Head and Neck Cancer
Conditions
Keywords
SCC Head and Neck Cancer
Brief summary
This is a single-arm, phase II trial to characterize the clinical outcome of standard of care, cetuximab concurrent with radiation, in a special population (head and neck cancer patients who cannot tolerate concurrent chemoradiotherapy due to advanced age, poor performance status or concurrent illness), and to determine if biomarker response to a loading dose of cetuximab is predictive of that outcome.
Detailed description
Primary Objective 1: Determine changes in tumor EGFR, pEGFR, downstream signaling and novel phosphoproteins following a loading dose of cetuximab in patients who are poor candidates for chemoradiation (age =70 years or with significant co-morbidities) and are therefore treated with cetuximab with radiation. Primary Objective 2: Characterize clinical outcomes, including local recurrence, progression-free survival and overall survival in these patients, and correlate these clinical outcomes with the changes in tumor EGFR, pEGFR, downstream signaling, and novel phosphoproteins. Primary Objective 3: Describe the toxicity, in particular mucositis/dysphagia, of this regimen. Secondary Objective 1: Conduct normal mucosa EGFR assessment for comparison with tumor sample. Secondary Objective 2: Correlate HPV presence and titer with p53 status and clinical outcome.
Interventions
DRUGCetuximab
Patients will receive a single dose of cetuximab 400 mg/m (Day 0). On day 7 (+/- 1 day), a repeat biopsy will be performed. Radiation concurrent with weekly cetuximab 250 mg/m.
RADIATION50-60 Gy and 70 Gy
Within approximately 4 days (after single dose of Cetuximab), definitive radiation will begin (70 Gy in 35 fractions to the gross tumor, 50-60 Gy to subclinical target volumes) concurrent with weekly cetuximab 250 mg/m.
Sponsors
University of Michigan Rogel Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
70 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have pathologically-confirmed, previously untreated, clinically accessible (without general anesthesia) locally advanced squamous cell carcinoma of the larynx, hypopharynx, oropharynx, oral cavity, or nonresectable head and neck squamous cell carcinomas of the skin. * Patients will be limited to: * ≥ 70 years of age, OR * with co-morbidities that preclude treatment with standard platinum-based chemotherapy, as determined by the treating physician, OR * KPS ≤ 80, OR * Creatinine clearance \< 30 cc/min * Laboratory criteria: * WBC \> 3500/ul * Granulocyte \> 1500/ul * Platelet count \> 100,000/ul * Total Bilirubin \< 1.5 X ULN * AST and ALT \< 2.5 X ULN * Patients must give documented informed consent to participate in this study.
Exclusion criteria
* Prior head and neck malignancy, or history of other prior non-head and neck malignancy within the past 3 years (excluding skin cancer and early stage treated prostate cancer). * Prior head and neck radiation or chemotherapy. * Documented evidence of distant metastases. * Patients with nasopharyngeal carcinoma. * Any medical or psychiatric illness, which, in the opinion of the principal investigator, would compromise the patient's ability to tolerate this treatment. * Patients with psychiatric/social situations that would limit compliance with study requirements are not eligible. * Patients with prior anti-epidermal growth-factor receptor antibody therapy (antibody or small molecule). * Patients residing in prison.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Tumor Phosphorylated EGFR (pEGFR) | At baseline (pre-loading dose) and day 7 post-loading dose | The ratio (fold change) of tumor pEGFR post-loading dose/pre-loading dose of cetuximab. Reported as the mean of fold changes across all participants who had an evaluable tumor sample. |
| Overall Survival Rate | At 1 and 2 Years | Percentage of participants alive at 1 and 2 years after enrollment. |
| Number of Participants With Treatment Related Toxicities | 3 years | Toxicities are measured by number of participants who experience one or more types or indicator of toxicity, shown as all grades and grades 3-4. As each participant could have multiple toxicities, the total number of incidents outnumbers the number of participants. Toxicities are graded according to the CTCAE v4. |
| Mean Change in Tumor Epidermal Growth Factor Receptor (EGFR) | At baseline (pre-loading dose) and day 7 post-loading dose | The ratio (fold change) of tumor EGFR post-loading dose/pre-loading dose of cetuximab. Reported as the mean of fold changes across all participants who had an evaluable tumor sample. |
| Progression Free Survival Rate | At 1 and 2 years | Percentage of participants who survived without recurrent disease, from the time of enrollment to 1 and 2 years. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Tumor pEGFR Level Relative to pEGFR in Normal Mucosa | At baseline (pre-loading dose) and day 7 post-loading dose | Normal mucosa pEGFR was assessed for comparison with pEGFR in tumor sample. The fold change in tumor pEGFR level post-loading dose/pre loading dose of cetuximab, relative to fold change in normal mucosa pEGFR level post-loading dose/pre-loading dose of cetuximab was summarized across all participants who had an evaluable tumor sample and normal mucosa sample. The value reported is the ratio of fold change in tumor/fold change in buccal pEGFR. |
| Change in Tumor EGFR Level Relative to EGFR in Normal Mucosa | At baseline (pre-loading dose) and day 7 post-loading dose | Normal mucosa EGFR was assessed for comparison with EGFR in tumor sample. The fold change in tumor EGFR level at post-loading dose/pre-loading dose of cetuximab, relative to fold change in normal mucosa EGFR level post-loading dose/pre-loading dose of cetuximab was summarized across all participants who had an evaluable tumor sample and normal mucosa sample. The value reported is the ratio of fold change in tumor/fold change in buccal EGFR. |
Countries
United States
Participant flow
Pre-assignment details
2 participants withdrew before receiving treatment
Participants by arm
| Arm | Count |
|---|---|
| Treatment: Cetuximab + RT Patients received a single loading dose of cetuximab and a cetuximab infusion delivered once a week during radiotherapy. | 21 |
| Total | 21 |
Baseline characteristics
| Characteristic | Treatment: Cetuximab + RT |
|---|---|
| Age, Continuous | 65.6 years |
| Cancer Location Auditory Canal | 1 Participants |
| Cancer Location Hypopharynx | 1 Participants |
| Cancer Location Oral Cavity | 2 Participants |
| Cancer Location Oropharynx | 16 Participants |
| Cancer Location Unknown primary | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants |
| HPV Status Negative | 6 Participants |
| HPV Status Positive | 10 Participants |
| HPV Status Unknown | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 17 Participants |
| Smoking Status No | 1 Participants |
| Smoking Status Yes, current | 7 Participants |
| Smoking Status Yes, past | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 12 / 21 |
| other Total, other adverse events | 20 / 21 |
| serious Total, serious adverse events | 12 / 21 |
Outcome results
Primary
Mean Change in Tumor Epidermal Growth Factor Receptor (EGFR)
The ratio (fold change) of tumor EGFR post-loading dose/pre-loading dose of cetuximab. Reported as the mean of fold changes across all participants who had an evaluable tumor sample.
Time frame: At baseline (pre-loading dose) and day 7 post-loading dose
Population: 15 participants had a sample size sufficient for EGFR analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment: Cetuximab + RT | Mean Change in Tumor Epidermal Growth Factor Receptor (EGFR) | 0.56 fold change |
Primary
Mean Change in Tumor Phosphorylated EGFR (pEGFR)
The ratio (fold change) of tumor pEGFR post-loading dose/pre-loading dose of cetuximab. Reported as the mean of fold changes across all participants who had an evaluable tumor sample.
Time frame: At baseline (pre-loading dose) and day 7 post-loading dose
Population: 10 participants had a sample size sufficient for pEGFR analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment: Cetuximab + RT | Mean Change in Tumor Phosphorylated EGFR (pEGFR) | 0.81 fold change |
Primary
Number of Participants With Treatment Related Toxicities
Toxicities are measured by number of participants who experience one or more types or indicator of toxicity, shown as all grades and grades 3-4. As each participant could have multiple toxicities, the total number of incidents outnumbers the number of participants. Toxicities are graded according to the CTCAE v4.
Time frame: 3 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment: Cetuximab + RT | Number of Participants With Treatment Related Toxicities | All grades: Dysphagia | 14 participants |
| Treatment: Cetuximab + RT | Number of Participants With Treatment Related Toxicities | All Grades: Cutaneous Toxicity | 16 participants |
| Treatment: Cetuximab + RT | Number of Participants With Treatment Related Toxicities | All Grades: Mucositis | 19 participants |
| Treatment: Cetuximab + RT | Number of Participants With Treatment Related Toxicities | All grades: Hematologic Toxicity | 3 participants |
| Treatment: Cetuximab + RT | Number of Participants With Treatment Related Toxicities | Grades 3-4: Cutaneous Toxicity | 4 participants |
| Treatment: Cetuximab + RT | Number of Participants With Treatment Related Toxicities | Grades 3-4: Mucositis | 8 participants |
| Treatment: Cetuximab + RT | Number of Participants With Treatment Related Toxicities | Grades 3-4: Dysphagia | 5 participants |
| Treatment: Cetuximab + RT | Number of Participants With Treatment Related Toxicities | Grades 3-4: Hematologic Toxicity | 0 participants |
Primary
Overall Survival Rate
Percentage of participants alive at 1 and 2 years after enrollment.
Time frame: At 1 and 2 Years
Population: Patients who completed the full course of cetuximab+RT or had cetuximab+RT stopped for toxicity.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment: Cetuximab + RT | Overall Survival Rate | 1 year | 68.8 percentage of participants |
| Treatment: Cetuximab + RT | Overall Survival Rate | 2 years | 47.6 percentage of participants |
Primary
Progression Free Survival Rate
Percentage of participants who survived without recurrent disease, from the time of enrollment to 1 and 2 years.
Time frame: At 1 and 2 years
Population: Patients who completed the full course of cetuximab+RT or had cetuximab+RT stopped for toxicity.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment: Cetuximab + RT | Progression Free Survival Rate | 1 year | 47.8 percentage of participants |
| Treatment: Cetuximab + RT | Progression Free Survival Rate | 2 year | 37.2 percentage of participants |
Secondary
Change in Tumor EGFR Level Relative to EGFR in Normal Mucosa
Normal mucosa EGFR was assessed for comparison with EGFR in tumor sample. The fold change in tumor EGFR level at post-loading dose/pre-loading dose of cetuximab, relative to fold change in normal mucosa EGFR level post-loading dose/pre-loading dose of cetuximab was summarized across all participants who had an evaluable tumor sample and normal mucosa sample. The value reported is the ratio of fold change in tumor/fold change in buccal EGFR.
Time frame: At baseline (pre-loading dose) and day 7 post-loading dose
Population: 6 participants had a sample size sufficient for EGFR analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment: Cetuximab + RT | Change in Tumor EGFR Level Relative to EGFR in Normal Mucosa | 0.84 ratio |
Secondary
Change in Tumor pEGFR Level Relative to pEGFR in Normal Mucosa
Normal mucosa pEGFR was assessed for comparison with pEGFR in tumor sample. The fold change in tumor pEGFR level post-loading dose/pre loading dose of cetuximab, relative to fold change in normal mucosa pEGFR level post-loading dose/pre-loading dose of cetuximab was summarized across all participants who had an evaluable tumor sample and normal mucosa sample. The value reported is the ratio of fold change in tumor/fold change in buccal pEGFR.
Time frame: At baseline (pre-loading dose) and day 7 post-loading dose
Population: 7 participants had a sample size sufficient for pEGFR analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment: Cetuximab + RT | Change in Tumor pEGFR Level Relative to pEGFR in Normal Mucosa | 4.69 ratio |
Post Hoc
Freedom From Local Regional Progression (FFLRP)
Percentage of participants without local or regional failure from the time of enrollment to 1 and 2 years.
Time frame: At 1 and 2 years
Population: Patients who completed the full course of cetuximab+RT or had cetuximab+RT stopped for toxicity.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment: Cetuximab + RT | Freedom From Local Regional Progression (FFLRP) | 1 year | 63.9 percentage of participants |
| Treatment: Cetuximab + RT | Freedom From Local Regional Progression (FFLRP) | 2 years | 51.2 percentage of participants |