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Squamous Cell Carcinoma of the Head and NeckPhase 1/2NCT01732640

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

A Phase 1/2 study testing Afatinib, Paclitaxel and Carboplatin in people with Squamous Cell Carcinoma of the Head and Neck, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 2 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Afatinib, Paclitaxel and Carboplatin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
9 participants
Where
2 sitesUnited States
Study dates
Dec 2012to Jan 2017
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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
  • CVA/TIA
  • Unstable angina
  • Myocardial infarction (with or without ST elevation)
  • Ability to understand and the willingness to sign a written informed consent document.

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

    Baltimore, Maryland, 21287

  • Vanderbilt Ingram Cancer Center

    Nashville, Tennessee, 37232

Other trials in United States

About this study

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

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.

Read more

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.

Read the 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.

Being tested
Afatinib, Paclitaxel, Carboplatin, Cisplatin, Intensity Modulated Radiation Therapy
Keywords
Squamous cell carcinoma of the head and neck
Medical subject headings
Squamous Cell Carcinoma of Head and Neck

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AfatinibDrug

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

    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.

  • PaclitaxelDrug

    Also called TaxolR, NSC 673089

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

  • CarboplatinDrug

    Also called cis-Diammine(1,1-cyclobutanedicarboxylato)platinum(II)

    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.

  • CisplatinDrug

    Also called Cis-diaminedichloroplatinum Cis-diaminedichloroplatinum (II), diaminedichloroplatinum, cis-platinum, platinum

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

  • Intensity Modulated Radiation TherapyRadiation

    Also called IMRT

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

Study groups in NCT01732640
Study groupRoleWhat they receive
Study ArmExperimentalEligible 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.
Receives: Drug: Afatinib; Drug: Paclitaxel; Drug: Carboplatin; Drug: Cisplatin; Radiation: Intensity Modulated Radiation Therapy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 1 Year (Average)

  2. 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.

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

  3. 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).

    Measured: 1 year (average)

Secondary outcomes (7)

  1. Overall Response After Chemoradiation

    To estimate the overall response rate after completion of chemoradiation.

    Measured: 5 Years

  2. 2 Year Progression Free Survival (PFS)

    To estimate the 2 year progression free survival.

    Measured: 2 Years

  3. Median Overall Survival at 2 Years

    To estimate the median overall survival.

    Measured: 2 Years

  4. Biological Marker Activity of Afatinib

    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.

    Measured: 5 Years

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

    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.

    Measured: 5 Years

  6. Correlate Standard Imaging Pre and Post Treatment

    To correlate the response with standard imaging CT/MRI and FDG PET pre and post treatment.

    Measured: 5 Years

  7. Overall Response After Chemoradiation

    To estimate the overall response rate after completion of chemoradiation

    Measured: 5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Nov 2012 (estimated)
  2. Study startDec 2012
  3. Primary completionNov 2016
  4. Study completionJan 2017

Why it stopped: Slow accrual and high levels of toxicity lead to early termination.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
9 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01732640
Sponsor's protocol ID
J1266
Other IDs
NA_00074085
Status last verified
Jun 2018
First submitted
12 Nov 2012
Last updated
26 Jul 2018
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 26705063

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Afatinib, Paclitaxel and Carboplatin in people with Squamous Cell Carcinoma of the Head and Neck, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 19 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 26 Jul 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 26 Jul 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum Tolerated Dose (MTD) of Afatinib (time frame: 1 Year (Average)). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01732640, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Jul 2018.

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