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

Phase 2

Completed

Conditions: Head and Neck Neoplasms

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

Registration Number: NCT01566435

Lead Sponsor: Washington University School of Medicine

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 30

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm 1-ACF Induction Therapy Followed by Chemoradiation Therapy	paclitaxel albumin-stabilized nanoparticle formulation	ACF Induction Therapy (Cycle 1 and Cycle 2 - each cycle is every 3 weeks) 1. nab-Paclitaxel 100 mg/m\^2 on Days 1, 8, and 15 2. Cisplatin 75 mg/m\^2 on Day 1 3. 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 1. Cisplatin 100 mg/m\^2 IV on Days 1, 22, and 43 2. 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. 3. If patient cannot receive cisplatin then he/she will receive cetuximab 250 mg/m\^2 IV week for 8 weeks
Arm 1-ACF Induction Therapy Followed by Chemoradiation Therapy	Fluorouracil	ACF Induction Therapy (Cycle 1 and Cycle 2 - each cycle is every 3 weeks) 1. nab-Paclitaxel 100 mg/m\^2 on Days 1, 8, and 15 2. Cisplatin 75 mg/m\^2 on Day 1 3. 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 1. Cisplatin 100 mg/m\^2 IV on Days 1, 22, and 43 2. 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. 3. If patient cannot receive cisplatin then he/she will receive cetuximab 250 mg/m\^2 IV week for 8 weeks
Arm 1-ACF Induction Therapy Followed by Chemoradiation Therapy	Intensity modulated radiation therapy	ACF Induction Therapy (Cycle 1 and Cycle 2 - each cycle is every 3 weeks) 1. nab-Paclitaxel 100 mg/m\^2 on Days 1, 8, and 15 2. Cisplatin 75 mg/m\^2 on Day 1 3. 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 1. Cisplatin 100 mg/m\^2 IV on Days 1, 22, and 43 2. 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. 3. If patient cannot receive cisplatin then he/she will receive cetuximab 250 mg/m\^2 IV week for 8 weeks
Arm 1-ACF Induction Therapy Followed by Chemoradiation Therapy	Quality-of-life assessment	ACF Induction Therapy (Cycle 1 and Cycle 2 - each cycle is every 3 weeks) 1. nab-Paclitaxel 100 mg/m\^2 on Days 1, 8, and 15 2. Cisplatin 75 mg/m\^2 on Day 1 3. 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 1. Cisplatin 100 mg/m\^2 IV on Days 1, 22, and 43 2. 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. 3. If patient cannot receive cisplatin then he/she will receive cetuximab 250 mg/m\^2 IV week for 8 weeks
Arm 1-ACF Induction Therapy Followed by Chemoradiation Therapy	Cisplatin	ACF Induction Therapy (Cycle 1 and Cycle 2 - each cycle is every 3 weeks) 1. nab-Paclitaxel 100 mg/m\^2 on Days 1, 8, and 15 2. Cisplatin 75 mg/m\^2 on Day 1 3. 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 1. Cisplatin 100 mg/m\^2 IV on Days 1, 22, and 43 2. 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. 3. If patient cannot receive cisplatin then he/she will receive cetuximab 250 mg/m\^2 IV week for 8 weeks
Arm 1-ACF Induction Therapy Followed by Chemoradiation Therapy	Cetuximab	ACF Induction Therapy (Cycle 1 and Cycle 2 - each cycle is every 3 weeks) 1. nab-Paclitaxel 100 mg/m\^2 on Days 1, 8, and 15 2. Cisplatin 75 mg/m\^2 on Day 1 3. 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 1. Cisplatin 100 mg/m\^2 IV on Days 1, 22, and 43 2. 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. 3. If patient cannot receive cisplatin then he/she will receive cetuximab 250 mg/m\^2 IV week for 8 weeks

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Complete Response (CR) by Clinical Exam at Primary Tumor Site	6 weeks (2 cycles of therapy)	* Response will be assessed by laryngoscopy. * CR: disappearance of all lesions

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Partial Response (PR) at Primary Tumor Site	6 weeks (2 cycles of therapy)	* 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
Number of Participants Per Anatomic Tumor Response by CT Scan	6 weeks (2 cycles of therapy)	* 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.
Metabolic Tumor Responses as Measured by FDG-PET/CT	6 weeks (2 cycles of therapy)	* 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
Overall Survival Rate	2 years	-Overall survival rate is the percentage of participants who are alive at 2 years.
Changes in Secreted Protein Acidic and Rich in Cysteine (SPARC) Expression by Immunohistochemistry (IHC) in Primary Tumor Tissue	6 weeks (2 cycles of therapy)	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.
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	6 weeks (2 cycles of therapy)	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.
Disease-free Survival (DFS) Rate	2 years
Progression-free Survival (PFS)	2 years	-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.
Quality of Life (QOL) as Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-H&N) Total Score	Through one year after completion of treatment	* 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.
Quality of Life (QOL) as Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-H&N) FACT-G Total Score	Through end of chemoradiation	* 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.
Quality of Life (QOL) as Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-H&N) Trial Outcome Index (TOI)	Through end of chemoradiation	* 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.
Adverse Events as Measured by Number of Participants That Experienced Each Common Adverse Event During ACF Induction Therapy	From start of treatment through 30 days after end of treatment	Assessed by NCI-CTCAE version 3