Modified FOLFOX Plus/Minus Nivolumab and Ipilimumab vs. FLOT Plus Nivolumab in Patients With Previously Untreated Advanced or Metastatic Gastric Cancer

NCT03647969 | Completed Phase 2 DMC

• 3 other identifiers: AIO-STO-04172017-002080-18CA209-9KG
• Study Type: interventional
• Target: 262
• Locations: 1 country
• Sites: 27

Brief Summary

Patients with Her2 negative, previously untreated metastatic esophagogastric adenocarcinoma will be treated with modified FOLFOX, with modified FOLFOX plus Nivolumab and Ipilimumab or FLOT plus Nivolumab. The groups will be compared for time until progression of the disease (primary endpoint) as well as for response to the treatment, overall survival, safety/tolerability of the treatment and quality of life.

Conditions

Adenocarcinoma of the Stomach; GastroEsophageal Cancer

Outcome Measures

Primary Outcomes (2)

• Progression-free survival (PFS) Arm A and B

  PFS, defined as time from randomization to the date of first observed disease progression as assessed by the investigator using CT criteria or death from any cause assessed every 8 weeks for up to 3 years Arm A versus Arm B

  Up to 3 years

• Progression-free Survival rate at 6 months Arm A2 and C

  PFS rate at 6 months is defined as proportion of patients being known to be alive and free of disease progression as assessed by the investigator using CT criteria at 6 months after randomization/enrolment

  6 months after randomization/enrolment

Secondary Outcomes (9)

• Progression-free survival (PFS) Arm A1, A2, C

  Up to 3 years

• Progression-free Survival rate at 6 months Arms A and B

  6 months after randomization

• Overall Response Rate (ORR)

  Up to 2 years

• Duration of response and disease stabilization

  Up to 3 years

• Overall survival (OS)

  Up to 3 years

Study Arms (4)

mFOLFOX/Nivolumab/Ipilimumab A/A1

EXPERIMENTAL

Nivolumab 240mg "Flatdose" i.v. d1 over 30 min every 2 weeks followed by Ipilimumab 1mg/kg i.v. d1 over 30 min every 6 weeks followed by FOLFOX Oxaliplatin 85 mg/m² iv 2hrs (day 1), Leucovorin 400 mg/m2 iv 2hrs (day 1), Fluorouracil 400 mg/m² iv bolus (day 1), and Fluorouracil 2400 mg/m² iv continuous infusion over 44 hours (day 1+2) every 2 weeks until disease progression or inacceptable toxicity or end of study treatment.

Drug: Nivolumab; Drug: Ipilimumab; Drug: mFOLFOX

mFOLFOX/Nivolumab/Ipilimumab sequential A2

EXPERIMENTAL

3 cycles of induction chemotherapy with FOLFOX: FOLFOX Oxaliplatin 85 mg/m² iv 2hrs (day 1), Leucovorin 400 mg/m2 iv 2hrs (day 1), Fluorouracil 400 mg/m² iv bolus (day 1), and Fluorouracil 2400 mg/m² iv continuous infusion over 44 hours (day 1+2) every 2 weeks followed by immunotherapy consisting of: 4 administrations of Nivolumab 240mg "Flatdose" i.v. d1 over 30 minutes every 2 weeks and 2 administrations of Ipilimumab 1mg/kg i.v. d1 over 30 minutes every 6 weeks Sequence as described may be repeated starting two weeks after last administration of immunotherapy once, or, if medically reasonable, for an unlimited number of repetitions upon investigator decision. After discontinuation of chemotherapy, immunotherapy will be continued consisting of: Nivolumab at 240mg "Flatdose" i.v. d1 every 2 weeks and Ipilimumab at 1mg/kg i.v. d1 every 6 weeks until disease progression or inacceptable toxicity or end of study treatment.

Drug: Nivolumab; Drug: Ipilimumab; Drug: mFOLFOX

mFOLFOX B

ACTIVE COMPARATOR

FOLFOX Oxaliplatin 85 mg/m² iv 2hrs (day 1), Leucovorin 400 mg/m2 iv 2hrs (day 1), Fluorouracil 400 mg/m² iv bolus (day 1), and Fluorouracil 2400 mg/m² iv continuous infusion over 44 hours (day 1+2) every 2 weeks until disease progression or inacceptable toxicity or end of study treatment.

Drug: mFOLFOX

FLOT/Nivolumab C

EXPERIMENTAL

Nivolumab 240mg "Flatdose" i.v. d1 every 2 weeks followed by FLOT: Docetaxel 50mg/², Oxaliplatin 85 mg/m², leucovorin 200 mg/m² on day 1 and fluorouracil 2600 mg/m² IV continuous infusion over 24 hours every 2 weeks until disease progression or inacceptable toxicity or end of study treatment. After completion or discontinuation of chemotherapy, immunotherapy may be continued consisting of: Nivolumab at 240mg "Flatdose" i.v. d1 every 2 weeks Chemotherapy can also be administered per local standard.

Drug: Nivolumab; Drug: FLOT

Interventions

Nivolumab DRUG

Nivolumab 240mg "Flatdose" i.v. d1 over 30 minutes every 2 weeks

FLOT/Nivolumab C; mFOLFOX/Nivolumab/Ipilimumab A/A1; mFOLFOX/Nivolumab/Ipilimumab sequential A2

Ipilimumab DRUG

1mg/kg i.v. d1 over 30 minutes every 6 weeks

mFOLFOX/Nivolumab/Ipilimumab A/A1; mFOLFOX/Nivolumab/Ipilimumab sequential A2

mFOLFOX DRUG

Oxaliplatin at a dose of 85 mg/m² iv over two hours (day 1), Leucovorin at a dose of 400 mg/m2 iv over two hours (day 1), Fluorouracil at a dose of 400 mg/m² iv bolus (day 1), and Fluorouracil at a dose of 2400 mg/m² iv continuous infusion over 44 hours (day 1+2) every 2 weeks

mFOLFOX B; mFOLFOX/Nivolumab/Ipilimumab A/A1; mFOLFOX/Nivolumab/Ipilimumab sequential A2

FLOT DRUG

Docetaxel at a dose of 50 mg/m² iv over one hour (day 1), Oxaliplatin at a dose of 85 mg/m² iv over two hours (day 1), Leucovorin\* at a dose of 200 mg/m² iv over one hour (day 1), Fluorouracil at a dose of 2600 mg/m² iv over 24 hours (day 1) every 2 weeks \* Note: Leucovorin can be replaced by sodium folinate that is given according to local guideline.

FLOT/Nivolumab C

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 GC or GEJ adenocarcinoma.
• Subjects must have HER2-negative disease defined as either IHC 0 or I+ or IHC 2+, the latter in combination with ISH-, as assessed locally on a primary or metastatic tumour.
• Subject must be previously untreated with systemic treatment 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 6 months prior to randomization/enrolment.
• Palliative radiotherapy is allowed and must be completed 2 weeks prior to randomization/enrolment.
• 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).
• Life expectancy \> 12 weeks
• Screening laboratory values must meet the following criteria (using NCI CTCAE v.4.03):
• WBC ≥ 2000/uL
• Neutrophils ≥ 1500/µL
• Platelets ≥ 100x10\^3/µL
• Hemoglobin ≥ 9.0 g/dL
• Serum creatinine ≤ 1.5 x ULN
• AST ≤ 3.0 x ULN (or ≤ 5.0X ULN if liver metastates are present)

You may not qualify if:

• Subjects with untreated symptomatic CNS metastases. Subjects are eligible if CNS metastases are asymptomatic (this includes patients with unknown CNS metastatic status who have no clinical signs of CNS metastases) or those with asymptomatic or symptomatic CNS who are adequately treated and are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to randomization/enrolment. 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/enrolment. Patients with unknown CNS metastatic status and any clinical signs indicative of CNS metastases are eligible if CNS metastases are excluded using CT and/or MRI scans, or CNS metastases are confirmed but adequately treated as described above.
• 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.
• All toxicities attributed to prior anti-cancer therapy other than hearing loss, alopecia and fatigue must have resolved to Grade 1 (NCI CTCAE version 4.03) or baseline before administration of study drug.
• \> Grade 1 peripheral neuropathy according to CTCAE version 4.0
• Known Dihydropyrimidine dehydrogenase (DPD) deficiency
• 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.
• Ascites which cannot be controlled with appropriate interventions.
• Unstable cardiac disease despite treatment, myocardial infarction within 6 months prior to study entry; congestive heart failure NYHA grade 3 and 4
• Significant acute or chronic infections including, among others:
• 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 drugs 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.

Sponsors & Collaborators

• Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest: lead

Study Sites (27)

Klinikum St. Marien Amberg

Amberg, Germany

Location

Klinikum Aschaffenburg

Aschaffenburg, Germany

Location

HELIOS Klinikum Bad Saarow

Bad Saarow, Germany

Location

Charité CVK

Berlin, Germany

Location

HELIOS Klinikum Berlin Buch

Berlin, Germany

Location

Klinikum Bielefeld

Bielefeld, Germany

Location

Städtisches Klinikum Dresden

Dresden, Germany

Location

Universitätsklinikum TU Dresden

Dresden, Germany

Location

Krankenhaus Nordwest

Frankfurt, 60488, Germany

Location

Agaplesion Markus KH Frankfurt

Frankfurt am Main, Germany

Location

Frankfurt Universitätsklinikum

Frankfurt am Main, Germany

Location

Hamburg Onkologische Schwerpunktpraxis Eppendorf

Hamburg, Germany

Location

Hämatologisch-Onkologische Praxis Altona (HOPA)

Hamburg, Germany

Location

Universitätsklinikum Jena

Jena, Germany

Location

Ortenau Klinikum Lahr

Lahr, Germany

Location

Klinikum Ludwigsburg

Ludwigsburg, Germany

Location

Universitätsklinikum Lübeck

Lübeck, Germany

Location

Universitätsmedizin Mannheim

Mannheim, Germany

Location

Universitätsklinikum Marburg

Marburg, Germany

Location

Klinikum der Universität München Großhadern

München, Germany

Location

Klinikum r.d. Isar

München, Germany

Location

Studienzentrum Onkologie Ravensburg

Ravensburg, Germany

Location

Universitätsklinikum Tübingen

Tübingen, Germany

Location

Universitätsklinikum Ulm

Ulm, Germany

Location

Klinikum Weiden

Weiden, Germany

Location

Helios Dr. Horst Schmidt Kliniken

Wiesbaden, Germany

Location

Klinikum Wolfsburg

Wolfsburg, Germany

Location

MeSH Terms

Interventions

Nivolumab; Ipilimumab

Intervention Hierarchy (Ancestors)

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

Study Officials

• Salah-Eddin Al-Batran, Prof. Dr.

  Krankenhaus Nordwest

  STUDY CHAIR

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: June 28, 2018
• First Posted: August 27, 2018
• Study Start: November 7, 2018
• Primary Completion: July 19, 2024
• Study Completion: July 19, 2024
• Last Updated: August 9, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

DE (27)