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

Phase 1

Terminated

• Conditions: Squamous Cell Carcinoma of the Head and Neck; Adenosquamous Cell Carcinoma; Basaloid Squamous Cell Carcinoma; Undifferentiated Carcinoma
• Interventions: Drug: Abraxane; Drug: Erbitux; Drug: Carboplatin; Radiation: Intensity Modulated Radiation Therapy

• Registration Number: NCT00570674
• Lead Sponsor: Dana-Farber Cancer Institute

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.

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 Timeline

• Study Start: 2007-11
• Study First Submitted: 2007-12-10
• Study First Submitted QC: 2007-12-10
• Study First Posted: 2007-12-11
• Primary Completion: 2013-10
• Study Completion: 2013-10
• Results First Submitted: 2016-10-18
• Results First Submitted QC: 2016-10-18
• Results First Posted: 2016-12-12
• Status Verified: 2017-10
• Last Update Submitted: 2017-10-10
• Last Update Posted: 2017-11-13

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 29

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Phase I Dose Level 3: AC-RT	Abraxane	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 1: ACE-RT	Erbitux	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 4: AC-RT	Abraxane	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: AC-RT	Intensity Modulated Radiation Therapy	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 2: AC-RT	Intensity Modulated Radiation Therapy	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 1: ACE-RT	Abraxane	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: ACE-RT	Intensity Modulated Radiation Therapy	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: AC-RT	Abraxane	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 -1: AC-RT	Intensity Modulated Radiation Therapy	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: AC-RT	Abraxane	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: AC-RT	Intensity Modulated Radiation Therapy	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 -1: AC-RT	Carboplatin	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: AC-RT	Carboplatin	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 1: ACE-RT	Carboplatin	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 3: AC-RT	Carboplatin	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: AC-RT	Carboplatin	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.

Primary Outcome Measures

Name	Time	Method
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.
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.
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

Name	Time	Method
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.
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.
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.
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-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.
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.
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.