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Avelumab in First-Line Maintenance Gastric Cancer (JAVELIN Gastric 100)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02625610
Recruitment Status : Completed
First Posted : December 9, 2015
Results First Posted : November 4, 2021
Last Update Posted : June 9, 2022
Sponsor:
Collaborator:
Merck KGaA, Darmstadt, Germany
Information provided by (Responsible Party):
EMD Serono ( EMD Serono Research & Development Institute, Inc. )

Brief Summary:
The purpose of this study was to demonstrate superiority of treatment with avelumab versus continuation of first-line chemotherapy.

Condition or disease Intervention/treatment Phase
Unresectable, Locally Advanced or Metastatic, Adenocarcinoma of the Stomach, or of the Gastro Esophageal Junction Drug: Avelumab Drug: Oxaliplatin Drug: 5-Fluorouracil Drug: Leucovorin Drug: Capecitabine Other: Best supportive care Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 499 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase III Open-label, Multicenter Trial of Maintenance Therapy With Avelumab (MSB0010718C) Versus Continuation of First-line Chemotherapy in Subjects With Unresectable, Locally Advanced or Metastatic, Adenocarcinoma of the Stomach, or of the Gastro-esophageal Junction
Actual Study Start Date : December 24, 2015
Actual Primary Completion Date : September 13, 2019
Actual Study Completion Date : June 3, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Avelumab

Arm Intervention/treatment
Experimental: Chemotherapy + Best Supportive Care (BSC)
In Maintenance Phase, participants continued the same regimen of oxaliplatin-fluoropyrimidine doublet chemotherapy (oxaliplatin + 5FU/LV or oxaliplatin + capecitabine) as they received during the Induction Phase until disease progression, significant clinical deterioration, unacceptable toxicity, or discontinuation. Participants who were not deemed eligible to receive chemotherapy at the dose and schedule specified above received BSC alone once every 3 weeks. BSC was defined as treatment administered with the intent to maximize quality of life without a specific antineoplastic regimen and was based on Investigator's discretion.
Drug: Oxaliplatin

Induction Phase: Oxaliplatin was administered at a dose of 85 mg per square meter (mg/m^2) as a continuous intravenous (IV) infusion on Day 1 along with leucovorin followed by 5-Fluorouracil every 2 weeks up to 12 weeks (or) Oxaliplatin at 130 mg/m^2 IV on Day 1 along with capecitabine twice daily for 2 weeks followed by a 1-week rest period given every 3 weeks up to 12 weeks.

Maintenance Phase: Participants were continued the same regimen of chemotherapy as they received during the Induction Phase until disease progression, significant clinical deterioration, unacceptable toxicity, or discontinuation.


Drug: 5-Fluorouracil
Induction Phase: 5-Fluorouracil was administered at a dose of 2600 mg/m^2 IV continuous infusion over 24 hours on Day 1 (or) 5-FU at 400 mg/m^2 IV push on Day 1 and 2400 mg/m^2 IV continuous infusion over 46-48 hours (Days 1 and 2) along with oxaliplatin and leucovorin every 2 weeks up to 12 weeks. Maintenance Phase: Participants were continued the same regimen of chemotherapy as they received during the Induction Phase until disease progression, significant clinical deterioration, unacceptable toxicity, or discontinuation.

Drug: Leucovorin

Induction Phase: Leucovorin was administered at a dose of 200 mg/m^2 IV (or) Leucovorin 400 mg/m^2 IV on Day 1 along with oxaliplatin and 5-FU every 2 weeks up to 12 weeks.

Maintenance Phase: Participants were continued the same regimen of chemotherapy as they received during the Induction Phase until disease progression, significant clinical deterioration, unacceptable toxicity, or discontinuation.


Drug: Capecitabine

Induction Phase: Capecitabine was administered at a dose of 1000 mg/m^2 twice daily for 2 weeks followed by a 1-week rest period given every 3 weeks along with oxaliplatin up to 12 weeks.

Maintenance Phase: Participants were continued the same regimen of chemotherapy as they received during the Induction Phase every 3 weeks until disease progression, significant clinical deterioration, unacceptable toxicity, or discontinuation.


Other: Best supportive care
Treatment administered with the intent to maximize Quality of Life (QoL) without a specific antineoplastic regimen. These may include for example antibiotics, analgesics, antiemetics, thoracentesis, paracentesis, blood transfusions, nutritional support (including jejunostomy), and focal external-beam radiation for control of pain, cough, dyspnea, or bleeding. Best supportive care were administered per institutional guidelines and participants were visit the clinic every 3 weeks.

Drug: Oxaliplatin
Induction Phase: Oxaliplatin will be administered at a dose of 85 mg per square meter (mg/m^2) as a continuous intravenous (IV) infusion on Day 1 along with leucovorin followed by 5-Fluorouracil every 2 weeks up to 12 weeks (or) Oxaliplatin at 130 mg/m^2 IV on Day 1 along with capecitabine twice daily for 2 weeks followed by a 1-week rest period given every 3 weeks up to 12 weeks.

Drug: 5-Fluorouracil
Induction Phase: 5-Fluorouracil will be administered at a dose of 2600 mg/m^2 IV continuous infusion over 24 hours on Day 1 (or) 5-FU at 400 mg/m^2 IV push on Day 1 and 2400 mg/m^2 IV continuous infusion over 46-48 hours (Days 1 and 2) along with oxaliplatin and leucovorin every 2 weeks up to 12 weeks.

Drug: Leucovorin
Induction Phase: Leucovorin will be administered at a dose of 200 mg/m^2 IV (or) Leucovorin 400 mg/m^2 IV on Day 1 along with oxaliplatin and 5-FU every 2 weeks up to 12 weeks.

Drug: Capecitabine
Induction Phase: Capecitabine will be administered at a dose of 1000 mg/m^2 twice daily for 2 weeks followed by a 1-week rest period given every 3 weeks along with oxaliplatin up to 12 weeks.

Experimental: Avelumab
In Maintenance phase, participants received avelumab as a 1-hour intravenous (IV) infusion at 10 milligrams per kilogram (mg/kg) once every 2-week treatment cycle until progressive disease or unacceptable toxicity or discontinuation.
Drug: Avelumab
Maintenance Phase: Intravenous (IV) infusion (10 mg/kg over 1 hour) once every 2 weeks.
Other Names:
  • MSB0010718C
  • Anti PD-L1




Primary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: From randomization into maintenance phase up to 1276 days ]
    Overall Survival was defined as the time from randomization to the date of death due to any cause. For participants who were still alive at the time of data analysis or who were lost to follow-up, OS time was censored at the date of last contact. OS was measured using Kaplan-Meier (KM) estimates.


Secondary Outcome Measures :
  1. Progression Free Survival (PFS) by Independent Review Committee (IRC) [ Time Frame: From randomization into maintenance phase up to 1276 days ]
    The PFS time was defined as the time from date of randomization until date of the first documentation of progressive disease (PD) or death due to any cause (whichever occurs first). PFS was assessed as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as per IRC. PD was defined as at least a 20 percent (%) increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was measured using Kaplan-Meier (KM) estimates.

  2. Best Overall Response (BOR) by Investigator Assessment [ Time Frame: From randomization into maintenance phase up to 1276 days ]
    BOR was determined by RECIST v1.1 per Investigator assessment and defined as best-confirmed response of any of following: complete response (CR), partial response (PR), stable disease (SD) and PD recorded from date of randomization until disease progression or recurrence. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in SLD of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or appearance of 1 or more new lesions. PR or CR confirmed at a subsequent tumor assessment, not sooner than 5 weeks after initial documentation or at an assessment later than the next assessment after the initial documentation of PR or CR. SD confirmed at least 6 weeks after randomization. Confirmed PD equal to progression <=2 weeks after date of randomization.

  3. Objective Response Rate (ORR) by Investigator Assessment [ Time Frame: From randomization into maintenance phase up to 1276 days ]
    The ORR defined as the percentage of all randomized participants with a confirmed best overall response (BOR) of partial response (PR),or complete response (CR) according to RECIST v1.1 and as per Investigator assessment. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions.

  4. Change From Baseline in European Quality of Life 5-dimensions (EQ-5D-5L) Health Outcome Questionnaire Through Composite Index Score up to Safety Follow-up (Up to 152.3 Weeks) [ Time Frame: Baseline, Week 3/4, Week 7, Week 13, Week 19, Week 25, Week 31, Week 37, Week 43, Week 49, Week 55, Week 61, Week 67, End of Treatment ( EOT up to 148 weeks) and Safety Follow-up (Up to 152.3 Weeks) ]
    EQ-5D-5L is comprised of the following 5 participant-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses are used to derive overall composite health state index score, with scores ranging from -0.594 to 1. A higher score indicates better health state.

  5. Change From Baseline in European Quality of Life 5-dimensions Health Outcome Questionnaire Through Visual Analogue Scale up to Safety Follow-up (Up to 152.3 Weeks) [ Time Frame: Baseline, Week 3/4, Week 7, Week 13, Week 19, Week 25, Week 31, Week 37, Week 43, Week 49, Week 55, Week 61, Week 67, End of Treatment ( EOT up to 148 weeks) and Safety Follow-up (Up to 152.3 Weeks) ]
    EQ-5D-5L is comprised of the following 5 participant-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses are used to derive overall score using a visual analog scale (VAS) that ranged from 0 to 100 millimeter (mm), where 0 is the worst health you can imagine and 100 is the best health you can imagine.

  6. Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) Global Health Status Scale Score up to Safety Follow-up (Up to 152.3 Weeks) [ Time Frame: Baseline, Week 3/4, Week 7, Week 13, Week 19, Week 25, Week 31, Week 37, Week 43, Week 49, Week 55, Week 61, Week 67, End of Treatment ( EOT up to 148 weeks) and Safety Follow-up (Up to 152.3 Weeks) ]
    European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life (QoL) in cancer participants. It consisted of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, role, cognitive, emotional, social), and 9 symptom scales/items (Fatigue, nausea and vomiting, pain, dyspnoea, sleep disturbance, appetite loss, constipation, diarrhea, financial impact. The EORTC QLQ-C30 GHS/QoL score ranges from 0 to 100; High score indicates better GHS/QoL. Score 0 represents: very poor physical condition and QoL. Score 100 represents: excellent overall physical condition and QoL.

  7. Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Stomach Cancer Specific (EORTC QLQ-STO22 ) Questionnaire Scores up to Safety Follow-up (Up to 152.3 Weeks) [ Time Frame: Baseline, Week 3/4, Week 7, Week 13, Week 19, Week 25, Week 31, Week 37, Week 43, Week 49, Week 55, Week 61, Week 67, End of Treatment ( EOT up to 148 weeks) and Safety Follow-up (Up to 152.3 Weeks) ]
    European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Stomach Cancer Specific (EORTC QLQ-STO22 ) supplements the EORTC QLQ-C30 to assess symptoms and treatment-related side effects commonly reported in participants. There are 22 questions which comprise 5 scales (dysphagia, pain, reflux symptom, dietary restrictions, and anxiety) and 4 single items (dry mouth, hair loss, taste, body image). Most questions use 4-point scale (1 'Not at all' to 4 'Very much'; 1 question was a yes or no answer). A linear transformation was used to standardize all scores and single-items to a scale of 0 to 100; higher score=better level of functioning or greater degree of symptoms.

  8. Maintenance Phase: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03) [ Time Frame: From randomization into maintenance phase up to 1276 days ]
    Adverse event (AE) was defined as any untoward medical occurrence in a participant, which does not necessarily have causal relationship with treatment. A serious AE was defined as an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged in participant hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs included both serious TEAEs and non-serious TEAEs. Number of participants with TEAEs and serious TEAEs were reported.

  9. Maintenance Phase: Number of Participants With Grade Change From Baseline to Worst On-Treatment Grade 4 Hematology Values [ Time Frame: From baseline up to 1276 days ]
    Blood samples were collected for the analysis of following hematology parameters: lymphocyte count, neutrophil count, white blood cells, platelet count, lipase, serum amylase, creatinine phosphokinase and creatinine. The hematology parameters were graded according to National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. An increase is defined as an increase in CTCAE grade relative to Baseline grade. Data for worst-case (Grade 4) post Baseline is presented. Only those participants with increase to grade 4 have been presented.

  10. Maintenance Phase: Number of Participants With Potentially Clinically Significant Abnormalities in Vital Signs [ Time Frame: From randomization into maintenance phase up to 1276 days ]
    Vital signs assessment included Systolic blood pressure (SBP), Diastolic blood pressure (DBP) and Pulse Rate (PR). Number of Participants with any potentially clinically significant abnormalities in vital signs were reported. Clinical significance was determined by the investigator.

  11. Maintenance Phase: Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities [ Time Frame: From randomization into maintenance phase up to 1276 days ]
    ECG parameters included heart rate, pulse rate intervals, QRS interval, QT interval corrected based on Fridericia's formula (QTcF) intervals and QTcB intervals. Clinical significance was determined by the investigator. Number of participants with potentially clinically significant ECG abnormalities were reported.

  12. Maintenance Phase: Number of Participants With Shift in Eastern Cooperative Oncology Group (ECOG) Performance Status Score to 1 or Higher Than 1 [ Time Frame: From randomization into maintenance phase up to 1276 days ]
    ECOG PS score is widely used by doctors and researchers to assess how a participants' disease is progressing, and is used to assess how the disease affects the daily living abilities of the participant, and determine appropriate treatment and prognosis. The score ranges from Grade 0 to Grade 5, where Grade 0 = Fully active, able to carry on all pre-disease performance without restriction, Grade 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade 2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair, Grade 5 = Death. Number of participants with shift in ECOG PS Score to 1 or Higher Than 1 were reported.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female participants greater than or equal to (>=) 18 years
  • Disease must be measurable by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)
  • Participants with histologically confirmed unresectable locally advanced or metastatic adenocarcinoma of the stomach or gastro-esophageal junction (GEJ)
  • Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at trial entry
  • Estimated life expectancy of more than 12 weeks
  • Adequate haematological, hepatic and renal functions defined by the protocol
  • Negative blood pregnancy test at Screening for women of childbearing potential
  • Highly effective contraception for both male and female participants if the risk of conception exists
  • Other protocol defined inclusion criteria could apply

Exclusion Criteria:

  • Prior therapy with any antibody or drug targeting T-cell coregulatory proteins
  • Concurrent anticancer treatment or immunosuppressive agents
  • Prior chemotherapy for unresectable locally advanced or metastatic adenocarcinoma of the stomach or gastro-esophageal junction (GEJ)
  • Tumor shown to be human epidermal growth factor 2 plus (HER2+)
  • Major surgery for any reason, except diagnostic biopsy, within 4 weeks of enrolment and/or if the participant has not fully recovered from the surgery within 4 weeks of enrolment
  • Participants receiving immunosuppressive agents (such as steroids) for any reason should be tapered off these drugs before initiation of the study treatment (with the exception of participants with adrenal insufficiency, who may continue corticosteroids at physiologic replacement dose, equivalent to <= 10 mg prednisone daily)
  • All participants with brain metastases, except those meeting the following criteria: a. Brain metastases have been treated locally, have not been progressing at least 2 months after completion of therapy, and no steroid maintenance therapy is required, and b. No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable)
  • Previous malignant disease (other than gastric cancer) within the last 5 years with the exception of basal or squamous cell carcinoma of the skin or carcinoma in situ (bladder, cervical, colorectal, breast)
  • Prior organ transplantation, including allogeneic stem-cell transplantation
  • Significant acute or chronic infections
  • Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent
  • Known severe hypersensitivity reactions to monoclonal antibodies, any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma)
  • Persisting toxicity related to prior therapy except alopecia
  • Neuropathy Grade > 3
  • Pregnancy or lactation
  • Known alcohol or drug abuse
  • History of uncontrolled intercurrent illness including hypertension, active infection, diabetes
  • Clinically significant (i.e., active) cardiovascular disease
  • All other significant diseases might impair the participant's tolerance of study treatment
  • Any psychiatric condition that would prohibit the understanding or rendering of informed consent and that would limit compliance with study requirements
  • Vaccination with live or live/attenuated viruses within 55 days of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines
  • Legal incapacity or limited legal capacity
  • Participants will be excluded from the Induction Phase and the Maintenance Phase if administration of their chemotherapy would be inconsistent with the current local labelling (SmPC) (e.g., in regard to contraindications, warnings/precautions or special provisions) for that chemotherapy. Investigators should check updated labelling via relevant websites at the time of entry into the Induction Phase and the Maintenance Phase
  • Other protocol defined exclusion criteria could apply

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02625610


Locations
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Sponsors and Collaborators
EMD Serono Research & Development Institute, Inc.
Merck KGaA, Darmstadt, Germany
Investigators
Layout table for investigator information
Study Director: Medical Responsible EMD Serono Research & Development Institute, Inc. a business of Merck KGaA, Darmstadt, Germany
  Study Documents (Full-Text)

Documents provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
Study Protocol  [PDF] July 17, 2019
Statistical Analysis Plan  [PDF] July 23, 2019

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: EMD Serono Research & Development Institute, Inc.
ClinicalTrials.gov Identifier: NCT02625610    
Other Study ID Numbers: EMR 100070-007
2015-003300-23 ( EudraCT Number )
First Posted: December 9, 2015    Key Record Dates
Results First Posted: November 4, 2021
Last Update Posted: June 9, 2022
Last Verified: May 2022
Keywords provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
Avelumab
Cancer
Unresectable
Locally advanced
Metastatic
Adenocarcinoma of the stomach
Gastro-esophageal junction
Additional relevant MeSH terms:
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Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Leucovorin
Fluorouracil
Capecitabine
Oxaliplatin
Avelumab
Levoleucovorin
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antidotes
Protective Agents
Vitamin B Complex
Vitamins
Micronutrients
Antineoplastic Agents, Immunological