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A Phase I/II Study Afatinib/Carboplatin/Paclitaxel Induction Chemotherapy Followed By Standard Chemoradiation In HPV-Negative Locally Advanced Stage III/IVa/IVb HNSCC.

Phase 1/Phase 2
18 Years
Open (Enrolling)
Squamous Cell Carcinoma of the Head and Neck

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Trial Information

A Phase I/II Study Afatinib/Carboplatin/Paclitaxel Induction Chemotherapy Followed By Standard Chemoradiation In HPV-Negative Locally Advanced Stage III/IVa/IVb HNSCC.

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

Physical exam, blood work and AE assessments will also be frequently performed during entire

Inclusion Criteria:

1. Patients must have a histologically confirmed diagnosis of squamous cell carcinoma,
operable or inoperable tumors stage III (T3 N0-1) and IVA-B ( T1-4 N2-3M0 or T4N0-
1M0) of oral cavity, oropharynx, hypopharynx, or larynx. Patients have to be
HPV-negative determined by HPV in situ hybridization or p16 immunostain. Patients
have to be HPV-negative determined by HPV in situ hybridization or p16 immunostain.

2. Patients must have measurable disease of primary or nodes by both clinical and
radiographic methods. To meet this criteria a lesion must be >= 2 cm in at least one
dimension by clinical exam AND by radiographic exam with CT or MRI. If radiographic
exam utilizes spiral CT, a lesion must be >= 1cm in at least one dimension.

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


- Unstable angina

- Myocardial infarction (with or without ST elevation)

9. Ability to understand and the willingness to sign a written informed consent

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)

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum Tolerated Dose (MTD)

Outcome Description:

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.

Outcome Time Frame:

1 Year (Average)

Safety Issue:


Principal Investigator

Shanthi Marur, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Sidney Kimmel Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

November 2012

Completion Date:

January 2017

Related Keywords:

  • Squamous Cell Carcinoma of the Head and Neck
  • Squamous cell carcinoma of the head and neck
  • Carcinoma
  • Carcinoma, Squamous Cell
  • Head and Neck Neoplasms



Vanderbilt Ingram Cancer Center Nashville, Tennessee  37232
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center Baltimore, Maryland  21231