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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 (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 : August 19, 2020
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

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 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 and in combination with pembrolizumab. This study will also evaluate the pharmacokinetics (PK) of zolbetuximab, oxaliplatin, fluorouracil (5-FU), and pembrolizumab, 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 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 pembrolizumab.

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 Phase 2

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 whose tumors have high or intermediate CLDN18.2 expression. For each cohort, the study consists of the following periods: pre-screening; screening; treatment; and follow-up for disease progression. In addition, there will be a survival follow-up period for Cohort 1A and Cohort 3B participants only. Tolerability of zolbetuximab in combination with pembrolizumab in Japanese participant(s) will be evaluated in Cohort 3B, if Japanese subjects are not enrolled in the Cohort 3A DLT assessment.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 112 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 and in combination with pembrolizumab in an unblinded fashion.
Primary Purpose: Treatment
Official Title: A Phase 2 Study of Zolbetuximab (IMAB362) as Monotherapy, in Combination With mFOLFOX6 and in Combination With Pembrolizumab in Subjects With Metastatic or Locally Advanced Unresectable Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma Whose Tumors Have High or Intermediate Claudin (CLDN) 18.2 Expression
Actual Study Start Date : June 29, 2018
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : October 2022

Resource links provided by the National Library of Medicine


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 12 mFOLFOX6 treatments (4 cycles). Beginning at cycle 5, participants may continue on 5-FU and leucovorin 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.

Experimental: Pembrolizumab plus zolbetuximab (Cohort 3A/3B)

Participants will be treated with zolbetuximab and pembrolizumab on a 21-day cycle. Cohort 3 consists of 2 parts: a safety lead in (Cohort 3A) and an expansion (Cohort 3B).

Cohort 3A: 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.

Cohort 3B: A zolbetuximab plus pembrolizumab combination expansion cohort (Cohort 3B) may be opened based on the tolerability of the dose in Cohort 3A.

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.




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

  47. 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.

  48. 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.

  49. DOR of zolbetuximab in combination with pembrolizumab by investigator assessment (Cohort 3) [ Time Frame: Up to 5 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 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.

  51. 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.

  52. DOR of zolbetuximab in combination with pembrolizumab by independent central reader (Cohort 3) [ Time Frame: Up to 5 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.

  53. 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.

  54. 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.

  55. PFS of zolbetuximab in combination with pembrolizumab by investigator assessment (Cohort 3) [ Time Frame: Up to 5 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. 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.

  57. 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.

  58. PFS of zolbetuximab in combination with pembrolizumab by independent central review (Cohort 3) [ Time Frame: Up to 5 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.

  59. 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.

  60. 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.

  61. ORR of zolbetuximab in combination with pembrolizumab by investigator assessment (Cohort 3) [ 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.

  62. 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.

  63. ORR of zolbetuximab in combination with pembrolizumab by independent central reader (Cohort 3) [ 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.

  64. 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.

  65. OS of zolbetuximab in combination with pembrolizumab (Cohort 3) [ Time Frame: Up to 11 months ]
    OS is defined as the time from the date of treatment start until the documented date of death from any cause.



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.


Layout table for eligibility information
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 6 months after the final study drug administration
  • Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 6 months after the final study drug administration.
  • Female subject must agree not to donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
  • 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.
  • Subject has radiographically-confirmed, locally advanced, unresectable or metastatic disease within 28 days prior to the first dose of study treatment
  • Subject has measurable disease according to RECIST 1.1 within 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 be outside the field of prior radiotherapy or must have documented progression following radiation therapy.

NOTE: This criterion is not applicable for subjects in Cohort 3A. Cohorts 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's tumor sample has CLDN18.2 expression (defined as moderate to strong membranous staining by central IHC testing) as follows:

Cohorts 1A, 2 and 3B: CLDN18.2 ≥ 75% of tumor cells demonstrating moderate to strong membranous staining as determined by central IHC testing. Cohort 3A: Subject's tumor expresses CLDN18.2 ≥ 50% of tumor cells demonstrating moderate to strong membranous staining as determined by central IHC testing.

  • Cohorts 1A and 3A Only:

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.

  • Cohort 2 Only:

    • 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.
  • Cohorts 1A, 2 and 3B:

    • 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.
  • Subject agrees not to 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 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 /dL).
    • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
    • Platelets ≥ 100 x 10^9/L
    • Albumin ≥ 2.5 g/dL
    • Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN in subjects without liver metastases (≤ 5 x ULN if liver metastases are present)
    • Estimated creatinine clearance ≥ 30 mL
    • Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) ≤ 1.5 x ULN (except for subjects receiving anticoagulation therapy)
  • Cohorts 3A and 3B Only: No prior checkpoint inhibitor therapy.
  • Cohort 3B Only:

    • Subject has disease progression on 2 prior regimens for their advanced disease, including fluoropyrimidine and platinum-containing chemotherapy, and if appropriate, HER2/neu-targeted therapy.
    • Subject has a tumor that is PD-L1 positive defined as a CPS ≥ 1 based on immunohistochemical staining with the Dako 22C3 PDL1 assay based on local or central 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. Subjects using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone or up to 10 mg per day of prednisone) receiving a single dose of systemic corticosteroids or receiving systemic corticosteroids as pre-medication for radiologic imaging contrast use are allowed.
  • 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.

NOTE: Screening for these infections should be conducted per local requirements.

  • For subjects who are negative for HBs Ag, but HBc Ab positive, an HB DNA test will be performed and if positive the subject will be excluded.
  • Subjects with positive hepatitis C (HCV) serology, but negative HCV RNA test results are eligible.
  • Subjects treated for HCV with undetectable viral load results are eligible.

    • 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 in 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 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 (Cohort 1) and ≤ 28 days (Cohort 2) prior to start of study treatment and has NOT any related toxicity.
    • Subject has another malignancy, for which treatment is required.
    • Cohort 2 Only, subject has any of the following:
  • Prior severe allergic reaction or intolerance to any component of mFOLFOX6 chemotherapeutics in this study
  • Known dihydropyrimidine dehydrogenase deficiency
  • 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 arrhymias (i.e. sustained ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes)
  • QTc interval >450 msec for male subjects; QTc interval >470 for female subjects
  • History or family history of congenital long QT syndrome
  • Cardiac arrhymias requiring anti-arrhythmic medications (Subjects with rate controlled atrial fibrillation for > 1 month prior to first dose of study treatment are eligible)

    - Cohort 3A and 3B Only, subject has any of the following:

  • Subjects with ongoing or previous autoimmune disease or interstitial lung disease, active diverticulitis or gastrointestinal ulcerative disease, or other uncontrolled or clinically significant medical disorders.
  • Subjects with 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.
  • Subject has known history of serious hypersensitivity reaction to a known ingredient of pembrolizumab.
  • Cohort 3B Only: Subject with known microsatellite instability-high or mismatch repair deficient tumors.

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.
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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: August 19, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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
claudiximab
IMAB362
Gastro-Esophageal Junction 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
Fluorouracil
Oxaliplatin
Pembrolizumab
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antidotes
Protective Agents
Vitamin B Complex
Vitamins
Micronutrients
Nutrients