Phase 2 Sequential and Concurrent Chemoradiation for Advanced Nasopharyngeal Carcinoma (NPC)

Study Overview
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Brief Summary
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This phase 2 trial is studying whether giving a combination of docetaxel, cisplatin, and fluorouracil chemotherapy followed by the combination of cisplatin with radiation therapy works in treating patients with advanced nasopharyngeal cancer. Drugs used in chemotherapy, such as docetaxel, cisplatin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Giving combination chemotherapy together with radiation therapy may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVE: • To establish the progression free survival rate at 2 years, using RECIST criteria, to induction treatment with docetaxel, cisplatin, and fluorouracil (TPF) followed by chemoradiotherapy of locoregionally advanced nasopharyngeal carcinoma (NPC) SECONDARY OBJECTIVE: • To evaluate complete response rates, safety and feasibility of TPF followed by chemoradiation in patients with NPC OUTLINE: This is a single site study. INDUCTION THERAPY: Patients receive docetaxel intravenously (IV) over 60 minutes on Day 1; cisplatin IV over 1 to 3 hours (or carboplatin IV over 30 minutes) on Day 1; and fluorouracil IV continuously over 24 hours on Days 1 to 5. Each cycle is 21 days, with treatment consisting of up to 3 cycles in the absence of disease progression or unacceptable toxicity. CONCURRENT CHEMO-RADIOTHERAPY: Beginning within 3 to 6 weeks after initiating the last course of induction chemotherapy, patients undergo 3-dimensional conformal or intensity-modulated radiotherapy once daily for 6.5 to 7 weeks. Patients also receive cisplatin IV over 1 hour (or carboplatin IV over 30 minutes) once weekly in weeks 1 to 6 in the absence of disease progression or unacceptable toxicity. All study treatment is admininstered over the course of 21 weeks. After completion of study treatment, patients are followed periodically for 24 months.

Official Title
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A Phase 2 Study of Sequential and Concurrent Chemoradiation for Patients With Advanced Nasopharyngeal Carcinoma (NPC)

Conditions
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Stage II Lymphoepithelioma of the Nasopharynx, Stage II Squamous Cell Carcinoma of the Nasopharynx, Stage III Lymphoepithelioma of the Nasopharynx, Stage III Squamous Cell Carcinoma of the Nasopharynx, Stage IV Lymphoepithelioma of the Nasopharynx, Stage IV Squamous Cell Carcinoma of the Nasopharynx

Intervention / Treatment
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* Drug: docetaxel
* Drug: cisplatin
* Drug: carboplatin
* Drug: fluorouracil
* Radiation: 3-dimensional conformal radiation therapy
* Radiation: intensity-modulated radiation therapy


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Histologically- or cytologically-confirmed nasopharyngeal carcinoma meeting the following criteria: WHO type I, II, or III Stage II to IVB disease (minimally T2a, N0, M0 or any T any, N1, M0) Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension as ≥ 20 mm by conventional techniques or as ≥ 10 mm by spiral CT scan Prior diagnostic surgery(s) at the primary site or neck allowed provided there is still measurable disease present Without known brain metastases Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 Life expectancy > 3 months Absolute neutrophil count (ANC) ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Total bilirubin ≤ 1.5 times upper limit of normal (ULN) Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤ 2.5 times ULN Creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 55 mL/min (NOTE: * Patients with creatinine > grade 1 but < grade 3, hearing loss ≥ grade 2, and peripheral neuropathy ≥ grade 2 are eligible provided they receive carboplatin in place of cisplatin throughout study treatment) Hearing loss < grade 2. Hearing loss grade 2 or greater attributable to tumor obstruction, when the bone conduction in the audiogram is consistent with less than grade 2, is permissible for cisplatin. Hearing loss will be evaluated by hearing in the best ear. If hearing loss is grade 2, patients are still eligible but should receive carboplatin throughout the protocol instead of cisplatin. Peripheral motor/sensory neuropathy < grade 2. If peripheral neuropathy is grade 2, patients are still eligible but should receive carboplatin throughout the protocol instead of cisplatin. Fertile patients must use effective contraception prior to and during study treatment EXCLUSION CRITERIA Uncontrolled intercurrent illness including, but not limited to, any of the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Psychiatric illness or social situations that preclude compliance with study requirements Clinically-significant cardiovascular disease Cerebrovascular accident within the past 6 months Myocardial infarction or unstable angina within the past 6 months New York Heart Association (NYHA) class II to IV congestive heart failure Serious and inadequately controlled cardiac arrhythmia Significant vascular disease (eg, aortic aneurysm, history of aortic dissection) Clinically-significant peripheral vascular disease History of allergic reaction attributed to compounds of similar chemical or biologic composition to docetaxel, cisplatin, carboplatin, fluorouracil, bevacizumab, or other agents used in this study Known brain metastases Concurrent combination antiretroviral therapy for HIV-positive patients Prior chemotherapy or radiotherapy for nasopharyngeal carcinoma Pregnant or nursing

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chemoradiation for Nasopharyngeal Carcinoma<br>INDUCTION THERAPY: Patients receive docetaxel intravenously (IV) over 60 minutes on Day 1; cisplatin IV over 1 to 3 hours (or carboplatin IV over 30 minutes) on Day 1; and fluorouracil IV continuously over 24 hours on Days 1 to 5. Each cycle is 21 days, with treatment consisting of up to 3 cycles in the absence of disease progression or unacceptable toxicity. CONCURRENT CHEMO-RADIOTHERAPY: Beginning within 3 to 6 weeks after initiating the last course of induction chemotherapy, patients undergo 3-dimensional conformal or intensity-modulated radiotherapy once daily for 6.5 to 7 weeks. Patients also receive cisplatin IV over 1 hour (or carboplatin IV over 30 minutes) once weekly in weeks 1 to 6 in the absence of disease progression or unacceptable toxicity. | Drug: docetaxel<br>* Given IV<br>* Other names: TXT;Drug: cisplatin<br>* Given IV<br>* Other names: DDP;Drug: carboplatin<br>* Given IV<br>* Other names: Paraplatin;Drug: fluorouracil<br>* Given IV<br>* Other names: 5-FU;Radiation: 3-dimensional conformal radiation therapy<br>* Undergo 3-dimensional conformal or intensity-modulated radiotherapy<br>* Other names: 3D-CRT;Radiation: intensity-modulated radiation therapy<br>* Undergo 3-dimensional conformal or intensity-modulated radiotherapy<br>* Other names: IMRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Progression-free Survival (PFS) at 2 Years After Chemo-radiotherapy | Progression-free survival (PFS) means to remain alive without disease progression. Progression is defined as either the appearance of one or more new cancer lesions, or a ≥ 20% increase in the sum of the longest diameters (LD) of target cancer lesions, compared the same measurement obtained at the start of treatment. This outcome reported as the number of patients remaining alive at 2 years following chemo-radiotherapy without disease progression, a number without dispersion. | up to 29 months (ie, 24 months post-chemoradiation) | 
| Median Progression-free Survival (PFS) | Progression-free survival (PFS) means to remain alive without disease progression. Progression is defined as either the appearance of one or more new cancer lesions, or a ≥ 20% increase in the sum of the longest diameters (LD) of target cancer lesions, compared the same measurement obtained at the start of treatment. This outcome reported as the median duration of PFS in months since chemo-radiotherapy, with full range. | up to 127 months (includes treatment period of up to 5 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival (OS) was assessed as the duration of time that study participants remained alive after chemoradiotherapy. The outcome is reported as median OS (with full range). | up to 127 months (includes treatment period of up to 5 months) | 
| Number of Participants With Adverse Events Resulting in Treatment Discontinuation | Adverse events during treatment were assessed as whether they were definitely-, probably-, or possibly-related to protocol treatment (ie, adverse reaction). The outcome is reported as the number of participants who discontinued treatment due to an adverse reaction. | 8 months | 
| Number of Participants With Treatment Response | Participants who completed 1 cycle of docetaxel, cisplatin, and 5-fluorouracil (TPF) were evaluated for response. Response was assessed for lesions designated as target (TL) and non-target (NTL) as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). The outcome is reported as a number without dispersion. TL Criterion: CR: Disappearance of lesions PR: 30% decrease in the sum of the longest diameter (LD) of lesions PD: 20% increase in the sum of the LD of lesions, or any new lesion SD: Neither sufficient shrinkage for PR nor sufficient increase for PD NTL Criterion: CR: Disappearance of lesions and normalization of tumor marker level PR / SD: Persistence of one or more lesion(s) and/or maintenance of tumor marker level above the normal limits (includes incomplete response / PR). PD: Appearance of one or more new lesions and/or unequivocal progression of existing lesions. | up to 29 months (ie, 24 months post-chemoradiation) |