A Phase I/II Study Afatinib/Carboplatin/Paclitaxel Induction Chemotherapy In HPV-Negative HNSCC.
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.
Squamous Cell Carcinoma of the Head and Neck
Radiation: Intensity Modulated Radiation Therapy
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|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|
- Maximum Tolerated Dose (MTD) [ Time Frame: 1 Year (Average) ] [ Designated as safety issue: Yes ]Phase I Objective: To determine the MTD or recommended Phase II dose of oral afatinib in a combination with carboplatin AUC 6 and paclitaxel 175mg/m2 q 21 days as an induction regimen in patients with AJCC stage III and IVA-B HPV(-) HNSCC of oral cavity, oropharynx, hypopharynx and larynx.
- Objective Tumor Response [ Time Frame: 5 years ] [ Designated as safety issue: No ]Phase II Objective: To estimate the objective tumor response rate to induction chemotherapy and toxicity in patients treated on the dose of afatinib determined as safe in phase I.
- Overall Response after Chemoradiation [ Time Frame: 5 Years ] [ Designated as safety issue: No ]To estimate the overall response rate after completion of chemoradiation.
- 2 Year Progression Free Survival (PFS) [ Time Frame: 5 Years ] [ Designated as safety issue: No ]To estimate the 2 year progression free survival.
- Median Overall Survival [ Time Frame: 5 Years ] [ Designated as safety issue: No ]To estimate the median overall survival.
- Biological Marker Activity of Afatinib [ Time Frame: 5 Years ] [ Designated as safety issue: No ]To estimate the biological marker activity of afatinib by serial sampling of tumor and blood samples from patients, and correlate with clinical and pathological response and outcomes. On- and off-target effects of afatinib will be assessed for the biological marker activity.
- Activity of Afatinib Based on Serial FLT-PET/CT and DW-MRI [ Time Frame: 5 Years ] [ Designated as safety issue: No ]To estimate the activity of afatinib by obtaining serial FLT-PET/CT and DW-MRI, And compare to standard of care CT images (which will be acquired at baseline and at the completion of treatment, and categorized per RECIST criteria) and correlated with response.
- Correlate Standard Imaging Pre and Post Treatment [ Time Frame: 5 Years ] [ Designated as safety issue: No ]To correlate the response with standard imaging CT/MRI and FDG PET pre and post treatment.
|Study Start Date:||November 2012|
|Estimated Study Completion Date:||January 2017|
|Estimated Primary Completion Date:||January 2017 (Final data collection date for primary outcome measure)|
Experimental: Study Arm
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 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.
Other Name: N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamideDrug: Paclitaxel
Induction chemotherapy: 175 mg/m2 day 1 every 21 days for 2 cycles (IV infusion as per institutional standard).
Other Names:Drug: Carboplatin
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.
Other Name: cis-Diammine(1,1-cyclobutanedicarboxylato)platinum(II)Drug: Cisplatin
Concurrent chemotherapy: 40 mg/m2 once weekly for 7 cycles (IV infusion as per institutional standard).
Other Names:Radiation: Intensity Modulated Radiation Therapy
Standard Fractionation 70 Gy /35 fractions at 2 Gy/day for 5 days per week.
Other Name: IMRT
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.
|Contact: Christine Chung, MDfirstname.lastname@example.org|
|Contact: Nancy Tsottles, RNemail@example.com|
|United States, Maryland|
|Johns Hopkins Sidney Kimmel Comprehensive Cancer Center||Recruiting|
|Baltimore, Maryland, United States, 21287|
|Contact: Christine Chung, MD 410-502-0678 firstname.lastname@example.org|
|Contact: Nancy Tsottles, RN 410-614-5483 email@example.com|
|United States, Tennessee|
|Vanderbilt Ingram Cancer Center||Recruiting|
|Nashville, Tennessee, United States, 37232|
|Contact: Jill Gilbert, MD 615-322-5000 firstname.lastname@example.org|
|Principal Investigator:||Christine Chung, MD||Sidney Kimmel Comprehensive Cancer Center|