Trial of 2 Cycles of Induction Chemo With Abraxane, Cetuximab, Cisplatin, & 5-FU for Advanced Head and Neck Cancer

Study Overview
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Brief Summary
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This phase two trial will determine the tumor response rate at the primary site and at involved regional nodes to two cycles of an IC regimen of weekly Abraxane and cetuximab given in combination with cisplatin and 5-FU in patients with local regionally advanced HNSCC.

Detailed Description
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Primary objective: To determine the clinical CR rate (CR-p) at the primary tumor site to an IC regimen of weekly Abraxane and cetuximab with CF (ACCF) given for two cycles (over 6 weeks) in patients with locally advanced non-metastatic HNSCC. The assessment of primary tumor site response will be performed by the treating physician by careful clinical examination using WHO criteria. Radiographic studies will also be performed to assess primary tumor site response but will be used primarily to confirm lack of disease progression that may not be detected based on clinical examination alone. The secondary objectives include: Document the clinical PR rate (PR-p) at the primary tumor site with this IC regimen Document the clinical CR and PR rates at the involved regional nodes (CR-n and PR-n) with this IC regimen Document the clinical overall CR rate (CR-o) (defined as achievement of a CR at the primary tumor site and at the involved regional nodes) and the clinical overall PR rate (PR-o) with this IC regimen Document the CR (CR-p, CR-n, and CR-o) and PR (PR-p, PR-n, and PR-o) rates by FDG uptake on PET scan after this IC regimen Document radiographic CR (CR-p, CR-n, and CR-o) and PR (PR-p, PR-n, and PR-o) rates as assessed by conventional CT scan using RECIST criteria after this IC regimen. Correlate primary tumor site, nodal and overall tumor response rates based on WHO criteria of assessment with that based on CT scan and FDG-PET/CT. Document and quantify SPARC expression by IHC in primary tumor tissue obtained at baseline in each patient and attempt to correlate these results with primary tumor site response to ACCF. Document and grade AE's with this IC regimen with a pre-planned safety analysis after the first ten patients have completed the IC regimen. Determine the overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) of this patient population.

Official Title
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Trial to Determine the CR Rate at the Primary Tumor Site After 2 Cycles of Induction Chemo With Abraxane, Cetuximab, Cisplatin, & 5-FU for Advanced Head & Neck Carcinoma Treated With Definitive Concurrent Cisplatin & Radiation Therapy

Conditions
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Squamous Cell Carcinoma of the Head and Neck

Intervention / Treatment
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* Drug: Abraxane
* Drug: Cetuximab
* Drug: Cetuximab
* Drug: Cisplatin
* Drug: 5-FU
* Radiation: Radiation (Post induction)
* Drug: Cisplatin
* Drug: Cetuximab


Participation Criteria
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Eligibility Criteria
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Inclusion Selected Stages 3 and 4a/b HNSCC: All patients must have T2-T4 primary tumors. Patients with T1 tumors will be excluded. Although most of these patients will have regional nodal disease, patients with no nodal disease will also be eligible. Oropharynx, hypopharynx, larynx, and oral cavity sub-sites only. Patients with nasopharyngeal, sinus and other sub-sites of the head and neck, or unknown primary SCC of the head and neck will NOT be eligible. Age ≥18 years Signed informed consent. ECOG Performance Status (PS) of 0-2 (Appendix 1). Adequate vital organ function (serum creatinine < 1.8 mg/dl, total bilirubin </= 1.5 mg/dl, ALT and AST </= 2.5 x ULN, alkaline phosphatase </= 2.5 x ULN) and hematopoietic function (ANC >/= 1500/ul, Platelets > 100,000/ul, HGB > 9.0 g/dl). Patients with reproductive potential must use an effective method of contraception to avoid pregnancy for the duration of the trial and for three months after completing treatment. If female of childbearing potential, the patient must have a negative pregnancy test. Exclusion Criteria: Peripheral neuropathy > Grade 1. Prior chemotherapy, EGFR targeted therapy or radiation therapy for HNSCC. History of prior invasive malignancy diagnosed within the last three years other than local stage non-melanoma skin cancer. Be taking cimetidine or allopurinol. Patients must discontinue taking the medication for one week before receiving treatment with Abraxane. Be taking cimetidine or allopurinol. Patients must discontinue taking the medication for one week before receiving treatment with Abraxane.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Induction chemotherapy followed by Radiation therapy plus Cisplatin Induction chemotherapy: Abraxane 100 mg/m2 IVPB, Day 1, 8, and 15 of cycles 1, 2, and 3. Cetuximab 400 mg/m2 IVPB, Day 1, cycle 1. Cetuximab 250 mg/m2 IVPB, Day 8 and 15 cycle 1, 2 and 3. Cisplatin 75 mg/m2 IVPB, Day 1, cycles 1, 2, and 3. 5-FU 750 mg/m2 CIVI, Day 1, 2 and 3, cycles 1, 2, and 3. Post-Induction: Radiation - Monday-Friday weeks 1-7 with concurrent Cisplatin 100 mg/m2 IVPB on radiation day 1, 22, and 42. | Drug: Abraxane<br>* 100 mg/m2 IVPB, Day 1, 8 and 15 of cycles 1, 2, and 3<br>Drug: Cetuximab<br>* 400 mg/m2 IVPB, Day 1, cycle 1<br>Drug: Cetuximab<br>* 250 mg IVPB, Day 8 and 15 cycle 1, Day 1, 8 and 15 of cycles 2 and 3<br>Drug: Cisplatin<br>* 75 mg/m2 IVPB Day 1, cycles 1, 2 and 3<br>Drug: 5-FU<br>* 750 mg/m2 CIVI Day 1, 2 and 3, cycles 1, 2 and 3<br>Radiation: Radiation (Post induction)<br>* Monday-Friday, weeks 1-7<br>Drug: Cisplatin<br>* (Post induction) Cisplatin 100 mg/m2 IVPB on radiation day 1, 22 and 42<br>|
| Experimental: 2<br>Induction chemotherapy followed by Radiation therapy plus Cetuximab Induction chemotherapy: Abraxane 100 mg/m2 IVPB, Day 1, 8, and 15 of cycles 1, 2, and 3. Cetuximab 400 mg/m2 IVPB, Day 1, cycle 1. Cetuximab 250 mg/m2 IVPB, Day 8 and 15 cycle 1, 2 and 3. Cisplatin 75 mg/m2 IVPB, Day 1, cycles 1, 2, and 3. 5-FU 750 mg/m2 CIVI, Day 1, 2 and 3, cycles 1, 2, and 3. Post-Induction: Radiation - Monday-Friday weeks 1-7 with concurrent Cetuximab (for patients who cannot receive cisplatin) will begin (+/- 3 days) before starting radiation therapy at 400 mg/m2 IVPB. Subsequent doses of cetuximab will be given weekly at 250 mg/m2 IVPB | Drug: Abraxane<br>* 100 mg/m2 IVPB, Day 1, 8 and 15 of cycles 1, 2, and 3<br>Drug: Cetuximab<br>* 400 mg/m2 IVPB, Day 1, cycle 1<br>Drug: Cetuximab<br>* 250 mg IVPB, Day 8 and 15 cycle 1, Day 1, 8 and 15 of cycles 2 and 3<br>Drug: Cisplatin<br>* 75 mg/m2 IVPB Day 1, cycles 1, 2 and 3<br>Drug: 5-FU<br>* 750 mg/m2 CIVI Day 1, 2 and 3, cycles 1, 2 and 3<br>Radiation: Radiation (Post induction)<br>* Monday-Friday, weeks 1-7<br>Drug: Cetuximab<br>* (Post-induction) Cetuximab (for patients who cannot receive cisplatin) will begin (+/- 3 days) before starting radiation therapy at 400 mg/m2 IVPB. Subsequent doses of cetuximab will be given weekly at 250 mg/m2 IVPB<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Complete Response Rate at the Primary Tumor | Clinical exam included laryngoscopy in office or operating room. Complete response rate includes complete response (CR) which is defined as 100% decrease in tumor size and it also includes near complete response (near CR) defined as 95-99% decrease in tumor size. | post-2 cycles of induction (approximately 42 days from start of treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Partial Response Rate at the Primary Tumor | Clinical exam included laryngoscopy in office or operating room. Partial response rate (PR) defined as 50% to 94% decrease in tumor size. | post-2 cycles of induction therapy (approximately 42 days from start of treatment) | 
| Clinical Complete and Partial Response Rates to the Involved Regional Nodes | Clinical exam consisted of physical exam of neck in office. Complete response rate includes complete response (CR) which is defined as 100% decrease in tumor size and near complete response (near CR) defined as 95-99% decrease in tumor size. Partial response rate defined as 50% to 94% decrease in tumor size. | post-2 cycles of induction therapy (approximately 42 days from start of treatment) | 
| Clinical Overall Complete and Partial Response Rates | Clinical exam included laryngoscopy in office or operating room. Clinical exam consisted of physical exam of neck in office. Complete response rate includes complete response (CR) which is defined as 100% decrease in tumor size and it also includes near complete response (near CR) defined as 95-99% decrease in tumor size. Partial response rate defined as 50% to 94% decrease in tumor size. | post-2 cycles of induction therapy (approximately 42 days) | 
| Complete and Partial Response Rates of Primary Tumor by FDG Uptake on PET Scan | Complete response rate defined as complete resolution of the metabolically active primary tumor. Partial response rate defined as 20% or greater decrease in maximum SUV [SUV g/ml) = ROI activity (mCi/ml) / (injected dose (mCi/body weight(g))] from baseline. No unequivocal metabolic progression of non-target disease, and no unequivocal new lesions. | post-2 cycles of induction therapy (approximately 42 days from start of treatment) | 
| Complete and Partial Response Rates of Involved Lymph Nodes by FDG Uptake on PET Scan | Complete response rate defined as complete resolution of the metabolically active primary tumor. Partial response rate defined as 20% or greater decrease in maximum SUV [SUV g/ml) = ROI activity (mCi/ml) / (injected dose (mCi/body weight(g))] from baseline. No unequivocal metabolic progression of non-target disease, and no unequivocal new lesions. | post-2 cycles of induction therapy (approximately 42 days from start of treatment) | 
| Radiographic Complete and Partial Response Rates of Primary Tumor as Assessed by Conventional CT Scan Using RECIST Criteria | Complete response rate per RECIST criteria is defined as disappearance of all target lesions. Partial response rate per RECIST criteria is defined as at least a 30% decrease in the sum of the longest diameter of target lesions taking as reference the baseline sum longest diameter. | post-2 cycles of induction therapy (approximately 42 days from start of treatment) | 
| Radiographic Complete and Partial Response Rates of Involved Lymph Nodes as Assessed by Conventional CT Scan Using RECIST Criteria | Complete response rate per RECIST criteria is defined as disappearance of all target lesions. Partial response rate per RECIST criteria is defined as at least a 30% decrease in the sum of the longest diameter of target lesions taking as reference the baseline sum longest diameter. | post-2 cycles of induction therapy (approximately 42 days from start of treatment) | 
| Radiographic Overall Complete and Partial Response Rates as Assessed by Conventional CT Scan Using RECIST Criteria | Complete response rate per RECIST criteria is defined as disappearance of all target lesions. Partial response rate per RECIST criteria is defined as at least a 30% decrease in the sum of the longest diameter of target lesions taking as reference the baseline sum longest diameter. | post-2 cycles of induction therapy (approximately 42 days from start of treatment) | 
| Correlate Primary Tumor Site Response Rates Based on Visual Categorical Criteria of Assessment With That Based on CT Scan and FDG-PET/CT | In the future, primary tumor site, nodal, and OTR by VCR (CR-x or PR-x = Y or N) will be compared with response based on CT scan (CR-x or PR-x = Y or N) using a test for difference in paired, binary values. Median standardized uptake value of FDG measured by PET/CT will be compared among those with or without response (CR-x or PR-x) using nonparametric Wilcoxon-Mann-Whitney tests. We are releasing results based on comparing actual responses from visual categorical response, CT scan, and FDG-PET/CT scan after 2 cycles. | post-2 cycles of induction therapy (approximately 42 days from start of treatment) | 
| Correlate Nodal Response Rates Based on Visual Categorical Criteria of Assessment With That Based on CT Scan and FDG-PET/CT | In the future, primary tumor site, nodal, and overall tumor response by visual categorical response (CR-x or PR-x = yes or no) will be compared with response based on CT scan (CR-x or PR-x = yes or no) using a test for difference in paired, binary values (e.g., McNemar's test). Median standardized uptake value of FDG measured by PET/CT will be compared among those with or without response (CR-x or PR-x) using nonparametric Wilcoxon-Mann-Whitney tests. At this point, we are releasing results based on comparing actual responses from visual categorical response, CT scan, and FDG-PET/CT scan after 2 cycles of induction. | post-2 cycles of induction therapy (approximately 42 days from start of treatment) | 
| Correlate Overall Tumor Response Rates Based on Visual Categorical Criteria of Assessment With That Based on CT Scan and FDG-PET/CT | In the future, primary tumor site, nodal, and overall tumor response by visual categorical response (CR-x or PR-x = yes or no) will be compared with response based on CT scan (CR-x or PR-x = yes or no) using a test for difference in paired, binary values (e.g., McNemar's test). Median standardized uptake value of FDG measured by PET/CT will be compared among those with or without response (CR-x or PR-x) using nonparametric Wilcoxon-Mann-Whitney tests. At this point, we are releasing results based on comparing actual responses from visual categorical response, CT scan, and FDG-PET/CT scan after 2 cycles of induction. | post-2 cycles of induction therapy (approximately 42 days from start of treatment) | 
| Correlate SPARC Expression by Immunohistochemistry (IHC) in Baseline Primary Tumor Tissue With Primary Tumor Site Complete Response Rate to Induction Chemotherapy | SPARC expression = Proportion of tumor cells SPARC-positive in 10 high-power fields | post-2 cycles of induction therapy (approximately 42 days from start of treatment) | 
| Correlate SPARC Expression by Immunohistochemistry (IHC) in Baseline Primary Tumor Tissue With Primary Tumor Site Partial Response Rate to Induction Chemotherapy | SPARC expression = Proportion of tumor cells SPARC-positive in 10 high-power fields | post-2 cycles of induction therapy (approximately 42 days from start of treatment) | 
| Correlate SPARC Expression (Intensity of Staining) by Immunohistochemistry (IHC) in Baseline Primary Tumor Tissue With Primary Tumor Site Complete Response Rate to Induction Chemotherapy | SPARC expression = intensity of SPARC staining in tumor | post-2 cycles of induction therapy (approximately 42 days from start of treatment) | 
| Correlate SPARC Expression (Intensity of Staining) by Immunohistochemistry (IHC) in Baseline Primary Tumor Tissue With Primary Tumor Site Partial Response Rate to Induction Chemotherapy | SPARC expression = intensity of SPARC staining in tumor | post-2 cycles of induction therapy (approximately 42 days from start of treatment) | 
| Adverse Events Experienced During Induction Chemotherapy in the First Ten Patients for a Pre-planned Safety Analysis |  | completion of the first 10 patients induction chemotherapy | 
| Overall Survival | Time from diagnosis to death or to last follow-up alive. | 10 years from completion of treatment | 
| Disease Free Survival | Time from complete response to death from any cause, to disease progression or to last follow-up alive. | 10 years from completion of treatment | 
| Time to Progression | Time from initiation of induction chemotherapy to death due to disease progression, to disease progression, or to last follow-up alive. | 10 years from completion of treatment |