Overview

This trial is active, not recruiting.

Condition squamous cell carcinoma of the head and neck
Treatments afatinib, paclitaxel, carboplatin, cisplatin, intensity modulated radiation therapy
Phase phase 1/phase 2
Targets HER2, EGFR, HER, HER4
Sponsor Sidney Kimmel Comprehensive Cancer Center
Collaborator Vanderbilt-Ingram Cancer Center
Start date December 2012
End date January 2017
Trial size 71 participants
Trial identifier NCT01732640, J1266, NA_00074085

Summary

Trial Objectives:

The objective is to investigate the efficacy and safety of afatinib with induction chemotherapy in primary unresected patients with locally advanced, HPV-negative, stage III or IVa/b HNSCC including oral cavity, oropharynx, hypopharynx, or larynx.

Primary Objective Phase I The primary objective of the phase I portion of the trial is to determine the maximum tolerated dose (MTD) or the recommended phase II dose of daily oral afatinib that is safe in combination with carboplatin AUC 6 and paclitaxel 175mg/m2 q 21 days as an induction regimen.

Primary Objective Phase 2 The primary objective of the phase 2 portion of the trial is to estimate the objective tumor response rate and toxicity with induction therapy in patients treated on the afatinib dose determined in Phase I.

Secondary Objectives The secondary objective of phase II is to estimate: 1) the overall response to entire treatment after completion of CRT, 2) progression-free survival (PFS) rate at 2 years, and 3) overall survival (OS) at 2 years.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Endpoint classification safety/efficacy study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
Eligible patients will begin with a 14-day lead-in period with afatinib alone. This will be followed immediately by 2 cycles of induction chemotherapy (IC) with carboplatin AUC 6 IV Day 1, paclitaxel 175mg/m2 IV Day 1, and oral afatinib as a continuous daily dosing. Each cycle is repeated every 21 days. After completion of 2 cycles of IC, patients will be assessed for response by CT/MRI and clinical exam. After the induction, all patients will receive Intensity Modulated Radiation Therapy (IMRT) with weekly cisplatin 40mg/m2 IV. Chemoradiotherapy (CRT) will begin 2-3 weeks after the completion of the second cycle of IC. The patients will be evaluated with a MRI or CT, and FDG PET approximately 12 weeks after completion of CRT.
afatinib N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide
Afatinib will be supplied as film-coated tablets. Available dosage strengths will be 20, 30, or 40 mg. Tablets will be supplied in HDPE, child-resistant, tamper-evident bottles.
paclitaxel TaxolR
Induction chemotherapy: 175 mg/m2 day 1 every 21 days for 2 cycles (IV infusion as per institutional standard).
carboplatin cis-Diammine(1,1-cyclobutanedicarboxylato)platinum(II)
Carboplatin is available as a sterile lyophilized powder in single-dose vials containing 50 mg, 150 mg, or 450 mg of carboplatin. Each vial contains equal parts by weight of carboplatin and mannitol. Commercial supplies of carboplatin will be used in this trial.
cisplatin Cis-diaminedichloroplatinum Cis-diaminedichloroplatinum (II)
Concurrent chemotherapy: 40 mg/m2 once weekly for 7 cycles (IV infusion as per institutional standard).
intensity modulated radiation therapy IMRT
Standard Fractionation 70 Gy /35 fractions at 2 Gy/day for 5 days per week.

Primary Outcomes

Measure
Maximum Tolerated Dose (MTD)
time frame: 1 Year (Average)
Objective Tumor Response
time frame: 5 years

Secondary Outcomes

Measure
Overall Response after Chemoradiation
time frame: 5 Years
2 Year Progression Free Survival (PFS)
time frame: 5 Years
Median Overall Survival
time frame: 5 Years
Biological Marker Activity of Afatinib
time frame: 5 Years
Activity of Afatinib Based on Serial FLT-PET/CT and DW-MRI
time frame: 5 Years
Correlate Standard Imaging Pre and Post Treatment
time frame: 5 Years

Eligibility Criteria

Male or female participants at least 18 years old.

Inclusion Criteria: 1. Patients must have a histologically confirmed diagnosis of squamous cell carcinoma, operable or inoperable tumors, stage III (T3N0-1) and IVA-B (T1-4 N2-3M0 or T4N0-1M0) of oral cavity, oropharynx, hypopharynx and larynx. For patients with oropharynx primary, either HPV negative or HPV positive with a > 10 pack year tobacco history or current smokers are eligible. HPV status should be determined before the enrollment in only non-smokers with oropharynx primary by HPV in-situ hybridization and/or p16 immunostain. 2. Patients must have measurable disease of primary, nodes or both by clinical and radiographic methods per RECIST v1.1.. 3. No prior therapy, including surgery with curative intent, chemotherapy, radiation therapy, immunotherapy, EGFR targeted therapies, or any other investigational agents. 4. Age >= 18 years. 5. ECOG performance status 0-1. 6. Patients must have normal hepatic, renal and bone marrow function. - Absolute neutrophil count >=1,000/ mm3 Count - Platelets >= 100,000/mm3 Count - Total serum bilirubin =< 1.5mg/dL Level: - AST and ALT =< 2.5 X ULN - Alkaline Phosphatase =< 2.5 X ULN - Total calculated creatinine clearance >= 60 mL/min 7. Patients with a history of a curatively treated malignancy must be disease-free for at least two years except for carcinoma in situ of cervix and/or non-melanomatous skin cancer. 8. Patients with the following within the last 6 months prior to pre-registration must be evaluated by a cardiologist and/or neurologist prior to entry into the study. - Congestive heart failure > NYHA Class II - CVA/TIA - Unstable angina - Myocardial infarction (with or without ST elevation) 9. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: 1. Any prior radiation above the clavicles. 2. Any prior invasive malignancy (unless non-melanomatous resectable skin or the DFS is 2 years or more). 3. History of allergic reactions attributed to compounds of similar chemical or biological composition to afatinib, or other agents used in study. 4. Cardiac left ventricular dysfunction with resting ejection fraction of less than institutional lower limit of normal ( if no lower limit of normal is defined in the institution, the lower limit is 50%) 5. Gastrointestinal tract disease resulting in an inability to take or absorb oral or enteral medication. 6. Baseline significant gastrointestinal symptoms with diarrhoea as a major symptom or a CTCAE Grade >1 diarrhoea of any etiology. 7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. 8. Women of childbearing potential and sexually active males are strongly advised to use an accepted and effective method of contraception. 9. Known pre-existing interstitial lung disease (ILD) 10. Pregnant women are excluded.

Additional Information

Official title A Phase I/II Study Afatinib/Carboplatin/Paclitaxel Induction Chemotherapy Followed By Standard Chemoradiation In HPV-Negative or High-risk HPV-Positive Locally Advanced Stage III/IVa/IVb HNSCC
Principal investigator Christine Chung, MD
Description This is a phase I/phase II prospective multicenter trial to investigate the efficacy and safety of afatinib with induction chemotherapy in primary unresected patients with HPV-negative locally advanced SCC stage III or IVa/b of oral cavity, oropharynx, hypopharynx, or larynx. The primary endpoint is overall response rate after the completion of induction chemotherapy. Eligible patients will begin with a 14 day lead-in period with afatinib alone. This will be followed immediately by 2 cycles of induction chemotherapy with carboplatin AUC 6 IV, paclitaxel 175mg/m2 day 1, and afatinib as a continuous daily dosing. Each cycle is repeated every 21 days. All patients will receive concurrent chemoradiotherapy beginning 2-3 weeks after the completion of the second cycle of induction chemotherapy (Refer to Study Schema in page 8 of the protocol). During the period of induction chemotherapy, a complete history and physical (including weight) and tumor assessment by physical examination on Day 1 of each cycle will be performed and documented. Complete blood count with differential and a comprehensive metabolic profile will be performed weekly. After completion of induction chemotherapy, reassessment with blood work, physical exam, CT/MRI of neck and nasopharyngolaryngoscopy will be performed. After the completion of CRT, the patient will have a MRI, CT, or FDG PET approximately 12 weeks after CRT. Follow-up will be standard of care from this point onwards. Physical exam, blood work and AE assessments will also be frequently performed during entire treatment.
Trial information was received from ClinicalTrials.gov and was last updated in October 2016.
Information provided to ClinicalTrials.gov by Sidney Kimmel Comprehensive Cancer Center.