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

Phase 2

Completed

Conditions: Squamous Cell Carcinoma of the Head and Neck

Interventions: Drug: Abraxane
Drug: Cetuximab
Drug: Cisplatin
Drug: 5-FU
Radiation: Radiation (Post induction)

Registration Number: NCT00736944

Lead Sponsor: Washington University School of Medicine

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 30

Inclusion Criteria

Not provided

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
1	Radiation (Post induction)	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.
1	Abraxane	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.
2	Abraxane	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
2	Radiation (Post induction)	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
1	Cetuximab	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.
1	Cisplatin	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.
1	5-FU	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.
2	Cisplatin	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
2	5-FU	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
2	Cetuximab	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

Primary Outcome Measures

Name	Time	Method
Clinical Complete Response Rate at the Primary Tumor	post-2 cycles of induction (approximately 42 days from start of treatment)	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.

Secondary Outcome Measures

Name	Time	Method
Complete and Partial Response Rates of Primary Tumor by FDG Uptake on PET Scan	post-2 cycles of induction therapy (approximately 42 days from start of treatment)	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.
Complete and Partial Response Rates of Involved Lymph Nodes by FDG Uptake on PET Scan	post-2 cycles of induction therapy (approximately 42 days from start of treatment)	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.
Radiographic Complete and Partial Response Rates of Primary Tumor as Assessed by Conventional CT Scan Using RECIST Criteria	post-2 cycles of induction therapy (approximately 42 days from start of treatment)	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.
Radiographic Complete and Partial Response Rates of Involved Lymph Nodes as Assessed by Conventional CT Scan Using RECIST Criteria	post-2 cycles of induction therapy (approximately 42 days from start of treatment)	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.
Radiographic Overall Complete and Partial Response Rates as Assessed by Conventional CT Scan Using RECIST Criteria	post-2 cycles of induction therapy (approximately 42 days from start of treatment)	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.
Correlate Primary Tumor Site Response Rates Based on Visual Categorical Criteria of Assessment With That Based on CT Scan and FDG-PET/CT	post-2 cycles of induction therapy (approximately 42 days from start of treatment)	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.
Clinical Partial Response Rate at the Primary Tumor	post-2 cycles of induction therapy (approximately 42 days from start of treatment)	Clinical exam included laryngoscopy in office or operating room. Partial response rate (PR) defined as 50% to 94% decrease in tumor size.
Clinical Complete and Partial Response Rates to the Involved Regional Nodes	post-2 cycles of induction therapy (approximately 42 days from start of treatment)	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.
Clinical Overall Complete and Partial Response Rates	post-2 cycles of induction therapy (approximately 42 days)	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.
Time to Progression	10 years from completion of treatment	Time from initiation of induction chemotherapy to death due to disease progression, to disease progression, or to last follow-up alive.
Correlate Nodal Response Rates Based on Visual Categorical Criteria of Assessment With That Based on CT Scan and FDG-PET/CT	post-2 cycles of induction therapy (approximately 42 days from start of treatment)	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.
Correlate Overall Tumor Response Rates Based on Visual Categorical Criteria of Assessment With That Based on CT Scan and FDG-PET/CT	post-2 cycles of induction therapy (approximately 42 days from start of treatment)	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.
Correlate SPARC Expression by Immunohistochemistry (IHC) in Baseline Primary Tumor Tissue With Primary Tumor Site Complete Response Rate to Induction Chemotherapy	post-2 cycles of induction therapy (approximately 42 days from start of treatment)	SPARC expression = Proportion of tumor cells SPARC-positive in 10 high-power fields
Correlate SPARC Expression by Immunohistochemistry (IHC) in Baseline Primary Tumor Tissue With Primary Tumor Site Partial Response Rate to Induction Chemotherapy	post-2 cycles of induction therapy (approximately 42 days from start of treatment)	SPARC expression = Proportion of tumor cells SPARC-positive in 10 high-power fields
Correlate SPARC Expression (Intensity of Staining) by Immunohistochemistry (IHC) in Baseline Primary Tumor Tissue With Primary Tumor Site Complete Response Rate to Induction Chemotherapy	post-2 cycles of induction therapy (approximately 42 days from start of treatment)	SPARC expression = intensity of SPARC staining in tumor
Correlate SPARC Expression (Intensity of Staining) by Immunohistochemistry (IHC) in Baseline Primary Tumor Tissue With Primary Tumor Site Partial Response Rate to Induction Chemotherapy	post-2 cycles of induction therapy (approximately 42 days from start of treatment)	SPARC expression = intensity of SPARC staining in tumor
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	10 years from completion of treatment	Time from diagnosis to death or to last follow-up alive.
Disease Free Survival	10 years from completion of treatment	Time from complete response to death from any cause, to disease progression or to last follow-up alive.