Head and Neck Cancer, Squamous Cell Carcinoma of the Head and Neck
Conditions
Keywords
Head and neck cancer, Squamous cell carcinoma, Metastatic, Recurrent, Phase II, Carboplatin, Paclitaxel, Cetuximab
Brief summary
This is a non-randomized, open-label phase II trial of 38 patients with recurrent or metastatic SCCHN. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 with good organ function and will be treated with six weekly cycles of carboplatin, paclitaxel and cetuximab. Following assessment of response, the treating physician at their discretion may continue to treat with weekly cetuximab as maintenance until disease progression. The study is designed to evaluate whether this regimen improves median overall survival (OS) as compared to an historical control population treated with a platinum plus 5-fluorouracil (5-FU). There is currently no agreed upon first line therapy for recurrent or metastatic SCCHN; regimen options are highly toxic, inconvenient and resource intensive. Our study regimen has been used extensively for induction therapy and off-protocol in palliative care, but treatment outcomes have yet to be defined by a clinical trial.
Detailed description
Because of their high response rates and low toxicity, the taxane, carboplatin, cetuximab regimens have frequently been adapted for use in the palliative setting. At UNC, we have observed high rates of response, leading to symptomatic benefit and low toxicity. Further, the regimen de-medicalizes the patient's life in several important ways. First, unlike with the EXTREME regimen, no PORT or 4 day infusion is required. Second, the regimen gives only six weeks of cytotoxic therapy. Finally, in our experience there is a low rate of severe toxicity and this, coupled with the high rate of response, may improve quality of life. We are not aware of any presented or published results on the use of this combination in palliative therapy; with the adoption of this regimen in clinical practice, documentation of its benefit via conduct of a clinical trial is needed. We propose a study designed to detect an improvement in median OS versus a historical control. The control arm from the EXTREME trial achieved a median OS of 7.4 months. We hypothesize that a less toxic and more effective 3-drug regimen will result in improved median OS compared with the control arm from EXTREME (median 7.4 months). The toxicity associated with EXTREME is primarily attributable to the cisplatin and 5FU cytotoxic backbone as its toxicity has been consistent in multiple studies of both palliative therapy and induction therapy. If a 4-month improvement in OS is achieved with acceptable toxicity, we will consider this regimen worth of further study. Secondary objectives will include characterizing changes in quality of life (QoL), symptoms and toxicities. Patients will be encouraged to co-enroll into the UNCseq protocol for further exploration of associations between genetic changes and clinical outcomes.
Interventions
DRUGCetuximab
400mg/m2 IV (in the vein) on day 1 of week 1 and 250mg/m2 IV (in the vein) on day 1 of weeks 2-6. Patients with stable disease may continue on maintenance therapy at the 250mg/m2 dose until disease progression.
DRUGPaclitaxel
135mg/m2 IV (in the vein) on day 1 of each 1 week for 6 weeks.
DRUGCarboplatin
AUC2, IV (in the vein) on day 1 of each 1 week for 6 weeks.
Sponsors
UNC Lineberger Comprehensive Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years old * Histologically or cytologically confirmed recurrent or metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN). All primary sites are eligible excluding WHO type III or EBV nasopharyngeal (WHO type I and WHO type II allowed as long as they are EBV negative) * ECOG performance status 0-1 * Adequate organ and marrow function as defined below. Laboratory tests should be completed within 14 days prior to registration: ANC greater than or equal to 1,500/mm3, Platelets greater than or equal to 100,000/mm3, HgB greater than 9g/dL (acceptable to reach this by transfusion), Total bilirubin less than or equal to 1.5mg/dL, Albumin greater than 2.5 g/dL, AST(SGOT)/ALT(SGPT) less than or equal to 2.5X institutional upper limit of normal, alkaline phosphatase less than or equal to 2.5 x upper limit of normal, GFR greater than 30 mL/min (by standard Cockroft and Gault formula or measured via 24 hour urine collection) * Women of childbearing potential (WOCBP) with negative serum or urine pregnancy test within 7 days of D1 of treatment * WOCBP and men must agree to use adequate contraception prior to study entry and for duration of treatment under this protocol; adequate contraception is defined as any medically recommended method (or combination of methods) per standard of care. * Cancer must be considered incurable by the treating clinician * Ability to understand and willingness to sign a written informed consent document
Exclusion criteria
* History of prior cumulative exposure to \> 300mg/m2 cisplatin, AUC of 18 of carboplatin, or their combined equivalent within one year prior to enrollment * Surgery or radiation within the four weeks prior to D1 of treatment under this protocol * Prior systemic chemotherapy unless it was part of definitive-intent (curative intent) treatment more than 6 months before study entry * Other active, invasive malignancy requiring ongoing therapy or expected to require systemic therapy within two years; localized squamous cell carcinoma of the skin, basal-cell carcinoma of the skin, carcinoma in-situ of the cervix, or other malignancies requiring locally ablative therapy only will not result in exclusion * Pregnant or lactating female
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Overall Survival | 36 months | Overall survival after treatment with weekly carboplatin, paclitaxel and cetuximab for 6 weeks with or without the addition of maintenance weekly cetuximab is defined as the time from D1 of treatment under this protocol until death as a result of any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression Free Survival | 36 months | Progression events will be defined per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions Progression free survival after treatment with weekly carboplatin, paclitaxel and cetuximab for 6 weeks with or without the addition of maintenance weekly cetuximab is defined as the time from Day 1 of treatment until progression or death as a result of any cause. |
| Overall Response Rate by Participants | 6 weeks | Number of complete response (CR) and partial response (PR) after study treatment with weekly carboplatin, paclitaxel, and cetuximab for 6 weeks. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT scan: CR is defined as disappearance of all target lesions; and PR as \>=30% decrease in the sum of the longest diameter of target lesions |
| Incidence of Adverse Events | 18 weeks | Grade 3 and 4 toxicities associated with this combined chemotherapy regimen as assessed by clinician assessment using the NCI Common Terminology Criteria for Adverse Events,a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care Activities of daily living (ADL). Grade 4 Life-threatening consequences; urgent intervention indicated. Describe patient reported symptoms associated with this regimen. |
| Head and Neck Quality of Life Assessments | Baseline, End of treatment (EOT), First follow-up visit (8-12 weeks after EOT) | Quality of life (QOL) as measured by the Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN) questionnaire. The FACT-HN is the FACT-General (FACT-G) and a head and neck cancer specific, 12 item subscale given at baseline, at end of treatment, and at first follow-up visit. The FACT-G is a 27 item measure of general QOL assessing function in 4 domains: physical well-being (PWB), social-family well-being (SFWB), emotional well-being (EWB) and functional well-being (FWB). Items are rated by patients on a Likert scale from 0 to 4, with all subscales summed to give a total score with a range of 0-148 Higher scores represent better QOL. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from the University of North Carolina at Chapel Hill Hospitals and Bon Secours Virginia Health System June 16, 2014 to February 27, 2017
Pre-assignment details
Nineteen subjects were consented to this trial. Of these, 3 were not eligible, 2 withdrew before treatment. 14 subjects were treated.
Participants by arm
| Arm | Count |
|---|---|
| Carboplatin, Paclitaxel and Cetuximab A 6 week course of weekly carboplatin, paclitaxel, and cetuximab will be administered to 38 patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Cetuximab may be continued if the patient and physician agree. Within 3 weeks of the end of protocol therapy, response will be assessed, and if the patient has achieved at least stable disease, the treating physician may continue to treat with weekly cetuximab at their discretion until disease progression. Patients will be followed for a maximum of 3 years after the end of the 6 week treatment phase.
Cetuximab: 400mg/m2 IV (in the vein) on day 1 of week 1 and 250mg/m2 IV (in the vein) on day 1 of weeks 2-6. Patients with stable disease may continue at the 250mg/m2 dose until disease progression.
Paclitaxel: 135mg/m2 IV (in the vein) on day 1 of each 1 week for 6 weeks.
Carboplatin: AUC2, IV (in the vein) on day 1 of each 1 week for 6 week | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 5 |
| Overall Study | Death | 1 |
| Overall Study | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Carboplatin, Paclitaxel and Cetuximab |
|---|---|
| Age, Continuous | 62 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| human papillomavirus (HPV) infection status Negative | 4 Participants |
| human papillomavirus (HPV) infection status Positive | 5 Participants |
| human papillomavirus (HPV) infection status Unknown | 5 Participants |
| M Stage M0 | 8 Participants |
| M Stage M1 | 6 Participants |
| N Stage N0 | 3 Participants |
| N Stage N1 | 1 Participants |
| N Stage N2b | 8 Participants |
| N Stage Not reported | 1 Participants |
| N Stage Nx | 1 Participants |
| P16 Negative | 5 Participants |
| P16 Positive | 5 Participants |
| P16 Unknown | 4 Participants |
| Primary Tumor Site Glottis | 1 Participants |
| Primary Tumor Site Hypopharynx | 1 Participants |
| Primary Tumor Site Lymph Nodes | 1 Participants |
| Primary Tumor Site Oral Cavity | 7 Participants |
| Primary Tumor Site Ororpharynx | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 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 | 1 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Region of Enrollment United States | 14 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 13 Participants |
| T Stage T1 | 1 Participants |
| T Stage T2 | 5 Participants |
| T Stage T3 | 2 Participants |
| T Stage T4a | 4 Participants |
| T Stage Tx | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 12 / 14 |
| other Total, other adverse events | 14 / 14 |
| serious Total, serious adverse events | 6 / 14 |
Outcome results
Primary
Median Overall Survival
Overall survival after treatment with weekly carboplatin, paclitaxel and cetuximab for 6 weeks with or without the addition of maintenance weekly cetuximab is defined as the time from D1 of treatment under this protocol until death as a result of any cause.
Time frame: 36 months
Population: Two patients who received treatment were not analyzed after they withdrew from the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carboplatin, Paclitaxel and Cetuximab | Median Overall Survival | 231 Days |
Secondary
Head and Neck Quality of Life Assessments
Quality of life (QOL) as measured by the Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN) questionnaire. The FACT-HN is the FACT-General (FACT-G) and a head and neck cancer specific, 12 item subscale given at baseline, at end of treatment, and at first follow-up visit. The FACT-G is a 27 item measure of general QOL assessing function in 4 domains: physical well-being (PWB), social-family well-being (SFWB), emotional well-being (EWB) and functional well-being (FWB). Items are rated by patients on a Likert scale from 0 to 4, with all subscales summed to give a total score with a range of 0-148 Higher scores represent better QOL.
Time frame: Baseline, End of treatment (EOT), First follow-up visit (8-12 weeks after EOT)
Population: Two patients who received treatment did not complete the measures at any timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Carboplatin, Paclitaxel and Cetuximab | Head and Neck Quality of Life Assessments | QOL at Baseline | 92.5 score on a scale |
| Carboplatin, Paclitaxel and Cetuximab | Head and Neck Quality of Life Assessments | QOL at End of Treatment | 87 score on a scale |
| Carboplatin, Paclitaxel and Cetuximab | Head and Neck Quality of Life Assessments | QOL at First Follow-up | 88 score on a scale |
Secondary
Incidence of Adverse Events
Grade 3 and 4 toxicities associated with this combined chemotherapy regimen as assessed by clinician assessment using the NCI Common Terminology Criteria for Adverse Events,a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care Activities of daily living (ADL). Grade 4 Life-threatening consequences; urgent intervention indicated. Describe patient reported symptoms associated with this regimen.
Time frame: 18 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Carboplatin, Paclitaxel and Cetuximab | Incidence of Adverse Events | Small Intestinal Obstruction | 1 incidents |
| Carboplatin, Paclitaxel and Cetuximab | Incidence of Adverse Events | Fatigue | 2 incidents |
| Carboplatin, Paclitaxel and Cetuximab | Incidence of Adverse Events | Gait Disturbance | 1 incidents |
| Carboplatin, Paclitaxel and Cetuximab | Incidence of Adverse Events | Infusion Related Reaction | 1 incidents |
| Carboplatin, Paclitaxel and Cetuximab | Incidence of Adverse Events | Sepsis | 1 incidents |
| Carboplatin, Paclitaxel and Cetuximab | Incidence of Adverse Events | Lymphocyte Count Decreased | 3 incidents |
| Carboplatin, Paclitaxel and Cetuximab | Incidence of Adverse Events | Neutrophil Count Decreased | 6 incidents |
| Carboplatin, Paclitaxel and Cetuximab | Incidence of Adverse Events | Platelet Count Decreased | 1 incidents |
| Carboplatin, Paclitaxel and Cetuximab | Incidence of Adverse Events | White Blood Cell Decreased | 7 incidents |
| Carboplatin, Paclitaxel and Cetuximab | Incidence of Adverse Events | Hypernatremia | 1 incidents |
| Carboplatin, Paclitaxel and Cetuximab | Incidence of Adverse Events | Hypoalbuminemia | 1 incidents |
| Carboplatin, Paclitaxel and Cetuximab | Incidence of Adverse Events | Hypomagnesemia | 1 incidents |
| Carboplatin, Paclitaxel and Cetuximab | Incidence of Adverse Events | Myalgia | 1 incidents |
| Carboplatin, Paclitaxel and Cetuximab | Incidence of Adverse Events | Pneumothorax | 1 incidents |
| Carboplatin, Paclitaxel and Cetuximab | Incidence of Adverse Events | Dry Skin | 1 incidents |
| Carboplatin, Paclitaxel and Cetuximab | Incidence of Adverse Events | Rash Acneiform | 5 incidents |
Secondary
Median Progression Free Survival
Progression events will be defined per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions Progression free survival after treatment with weekly carboplatin, paclitaxel and cetuximab for 6 weeks with or without the addition of maintenance weekly cetuximab is defined as the time from Day 1 of treatment until progression or death as a result of any cause.
Time frame: 36 months
Population: Two patients who received treatment were not analyzed after they withdrew from the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carboplatin, Paclitaxel and Cetuximab | Median Progression Free Survival | 132 Days |
Secondary
Overall Response Rate by Participants
Number of complete response (CR) and partial response (PR) after study treatment with weekly carboplatin, paclitaxel, and cetuximab for 6 weeks. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT scan: CR is defined as disappearance of all target lesions; and PR as \>=30% decrease in the sum of the longest diameter of target lesions
Time frame: 6 weeks
Population: Two patients who received treatment were not analyzed after they withdrew from the study.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Carboplatin, Paclitaxel and Cetuximab | Overall Response Rate by Participants | CR | 1 Participants |
| Carboplatin, Paclitaxel and Cetuximab | Overall Response Rate by Participants | PR | 6 Participants |
| Carboplatin, Paclitaxel and Cetuximab | Overall Response Rate by Participants | Neither CR nor PR | 5 Participants |