CHANGE2: Phase III Trial to Assess Efficacy and Safety of Cetuximab for the Treatment of Chinese Participants With Head and Neck Cancer

• Sponsor: Merck KGaA, Darmstadt, Germany (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02383966
• Collaborator: (none)
• Enrollment: 243
• Location: 1
• Arms: 2
• Actual Duration (Months): 76.7
• Patients Per Site Per Month: 3.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Squamous Cell of Head and Neck	Drug: Cetuximab; Drug: Cisplatin/Carboplatin; Drug: 5-fluorouracil	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 243 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Open-label, Phase III Trial to Assess Efficacy and Safety of Cetuximab When Given in Combination With Cisplatin Plus 5 Fluorouracil Versus Cisplatin Plus 5-fluorouracil Alone for the First-line Treatment of Chinese Subjects With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck
• Actual Study Start Date: Jul 31, 2015
• Actual Primary Completion Date: Jan 19, 2018
• Actual Study Completion Date: Dec 20, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil	Drug: Cetuximab; 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.; Other Names: Erbitux ; Drug: Cisplatin/Carboplatin; 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.; Drug: 5-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.; Other Names: 5-FU
Active Comparator: Cisplatin/Carboplatin + 5-Flurouracil	Drug: Cisplatin/Carboplatin; 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.; Drug: 5-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.; Other Names: 5-FU

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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 exclusion criteria could apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research site	Darmstadt		Germany

Sponsors and Collaborators

• Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Medical Responsible, Merck KGaA, Darmstadt, Germany

Study Documents (Full-Text)

• Study Protocol - Feb 26, 2018
• Statistical Analysis Plan - Apr 16, 2018

More Information

Additional Information:

• Trial Awareness and Transparency website

Publications

None provided.

• Responsible Party: Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT02383966
• Other Study ID Numbers: EMR062202-060
• First Posted: Mar 10, 2015
• Last Update Posted: May 13, 2022
• Last Verified: Apr 1, 2022

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Carboplatin; Fluorouracil; Cetuximab

Study Results

Participant Flow

Recruitment Details	First participant signed informed consent: 31 Jul 2015, Clinical data cut-off: 19 Jan 2018.

Arm/Group Title	Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil	Cisplatin/Carboplatin + 5-Flurouracil
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	164	79
COMPLETED	138	72
NOT COMPLETED	26	7

Baseline Characteristics

Arm/Group Title	Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil	Cisplatin/Carboplatin + 5-Flurouracil	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	164	79	243
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.1 (9.52)	57.0 (8.99)	57.1 (9.34)
Sex: Female, Male (Count of Participants)
Female	18 11%	12 15.2%	30 12.3%
Male	146 89%	67 84.8%	213 87.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	0 0%	0 0%	0 0%
Unknown or Not Reported	164 100%	79 100%	243 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	164 100%	79 100%	243 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS) Time, as Assessed by an Independent Review Committee (IRC)
Description	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)

Outcome Measure Data

Analysis Population Description

ITT analysis set included all participants who were randomized to study treatment.

Arm/Group Title	Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil	Cisplatin/Carboplatin + 5-Flurouracil
Arm/Group Description	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.	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.
Measure Participants	164	79
Median (95% Confidence Interval) [months]	5.5	4.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil, Cisplatin/Carboplatin + 5-Flurouracil
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.566
	Confidence Interval	(2-Sided) 95%; 0.400 to 0.803
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression-free Survival (PFS) Time, as Assessed by the Investigator
Description	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)

Outcome Measure Data

Analysis Population Description

ITT analysis set included all participants who were randomized to study treatment.

Arm/Group Title	Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil	Cisplatin/Carboplatin + 5-Flurouracil
Arm/Group Description	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.	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.
Measure Participants	164	79
Median (95% Confidence Interval) [months]	5.5	4.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil, Cisplatin/Carboplatin + 5-Flurouracil
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.568
	Confidence Interval	(2-Sided) 95%; 0.406 to 0.795
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Overall Survival (OS) Time
Description	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)

Outcome Measure Data

Analysis Population Description

ITT analysis set included all participants who were randomized to study treatment.

Arm/Group Title	Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil	Cisplatin/Carboplatin + 5-Flurouracil
Arm/Group Description	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.	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.
Measure Participants	164	79
Median (95% Confidence Interval) [months]	10.2	8.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil, Cisplatin/Carboplatin + 5-Flurouracil
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.705
	Confidence Interval	(2-Sided) 95%; 0.502 to 0.991
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Best Overall Response Rate (ORR)
Description	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)

Outcome Measure Data

Analysis Population Description

ITT analysis set included all participants who were randomized to study treatment.

Arm/Group Title	Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil	Cisplatin/Carboplatin + 5-Flurouracil
Arm/Group Description	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.	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.
Measure Participants	164	79
Number (95% Confidence Interval) [percentage of participants]	50 30.5%	26.6 33.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil, Cisplatin/Carboplatin + 5-Flurouracil
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.76
	Confidence Interval	(2-Sided) 95%; 1.52 to 5.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	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)

Outcome Measure Data

Analysis Population Description

ITT analysis set included all participants who were randomized to study treatment.

Arm/Group Title	Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil	Cisplatin/Carboplatin + 5-Flurouracil
Arm/Group Description	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.	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.
Measure Participants	164	79
Number (95% Confidence Interval) [percentage of participants]	75.6 46.1%	59.5 75.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil, Cisplatin/Carboplatin + 5-Flurouracil
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.14
	Confidence Interval	(2-Sided) 95%; 1.15 to 3.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Duration of Response (DOR)
Description	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)

Outcome Measure Data

Analysis Population Description

ITT analysis set included all participants who were randomized to study treatment.

Arm/Group Title	Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil	Cisplatin/Carboplatin + 5-Flurouracil
Arm/Group Description	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.	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.
Measure Participants	164	79
Median (95% Confidence Interval) [Weeks]	18.1	13.9

7. Secondary Outcome

Title	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
Description	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)

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who had received at least 1 dose of any trial treatment.

Arm/Group Title	Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil	Cisplatin/Carboplatin + 5-Flurouracil
Arm/Group Description	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.	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.
Measure Participants	163	76
TEAEs	163 99.4%	75 94.9%
TESAEs	46 28%	21 26.6%
TEAEs Leading to Death	11 6.7%	8 10.1%
AEs Leading to Discontinuation	27 16.5%	8 10.1%

Adverse Events

Time Frame	Time from date of randomization up to data cutoff (assessed up to 904 days)
Adverse Event Reporting Description	Treatment emergent serious and non-serious adverse events are reported below.
Arm/Group Title	Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil		Cisplatin/Carboplatin + 5-Flurouracil
Arm/Group Description	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.		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.
All Cause Mortality
	Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil		Cisplatin/Carboplatin + 5-Flurouracil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	105/163 (64.4%)		54/76 (71.1%)
Serious Adverse Events
	Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil		Cisplatin/Carboplatin + 5-Flurouracil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	46/163 (28.2%)		21/76 (27.6%)
Blood and lymphatic system disorders
Anaemia	1/163 (0.6%)		2/76 (2.6%)
Febrile neutropenia	0/163 (0%)		1/76 (1.3%)
Thrombocytopenia	2/163 (1.2%)		2/76 (2.6%)
Cardiac disorders
Atrial fibrillation	0/163 (0%)		1/76 (1.3%)
Cardiac arrest	1/163 (0.6%)		0/76 (0%)
Cardiac failure	1/163 (0.6%)		0/76 (0%)
Cardiopulmonary failure	1/163 (0.6%)		0/76 (0%)
Gastrointestinal disorders
Diarrhoea	2/163 (1.2%)		1/76 (1.3%)
Dysphagia	1/163 (0.6%)		0/76 (0%)
Glossodynia	1/163 (0.6%)		0/76 (0%)
Haematemesis	0/163 (0%)		1/76 (1.3%)
Mouth ulceration	1/163 (0.6%)		0/76 (0%)
Oesophageal polyp	1/163 (0.6%)		0/76 (0%)
Stomatitis	0/163 (0%)		1/76 (1.3%)
Upper gastrointestinal haemorrhage	1/163 (0.6%)		0/76 (0%)
Vomiting	1/163 (0.6%)		0/76 (0%)
General disorders
Death	2/163 (1.2%)		0/76 (0%)
Pain	1/163 (0.6%)		0/76 (0%)
Infections and infestations
Infected fistula	0/163 (0%)		1/76 (1.3%)
Lung infection	6/163 (3.7%)		4/76 (5.3%)
Oral infection	0/163 (0%)		1/76 (1.3%)
Otitis media acute	1/163 (0.6%)		0/76 (0%)
Pneumonia	2/163 (1.2%)		0/76 (0%)
Septic shock	0/163 (0%)		1/76 (1.3%)
Soft tissue infection	1/163 (0.6%)		0/76 (0%)
Tracheostomy infection	1/163 (0.6%)		0/76 (0%)
Upper respiratory tract infection	0/163 (0%)		2/76 (2.6%)
Wound infection	1/163 (0.6%)		0/76 (0%)
Injury, poisoning and procedural complications
Ankle fracture	0/163 (0%)		1/76 (1.3%)
Lower limb fracture	1/163 (0.6%)		0/76 (0%)
Vascular access complication	1/163 (0.6%)		0/76 (0%)
Investigations
Acid base balance abnormal	1/163 (0.6%)		0/76 (0%)
Alanine aminotransferase increased	1/163 (0.6%)		0/76 (0%)
Aspartate aminotransferase increased	1/163 (0.6%)		0/76 (0%)
Blood creatinine increased	1/163 (0.6%)		0/76 (0%)
Gamma-glutamyltransferase increased	1/163 (0.6%)		0/76 (0%)
Neutrophil count decreased	0/163 (0%)		1/76 (1.3%)
Platelet count decreased	1/163 (0.6%)		1/76 (1.3%)
White blood cell count decreased	0/163 (0%)		2/76 (2.6%)
Metabolism and nutrition disorders
Cachexia	0/163 (0%)		1/76 (1.3%)
Electrolyte imbalance	1/163 (0.6%)		0/76 (0%)
Hypokalaemia	1/163 (0.6%)		0/76 (0%)
Hypomagnesaemia	2/163 (1.2%)		0/76 (0%)
Musculoskeletal and connective tissue disorders
Fistula	0/163 (0%)		1/76 (1.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Oncologic complication	0/163 (0%)		1/76 (1.3%)
Tumor haemorrhage	1/163 (0.6%)		3/76 (3.9%)
Tumor pain	1/163 (0.6%)		0/76 (0%)
Nervous system disorders
Cerebral infarction	2/163 (1.2%)		0/76 (0%)
Cerebrovascular insufficiency	1/163 (0.6%)		0/76 (0%)
Renal and urinary disorders
Renal failure	0/163 (0%)		1/76 (1.3%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/163 (0.6%)		0/76 (0%)
Asthma	1/163 (0.6%)		0/76 (0%)
Dyspnoea	5/163 (3.1%)		0/76 (0%)
Haemoptysis	1/163 (0.6%)		0/76 (0%)
Laryngeal obstruction	1/163 (0.6%)		0/76 (0%)
Laryngeal oedema	0/163 (0%)		1/76 (1.3%)
Laryngeal pain	1/163 (0.6%)		0/76 (0%)
Obstructive airways disorder	0/163 (0%)		2/76 (2.6%)
Pleural effusion	1/163 (0.6%)		0/76 (0%)
Pneumonitis	1/163 (0.6%)		0/76 (0%)
Pulmonary embolism	1/163 (0.6%)		0/76 (0%)
Respiratory failure	2/163 (1.2%)		0/76 (0%)
Vascular disorders
Deep vein thrombosis	0/163 (0%)		1/76 (1.3%)
Peripheral artery occlusion	1/163 (0.6%)		0/76 (0%)
Venous haemorrhage	1/163 (0.6%)		0/76 (0%)
Venous thrombosis limb	1/163 (0.6%)		0/76 (0%)
Other (Not Including Serious) Adverse Events
	Cetuximab + Cisplatin/Carboplatin + 5-Fluorouracil		Cisplatin/Carboplatin + 5-Flurouracil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	163/163 (100%)		73/76 (96.1%)
Blood and lymphatic system disorders
Anaemia	73/163 (44.8%)		36/76 (47.4%)
Leukopenia	55/163 (33.7%)		24/76 (31.6%)
Neutropenia	58/163 (35.6%)		22/76 (28.9%)
Thrombocytopenia	23/163 (14.1%)		7/76 (9.2%)
Cardiac disorders
Palpitations	7/163 (4.3%)		4/76 (5.3%)
Gastrointestinal disorders
Abdominal distension	15/163 (9.2%)		3/76 (3.9%)
Abdominal pain	11/163 (6.7%)		1/76 (1.3%)
Constipation	73/163 (44.8%)		31/76 (40.8%)
Diarrhoea	44/163 (27%)		10/76 (13.2%)
Gastrooesophageal reflux disease	12/163 (7.4%)		1/76 (1.3%)
Mouth ulceration	30/163 (18.4%)		8/76 (10.5%)
Nausea	93/163 (57.1%)		51/76 (67.1%)
Oral pain	9/163 (5.5%)		3/76 (3.9%)
Stomatitis	44/163 (27%)		13/76 (17.1%)
Vomiting	60/163 (36.8%)		37/76 (48.7%)
General disorders
Asthenia	40/163 (24.5%)		17/76 (22.4%)
Chest discomfort	10/163 (6.1%)		4/76 (5.3%)
Facial pain	2/163 (1.2%)		6/76 (7.9%)
Fatigue	9/163 (5.5%)		1/76 (1.3%)
Pyrexia	42/163 (25.8%)		12/76 (15.8%)
Malaise	12/163 (7.4%)		8/76 (10.5%)
Infections and infestations
Lung infection	16/163 (9.8%)		2/76 (2.6%)
Paronychia	13/163 (8%)		0/76 (0%)
Upper respiratory tract infection	13/163 (8%)		4/76 (5.3%)
Investigations
Alanine aminotransferase increased	12/163 (7.4%)		4/76 (5.3%)
Aspartate aminotransferase increased	9/163 (5.5%)		2/76 (2.6%)
Blood creatinine increased	4/163 (2.5%)		4/76 (5.3%)
Haemoglobin decreased	14/163 (8.6%)		5/76 (6.6%)
Lymphocyte count decreased	6/163 (3.7%)		5/76 (6.6%)
Neutrophil count decreased	47/163 (28.8%)		20/76 (26.3%)
Platelet count decreased	20/163 (12.3%)		11/76 (14.5%)
Red blood cell count decreased	11/163 (6.7%)		6/76 (7.9%)
Weight decreased	103/163 (63.2%)		31/76 (40.8%)
Weight increased	9/163 (5.5%)		3/76 (3.9%)
White blood cell count decreased	62/163 (38%)		25/76 (32.9%)
White blood cell count increased	4/163 (2.5%)		5/76 (6.6%)
Metabolism and nutrition disorders
Decreased appetite	67/163 (41.1%)		34/76 (44.7%)
Hyperuricaemia	1/163 (0.6%)		4/76 (5.3%)
Hypoalbuminaemia	22/163 (13.5%)		13/76 (17.1%)
Hypocalcaemia	32/163 (19.6%)		9/76 (11.8%)
Hypochloraemia	26/163 (16%)		12/76 (15.8%)
Hypokalaemia	56/163 (34.4%)		18/76 (23.7%)
Hypomagnesaemia	40/163 (24.5%)		7/76 (9.2%)
Hyponatraemia	44/163 (27%)		21/76 (27.6%)
Hypoproteinaemia	12/163 (7.4%)		6/76 (7.9%)
Musculoskeletal and connective tissue disorders
Neck pain	12/163 (7.4%)		3/76 (3.9%)
Nervous system disorders
Dizziness	23/163 (14.1%)		12/76 (15.8%)
Headache	10/163 (6.1%)		5/76 (6.6%)
Poor quality sleep	10/163 (6.1%)		5/76 (6.6%)
Psychiatric disorders
Depressed mood	4/163 (2.5%)		7/76 (9.2%)
Insomnia	16/163 (9.8%)		4/76 (5.3%)
Respiratory, thoracic and mediastinal disorders
Cough	30/163 (18.4%)		12/76 (15.8%)
Oropharyngeal pain	15/163 (9.2%)		2/76 (2.6%)
Productive cough	21/163 (12.9%)		6/76 (7.9%)
Skin and subcutaneous tissue disorders
Alopecia	9/163 (5.5%)		4/76 (5.3%)
Dermatitis acneiform	35/163 (21.5%)		0/76 (0%)
Dry skin	12/163 (7.4%)		0/76 (0%)
Palmar-plantar erythrodysaesthesia syndrome	12/163 (7.4%)		2/76 (2.6%)
Pruritus	15/163 (9.2%)		0/76 (0%)
Rash	77/163 (47.2%)		1/76 (1.3%)
Vascular disorders
Hypertension	4/163 (2.5%)		5/76 (6.6%)
Hypotension	10/163 (6.1%)		1/76 (1.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.