ILUSTRO - 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 Tumors are Claudin (CLDN) 18.2 Positive - 8951-CL-0103

Studio Clinico

Patologia: Neoplasie dello stomaco

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: No

Fase di studio: II

Richiesta mandatoria di tessuto: Sì

Linee di trattamento: Prima linea

Criteri di inclusione: 

Subject is eligible for the study if all of the following apply:
1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act [HIPAA] Authorization for US sites) must be obtained from the subject or legally authorized representative prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
2. Subject is considered an adult according to local regulation at the time of signing informed consent.
3. Female subject is eligible to participate if she is not pregnant and at least one of the following conditions applies: a.Not a woman of child-bearing potential (WOCBP) as defined in Appendix 12.6 Contraception Requirements OR b. WOCBP who agrees to follow the contraceptive guidance as defined in Appendix 12.6 Contraception Requirements 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
4. 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.
5. 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.
6. A sexually active male subject with a female partner(s) who is of child-bearing potential must agree to use contraception as detailed in Appendix 12.6 Contraception Requirements during the treatment period and for at least 6 months after the final study drug administration.
7. 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.
8. 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.

Specific to Cohorts 4A and 4B:
1. 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.
2. 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).
3. Subject has a gastric or GEJ tumor that is HER2-negative as determined by local or central testing.
4. Subject has not received prior checkpoint inhibitor therapy.

Specific to Cohort 4B Only:
1. Subject must have an additional available tumor specimen collected within 3 months prior to the first dose of study treatment.
2. 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.

Criteri di esclusione: 

Waivers to the exclusion criteria will NOT be allowed. 
Subject who meets any of the following exclusion criteria prior to enrollment is not eligible for enrollment:
1. Subject has had prior severe allergic reaction or intolerance to known ingredients of zolbetuximab or other monoclonal antibodies, including humanized or chimeric antibodies.
2. Subject has known immediate or delayed hypersensitivity or contraindication to any component of study treatment.
3. Subject has received other investigational agents or devices concurrently or within 28 days prior to first dose of study treatment.
4. 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.
5. Subject has a complete gastric outlet syndrome or a partial gastric outlet syndrome with persistent recurrent vomiting.
6. Per investigator judgment, subject has significant gastric bleeding and/or untreated gastric ulcers that would preclude the subject from participation per investigator judgment.
7. Subject has history of central nervous system metastases and/or carcinomatous meningitis from gastric/GEJ cancer. 
8. 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 virus (HCV) serology, but negative HCV RNA test results are eligible.
● Subjects treated for HCV with undetectable viral load results are eligible.
9. 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. 
10. Subject has active infection requiring systemic therapy that has not completely resolved within 7 days prior to the start of study treatment.
11. Subject has active autoimmune disease that has required systemic treatment within the past 3 months prior to the start of study treatment. 
12. Subject has a clinically significant disease or co-morbidity that in the opinion of the investigator may adversely affect the safe delivery of treatment within this study or make the subject unsuitable for study participation.
13. Subject has psychiatric illness or social situations that would preclude study compliance per investigator’s judgment.
14. Subject has had a major surgical procedure ≤ 28 days before start of study treatment.
15. Subject is without complete recovery from a major surgical procedure ≤ 14 days before start of study treatment.
16. 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.
17. Subject has another malignancy for which treatment is required, per investigator’s clinical judgment. 
18. Cohorts 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) (screening for DPD deficiency should be conducted per local requirements).
● 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 per investigator’s judgment.
● History of clinically significant ventricular arrhythmias (i.e., sustained ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes). 
● QTc interval > 450 msec for male subjects; QTc interval > 470 msec for female subjects.
● 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). 
19. 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: Subject has microsatellite instability-high or mismatch repair deficient tumors.

Schema di trattamento: 

In Cohort 4A, the tolerability and safety of zolbetuximab in combination with mFOLFOX6 and nivolumab will be valuated during the 2-week DLT assessment period. Initially, 3 subjects will be enrolled into Cohort 4A and receive the zolbetuximab loading dose of 800 mg/m2 in combination with nivolumab 240 mg and mFOLFOX6 on cycle 1 day 1, followed by zolbetuximab 400 mg/m2 in combination with nivolumab 240 mg and mFOLFOX6 every 2 weeks [days 15 and 29] (1 cycle = 6 weeks). Zolbetuximab will be administered first, followed by the nivolumab and then mFOLFOX6. Any of the zolbetuximab, mFOLFOX6 and/or nivolumab-related AEs specified as the DLTs will be assessed. Subjects will receive up to 12 mFOLFOX6 treatments (4 cycles).

In 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. Imaging in Cohort 4A and 4B will be performed every 8 weeks for the first 56 weeks, and then every 12 weeks thereafter.

Trattamento sperimentale: 

zolbetuximab in combination with mFOLFOX6 and nivolumab

Trattamento di controllo: 

NA

Obiettivi secondari dello studio: 

Pharmacokinetics (PK) of zolbetuximab: Area Under the Concentration-time Curve from the Time of Dosing Extrapolated to Time Infinity (AUCinf)[ Time Frame: Up to 16 months ]
AUCinf will be derived from the PK serum samples collected.
PK of zolbetuximab: Area Under the Concentration-time Curve from the Time of Dosing Extrapolated to Time Infinity Percentage (AUCinf (%extrap)) [ Time Frame: Up to 16 months ]
AUCinf (%extrap) will be derived from the PK serum samples collected.
PK of zolbetuximab: Area Under the Concentration-time Curve from the Time of Dosing Until the Last Measurable Concentration (AUClast) [ Time Frame: Up to 16 months ]
AUClast will be derived from the PK serum samples collected.
PK of zolbetuximab: Area Under the Concentration-Time Curve from the Time of Dosing to the Start of the Next Dosing Interval (AUCtau) [ Time Frame: Up to 16 months ]
AUCtau will be derived from the PK serum samples collected.
PK of zolbetuximab: Maximum Concentration (Cmax) [ Time Frame: Up to 16 months ]
Cmax will be derived from the PK serum samples collected.
PK of zolbetuximab: Concentration Immediately Prior to Dosing (Ctrough) [ Time Frame: Up to 16 months] Ctrough will be derived from the PK serum samples collected.
PK of zolbetuximab: Time of Maximum Concentration (Tmax) [ Time Frame: Up to 16 months ]
Tmax will be derived from the PK serum samples collected.
PK of zolbetuximab: Terminal Elimination Half-life (T1/2) [ Time Frame: Up to 16 months ]
T1/2 will be derived from the PK serum samples collected.
PK of zolbetuximab: Time of the last measurable concentration (Tlast) [ Time Frame: Up to 16 months ]
Tlast will be derived from the PK serum samples collected.
PK of zolbetuximab: Clearance (CL) [ Time Frame: Up to 16 months ]
CL will be derived from the PK serum samples collected.
PK of zolbetuximab: Volume of Distribution During the Terminal Phase (Vz) [ Time Frame: Up to 16 months ]Vz will be derived from the PK serum samples collected.
Safety and tolerability assessed by adverse events (AEs) [ 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.
Number of participants with electrocardiogram (ECG) abnormalities and or adverse events [ Time Frame: Up to 14 months ]
Number of participants with potentially clinically significant ECG values.
Number of participants with vital signs abnormalities and or adverse events [ Time Frame: Up to 14 months ]
Number of participants with potentially clinically significant vital sign values.
Number of participants with European Cooperative Oncology Group (ECOG) performance status abnormalities and or adverse events [ 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.
Number of participants with laboratory assessments abnormalities and or adverse events [ Time Frame: Up to 14 months]
Number of participants with potentially clinically significant laboratory values.
Number of anti-drug antibody (ADA) Positive Participants[ Time Frame: Up to 16 months ]
Immunogenicity will be measured by the number of participants that are ADA positive.
Health Related Quality of Life (HRQoL) measured by the Quality of Life Questionnaire - Core Questionnaire (QLQ-C30) questionnaire[ 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.
HRQoL measured by the Oesophago-Gastric Module (EORTC QLQ-OG-25) questionnaire [ Time Frame: Up to 16 months ]

Pharmacokinetics (PK) of zolbetuximab: Area Under the Concentration-time Curve from the Time of Dosing Extrapolated to Time Infinity (AUCinf)[ Time Frame: Up to 16 months ]
AUCinf will be derived from the PK serum samples collected.
PK of zolbetuximab: Area Under the Concentration-time Curve from the Time of Dosing Extrapolated to Time Infinity Percentage (AUCinf (%extrap)) [ Time Frame: Up to 16 months ]
AUCinf (%extrap) will be derived from the PK serum samples collected.
PK of zolbetuximab: Area Under the Concentration-time Curve from the Time of Dosing Until the Last Measurable Concentration (AUClast) [ Time Frame: Up to 16 months ]
AUClast will be derived from the PK serum samples collected.
PK of zolbetuximab: Area Under the Concentration-Time Curve from the Time of Dosing to the Start of the Next Dosing Interval (AUCtau) [ Time Frame: Up to 16 months ]
AUCtau will be derived from the PK serum samples collected.
PK of zolbetuximab: Maximum Concentration (Cmax) [ Time Frame: Up to 16 months ]
Cmax will be derived from the PK serum samples collected.
PK of zolbetuximab: Concentration Immediately Prior to Dosing (Ctrough) [ Time Frame: Up to 16 months] Ctrough will be derived from the PK serum samples collected.
PK of zolbetuximab: Time of Maximum Concentration (Tmax) [ Time Frame: Up to 16 months ]
Tmax will be derived from the PK serum samples collected.
PK of zolbetuximab: Terminal Elimination Half-life (T1/2) [ Time Frame: Up to 16 months ]
T1/2 will be derived from the PK serum samples collected.
PK of zolbetuximab: Time of the last measurable concentration (Tlast) [ Time Frame: Up to 16 months ] Tlast will be derived from the PK serum samples collected.
PK of zolbetuximab: Clearance (CL) [ Time Frame: Up to 16 months ]
CL will be derived from the PK serum samples collected.
PK of zolbetuximab: Volume of Distribution During the Terminal Phase (Vz) [ Time Frame: Up to 16 months ]Vz will be derived from the PK serum samples collected.
Safety and tolerability assessed by adverse events (AEs) [ 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.
Number of participants with electrocardiogram (ECG) abnormalities and or adverse events [ Time Frame: Up to 14 months ]
Number of participants with potentially clinically significant ECG values.
Number of participants with vital signs abnormalities and or adverse events [ Time Frame: Up to 14 months ]
Number of participants with potentially clinically significant vital sign values.
Number of participants with European Cooperative Oncology Group (ECOG) performance status abnormalities and or adverse events [ 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.
Number of participants with laboratory assessments abnormalities and or adverse events [ Time Frame: Up to 14 months]
Number of participants with potentially clinically significant laboratory values.
Number of anti-drug antibody (ADA) Positive Participants[ Time Frame: Up to 16 months ]
Immunogenicity will be measured by the number of participants that are ADA positive.
Health Related Quality of Life (HRQoL) measured by the Quality of Life Questionnaire - Core Questionnaire (QLQ-C30) questionnaire[ 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.
HRQoL measured by the Oesophago-Gastric Module (EORTC QLQ-OG-25) questionnaire [ 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.
HRQoL measured by the Global Pain (GP) questionnaire [ Time Frame: Up to 16 months ]
The GP instrument is a single assessment of overall pain.
HRQoL measured by the EuroQOL Five Dimensions Questionnaire 5L (EQ-5D-5L) questionnaire [ 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.
HRQoL measured by the Health Resource Utilization (HRU) questionnaire [ 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.
DCR of zolbetuximab in combination with mFOLFOX6 (with nivolumab) by investigator assessment [ 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. DOR of zolbetuximab in combination with mFOLFOX6 (with nivolumab) by investigator assessment [ 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.
PFS of zolbetuximab in combination with mFOLFOX6 (with nivolumab) by investigator assessment [ 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.
ORR of zolbetuximab in combination with mFOLFOX6 (with nivolumab) by investigator assessment [ 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.OS of zolbetuximab in combination with mFOLFOX6 and nivolumab [ 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.

Centri partecipanti

Nord Italia

Centro Italia

Sud Italia e isole

Informazioni Generali

Protocollo

Numero di iscrizione a registro: 2017-002566-50

Data di inserimento: 15.03.2024

Promotore

Astellas Pharma Global Development Inc. (APGD)

Principal Investigator ITALIA

Riferimento: Dr. Info non disponibile

Telefono: 00000

Email: nd@nd.it

Localita: nd