Head and Neck Neoplasms
Conditions
Brief summary
This study will compare the effects of pemetrexed plus cisplatin versus cisplatin alone in head and neck cancer patients.
Interventions
DRUGpemetrexed
500 mg/m\^2, IV, every 21 days, six 21 day cycles
DRUGcisplatin
75 mg/m\^2, administered IV, every 21 days, six 21 day cycles
DRUGplacebo
Approximately 100 mL normal saline administered IV, every 21 days, six 21 day cycles
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* You must have head and neck cancer that has returned and cannot be treated with surgery or other types of treatment. OR You must have head and neck cancer that was just found and has spread to other parts of your body. * You must have a performance status of 0,1 or 2. This means that you must at least be able to get around, be able to take care of yourself and must be up and about most of the day. * Your test results must show that your liver, kidneys and blood cells are working normally. * You must understand and sign the form that gives your agreement to willingly be part of the study. * You must be at least 18 years of age.
Exclusion criteria
* You cannot have previously been given other treatment for cancer that has spread to other parts of your body. * You cannot have a serious sickness that might keep you from finishing the study (for example a bad infection). * You cannot have any extra fluid in your chest or bowel area unless your doctor tells you it can be drained before you join the study. * You cannot have any cancer called nasopharyngeal cancer, paranasal sinus cancer, lip cancer, or salivary gland cancer. * If you are taking high dose aspirin or other medicines called non-steroidal anti-inflammatory drugs and cannot stop taking them for at least 5 days, you cannot be in the study. Your doctor or a member of the study team can explain which drugs are non-steroidal anti-inflammatory drugs.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Baseline to date of death from any cause up to 36 months | OS duration is defined as the time from the date of randomization to the date of death from any cause. For each participant who is not known to have died as of the data-inclusion cut-off date, OS duration will be censored at the date of the participant's last contact prior to that cut-off date. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | baseline to measured progressive disease up to 33 months | Objective PFS is defined as the time from date of randomization to date of objectively determined progressive disease (PD) or death from any cause, whichever comes first. PD was defined by Response Evaluation Criteria in Solid Tumors (RECIST). PD=at least a 20% increase in sum of longest diameter of target lesions. For participants who are not known to have died as of the data-inclusion cut-off date, and who do not have progressive disease, PFS will be censored at the date of the last objective progression-free disease assessment prior to the date of any subsequent systemic anticancer therapy. |
| Percent of Participants With a Tumor Response (Response Rate) | Baseline to progressive disease or discontinuation of study treatment up to 11 months | Tumor Response is evaluated as CR (Complete Response) or PR (Partial Response) per Response Evaluation Criteria in Solid Tumors (RECIST criteria). Possible evaluations include: CR: Disappearance of all target lesions. PR: At least a 30% decrease in the size of target lesions. Response rate (%) = (number of participants with CR+PR/number of participants)\*100 |
| Duration of Response (DoR) | time of response to progressive disease up to 24 months | DoR is time from first observation of complete response (CR) or partial response (PR) to first observation of PD or death. Response is objective status of CR or PR using RECIST criteria. CR is disappearance of lesions. PR is \>30% decrease in size of lesions. Responder is any participant with CR or PR. PD is at least 20% increase in sum of longest diameter of target lesions. For participants alive as of data-inclusion cut-off date and who do not have PD, DoR will be censored at date of last objective progression-free disease assessment before date of any subsequent systemic anticancer therapy. |
| Time to Treatment Worsening in Functional Assessment of Cancer Therapy - Head and Neck Cancer (FACT-H&N) Total Score | Baseline (</=Day 1 of first dose) and Day 1 of every subsequent cycle to 30-day post-study completion up to 33 months | FACT-H&N consists of 39 items with 5-point rating scale from 0 (not at all) to 4 (very much). FACT-H&N Total score ranges from 0 to 148. Higher score represents a better quality of life. Time to worsening was defined as the first date of worsening in the FACT H&N Total score that was considered at least the prospectively defined minimally important difference (MID) as compared with participant's baseline score, or date of death from any cause. The MID for FACT H&N Total score was a decrease of 12 points. |
| Correlation Between Biomarkers and Treatment Effect | Baseline | Correlation between highly up/downregulated genes and clinical response (Overall Survival (OS) and Progression-Free Survival (PFS)). OS is is defined as the time from the date of randomization to the date of death from any cause. PFS is defined as the time from the date of randomization to the date of objectively determined progressive disease or death from any cause, whichever comes first. 0 participants were analyzed; Reason: The relatively low number of samples collected would not have yielded a meaningful genomic analysis and the decision was made to not analyze the data. |
Countries
Argentina, Belgium, Brazil, China, Denmark, France, Germany, Hungary, India, Italy, Mexico, Netherlands, Poland, Puerto Rico, Romania, Russia, South Africa, South Korea, Spain, Taiwan, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pemetrexed/Cisplatin Pemetrexed 500 milligrams per meter square (mg/m\^2) administered intravenously (IV) plus cisplatin 75 mg/m\^2 IV on Day 1 every 21 days.
Pretreatment - Both Treatment Arms: Dexamethasone administered orally (po): 4 milligrams (mg) twice daily (BID) taken on the day before, the day of, and day after study treatment.
Vitamin B12 administered intramuscularly (im): 1000 micrograms (μg) taken 1 to 2 weeks before treatment and every 9 weeks until 3 weeks after last treatment dose.
Folic Acid administered orally (po): 350 μg to 1000 μg taken 1 to 2 weeks before treatment and continue daily until 3 weeks after last treatment dose. | 398 |
| Placebo/Cisplatin Placebo (approximately 100 mL normal saline) administered IV plus cisplatin 75 mg/m\^2 on Day 1 every 21 days.
Pretreatment - Both Treatment Arms: Dexamethasone administered orally (po): 4 milligrams (mg) twice daily (BID) taken on the day before, the day of, and day after study treatment.
Vitamin B12 administered intramuscularly (im): 1000 micrograms (μg) taken 1 to 2 weeks before treatment and every 9 weeks until 3 weeks after last treatment dose.
Folic Acid administered orally (po): 350 μg to 1000 μg taken 1 to 2 weeks before treatment and continue daily until 3 weeks after last treatment dose. | 397 |
| Total | 795 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 37 | 32 |
| Overall Study | Death Due to AE (Other Causes) | 27 | 15 |
| Overall Study | Death Due to Procedural Related AE | 0 | 1 |
| Overall Study | Death Due to Study Disease | 26 | 29 |
| Overall Study | Death Due to Study Drug Related AE | 11 | 1 |
| Overall Study | Entry Criteria Not Met | 4 | 8 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Physician Decision | 10 | 16 |
| Overall Study | Progressive Disease | 180 | 217 |
| Overall Study | Protocol Violation | 4 | 2 |
| Overall Study | Withdrawal by Subject | 28 | 21 |
Baseline characteristics
| Characteristic | Total | Pemetrexed/Cisplatin | Placebo/Cisplatin |
|---|---|---|---|
| Age Continuous | 57.62 years STANDARD_DEVIATION 9.44 | 57.45 years STANDARD_DEVIATION 9.54 | 57.78 years STANDARD_DEVIATION 9.36 |
| Distant Metastasis No | 320 Participants | 165 Participants | 155 Participants |
| Distant Metastasis Yes | 475 Participants | 233 Participants | 242 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 | 180 Participants | 90 Participants | 90 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 | 510 Participants | 257 Participants | 253 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 | 104 Participants | 51 Participants | 53 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Missing Data | 1 Participants | 0 Participants | 1 Participants |
| Previously Treated for Head and Neck Cancer (HNC) No | 74 Participants | 35 Participants | 39 Participants |
| Previously Treated for Head and Neck Cancer (HNC) Yes | 721 Participants | 363 Participants | 358 Participants |
| Primary Site of Disease Hypopharynx | 122 Participants | 63 Participants | 59 Participants |
| Primary Site of Disease Larynx | 205 Participants | 103 Participants | 102 Participants |
| Primary Site of Disease Oral Cavity | 261 Participants | 138 Participants | 123 Participants |
| Primary Site of Disease Oropharynx | 192 Participants | 86 Participants | 106 Participants |
| Primary Site of Disease Other | 15 Participants | 8 Participants | 7 Participants |
| Prior Treatment with Platinum-Based Therapy No | 441 Participants | 213 Participants | 228 Participants |
| Prior Treatment with Platinum-Based Therapy Yes | 354 Participants | 185 Participants | 169 Participants |
| Race/Ethnicity, Customized African | 29 Participants | 17 Participants | 12 Participants |
| Race/Ethnicity, Customized Caucasian | 476 Participants | 243 Participants | 233 Participants |
| Race/Ethnicity, Customized East Asian | 120 Participants | 55 Participants | 65 Participants |
| Race/Ethnicity, Customized Hispanic | 27 Participants | 11 Participants | 16 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized West Asian (Indian sub-continent) | 142 Participants | 72 Participants | 70 Participants |
| Region of Enrollment Argentina | 15 participants | 5 participants | 10 participants |
| Region of Enrollment Belgium | 17 participants | 7 participants | 10 participants |
| Region of Enrollment Brazil | 28 participants | 16 participants | 12 participants |
| Region of Enrollment China | 12 participants | 5 participants | 7 participants |
| Region of Enrollment Denmark | 10 participants | 7 participants | 3 participants |
| Region of Enrollment France | 6 participants | 3 participants | 3 participants |
| Region of Enrollment Germany | 98 participants | 50 participants | 48 participants |
| Region of Enrollment Hungary | 45 participants | 23 participants | 22 participants |
| Region of Enrollment India | 147 participants | 72 participants | 75 participants |
| Region of Enrollment Italy | 40 participants | 19 participants | 21 participants |
| Region of Enrollment Korea, Republic of | 53 participants | 29 participants | 24 participants |
| Region of Enrollment Mexico | 17 participants | 9 participants | 8 participants |
| Region of Enrollment Netherlands | 19 participants | 8 participants | 11 participants |
| Region of Enrollment Poland | 20 participants | 10 participants | 10 participants |
| Region of Enrollment Romania | 42 participants | 20 participants | 22 participants |
| Region of Enrollment Russian Federation | 43 participants | 23 participants | 20 participants |
| Region of Enrollment South Africa | 20 participants | 11 participants | 9 participants |
| Region of Enrollment Spain | 60 participants | 31 participants | 29 participants |
| Region of Enrollment Taiwan | 46 participants | 21 participants | 25 participants |
| Region of Enrollment United States | 57 participants | 29 participants | 28 participants |
| Sex: Female, Male Female | 109 Participants | 56 Participants | 53 Participants |
| Sex: Female, Male Male | 686 Participants | 342 Participants | 344 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 343 / 392 | 316 / 385 |
| serious Total, serious adverse events | 185 / 392 | 132 / 385 |
Outcome results
Primary
Overall Survival (OS)
OS duration is defined as the time from the date of randomization to the date of death from any cause. For each participant who is not known to have died as of the data-inclusion cut-off date, OS duration will be censored at the date of the participant's last contact prior to that cut-off date.
Time frame: Baseline to date of death from any cause up to 36 months
Population: Intention to Treat (ITT) Population - defines the treatment group as those to which participants were assigned by random allocation, even if a participant did not take the assigned treatment, did not receive the correct treatment, or otherwise did not follow the protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed/Cisplatin | Overall Survival (OS) | 7.33 Months |
| Placebo/Cisplatin | Overall Survival (OS) | 6.28 Months |
p-value: 0.08295% CI: [0.75, 1.02]Stratified Log Rank
Secondary
Correlation Between Biomarkers and Treatment Effect
Correlation between highly up/downregulated genes and clinical response (Overall Survival (OS) and Progression-Free Survival (PFS)). OS is is defined as the time from the date of randomization to the date of death from any cause. PFS is defined as the time from the date of randomization to the date of objectively determined progressive disease or death from any cause, whichever comes first. 0 participants were analyzed; Reason: The relatively low number of samples collected would not have yielded a meaningful genomic analysis and the decision was made to not analyze the data.
Time frame: Baseline
Population: Zero participants were analyzed because the relatively low number of samples collected would not have yielded a meaningful genomic analysis.
Secondary
Duration of Response (DoR)
DoR is time from first observation of complete response (CR) or partial response (PR) to first observation of PD or death. Response is objective status of CR or PR using RECIST criteria. CR is disappearance of lesions. PR is \>30% decrease in size of lesions. Responder is any participant with CR or PR. PD is at least 20% increase in sum of longest diameter of target lesions. For participants alive as of data-inclusion cut-off date and who do not have PD, DoR will be censored at date of last objective progression-free disease assessment before date of any subsequent systemic anticancer therapy.
Time frame: time of response to progressive disease up to 24 months
Population: ITT population with a confirmed best response of complete response (CR) or partial response (PR).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed/Cisplatin | Duration of Response (DoR) | 5.29 Months |
| Placebo/Cisplatin | Duration of Response (DoR) | 4.37 Months |
p-value: 0.81195% CI: [0.56, 1.53]Stratified Log Rank
Secondary
Percent of Participants With a Tumor Response (Response Rate)
Tumor Response is evaluated as CR (Complete Response) or PR (Partial Response) per Response Evaluation Criteria in Solid Tumors (RECIST criteria). Possible evaluations include: CR: Disappearance of all target lesions. PR: At least a 30% decrease in the size of target lesions. Response rate (%) = (number of participants with CR+PR/number of participants)\*100
Time frame: Baseline to progressive disease or discontinuation of study treatment up to 11 months
Population: Intention to Treat (ITT) Population - defines the treatment group as those to which participants were assigned by random allocation, even if a participant did not take the assigned treatment, did not receive the correct treatment, or otherwise did not follow the protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pemetrexed/Cisplatin | Percent of Participants With a Tumor Response (Response Rate) | 12.1 Percentage of participants |
| Placebo/Cisplatin | Percent of Participants With a Tumor Response (Response Rate) | 8.1 Percentage of participants |
p-value: 0.061Unadjusted normal distribution
Secondary
Progression-free Survival (PFS)
Objective PFS is defined as the time from date of randomization to date of objectively determined progressive disease (PD) or death from any cause, whichever comes first. PD was defined by Response Evaluation Criteria in Solid Tumors (RECIST). PD=at least a 20% increase in sum of longest diameter of target lesions. For participants who are not known to have died as of the data-inclusion cut-off date, and who do not have progressive disease, PFS will be censored at the date of the last objective progression-free disease assessment prior to the date of any subsequent systemic anticancer therapy.
Time frame: baseline to measured progressive disease up to 33 months
Population: Intention to Treat (ITT) Population - defines the treatment group as those to which participants were assigned by random allocation, even if a participant did not take the assigned treatment, did not receive the correct treatment, or otherwise did not follow the protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed/Cisplatin | Progression-free Survival (PFS) | 3.61 months |
| Placebo/Cisplatin | Progression-free Survival (PFS) | 2.79 months |
p-value: 0.16695% CI: [0.76, 1.03]Stratified Log Rank
Secondary
Time to Treatment Worsening in Functional Assessment of Cancer Therapy - Head and Neck Cancer (FACT-H&N) Total Score
FACT-H&N consists of 39 items with 5-point rating scale from 0 (not at all) to 4 (very much). FACT-H&N Total score ranges from 0 to 148. Higher score represents a better quality of life. Time to worsening was defined as the first date of worsening in the FACT H&N Total score that was considered at least the prospectively defined minimally important difference (MID) as compared with participant's baseline score, or date of death from any cause. The MID for FACT H&N Total score was a decrease of 12 points.
Time frame: Baseline (</=Day 1 of first dose) and Day 1 of every subsequent cycle to 30-day post-study completion up to 33 months
Population: Intention to treat (ITT) population with at least Baseline data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed/Cisplatin | Time to Treatment Worsening in Functional Assessment of Cancer Therapy - Head and Neck Cancer (FACT-H&N) Total Score | 3.29 Months |
| Placebo/Cisplatin | Time to Treatment Worsening in Functional Assessment of Cancer Therapy - Head and Neck Cancer (FACT-H&N) Total Score | 2.89 Months |
p-value: 0.295% CI: [0.69, 1.07]Stratified Log Rank