Carcinoma, Squamous Cell of Head and Neck
Conditions
Brief summary
This trial aimed to assess efficacy and safety of cetuximab when given in combination with chemotherapy compared with chemotherapy alone in Chinese participants with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) as the first-line treatment.
Interventions
DRUGCetuximab
Participants received Cetuximab as an intravenous infusion at an initial dose of 400 milligrams per square meter (mg/m\^2) on Day 1 and a subsequent dose of 250 mg/m\^2 on Day 8 and Day 15 of each 21-day treatment cycle.
Cisplatin or Carboplatin (at an equivalent dose in case of intolerability of cisplatin) was administered at a dose of 75 mg/m\^2 as an intravenous infusion on Day 1 of each 21-day treatment cycle.
DRUG5-fluorouracil
Participants received 5-fluorouracil (FU) at a dose of 750 mg/m\^2/day as a continuous intravenous infusion over 24 hours a day from Day 1 to Day 5 of each 21-day treatment cycle.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed diagnosis of SCCHN * Recurrent and/or metastatic SCCHN, not suitable for local-regional treatment * Presence of at least 1 measurable lesion according to RECIST Version 1.1 * Signed written informed consent before any trial-related activities are carried out * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Other protocol-defined inclusion criteria could apply
Exclusion criteria
* Prior systemic chemotherapy, except if given as part of multimodal treatment for locally advanced disease, that was completed within 6 months before randomization * Surgery (excluding prior biopsy for diagnosis) or irradiation within 4 weeks before trial entry * Previous treatment with monoclonal antibody or signal transduction inhibitors targeting epidermal growth factor receptor * Nasopharyngeal carcinoma * Known central nervous system metastasis and/or leptomeningeal disease * Medical or psychological condition that would not permit the participant to complete the trial or sign informed consent * Legal incapacity or limited legal capacity * Other protocol-defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Time, as Assessed by an Independent Review Committee (IRC) | Every 6 weeks starting from the date of randomization until occurrence of PD, assessed up to data-cutoff (904 days) | PFS time was defined as the time in months from the date of randomization until first observation of PD (based on imaging as assessed by IRC), or death due to any cause when death occurs within 60 days after the last tumor assessment or randomization (whichever is later). PD is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on trial; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 millimeter. PFS was measured using Kaplan-Meier (KM) estimates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) Time | Time from date of randomization up to data cutoff (assessed up to 904 days) | The OS time was defined as the time from randomization to the date of death. If a participant was alive at the time of analysis, survival time was censored at the last date when the participant was known to be alive. If this date was after data cut-off, participants were censored at the date of data cut-off. OS was measured using Kaplan-Meier (KM) estimates. |
| Best Overall Response Rate (ORR) | Every 6 weeks starting from the date of randomization until occurrence of PD, assessed up to data-cutoff (904 days) | The Best ORR was based on imaging and classified according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria. The BOR rate was defined as the number of participants whose BOR was either complete response (CR) or partial response (PR), relative to the number of participants belonging to the trial set of interest. CR was defined as disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must had reduction in short axis to less than (\<) 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Progression-free Survival (PFS) Time, as Assessed by the Investigator | Every 6 weeks starting from the date of randomization until occurrence of PD, assessed up to data-cutoff (904 days) | PFS time was defined as the time in months from the date of randomization until first observation of PD (radiologically confirmed by Investigator), or death due to any cause when death occurs within 60 days after the last tumor assessment or randomization (whichever is later). PD is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on trial; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 millimeter. PFS was measured using Kaplan-Meier (KM) estimates. |
| Duration of Response (DOR) | Every 6 weeks starting from the date of randomization until occurrence of PD, assessed up to data-cutoff (904 days) | DOR was determined for participants whose BOR was either CR or PR. It was defined as the time from the first assessment of CR or PR until the event defining PFS time. PFS time was defined as the time in months from the date of randomization until first observation of PD (based on imaging as assessed by IRC), or death due to any cause when death occurs within 60 days after the last tumor assessment or randomization (whichever is later). CR was defined as disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must had reduction in short axis to less than (\<) 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Emergent Adverse Events Leading to Death and AEs Leading to Discontinuation | Time from date of randomization up to data cutoff (assessed up to 904 days) | An Adverse event (AE) was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug that were absent before treatment or that worsened relative to pre-treatment state up to 30 days after last administration. TEAEs included both Serious TEAEs and non-serious TEAEs. |
| Disease Control Rate (DCR) | Every 6 weeks starting from the date of randomization until occurrence of PD, assessed up to data-cutoff (904 days) | The DCR was based on imaging and classified according to RECIST Version 1.1 criteria. The DCR was defined as the number of participants whose Best Overall Response is either CR, PR or stable disease (SD), divided by the number of participants belonging to the trial set of interest multiplied by 100. CR was defined as disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must had reduction in short axis to less than (\<) 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on trial. |
Countries
Germany
Participant flow
Recruitment details
First participant signed informed consent: 31 Jul 2015, Clinical data cut-off: 19 Jan 2018.
Participants by arm
| Arm | Count |
|---|---|
| Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil Participants received Cetuximab as an intravenous infusion at an initial dose of 400 milligrams per square meter (mg/m\^2) on Day 1 and a subsequent dose of 250 mg/m\^2 on Day 8 and Day 15 of each 21-day treatment cycle. Cisplatin or Carboplatin (at an equivalent dose in case of intolerability of cisplatin) was administered at a dose of 75 mg/m\^2 as an intravenous infusion on Day 1 of each 21-day treatment cycle. After the administration of cisplatin or carboplatin, participants received 5-fluorouracil (5-FU) at a dose of 750 mg/m\^2/day as a continuous intravenous infusion over 24 hours a day from Day 1 to Day 5 of each 21-day treatment cycle. All treatments were administered up to a maximum of 6 treatment cycles, post this participants without progressive disease (PD) continued to receive monotherapy with cetuximab until occurrence of disease progression or unacceptable toxicity. | 164 |
| Cisplatin/Carboplatin + 5-Flurouracil Participants received cisplatin or carboplatin (at an equivalent dose in case of intolerability of cisplatin) was administered at a dose of 75 mg/m\^2 as an intravenous infusion on Day 1 of each 21-day treatment cycle. After the administration of cisplatin or carboplatin, participants received 5-fluorouracil (FU) at a dose of 750 mg/m\^2/day as a continuous intravenous infusion over 24 hours a day from Day 1 to Day 5 of each 21-day treatment cycle. All treatments were administered up to a maximum of 6 treatment cycles. | 79 |
| Total | 243 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Ongoing at clinical cut-off date | 25 | 4 |
| Overall Study | Randomized, but not treated | 1 | 3 |
Baseline characteristics
| Characteristic | Cisplatin/Carboplatin + 5-Flurouracil | Total | Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil |
|---|---|---|---|
| Age, Continuous | 57.0 years STANDARD_DEVIATION 8.99 | 57.1 years STANDARD_DEVIATION 9.34 | 57.1 years STANDARD_DEVIATION 9.52 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 79 Participants | 243 Participants | 164 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 79 Participants | 243 Participants | 164 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 12 Participants | 30 Participants | 18 Participants |
| Sex: Female, Male Male | 67 Participants | 213 Participants | 146 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 105 / 163 | 54 / 76 |
| other Total, other adverse events | 163 / 163 | 73 / 76 |
| serious Total, serious adverse events | 46 / 163 | 21 / 76 |
Outcome results
Primary
Progression-free Survival (PFS) Time, as Assessed by an Independent Review Committee (IRC)
PFS time was defined as the time in months from the date of randomization until first observation of PD (based on imaging as assessed by IRC), or death due to any cause when death occurs within 60 days after the last tumor assessment or randomization (whichever is later). PD is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on trial; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 millimeter. PFS was measured using Kaplan-Meier (KM) estimates.
Time frame: Every 6 weeks starting from the date of randomization until occurrence of PD, assessed up to data-cutoff (904 days)
Population: ITT analysis set included all participants who were randomized to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil | Progression-free Survival (PFS) Time, as Assessed by an Independent Review Committee (IRC) | 5.5 months |
| Cisplatin/Carboplatin + 5-Flurouracil | Progression-free Survival (PFS) Time, as Assessed by an Independent Review Committee (IRC) | 4.2 months |
95% CI: [0.4, 0.803]
Secondary
Best Overall Response Rate (ORR)
The Best ORR was based on imaging and classified according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria. The BOR rate was defined as the number of participants whose BOR was either complete response (CR) or partial response (PR), relative to the number of participants belonging to the trial set of interest. CR was defined as disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must had reduction in short axis to less than (\<) 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Every 6 weeks starting from the date of randomization until occurrence of PD, assessed up to data-cutoff (904 days)
Population: ITT analysis set included all participants who were randomized to study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil | Best Overall Response Rate (ORR) | 50 percentage of participants |
| Cisplatin/Carboplatin + 5-Flurouracil | Best Overall Response Rate (ORR) | 26.6 percentage of participants |
95% CI: [1.52, 5.45]
Secondary
Disease Control Rate (DCR)
The DCR was based on imaging and classified according to RECIST Version 1.1 criteria. The DCR was defined as the number of participants whose Best Overall Response is either CR, PR or stable disease (SD), divided by the number of participants belonging to the trial set of interest multiplied by 100. CR was defined as disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must had reduction in short axis to less than (\<) 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on trial.
Time frame: Every 6 weeks starting from the date of randomization until occurrence of PD, assessed up to data-cutoff (904 days)
Population: ITT analysis set included all participants who were randomized to study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil | Disease Control Rate (DCR) | 75.6 percentage of participants |
| Cisplatin/Carboplatin + 5-Flurouracil | Disease Control Rate (DCR) | 59.5 percentage of participants |
95% CI: [1.15, 3.95]
Secondary
Duration of Response (DOR)
DOR was determined for participants whose BOR was either CR or PR. It was defined as the time from the first assessment of CR or PR until the event defining PFS time. PFS time was defined as the time in months from the date of randomization until first observation of PD (based on imaging as assessed by IRC), or death due to any cause when death occurs within 60 days after the last tumor assessment or randomization (whichever is later). CR was defined as disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must had reduction in short axis to less than (\<) 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Every 6 weeks starting from the date of randomization until occurrence of PD, assessed up to data-cutoff (904 days)
Population: ITT analysis set included all participants who were randomized to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil | Duration of Response (DOR) | 18.1 Weeks |
| Cisplatin/Carboplatin + 5-Flurouracil | Duration of Response (DOR) | 13.9 Weeks |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Emergent Adverse Events Leading to Death and AEs Leading to Discontinuation
An Adverse event (AE) was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug that were absent before treatment or that worsened relative to pre-treatment state up to 30 days after last administration. TEAEs included both Serious TEAEs and non-serious TEAEs.
Time frame: Time from date of randomization up to data cutoff (assessed up to 904 days)
Population: Safety analysis set included all participants who had received at least 1 dose of any trial treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Emergent Adverse Events Leading to Death and AEs Leading to Discontinuation | TEAEs | 163 Participants |
| Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Emergent Adverse Events Leading to Death and AEs Leading to Discontinuation | TESAEs | 46 Participants |
| Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Emergent Adverse Events Leading to Death and AEs Leading to Discontinuation | TEAEs Leading to Death | 11 Participants |
| Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Emergent Adverse Events Leading to Death and AEs Leading to Discontinuation | AEs Leading to Discontinuation | 27 Participants |
| Cisplatin/Carboplatin + 5-Flurouracil | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Emergent Adverse Events Leading to Death and AEs Leading to Discontinuation | AEs Leading to Discontinuation | 8 Participants |
| Cisplatin/Carboplatin + 5-Flurouracil | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Emergent Adverse Events Leading to Death and AEs Leading to Discontinuation | TEAEs | 75 Participants |
| Cisplatin/Carboplatin + 5-Flurouracil | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Emergent Adverse Events Leading to Death and AEs Leading to Discontinuation | TEAEs Leading to Death | 8 Participants |
| Cisplatin/Carboplatin + 5-Flurouracil | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Emergent Adverse Events Leading to Death and AEs Leading to Discontinuation | TESAEs | 21 Participants |
Secondary
Overall Survival (OS) Time
The OS time was defined as the time from randomization to the date of death. If a participant was alive at the time of analysis, survival time was censored at the last date when the participant was known to be alive. If this date was after data cut-off, participants were censored at the date of data cut-off. OS was measured using Kaplan-Meier (KM) estimates.
Time frame: Time from date of randomization up to data cutoff (assessed up to 904 days)
Population: ITT analysis set included all participants who were randomized to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil | Overall Survival (OS) Time | 10.2 months |
| Cisplatin/Carboplatin + 5-Flurouracil | Overall Survival (OS) Time | 8.4 months |
95% CI: [0.502, 0.991]
Secondary
Progression-free Survival (PFS) Time, as Assessed by the Investigator
PFS time was defined as the time in months from the date of randomization until first observation of PD (radiologically confirmed by Investigator), or death due to any cause when death occurs within 60 days after the last tumor assessment or randomization (whichever is later). PD is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on trial; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 millimeter. PFS was measured using Kaplan-Meier (KM) estimates.
Time frame: Every 6 weeks starting from the date of randomization until occurrence of PD, assessed up to data-cutoff (904 days)
Population: ITT analysis set included all participants who were randomized to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil | Progression-free Survival (PFS) Time, as Assessed by the Investigator | 5.5 months |
| Cisplatin/Carboplatin + 5-Flurouracil | Progression-free Survival (PFS) Time, as Assessed by the Investigator | 4.6 months |
95% CI: [0.406, 0.795]