Induction Chemotherapy With ACF Followed by Chemoradiation Therapy for Adv. Head & Neck Cancer

Study Overview
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Brief Summary
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This phase II trial studies the safety and effectiveness of an induction chemotherapy (ACF) consisting of paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel), cisplatin and fluorouracil followed by chemoradiation therapy in treating patients with stage III-IV squamous cell cancer of the head and neck. ACF may be an effective way to reduce or downgrade locally aggressive tumors, and improve the chance of eradication by chemoradiation.

Detailed Description
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Compared to the standard induction regimen of TPF (docetaxel, cisplatin, and 5-FU), the ACCF (nab-paclitaxel, cisplatin, cetuximab, and 5-FU) regimen included two therapeutic changes: nab-paclitaxel was substituted for docetaxel and cetuximab was added. The investigators propose to eliminate cetuximab from the ACCF regimen to isolate the treatment effects of nab-paclitaxel when given with cisplatin and 5-FU. The primary objective of the ACF proposal is to determine the complete (CR) rate by clinical examination at the primary tumor site following two cycles of ACF. An important secondary objective will be to compare the tumor response rates at the primary site following two cycles of ACF to our historical experience following two cycles of ACCF (protocol # ABX 218/HRPO# 08-0911). In addition, the investigators will compare adverse events (AEs) between patients who receive ACF to the historical group given ACCF. From these two comparisons, we aim to determine if either ACF or ACCF is superior based on a balance of efficacy (using the surrogate prognostic endpoint of CR rate at primary tumor site) and toxicity.

Official Title
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Phase II Trial of Nab-Paclitaxel, Cisplatin, and 5-FU (ACF) as Induction Therapy Followed by Definitive Concurrent Chemoradiation for Locally Advanced Squamous Cell Carcinoma of the Head and Neck (HNSCC)

Conditions
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Head and Neck Neoplasms

Intervention / Treatment
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* Drug: paclitaxel albumin-stabilized nanoparticle formulation
* Drug: Cisplatin
* Drug: Fluorouracil
* Radiation: Intensity modulated radiation therapy
* Drug: Cetuximab
* Procedure: Quality-of-life assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have selected stage III or IVa/b head and neck squamous cell carcinoma (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 Patient must have disease at the oropharynx, hypopharynx, larynx, or oral cavity sub-sites Patient must have measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 10 mm with CT scan Patient must be >= 18 years of age. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Patient must have adequate bone marrow and organ function as defined below: Absolute neutrophil count (ANC) >= 1500/mcL Platelets > 100,000/mcL Hemoglobin > 9.0 g/dL Total bilirubin =< 1.5 mg/dL Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) Alkaline phosphatase =< 2.5 x ULN Serum creatinine < 1.8 mg/dL Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, for the duration of study participation, and for 3 months after completing treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately Patient must be able to understand and willing to sign an Institutional Review Board (IRB)-approved written informed consent document Patient with uncontrolled diabetes or fasting blood glucose level of greater than 200 mg/dL will be eligible for enrollment but will not be evaluable for PET imaging Exclusion Criteria: Patient must not have had prior chemotherapy, prior epidermal growth factor receptor (EGFR) targeted therapy, or prior radiation therapy for HNSCC Patient must not have disease at the nasopharyngeal, sinus, or other sub-site not specified in the inclusion criteria; patient must not have unknown primary squamous cell carcinoma of the head and neck Patient must not have a history of prior invasive malignancy diagnosed within 3 years prior to study enrollment other than local stage non-melanoma skin cancer Patient must not be receiving any other investigational agents Patient must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to any of the agents used in this study Patient must not be taking cimetidine or allopurinol. If currently taking either of these medications, patient must discontinue for one week before receiving treatment with nab-paclitaxel Patient must not have an uncontrolled intercurrent illness including, but not limited to, ongoing or active serious infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or serious psychiatric illness/social situations that would limit compliance with study requirements Patient must not be pregnant and/or breastfeeding; a negative serum or urine pregnancy test is required at screening for all female patients of childbearing potential Patient must not be known to be human immunodeficiency virus (HIV)-positive on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with the study agents; in addition, these patients are at increased risk of lethal infections when treated with marrow suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated Patient must not have peripheral neuropathy > grade 1

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1-ACF Induction Therapy Followed by Chemoradiation Therapy<br>ACF Induction Therapy (Cycle 1 and Cycle 2 - each cycle is every 3 weeks) nab-Paclitaxel 100 mg/m^2 on Days 1, 8, and 15 Cisplatin 75 mg/m^2 on Day 1 5-FU 750 mg/m^2 on Days 1-3 If patient has complete or partial response, he/she will receive an additional ACF cycle (cycle 3). If patient has stable disease or progressive disease will not receive the third cycle of ACF. Definitive Therapy Cisplatin 100 mg/m^2 IV on Days 1, 22, and 43 Intensity modulated radiation therapy (IMRT) 7000 cGy in 35 fractions of 200 cGy each over 7 weeks. A dose of 6300 cGy in 35 fractions is optional and may be delivered to area considered to be at intermediate risk. Additional regions in the ipsilateral and contralateral neck at risk for microscopic disease in the cervical lymph nodes will receive 5600 cGy in 35 fractions. If patient cannot receive cisplatin then he/she will receive cetuximab 250 mg/m^2 IV week for 8 weeks | Drug: paclitaxel albumin-stabilized nanoparticle formulation<br> <br> * Other names: nab-paclitaxel, nanoparticle;Drug: Cisplatin<br> <br> * Other names: Neoplatin;Drug: Fluorouracil<br> <br> * Other names: 5-fluorouracil, 5-Fluracil, 5-FU, Adrucil, Efudex, FU;Radiation: Intensity modulated radiation therapy<br> <br> * Other names: IMRT;Drug: Cetuximab<br> <br> * Other names: Anti-EGFR Monoclonal Antibody, C225, C225 monoclonal antibody, IMC-C225, MOAB C225, monoclonal antibody C225;Procedure: Quality-of-life assessment<br>* ACF baseline, IMRT baseline, Day 7, Week 12, months 6 and 12<br>* Other names: FACT/GOG-NTX-4;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Response (CR) by Clinical Exam at Primary Tumor Site | Response will be assessed by laryngoscopy. CR: disappearance of all lesions | 6 weeks (2 cycles of therapy) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Partial Response (PR) at Primary Tumor Site | Response will be assessed by laryngoscopy. PR: at least 30% decrease in the sum of the longest diameter of target lesions taking as reference the baseline sum longest diameter | 6 weeks (2 cycles of therapy) | 
| Number of Participants Per Anatomic Tumor Response by CT Scan | Response assessed using RECIST criteria version 1.0 Complete response: disappearance of all target lesions Partial response: at least 30% decrease in the sum of the longest diameter of target lesions taking as reference the baseline sum longest diameter Non-complete response/non-progression: persistence of one or more non-target lesion and/or maintenance of tumor marker level above the upper limits of normal. Progression: at least a 20% increase in the sum of the LD of target lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. | 6 weeks (2 cycles of therapy) | 
| Metabolic Tumor Responses as Measured by FDG-PET/CT | Complete metabolic response (CMR): Complete resolution of all metabolically active target and non-target lesions, and no interval development of new lesions Partial metabolic response (PMR): 20% or greater decrease in max SUV from baseline, no metabolic progression of non-target lesions and no new lesions and/or decrease in total number of non-target lesions, no new lesions Stable metabolic disease (SMD) - does not qualify for CMR, PMR, or PMD Progressive metabolic disease (PMD): development of one or more metabolically active lesions or 20% or greater increased in max SUV from baseline, new metabolically active lesions | 6 weeks (2 cycles of therapy) | 
| Overall Survival Rate | -Overall survival rate is the percentage of participants who are alive at 2 years. | 2 years | 
| Adverse Events as Measured by Number of Participants That Experienced Each Common Adverse Event During ACF Induction Therapy | Assessed by NCI-CTCAE version 3 | From start of treatment through 30 days after end of treatment | 
| Changes in Secreted Protein Acidic and Rich in Cysteine (SPARC) Expression by Immunohistochemistry (IHC) in Primary Tumor Tissue | SPARC and Ki-67 expression will be assessed at this institution by IHC stains performed on clinically available tumor specimens (paraffin blocks). The specimens will be collected retrospectively from prior biopsies (pre treatment and following 2 cycles of ACF) that will have consisted of a minimum of two needle cores (16-18 gauge) or two small incisional/excisional pieces of tumor. These will have been placed in 2% buffered formalin and transported to the surgical pathology processing lab. | 6 weeks (2 cycles of therapy) | 
| Complete Response (CR) or Partial Response (PR) at Regional (Neck) Nodes as Measured by Clinical Exam |  | 6 weeks (2 cycles of therapy) | 
| Changes in Ki-67 Expression by Immunohistochemistry (IHC) in Primary Tumor Tissue | Ki-67 expression will be assessed at this institution by IHC stains performed on clinically available tumor specimens (paraffin blocks). The specimens will be collected retrospectively from prior biopsies (pre treatment and following 2 cycles of ACF) that will have consisted of a minimum of two needle cores (16-18 gauge) or two small incisional/excisional pieces of tumor. These will have been placed in 2% buffered formalin and transported to the surgical pathology processing lab. | 6 weeks (2 cycles of therapy) | 
| Disease-free Survival (DFS) Rate |  | 2 years | 
| Progression-free Survival (PFS) | -Progression: at least a 20% increase in the sum of the longest diameter (LD) of target lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. | 2 years | 
| Quality of Life (QOL) as Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-H&N) Total Score | Includes 39 questions: 7 in physical well-being, 6 in emotional well-being, 7 in functional well-being, and 12 in head & neck Scored from 0 (not at all) to 4 (very much) Higher scores indicated worse physical and emotional well-being and better social/family and functional well-being The FACT-H&N Total Score (range 0-148) measures the sum of the physical, social, emotional, functional, and HNCS domains The maximum score of 148 reflects the best quality of life. | Through one year after completion of treatment | 
| Quality of Life (QOL) as Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-H&N) FACT-G Total Score | Includes 39 questions: 7 in physical well-being, 6 in emotional well-being, 7 in functional well-being, and 12 in head & neck Scored from 0 (not at all) to 4 (very much) Higher scores indicated worse physical and emotional well-being and better social/family and functional well-being The FACT-G Total Score (range 0-108) measures the sum of the physical, social, emotional, and functional domains but excludes the HNCS domain The maximum score of 108 reflects the best quality of life. | Through end of chemoradiation | 
| Quality of Life (QOL) as Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-H&N) Trial Outcome Index (TOI) | Includes 39 questions: 7 in physical well-being, 6 in emotional well-being, 7 in functional well-being, and 12 in head & neck Scored from 0 (not at all) to 4 (very much) Higher scores indicated worse physical and emotional well-being and better social/family and functional well-being The FACT-H&N TOI (range 0-96) measures the total score for the physical, functional, and HNCS domains but excludes the emotional and social domains The maximum score of 96 reflects the best quality of life. | Through end of chemoradiation |