Head and Neck Cancer
Conditions
Keywords
recurrent squamous cell carcinoma of the hypopharynx, recurrent squamous cell carcinoma of the larynx, recurrent verrucous carcinoma of the larynx, recurrent squamous cell carcinoma of the lip and oral cavity, recurrent verrucous carcinoma of the oral cavity, metastatic squamous neck cancer with occult primary squamous cell carcinoma, recurrent metastatic squamous neck cancer with occult primary, recurrent squamous cell carcinoma of the oropharynx
Brief summary
RATIONALE: Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs, such as pemetrexed and erlotinib, may make tumor cells more sensitive to radiation therapy. Erlotinib and pemetrexed may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving intensity-modulated radiation therapy together with pemetrexed and erlotinib may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of erlotinib when given together with intensity-modulated radiation therapy and pemetrexed and to see how well they work in treating patients with recurrent or second primary head and neck cancer.
Detailed description
OBJECTIVES: Primary * Evaluate the acute toxicity and feasibility of intensity modulated radiotherapy (IMRT) in combination with radiosensitizing drugs pemetrexed disodium and erlotinib hydrochloride in patients with recurrent or second primary squamous cell carcinoma of the head and neck. (Phase I) * Determine the maximum tolerated dose and recommended phase II dose of erlotinib hydrochloride in these patients. (Phase I) * Determine progression-free survival (PFS) at 1 year in these patients. (Phase II) Secondary * Determine median PFS, median overall survival (OS), and OS at 1 and 2 years in these patients. * Determine objective tumor response as measured by CT scan or MRI in these patients. * Evaluate the acute and chronic toxicity of IMRT in combination with radiosensitizing drugs pemetrexed disodium and erlotinib hydrochloride in these patients. * Evaluate the impact of treatment on quality of life as measured by FACT-H&N, PSS-HN, MD Anderson Dysphagia Inventory (MDADI), and swallowing by direct functional measurements at different time points. * Evaluate the level of phosphorylation of different tyrosine residues within the cytoplasmic domain of EGFR, bound adaptors, as well as markers of downstream pathways activation by nano LC-MS/MS in tumor tissue and correlate with levels of P-AKT and P-ERK by immunohistochemistry and with response to treatment. * Measure the levels of TS and p53 and correlate with treatment response. OUTLINE: This is a phase I, dose-escalation study of erlotinib hydrochloride followed by a phase II study. * Phase I: Patients undergo intensity modulated radiotherapy (IMRT) once daily, 5 days a week, for 6 weeks. Patients receive pemetrexed disodium IV over 10 minutes on day 1 of radiotherapy. Treatment with pemetrexed disodium repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients also receive oral erlotinib hydrochloride once daily beginning on day 1 of radiotherapy and continuing for up to 2 years in the absence of disease progression or unacceptable toxicity. * Phase II: Patients undergo IMRT and receive pemetrexed sodium as in phase I. Patients also receive erlotinib hydrochloride at the maximum tolerated dose determined in phase I. Quality of life is assessed at baseline, weekly during treatment, at 1, 6, and 12 months, and then annually thereafter. After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 1 year, and then annually thereafter.
Interventions
DRUGerlotinib hydrochloride
DRUGpemetrexed disodium
PROCEDUREquality-of-life assessment
RADIATIONintensity-modulated radiation therapy
Sponsors
National Cancer Institute (NCI)
Wake Forest University Health Sciences
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
Inclusion: \* Histologically or cytologically confirmed diagnosis of recurrent or second primary squamous cell carcinoma (SCC) of the head and neck, including any of the following: * Oral cavity * Oropharynx * Hypopharynx * Larynx * Recurrent neck metastases with unknown primary Exception from pathology confirmation of tumor recurrence is accepted for patients who originally had pathologically confirmed SCC of the Head and Neck, the new tumor is located in the head and neck area and it is clinically considered as a recurrence of the original tumor, and a tumor biopsy is technically difficult and would expose the patient to unjustified risk. The treating physicians should agree and document the clinical definition of tumor recurrence and should document the increased risk for biopsy. * Measurable disease by CT scan or MRI OR evaluable disease * No definitive evidence of distant metastasis * Unresectable disease by a preliminary ENT evaluation OR refused surgery * Patients may have received chemotherapy as a component of their primary tumor treatment but not for recurrent or metastatic disease. No prior treatment with systemic anti-EGFR inhibitors or Pemetrexed is permitted * Has undergone prior head and neck radiotherapy (for SCC of the head and neck) to a dose of ≤ 72 Gy that involved most of the recurrent tumor (\> 75%) OR has a second primary tumor volume in areas previously irradiated to \> 45 Gy * The entire tumor volume must be included in a treatment field that limits the total spinal cord dose to 54 Gy (prior plus planned dose) * Must have disease recurrence or persistence for ≥ 6 months after completion of prior radiotherapy * ECOG performance status 0-1 * Age ≥ 18 years * ANC \> 1,500/µL * Platelet count \> 100,000/µL * Total bilirubin \< 1.5 times upper limit of normal (ULN) * AST/ALT \< 2 times ULN * Creatinine \< 1.5 times ULN * Willing and able to take folic acid and vitamin B12 supplementation * Recovered from prior surgery, chemotherapy, or radiotherapy * At least 6 months since prior radiotherapy * At least 5 days since prior aspirin or other non-steroidal anti-inflammatory agents (8 days for long acting agents \[e.g., piroxicam\]) * Fertile patients must use effective contraception Exclusion: * Nasopharyngeal carcinoma * Concurrent uncontrolled illness, including, but not limited to, any of the following: * Ongoing or active infection * Psychiatric illness or social situation that would limit compliance with study requirements * Significant history of uncontrolled cardiac disease (i.e., uncontrolled hypertension; unstable angina; recent myocardial infarction \[within the past 3 months\]; uncontrolled congestive heart failure; or cardiomyopathy with decreased ejection fraction) * Active interstitial lung disease * Presence of third space fluid that cannot be controlled by drainage * Other concurrent investigational agents * Pregnant or nursing * HIV positive
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose of Erlotinib Hydrochloride (Phase I) | 56 Days | Dose at which 100% of participants tolerated the dose |
| Progression-free Survival (PFS) at 1 Year (Phase II) | 1 year | Determine Progression Free Survival at 1 year defined as the percentage of patients who are alive at 1 year after beginning of their concurrent re-irradiation and chemotherapy without loco-regional progression of their disease as measured by CT scan or MRI. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 1 and 2 years | Overall survival of participants reported after 2 years. |
| Evaluation of Acute and Chronic Toxicity | 1 year | Evaluate acute and chronic toxicity of the combined re-irradiation with radiosensitizing drugs: Pemetrexed and Erlotinib. Adverse events with Common Toxicity Criteria grades of 4 and 5 are reported for phase I and II. |
| Change in Quality of Life- FACT H&N | baseline and 12 months | The Functional Assessment of Cancer Therapy-Head and Neck (FACT H&N) consists of 27 core items which assess patient function in four domains: Physical, Social/Family, Emotional, and Functional well-being, which is further supplemented by 12 site specific items to assess for head and neck related symptoms. Each item is rated on a 0 to 4 Likert type scale, and then combined to produce subscale scores for each domain. Score range is 0-156. Higher scores denotes better outcomes |
| Median Progression Free Survival | 2 years | Median Progression Free Survival of participants reported after 2 years. |
| Change in Quality of Life: MDADI | baseline and 12 months | The M.D. Anderson Dysphagia Inventory (MDADI) was used to assess effects of dysphagia on the quality of life of patients with head and neck cancer. It incorporates 3 domains (emotional, functional, and physical) as well as 1 global question. Each subscale with five possible responses scored on a scale of 1 to 5 (strongly agree, agree, no opinion, disagree and strongly disagree). Scores range from 0 (extremely low functioning) to 100 (higher functioning). Higher MDADI score represents better day-to-day functioning and better quality of life. |
| Evaluation of Biomarkers | throughout study completion, up to 2 years | — |
| Objective Tumor Response | 1 year | Objective Tumor Response reported on participants at 1 year (complete, partial, progression, or stable response). |
| Change in Quality of Life: PSS-HN | baseline and 6 months | The Performance Status Scale for Head & Neck Cancer Patients (PSS-HN) is s designed to evaluate performance in areas of functioning most likely affected by head and neck cancer and its treatment, specifically Normalcy of Diet, Eating in Public, and Understandability of Speech. Each subscale is rated from 0 to 100, with higher scores indicating better performance |
| Median Overall Survival | up to 5 years | Median Overall Survival of participants reported after 2 years. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Erlotinib Erlotinib
erlotinib hydrochloride
pemetrexed disodium
quality-of-life assessment
intensity-modulated radiation therapy | 27 |
| Total | 27 |
Baseline characteristics
| Characteristic | Erlotinib |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 7 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Age, Continuous | 62.96 years STANDARD_DEVIATION 7.87 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 0 Participants |
| Race (NIH/OMB) White | 25 Participants |
| Region of Enrollment United States | 27 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 4 | 6 / 6 | 5 / 5 | 8 / 12 |
| other Total, other adverse events | 4 / 4 | 6 / 6 | 5 / 5 | 11 / 11 |
| serious Total, serious adverse events | 3 / 4 | 6 / 6 | 5 / 5 | 5 / 11 |
Outcome results
Primary
Maximum Tolerated Dose of Erlotinib Hydrochloride (Phase I)
Dose at which 100% of participants tolerated the dose
Time frame: 56 Days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Erlotinib | Maximum Tolerated Dose of Erlotinib Hydrochloride (Phase I) | 125 mg |
Primary
Progression-free Survival (PFS) at 1 Year (Phase II)
Determine Progression Free Survival at 1 year defined as the percentage of patients who are alive at 1 year after beginning of their concurrent re-irradiation and chemotherapy without loco-regional progression of their disease as measured by CT scan or MRI.
Time frame: 1 year
Population: Data corresponds to Phase II patients.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Erlotinib | Progression-free Survival (PFS) at 1 Year (Phase II) | 5 Participants |
Secondary
Change in Quality of Life- FACT H&N
The Functional Assessment of Cancer Therapy-Head and Neck (FACT H&N) consists of 27 core items which assess patient function in four domains: Physical, Social/Family, Emotional, and Functional well-being, which is further supplemented by 12 site specific items to assess for head and neck related symptoms. Each item is rated on a 0 to 4 Likert type scale, and then combined to produce subscale scores for each domain. Score range is 0-156. Higher scores denotes better outcomes
Time frame: baseline and 12 months
Population: Data not collected for all participants at 12 months. Data corresponds to Phase II patients.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Erlotinib | Change in Quality of Life- FACT H&N | baseline | 84.87 units on a scale | Standard Deviation 8.19 |
| Erlotinib | Change in Quality of Life- FACT H&N | 12 months | 88.61 units on a scale | Standard Deviation 18.64 |
Secondary
Change in Quality of Life: MDADI
The M.D. Anderson Dysphagia Inventory (MDADI) was used to assess effects of dysphagia on the quality of life of patients with head and neck cancer. It incorporates 3 domains (emotional, functional, and physical) as well as 1 global question. Each subscale with five possible responses scored on a scale of 1 to 5 (strongly agree, agree, no opinion, disagree and strongly disagree). Scores range from 0 (extremely low functioning) to 100 (higher functioning). Higher MDADI score represents better day-to-day functioning and better quality of life.
Time frame: baseline and 12 months
Population: Data not collected on all participants at 12 months. Data corresponds to Phase II patients.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Erlotinib | Change in Quality of Life: MDADI | baseline- global | 64.44 units on a scale | Standard Deviation 26.03 |
| Erlotinib | Change in Quality of Life: MDADI | 12 months- global | 90.0 units on a scale | Standard Deviation 14.14 |
| Erlotinib | Change in Quality of Life: MDADI | baseline- emotion | 70.37 units on a scale | Standard Deviation 9.2 |
| Erlotinib | Change in Quality of Life: MDADI | 12 months- emotion | 78.33 units on a scale | Standard Deviation 2.36 |
| Erlotinib | Change in Quality of Life: MDADI | baseline- function | 65.78 units on a scale | Standard Deviation 12.98 |
| Erlotinib | Change in Quality of Life: MDADI | 12 months- function | 84.0 units on a scale | Standard Deviation 5.66 |
| Erlotinib | Change in Quality of Life: MDADI | baseline- physical | 60.0 units on a scale | Standard Deviation 7.91 |
| Erlotinib | Change in Quality of Life: MDADI | 12 months- physical | 73.75 units on a scale | Standard Deviation 8.84 |
Secondary
Change in Quality of Life: PSS-HN
The Performance Status Scale for Head & Neck Cancer Patients (PSS-HN) is s designed to evaluate performance in areas of functioning most likely affected by head and neck cancer and its treatment, specifically Normalcy of Diet, Eating in Public, and Understandability of Speech. Each subscale is rated from 0 to 100, with higher scores indicating better performance
Time frame: baseline and 6 months
Population: Data not collected for all participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Erlotinib | Change in Quality of Life: PSS-HN | Eating Baseline | 56.25 units on a scale | Standard Deviation 34.72 |
| Erlotinib | Change in Quality of Life: PSS-HN | Eating 6 months | 43.75 units on a scale | Standard Deviation 23.94 |
| Erlotinib | Change in Quality of Life: PSS-HN | Speech Baseline | 81.25 units on a scale | Standard Deviation 11.57 |
| Erlotinib | Change in Quality of Life: PSS-HN | Speech 6 months | 75.0 units on a scale | Standard Deviation 20.41 |
| Erlotinib | Change in Quality of Life: PSS-HN | Diet Baseline | 44.44 units on a scale | Standard Deviation 44.47 |
| Erlotinib | Change in Quality of Life: PSS-HN | Diet 6 months | 25.0 units on a scale | Standard Deviation 50 |
Secondary
Evaluation of Acute and Chronic Toxicity
Evaluate acute and chronic toxicity of the combined re-irradiation with radiosensitizing drugs: Pemetrexed and Erlotinib. Adverse events with Common Toxicity Criteria grades of 4 and 5 are reported for phase I and II.
Time frame: 1 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Erlotinib | Evaluation of Acute and Chronic Toxicity | phase I | 18 events |
| Erlotinib | Evaluation of Acute and Chronic Toxicity | phase II | 6 events |
Secondary
Evaluation of Biomarkers
Time frame: throughout study completion, up to 2 years
Population: Patients refused biopsy, so no data collected.
Secondary
Median Overall Survival
Median Overall Survival of participants reported after 2 years.
Time frame: up to 5 years
Population: Data corresponds to Phase II patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Erlotinib | Median Overall Survival | 1.01 years |
Secondary
Median Progression Free Survival
Median Progression Free Survival of participants reported after 2 years.
Time frame: 2 years
Population: Data corresponds to Phase II patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Erlotinib | Median Progression Free Survival | .71 years |
Secondary
Objective Tumor Response
Objective Tumor Response reported on participants at 1 year (complete, partial, progression, or stable response).
Time frame: 1 year
Population: Data corresponds to Phase II patients.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Erlotinib | Objective Tumor Response | Partial | 5 Participants |
| Erlotinib | Objective Tumor Response | Complete | 7 Participants |
| Erlotinib | Objective Tumor Response | Progression | 4 Participants |
| Erlotinib | Objective Tumor Response | Stable | 2 Participants |
Secondary
Overall Survival
Overall survival of participants reported after 2 years.
Time frame: 1 and 2 years
Population: Data corresponds to Phase II patients.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Erlotinib | Overall Survival | 1 year | 9 Participants |
| Erlotinib | Overall Survival | 2 years | 7 Participants |