Ipilimumab or FOLFOX in Combination With Nivolumab and Trastuzumab in HER2 Positive EsophagoGastric Adenocarcinoma

NCT03409848 | Completed Phase 2 DMC

• 3 other identifiers: AIO-STO-02172017-000624-10CA209-99R
• Study Type: interventional
• Target: 97
• Locations: 1 country
• Sites: 35

Brief Summary

The INTEGA study assesses therapy Options for advanced or metastatic esophagogastric Adenocarcinoma in patients overexpressing human epidermal receptor type 2 (HER2 positive patients). Current treatment options in this situation include chemotherapy based palliative treatment in combination withTrastuzumab. Recent studies have shown that immunotherapy with Nivolumab or Ipilimumab after previous chemotherapy can also improve survival in esophagogastric cancer. This study assesses the efficacy of two experimental first line treatment strategies: A) Chemo-free immunotherapy with Trastuzumab, Nivolumab and Ipilimumab and B) addition of Nivolumab to the standard regimen (FOLFOX chemotherapy and Trastuzumab).

Conditions

Gastric Cancer; Esophageal Cancer; Adenocarcinoma Gastric; HER2 Positive Gastric Cancer; Metastatic Gastric Cancer; GastroEsophageal Cancer

Outcome Measures

Primary Outcomes (1)

• Overall Survival

  Overall survival including milestone rate at 12 months

  Milestone at 12 months, max observation period 48 months

Secondary Outcomes (11)

• Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

  48 months

• Progression Free Survival

  48 months

• Response Rate

  15 months

• Health related Quality of Life

  48 months

• Health related Quality of Life

  48 months

Study Arms (2)

A: Chemo-free immunotherapy

EXPERIMENTAL

Week 1-12 Trastuzumab 6mg/kg d1 every 3 weeks (loading dose 8mg/kg) Nivolumab 1mg/kg i.v. d1 every 3 weeks Ipilimumab 3mg/kg i.v. d1 every 3 weeks Week 13 till EOT (max treatment period 12 months) Trastuzumab 4mg/kg d1 every 2 weeks Nivolumab 240mg i.v. d1 every 2 weeks

Drug: Nivolumab; Drug: Ipilimumab

B: Chemo- / immunotherapy

EXPERIMENTAL

Trastuzumab 4mg/kg d1 every 2 weeks (loading dose 6mg/kg) Nivolumab 240mg i.v. d1 every 2 weeks mFOLFOX6 every 2 weeks Oxaliplatin at a dose of 85 mg/m2 IV over two hours (day 1) 5-FU 400 mg/m2 IV bolus (day 1) LV at a dose of 400 mg/m2 iv over two hours (day 1) 5-FU at a dose of 2400 mg/m2 IV over 46 hours (day 1-3) Max Treatment period 12 months

Drug: Nivolumab

Interventions

Nivolumab DRUG

Addition of Nivolumab to Standard therapy (chemotherapy and Trastuzumab)

B: Chemo- / immunotherapy

Ipilimumab DRUG

Chemo-free immunotherapy with Nivolumab, Ipilimumab, Trastuzumab

A: Chemo-free immunotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All subjects must have inoperable, advanced or metastatic esophagogastric adenocarcinoma
• 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))
• Subject must be previously untreated with systemic treatment (including HER 2 inhibitors) given as primary therapy for advanced or metastatic disease.
• 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.
• Subjects must have measurable or evaluable non-measurable disease as assessed by the investigator, according to RECIST v1.1 (Appendix D).
• ECOG performance status score of 0 or 1 (Appendix B).
• Screening laboratory values must meet the following criteria (using NCI CTCAE v.4.03 ):
• WBC ≥ 2000/µL
• Neutrophils ≥ 1500/uL
• Platelets ≥ 100x10\^3/µL
• Hemoglobin ≥ 9.0 g/dL
• eGFR ≥ 30ml/min (e.g. MDRD formula, appendix G)
• AST ≤ 3.0 x ULN (or ≤ 5.0X ULN if liver metastases are present)
• ALT ≤ 3.0 x ULN (or ≤ 5.0X ULN if liver metastases are present)
• Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome who must have a total bilirubin level of \< 3.0 x ULN)

You may not qualify if:

• 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 \< 10 mg daily prednisone (or equivalent) for at least 2 weeks prior to randomization.
• History of exposure to the following cumulative doses of anthracyclines (epirubicin \> 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
• Abnormal baseline LVEF, assessed by echocardiogram \[ECHO\], multigated acquisition (MUGA) scan, or cardiac magnetic resonance imaging (MRI) scan
• 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.
• 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.
• 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.
• 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.
• 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.
• Significant acute or chronic infections including, among others:
• Any positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Any positive test result for hepatitis B virus or hepatitis C virus indicating acute or chronic infection.
• History of allergy or hypersensitivity to study drug or any constituent of the products
• Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
• Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts \[§ 40 Abs. 1 S. 3 Nr. 3a AMG\].

Sponsors & Collaborators

• AIO-Studien-gGmbH: lead
• Bristol-Myers Squibb: collaborator

Study Sites (35)

Gesundheitszentrum St. Marien Amberg - MVZ

Amberg, 92224, Germany

Location

Gesundheitszentrum Wetterau - Facharztzentrum

Bad Nauheim, 61231, Germany

Location

Helios Klinikum Bad Saarow - Hämatologie, Onkologie und Palliativmedizin

Bad Saarow, 15526, Germany

Location

Charité Universitätsmedizin Campus Virchow Klinikum - Hämatologie / Onkologie

Berlin, 13353, Germany

Location

Ev. Waldkrankenhaus Spandau - Onkologisches Zentrum

Berlin, 13589, Germany

Location

St. Josef Hospital Bochum - Hämatologie, Onkologie und Palliativmedizin

Bochum, 44791, Germany

Location

Schwerpunktpraxis Hämatologie und Onkologie Bottrop

Bottrop, 46236, Germany

Location

MVZ Klinikum Coburg

Coburg, 96450, Germany

Location

BAG Onkologische Gemeinschaftspraxis Dresden

Dresden, 01307, Germany

Location

Kliniken Essen-Mitte - Klinik für Internistische Onkologie und Hämatologie

Essen, 45136, Germany

Location

Krankenhaus Nordwest - Institut für klinische Forschung

Frankfurt a.M., 60488, Germany

Location

Uniklinikum Frankfurt - Med. I

Frankfurt a.M., 60590, Germany

Location

Universitätsklinikum Halle (Saale) - Innere Med. I

Halle, 06120, Germany

Location

Universitätsklinikum Hamburg Eppendorf - II. Med.

Hamburg, 20246, Germany

Location

HOPE - Hämatologisch-onkologische Praxis Eppendorf

Hamburg, 20249, Germany

Location

Med. Hochschule Hannover - Gastroenterologie, Hepatologie und Endokrinologie

Hanover, 30625, Germany

Location

Universitätsklinikum Jena - Innere Med. Hämatologie und Onkologie

Jena, 07740, Germany

Location

DRK Kliniken Nordhessen - Klinik für interdisziplinäre Onkologie

Kassel, 34121, Germany

Location

Klinikum Kassel - Onkologie und Hämatologie

Kassel, 34125, Germany

Location

Ortenau-Klinikum Lahr - Sektion Hämatologie und Onkologie

Lahr, 77933, Germany

Location

MVZ-Mitte - Onkologische Schwerpunktpraxis Leipzig

Leipzig, 04103, Germany

Location

Universitätsklinikum Leipzig - Krebszentrum

Leipzig, 04109, Germany

Location

Klinikum Magdeburg - Hämatologie und Onkologie

Magdeburg, 39130, Germany

Location

Universitätsklinikum Marburg - Hämatologie, Onkologie und Immunologie

Marburg, 35032, Germany

Location

Kliniken Maria Hilf Mönchengladbach - Hämatologie, Onkologie und Gastroenterologie

Mönchengladbach, 41063, Germany

Location

Stauferklinikum Schwäbisch Gmünd - Innere Med.

Mutlangen, 73557, Germany

Location

Klinikum der LMU München - Med. III

München, 81377, Germany

Location

Klinikum rechts der Isar der TU München - Innere Med. III

München, 81675, Germany

Location

Klinikum Oldenburg - Universitätsklinikum für Innere Med. - Onkologie und Hämatologie

Oldenburg, 26133, Germany

Location

Ermstalklinik Reutlingen - Med. I

Reutlingen, 72764, Germany

Location

Elblandklinikum Riesa - Innere Med.

Riesa, 01589, Germany

Location

Leopoldina Krankenhaus Schweinfurt - Med. III

Schweinfurt, 97422, Germany

Location

Universitätsklinikum Ulm - Innere Med. I

Ulm, 89081, Germany

Location

Marien-Hospital Wesel - Med. II

Wesel, 46483, Germany

Location

Klinikum Wolfsburg - Med. II

Wolfsburg, 38440, Germany

Location

Related Publications (2)

• Stein A, Paschold L, Tintelnot J, Goekkurt E, Henkes SS, Simnica D, Schultheiss C, Willscher E, Bauer M, Wickenhauser C, Thuss-Patience P, Lorenzen S, Ettrich T, Riera-Knorrenschild J, Jacobasch L, Kretzschmar A, Kubicka S, Al-Batran SE, Reinacher-Schick A, Pink D, Sinn M, Lindig U, Hiegl W, Hinke A, Hegewisch-Becker S, Binder M. Efficacy of Ipilimumab vs FOLFOX in Combination With Nivolumab and Trastuzumab in Patients With Previously Untreated ERBB2-Positive Esophagogastric Adenocarcinoma: The AIO INTEGA Randomized Clinical Trial. JAMA Oncol. 2022 Aug 1;8(8):1150-1158. doi: 10.1001/jamaoncol.2022.2228.

  PMID: 35737383 DERIVED

• Tintelnot J, Goekkurt E, Binder M, Thuss-Patience P, Lorenzen S, Knorrenschild JR, Kretzschmar A, Ettrich T, Lindig U, Jacobasch L, Pink D, Al-Batran SE, Hinke A, Hegewisch-Becker S, Nilsson S, Bokemeyer C, Stein A. Ipilimumab or FOLFOX with Nivolumab and Trastuzumab in previously untreated HER2-positive locally advanced or metastatic EsophagoGastric Adenocarcinoma - the randomized phase 2 INTEGA trial (AIO STO 0217). BMC Cancer. 2020 Jun 1;20(1):503. doi: 10.1186/s12885-020-06958-3.

  PMID: 32487035 DERIVED

Related Links

• AIO - Working Group for Medical Oncology from the German Cancer Society
• AIO-Studien-gGmbH

MeSH Terms

Conditions

Stomach Neoplasms; Esophageal Neoplasms

Interventions

Nivolumab; Ipilimumab

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Head and Neck Neoplasms; Esophageal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Alexander Stein, Dr.

  HOPE - Hämatologisch-onkologische Praxis Eppendorf

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 3, 2018
• First Posted: January 24, 2018
• Study Start: March 1, 2018
• Primary Completion: March 5, 2022
• Study Completion: March 5, 2022
• Last Updated: May 18, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

DE (35)