Abraxane in Combination With Carboplatin, Erbitux and IMRT for Locally Advanced Squamous Cancer of the Head and Neck

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00570674
• Collaborator: Celgene Corporation (Industry)
• Enrollment: 29
• Arms: 5
• Duration (Months): 71

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Squamous Cell Carcinoma of the Head and Neck; Basaloid Squamous Cell Carcinoma; Undifferentiated Carcinoma; Adenosquamous Cell Carcinoma	Drug: Abraxane; Drug: Erbitux; Drug: Carboplatin; Radiation: Intensity Modulated Radiation Therapy	Phase 1/Phase 2

Detailed Description

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 Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Trial of Abraxane in Combination With Carboplatin, Erbitux and Intensity Modulated Radiation Therapy (IMRT)for Treatment of Locally Advanced Squamous Cancer of the Head and Neck
• Study Start Date: Nov 1, 2007
• Actual Primary Completion Date: Oct 1, 2013
• Actual Study Completion Date: Oct 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase I Dose Level 1: ACE-RT Phase I Dose Level 1 participants received Abraxane 20mg/m2 IV then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. One dose (400 mg/m2 IV) of Erbitux was given prior to start of radiation, then weekly at 250 mg/m2 IV. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.	Drug: Abraxane; Other Names: paclitaxel ; Drug: Erbitux; Other Names: cetuximab ; Drug: Carboplatin; Other Names: paraplatin ; Radiation: Intensity Modulated Radiation Therapy; Other Names: IMRT
Experimental: Phase I Dose Level -1: AC-RT Phase I Dose Level -1 participants received Abraxane 20mg/m2 IV then carboplatin AUC 1.5 weekly IV during the period of radiotherapy for a total of 7 weeks. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.	Drug: Abraxane; Other Names: paclitaxel ; Drug: Carboplatin; Other Names: paraplatin ; Radiation: Intensity Modulated Radiation Therapy; Other Names: IMRT
Experimental: Phase I Dose Level 2: AC-RT Phase I Dose Level 2 participants received Abraxane 30mg/m2 IV then carboplatin AUC 1.5 weekly IV during the period of radiotherapy for a total of 7 weeks. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.	Drug: Abraxane; Other Names: paclitaxel ; Drug: Carboplatin; Other Names: paraplatin ; Radiation: Intensity Modulated Radiation Therapy; Other Names: IMRT
Experimental: Phase I Dose Level 3: AC-RT Phase I Dose Level 3 participants received Abraxane 40mg/m2 IV then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.	Drug: Abraxane; Other Names: paclitaxel ; Drug: Carboplatin; Other Names: paraplatin ; Radiation: Intensity Modulated Radiation Therapy; Other Names: IMRT
Experimental: Phase I Dose Level 4: AC-RT Phase I Dose Level 4 participants received Abraxane 50mg/m2 IV then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.	Drug: Abraxane; Other Names: paclitaxel ; Drug: Carboplatin; Other Names: paraplatin ; Radiation: Intensity Modulated Radiation Therapy; Other Names: IMRT

Outcome Measures

Primary Outcome Measures

1. Abraxane Maximum Tolerated Dose (MTD) [Phase I] [Adverse event assessments occurred weekly on treatment; The observation period for MTD evaluation incorporated the 7 weeks of treatment.]

   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.

2. Dose Limiting Toxicity (DLT) [Phase I] [Adverse event assessments occurred weekly on treatment; The observation period for DLT evaluation incorporated the 7 weeks of treatment.]

   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.

3. 2-Year Disease-Free Survival [Phase II] [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.]

   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.

Secondary Outcome Measures

1. Overall Response Rate [Phase I] [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).]

   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.

2. 2-Year Overall Survival [Phase I] [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.]

   2-year overall survival is the proportion of patients alive at 2-years from study entry.

3. Duration PEG Therapy [Assessed until time of PEG removal which was up to 18.4 months in this study cohort.]

   Estimated as the time from registration to the date of PEG removal.

4. Change in FACT-H&N Score From Baseline to 4 Months [baseline and 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.

5. Change in FACT-H&N Score From Baseline to 6 Months [Baseline and 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.

6. Change in FACT-H&N Score From Baseline to 12 Months [Baseline and 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.

7. Change in FACT-H&N Score From Baseline to 24 Months [Baseline and 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically or cytologically proven squamous cell carcinoma of th head and neck or its variants. Primary tumor sites eligible include nasopharynx, oral cavity, oropharynx, hypopharynx, larynx, or unknown primary SSCHN. Although they have squamous histology, tumors of the skin, nasal cavity and paranasal sinuses are excluded because their responsiveness to chemotherapy and radiotherapy may differ.

• Stage III or IV disease, without evidence of distant metastasis, according to the American Joint Committee on Cancer.

• Measurable disease, according to RECIST.

• Treatment-naive SSCHN, i.e. no prior chemotherapy, radiotherapy or attempted complete resection.

• < CTCAE v3.0 Grade 2 neuropathy

• 18 years of age or older

• ECOG Performance Status of 0 or 1

• No active alcohol addiction or other condition that, in the opinion of the study investigators, would interfere with the subject's ability to comply with the treatment plan.

• Lab values as outlined in the protocol

• Negative pregnancy test within 7 days of study entry

Exclusion Criteria:

• Pregnant or breast-feeding women, or women and men of childbearing potential not willing to use adequate contraception while receiving treatment and for at least 6 months thereafter.

• Symptomatic peripheral neuropathy Grade 2 or greater by CTCAE v3.0

• History of other malignancy within the previous 5 years, except for non-melanoma skin cancer, carcinoma in situ of the cervix, bladder or head and neck.

• Prior therapeutic radiation to the head and neck

• Other serious illness or medical conditions, including but not limited to: unstable cardiac disease or myocardial infarction within 6 months prior to study entry; history of significant neurologic disorder, including advanced dementia or uncontrolled seizure disorder; clinically significant uncontrolled infection; active peptic ulcer disease defined as unhealed or clinically active ulcer; hypercalcemia; active drug addiction including cocaine or intravenous drug use, defined as occuring within 6 months preceding diagnosis; chronic obstructive pulmonary disease; autoimmune disease requiring active therapy; severe psoriasis; chronic uncontrolled diarrhea.

• Patients who experienced involuntary weight loss of more than 20% of their body weight in the two months preceding study entry

• Concurrent treatment with any other anticancer therapy

• Prior therapy that targets the EGFR pathway

• Participation in an investigational drug trial within 30 days of study entry

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• Celgene Corporation

Investigators

• Principal Investigator: Roy B. Tishler, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Roy B. Tishler, MD, Radiation Oncologist, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT00570674
• Other Study ID Numbers: 07-069
• First Posted: Dec 11, 2007
• Last Update Posted: Nov 13, 2017
• Last Verified: Oct 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Roy B. Tishler, MD, Radiation Oncologist, Dana-Farber Cancer Institute: SSCHN; Abraxane; IMRT
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms; Carcinoma, Adenosquamous; Paclitaxel; Carboplatin; Cetuximab; Albumin-Bound Paclitaxel

Study Results

Participant Flow

Recruitment Details	29 participants were enrolled between November 2007 and August 2011.

Arm/Group Title	Phase I Dose Level 1: ACE-RT	Phase I Dose Level -1: AC-RT	Phase I Dose Level 2: AC-RT	Phase I Dose Level 3: AC-RT	Phase I Dose Level 4: AC-RT	Phase I Dose Level 4 Expansion Cohort: AC-RT	All Phase II Participants
Arm/Group Description	Phase I Dose Level 1 participants received Abraxane 20mg/m2 IV then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. One dose (400 mg/m2 IV) of Erbitux was given prior to start of radiation, then weekly at 250 mg/m2 IV. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.	Phase I Dose Level -1 participants received Abraxane 20mg/m2 IV then carboplatin AUC 1.5 weekly IV during the period of radiotherapy for a total of 7 weeks. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.	Phase I Dose Level 2 participants received Abraxane 30mg/m2 IV then carboplatin AUC 1.5 weekly IV during the period of radiotherapy for a total of 7 weeks. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.	Phase I Dose Level 3 participants received Abraxane 40mg/m2 IV then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.	Phase I Dose Level 4 participants received Abraxane 50mg/m2 IV then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.	Phase I Dose Level 4 participants received Abraxane 50mg/m2 IV then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions. If no DLTs are observed at dose level 4 then ten additional participants (expansion cohort) will be enrolled at that dose level.	Participants received Abraxane according to the established recommended Phase II dose of Abraxane (50mg/m2 IV) then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.
Period Title: Overall Study
STARTED	6	3	4	3	3	10	0
Treated	6	3	3	3	3	10	0
PEG Evaluable	6	3	3	3	2	10	0
COMPLETED	6	3	3	3	3	10	0
NOT COMPLETED	0	0	1	0	0	0	0

Baseline Characteristics

Arm/Group Title	All Phase I Participants
Arm/Group Description	Participants received Abraxane according to the established dose escalation schedule 50mg/m2 IV then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. For Dose Level 1 participants, one dose (400 mg/m2 IV) of Erbitux was given prior to start of radiation, then weekly at 250 mg/m2 IV. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.
Overall Participants	28
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60
Sex: Female, Male (Count of Participants)
Female	6 21.4%
Male	22 78.6%
Region of Enrollment (Count of Participants)
United States	28 100%
Primary Tumor Site (Count of Participants)
Oral cavity	3 10.7%
Oropharynx	17 60.7%
Larynx	4 14.3%
Unknown Primary	2 7.1%
Other	2 7.1%

Outcome Measures

1. Primary Outcome

Title	Abraxane Maximum Tolerated Dose (MTD) [Phase I]
Description	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.

Outcome Measure Data

Analysis Population Description

The MTD was not reached on this trial but the recommended phase II dose was the highest dose of Abraxane evaluated.

Arm/Group Title	All Phase I Participants
Arm/Group Description	Participants received Abraxane according to the established dose escalation schedule then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. For Dose Level 1 participants, one dose (400 mg/m2 IV) of Erbitux was given prior to start of radiation, then weekly at 250 mg/m2 IV. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.
Measure Participants	28
Number [mg weekly]	50

2. Primary Outcome

Title	Dose Limiting Toxicity (DLT) [Phase I]
Description	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.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients in the dose escalation cohorts.While no DLTs were observed in the first 3 DL 1 patients, the cohort was expanded to 6 patients due to safety and tolerability concerns. Upon further review, it was resolved that the Abraxane dose should not be increased in the setting of concurrent Erbitux.

Arm/Group Title	Phase I Dose Level 1: ACE-RT	Phase I Dose Level -1: AC-RT	Phase I Dose Level 2: AC-RT	Phase I Dose Level 3: AC-RT	Phase I Dose Level 4: AC-RT
Arm/Group Description	Phase I Dose Level 1 participants received Abraxane 20mg/m2 IV then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. One dose (400 mg/m2 IV) of Erbitux was given prior to start of radiation, then weekly at 250 mg/m2 IV. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.	Phase I Dose Level -1 participants received Abraxane 20mg/m2 IV then carboplatin AUC 1.5 weekly IV during the period of radiotherapy for a total of 7 weeks. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.	Phase I Dose Level 2 participants received Abraxane 30mg/m2 IV then carboplatin AUC 1.5 weekly IV during the period of radiotherapy for a total of 7 weeks. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.	Phase I Dose Level 3 participants received Abraxane 40mg/m2 IV then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.	Phase I Dose Level 4 participants received Abraxane 50mg/m2 IV then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.
Measure Participants	6	3	3	3	3
Number [Participants with DLT]	0 0%	0 NaN	0 NaN	0 NaN	0 NaN

3. Primary Outcome

Title	2-Year Disease-Free Survival [Phase II]
Description	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.

Outcome Measure Data

Analysis Population Description

The phase II portion planned to enroll 34 participants including the phase I expansion cohort but the study did not continue beyond phase I.

Arm/Group Title	All Phase II Participants
Arm/Group Description	Participants received Abraxane according to the established recommended Phase II dose of Abraxane (50mg/m2 IV) then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.
Measure Participants	0

4. Secondary Outcome

Title	Overall Response Rate [Phase I]
Description	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).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated phase I patients. Reporting within dose cohorts is not preferred given the small sample sizes.

Arm/Group Title	All Phase I Participants
Arm/Group Description	Participants received Abraxane according to the established dose escalation schedule then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. For Dose Level 1 participants, one dose (400 mg/m2 IV) of Erbitux was given prior to start of radiation, then weekly at 250 mg/m2 IV. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.
Measure Participants	28
Number (95% Confidence Interval) [proportion of participants]	.964 3.4%

5. Secondary Outcome

Title	2-Year Overall Survival [Phase I]
Description	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.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated phase I patients. Reporting within dose cohorts is not preferred given the small sample sizes.

Arm/Group Title	All Phase I Participants
Arm/Group Description	Participants received Abraxane according to the established dose escalation schedule then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. For Dose Level 1 participants, one dose (400 mg/m2 IV) of Erbitux was given prior to start of radiation, then weekly at 250 mg/m2 IV. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.
Measure Participants	28
Number (95% Confidence Interval) [proportion of participants]	.929 3.3%

6. Secondary Outcome

Title	Duration PEG Therapy
Description	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.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all patients with date of PEG removal (evaluable). Reporting within dose cohorts is not preferred given the small sample sizes.

Arm/Group Title	All Phase I Participants
Arm/Group Description	Participants received Abraxane according to the established dose escalation schedule then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. For Dose Level 1 participants, one dose (400 mg/m2 IV) of Erbitux was given prior to start of radiation, then weekly at 250 mg/m2 IV. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.
Measure Participants	27
Mean (Full Range) [months]	5.4

7. Secondary Outcome

Title	Change in FACT-H&N Score From Baseline to 4 Months
Description	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 4 months

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of patients with evaluable data at the 2 assessment timepoints: baseline and 4 months.

Arm/Group Title	All Phase I Participants
Arm/Group Description	Participants received Abraxane according to the established dose escalation schedule 50mg/m2 IV then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. For Dose Level 1 participants, one dose (400 mg/m2 IV) of Erbitux was given prior to start of radiation, then weekly at 250 mg/m2 IV. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.
Measure Participants	15
Median (Full Range) [units on a scale]	-21

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Phase I Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	Sign test
	Comments

8. Secondary Outcome

Title	Change in FACT-H&N Score From Baseline to 6 Months
Description	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

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of patients with evaluable data at the 2 assessment timepoints: baseline and 6 months.

Arm/Group Title	All Phase I Participants
Arm/Group Description	Participants received Abraxane according to the established dose escalation schedule then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. For Dose Level 1 participants, one dose (400 mg/m2 IV) of Erbitux was given prior to start of radiation, then weekly at 250 mg/m2 IV. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.
Measure Participants	19
Median (Full Range) [units on a scale]	-9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Phase I Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	Sign test
	Comments

9. Secondary Outcome

Title	Change in FACT-H&N Score From Baseline to 12 Months
Description	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

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of patients with evaluable data at the 2 assessment timepoints: baseline and 12 months.

Arm/Group Title	All Phase I Participants
Arm/Group Description	Participants received Abraxane according to the established dose escalation schedule 50mg/m2 IV then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. For Dose Level 1 participants, one dose (400 mg/m2 IV) of Erbitux was given prior to start of radiation, then weekly at 250 mg/m2 IV. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.
Measure Participants	17
Median (Full Range) [units on a scale]	-4.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Phase I Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.52
	Comments
	Method	Sign test
	Comments

10. Secondary Outcome

Title	Change in FACT-H&N Score From Baseline to 24 Months
Description	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

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of patients with evaluable data at the 2 assessment timepoints: baseline and 24 months.

Arm/Group Title	All Phase I Participants
Arm/Group Description	Participants received Abraxane according to the established dose escalation schedule 50mg/m2 IV then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. For Dose Level 1 participants, one dose (400 mg/m2 IV) of Erbitux was given prior to start of radiation, then weekly at 250 mg/m2 IV. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.
Measure Participants	12
Median (Full Range) [units on a scale]	4.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Phase I Participants
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.39
	Comments
	Method	Sign test
	Comments

Adverse Events

Time Frame	Participants were assessed weekly on treatment and at weeks 4 and 8 post treatment. Treatment duration was a mean (range) of 7.8 weeks (6.6-10.1).
Adverse Event Reporting Description	Maximum grade toxicity by type was first calculated including adverse events with treatment-attribution of possibly, probably or definitely related to either chemotherapy or radiation therapy. Serious and Other AEs were defined as grades 3-5 and grades 1-2, respectively, per CTCAEv3.
Arm/Group Title	All Phase I Participants
Arm/Group Description	Participants received Abraxane according to the established dose escalation schedule then carboplatin AUC 1.5 IV weekly during the period of radiotherapy for a total of 7 weeks. For Dose Level 1 participants, one dose (400 mg/m2 IV) of Erbitux was given prior to start of radiation, then weekly at 250 mg/m2 IV. Intensity-modulated radiotherapy (IMRT) was delivered 5 days per week with the prescribed dose of 70 Gy to the gross tumor volume, given in 2 Gy daily fractions for a total of 35 fractions.
All Cause Mortality
	All Phase I Participants
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	All Phase I Participants
	Affected / at Risk (%)	# Events
Total	26/28 (92.9%)
Blood and lymphatic system disorders
Febrile neutropenia	1/28 (3.6%)
Gastrointestinal disorders
Distention/bloating, abdominal	1/28 (3.6%)
Dry mouth	1/28 (3.6%)
Dysphagia	17/28 (60.7%)
Muco/stomatitis by exam, oral cavity	18/28 (64.3%)
Nausea	2/28 (7.1%)
Salivary	1/28 (3.6%)
Vomiting	1/28 (3.6%)
Abdomen, pain	1/28 (3.6%)
Oral cavity, pain	3/28 (10.7%)
General disorders
Fatigue	1/28 (3.6%)
Edema head and neck	1/28 (3.6%)
Injury, poisoning and procedural complications
Chemoradiation dermatitis	8/28 (28.6%)
Investigations
Leukocytes	1/28 (3.6%)
Weight loss	1/28 (3.6%)
Nervous system disorders
Dizziness	1/28 (3.6%)
Syncope	1/28 (3.6%)
Psychiatric disorders
Confusion	1/28 (3.6%)
Anxiety	1/28 (3.6%)
Depression	1/28 (3.6%)
Respiratory, thoracic and mediastinal disorders
Voice changes/dysarthria	1/28 (3.6%)
Skin and subcutaneous tissue disorders
Rash: acne/acneiform	1/28 (3.6%)
Skin-other	1/28 (3.6%)
Vascular disorders
Thrombosis/thrombus/embolism	1/28 (3.6%)
Other (Not Including Serious) Adverse Events
	All Phase I Participants
	Affected / at Risk (%)	# Events
Total	28/28 (100%)
Blood and lymphatic system disorders
Hemoglobin	5/28 (17.9%)
Ear and labyrinth disorders
External ear, pain	2/28 (7.1%)
Hearing w/w-o audiogr in monitor prg	1/28 (3.6%)
Middle ear, pain	4/28 (14.3%)
Otitis, middle ear (non-infectious)	1/28 (3.6%)
Eye disorders
Keratitis	1/28 (3.6%)
Tearing	1/28 (3.6%)
Gastrointestinal disorders
Abdomen, pain	6/28 (21.4%)
Constipation	23/28 (82.1%)
Diarrhea w/o prior colostomy	19/28 (67.9%)
Dry mouth	26/28 (92.9%)
Dyspepsia	8/28 (28.6%)
Dysphagia	9/28 (32.1%)
Esophagitis	1/28 (3.6%)
Fistula, Pancreas	1/28 (3.6%)
Flatulence	1/28 (3.6%)
GI-other	3/28 (10.7%)
Hemorrhoids	1/28 (3.6%)
Muco/stomatitis by exam, oral cavity	9/28 (32.1%)
Muco/stomatitis by exam, stomach	1/28 (3.6%)
Nausea	25/28 (89.3%)
Oral cavity, pain	21/28 (75%)
Salivary	21/28 (75%)
Ulcer, duodenum	1/28 (3.6%)
Ulcer, small bowel NOS	1/28 (3.6%)
Vomiting	16/28 (57.1%)
General disorders
Edema head and neck	14/28 (50%)
Edema limb	1/28 (3.6%)
Edema trunk/genital	1/28 (3.6%)
Fatigue	20/28 (71.4%)
Fever w/o neutropenia	5/28 (17.9%)
Injection site reaction	1/28 (3.6%)
Pain-other	4/28 (14.3%)
Rigors/chills	1/28 (3.6%)
Hepatobiliary disorders
Fistula, Biliary Treet	1/28 (3.6%)
Immune system disorders
Allergy-other	1/28 (3.6%)
Infections and infestations
Infection Gr0-2 neut, lung	1/28 (3.6%)
Infection Gr0-2 neut, oral cavity	3/28 (10.7%)
Infection Gr0-2 neut, skin	2/28 (7.1%)
Infection-other	16/28 (57.1%)
Injury, poisoning and procedural complications
Bruising	1/28 (3.6%)
Chemoradiation dermatitis	18/28 (64.3%)
Radiation dermatitis	1/28 (3.6%)
Investigations
Leukocytes	2/28 (7.1%)
Neutrophils	4/28 (14.3%)
Platelets	3/28 (10.7%)
Weight loss	7/28 (25%)
Metabolism and nutrition disorders
Anorexia	4/28 (14.3%)
Dehydration	18/28 (64.3%)
Hyperglycemia	1/28 (3.6%)
Hyperkalemia	2/28 (7.1%)
Hypokalemia	1/28 (3.6%)
Hypomagnesemia	1/28 (3.6%)
Hyponatremia	1/28 (3.6%)
Musculoskeletal and connective tissue disorders
Back, pain	2/28 (7.1%)
Extremity-limb, pain	1/28 (3.6%)
Lymphedema-related fibrosis	1/28 (3.6%)
Neck, pain	1/28 (3.6%)
Nervous system disorders
Dizziness	1/28 (3.6%)
Head/headache	2/28 (7.1%)
Neuropathy CN IX pharynx ear tongue	1/28 (3.6%)
Taste disturbance	25/28 (89.3%)
Psychiatric disorders
Agitation	1/28 (3.6%)
Anxiety	5/28 (17.9%)
Confusion	4/28 (14.3%)
Depression	5/28 (17.9%)
Insomnia	3/28 (10.7%)
Renal and urinary disorders
Urinary frequency/urgency	1/28 (3.6%)
Respiratory, thoracic and mediastinal disorders
Aspiration	1/28 (3.6%)
Cough	3/28 (10.7%)
Edema, larynx	1/28 (3.6%)
Pleura, pain	1/28 (3.6%)
Stenosis (incl anastomotic) pharynx	1/28 (3.6%)
Throat/pharynx/larynx, pain	7/28 (25%)
Voice changes/dysarthria	6/28 (21.4%)
Skin and subcutaneous tissue disorders
Alopecia	3/28 (10.7%)
Dry skin	3/28 (10.7%)
Erythema multiforme	5/28 (17.9%)
Nail changes	4/28 (14.3%)
Pruritus/itching	1/28 (3.6%)
Rash/desquamation	4/28 (14.3%)
Rash: acne/acneiform	5/28 (17.9%)
Skin breakdown/decubitus ulcer	1/28 (3.6%)
Skin-other	2/28 (7.1%)
Ulceration	1/28 (3.6%)
Vascular disorders
Hypertension	1/28 (3.6%)
Hypotension	1/28 (3.6%)

Limitations/Caveats

The phase II portion planned to enroll 34 participants including the expansion cohort but the study did not continue beyond phase I given the importance of HPV status as a prognostic factor to guide treatment decisions.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.