inoperable, advanced or metastatic untreated HER2 positive locally advanced or metastastic EsophagoGastric Adenocarcinoma MedDRA version: 21.1 Level: PT Classification code 10017758 Term: Gastric cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: PT Classification code 10001141 Term: Adenocarcinoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version:
Conditions
Interventions
Trade Name: Herceptin®
Product Name: Trastuzumab
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: TRASTUZUMAB
CAS Number: 180288-69-1
Concentration unit: mg m
Sponsors
AIO-Studien-gGmbH
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. All subjects must have inoperable, advanced or metastatic esophagogastric adenocarcinoma. 2. Subjects must have HER2-positive disease defined as either IHC 3+ or IHC 2+, the latter in combination with ISH+, as assessed locally on a primary or metastatic tumour (Note: Availability of formalin-fixed paraffin-embedded (FFPE) representative tumor tissue for central confirmation of HER2 is mandatory (Preferably fresh biopsy)) 3. Subject must be previously untreated with systemic treatment (including HER 2 inhibitors) given as primary therapy for advanced or metastatic disease. 4. Prior adjuvant or neoadjuvant chemotherapy, radiotherapy and/or chemoradiotherapy are permitted as long as the last administration of the last regimen (whichever was given last) occurred at least 3 months prior to randomization. 5. Subjects must have measurable or evaluable non-measurable disease as assessed by the investigator, according to RECIST v1.1 (Appendix D). 6. ECOG performance status score of 0 or 1 (Appendix B). 7. Screening laboratory values must meet the following criteria (using NCI CTCAE v.4.03 ): o WBC = 2000/µL o Neutrophils = 1500/uL o Platelets = 100x10^3/µL o Hemoglobin = 9.0 g/dL o eGFR = 30ml/min o AST = 3.0 x ULN (or = 5.0X ULN if liver metastates are present) o ALT = 3.0 x ULN (or = 5.0X ULN if liver metastates are present) o Total Bilirubin = 1.5 x ULN (except subjects with Gilbert Syndrome who must have a total bilirubin level of =65 years) yes F.1.
Exclusion criteria
Exclusion criteria: 1. Malignancies other than disease under study within 5 years prior to inclusion, with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year OS > 90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent) 2. Subjects with untreated known CNS metastases. Subjects are eligible if CNS metastases are adequately treated and subjects are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to randomization. In addition, subjects must be either off corticosteroids, or on a stable or decreasing dose of 720 mg/m², doxorubicin or liposomal doxorubicin > 360 mg/m², mitoxantrone > 120 mg/m² and idarubicin > 90 mg/m2, other (e.g., liposomal doxorubicin or other anthracycline greater than the equivalent of 360 mg/m² of doxorubicin). If more than one anthracycline has been used, then the cumulative dose must not exceed the equivalent of 360 mg/m² of doxorubicin 4. Abnormal baseline LVEF, assessed by echocardiogram, multigated acquisition (MUGA) scan, or cardiac magnetic resonance imaging (MRI) scan 5. Subjects with active, known, or suspected autoimmune disease. Subjects with Type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, or skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll. For any cases of uncertainty, it is recommended that the medical monitor be consulted prior to signing informed consent. 6. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. 7. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways. 8. Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1); however, alopecia, sensory neuropathy Grade = 2, or other Grade = 2 not constituting a safety risk based on investigator’s judgment are acceptable. 9. Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the subject to receive study drug. 10. Significant acute or chronic infections including, among others: o Any positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) o Any positive test result for hepatitis B virus or hepatitis C virus indicating acute or chronic infection. 11. History of allergy or hypersensitivity to study drug or any constituent of the products 12. History of allogeneic tissue/ solid organ transplant 13. Participation in another clinical study with an investigational p
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective is to determine the clinical performance of ipilimumab or FOLFOX in combination with nivolumab and trastuzumab in patients with previously untreated HER2 positive locally advanced or metastatic esophagogastric adenocarcinoma in terms of overall survival.;Secondary Objective: The main secondary objective is to determine safety and tolerability, according to NCI CTC AE v4.03 and to the obtained data on vital signs, clinical parameters and feasibility of the regimen. Further secondary objectives are to determine efficacy in terms of progression free survival and objective response rate acc. to RECIST v1.1 of the experimental regimen. In addition immune response signatures (e.g. TiL repertoire and NGS immunoprofiling of immunoglobuline and T-cell receptor rearrangements), changes in HER2 and PD-L1 status in CTC and ctDNA and PD-L1 status in biopsy will be correlated with efficacy. Imaging wii be centrally review and ORR and PFS will be determined according to modified RECIST. ;Primary end point(s): • Overall Survival including milestone rate @ 12 months;Timepoint(s) of evaluation of this end point: End of study (EoS) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Safety and tolerability (acc. to NCI CTC AE v4.03 and to the obtained data on vital signs, clinical parameters and feasibility of the regimen) • Progression Free Survival (PFS) according to RECIST v1.1 • Response Rate (RR) according to RECIST v1.1 • Quality of life (EORTC QLQ-C30 and STO-22) • Translational research (correlation of immune response signatures, changes in HER2 and PD-L1 and HER signaling status in tissue, CTC and ctDNA with efficacy • central imaging review and determination of ORR and PFS according to modified RECIST);Timepoint(s) of evaluation of this end point: End of study (EoS) | — |
Countries
Germany
Contacts
Public ContactAIO-Studien-gGmbH
AIO-Studien-gGmbH
Outcome results
None listed