Clinical trial NCT03409848: Ipilimumab or FOLFOX in Combination With Nivolumab and Trastuzumab in HER2 Positive EsophagoGastric Adenocarcinoma
Official title: Ipilimumab or FOLFOX in Combination With Nivolumab and Trastuzumab in Previously Untreated HER2 Positive Locally Advanced or Metastatic EsophagoGastric Adenocarcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Gastric Cancer
Esophageal Cancer
Adenocarcinoma Gastric
HER2 Positive Gastric Cancer
Metastatic Gastric Cancer
GastroEsophageal Cancer
Lead sponsor: AIO-Studien-gGmbH
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2018-01-24
Enrollment: 97
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Detailed description: Gastric cancer is the fifth most common cancer in the world, and the third leading cause of cancer death in both sexes worldwide.

Surgical resection is currently the only curative treatment option for gastric cancer; however, \~50% of patients have metastatic disease at the time of diagnosis and chemotherapy is the mainstay of palliation in this setting.

Trastuzumab, in combination with chemotherapy, significantly improved survival in patients with overexpression of HER2.

In regard of the very limited therapeutic landscape of HER2 positive EGA, compared to breast cancer, further treatment options to relevantly improve the outcome is warranted. The integration of check-point inhibitors (e.g. Nivolumab, Ipilimumab) into the first line setting either within a chemotherapy-free combination arm or within an intensified standard arm of FOLFOX and trastuzumab with nivolumab may be able to improve the current limited survival of median 14 months.

Eligibility 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 ):

   * 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)
8. Males and Females, ≥ 18 years of age
9. Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal subject care.
10. Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study.
11. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug. Women must not be breastfeeding.
12. WOCBP must use a highly effective method(s) of contraception for a period of 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo 5 half-lives. The terminal half-lives of nivolumab and ipilimumab are approximately 25 days and 15 days, respectively. WOCBP should use an adequate method to avoid pregnancy for approximately 5 months (30 days plus the time required for nivolumab to undergo 5 half-lives) after the last dose of investigational drug.
13. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo 5 half-lives. The terminal half-lives of nivolumab and ipilimumab are approximately 25 days and 15 days, respectively. Males who are sexually active with WOCBP must continue contraception for approximately 7 months (90 days plus the time required for nivolumab to undergo 5 half-lives) after the last dose of investigational drug. In addition, male subjects must be willing to refrain from sperm donation during this time.

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 \< 10 mg daily prednisone (or equivalent) for at least 2 weeks prior to randomization.
3. 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
4. Abnormal baseline LVEF, assessed by echocardiogram \[ECHO\], 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:

    * 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.
11. History of allergy or hypersensitivity to study drug or any constituent of the products
12. Participation in another clinical study with an investigational product during the last 30 days before inclusion
13. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
14. 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 \[§ 40 Abs. 1 S. 3 Nr. 3a AMG\].

Primary outcomes:
measure: Overall Survival
timeFrame: Milestone at 12 months, max observation period 48 months
Secondary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
timeFrame: 48 months
measure: Progression Free Survival
timeFrame: 48 months
measure: Response Rate
timeFrame: 15 months
measure: Health related Quality of Life
timeFrame: 48 months
measure: Health related Quality of Life
timeFrame: 48 months
measure: Translational research tumor block
timeFrame: 48 months
measure: Translational research blood - immunoprofiling
timeFrame: Up to 7 weeks
measure: Translational research blood - circulating Tumor cells (CTC)
timeFrame: 48 months
measure: Translational research blood - circulating Tumor DNA (ctDNA)
timeFrame: 48 months
measure: Central Imaging Review - ORR
timeFrame: 48 months
measure: Central Imaging Review - PFS
timeFrame: 48 months
Other outcomes:
Locations:
city: Amberg
country: Germany
facility: Gesundheitszentrum St. Marien Amberg - MVZ
city: Bad Nauheim
country: Germany
facility: Gesundheitszentrum Wetterau - Facharztzentrum
city: Bad Saarow
country: Germany
facility: Helios Klinikum Bad Saarow - Hämatologie, Onkologie und Palliativmedizin
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Campus Virchow Klinikum - Hämatologie / Onkologie
city: Berlin
country: Germany
facility: Ev. Waldkrankenhaus Spandau - Onkologisches Zentrum
city: Bochum
country: Germany
facility: St. Josef Hospital Bochum - Hämatologie, Onkologie und Palliativmedizin
city: Bottrop
country: Germany
facility: Schwerpunktpraxis Hämatologie und Onkologie Bottrop
city: Coburg
country: Germany
facility: MVZ Klinikum Coburg
city: Dresden
country: Germany
facility: BAG Onkologische Gemeinschaftspraxis Dresden
city: Essen
country: Germany
facility: Kliniken Essen-Mitte - Klinik für Internistische Onkologie und Hämatologie
city: Frankfurt a.M.
country: Germany
facility: Krankenhaus Nordwest - Institut für klinische Forschung
city: Frankfurt a.M.
country: Germany
facility: Uniklinikum Frankfurt - Med. I
city: Halle (Saale)
country: Germany
facility: Universitätsklinikum Halle (Saale) - Innere Med. I
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg Eppendorf - II. Med.
city: Hamburg
country: Germany
facility: HOPE - Hämatologisch-onkologische Praxis Eppendorf
city: Hannover
country: Germany
facility: Med. Hochschule Hannover - Gastroenterologie, Hepatologie und Endokrinologie
city: Jena
country: Germany
facility: Universitätsklinikum Jena - Innere Med. Hämatologie und Onkologie
city: Kassel
country: Germany
facility: DRK Kliniken Nordhessen - Klinik für interdisziplinäre Onkologie
city: Kassel
country: Germany
facility: Klinikum Kassel - Onkologie und Hämatologie
city: Lahr
country: Germany
facility: Ortenau-Klinikum Lahr - Sektion Hämatologie und Onkologie
city: Leipzig
country: Germany
facility: MVZ-Mitte - Onkologische Schwerpunktpraxis Leipzig
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig - Krebszentrum
city: Magdeburg
country: Germany
facility: Klinikum Magdeburg - Hämatologie und Onkologie
city: Marburg
country: Germany
facility: Universitätsklinikum Marburg - Hämatologie, Onkologie und Immunologie
city: Mutlangen
country: Germany
facility: Stauferklinikum Schwäbisch Gmünd - Innere Med.
city: Mönchengladbach
country: Germany
facility: Kliniken Maria Hilf Mönchengladbach - Hämatologie, Onkologie und Gastroenterologie
city: München
country: Germany
facility: Klinikum der LMU München - Med. III
city: München
country: Germany
facility: Klinikum rechts der Isar der TU München - Innere Med. III
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg - Universitätsklinikum für Innere Med. - Onkologie und Hämatologie
city: Reutlingen
country: Germany
facility: Ermstalklinik Reutlingen - Med. I
city: Riesa
country: Germany
facility: Elblandklinikum Riesa - Innere Med.
city: Schweinfurt
country: Germany
facility: Leopoldina Krankenhaus Schweinfurt - Med. III
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm - Innere Med. I
city: Wesel
country: Germany
facility: Marien-Hospital Wesel - Med. II
city: Wolfsburg
country: Germany
facility: Klinikum Wolfsburg - Med. II
Study officials:
affiliation: HOPE - Hämatologisch-onkologische Praxis Eppendorf
name: Alexander Stein, Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.