The purpose of the Phase I part of this research study is to determine the safest and most effective dose of Abraxane when given in combination with carboplatin and Erbitux during radiation therapy for head and neck cancer. The purpose of the Phase II part of this study is to determine the effects of the treatment on head and neck cancers, as well as to further study the safety of this treatment.
Primary Objectives 1. Phase I-To identify the maximally tolerated dose (MTD) of Abraxane given with carboplatin plus concurrent IMRT (AC-RT) 2. Phase II-To evaluate efficacy in the phase II portion of the study by evaluating 2-year disease-free survival Secondary Objectives 1. To evaluate the safety and tolerability 2. To estimate the overall response rate 3. To estimate 2-year overall survival 4. To evaluate functional outcome at 2 years with respect to speech, swallowing and overall quality of life (QoL), by determining mean duration of PEG-dependence and change in FACT-HN scores from baseline to 3, 6, 12 and 24 months. STATISTICAL DESIGN: The Phase I study followed a standard 3+3 dose escalation design. Four potential dose levels of Abraxane ultimately were under evaluation including a de-escalation dose level -1. \[Note: Erbitux was originally planned to be given with carboplatin and Abraxane, but removed due to toxicity experienced at dose level 1.\] The DLT observation period is the 7 weeks of treatment. The Phase I incorporated a10-patient expansion cohort to ensure that the toxicity at the MTD for AC-RT was acceptable. Planned enrollment for the Phase II study was 34 patients primarily to test whether 2-year disease-free survival was consistent with 75% rate as opposed to the null hypothesis of 53.5% based on prior research (RTOG 99-14).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
29
Abraxane Maximum Tolerated Dose (MTD) [Phase I]
The Abraxane MTD in combination with carboplatin and concurrent IMRT is determined by the number of participants who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The MTD is defined as the highest dose at which fewer than one-third of participants experience a DLT. If no DLTs are observed then the MTD is not reached but the highest dose may then be the recommended phase II dose.
Time frame: Adverse event assessments occurred weekly on treatment; The observation period for MTD evaluation incorporated the 7 weeks of treatment.
Dose Limiting Toxicity (DLT) [Phase I]
Dose limiting toxicities (DLT) were defined as treatment-related: 1) grade 3-4 non-hematological toxicity excluding untreated nausea, vomiting and diarrhea; dysphagia, esophagitis, mucositis/stomatitis, dermatitis/rash, 2) Grade 3 or greater febrile neutropenia occurring during chemoradiotherapy, 3) Grade 4 neutropenia lasting \>/= 7 days and 4) Grade 3 thrombocytopenia. Grade 4 toxicities resulting in a treatment breaks \> 7 days were considered DLTs.
Time frame: Adverse event assessments occurred weekly on treatment; The observation period for DLT evaluation incorporated the 7 weeks of treatment.
2-Year Disease-Free Survival [Phase II]
Disease-free survival (DFS) is defined as the time from registration to the earlier of disease recurrence or death from any cause. Patients alive without a recurrence are censored at the date of last disease evaluation. 2-year disease-free survival is the probability of patients remaining alive and progression-free at 2-years from study entry estimated using Kaplan-Meier methods. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or equivocal progression of non-target.
Time frame: Disease assessments occurred 8-10 weeks following treatment end then every 4-6 weeks (yr 1), every 8-10 weeks (yr 2), quarterly (yr 3) and semiannually up to 2 yrs since last pt enrolled.
Overall Response Rate [Phase I]
Overall response (OR) rate was defined as achieving partial response (PR) or complete response (CR) based on RECIST 1.0 criteria on treatment. Per RECIST 1.0 for target lesions, CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. To be assigned a status of CR or PR, changes in tumor measurements must be confirmed by repeat assessments performed no fewer than 4 weeks after the response criteria are first met. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
Time frame: The primary re-staging assessment for response occurred 8-10 weeks following completion of treatment. Treatment duration was a mean (range) of 7.8 weeks (6.6-10.1).
2-Year Overall Survival [Phase I]
2-year overall survival is the proportion of patients alive at 2-years from study entry.
Time frame: All patients were followed for survival for a minimum of 2 years. Median survival follow-up was 44.7 months (range 10-70) in this study cohort.
Duration PEG Therapy
Estimated as the time from registration to the date of PEG removal.
Time frame: Assessed until time of PEG removal which was up to 18.4 months in this study cohort.
Change in FACT-H&N Score From Baseline to 4 Months
The FACT-H\&N is a multidimensional, self-report QoL instrument specifically designed for use with head and neck cancer patients. It is comprised of 27 core items from the FACT-G (Version 4), an established survey which assesses the impact of cancer therapy in four domains: physical, social/family, emotional, and functional. \[Cella, D, et al. JCO 1993(11)\]. It is supplemented with a validated measure of 12 site specific items to assess for head and neck related symptoms. \[D'Antonio L, Zimmerman G, et al. Cancer 1996 (77)\] Each item is rated on a 0 to 4 Likert type scale, and then combined to produce subscale scores for each domain, as well as a global QoL score (range: 0-156). Higher scores represent better QoL. The change score is calculated as post-baseline less baseline; therefore, a negative value indicates a decrease in score and correspondingly a decrease in QoL.
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Time frame: baseline and 4 months
Change in FACT-H&N Score From Baseline to 6 Months
he FACT-H\&N is a multidimensional, self-report QoL instrument specifically designed for use with head and neck cancer patients. It is comprised of 27 core items from the FACT-G (Version 4), an established survey which assesses the impact of cancer therapy in four domains: physical, social/family, emotional, and functional. \[Cella, D, et al. JCO 1993(11)\]. It is supplemented with a validated measure of 12 site specific items to assess for head and neck related symptoms. \[D'Antonio L, Zimmerman G, et al. Cancer 1996 (77)\] Each item is rated on a 0 to 4 Likert type scale, and then combined to produce subscale scores for each domain, as well as a global QoL score (range: 0-156). Higher scores represent better QoL. The change score is calculated as post-baseline less baseline; therefore, a negative value indicates a decrease in score and correspondingly a decrease in QoL.
Time frame: Baseline and 6 months
Change in FACT-H&N Score From Baseline to 12 Months
The FACT-H\&N is a multidimensional, self-report QoL instrument specifically designed for use with head and neck cancer patients. It is comprised of 27 core items from the FACT-G (Version 4), an established survey which assesses the impact of cancer therapy in four domains: physical, social/family, emotional, and functional. \[Cella, D, et al. JCO 1993(11)\]. It is supplemented with a validated measure of 12 site specific items to assess for head and neck related symptoms. \[D'Antonio L, Zimmerman G, et al. Cancer 1996 (77)\] Each item is rated on a 0 to 4 Likert type scale, and then combined to produce subscale scores for each domain, as well as a global QoL score (range: 0-156). Higher scores represent better QoL. The change score is calculated as post-baseline less baseline; therefore, a negative value indicates a decrease in score and correspondingly a decrease in QoL.
Time frame: Baseline and 12 months
Change in FACT-H&N Score From Baseline to 24 Months
The FACT-H\&N is a multidimensional, self-report QoL instrument specifically designed for use with head and neck cancer patients. It is comprised of 27 core items from the FACT-G (Version 4), an established survey which assesses the impact of cancer therapy in four domains: physical, social/family, emotional, and functional. \[Cella, D, et al. JCO 1993(11)\]. It is supplemented with a validated measure of 12 site specific items to assess for head and neck related symptoms. \[D'Antonio L, Zimmerman G, et al. Cancer 1996 (77)\] Each item is rated on a 0 to 4 Likert type scale, and then combined to produce subscale scores for each domain, as well as a global QoL score (range: 0-156). Higher scores represent better QoL. The change score is calculated as post-baseline less baseline; therefore, a negative value indicates a decrease in score and correspondingly a decrease in QoL.
Time frame: Baseline and 24 months