Head and Neck Cancer, Mucositis
Conditions
Keywords
palifermin, Clinical Trial, Oncology, Head & Neck
Brief summary
Oral Mucositis associated with adjuvant radiation and concurrent chemotherapy in postoperative Head and Neck setting
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 bolus dose of palifermin or placebo at 120 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
Administered by intravenous (IV) bolus injection
DRUGpalifermin
Administered by intravenous (IV) bolus injection
RADIATIONRadiotherapy
Once daily irradiation of 20 centigray (cGy)/day x 33 fractions for a total target dose of 6600 cGy (conventional radiation therapy using standard fractionation \[one fraction per day\])
DRUGCisplatin
100 mg/m\^2 intravenously (IV) on days 1, 22 and 43.
Sponsors
Amgen
Swedish Orphan Biovitrum
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* History of newly diagnosed histologically confirmed squamous cell carcinoma (American Joint Committee on Cancer \[AJCC\] Stage II, III, IVA, or IVB) involving either the oral cavity, oropharynx, nasopharynx, hypopharynx, or larynx, post surgical resection (R0, R1) * Scheduled to receive adjuvant concurrent chemoradiation treatment within 12 weeks of surgery * High-risk subject defined by presence of at least one of the following: R1 resection margins; T3 or T4 tumor stage; 3 or more positive lymph node metastases; \<3 lymph node metastases with extracapsular extension of the disease * Radiation treatment field to receive planned dose of at least 50Gy to areas of the oral cavity/oropharynx mucosa that can be visualized
Exclusion criteria
* Tumors of the lips, paranasal sinuses, salivary glands, or of unknown primary tumors * Metastatic disease (M1) / Stage IV C * Presence or history of any other primary malignancy * History of pancreatitis * Prior radiotherapy to the site of disease * Prior chemotherapy * Other investigational procedures * Thirty days or less since receiving an investigational product or device in another clinical trial. Current enrollment in another clinical trial is not permitted unless the sole purpose of the trial is for long-term follow-up/survival data
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) | Up to Week 12 (or Week 15 for participants with severe OM was not resolved by Week 12) | An adverse event is an undesirable medical occurrence (sign, symptom, or diagnosis) or worsening of a pre-existing medical condition occurring after start of study drug up to the end of acute oral mucositis (OM) evaluation phase, whether or not considered to be study drug related. If severe OM was not resolved by Week 12, AEs were documented until resolution of severe OM or Week 15, whichever occurred first. A serious AE is any event that is fatal, life threatening, requires or prolongs hospitalization, is a persistent or significant disability/incapacity or is a congenital anomaly/birth defect. The intensity of AEs was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v3 based on the following: Grade 1 = Mild AE, Grade 2 = Moderate AE, Grade 3 = Severe AE, Grade 4 = Life-threatening or disabling AE, Grade 5 = Death related to AE. A Protocol-specific Limiting Toxicity (PSLT) is any non-hematologic Grade 3 or 4 AE considered related to study drug. |
| Ratio of Ki67-positive Cells Before and After Palifermin Treatment | Day -3 predose and 24 or 48 hours post-dose | The effect of palifermin on cell proliferation was to be assayed by staining for the cell cycle proliferation marker Ki67 in buccal mucosal biopsy samples taken prior to the first dose and either 24 or 48 hours after the first dose. Due to the small sample size, this analysis was not performed. |
| Pharmacokinetics of Palifermin | Day -3, predose and at 2, 5, 15, 30, 60, and 90 minutes and 2, 4, 6, 8, 10, 12, 24 and 48 hours after the first dose | Due to the small sample size this analysis was not performed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Severe Oral Mucositis (OM) (Adapted RTOG/EORTC Grade ≥3) | Assessed daily up to Week 12 (or Week 15 if severe oral mucositis not resolved ≤ adapted RTOG/EORTC Grade 2 by Week 12). | The adapted RTOG/EORTC mucositis assessment scale as follows: Grade 0 = no change; Grade 1 = mild enanthema, mild pain; Grade 2 = patchy mucositis, moderate edema, moderate pain; Grade 3 = confluent fibrinous mucositis, massive edema, massive pain; Grade 4 = extensive ulceration, confluent necrosis, massive hemorrhage. Due to the small sample size this analysis was not performed. |
| Overall Survival | During long-term follow-up phase, until December 2015 | Deaths during long-term follow up of subject participating in the acute phase of the study receiving placebo or Palifermin. |
| Patient-Reported Mouth and Throat Soreness Score | Assessed daily up to Week 12 (or Week 15 if severe oral mucositis not resolved ≤ adapted RTOG/EORTC Grade 2 by Week 12). | The average patient-reported mouth and throat soreness (MTS) score as reported on question 3 of the Oral Mucositis Questionnaire for Head and Neck Cancer \[OMQ-HN\]): 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). Due to the small sample size this analysis was not performed. |
| Number of Participants With Disease Progression by Week 12 | Up to Week 12 | Disease progression was determined by clinical examination and histopathologic examination by the Investigator. |
Participant flow
Recruitment details
After recruitment of 5 participants, the study was closed to further enrollment due to administrative changes at the study center (ie, departure of principal investigator) and slow enrollment.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Three days before the start of radiotherapy (Day -3), participants received a single intravenous (IV) bolus injection of matching placebo. During radiotherapy (beginning on Day 1), participants received a weekly single IV bolus injection of matching placebo after the last radiation fraction of that week (usually on Fridays) until grade ≥3 oral mucositis occurred, or for a maximum 8 doses (completion of radiotherapy). Participants also received cisplatin 100 mg/m\^2 on days 1, 22 and 43. | 2 |
| Palifermin Three days before the start of radiotherapy (Day -3), participants received a single intravenous (IV) bolus injection of palifermin at 120 μg/kg. During radiotherapy (beginning on Day 1), participants received a weekly single IV bolus injection of palifermin at 120 μg/kg after the last radiation fraction of that week (usually on Fridays) until grade ≥3 oral mucositis occurred, or for a maximum 8 doses (completion of radiotherapy). Participants also received cisplatin 100 mg/m\^2 on days 1, 22 and 43. | 3 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Occurrence of grade 3 oral mucositis | 2 | 2 |
Baseline characteristics
| Characteristic | Placebo | Palifermin | Total |
|---|---|---|---|
| Age, Continuous | 53.0 years | 52.0 years | 52.0 years |
| Race/Ethnicity, Customized White or Caucasian | 2 participants | 3 participants | 5 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 2 | 3 / 3 |
| serious Total, serious adverse events | 0 / 2 | 2 / 3 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs)
An adverse event is an undesirable medical occurrence (sign, symptom, or diagnosis) or worsening of a pre-existing medical condition occurring after start of study drug up to the end of acute oral mucositis (OM) evaluation phase, whether or not considered to be study drug related. If severe OM was not resolved by Week 12, AEs were documented until resolution of severe OM or Week 15, whichever occurred first. A serious AE is any event that is fatal, life threatening, requires or prolongs hospitalization, is a persistent or significant disability/incapacity or is a congenital anomaly/birth defect. The intensity of AEs was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v3 based on the following: Grade 1 = Mild AE, Grade 2 = Moderate AE, Grade 3 = Severe AE, Grade 4 = Life-threatening or disabling AE, Grade 5 = Death related to AE. A Protocol-specific Limiting Toxicity (PSLT) is any non-hematologic Grade 3 or 4 AE considered related to study drug.
Time frame: Up to Week 12 (or Week 15 for participants with severe OM was not resolved by Week 12)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events (AEs) | Severe AE (Grade 3, 4 or 5) | 0 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Treatment related severe AE (Grade 3, 4 or 5) | 0 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Serious adverse event | 0 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Study Discontinuation Due to AE | 0 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Treatment related adverse event | 0 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Protocol Specific Limiting Toxicity (PSLT) | 0 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Any adverse event | 2 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Deaths | 0 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Treatment related serious AE | 0 participants |
| Palifermin | Number of Participants With Adverse Events (AEs) | Deaths | 1 participants |
| Palifermin | Number of Participants With Adverse Events (AEs) | Any adverse event | 3 participants |
| Palifermin | Number of Participants With Adverse Events (AEs) | Serious adverse event | 2 participants |
| Palifermin | Number of Participants With Adverse Events (AEs) | Severe AE (Grade 3, 4 or 5) | 2 participants |
| Palifermin | Number of Participants With Adverse Events (AEs) | Treatment related adverse event | 1 participants |
| Palifermin | Number of Participants With Adverse Events (AEs) | Treatment related serious AE | 1 participants |
| Palifermin | Number of Participants With Adverse Events (AEs) | Treatment related severe AE (Grade 3, 4 or 5) | 1 participants |
| Palifermin | Number of Participants With Adverse Events (AEs) | Study Discontinuation Due to AE | 0 participants |
| Palifermin | Number of Participants With Adverse Events (AEs) | Protocol Specific Limiting Toxicity (PSLT) | 0 participants |
Primary
Pharmacokinetics of Palifermin
Due to the small sample size this analysis was not performed.
Time frame: Day -3, predose and at 2, 5, 15, 30, 60, and 90 minutes and 2, 4, 6, 8, 10, 12, 24 and 48 hours after the first dose
Primary
Ratio of Ki67-positive Cells Before and After Palifermin Treatment
The effect of palifermin on cell proliferation was to be assayed by staining for the cell cycle proliferation marker Ki67 in buccal mucosal biopsy samples taken prior to the first dose and either 24 or 48 hours after the first dose. Due to the small sample size, this analysis was not performed.
Time frame: Day -3 predose and 24 or 48 hours post-dose
Secondary
Number of Participants With Disease Progression by Week 12
Disease progression was determined by clinical examination and histopathologic examination by the Investigator.
Time frame: Up to Week 12
Population: Tumor response data was missing for one participant.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Disease Progression by Week 12 | 1 participants |
| Palifermin | Number of Participants With Disease Progression by Week 12 | 0 participants |
Secondary
Number of Participants With Severe Oral Mucositis (OM) (Adapted RTOG/EORTC Grade ≥3)
The adapted RTOG/EORTC mucositis assessment scale as follows: Grade 0 = no change; Grade 1 = mild enanthema, mild pain; Grade 2 = patchy mucositis, moderate edema, moderate pain; Grade 3 = confluent fibrinous mucositis, massive edema, massive pain; Grade 4 = extensive ulceration, confluent necrosis, massive hemorrhage. Due to the small sample size this analysis was not performed.
Time frame: Assessed daily up to Week 12 (or Week 15 if severe oral mucositis not resolved ≤ adapted RTOG/EORTC Grade 2 by Week 12).
Secondary
Overall Survival
Deaths during long-term follow up of subject participating in the acute phase of the study receiving placebo or Palifermin.
Time frame: During long-term follow-up phase, until December 2015
Population: Subjects who received placebo duringthe acute phase of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Overall Survival | 2 Participants |
| Palifermin | Overall Survival | 2 Participants |
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 Questionnaire for Head and Neck Cancer \[OMQ-HN\]): 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). Due to the small sample size this analysis was not performed.
Time frame: Assessed daily up to Week 12 (or Week 15 if severe oral mucositis not resolved ≤ adapted RTOG/EORTC Grade 2 by Week 12).