Multimodality Risk Adapted Tx Including Induction Chemo for SCCHN Amenable to Transoral Surgery

Study Overview
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Brief Summary
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The purpose of this study is to see if a three method risk adapted design using induction chemotherapy, transoral surgery and radiation chemotherapy will lessen toxic effects and make treatment of squamous cell carcinoma of the head and neck (SCCHN) better.

Detailed Description
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This is a single-arm non-randomized two-stage phase II trial in previously untreated patients with squamous cell carcinoma of the head and neck (SCCHN) arising in the oral cavity, oropharynx, or supraglottic larynx amenable to a transoral surgical approach. Treatment will consist of 3 parts: neoadjuvant induction with weekly carboplatin and paclitaxel in combination with daily lapatinib for 6 weeks (PART 1) prior to transoral surgery (PART 2). Post-operative treatment (PART 3) will vary depending on the risk category assigned to the patient following surgery as follows: no further treatment or treatment limited to involved field radiation (low risk), ipsilateral radiation concurrent with weekly chemotherapy ( medium risk); or cisplatin every 3 weeks and daily lapatinib concurrent with bilateral radiation (high risk).

Official Title
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Multimodality Risk Adapted Therapy Including Carboplatin/Paclitaxel/Lapatinib as Induction for Squamous Cell Carcinoma of the Head and Neck Amenable to Transoral Surgical Approaches

Conditions
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Head and Neck Cancer, Squamous Cell Carcinoma of the Head and Neck

Intervention / Treatment
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* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: Lapatinib
* Drug: Cisplatin
* Drug: Cisplatin
* Radiation: Ipsilateral Radiation
* Radiation: Bilateral Radiation
* Procedure: Transoral Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously untreated, histologically proven primary squamous cell carcinoma arising in the oral cavity, oropharynx, or supraglottic larynx, and amenable to transoral approach Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (see Appendix C) Measurable disease as per Response Evaluation Criteria In Solid Tumors (RECIST1.1) Age ≥18 years Adequate bone marrow function as demonstrated by: Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3; Hgb > 10 g/dL (use of transfusion to reach this threshold prior to study initiation is acceptable); Platelet count ≥ 100,000/mm3 Adequate hepatic and renal function as demonstrated by: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN); Total serum bilirubin ≤1.5 mg/dL; Creatinine clearance (CrCL) ≥ 40ml/min as measured via Cockcroft-Gault Left ventricular ejection fraction (LVEF) must be > the lower limit of normal (LLN) per institutional standards by either echocardiography or radionuclide-based multiple gated acquisition (MUGA) Negative serum human chorionic gonadotropin (β-hCG) pregnancy test within 72 hours of day 1 of induction chemotherapy in women of child-bearing potential All males and females of childbearing potential must agree to use adequate contraception during the study. Adequate contraception is defined as any medically recommended method (or combination of methods) as per standard of care. Females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy Signed an institutional review board (IRB)-approved informed consent document for this protocol. Exclusion Criteria: tumor 1-node 0 (T1N0) disease or tumor 2-node 0 (T2N0) disease Any metastatic disease Not considered eligible for any of the chemotherapy agents included in the induction regimen. Current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment) Major surgery within 3 weeks prior to day 1 of study treatment from which the patient has not completely recovered Current use of a prohibited medication or requires any of these medications during treatment with lapatinib prior to study entry Receiving any investigational agent currently, or within 2 weeks of Day 1 of treatment on this study Active, serious infection, medical, or psychiatric condition that would represent an inappropriate risk to the patient or would likely compromise achievement of the primary study objective, including unstable angina, serious uncontrolled cardiac arrhythmia, uncontrolled infection, or myocardial infarction ≤ 6 months prior to study entry Adequate swallowing function or gastric-tube for drug administration. Of note, lapatinib can be administered via G-tube in a slurry for patients who cannot swallow Other prior or concomitant malignancies with the exception of: Non-melanoma skin cancer; In-situ malignancy; Low-risk prostate cancer after curative therapy; Other cancer for which the patient has been disease free for ≥ 3 years Pregnant or lactating women, or adults of reproductive potential who do not agree to use adequate contraception during study treatment (see definition of adequate contraception

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Non-Randomized Single-Arm<br>All participants will receive induction chemotherapy and transoral surgery. Following surgery, participants will be stratified into a risk category (low, medium, or high). Subjects in the low risk category will receive no further treatment after their transoral surgery. Subjects in the medium risk category will receive ipsilateral radiation concurrent with weekly cisplatin, and subjects in the high risk category will receive cisplatin every three weeks with concurrent bilateral radiation. | Drug: Carboplatin<br>* Weekly carboplatin given intravenously for 6 weeks during induction chemotherapy.<br>* Other names: Paraplatin;Drug: Paclitaxel<br>* Weekly paclitaxel given intravenously prior to carboplatin infusion for 6 weeks during induction chemotherapy.<br>* Other names: Taxol;Drug: Lapatinib<br>* Lapatinib (1000mg) taken by mouth once a day either one hour before or one hour after a meal for 6 weeks during induction chemotherapy. Participants deemed high risk following transoral surgery will additionally take lapatinib daily concurrently with their chemoradiation therapy.<br>* Other names: Tykerb;Drug: Cisplatin<br>* Weekly cisplatin given intravenously for 6 weeks concurrent with ipsilateral radiation. Alternative regimens may be substituted for cisplatin in patients who are not candidates for cisplatin at the discretion of the investigator. If carboplatin is used, a maximum of 125 mL/min must be used, as per standard of care.<br>* Other names: Platinol;Drug: Cisplatin<br>* Cisplatin given once every 3 week cycle intravenously for 5-7 weeks concurrent with bilateral radiation and daily lapatinib. Alternative regimens may be substituted for cisplatin in patients who are not candidates for cisplatin at the discretion of the investigator. If carboplatin is used, a maximum of 125 mL/min must be used, as per standard of care.<br>* Other names: Platinol;Radiation: Ipsilateral Radiation<br>* After transoral surgery, subjects deemed medium risk will receive ipsilateral radiation as per standard of care 5 days/week for 6 weeks concurrent with weekly cisplatin.<br>* Other names: Radiation therapy;Radiation: Bilateral Radiation<br>* After transoral surgery, subjects deemed high risk will receive bilateral radiation as per standard of care 5 days/week for 5-7 weeks concurrent with cisplatin every 3 weeks and daily lapatinib.<br>* Other names: Radiation therapy;Procedure: Transoral Surgery<br>* Transoral resection by robotic or microscopic approach, which will be at the discretion of the treating surgeon.<br>* Other names: Surgery;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Evaluation of target lesions through tumor imaging (CT scan, MRI, and/or chest x-ray) at 3-5 weeks post induction chemotherapy. Overall response rate will be based on RECIST criteria. Overall response rate (ORR) is defined as the number of patients who have a partial or complete response to therapy. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | 11 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of 3 Part Therapy | Percentage of patients successfully completing 3 part therapy will be used to assess the feasibility of 3 part therapy consisting of induction chemotherapy, surgery, and risk-adapted use of chemoradiation. | 2 years | 
| Number of Patients Who Decreased in Risk Level Post Induction Chemotherapy. | Number of patients who no longer need radiation (have decreases in risk level post induction therapy). Estimations of Risk level pre-induction will be based on physical examination and imaging, post-induction risk level will be determined based on pathologic evaluation or surgical specimen. | 11 weeks | 
| Overall Survival | Overall survival is measured from the time the patient goes on treatment until death. | 15 years | 
| Progression-Free Survival | Progression-free survival associated with 3 part therapy consisting of induction chemotherapy, surgery and risk-adapted use of chemoradiation. Defined as per RECIST criteria. Physical examination, imaging of target lesions by CT scan or MRI and chest imaging (CT or Chest x-ray, if clinically indicated) every 3 months (+/- 30 days) for 18 months following end of treatment. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | 15 years | 
| Voice and Swallowing Function- MD Anderson Dysphagia Inventory (MDADI) | The MD Anderson Dysphagia Inventory (MDADI) is a 20 item assessment designed to measure voice and swallowing function. Participants were asked 13 symptom questions and 6 interference items (walking, working) and asked id the 1- strongly agree to 5 strongly disagree. Scores were summed for a range of 20-100. The lower the score the worse the outcomes. | Pre-treatment up to 1 year post surgery | 
| Voice and Swallowing Function - Voice-Related Quality of Life Assessment (VRQOL) | The Voice-Related Quality of Life Tool is a 10 item list of possible voice-related problems. The participant answers 1-5 with 1 being none, not a problem to 5, problem is as bad as it can be. An algorithm is used to calculate the scores, so that sum scores range from 0 to 100, where 0 indicates poor V-RQOL and 100 indicates good V-RQOL | Pre-treatment up to 1 year post surgery | 
| Estimate the Pathologic Complete Response Rate at the Primary Site and in the Neck Following Induction Chemotherapy | Pathologic complete response (pCR) is the disappearance of all signs of cancer in tissue samples removed during surgery or biopsy (pT0). Also called pathologic complete remission. Pathologic Partial Response (pPR), is the presence of only non-invasive cancer in tissue samples (<pT2) | 11 weeks | 
| Response Rates at the Primary Site | Evaluation of target lesions through tumor imaging (CT scan, MRI, and/or chest x-ray) at 3-5 weeks post induction chemotherapy. Overall response rate will be based on RECIST criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions. | 11 weeks | 
| Number of Subjects Who Experience Grade 3/4 Adverse Events According to CTCAE 4.0 | The NCI Common Terminology Criteria for Adverse Events is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. | 18 weeks | 
| the Kinome Response to Induction Chemotherapy | Describe the kinome response to induction chemotherapy (lapatinib, paclitaxel, and carboplatin) in patients who consent to this optional evaluation via co-enrollment in LCCC0121 | 11 weeks | 
| Response Rates at the Neck. | Evaluation of target lesions through tumor imaging (CT scan, MRI, and/or chest x-ray) at 3-5 weeks post induction chemotherapy. Overall response rate will be based on RECIST criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for neck lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions. | 11 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase II, Head and neck cancer, Squamous Cell Carcinoma, Transoral Surgery, Induction Chemotherapy, Carboplatin, Paclitaxel, Lapatinib