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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by Sidney Kimmel Comprehensive Cancer Center
Sponsor:
Collaborators:
Vanderbilt-Ingram Cancer Center
National Comprehensive Cancer Network
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT01732640
First received: November 12, 2012
Last updated: March 23, 2014
Last verified: March 2014
  Purpose

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.


Condition Intervention Phase
Squamous Cell Carcinoma of the Head and Neck
Drug: Afatinib
Drug: Paclitaxel
Drug: Carboplatin
Drug: Cisplatin
Radiation: Intensity Modulated Radiation Therapy
Phase 1
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by Sidney Kimmel Comprehensive Cancer Center:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Estimated Enrollment: 71
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)
Arms Assigned Interventions
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.
Drug: Afatinib
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-butenamide
Drug: Paclitaxel
Induction chemotherapy: 175 mg/m2 day 1 every 21 days for 2 cycles (IV infusion as per institutional standard).
Other Names:
  • TaxolR
  • NSC 673089
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:
  • Cis-diaminedichloroplatinum Cis-diaminedichloroplatinum (II)
  • diaminedichloroplatinum
  • cis-platinum
  • platinum
  • Platinol
  • Platinol-AQ
  • DDP
  • CDDP
  • DACP
  • NSC 119875 R R
Radiation: Intensity Modulated Radiation Therapy
Standard Fractionation 70 Gy /35 fractions at 2 Gy/day for 5 days per week.
Other Name: IMRT

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01732640

Contacts
Contact: Christine Chung, MD 410-502-0678 cchung11@jhmi.edu
Contact: Nancy Tsottles, RN 410-614-5483 tsottna@jhmi.edu

Locations
United States, Maryland
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: Christine Chung, MD    410-502-0678    cchung11@jhmi.edu   
Contact: Nancy Tsottles, RN    410-614-5483    tsottna@jhmi.edu   
United States, Tennessee
Vanderbilt Ingram Cancer Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Jill Gilbert, MD    615-322-5000    jill.gilbert@vanderbilt.edu   
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center
Vanderbilt-Ingram Cancer Center
National Comprehensive Cancer Network
Investigators
Principal Investigator: Christine Chung, MD Sidney Kimmel Comprehensive Cancer Center
  More Information

No publications provided

Responsible Party: Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT01732640     History of Changes
Other Study ID Numbers: J1266, NA_00074085
Study First Received: November 12, 2012
Last Updated: March 23, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board
United States: Data and Safety Monitoring Board

Keywords provided by Sidney Kimmel Comprehensive Cancer Center:
Squamous cell carcinoma of the head and neck

Additional relevant MeSH terms:
Carcinoma, Squamous Cell
Carcinoma
Head and Neck Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Neoplasms by Site
Carboplatin
Paclitaxel
Cisplatin
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Radiation-Sensitizing Agents

ClinicalTrials.gov processed this record on September 18, 2014