Bortezomib With or Without Irinotecan in Treating Patients With Locally Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

Study Overview
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Brief Summary
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This randomized phase II trial is studying bortezomib and irinotecan to see how well they work compared to bortezomib alone in treating patients with locally recurrent or metastatic squamous cell carcinoma of the head and neck. Bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bortezomib together with irinotecan may kill more tumor cells. It is not yet known whether giving bortezomib together with irinotecan is more effective than bortezomib alone in treating head and neck cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the activity of combination of PS-341 (bortezomib) and irinotecan in patients with locally advanced, recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) and the response rate of single agent PS-341 (followed by irinotecan at time of progression). SECONDARY OBJECTIVES: I. To continue exploring the toxicity of PS-341 alone and the combination of PS-341 and irinotecan in this patient population. II. To evaluate time to progression, overall survival and response to irinotecan and PS-341 when given after PS-341 alone. III. To evaluate the relationship between pre-treatment nuclear localization of NF-kB, and NF-kB regulated gene expression in tissue (Cyclin D1, IAP1, Bcl-XL, Topo I), and serum (IL-6, IL-8, GRO-1 and VEGF) and response. OUTLINE: Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11 and irinotecan IV over 90 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive bortezomib as in arm I. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients may cross over to arm I. Patients are followed every 3-6 months for up to 3 years.

Official Title
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Phase II Two Arm Trial of the Proteasome Inhibitor, PS-341 (Velcade TM) in Combination With Irinotecan or PS-341 Alone Followed by the Addition of Irinotecan at Time of Progression in Patients With Locally Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Conditions
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Recurrent Verrucous Carcinoma of the Larynx, Recurrent Squamous Cell Carcinoma of the Hypopharynx, Recurrent Squamous Cell Carcinoma of the Larynx, Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity, Recurrent Squamous Cell Carcinoma of the Nasopharynx, Recurrent Squamous Cell Carcinoma of the Oropharynx, Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Recurrent Verrucous Carcinoma of the Oral Cavity, Stage IV Squamous Cell Carcinoma of the Hypopharynx, Stage IV Squamous Cell Carcinoma of the Larynx, Stage IV Squamous Cell Carcinoma of the Nasopharynx, Stage IV Verrucous Carcinoma of the Larynx, Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage IVA Squamous Cell Carcinoma of the Oropharynx, Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Stage IVA Verrucous Carcinoma of the Oral Cavity, Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage IVB Squamous Cell Carcinoma of the Oropharynx, Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Stage IVB Verrucous Carcinoma of the Oral Cavity, Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage IVC Squamous Cell Carcinoma of the Oropharynx, Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Stage IVC Verrucous Carcinoma of the Oral Cavity, Tongue Cancer

Intervention / Treatment
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* Drug: bortezomib
* Drug: irinotecan hydrochloride
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients may have had one (0-1) prior chemotherapy regimen for recurrent or metastatic SCCHN; chemotherapy for recurrent or metastatic disease must have been completed at least 4 weeks prior to study entry Patients must not have been previously treated with irinotecan or bortezomib Patients must not be receiving radiation treatment Patients must have histologically confirmed squamous cell carcinoma of the head and neck Patients must have biopsy for histological confirmation of recurrent or metastatic disease if disease is now recurrent or metastatic after prior disease free-interval NOTE: If patient has had a complete response (of any duration) but now has suspected recurrent disease (regardless of the time interval), the patient will need a biopsy for confirmation of SCCHN Disease must not be amenable to potentially curative local therapies or patient must have refused such options Patients must not have nasopharyngeal subtypes WHO II or III. Patients may have nasopharyngeal WHO I; salivary gland primaries are excluded from study SUBTYPES OF NASOPHARYNGEAL CARCINOMA (NPC) WHO type 1 - keratinizing SCC WHO type 2 - nonkeratinizing epidermoid carcinoma WHO type 3 - undifferentiated carcinoma Patients must have measurable disease Baseline measurements and evaluations must be obtained within 4 weeks of registration to the study Measurable disease limited to a pre-irradiated location must be biopsy proven to be squamous cell carcinoma Must have at least one objective measurable disease parameter; baseline measurements and evaluations must be obtained within 4 weeks of registration to the study; all areas of disease should be recorded and mapped out in order to assess response and uniformity of response to therapy Radiographic findings are acceptable providing that clear-cut measurement can be made Measurable disease limited to a pre-irradiated location must be biopsy-proven to be squamous cell carcinoma Patients must have ECOG performance status 0 or 1 Patients must not have grade 2 or higher peripheral neuropathy within 2 weeks of study entry Leukocytes >= 3,000/uL Absolute neutrophil count >= 1,500/uL Platelets >= 100,000/uL Total bilirubin within normal institutional limits AST(SGOT) and ALT(SGPT) =< 2.5 x institutional upper limit of normal Creatinine within normal institutional limits OR Creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal Patients must have had no prior invasive malignancy unless the disease-free interval is 5 years or more Women must not be pregnant or breast-feeding due to the fact that the teratogenic or abortifacient effects of PS-341are unknown; the effect of PS-341 on the nursing infant are also unknown; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events Patients must not have history of allergic reactions to PS-341 or allergic reaction attributed to compounds of similar chemical or biologic composition to PS-341 including boron or mannitol Patients must not have uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements ELIGIBILITY FOR RE-REGISTRATION TO ARM A (FOR ARM B PATIENTS AT THE TIME OF PROGRESSION Patients must have ECOG performance status 0 or 1 Leukocytes >= 3,000/uL Absolute neutrophil count >- 1,500/uL Platelets >= 100,000/uL Total bilirubin within normal institutional limits AST(SGOT) and ALT(SGPT) =< 2.5 x institutional upper limit of normal Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (bortezomib, irinotecan hydrochloride)<br>Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11 and irinotecan IV over 90 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity | Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;Drug: irinotecan hydrochloride<br>* Given IV<br>* Other names: U-101440E;Other: laboratory biomarker analysis<br>* Optional correlative studies<br>|
| Experimental: Arm II (bortezomib)<br>Patients receive bortezomib as in arm I. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients may cross over to arm I. | Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;Other: laboratory biomarker analysis<br>* Optional correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate on Step 1 | Tumor response was evaluated via Response Evaluation Criteria In Solid Tumors (RECIST) v1.0, and response rate was defined as the proportion of patients with a complete response or partial response among all eligible and treated patients. Complete response was defined as disappearance of all tumor lesions. Partial response was defined as at least a 30% decrease in the sum of the longest diameters of target lesions. | Tumor response was assessed every 2 cycles until progression or intolerable toxicity with maximum of 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate on Step 2 | Tumor response was evaluated via Response Evaluation Criteria In Solid Tumors (RECIST) v1.0, and response rate was defined as the proportion of patients with a complete response or partial response among all eligible and treated patients. Complete response was defined as disappearance of all tumor lesions. Partial response was defined as at least a 30% decrease in the sum of the longest diameters of target lesions. | Tumor response was assessed after every 2 cycles until progression or intolerable toxicity with maximum of 3 years | 
| Progression-free Survival on Step 1 | Progression-free survival was defined as time from registration to step 1 to disease recurrence or death from any cause, whichever occurred first. Disease progression was measured by Response Evaluation Criteria In Solid Tumors (RECIST) v1.0, and defined as at least a 20% increase in the sum of the longest diameters of target lesions. | Every 3 months for first 2 years from protocol entry, then every 6 months until 3 years from study entry | 
| Overall Survival on Step 1 | Overall survival was defined as time from registration on step 1 to death from any cause. It was evaluated in all 61 eligible and treated patients. | Survival was assessed every 3 month within 2 years and every 6 months betwen 2 and 3 years |