Head and Neck Cancer, Mucositis, Solid Tumors, Squamous Cell Carcinoma, Stomatitis
Conditions
Keywords
SCCHN, Palifermin, Mucositis, Oral Cavity, Oropharynx, Nasopharynx, Hypopharynx, Larynx, Mouth Pain, Mouth Sores, Radiation Therapy, Radiotherapy, Radiochemotherapy, Concurrent Chemotherapy, Xerostomia, Stomatitis, Mucosa, KGF, rHuKGF, Keratinocyte Growth Factor, HNC, Head and Neck Cancer, Oral Mucositis
Brief summary
The purpose of this research study is to test the safety and effectiveness of palifermin to determine if weekly doses can be safely administered to reduce the incidence (occurrence of), duration (length of time) and severity (amount of pain) of oral mucositis (painful sores in the mouth). Mucositis is a common side effect for patients receiving chemotherapy (cancer-killing drug) and radiotherapy (cancer-killing x-rays) for the treatment of head and neck cancer (HNC).
Detailed description
This study consisted of 2 phases. The acute oral mucositis (OM) evaluation phase includes the time from randomization to the time of severe OM (WHO Grade 3 or 4) resolution (up to Week 12 or up to Week 15 for participants whose severe OM is not resolved at Week 12). In the acute OM evaluation phase, participants were randomized to receive either a single IV dose of palifermin or placebo at 180 μg/kg, 3 days before the start of radiotherapy, plus 7 once-weekly palifermin or placebo doses at the same dose level during a 7-week radio/chemotherapy course. In the long-term follow up phase, participants are followed until death, withdrawal of consent, or loss to follow-up. The long-term follow up phase is still ongoing.
Interventions
DRUGPlacebo
DRUGpalifermin
Commercially available cisplatin was administered as an intravenous infusion at a dose of 100 mg/m\^2 on Days 1, 22, and 43.
RADIATIONRadiotherapy
Radiotherapy was delivered in 200 cGy daily fractions, 5 days a week.
Sponsors
Amgen
Swedish Orphan Biovitrum
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
Key Inclusion Criteria: * Histologically documented squamous cell carcinoma involving either the oral cavity, oropharynx, nasopharynx, hypopharynx, or larynx * Newly diagnosed, locally advanced stage head and neck cancer (unresectable/unresected disease); American Joint Committee on Cancer \[AJCC\] Stage III, IVA or IVB amenable to radiotherapy with concurrent chemotherapy as the definitive treatment modality * At least 50 Gray of radiation treatment to areas of the oral cavity/oropharynx mucosa that can be visualized * Concurrent chemotherapy regimen of Cisplatin 100mg/m\^2 on days 1, 22, and 43 * Eastern Cooperative Oncology Group (ECOG) performance status (PS) less than or equal to 2 * Adequate hematologic, renal and hepatic function * Negative pregnancy test by serum or urine * Signed informed consent Key
Exclusion criteria
\- Presence or history of any other primary malignancy (other than curatively treated in situ cervical cancer, or basal cell carcinoma of the skin without evidence of disease for greater than 3 years)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Severe (Grade 3 or 4) Oral Mucositis | Up to Week 15 | Participants underwent evaluations of oral mucosal (OM) surfaces (mucositis assessments) 2 times weekly throughout radio/chemotherapy, and 2 times weekly thereafter until severe OM returned to grade ≤ 2 or until Week 15. During each evaluation, the following anatomical areas were assessed: upper lip; lower lip; right cheek; left cheek; right ventral & lateral tongue; left ventral & lateral tongue; floor of the mouth; hard palate; soft palate. A trained evaluator documented the findings using the World Health Organization (WHO) oral toxicity scale according to the following: Grade 0 = None; Grade 1 = Soreness, erythema; Grade 2 = Erythema, ulcers, ability to eat solids; Grade 3 = Ulcers, requires liquid diet; Grade 4 = Alimentation not possible. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Onset of Severe (WHO Grade 3 or 4) Oral Mucositis | Up to 15 weeks | Time to onset of severe (WHO Grade 3 or 4) oral mucositis (OM) was analyzed using the Kaplan-Meier procedure. Participants without an assessed event by the end of the acute OM evaluation phase were censored at the date of last assessment for severe OM. |
| Number of Participants With Xerostomia at Month 4 (Grade 2 or Higher) | Month 4 | The number of participants with grade 2 or higher xerostomia (dryness of the oral mucosa) at the Month 4 visit, graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 Dry Mouth/Xerostomia scale. |
| Patient-Reported Mouth and Throat Soreness Score | Assessed twice a week for up to 15 weeks. | The average patient-reported mouth and throat soreness (MTS) score as reported on question 3 of the Oral Mucositis Weekly Questionnaire for Head and Neck Cancer \[OMWQ-HN\]): How much mouth and throat soreness did you experience in the past 24 hours? Participants answered on a scale from 0 (no soreness) to 4 (extreme soreness). For each participant, an average patient-reported mouth and throat soreness score was calculated by dividing the sum of the MTS scores at each assessment by the total number of assessments. |
| Duration of Severe (WHO Grade 3 or 4) Oral Mucositis | Up to 15 weeks | The duration of severe oral mucositis (OM) was calculated as the number of days from the onset of severe OM (first time a WHO grade 3 or 4 was observed) to the day when severe OM was resolved (first time WHO grade 2 or less was observed after last WHO grade 3 or 4). Durations of 0 days were assigned to those participants who did not experience any WHO grade 3 or 4 during the study. |
| Number of Participants With Unplanned Breaks in Cisplatin Chemotherapy Treatment | During the 7 weeks of chemotherapy treatment | Cisplatin was administered on Days 1, 22, and 43. An unplanned break in cisplatin refers to a delay of ≥ 5 days from the scheduled Day 22 or Day 43 cisplatin administration or a discontinuation of cisplatin for any reason. |
| Number of Participants With Unplanned Breaks in Radiotherapy | During the 7 weeks of radiotherapy | Participants with a duration of 5 days or more without an administration of radiotherapy or who discontinue radiotherapy prior to completion of planned radiotherapy were considered to have an unplanned break in radiotherapy. |
| Total Dose of Opioid Analgesics Used for Mucositis Within 15 Weeks | Up to 15 weeks | The total dose of opioid analgesics (mg of intravenous \[IV\] morphine equivalents) used by all participants. Participants with at least one reported administration of opioid analgesic (parenteral, peroral or transdermal) were considered to have received opioid analgesics. The total dose of opioid analgesics is the sum of all opioid analgesic administrations that have been converted to morphine equivalents. |
Participant flow
Recruitment details
This study was conducted from 03 August 2005 (first participant enrolled) to 11 September 2007 (last participant's last visit at 4 months of follow-up) at 46 study centers in the United States, Canada, and Europe At the time of this report, the long-term safety follow-up period is ongoing.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received a single IV dose of placebo three days before the start of radiotherapy, and then 7 once weekly placebo doses during a 7-week radiotherapy/chemotherapy course. | 94 |
| Palifermin Participants received a single intravenous dose of palifermin at 180 μg/kg three days before the start of radiotherapy, and then 7 once weekly palifermin doses at the same dose level during a 7-week radiotherapy/chemotherapy course. | 94 |
| Total | 188 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 4 |
| Overall Study | Death | 3 | 5 |
| Overall Study | Ineligibility determined | 0 | 1 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 6 | 4 |
Baseline characteristics
| Characteristic | Total | Palifermin | Placebo |
|---|---|---|---|
| Age, Continuous | 55.5 years STANDARD_DEVIATION 8.5 | 55.5 years STANDARD_DEVIATION 8.6 | 55.4 years STANDARD_DEVIATION 8.3 |
| Disease Stage Stage III | 55 participants | 26 participants | 29 participants |
| Disease Stage Stage IV A | 114 participants | 60 participants | 54 participants |
| Disease Stage Stage IV B | 19 participants | 8 participants | 11 participants |
| Race/Ethnicity, Customized American Indian/ Alaska Native | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Black | 9 participants | 7 participants | 2 participants |
| Race/Ethnicity, Customized Caucasian | 173 participants | 83 participants | 90 participants |
| Race/Ethnicity, Customized Hispanic | 5 participants | 3 participants | 2 participants |
| Sex: Female, Male Female | 29 Participants | 15 Participants | 14 Participants |
| Sex: Female, Male Male | 159 Participants | 79 Participants | 80 Participants |
| Tumor Site Hypopharynx | 36 participants | 14 participants | 22 participants |
| Tumor Site Larynx | 25 participants | 16 participants | 9 participants |
| Tumor Site Nasopharynx | 7 participants | 4 participants | 3 participants |
| Tumor Site Oral Cavity | 14 participants | 5 participants | 9 participants |
| Tumor Site Oropharynx | 106 participants | 55 participants | 51 participants |
| Weight | 73.2 kilograms STANDARD_DEVIATION 16.1 | 74.5 kilograms STANDARD_DEVIATION 16.4 | 71.8 kilograms STANDARD_DEVIATION 15.7 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 81 / 91 | 89 / 94 |
| serious Total, serious adverse events | 25 / 91 | 35 / 94 |
Outcome results
Primary
Number of Participants With Severe (Grade 3 or 4) Oral Mucositis
Participants underwent evaluations of oral mucosal (OM) surfaces (mucositis assessments) 2 times weekly throughout radio/chemotherapy, and 2 times weekly thereafter until severe OM returned to grade ≤ 2 or until Week 15. During each evaluation, the following anatomical areas were assessed: upper lip; lower lip; right cheek; left cheek; right ventral & lateral tongue; left ventral & lateral tongue; floor of the mouth; hard palate; soft palate. A trained evaluator documented the findings using the World Health Organization (WHO) oral toxicity scale according to the following: Grade 0 = None; Grade 1 = Soreness, erythema; Grade 2 = Erythema, ulcers, ability to eat solids; Grade 3 = Ulcers, requires liquid diet; Grade 4 = Alimentation not possible.
Time frame: Up to Week 15
Population: The Full Analysis Set included all randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Severe (Grade 3 or 4) Oral Mucositis | No | 29 participants |
| Placebo | Number of Participants With Severe (Grade 3 or 4) Oral Mucositis | Yes | 62 participants |
| Placebo | Number of Participants With Severe (Grade 3 or 4) Oral Mucositis | Unknown | 3 participants |
| Palifermin | Number of Participants With Severe (Grade 3 or 4) Oral Mucositis | Yes | 51 participants |
| Palifermin | Number of Participants With Severe (Grade 3 or 4) Oral Mucositis | No | 43 participants |
| Palifermin | Number of Participants With Severe (Grade 3 or 4) Oral Mucositis | Unknown | 0 participants |
Comparison: Sample size calculations were based on the number of participants needed to detect, with 90% power and 5% type 1 error rate, at least a 25% difference in the incidence of severe OM between the treatment groups. A 25% absolute reduction in the incidence of severe OM from the placebo group was considered by investigators as clinically meaningful in this clinical setting.p-value: 0.041Cochran-Mantel-Haenszel
Secondary
Duration of Severe (WHO Grade 3 or 4) Oral Mucositis
The duration of severe oral mucositis (OM) was calculated as the number of days from the onset of severe OM (first time a WHO grade 3 or 4 was observed) to the day when severe OM was resolved (first time WHO grade 2 or less was observed after last WHO grade 3 or 4). Durations of 0 days were assigned to those participants who did not experience any WHO grade 3 or 4 during the study.
Time frame: Up to 15 weeks
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Duration of Severe (WHO Grade 3 or 4) Oral Mucositis | 26.0 days |
| Palifermin | Duration of Severe (WHO Grade 3 or 4) Oral Mucositis | 5.0 days |
p-value: 0.016Cochran-Mantel-Haenszel
Comparison: To protect the overall type 1 error, the Hochberg procedure was used to adjust for multiple statistical testing of the secondary efficacy endpoints.p-value: 0.1122Cochran-Mantel-Haenszel
Secondary
Number of Participants With Unplanned Breaks in Cisplatin Chemotherapy Treatment
Cisplatin was administered on Days 1, 22, and 43. An unplanned break in cisplatin refers to a delay of ≥ 5 days from the scheduled Day 22 or Day 43 cisplatin administration or a discontinuation of cisplatin for any reason.
Time frame: During the 7 weeks of chemotherapy treatment
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Unplanned Breaks in Cisplatin Chemotherapy Treatment | 42 participants |
| Palifermin | Number of Participants With Unplanned Breaks in Cisplatin Chemotherapy Treatment | 49 participants |
p-value: 0.3417Cochran-Mantel-Haenszel
p-value: 0.6835Cochran-Mantel-Haenszel
Secondary
Number of Participants With Unplanned Breaks in Radiotherapy
Participants with a duration of 5 days or more without an administration of radiotherapy or who discontinue radiotherapy prior to completion of planned radiotherapy were considered to have an unplanned break in radiotherapy.
Time frame: During the 7 weeks of radiotherapy
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Unplanned Breaks in Radiotherapy | 11 participants |
| Palifermin | Number of Participants With Unplanned Breaks in Radiotherapy | 13 participants |
p-value: 0.9587Cochran-Mantel-Haenszel
p-value: 0.9587Cochran-Mantel-Haenszel
Secondary
Number of Participants With Xerostomia at Month 4 (Grade 2 or Higher)
The number of participants with grade 2 or higher xerostomia (dryness of the oral mucosa) at the Month 4 visit, graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 Dry Mouth/Xerostomia scale.
Time frame: Month 4
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Xerostomia at Month 4 (Grade 2 or Higher) | Unknown | 18 participants |
| Placebo | Number of Participants With Xerostomia at Month 4 (Grade 2 or Higher) | Yes | 57 participants |
| Placebo | Number of Participants With Xerostomia at Month 4 (Grade 2 or Higher) | No | 19 participants |
| Palifermin | Number of Participants With Xerostomia at Month 4 (Grade 2 or Higher) | Yes | 37 participants |
| Palifermin | Number of Participants With Xerostomia at Month 4 (Grade 2 or Higher) | No | 31 participants |
| Palifermin | Number of Participants With Xerostomia at Month 4 (Grade 2 or Higher) | Unknown | 26 participants |
p-value: 0.0463Cochran-Mantel-Haenszel
p-value: 0.2314Cochran-Mantel-Haenszel
Secondary
Patient-Reported Mouth and Throat Soreness Score
The average patient-reported mouth and throat soreness (MTS) score as reported on question 3 of the Oral Mucositis Weekly Questionnaire for Head and Neck Cancer \[OMWQ-HN\]): How much mouth and throat soreness did you experience in the past 24 hours? Participants answered on a scale from 0 (no soreness) to 4 (extreme soreness). For each participant, an average patient-reported mouth and throat soreness score was calculated by dividing the sum of the MTS scores at each assessment by the total number of assessments.
Time frame: Assessed twice a week for up to 15 weeks.
Population: The Patient Reported Outcome-evaluable analysis set included all randomized patients with a valid Baseline assessment for MTS question 3 of the OMWQ-HN and either:~* At least 1 completed assessment each week for MTS up to withdrawal/Week 8, whichever came first, or~* 70% or greater overall compliance for MTS until withdrawal/Week 8.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Patient-Reported Mouth and Throat Soreness Score | 1.86 units on a scale | Standard Deviation 0.65 |
| Palifermin | Patient-Reported Mouth and Throat Soreness Score | 1.66 units on a scale | Standard Deviation 0.73 |
p-value: 0.0712Cochran-Mantel-Haenszel
p-value: 0.2849Cochran-Mantel-Haenszel
Secondary
Time to Onset of Severe (WHO Grade 3 or 4) Oral Mucositis
Time to onset of severe (WHO Grade 3 or 4) oral mucositis (OM) was analyzed using the Kaplan-Meier procedure. Participants without an assessed event by the end of the acute OM evaluation phase were censored at the date of last assessment for severe OM.
Time frame: Up to 15 weeks
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Onset of Severe (WHO Grade 3 or 4) Oral Mucositis | 35.0 days |
| Palifermin | Time to Onset of Severe (WHO Grade 3 or 4) Oral Mucositis | 47.0 days |
p-value: 0.026195% CI: [0.4546, 0.9592]Stratified Log-Rank test
p-value: 0.1566Stratified Log-Rank test
Secondary
Total Dose of Opioid Analgesics Used for Mucositis Within 15 Weeks
The total dose of opioid analgesics (mg of intravenous \[IV\] morphine equivalents) used by all participants. Participants with at least one reported administration of opioid analgesic (parenteral, peroral or transdermal) were considered to have received opioid analgesics. The total dose of opioid analgesics is the sum of all opioid analgesic administrations that have been converted to morphine equivalents.
Time frame: Up to 15 weeks
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Total Dose of Opioid Analgesics Used for Mucositis Within 15 Weeks | 1219.55 mg of IV morphine equivalents | Standard Deviation 1769.29 |
| Palifermin | Total Dose of Opioid Analgesics Used for Mucositis Within 15 Weeks | 1243.31 mg of IV morphine equivalents | Standard Deviation 2700.28 |
p-value: 0.2384Cochran-Mantel-Haenszel
p-value: 0.6835Cochran-Mantel-Haenszel