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Gastric CancerPhase 2INTEGANCT03409848

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

A Phase 2 study testing Nivolumab and Ipilimumab in people with Gastric Cancer and Esophageal Cancer, run by AIO-Studien-gGmbH at 35 sites in Germany.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Nivolumab and Ipilimumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
97 participants
Where
35 sitesGermany
Study dates
1 Mar 2018to 5 Mar 2022
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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).
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  • 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)
  • Males and Females, ≥ 18 years of age
  • 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.
  • Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study.
  • 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.
  • 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.
  • 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.

Who cannot join

  • 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)
  • 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.
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  • 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
  • Participation in another clinical study with an investigational product during the last 30 days before inclusion
  • 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].

Trial locations and contacts

35 sites in 1 country.

35 sites in 1 country

Germany35 sites

  • Gesundheitszentrum St. Marien Amberg - MVZ

    Amberg, 92224

  • Gesundheitszentrum Wetterau - Facharztzentrum

    Bad Nauheim, 61231

  • Helios Klinikum Bad Saarow - Hämatologie, Onkologie und Palliativmedizin

    Bad Saarow, 15526

  • Charité Universitätsmedizin Campus Virchow Klinikum - Hämatologie / Onkologie

    Berlin, 13353

  • Ev. Waldkrankenhaus Spandau - Onkologisches Zentrum

    Berlin, 13589

  • St. Josef Hospital Bochum - Hämatologie, Onkologie und Palliativmedizin

    Bochum, 44791

  • Schwerpunktpraxis Hämatologie und Onkologie Bottrop

    Bottrop, 46236

  • MVZ Klinikum Coburg

    Coburg, 96450

  • BAG Onkologische Gemeinschaftspraxis Dresden

    Dresden, 01307

  • Kliniken Essen-Mitte - Klinik für Internistische Onkologie und Hämatologie

    Essen, 45136

  • Krankenhaus Nordwest - Institut für klinische Forschung

    Frankfurt a.M., 60488

  • Uniklinikum Frankfurt - Med. I

    Frankfurt a.M., 60590

  • Universitätsklinikum Halle (Saale) - Innere Med. I

    Halle, 06120

  • Universitätsklinikum Hamburg Eppendorf - II. Med.

    Hamburg, 20246

  • HOPE - Hämatologisch-onkologische Praxis Eppendorf

    Hamburg, 20249

  • Med. Hochschule Hannover - Gastroenterologie, Hepatologie und Endokrinologie

    Hanover, 30625

  • Universitätsklinikum Jena - Innere Med. Hämatologie und Onkologie

    Jena, 07740

  • DRK Kliniken Nordhessen - Klinik für interdisziplinäre Onkologie

    Kassel, 34121

  • Klinikum Kassel - Onkologie und Hämatologie

    Kassel, 34125

  • Ortenau-Klinikum Lahr - Sektion Hämatologie und Onkologie

    Lahr, 77933

  • MVZ-Mitte - Onkologische Schwerpunktpraxis Leipzig

    Leipzig, 04103

  • Universitätsklinikum Leipzig - Krebszentrum

    Leipzig, 04109

  • Klinikum Magdeburg - Hämatologie und Onkologie

    Magdeburg, 39130

  • Universitätsklinikum Marburg - Hämatologie, Onkologie und Immunologie

    Marburg, 35032

  • Kliniken Maria Hilf Mönchengladbach - Hämatologie, Onkologie und Gastroenterologie

    Mönchengladbach, 41063

  • Klinikum der LMU München - Med. III

    München, 81377

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

    München, 81675

  • Stauferklinikum Schwäbisch Gmünd - Innere Med.

    Mutlangen, 73557

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

    Oldenburg, 26133

  • Ermstalklinik Reutlingen - Med. I

    Reutlingen, 72764

  • Elblandklinikum Riesa - Innere Med.

    Riesa, 01589

  • Leopoldina Krankenhaus Schweinfurt - Med. III

    Schweinfurt, 97422

  • Universitätsklinikum Ulm - Innere Med. I

    Ulm, 89081

  • Marien-Hospital Wesel - Med. II

    Wesel, 46483

  • Klinikum Wolfsburg - Med. II

    Wolfsburg, 38440

Other trials in Germany

About this study

Official title: Ipilimumab or FOLFOX in Combination With Nivolumab and Trastuzumab in Previously Untreated HER2 Positive Locally Advanced or Metastatic EsophagoGastric Adenocarcinoma

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).

Read the 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.

Being tested
Nivolumab, Ipilimumab
Medical subject headings
Stomach Neoplasms, Esophageal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NivolumabDrug

    Addition of Nivolumab to Standard therapy (chemotherapy and Trastuzumab)

  • NivolumabDrug

    Chemo-free immunotherapy with Nivolumab, Ipilimumab, Trastuzumab

  • IpilimumabDrug

    Chemo-free immunotherapy with Nivolumab, Ipilimumab, Trastuzumab

Study groups in NCT03409848
Study groupRoleWhat they receive
A: Chemo-free immunotherapyExperimentalWeek 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
Receives: Drug: Nivolumab; Drug: Ipilimumab
B: Chemo- / immunotherapyExperimentalTrastuzumab 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
Receives: Drug: Nivolumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Overall Survival

    Overall survival including milestone rate at 12 months

    Measured: Milestone at 12 months, max observation period 48 months

Secondary outcomes (11)

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

    according to Common Terminology Criteria for Adverse Events and to the obtained data on vital signs, clinical parameters and feasibility of the regimen

    Measured: 48 months

  2. Progression Free Survival

    Response Evaluation Criteria in Solid Tumors (RECIST 1.1.)

    Measured: 48 months

  3. Response Rate

    Response Rate (RR) according to RECIST v1.1

    Measured: 15 months

  4. Health related Quality of Life

    EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer - Quality of Life Core Questionnaire (30 items) Version 3.0. The QLQ-C30 is composed of multi-item scales and single-item measures, including five functional scales, three symptom scales, a global health status / QoL scale, and six single items.

    All of the scales and single-item measures have a score range from 0 to 100. A high score shows a high response level. A high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems

    Measured: 48 months

  5. Health related Quality of Life

    EORTC STO-22 (European Organisation for Research and Treatment of Cancer - Quality of Life Questionnaire Gastric Module (STO = stomach) (22 items), comprising five multi-item and four single-item subscales. The multi-item subscales include questions about dysphagia (4 items), dietary restriction (5 items), pain (3 items), upper gastro-esophageal symptoms such as reflux (3 items), and emotional problems such as anxiety (3 items). The single-item subscales include questions related to four gastric cancer-specific symptoms: dry mouth, body image, hair loss, and problems with taste. Items are assessed on a 4-level numerical scale with 1= "not at all", 2= "a little", 3= "quite a bit", and 4= "very much". Scores are linearly converted and summated into a scaled score from 0 to 100, with a higher score representing a worse QOL.

    Measured: 48 months

  6. Translational research tumor block

    Tumor-infiltrating lymphocytes (TiL) repertoire determination from tumor

    Measured: 48 months

  7. Translational research blood - immunoprofiling

    Liquid biopsy next-generation sequencing (NGS) immunoprofiling (TCRβ \& IgH) before treatment initiation and before second cycle to determine response predictive immune signature

    Measured: Up to 7 weeks

  8. Translational research blood - circulating Tumor cells (CTC)

    CTC will be evaluated for changes in HER2 and PD-L1 status

    Measured: 48 months

  9. Translational research blood - circulating Tumor DNA (ctDNA)

    ctDNA will be evaluated for HER signaling alterations

    Measured: 48 months

  10. Central Imaging Review - ORR

    Retrospective central radiological review of ORR according to modified RECIST

    Measured: 48 months

  11. Central Imaging Review - PFS

    Retrospective central radiological review of PFS according to modified RECIST

    Measured: 48 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Jan 2018
  2. Study start1 Mar 2018
  3. Primary completion5 Mar 2022
  4. Study completion5 Mar 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
97 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03409848
Sponsor's protocol ID
AIO-STO-0217
Other IDs
2017-000624-10, CA209-99R, 2017
Acronym
INTEGA
Status last verified
May 2022
First submitted
3 Jan 2018
Last updated
18 May 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 35737383

  • 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.

    PubMed 32487035

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Nivolumab and Ipilimumab in people with Gastric Cancer and Esophageal Cancer, run by AIO-Studien-gGmbH at 35 sites in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 21 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 May 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 35 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall Survival (time frame: Milestone at 12 months, max observation period 48 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03409848, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 May 2022.

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