A Phase I/II Study Afatinib/Carboplatin/Paclitaxel Induction Chemotherapy In HPV-Negative HNSCC.

Phase 1

Terminated

• Conditions: Squamous Cell Carcinoma of the Head and Neck
• Interventions: Drug: Afatinib; Drug: Paclitaxel; Drug: Carboplatin; Drug: Cisplatin; Radiation: Intensity Modulated Radiation Therapy

• Registration Number: NCT01732640
• Lead Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief 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.

Detailed 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.

Study Timeline

• Study First Submitted: 2012-11-12
• Study First Submitted QC: 2012-11-19
• Study First Posted: 2012-11-26
• Study Start: 2012-12
• Primary Completion: 2016-11
• Study Completion: 2017-01
• Results First Submitted: 2017-07-28
• Status Verified: 2018-06
• Results First Submitted QC: 2018-06-29
• Last Update Submitted: 2018-06-29
• Results First Posted: 2018-07-26
• Last Update Posted: 2018-07-26

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 9

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Study Arm	Intensity Modulated Radiation Therapy	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.
Study Arm	Paclitaxel	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.
Study Arm	Afatinib	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.
Study Arm	Carboplatin	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.
Study Arm	Cisplatin	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.

Primary Outcome Measures

Name	Time	Method
Objective Tumor Response	After completion of 2 cycles of induction chemotherapy (at least 8 weeks)	Patients were accessed for response by CT/MRI and clinical exam. Partial response was defined as a greater than 30 % reduction in tumor size.
Maximum Tolerated Dose (MTD) of Afatinib	1 Year (Average)	The maximally tolerated dose (MTD) was defined as the dose of afatinib in which \<2 of 6 patients experience a DLT with the next higher dose having at least 2 of up to 6 patients experiencing a DLT. No dose escalations or de-escalations are permitted within each subject's treatment.
Number of Participants With Dose Limiting Toxicities	1 year (average)	Grade 3 or 4 neutropenia (ie. absolute neutrophil count \<1000 cells/mm\^3) that was associated with a fever\>38.5 degrees C or lasting longer than 5 days, grade 3 thrombocytopenia with bleeding or grade 4 thrombocytopenia, and any grade 3 or 4 non-hematologic toxicity per CTCAE criteria which were probably or definitely related to study therapy. During the chemoradiation, an event of stomatitis, pharyngitis, mucositis, or dermatitis was not considered to be a dose limiting toxicity unless it was a grade 4 that did resolve to \<grade 2 with a radiation treatment break (not to exceed 10 days) or with withholding chemotherapy (not to exceed 2 weekly doses).

Secondary Outcome Measures

Name	Time	Method
Biological Marker Activity of Afatinib	5 Years	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.
Correlate Standard Imaging Pre and Post Treatment	5 Years	To correlate the response with standard imaging CT/MRI and FDG PET pre and post treatment.
Overall Response After Chemoradiation	5 years	To estimate the overall response rate after completion of chemoradiation
Activity of Afatinib Based on Serial FLT-PET/CT and DW-MRI	5 Years	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.
2 Year Progression Free Survival (PFS)	2 Years	To estimate the 2 year progression free survival.
Median Overall Survival at 2 Years	2 Years	To estimate the median overall survival.

Trial Locations

Locations (2)

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center; 🇺🇸 Baltimore, Maryland, United States

Vanderbilt Ingram Cancer Center; 🇺🇸 Nashville, Tennessee, United States