up to 16 months ]
    T1/2 will be derived from the PK serum samples collected.

  9. PK of zolbetuximab: Time of the last measurable concentration (Tlast) (Cohorts 1A, 2, 3A, 4 and 5) [ Time Frame: Up to 16 months ]
    Tlast will be derived from the PK serum samples collected.

  10. PK of zolbetuximab: Clearance (CL) (Cohorts 1A, 2, 3A, 4 and 5) [ Time Frame: Up to 16 months ]
    CL will be derived from the PK serum samples collected.

  11. PK of zolbetuximab: Volume of Distribution During the Terminal Phase (Vz) (Cohorts 1A, 2, 3A, 4 and 5) [ Time Frame: Up to 16 months ]
    Vz will be derived from the PK serum samples collected.

  12. PK of oxaliplatin: AUCinf (Cohort 2) [ Time Frame: Up to 16 months ]
    AUCinf will be derived from the PK plasma samples collected.

  13. PK of oxaliplatin: AUCinf (%extrap) (Cohort 2) [ Time Frame: Up to 16 months ]
    AUCinf (%extrap) will be derived from the PK plasma samples collected.

  14. PK of oxaliplatin: AUClast (Cohort 2) [ Time Frame: Up to 16 months ]
    AUClast will be derived from the PK plasma samples collected.

  15. PK of oxaliplatin: Cmax (Cohort 2) [ Time Frame: Up to 16 months ]
    Cmax will be derived from the PK plasma samples collected.

  16. PK of oxaliplatin: Tmax (Cohort 2) [ Time Frame: Up to 16 months ]
    Tmax will be derived from the PK plasma samples collected.

  17. PK of oxaliplatin: T1/2 (Cohort 2) [ Time Frame: Up to 16 months ]
    T1/2 will be derived from the PK plasma samples collected.

  18. PK of oxaliplatin: Tlast (Cohort 2) [ Time Frame: Up to 16 months ]
    Tlast will be derived from the PK plasma samples collected.

  19. PK of oxaliplatin: CL (Cohort 2) [ Time Frame: Up to 16 months ]
    TL will be derived from the PK plasma samples collected.

  20. PK of oxaliplatin: Vz (Cohort 2) [ Time Frame: Up to 16 months ]
    Vz will be derived from the PK plasma samples collected.

  21. PK of fluorouracil bolus (5-FU): AUCinf (Cohort 2) [ Time Frame: Up to 16 months ]
    AUCinf will be derived from the PK plasma samples collected.

  22. PK of fluorouracil bolus (5-FU): AUCinf (%extrap) (Cohort 2) [ Time Frame: Up to 16 months ]
    AUCinf (%extrap) will be derived from the PK plasma samples collected.

  23. PK of fluorouracil bolus (5-FU): AUClast (Cohort 2) [ Time Frame: Up to 16 months ]
    AUClast will be derived from the PK plasma samples collected.

  24. PK of fluorouracil bolus (5-FU): Cmax (Cohort 2) [ Time Frame: Up to 16 months ]
    Cmax will be derived from the PK plasma samples collected.

  25. PK of fluorouracil bolus (5-FU): Tmax (Cohort 2) [ Time Frame: Up to 16 months ]
    Tmax will be derived from the PK plasma samples collected.

  26. PK of fluorouracil bolus (5-FU): T1/2 (Cohort 2) [ Time Frame: Up to 16 months ]
    T1/2 will be derived from the PK plasma samples collected.

  27. PK of fluorouracil bolus (5-FU): Tlast (Cohort 2) [ Time Frame: Up to 16 months ]
    Tlast will be derived from the PK plasma samples collected.

  28. PK of fluorouracil bolus (5-FU): CL (Cohort 2) [ Time Frame: Up to 16 months ]
    CL will be derived from the PK plasma samples collected.

  29. PK of fluorouracil bolus (5-FU): Vz (Cohort 2) [ Time Frame: Up to 16 months ]
    Vz will be derived from the PK plasma samples collected.

  30. Safety and tolerability assessed by adverse events (AEs) (Cohorts 1A, 2, 3A, 4 and 5) [ Time Frame: Up to 16 months ]
    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.

  31. Number of participants with electrocardiogram (ECG) abnormalities and or adverse events (Cohorts 1A, 2, 3A, 4 and 5) [ Time Frame: Up to 14 months ]
    Number of participants with potentially clinically significant ECG values.

  32. Number of participants with vital signs abnormalities and or adverse events (Cohorts 1A, 2, 3A, 4 and 5) [ Time Frame: Up to 14 months ]
    Number of participants with potentially clinically significant vital sign values.

  33. Number of participants with European Cooperative Oncology Group (ECOG) performance status abnormalities and or adverse events (Cohorts 1A, 2, 3A, 4 and 5) [ Time Frame: Up to 14 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.

  34. Number of participants with laboratory assessments abnormalities and or adverse events (Cohorts 1A, 2, 3A, 4 and 5) [ Time Frame: Up to 14 months ]
    Number of participants with potentially clinically significant laboratory values.

  35. Number of anti-drug antibody (ADA) Positive Participants (Cohorts 1A, 2, 3A, 4 and 5) [ Time Frame: Up to 16 months ]
    Immunogenicity will be measured by the number of participants that are ADA positive.

  36. 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) [ Time Frame: Up to 16 months ]
    The EORTC-QLQ-C30 is a cancer-specific instrument consisting of 5 functional domain scales: physical, role, emotional, social and cognitive.

  37. HRQoL measured by the Oesophago-Gastric Module (EORTC QLQ-OG-25) questionnaire (Cohorts 1A, 2, 3A, 4 and 5) [ Time Frame: Up to 16 months ]
    The EORTC-QLQ-OG25 instrument evaluates GC- and GEJC-specific symptoms such as stomach discomfort, difficulties eating and swallowing and indigestion.

  38. HRQoL measured by the Global Pain (GP) questionnaire (Cohorts 1A, 2, 3A, 4 and 5) [ Time Frame: Up to 16 months ]
    The GP instrument is a single assessment of overall pain.

  39. HRQoL measured by the EuroQOL Five Dimensions Questionnaire 5L (EQ-5D-5L) questionnaire (Cohorts 1A, 2, 3A, 4 and 5) [ Time Frame: Up to 16 months ]
    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.

  40. HRQoL measured by the Health Resource Utilization (HRU) questionnaire (Cohorts 1A, 2, 3A, 4 and 5) [ Time Frame: Up to 16 months ]
    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.

  41. Disease Control Rate (DCR) of zolbetuximab as a single agent by investigator assessment (Cohort 1A) [ Time Frame: Up to 3 months ]
    The DCR is defined as the proportion of subjects with complete or partial objective response, or stable disease based on RECIST V1.1.

  42. DCR of zolbetuximab in combination with mFOLFOX6 by investigator assessment (Cohort 2) [ Time Frame: Up to 13 months ]
    The DCR is defined as the proportion of subjects with complete or partial objective response, or stable disease based on RECIST V1.1.

  43. DCR of zolbetuximab in combination with mFOLFOX6 (with nivolumab) by investigator assessment (Cohort 4) [ Time Frame: up to 13 months ]
    DCR is defined as the proportion of subjects with complete or partial objective response, or stable disease based on RECIST V1.1.

  44. DCR of zolbetuximab as a single agent by independent central reader (Cohort 1A) [ Time Frame: Up to 3 months ]
    The DCR is defined as the proportion of subjects with complete or partial objective response, or stable disease based on RECIST V1.1.

  45. DCR of zolbetuximab in combination with mFOLFOX6 by Independent central reader (Cohort 2) [ Time Frame: Up to 13 months ]
    The DCR is defined as the proportion of subjects with complete or partial objective response, or stable disease based on RECIST V1.1.

  46. Duration of Response (DOR) of zolbetuximab as a single agent by investigator assessment (Cohort 1A) [ Time Frame: Up to 3 months ]
    DOR is defined as the time from the date of the first response CR/PR (whichever is first recorded) to the date of radiographical progression/death or date of censoring.

  47. DOR of zolbetuximab in combination with mFOLFOX6 by investigator assessment (Cohort 2) [ Time Frame: Up to 13 months ]
    DOR is defined as the time from the date of the first response CR/PR (whichever is first recorded) to the date of radiographical progression/death or date of censoring.

  48. DOR of zolbetuximab in combination with mFOLFOX6 (with nivolumab) by investigator assessment (Cohort 4) [ Time Frame: up to 13 months ]
    DOR is defined as the time from the date of the first response CR/PR (whichever is first recorded) to the date of radiographical progression/death or date of censoring.

  49. DOR of zolbetuximab as a single agent by independent central reader (Cohort 1A) [ Time Frame: Up to 3 months ]
    DOR is defined as the time from the date of the first response CR/PR (whichever is first recorded) to the date of radiographical progression/death or date of censoring.

  50. DOR of zolbetuximab in combination with mFOLFOX6 by independent central reader (Cohort 2) [ Time Frame: Up to 13 months ]
    DOR is defined as the time from the date of the first response CR/PR (whichever is first recorded) to the date of radiographical progression/death or date of censoring.

  51. Progression Free Survival (PFS) of zolbetuximab as a single agent by investigator assessment (Cohort 1A) [ Time Frame: Up to 3 months ]
    PFS is defined as the time from date of treatment start until the date of radiological disease progression assessed by independent radiographic reviewer (IRR), or until death due to any cause.

  52. PFS of zolbetuximab in combination with mFOLFOX6 by investigator assessment (Cohort 2) [ Time Frame: Up to 13 months ]
    PFS is defined as the time from date of treatment start until the date of radiological disease progression assessed by independent radiographic reviewer (IRR), or until death due to any cause.

  53. PFS of zolbetuximab in combination with mFOLFOX6 (with nivolumab) by investigator assessment (Cohort 4) [ Time Frame: up to 13 months ]
    PFS is defined as the time from date of treatment start until the date of radiological disease progression assessed by independent radiographic reviewer (IRR), or until death due to any cause.

  54. PFS of zolbetuximab as a single agent by independent central review (Cohort 1A) [ Time Frame: Up to 3 months ]
    PFS is defined as the time from date of treatment start until the date of radiological disease progression assessed by independent radiographic reviewer (IRR), or until death due to any cause.

  55. PFS of zolbetuximab in combination with mFOLFOX6 by independent central review (Cohort 2) [ Time Frame: Up to 13 months ]
    PFS is defined as the time from date of treatment start until the date of radiological disease progression assessed by independent radiographic reviewer (IRR), or until death due to any cause.

  56. ORR of zolbetuximab as a single agent by investigator assessment (Cohort 1A) [ Time Frame: Up to 3 months ]
    The ORR is defined as the proportion of subjects with complete or partial objective response based on RECIST V1.1.

  57. ORR of zolbetuximab in combination with mFOLFOX6 by investigator assessment (Cohort 2) [ Time Frame: Up to 13 months ]
    The ORR is defined as the proportion of subjects with complete or partial objective response based on RECIST V1.1.

  58. ORR of zolbetuximab in combination with mFOLFOX6 (with nivolumab) by investigator assessment (Cohort 4) [ Time Frame: up to 13 months ]
    The ORR is defined as the proportion of subjects with complete or partial objective response based on RECIST V1.1.

  59. ORR of zolbetuximab in combination with mFOLFOX6 by independent central reader (Cohort 2) [ Time Frame: Up to 13 months ]
    The ORR is defined as the proportion of subjects with complete or partial objective response based on RECIST V1.1.

  60. ORR of zolbetuximab in combination with pembrolizumab by independent central reader (Cohort 3A) [ Time Frame: Up to 5 months ]
    The ORR is defined as the proportion of subjects with complete or partial objective response based on RECIST V1.1.

  61. Overall Survival (OS) of zolbetuximab as a single agent (Cohort 1A) [ Time Frame: Up to 7 months ]
    OS is defined as the time from the date of treatment start until the documented date of death from any cause.

  62. OS of zolbetuximab in combination with mFOLFOX6 and nivolumab (Cohort 4B) [ Time Frame: up to 56 Months ]
    OS is defined as the time from the date of treatment start until the documented date of death from any cause.

  63. OS of zolbetuximab in combination with FLOT (Cohort 5) [ Time Frame: Up to 72 months ]
    OS is defined as the time from the date of treatment start until the documented date of death from any cause.

  64. Percentage of participants with surgical complications (Cohort 5) [ Time Frame: Up to 8 months ]
    Percentage of participants with surgical complications will be reported.

  65. Percentage of participants with surgical mortality as defined by death within 30 days of surgery (Cohort 5) [ Time Frame: Up to 30 days ]
    Percentage of participants with surgical mortality as defined by death within 30 days of surgery will be reported.

  66. Percentage of participants able to complete preoperative chemotherapy (Cohort 5) [ Time Frame: Up to 2 months ]
    Percentage of participants able to complete preoperative chemotherapy will be reported.

  67. Percentage of participants with perioperative mortality and morbidity at 30 days and 90 days post last dose (Cohort 5) [ Time Frame: Up to 3 months ]
    Percentage of participants with perioperative mortality and morbidity at 30 days and 90 days post last dose will be reported.

  68. Percentage of participants able to start postoperative chemotherapy (Cohort 5) [ Time Frame: Up to 7 months ]
    Percentage of participants able to start postoperative chemotherapy will be reported.

  69. Percentage of participants able to complete postoperative chemotherapy (Cohort 5) [ Time Frame: Up to 9 months ]
    Percentage of participants able to complete postoperative chemotherapy will be reported.

  70. Percentage of participants with radiological response at restaging (Cohort 5) [ Time Frame: Up to 5 months ]
    Radiological response will include complete response and partial response.

  71. Percentage of subjects with pathological response (ypTNM) (Cohort 5) [ Time Frame: Up to 5 months ]
    Pathological response (ypTNM) will include ypCR, ypPR

  72. Disease-free Survival (DFS) (Cohort 5) [ Time Frame: Up to 70 months ]
    DFS is defined as the time from date of treatment start until the date of radiological disease recurrence or until death due to any cause, whichever is earliest.

  73. Minimal Residual Disease (Cohort 5) [ Time Frame: Up to 37 months ]
    Minimal residual disease and disease recurrence as measured by circulating tumor DNA (ctDNA) will be summarized.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03505320


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

Locations
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Sponsors and Collaborators
Astellas Pharma Global Development, Inc.
Investigators
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Study Director: Global Medical Lead Astellas Pharma Global Development, Inc.
More Information
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Responsible Party: Astellas Pharma Global Development, Inc.
ClinicalTrials.gov Identifier: NCT03505320    
Other Study ID Numbers: 8951-CL-0103
2017-002566-50 ( EudraCT Number )
First Posted: April 23, 2018    Key Record Dates
Last Update Posted: May 9, 2024
Last Verified: April 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as compounds terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
URL: https://www.clinicalstudydatarequest.com/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. ):
zolbetuximab
oxaliplatin
fluorouracil
docetaxel
claudiximab
 IMAB362
Gastro-Esophageal Junction cancer
locoregional gastric cancer
Pembrolizumab
Gastric cancer
Additional relevant MeSH terms:
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Adenocarcinoma
Stomach Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Leucovorin
Folic Acid
Docetaxel
 Pembrolizumab
Nivolumab
Oxaliplatin
Fluorouracil
Levoleucovorin
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Immune Checkpoint Inhibitors
Antimetabolites
Antimetabolites, Antineoplastic
Immunosuppressive Agents