Head and Neck Cancer
Conditions
Keywords
Head and Neck Cancer
Brief summary
The purpose of this trial is to investigate the efficacy of cetuximab in combination with chemotherapy in comparison to chemotherapy alone in patients with recurrent or metastatic head and neck cancer. Overall survival will be taken as the primary measure of efficacy.
Interventions
DRUGCetuximab + Platinum (Cisplatin or Carboplatin) + 5Fluorouracil (5-FU)
Subjects in will receive initial dose of 400 mg/m\^2 cetuximab (over 2 hours) followed by weekly doses of 250 mg/m\^2 (over 1 hour). All doses will be given by intravenous (IV) infusion. Subjects will receive either Cisplatin (100 mg/m\^2 on day 1) + 5-FU (1000 mg/m\^2 continuous IV from day 1 to day 4) every 3 weeks or Carboplatin (Area under the curve (AUC) 5 IV on day 1) + 5-FU (1000 mg/m\^2 continuous IV from day 1 to day 4) every 3 weeks
DRUGPlatinum (Cisplatin or Carboplatin) + 5-FU
All doses will be given by IV infusion. Subjects will receive either Cisplatin (100 mg/m\^2 on day 1) + 5-FU (1000 mg/m\^2 continuous IV from day 1 to day 4) every 3 weeks or Carboplatin (AUC 5 IV on day 1) + 5-FU (1000 mg/m\^2 continuous IV from day 1 to day 4) every 3 weeks
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 squamous cell carcinoma of the head and neck (SCCHN) * Recurrent and/or metastatic SCCHN, not suitable for local therapy
Exclusion criteria
* Prior systemic chemotherapy, except if given as part of a multimodal treatment for locally advanced disease which was completed more than 6 months prior to study entry * Surgery (excluding prior diagnostic biopsy), or irradiation within 4 weeks before study entry * Nasopharyngeal carcinoma
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival Time (OS) | time from randomization to death or last day known to be alive, reported between day of first patient randomised, 21 Dec 2004, until cut-off date 12 Mar 2007 | Time from randomization to death. Patients without event are censored at the last date known to be alive or at the clinical cut-off date, whatever is earlier. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response | evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 21 Dec 2004, until cut-off date 12 Mar 2007 | The best overall response rate is defined as the percentage of subjects having achieved confirmed Complete Response + Partial Response as the best overall response according to radiological assessments according to investigator (based on modified WHO criteria). |
| Disease Control | evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 21 Dec 2004, until cut-off date 12 Mar 2007 | The disease control rate is defined as the percentage of subjects having achieved confirmed Complete Response + Partial Response + Stable Disease as best overall response according to radiological assessments according to investigator (based on modified WHO criteria). |
| Time to Treatment Failure | Time from randomization to treatment failure or last tumor assessment, reported between day of first patient randomised, 21 Dec 2004, until cut-off date 12 Mar 2007 | Time from randomization to date of the first occurrence of; progression, discontinuation of treatment due to progression or adverse event, start of new anticancer therapy, withdrawal of consent, or death (within 60 days of last tumor assessment). Patients without event are censored on the date of last tumor assessment. |
| Progression-free Survival Time (PFS) | time from randomization to disease progression, death or last tumor assessment, reported between day of first patient randomised, 21 Dec 2004, until cut-off date 12 Mar 2007 | Duration from randomization until radiological progression according to investigator (based on modified World Health Organisation (WHO) criteria) or death due to any cause. Only deaths within 60 days of last tumor assessment are considered. Patients without event are censored on the date of last tumor assessment. |
| Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status | at baseline, day 1 of cycle 3, first 6-weekly evaluation following completion of chemotherapy, 6 & 12 months after randomization, reported between day of first patient randomised, 21 Dec 2004,until cut-off date, 12 Mar 2007 | Mean global health status scores (EORTC QLQ-C30) against time for each treatment group. Scores were derived from mutually exclusive sets of items, with scale scores ranging from 0 to 100 after a linear transformation. Higher scores indicate a better QoL. |
| Quality of Life Assessment (EORTC QLQ-C30) Social Functioning | at baseline, day 1 of cycle 3, first 6-weekly evaluation following completion of chemotherapy, 6 & 12 months after randomization, reported between day of first patient randomised, 21 Dec 2004,until cut-off date, 12 Mar 2007 | Mean social functioning scores (EORTC QLQ-C30) against time for each treatment group. Scores were derived from mutually exclusive sets of items, with scale scores ranging from 0 to 100 after a linear transformation. Higher scores indicate a higher level of social functioning. |
| Safety - Number of Patients Experiencing Any Adverse Event | time from first dose up to 30 after last dose of study treatment, reported between day of first dose of study treatment, 22 Dec 2004, until cut-off date 12 Mar 2007 | Please refer to Adverse Events section for further details |
| Duration of Response | time from first assessment of Complete Response or Partial Response to disease progression, death or last tumor assessment, reported between day of first patient randomised, 21 Dec 2004, until cut-off date 12 Mar 2007 | Time from first assessment of Complete Response or Partial Response to disease progression or death (within 60 days of last tumor assessment). Patients without event are censored on the date of last tumor assessment. Tumor assessments based on modified WHO criteria. |
Countries
Austria, Belgium, Czechia, France, Germany, Hungary, Italy, Netherlands, Poland, Portugal, Russia, Slovakia, Spain, Sweden, Switzerland, Ukraine, United Kingdom
Participant flow
Recruitment details
First/last subject(informed consent): 14Dec 2004/28 Dec2005. Clinical cut-off: 12 Mar 2007. 80 centers in Europe: Austria (3), Belgium (5), Czech Republic (2), France (12),Germany (8), Hungary (4), Italy (5), Netherlands (4), Poland (5), Portugal (3), Russia (4), Slovakia (2), Spain (9), Sweden (3), Switzerland (3), UK (4), and Ukraine (4).
Pre-assignment details
477 subjects screened. 41 ineligible for treatment at end of screening (inclusion/exclusion criteria not fulfilled (30),death (3),consent withdrawal(3), symptomatic deterioration(2),non-compliance with timelines(1),refusal to continue study procedures (1), missing (1).436 eligible for treatment; however 6 of the ineligible patients were randomized
Participants by arm
| Arm | Count |
|---|---|
| Cetuximab Plus Chemotherapy Subjects in will receive initial dose of 400 mg/m\^2 cetuximab (over 2 hours) followed by weekly doses of 250 mg/m\^2 (over 1 hour). All doses will be given by intravenous (IV) infusion. Subjects will receive either Cisplatin (100 mg/m\^2 on day 1) + 5-FU (1000 mg/m\^2 continuous IV from day 1 to day 4) every 3 weeks or Carboplatin (Area under the curve (AUC) 5 IV on day 1) + 5-FU (1000 mg/m\^2 continuous IV from day 1 to day 4) every 3 weeks. | 222 |
| Chemotherapy Alone All doses will be given by IV infusion. Subjects will receive either Cisplatin (100 mg/m\^2 on day 1) + 5-FU (1000 mg/m\^2 continuous IV from day 1 to day 4) every 3 weeks or Carboplatin (AUC 5 IV on day 1) + 5-FU (1000 mg/m\^2 continuous IV from day 1 to day 4) every 3 weeks. | 220 |
| Total | 442 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | investigational study phase ongoing | 7 | 1 |
Baseline characteristics
| Characteristic | Cetuximab Plus Chemotherapy | Chemotherapy Alone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 39 Participants | 38 Participants | 77 Participants |
| Age, Categorical Between 18 and 65 years | 183 Participants | 182 Participants | 365 Participants |
| Age, Continuous | 57.1 years STANDARD_DEVIATION 8 | 56.7 years STANDARD_DEVIATION 8.7 | 56.9 years STANDARD_DEVIATION 8.3 |
| Region of Enrollment Austria | 4 participants | 10 participants | 14 participants |
| Region of Enrollment Belgium | 14 participants | 16 participants | 30 participants |
| Region of Enrollment Czech Republic | 4 participants | 5 participants | 9 participants |
| Region of Enrollment France | 45 participants | 31 participants | 76 participants |
| Region of Enrollment Germany | 18 participants | 14 participants | 32 participants |
| Region of Enrollment Hungary | 19 participants | 24 participants | 43 participants |
| Region of Enrollment Italy | 14 participants | 12 participants | 26 participants |
| Region of Enrollment Netherlands | 4 participants | 6 participants | 10 participants |
| Region of Enrollment Poland | 18 participants | 18 participants | 36 participants |
| Region of Enrollment Portugal | 3 participants | 6 participants | 9 participants |
| Region of Enrollment Russian Federation | 9 participants | 7 participants | 16 participants |
| Region of Enrollment Slovakia | 3 participants | 1 participants | 4 participants |
| Region of Enrollment Spain | 38 participants | 41 participants | 79 participants |
| Region of Enrollment Sweden | 3 participants | 4 participants | 7 participants |
| Region of Enrollment Switzerland | 4 participants | 4 participants | 8 participants |
| Region of Enrollment Ukraine | 18 participants | 16 participants | 34 participants |
| Region of Enrollment United Kingdom | 4 participants | 5 participants | 9 participants |
| Sex: Female, Male Female | 25 Participants | 18 Participants | 43 Participants |
| Sex: Female, Male Male | 197 Participants | 202 Participants | 399 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 214 / 219 | 198 / 215 |
| serious Total, serious adverse events | 110 / 219 | 102 / 215 |
Outcome results
Primary
Overall Survival Time (OS)
Time from randomization to death. Patients without event are censored at the last date known to be alive or at the clinical cut-off date, whatever is earlier.
Time frame: time from randomization to death or last day known to be alive, reported between day of first patient randomised, 21 Dec 2004, until cut-off date 12 Mar 2007
Population: Primary analysis on Intent to Treat (ITT) population (allocation to treatment groups as randomized).~Analysis performed after the required number of 340 deaths had been reported (expected effect: 36% increase in median survival time, power = 80%, alpha=5% (two-sided)). The Clinical cut-off date was 12 Mar 2007.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab Plus Chemotherapy | Overall Survival Time (OS) | 10.1 months |
| Chemotherapy Alone | Overall Survival Time (OS) | 7.4 months |
Comparison: The primary analysis tested the equality of OS between treatment groups applying a 2-sided stratified log-rank test (α=5%), taking into account the strata used for randomization (previous chemotherapy (CTX) \[no vs. yes\] and Karnofsky Performance Status (KPS) \[\<80 vs. ≥80\]).~Median overall survival was estimated using the Kaplan-Meier method. The Hazard Ratio (HR) of cetuximab + CTX over CTX alone was calculated using the Cox proportional hazards model stratified by randomization strata.p-value: 0.03695% CI: [0.644, 0.986]Stratified Log Rank
Secondary
Best Overall Response
The best overall response rate is defined as the percentage of subjects having achieved confirmed Complete Response + Partial Response as the best overall response according to radiological assessments according to investigator (based on modified WHO criteria).
Time frame: evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 21 Dec 2004, until cut-off date 12 Mar 2007
Population: Analysis on ITT population (allocation to treatment groups as randomized). Analysis performed at clinical cut off date, determined by primary endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab Plus Chemotherapy | Best Overall Response | 35.6 percentage of participants |
| Chemotherapy Alone | Best Overall Response | 19.5 percentage of participants |
Comparison: A Cochran-Mantel-Haenszel (CMH) test was performed using the randomization strata previous CTX (no vs. yes) and KPS (\<80 vs. ≥80). Treatment group comparisons were performed two-sided with α=5%.p-value: 0.000195% CI: [1.504, 3.6]Cochran-Mantel-Haenszel
Secondary
Disease Control
The disease control rate is defined as the percentage of subjects having achieved confirmed Complete Response + Partial Response + Stable Disease as best overall response according to radiological assessments according to investigator (based on modified WHO criteria).
Time frame: evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 21 Dec 2004, until cut-off date 12 Mar 2007
Population: Analysis on ITT population (allocation to treatment groups as randomized). Analysis performed at clinical cut off date, determined by primary endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab Plus Chemotherapy | Disease Control | 81.1 percentage of participants |
| Chemotherapy Alone | Disease Control | 60.0 percentage of participants |
Comparison: A Cochran-Mantel-Haenszel (CMH) test was performed using the randomization strata previous CTX (no vs. yes) and KPS (\<80 vs. ≥80). Treatment group comparisons were performed two-sided with α=5%.p-value: <0.000195% CI: [1.87, 4.441]Cochran-Mantel-Haenszel
Secondary
Duration of Response
Time from first assessment of Complete Response or Partial Response to disease progression or death (within 60 days of last tumor assessment). Patients without event are censored on the date of last tumor assessment. Tumor assessments based on modified WHO criteria.
Time frame: time from first assessment of Complete Response or Partial Response to disease progression, death or last tumor assessment, reported between day of first patient randomised, 21 Dec 2004, until cut-off date 12 Mar 2007
Population: Analysis on ITT population (allocation to treatment groups as randomized). Analysis performed at clinical cut off date, determined by primary endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab Plus Chemotherapy | Duration of Response | 5.6 months |
| Chemotherapy Alone | Duration of Response | 4.7 months |
Comparison: To test the equality of duration of response between treatment groups, the two-sided stratified log-rank test (α=5%) was used taking strata used for randomization into account (previous CTX \[no vs. yes\] and KPS \[\<80 vs. ≥80\]).~Median duration of response was estimated using the Kaplan-Meier method. The HR of cetuximab + CTX over CTX alone was calculated using the Cox proportional hazards model stratified by randomization strata.p-value: 0.2195% CI: [0.497, 1.168]Stratified Log Rank
Secondary
Progression-free Survival Time (PFS)
Duration from randomization until radiological progression according to investigator (based on modified World Health Organisation (WHO) criteria) or death due to any cause. Only deaths within 60 days of last tumor assessment are considered. Patients without event are censored on the date of last tumor assessment.
Time frame: time from randomization to disease progression, death or last tumor assessment, reported between day of first patient randomised, 21 Dec 2004, until cut-off date 12 Mar 2007
Population: Analysis on ITT population (allocation to treatment groups as randomized). Analysis performed at clinical cut off date, determined by primary endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab Plus Chemotherapy | Progression-free Survival Time (PFS) | 5.6 months |
| Chemotherapy Alone | Progression-free Survival Time (PFS) | 3.3 months |
Comparison: To test the equality of PFS between treatment groups, a two-sided stratified log-rank test (α=5%)was used, taking into account strata used for randomization (previous CTX \[yes/no\] and KPS \[\<80 vs. ≥80\]).~Median PFS time was estimated using the Kaplan-Meier method. The HR of cetuximab + CTX over CTX alone was calculated using the Cox proportional hazards model stratified by randomization strata.p-value: <0.000195% CI: [0.431, 0.672]Stratified Log Rank
Secondary
Quality of Life Assessment (EORTC QLQ-C30) Social Functioning
Mean social functioning scores (EORTC QLQ-C30) against time for each treatment group. Scores were derived from mutually exclusive sets of items, with scale scores ranging from 0 to 100 after a linear transformation. Higher scores indicate a higher level of social functioning.
Time frame: at baseline, day 1 of cycle 3, first 6-weekly evaluation following completion of chemotherapy, 6 & 12 months after randomization, reported between day of first patient randomised, 21 Dec 2004,until cut-off date, 12 Mar 2007
Population: Of 361 ITT subjects from countries with EORTC QLQ-C30 available, 291 completed ≥1 evaluable questionnaire. Only time points where ≥ 20% of patients completing a baseline questionnaire remained in the population were analysed. Numbers at each timepoint were (cetuximab +chemotherapy/chemotherapy alone): Baseline:123/109; Cycle3:87/69; Month6:48/23
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cetuximab Plus Chemotherapy | Quality of Life Assessment (EORTC QLQ-C30) Social Functioning | At baseline | 62.14 scores on a scale | Standard Error 4.459 |
| Cetuximab Plus Chemotherapy | Quality of Life Assessment (EORTC QLQ-C30) Social Functioning | At cycle 3 | 64.64 scores on a scale | Standard Error 4.663 |
| Cetuximab Plus Chemotherapy | Quality of Life Assessment (EORTC QLQ-C30) Social Functioning | Month 6 | 61.27 scores on a scale | Standard Error 5.347 |
| Chemotherapy Alone | Quality of Life Assessment (EORTC QLQ-C30) Social Functioning | At baseline | 62.05 scores on a scale | Standard Error 4.73 |
| Chemotherapy Alone | Quality of Life Assessment (EORTC QLQ-C30) Social Functioning | At cycle 3 | 60.67 scores on a scale | Standard Error 5.176 |
| Chemotherapy Alone | Quality of Life Assessment (EORTC QLQ-C30) Social Functioning | Month 6 | 65.72 scores on a scale | Standard Error 7.122 |
Secondary
Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status
Mean global health status scores (EORTC QLQ-C30) against time for each treatment group. Scores were derived from mutually exclusive sets of items, with scale scores ranging from 0 to 100 after a linear transformation. Higher scores indicate a better QoL.
Time frame: at baseline, day 1 of cycle 3, first 6-weekly evaluation following completion of chemotherapy, 6 & 12 months after randomization, reported between day of first patient randomised, 21 Dec 2004,until cut-off date, 12 Mar 2007
Population: Of 361 ITT subjects from countries with EORTC QLQ-C30 available, 291 completed ≥1 evaluable questionnaire. Only time points where ≥ 20% of patients completing a baseline questionnaire remained in the population were analysed. Numbers at each timepoint were (cetuximab+chemotherapy/chemotherapy alone): Baseline: 121/106; Cycle3:87/67; Month6:48/22
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cetuximab Plus Chemotherapy | Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status | At baseline | 50.74 scores on a scale | Standard Error 3.519 |
| Cetuximab Plus Chemotherapy | Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status | At cycle 3 | 52.68 scores on a scale | Standard Error 3.724 |
| Cetuximab Plus Chemotherapy | Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status | Month 6 | 55.30 scores on a scale | Standard Error 4.282 |
| Chemotherapy Alone | Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status | At baseline | 45.15 scores on a scale | Standard Error 3.745 |
| Chemotherapy Alone | Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status | At cycle 3 | 45.48 scores on a scale | Standard Error 4.153 |
| Chemotherapy Alone | Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status | Month 6 | 42.49 scores on a scale | Standard Error 5.959 |
Secondary
Safety - Number of Patients Experiencing Any Adverse Event
Please refer to Adverse Events section for further details
Time frame: time from first dose up to 30 after last dose of study treatment, reported between day of first dose of study treatment, 22 Dec 2004, until cut-off date 12 Mar 2007
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab Plus Chemotherapy | Safety - Number of Patients Experiencing Any Adverse Event | 218 participants |
| Chemotherapy Alone | Safety - Number of Patients Experiencing Any Adverse Event | 208 participants |
Secondary
Time to Treatment Failure
Time from randomization to date of the first occurrence of; progression, discontinuation of treatment due to progression or adverse event, start of new anticancer therapy, withdrawal of consent, or death (within 60 days of last tumor assessment). Patients without event are censored on the date of last tumor assessment.
Time frame: Time from randomization to treatment failure or last tumor assessment, reported between day of first patient randomised, 21 Dec 2004, until cut-off date 12 Mar 2007
Population: Analysis on ITT population (allocation to treatment groups as randomized). Analysis performed at clinical cut off date, determined by primary endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab Plus Chemotherapy | Time to Treatment Failure | 4.8 months |
| Chemotherapy Alone | Time to Treatment Failure | 3.0 months |
Comparison: Treatment groups were compared applying a two-sided stratified log-rank test (α=5%), taking into account strata used for randomization (previous CTX \[yes/no\] and KPS \[\<80 vs. ≥80\]).~Median time to treatment failure was estimated using the Kaplan-Meier method. The HR of cetuximab + CTX over CTX alone was calculated using the Cox proportional hazards model stratified by randomization strata.p-value: <0.000195% CI: [0.484, 0.727]Stratified Log Rank