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

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ClinicalTrials.gov Identifier: NCT03647969
Recruitment Status : Recruiting
First Posted : August 27, 2018
Last Update Posted : April 30, 2019
Sponsor:
Information provided by (Responsible Party):
IKF Klinische Krebsforschung GmbH at Krankenhaus Nordwest

Tracking Information
First Submitted Date  ICMJE June 28, 2018
First Posted Date  ICMJE August 27, 2018
Last Update Posted Date April 30, 2019
Actual Study Start Date  ICMJE November 7, 2018
Estimated Primary Completion Date July 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 24, 2018)
Progression-free survival (PFS) [ Time Frame: Up to 3 years ]
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
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03647969 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 17, 2018)
  • Overall Response Rate (ORR) [ Time Frame: Up to 2 years ]
    ORR defined as proportion of patients with complete or partial response (CR + PR) as assessed according to RECIST criteria every 8 weeks for up to 2 years
  • Duration of response and disease stabilization [ Time Frame: Up to 3 years ]
    Duration of response and disease stabilization defined as time from documentation of tumor response (CR, PR) or disease stabilization (SD) according to RECIST criteria to disease progression or death for up to 3 years
  • Overall survival (OS) [ Time Frame: Up to 3 years ]
    Overall survival according to Kaplan-Meier assessed from randomization to the date of death from any cause
  • Incidence and severity of adverse events [ Time Frame: Up to 27 months ]
    incidence and severity of adverse events according to CTCAE (Common Terminology Criteria for Adverse Events) Version 4.03 criteria as assessed every 2 weeks during treatment and until 100 days after the last dose of study drug
  • Patient reported outcomes: Quality of life [ Time Frame: Up to 3 years ]
    Quality of life as measured by questionnaire EORTC-QLQ-C30 from randomization every 8 weeks until EOT and afterwards every 3 months until first observed disease progression or death for up to 3 years
Original Secondary Outcome Measures  ICMJE
 (submitted: August 24, 2018)
  • Overall Response Rate (ORR) [ Time Frame: Up to 2 years ]
    ORR defined as proportion of patients with complete or partial response (CR + PR) as assessed according to RECIST criteria every 8 weeks for up to 2 years
  • Duration of response and disease stabilization [ Time Frame: Up to 3 years ]
    Duration of response and disease stabilization defined as time from documentation of tumor response (CR, PR) or disease stabilization (SD) according to RECIST criteria to disease progression or death for up to 3 years
  • Overall survival (OS) [ Time Frame: Up to 3 years ]
    Overall survival according to Kaplan-Meier assessed from randomization to the date of death from any cause
  • Incidence and severity of adverse events according to CTC criteria [ Time Frame: Up to 27 months ]
    incidence and severity of adverse events according to CTC criteria as assessed every 2 weeks during treatment and until 100 days after the last dose of study drug
  • Patient reported outcomes: Quality of life [ Time Frame: Up to 3 years ]
    Quality of life as measured by questionnaire EORTC-QLQ-C30 from randomization every 8 weeks until EOT and afterwards every 3 months until first observed disease progression or death for up to 3 years
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Modified FOLFOX Plus/Minus Nivolumab and Ipilimumab in Patients With Previously Untreated Advanced or Metastatic Gastric Cancer
Official Title  ICMJE Modified FOLFOX Plus/Minus Nivolumab and Ipilimumab in Patients With Previously Untreated Advanced or Metastatic Adenocarcinoma of the Stomach or Gastroesophageal Junction - A Randomized Phase 2 Trial.
Brief Summary Patients with Her2 negative, previously untreated metastatic esophagogastric adenocarcinoma will be treated with modified FOLFOX or with modified FOLFOX plus Nivolumab and Ipilimumab. 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.
Detailed Description

This is a randomized, open labelled multicenter phase II trial. Patients with Her2 negative, previously untreated metastatic esophagogastric adenocarcinoma will be randomized to receive either modified FOLFOX (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) alone or modified FOLFOX plus Nivolumab (240mg "Flatdose" i.v. d1 every 2 weeks) and Ipilimumab (1mg/kg i.v. d1 every 6 weeks) for a maximum of 24 months or until disease progression or inacceptable toxicity or end of study treatment.

The primary objective is to determine the clinical performance of ipilimumab in combination with nivolumab and FOLFOX in patients with previously untreated HER2 negative locally advanced or metastatic esophagogastric adenocarcinoma in terms of progression free survival (acc. to RECIST v1.1).

Secondary objectives are to determine efficacy in terms of objective response rate (acc. to RECIST v1.1) and overall survival, as well as tolerability (acc. to NCI CTC AE v4.03) of the experimental regimen. In addition histopathological types and molecular parameters such as immune cell composition and PD-L1 expression as determined by quantitative mRNA (RT-PCR) will be correlated with efficacy in an exploratory analysis.

118 subjects (59 in the control and 59 in the experimental treatment group) will be randomized.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Adenocarcinoma of the Stomach
  • GastroEsophageal Cancer
Intervention  ICMJE
  • Drug: mFOLFOX, Nivolumab, Ipilimumab
    Nivolumab 240mg "Flatdose" i.v. d1 over 30 minutes every 2 weeks Ipilimumab 1mg/kg i.v. d1 over 30 minutes every 6 weeks 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
  • Drug: mFOLFOX
    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
Study Arms  ICMJE
  • Experimental: mFOLFOX/Nivolumab/Ipilimumab
    Nivolumab 240mg "Flatdose" i.v. d1 over 30 minutes every 2 weeks until disease progression or inacceptable toxicity follow Ipilimumab 1mg/kg i.v. d1 over 30 minutes every 6 weeks until disease progression or inacceptable toxicity followed by FOLFOX 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 until disease progression or inacceptable toxicity or end of study treatment.
    Intervention: Drug: mFOLFOX, Nivolumab, Ipilimumab
  • Active Comparator: mFOLFOX
    FOLFOX 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 until disease progression or inacceptable toxicity or end of study treatment.
    Intervention: Drug: mFOLFOX
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 24, 2018)
118
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date July 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. All subjects must have inoperable, advanced or metastatic GC or GEJ adenocarcinoma.
  2. 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.
  3. Subject must be previously untreated with systemic treatment 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 6 months prior to randomization.
  5. Palliative radiotherapy is allowed and must be completed 2 weeks prior to randomization.
  6. Subjects must have measurable or evaluable non-measurable disease as assessed by the investigator, according to RECIST v1.1 (Appendix D).
  7. ECOG performance status score of 0 or 1 (Appendix B).
  8. Life expectancy > 12 weeks
  9. Screening laboratory values must meet the following criteria (using NCI CTCAE v.4.03):

    1. WBC ≥ 2000/uL
    2. Neutrophils ≥ 1500/µL
    3. Platelets ≥ 100x103/µL
    4. Hemoglobin ≥ 9.0 g/dL
    5. Serum creatinine ≤ 1.5 x ULN
    6. AST ≤ 3.0 x ULN (or ≤ 5.0X ULN if liver metastates are present)
    7. ALT ≤ 3.0 x ULN (or ≤ 5.0X ULN if liver metastates are present)
    8. Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome who must have a total bilirubin level of < 3.0 x ULN)
  10. Males and Females* ≥ 18 years of age

    *There are no data that indicate special gender distribution. Therefore patients will be enrolled in the study gender-independently.

  11. 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.
  12. Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study.
  13. 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.
  14. WOCBP must agree to follow instructions for 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.
  15. 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 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. 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. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. > Grade 1 peripheral neuropathy according to CTCAE version 4.0
  8. Known Dihydropyrimidine dehydrogenase (DPD) deficiency
  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. Ascites which cannot be controlled with appropriate interventions.
  11. Unstable cardiac disease despite treatment, myocardial infarction within 6 months prior to study entry; congestive heart failure NYHA grade 3 and 4
  12. Significant acute or chronic infections including, among others:

    1. Positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
    2. Any positive test result for hepatitis B virus or hepatitis C virus indicating acute or chronic infection.
  13. History of allergy or hypersensitivity to study drugs or any constituent of the products
  14. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
  15. 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].
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Salah Eddin Al-Batran, Prof. Dr. +496976014420 albatran@ikf-khnw.de
Contact: Claudia Pauligk, Dr. +496976013906 pauligk.claudia@ikf-khnw.de
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03647969
Other Study ID Numbers  ICMJE AIO-STO-0417
2017-002080-18 ( EudraCT Number )
CA209-9KG ( Other Grant/Funding Number: Bristol Myers-Squibb )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: No IPD will be shared
Responsible Party IKF Klinische Krebsforschung GmbH at Krankenhaus Nordwest
Study Sponsor  ICMJE IKF Klinische Krebsforschung GmbH at Krankenhaus Nordwest
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Salah Eddin Al-Batran, Prof. Dr. Krankenhaus Nordwest
PRS Account IKF Klinische Krebsforschung GmbH at Krankenhaus Nordwest
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP