Dysphagia, Lung Cancer, Non-Small Cell Lung Cancer
Conditions
Keywords
dysphagia, palifermin, KGF, chemoradiotherapy, NSCLC, non-small cell lung cancer, lung cancer, supportive care, clinical trial, consolidation chemotherapy, radiotherapy
Brief summary
The purpose of this study is to determine if palifermin will reduce the incidence of dysphagia in patients receiving concurrent chemoradiotherapy followed by consolidation chemotherapy for treatment of unresectable stage III Non-Small Cell Lung Cancer (NSCLC).
Detailed description
During the acute dysphagia evaluation phase (the period lasting from the administration of the first dose of investigational product through Week 12 (or up to Week 16 if dysphagia is not resolved to CTCAE v3.0 grade ≤ 1 by Week 12) participants underwent acute dysphagia assessments twice weekly. All participants were followed for disease progression, second primary tumors, other malignancies, and overall survival until death or loss to follow-up during the long term follow-up (still ongoing).
Interventions
DRUGPalifermin
DRUGPlacebo
RADIATIONRadiotherapy
DRUGPaclitaxel
DRUGCarboplatin
Sponsors
Amgen
Swedish Orphan Biovitrum
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with a histologically or cytologically proven diagnosis of NSCLC * Unresectable (locally advanced) stage IIIa or IIIb disease * Initial radiotherapy field of treatment to encompass greater than or equal to 30% of the esophagus * Life expectancy greater than or equal to 6 months * Estimated weight loss less than or equal to 10% in the 3 months before study randomization * Measurable disease * 18 years of age or older * Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2 * Hemoglobin (hgb) greater than or equal to 10 g/dL without transfusional support or growth factor use in the 4 weeks before study randomization * Absolute neutrophil count (ANC) greater than or equal to 1.5 x 10\^9/L without growth factor use in the 2 weeks before study randomization * Platelet count greater than or equal to 100 x 10\^9/L * Serum bilirubin less than or equal to 1.5 x institutional upper limit of normal (ULN) * Serum creatinine less than or equal to 2.0 mg/dL (Note: Patients with a serum creatinine greater than or equal to 1.4 and less than or equal to 2.0 mg/dL must demonstrate a 24-hour urinary creatinine clearance greater than or equal to 50 mL/min) * Females of childbearing potential: negative serum or urine pregnancy test * Patient must give written informed consent before participating in any study-specific procedure, randomization, or receiving investigational product. * Patients with reproductive capability must agree to practice adequate contraception methods.
Exclusion criteria
* Metastatic disease (M1)/stage 4 NSCLC * Pleural or pericardial effusion greater than 100 ml in volume as documented by appropriate imaging (positron emission tomography \[PET\], computed tomography \[CT\] scan or ultrasound). If an effusion greater than 100 ml is documented by cytology to be free from malignancy and the investigator feels the patient is capable of receiving chemo/radiotherapy for their primary disease/ NSCLC, the investigator should discuss the patient with the study physician at Amgen. Effusions smaller than 100 ml would be acceptable, unless the investigator suspects that the effusion is malignant, in which case the effusions should be evaluated by cytology. Sponsor approval must be obtained before patient is randomized. * Plan to remove the tumor surgically before completing the protocol chemo/radiotherapy course * Shielding of any part of the esophagus during radiotherapy (including posterior spinal cord shielding) * Prior chemotherapy, radiotherapy, or surgery for NSCLC * Prior invasive malignancy during the past 3 years other than non-melanomatous skin cancer. Note: Patients with prior surgically-cured malignancies \[eg, stage I breast cancer or prostate cancer, in-situ carcinoma of the cervix, etc\] are not excluded; however, sponsor approval must be obtained before patient is randomized. * Presence or history of dysphagia or conditions predisposing to dysphagia (eg, uncontrolled gastroesophageal reflux disease \[GERD\], dyspepsia, etc) * History of pancreatitis * Four weeks or less since completion of treatment using an investigational product/device in another clinical study or presence of any unresolved toxicity from previous treatment * Previous treatment on this study or with a fibroblast growth factor * Known to be sero-positive for human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV) * Pregnant or breastfeeding women * Known sensitivity to E. coli derived products * Compromised ability of the patient to give written informed consent and/or to comply with study procedures * Refusal to sign an informed consent form to participate in this study, and sign the hospital information release form, if applicable * Unwilling or unable to complete the patient reported outcome (PRO) questionnaires * Psychological, social, familial, or geographical reasons that would prevent regular follow-up
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Grade 2 or Higher Dysphagia | Start of treatment through Week 16 | Participants underwent acute dysphagia assessments twice weekly during Weeks 1 through 7, and twice weekly thereafter (Weeks 8 through 12) and once weekly after Week 12 until dysphagia resolved to grade ≤ 1 but not beyond Week 16. Dysphagia (difficulty swallowing) was graded using the Common Terminology Criteria for Adverse Events, Version 3.0 (CTCAE v3.0) dysphagia scale according to the following: Grade 1: Symptomatic, able to eat regular diet; Grade 2: Symptomatic and altered eating/swallowing (e.g., altered dietary habits, oral supplements), IV fluids indicated \<24 hours; Grade 3: Symptomatic and severely altered eating/swallowing (e.g., inadequate oral caloric or fluid intake), IV fluids, tube feedings, or total parenteral nutrition (TPN) indicated ≥24 hours; Grade 4: Life-threatening consequences (e.g., obstruction, perforation). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximal Dysphagia Grade | Start of treatment through Week 16 | The mean maximal grade of dysphagia for each participant during the study. Dysphagia (difficulty swallowing) was graded using the Common Terminology Criteria for Adverse Events, Version 3.0 (CTCAE v3.0) dysphagia scale according to the following: Grade 1: Symptomatic, able to eat regular diet; Grade 2: Symptomatic and altered eating/swallowing (e.g., altered dietary habits, oral supplements), IV fluids indicated \<24 hours; Grade 3: Symptomatic and severely altered eating/swallowing (e.g., inadequate oral caloric or fluid intake), IV fluids, tube feedings, or total parenteral nutrition (TPN) indicated ≥24 hours; Grade 4: Life-threatening consequences (e.g., obstruction, perforation). |
| Number of Participants With Severe (Grade 3 or Higher) Dysphagia | Start of treatment through Week 16 | Participants underwent acute dysphagia assessments twice weekly during Weeks 1 through 7, and twice weekly thereafter (Weeks 8 through 12) and once weekly after Week 12 until dysphagia resolved to grade ≤ 1 but not beyond Week 16. Dysphagia (difficulty swallowing) was graded using the Common Terminology Criteria for Adverse Events, Version 3.0 (CTCAE v3.0) dysphagia scale according to the following: Grade 1: Symptomatic, able to eat regular diet; Grade 2: Symptomatic and altered eating/swallowing (e.g., altered dietary habits, oral supplements), IV fluids indicated \<24 hours; Grade 3: Symptomatic and severely altered eating/swallowing (e.g., inadequate oral caloric or fluid intake), IV fluids, tube feedings, or total parenteral nutrition (TPN) indicated ≥24 hours; Grade 4: Life-threatening consequences (e.g., obstruction, perforation). |
| Number of Participants With Unplanned Breaks in Radiotherapy | Week 1 to Week 6 | The number of participants with unplanned breaks in radiotherapy of ≥ 5 days or who discontinued radiotherapy during Week 1 to Week 6. |
| Duration of Grade 2 or Higher Dysphagia | Start of treatment through Week 16 | Duration of grade 2 or higher dysphagia was calculated in days from the onset (first occurrence of grade ≥ 2) to the resolution (grade ≤ 1 after the last grade ≥ 2) of dysphagia. Participants with no assessments were assumed as having grade ≥ 2 dysphagia and with a duration of the mean duration of all participants. |
| Number of Participants Hospitalized | Baseline to Week 16 | — |
| Maximal Body Weight Loss | Baseline through Week 12 | Maximal weight loss observed from Baseline through to Week 12. |
| Maximal Eastern Cooperative Oncology Group (ECOG) Performance Status Increase | Baseline through Week 12 | Maximal increase from Baseline in Eastern Cooperative Oncology Group (ECOG) performance status. ECOG is a scale to assess how a patient's disease is progressing, how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis. Grade 0: Fully active, able to carry on all pre-disease performance without restriction; Grade 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; Grade 2: Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours; Grade 3: Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; Grade 4: Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair; Grade 5: Dead. |
Participant flow
Recruitment details
This study was conducted from 06 January 2005 until 20 December 2007 (last participant's last visit for the acute dysphagia evaluation phase). At the time of this report, the long-term safety follow-up period is ongoing.
Pre-assignment details
100 patients were initially enrolled at 25 sites, however, data from one site could not be used and is excluded from this results analysis.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received a single intravenous (IV) dose of placebo administered 3 days before the initiation of concurrent chemo/radiotherapy, then once weekly during Weeks 1 through 6, typically for a total of 7 doses. | 46 |
| Palifermin Participants received a single IV dose of palifermin at 180 μg/kg administered 3 days before the initiation of concurrent chemo/radiotherapy, then once weekly during Weeks 1 through 6, typically for a total of 7 doses. | 49 |
| Total | 95 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 2 |
| Overall Study | Death | 4 | 2 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Other | 3 | 0 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 3 |
Baseline characteristics
| Characteristic | Placebo | Total | Palifermin |
|---|---|---|---|
| Age, Continuous | 64.2 years STANDARD_DEVIATION 7.7 | 62.9 years STANDARD_DEVIATION 8.9 | 61.6 years STANDARD_DEVIATION 9.8 |
| Disease Stage Stage 3A | 14 participants | 33 participants | 19 participants |
| Disease Stage Stage 3B | 32 participants | 62 participants | 30 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 0 | 21 participants | 42 participants | 21 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 1 | 23 participants | 49 participants | 26 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 2 | 2 participants | 4 participants | 2 participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African-American | 2 Participants | 4 Participants | 2 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Japanese | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White or Causcasian | 43 Participants | 86 Participants | 43 Participants |
| Randomization Strata 3A, 0-1, <5% | 10 participants | 21 participants | 11 participants |
| Randomization Strata 3A, 0-1, 5-10% | 4 participants | 10 participants | 6 participants |
| Randomization Strata 3A, 2, <5% | 1 participants | 3 participants | 2 participants |
| Randomization Strata 3A, 2, 5-10% | 1 participants | 1 participants | 0 participants |
| Randomization Strata 3B, 0-1, <5% | 24 participants | 49 participants | 25 participants |
| Randomization Strata 3B, 0-1, 5-10% | 6 participants | 11 participants | 5 participants |
| Randomization Strata 3B, 2, <5% | 0 participants | 0 participants | 0 participants |
| Randomization Strata 3B, 2, 5-10% | 0 participants | 0 participants | 0 participants |
| Sex: Female, Male Female | 14 Participants | 29 Participants | 15 Participants |
| Sex: Female, Male Male | 32 Participants | 66 Participants | 34 Participants |
| Weight Loss Over Last 3 Months < 5% | 35 participants | 72 participants | 37 participants |
| Weight Loss Over Last 3 Months 5 - 10% | 11 participants | 23 participants | 12 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 45 / 46 | 48 / 48 |
| serious Total, serious adverse events | 30 / 46 | 21 / 48 |
Outcome results
Primary
Number of Participants With Grade 2 or Higher Dysphagia
Participants underwent acute dysphagia assessments twice weekly during Weeks 1 through 7, and twice weekly thereafter (Weeks 8 through 12) and once weekly after Week 12 until dysphagia resolved to grade ≤ 1 but not beyond Week 16. Dysphagia (difficulty swallowing) was graded using the Common Terminology Criteria for Adverse Events, Version 3.0 (CTCAE v3.0) dysphagia scale according to the following: Grade 1: Symptomatic, able to eat regular diet; Grade 2: Symptomatic and altered eating/swallowing (e.g., altered dietary habits, oral supplements), IV fluids indicated \<24 hours; Grade 3: Symptomatic and severely altered eating/swallowing (e.g., inadequate oral caloric or fluid intake), IV fluids, tube feedings, or total parenteral nutrition (TPN) indicated ≥24 hours; Grade 4: Life-threatening consequences (e.g., obstruction, perforation).
Time frame: Start of treatment through Week 16
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Grade 2 or Higher Dysphagia | Yes | 32 participants |
| Placebo | Number of Participants With Grade 2 or Higher Dysphagia | No | 13 participants |
| Placebo | Number of Participants With Grade 2 or Higher Dysphagia | No assessment | 1 participants |
| Palifermin | Number of Participants With Grade 2 or Higher Dysphagia | Yes | 30 participants |
| Palifermin | Number of Participants With Grade 2 or Higher Dysphagia | No | 18 participants |
| Palifermin | Number of Participants With Grade 2 or Higher Dysphagia | No assessment | 1 participants |
p-value: 0.355Cochran-Mantel-Haenszel
Secondary
Duration of Grade 2 or Higher Dysphagia
Duration of grade 2 or higher dysphagia was calculated in days from the onset (first occurrence of grade ≥ 2) to the resolution (grade ≤ 1 after the last grade ≥ 2) of dysphagia. Participants with no assessments were assumed as having grade ≥ 2 dysphagia and with a duration of the mean duration of all participants.
Time frame: Start of treatment through Week 16
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Duration of Grade 2 or Higher Dysphagia | 32.4 days | Standard Deviation 30.1 |
| Palifermin | Duration of Grade 2 or Higher Dysphagia | 25.3 days | Standard Deviation 28 |
p-value: 0.3189Cochran-Mantel-Haenszel
Secondary
Maximal Body Weight Loss
Maximal weight loss observed from Baseline through to Week 12.
Time frame: Baseline through Week 12
Population: Full analysis set with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximal Body Weight Loss | 4.63 kilograms | Standard Deviation 4.13 |
| Palifermin | Maximal Body Weight Loss | 5.44 kilograms | Standard Deviation 4.33 |
p-value: 0.1996Cochran-Mantel-Haenszel
Secondary
Maximal Dysphagia Grade
The mean maximal grade of dysphagia for each participant during the study. Dysphagia (difficulty swallowing) was graded using the Common Terminology Criteria for Adverse Events, Version 3.0 (CTCAE v3.0) dysphagia scale according to the following: Grade 1: Symptomatic, able to eat regular diet; Grade 2: Symptomatic and altered eating/swallowing (e.g., altered dietary habits, oral supplements), IV fluids indicated \<24 hours; Grade 3: Symptomatic and severely altered eating/swallowing (e.g., inadequate oral caloric or fluid intake), IV fluids, tube feedings, or total parenteral nutrition (TPN) indicated ≥24 hours; Grade 4: Life-threatening consequences (e.g., obstruction, perforation).
Time frame: Start of treatment through Week 16
Population: Full analysis set participants with dysphagia assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximal Dysphagia Grade | 1.9 grade | Standard Deviation 1 |
| Palifermin | Maximal Dysphagia Grade | 1.8 grade | Standard Deviation 0.9 |
p-value: 0.5086Cochran-Mantel-Haenszel
Secondary
Maximal Eastern Cooperative Oncology Group (ECOG) Performance Status Increase
Maximal increase from Baseline in Eastern Cooperative Oncology Group (ECOG) performance status. ECOG is a scale to assess how a patient's disease is progressing, how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis. Grade 0: Fully active, able to carry on all pre-disease performance without restriction; Grade 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; Grade 2: Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours; Grade 3: Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; Grade 4: Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair; Grade 5: Dead.
Time frame: Baseline through Week 12
Population: Full analysis set participants with available ECOG data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximal Eastern Cooperative Oncology Group (ECOG) Performance Status Increase | 1.5 units on a scale | Standard Deviation 1.3 |
| Palifermin | Maximal Eastern Cooperative Oncology Group (ECOG) Performance Status Increase | 0.9 units on a scale | Standard Deviation 1.1 |
p-value: 0.0621Cochran-Mantel-Haenszel
Secondary
Number of Participants Hospitalized
Time frame: Baseline to Week 16
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants Hospitalized | Not hospitalized | 15 participants |
| Placebo | Number of Participants Hospitalized | Hospitalized | 31 participants |
| Palifermin | Number of Participants Hospitalized | Hospitalized | 34 participants |
| Palifermin | Number of Participants Hospitalized | Not hospitalized | 15 participants |
p-value: 0.8639Cochran-Mantel-Haenszel
Secondary
Number of Participants With Severe (Grade 3 or Higher) Dysphagia
Participants underwent acute dysphagia assessments twice weekly during Weeks 1 through 7, and twice weekly thereafter (Weeks 8 through 12) and once weekly after Week 12 until dysphagia resolved to grade ≤ 1 but not beyond Week 16. Dysphagia (difficulty swallowing) was graded using the Common Terminology Criteria for Adverse Events, Version 3.0 (CTCAE v3.0) dysphagia scale according to the following: Grade 1: Symptomatic, able to eat regular diet; Grade 2: Symptomatic and altered eating/swallowing (e.g., altered dietary habits, oral supplements), IV fluids indicated \<24 hours; Grade 3: Symptomatic and severely altered eating/swallowing (e.g., inadequate oral caloric or fluid intake), IV fluids, tube feedings, or total parenteral nutrition (TPN) indicated ≥24 hours; Grade 4: Life-threatening consequences (e.g., obstruction, perforation).
Time frame: Start of treatment through Week 16
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Severe (Grade 3 or Higher) Dysphagia | Yes | 13 participants |
| Placebo | Number of Participants With Severe (Grade 3 or Higher) Dysphagia | No | 32 participants |
| Placebo | Number of Participants With Severe (Grade 3 or Higher) Dysphagia | No assessment | 1 participants |
| Palifermin | Number of Participants With Severe (Grade 3 or Higher) Dysphagia | Yes | 11 participants |
| Palifermin | Number of Participants With Severe (Grade 3 or Higher) Dysphagia | No | 37 participants |
| Palifermin | Number of Participants With Severe (Grade 3 or Higher) Dysphagia | No assessment | 1 participants |
p-value: 0.4976Cochran-Mantel-Haenszel
Secondary
Number of Participants With Unplanned Breaks in Radiotherapy
The number of participants with unplanned breaks in radiotherapy of ≥ 5 days or who discontinued radiotherapy during Week 1 to Week 6.
Time frame: Week 1 to Week 6
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Unplanned Breaks in Radiotherapy | Yes | 15 participants |
| Placebo | Number of Participants With Unplanned Breaks in Radiotherapy | No | 29 participants |
| Placebo | Number of Participants With Unplanned Breaks in Radiotherapy | Did not receive radiotherapy | 2 participants |
| Palifermin | Number of Participants With Unplanned Breaks in Radiotherapy | Yes | 9 participants |
| Palifermin | Number of Participants With Unplanned Breaks in Radiotherapy | No | 38 participants |
| Palifermin | Number of Participants With Unplanned Breaks in Radiotherapy | Did not receive radiotherapy | 2 participants |
p-value: 0.1115Cochran-Mantel-Haenszel