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

NCT01732640 | Terminated Phase 1 Results DMC

• 2 other identifiers: J1266NA_00074085
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 2

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.

Conditions

Squamous Cell Carcinoma of the Head and Neck

Keywords

Squamous cell carcinoma of the head and neck

Outcome Measures

Primary Outcomes (3)

• Maximum Tolerated Dose (MTD) of Afatinib

  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.

  1 Year (Average)

• Objective Tumor Response

  Patients were accessed for response by CT/MRI and clinical exam. Partial response was defined as a greater than 30 % reduction in tumor size.

  After completion of 2 cycles of induction chemotherapy (at least 8 weeks)

• Number of Participants With Dose Limiting Toxicities

  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).

  1 year (average)

Secondary Outcomes (7)

• Overall Response After Chemoradiation

  5 Years

• 2 Year Progression Free Survival (PFS)

  2 Years

• Median Overall Survival at 2 Years

  2 Years

• Biological Marker Activity of Afatinib

  5 Years

• Activity of Afatinib Based on Serial FLT-PET/CT and DW-MRI

  5 Years

Study Arms (1)

Study 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.

Drug: Afatinib; Drug: Paclitaxel; Drug: Carboplatin; Drug: Cisplatin; Radiation: Intensity Modulated Radiation Therapy

Interventions

Afatinib DRUG

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.

Also known as: N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide

Study Arm

Paclitaxel DRUG

Induction chemotherapy: 175 mg/m2 day 1 every 21 days for 2 cycles (IV infusion as per institutional standard).

Also known as: TaxolR, NSC 673089

Study Arm

Carboplatin DRUG

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.

Also known as: cis-Diammine(1,1-cyclobutanedicarboxylato)platinum(II)

Study Arm

Cisplatin DRUG

Concurrent chemotherapy: 40 mg/m2 once weekly for 7 cycles (IV infusion as per institutional standard).

Also known as: Cis-diaminedichloroplatinum Cis-diaminedichloroplatinum (II), diaminedichloroplatinum, cis-platinum, platinum, Platinol, Platinol-AQ, DDP, CDDP, DACP, NSC 119875 R R

Study Arm

Intensity Modulated Radiation Therapy RADIATION

Standard Fractionation 70 Gy /35 fractions at 2 Gy/day for 5 days per week.

Also known as: IMRT

Study Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Patients must have measurable disease of primary, nodes or both by clinical and radiographic methods per RECIST v1.1..
• No prior therapy, including surgery with curative intent, chemotherapy, radiation therapy, immunotherapy, EGFR targeted therapies, or any other investigational agents.
• Age \>= 18 years.
• ECOG performance status 0-1.
• 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
• 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.
• 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

You may not qualify if:

• Any prior radiation above the clavicles.
• Any prior invasive malignancy (unless non-melanomatous resectable skin or the DFS is 2 years or more).
• History of allergic reactions attributed to compounds of similar chemical or biological composition to afatinib, or other agents used in study.
• 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%)
• Gastrointestinal tract disease resulting in an inability to take or absorb oral or enteral medication.
• Baseline significant gastrointestinal symptoms with diarrhoea as a major symptom or a CTCAE Grade \>1 diarrhoea of any etiology.
• 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.
• Women of childbearing potential and sexually active males are strongly advised to use an accepted and effective method of contraception.
• Known pre-existing interstitial lung disease (ILD)
• Pregnant women are excluded.

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead
• Vanderbilt-Ingram Cancer Center: collaborator
• National Comprehensive Cancer Network: collaborator

Study Sites (2)

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, 21287, United States

Location

Vanderbilt Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

Related Publications (1)

• Chung CH, Rudek MA, Kang H, Marur S, John P, Tsottles N, Bonerigo S, Veasey A, Kiess A, Quon H, Cmelak A, Murphy BA, Gilbert J. A phase I study afatinib/carboplatin/paclitaxel induction chemotherapy followed by standard chemoradiation in HPV-negative or high-risk HPV-positive locally advanced stage III/IVa/IVb head and neck squamous cell carcinoma. Oral Oncol. 2016 Feb;53:54-9. doi: 10.1016/j.oraloncology.2015.11.020. Epub 2015 Dec 17.

  PMID: 26705063 RESULT

MeSH Terms

Conditions

Squamous Cell Carcinoma of Head and Neck

Interventions

Afatinib; Paclitaxel; Carboplatin; Cisplatin; Platinum; Radiotherapy, Intensity-Modulated

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Head and Neck Neoplasms; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Amides; Organic Chemicals; Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes; Coordination Complexes; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Metals, Heavy; Elements; Transition Elements; Metals; Radiotherapy, Conformal; Radiotherapy, Computer-Assisted; Radiotherapy; Therapeutics

Limitations and Caveats

Slow accrual and high levels of toxicity lead to early termination.

Results Point of Contact

• Title: Hao Wang
• Organization: Johns Hopkins University

hwang76@jhmi.edu

410-614-3426

Study Officials

• Christine Chung, MD

  Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 12, 2012
• First Posted: November 26, 2012
• Study Start: December 1, 2012
• Primary Completion: November 1, 2016
• Study Completion: January 1, 2017
• Last Updated: July 26, 2018
• Results First Posted: July 26, 2018

Record last verified: 2018-06

Locations

US (2)