Clinical Trials List
Protocol NumberYO28322
2013-03-01 - 2016-10-31
Phase III
Terminated3
Study ended1
ICD-10D00.2
Carcinoma in situ of stomach
ICD-9230.2
Carcinoma in situ of stomach
A RANDOMIZED, PHASE III, MULTICENTER, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY EVALUATING THE EFFICACY AND SAFETY OF ONARTUZUMAB (MetMAb) IN COMBINATION WITH 5-FLUOROURACIL, FOLINIC ACID, AND OXALIPLATIN (mFOLFOX6) IN PATIENTS WITH METASTATIC HER2-NEGATIVE, MET-POSITIVE GASTROESOPHAGEAL CANCER
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Trial Applicant
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Sponsor
F. Hoffmann-La Roche Ltd
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Trial scale
Multi-Regional Multi-Center
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Update
2025/08/20
Investigators and Locations
The Actual Total Number of Participants Enrolled
0 Terminated
The Actual Total Number of Participants Enrolled
0 Terminated
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Yu-Min Liao Division of Hematology & Oncology
- Ching-Chan Lin Division of Hematology & Oncology
- Chang-Fang Chiu Division of Hematology & Oncology
Condition/Disease
METASTATIC HER2-NEGATIVE, MET-POSITIVE GASTROESOPHAGEAL CANCER
Objectives
Co-Primary Objectives
The co-primary objectives for this study are as follows:
• To evaluate the efficacy of onartuzumab + mFOLFOX6 compared with
placebo + mFOLFOX6 as measured by overall survival (OS) in patients with previously
untreated HER2–negative metastatic gastroesophageal cancer (GEC) classified as
Met-IHC 2+ or 3+ (Met 2+/3+ subgroup)
• To evaluate the efficacy of onartuzumab + mFOLFOX6 compared with
placebo + mFOLFOX6 as measured by OS in patients with previously untreated
HER2-negative metastatic GEC classified as Met-IHC 1+, 2+, or 3+ (intent-to-treat
[ITT] population)
Secondary Objectives
The secondary objectives for this study are as follows:
• To evaluate the efficacy of onartuzumab + mFOLFOX6 relative to placebo + mFOLFOX6 as
measured by PFS and ORR in the Met 2+/3+ subgroup and in the ITT population
• To evaluate the safety of onartuzumab + mFOLFOX6 compared with
placebo + mFOLFOX6 in patients with metastatic HER2-negative, Met-positive GEC,
focusing on all adverse events, National Cancer Institute Common Terminology Criteria for
Adverse Events (NCI CTCAE v4.0) Grade ≥ 3 adverse events, and Grade ≥ 3 laboratory
toxicities
• To compare patient-reported outcomes (PROs) following treatment with
onartuzumab + mFOLFOX6 relative to placebo + mFOLFOX6, as measured by the EORTC
QLQ-C30 and its gastric cancer module (the QLQ-STO22)
• To characterize the pharmacokinetics of onartuzumab when given with mFOLFOX6
• To evaluate serum levels and incidence of anti-therapeutic antibodies (ATAs)
against onartuzumab
Test Drug
ONARTUZUMAB (MetMAb)
Active Ingredient
ONARTUZUMAB
Dosage Form
Dosage
600mg / 10 ml / Vial, 900 / 15 ml / Vial
Endpoints
Co-Primary Efficacy Endpoints
Overall Survival. OS is defined as the time from randomization to death due to any
cause. Data for patients who are not reported as having died at the time of analysis will
be censored at the date when they were last known to be alive.
The two treatment comparisons of OS will be based on a stratified log-rank test at:
1) a one-sided significance level of 0.00577 for the Met 2+/3+ subgroup (see Section
6.1), and 2) a one-sided significance level of 0.02 for the ITT population. The
stratification factors are Met expression (level I, II, III, IV, or V), world region (Asia-Pacific
vs. other), and prior gastrectomy (yes vs. no).
Results from an unstratified log-rank test will also be presented. Kaplan−Meier
methodology will be used to estimate median OS for each treatment arm, and the
Kaplan−Meier curve will be constructed to provide a visual description of the difference
between the treatment arms. Estimates of the treatment effect will be expressed as HRs
using a stratified Cox model, including 95% confidence intervals (CIs).
6.4.2 Secondary Efficacy Endpoints
If the primary endpoint of OS is statistically significant in either or both of the co-primary
comparisons at the individually specified significance level (0.00577 for the Met 2+/3+
subgroup and 0.02 for the ITT population), the secondary endpoints of PFS and ORR for
each population will be tested in order (i.e., PFS followed by ORR), each at the same
significance level of the primary endpoint in the same population.
Progression-Free Survival. PFS is defined as the time between date of randomization
and the date of first documented disease progression or death, whichever occurs first.
Disease progression will be determined based on investigator assessment using
RECIST v1.1. Patients who have not experienced disease progression or death at the
time of analysis will be censored at the time of the last tumor assessment. Patients with
no post-baseline tumor assessment will be censored at the randomization date.
PFS will be analyzed in the same method as OS.
Objective Response Rate. Objective response is defined as a CR or PR assessed by
the investigator based on RECIST v1.1. Patients without a post-baseline tumor
assessment will be considered as non-responders. The analysis population for ORR will
be all randomized patients. An estimate of ORR and its 95% CI will be calculated using
the Blyth-Still-Casella method for each treatment arm. CIs for the difference in ORRs
between the two arms will be determined using the normal approximation to the binomial
distribution. The ORR will be compared between the two treatment arms using the
stratified Mantel-Haenszel test.
Overall Survival. OS is defined as the time from randomization to death due to any
cause. Data for patients who are not reported as having died at the time of analysis will
be censored at the date when they were last known to be alive.
The two treatment comparisons of OS will be based on a stratified log-rank test at:
1) a one-sided significance level of 0.00577 for the Met 2+/3+ subgroup (see Section
6.1), and 2) a one-sided significance level of 0.02 for the ITT population. The
stratification factors are Met expression (level I, II, III, IV, or V), world region (Asia-Pacific
vs. other), and prior gastrectomy (yes vs. no).
Results from an unstratified log-rank test will also be presented. Kaplan−Meier
methodology will be used to estimate median OS for each treatment arm, and the
Kaplan−Meier curve will be constructed to provide a visual description of the difference
between the treatment arms. Estimates of the treatment effect will be expressed as HRs
using a stratified Cox model, including 95% confidence intervals (CIs).
6.4.2 Secondary Efficacy Endpoints
If the primary endpoint of OS is statistically significant in either or both of the co-primary
comparisons at the individually specified significance level (0.00577 for the Met 2+/3+
subgroup and 0.02 for the ITT population), the secondary endpoints of PFS and ORR for
each population will be tested in order (i.e., PFS followed by ORR), each at the same
significance level of the primary endpoint in the same population.
Progression-Free Survival. PFS is defined as the time between date of randomization
and the date of first documented disease progression or death, whichever occurs first.
Disease progression will be determined based on investigator assessment using
RECIST v1.1. Patients who have not experienced disease progression or death at the
time of analysis will be censored at the time of the last tumor assessment. Patients with
no post-baseline tumor assessment will be censored at the randomization date.
PFS will be analyzed in the same method as OS.
Objective Response Rate. Objective response is defined as a CR or PR assessed by
the investigator based on RECIST v1.1. Patients without a post-baseline tumor
assessment will be considered as non-responders. The analysis population for ORR will
be all randomized patients. An estimate of ORR and its 95% CI will be calculated using
the Blyth-Still-Casella method for each treatment arm. CIs for the difference in ORRs
between the two arms will be determined using the normal approximation to the binomial
distribution. The ORR will be compared between the two treatment arms using the
stratified Mantel-Haenszel test.
Inclution Criteria
Patients must meet the following criteria for study entry:
• Ability and willingness to provide written informed consent and to comply with the
study protocol
• Male or female, 18 years of age or older
• ECOG performance status of 0 or 1
• Life expectancy > 3 months
• Histologically confirmed adenocarcinoma of the stomach or GEJ with inoperable
metastatic disease not amenable to curative therapy
• Adequate archival or newly obtained formalin-fixed paraffin-embedded (FFPE)
tissue for central IHC assay of Met receptor and HER2 status
See Section 4.5.1.10 for tissue requirements.
• Tumor (either primary or metastatic lesion) defined as Met positive by IHC (≥ 50% of
tumor cells with membrane and/or cytoplasmic staining at weak, moderate, or high
intensity; see Appendix 3)
• Measurable disease or non-measurable but evaluable disease, according to the
Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
Patients with peritoneal disease would generally be regarded as having
evaluable disease and be allowed to enter the trial.
• For women who are not postmenopausal (12 months of amenorrhea) or surgically
sterile (absence of ovaries and/or uterus): agreement to use an adequate method
of contraception (a method with a failure rate of < 1% per year, such as hormonal
implants, combined oral contraceptives, or a vasectomized partner) during the
treatment period and for at least 90 days after the last dose of onartuzumab/placebo
and 6 months after the last dose of oxaliplatin
• For men: agreement to use a barrier method of contraception during the treatment
period and for at least 90 days after the last dose of onartuzumab/placebo and
6 months after the last dose of oxaliplatin
• Ability and willingness to provide written informed consent and to comply with the
study protocol
• Male or female, 18 years of age or older
• ECOG performance status of 0 or 1
• Life expectancy > 3 months
• Histologically confirmed adenocarcinoma of the stomach or GEJ with inoperable
metastatic disease not amenable to curative therapy
• Adequate archival or newly obtained formalin-fixed paraffin-embedded (FFPE)
tissue for central IHC assay of Met receptor and HER2 status
See Section 4.5.1.10 for tissue requirements.
• Tumor (either primary or metastatic lesion) defined as Met positive by IHC (≥ 50% of
tumor cells with membrane and/or cytoplasmic staining at weak, moderate, or high
intensity; see Appendix 3)
• Measurable disease or non-measurable but evaluable disease, according to the
Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
Patients with peritoneal disease would generally be regarded as having
evaluable disease and be allowed to enter the trial.
• For women who are not postmenopausal (12 months of amenorrhea) or surgically
sterile (absence of ovaries and/or uterus): agreement to use an adequate method
of contraception (a method with a failure rate of < 1% per year, such as hormonal
implants, combined oral contraceptives, or a vasectomized partner) during the
treatment period and for at least 90 days after the last dose of onartuzumab/placebo
and 6 months after the last dose of oxaliplatin
• For men: agreement to use a barrier method of contraception during the treatment
period and for at least 90 days after the last dose of onartuzumab/placebo and
6 months after the last dose of oxaliplatin
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Cancer-Related Criteria
• HER2-positive tumor (primary tumor or metastasis)
HER2-positivity is defined as either IHC 3+ or IHC 2+/ISH+; ISH positivity is
defined as a HER2:CEP17 ratio of ≥ 2.0.
• Previous chemotherapy for locally advanced or metastatic gastric carcinoma
Patients may have received either neoadjuvant or adjuvant chemotherapy as
long as it was completed at least 6 months prior to randomization.
• Prior exposure to experimental treatment targeting either the HGF or Met pathway
• History of another malignancy within the previous 5 years, except for appropriately
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I
uterine cancer, localized prostate cancer that has been treated surgically with curative
intent and presumed cured, or other malignancies with an expected curative outcome
Hematologic, Biochemical, and Organ Function
• Granulocyte count < 1500/mm3
, platelet count < 100,000/mm3
,
and hemoglobin < 9.0 g/dL within 7 days prior to enrollment
• Partial thromboplastin time (PTT), international normalized ratio (INR),
or prothrombin time (PT) > 1.5 x the upper limit of normal (ULN), except for patients
receiving anticoagulation therapy
• AST (SGOT), ALT (SGPT), alkaline phosphatase (ALP) ≥ 2.5 × ULN (≥ 5 × ULN
with liver metastases)
• Total bilirubin ≥ 1.5 × ULN (except in patients diagnosed with Gilbert’s disease)
• Serum calcium > ULN (corrected for low serum albumin concentrations)
Corrected calcium (mg/dL) = serum Ca2+ + [(4.0–measured serum albumin) x
0.8]
Corrected calcium (mmol/L) = serum Ca2+ + 0.02 × (40–serum albumin)
• Serum creatinine > 1.5 × ULN or calculated creatinine clearance < 60 mL/min
(Cockcroft and Gault 1976)
• Uncontrolled diabetes as evidenced by fasting serum glucose level > 200 mg/dL
General
• Pregnancy or lactation
• Receipt of an investigational drug within 28 days prior to initiation of study drug
• Clinically significant gastrointestinal abnormalities, apart from gastric cancer,
including uncontrolled inflammatory gastrointestinal diseases (Crohn’s disease,
ulcerative colitis, etc.)
• Significant history of cardiac disease (i.e., unstable angina, congestive heart failure,
as defined by the New York Heart Association [NYHA] as Class II, III, or IV) within
6 months prior to Day 1 of Cycle 1, myocardial infarction within the previous year, or
current cardiac ventricular arrhythmias requiring medication
• Significant vascular disease (such as aortic aneurysm requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to Day 1 of Cycle 1
• Serious (Grade ≥ 3) active infection at the time of randomization, or other serious
underlying medical conditions that would impair the ability of the patient to receive
protocol treatment
• Known active infection with human immunodeficiency virus (HIV), hepatitis B virus
(HBV), or hepatitis C virus (HCV), or known HIV-seropositivity.
• Radiotherapy within 4 weeks before start of study treatment (2-week interval
allowed following palliative radiotherapy given to peripheral bone metastatic site and
patient has recovered from all acute toxicities)
• Major surgery within 4 weeks before start of study treatment, without complete
recovery
• Any condition (e.g., psychological, geographical, etc.) that does not permit
compliance with study and follow-up procedures
• Peripheral neuropathy (NCI CTCAE v4.0, Grade > 1)
Absence of deep tendon reflexes as the sole neurologic abnormality does not
render the patient ineligible.
• Prior unanticipated severe reaction to fluoropyrimidine therapy (with or without
documented dihydropyrimidine dehydrogenase [DPD] deficiency) or patients with
known DPD deficiency
• Known sensitivity or contraindication to any component of study treatment
• Active (significant or uncontrolled) gastrointestinal bleeding
Cancer-Related Criteria
• HER2-positive tumor (primary tumor or metastasis)
HER2-positivity is defined as either IHC 3+ or IHC 2+/ISH+; ISH positivity is
defined as a HER2:CEP17 ratio of ≥ 2.0.
• Previous chemotherapy for locally advanced or metastatic gastric carcinoma
Patients may have received either neoadjuvant or adjuvant chemotherapy as
long as it was completed at least 6 months prior to randomization.
• Prior exposure to experimental treatment targeting either the HGF or Met pathway
• History of another malignancy within the previous 5 years, except for appropriately
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I
uterine cancer, localized prostate cancer that has been treated surgically with curative
intent and presumed cured, or other malignancies with an expected curative outcome
Hematologic, Biochemical, and Organ Function
• Granulocyte count < 1500/mm3
, platelet count < 100,000/mm3
,
and hemoglobin < 9.0 g/dL within 7 days prior to enrollment
• Partial thromboplastin time (PTT), international normalized ratio (INR),
or prothrombin time (PT) > 1.5 x the upper limit of normal (ULN), except for patients
receiving anticoagulation therapy
• AST (SGOT), ALT (SGPT), alkaline phosphatase (ALP) ≥ 2.5 × ULN (≥ 5 × ULN
with liver metastases)
• Total bilirubin ≥ 1.5 × ULN (except in patients diagnosed with Gilbert’s disease)
• Serum calcium > ULN (corrected for low serum albumin concentrations)
Corrected calcium (mg/dL) = serum Ca2+ + [(4.0–measured serum albumin) x
0.8]
Corrected calcium (mmol/L) = serum Ca2+ + 0.02 × (40–serum albumin)
• Serum creatinine > 1.5 × ULN or calculated creatinine clearance < 60 mL/min
(Cockcroft and Gault 1976)
• Uncontrolled diabetes as evidenced by fasting serum glucose level > 200 mg/dL
General
• Pregnancy or lactation
• Receipt of an investigational drug within 28 days prior to initiation of study drug
• Clinically significant gastrointestinal abnormalities, apart from gastric cancer,
including uncontrolled inflammatory gastrointestinal diseases (Crohn’s disease,
ulcerative colitis, etc.)
• Significant history of cardiac disease (i.e., unstable angina, congestive heart failure,
as defined by the New York Heart Association [NYHA] as Class II, III, or IV) within
6 months prior to Day 1 of Cycle 1, myocardial infarction within the previous year, or
current cardiac ventricular arrhythmias requiring medication
• Significant vascular disease (such as aortic aneurysm requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to Day 1 of Cycle 1
• Serious (Grade ≥ 3) active infection at the time of randomization, or other serious
underlying medical conditions that would impair the ability of the patient to receive
protocol treatment
• Known active infection with human immunodeficiency virus (HIV), hepatitis B virus
(HBV), or hepatitis C virus (HCV), or known HIV-seropositivity.
• Radiotherapy within 4 weeks before start of study treatment (2-week interval
allowed following palliative radiotherapy given to peripheral bone metastatic site and
patient has recovered from all acute toxicities)
• Major surgery within 4 weeks before start of study treatment, without complete
recovery
• Any condition (e.g., psychological, geographical, etc.) that does not permit
compliance with study and follow-up procedures
• Peripheral neuropathy (NCI CTCAE v4.0, Grade > 1)
Absence of deep tendon reflexes as the sole neurologic abnormality does not
render the patient ineligible.
• Prior unanticipated severe reaction to fluoropyrimidine therapy (with or without
documented dihydropyrimidine dehydrogenase [DPD] deficiency) or patients with
known DPD deficiency
• Known sensitivity or contraindication to any component of study treatment
• Active (significant or uncontrolled) gastrointestinal bleeding
The Estimated Number of Participants
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Taiwan
18 participants
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Global
800 participants
