Overview

This research study is a phase Ib/II, single-arm, non-randomized, non-blind, multicenter study designed to determine whether Afatinib is effective and safe in patients with locoregionally unresectable and / or metastatic HNSCC with Fanconi Anemia.

The main hypothesis, based on preclinical evidence, is that treatment with afatinib, an epithelial growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), could be an effective treatment option to control cancer for patients with FA - HNSCC.

Eligibility

Inclusion Criteria:

1. Written informed consent according to local guidelines, must be signed and dated by the participant and investigator prior to performing any protocol procedure.
2. Patient is ≥ 18 years of age.
3. Confirmed diagnosis of Fanconi anemia.
4. Histologically or cytologically confirmed unresectable or locoregionally advanced squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, larynx, nasopharynx, paranasal sinuses or salivary glands. Patients with distal metastasis (M1, American Joint Cancer Committee (AJCC) 8th ed.) are also eligible.
5. Tumor not a candidate for resection prior to Afatinib due to technical inability to resect (tumor fixation / invasion in the skull base, cervical vertebrae, nasopharynx or fixed lymph nodes) and / or low surgical cure [T3-T4, N2-N3; , AJCC 8th ed.]).
6. Patients must have at least 1 measurable lesion by computed tomography (CT) scan or magnetic resonance imaging (MRI) as defined by RECIST v1.1.
7. Previous anticancer treatment is allowed if it ends 6 weeks or 5 half-lives, whichever is shorter, before the expected date of start of the study treatment.
8. Previous locoregional treatments such as radiotherapy are allowed.
9. Eastern Cooperative Oncology Group (ECOG) performance status < 2 at inclusion.
10. Adequate organ and bone marrow functions, as defined below:
    1. Neutrophils > 1000 cells / microliter.
    2. Platelets > 50,000 cells / microliter.
    3. Hemoglobin > 8 g / dL
    4. Creatinine < 1.5 x upper limit normal (ULN) with clearance > 50 mL / min.
    5. Total bilirubin < 1.5 x ULN. Note: patients with Gilbert's may be included with bilirubin <2 x ULN.
    6. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x ULN or < 5 ULN if liver metastases are present.
    7. International normalized ratio (INR) and prothrombin time (PT) <1.5 x ULN.
11. Female patients must either:
    1. Be of non-childbearing potential:

       Postmenopausal *(defined as at least 1 year without any menses) prior to screening , or Documented surgically sterile (e.g.hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or bilateral tubal occlusion).

       *Those who are amenorrheic due to an alternative medical cause are not considered postmenopausal and must follow the criteria for childbearing potential subjects.

       OR

    2. If of childbearing potential:

     Agree not to try to become pregnant during the study and for at least 1 months after
     the final study drug administration, And have a negative urine or serum pregnancy
     test within 7 days prior to Day 1 (females with false positive results and
     documented verification of negative pregnancy status are eligible for
     participation), And if heterosexually active, agree to abstinence (if in line with
     the usual preferred lifestyle of the patient) or consistently use a condom plus 1
     form of highly effective birth control per locally accepted standards starting at
     screening and throughout the study period and for at least 1 month after the final
     study drug administration.

12. Female patients must agree not to breastfeed or donate ovules starting at screening

     and throughout the study period, and for at least 1 month after the final study drug
     administration.

13. Male patients must not donate sperm starting at screening and throughout the study

period, and for at least 1 month after the final study drug administration.

14. Male patients with a partner with childbearing potential, or who is pregnant or

     breastfeeding must agree to abstinence or use a condom plus 1 form of highly
     effective birth control throughout the study period and for at least 1 month after
     the final study drug administration.

15. Patient agrees not to participate in another interventional study while on treatment

in the present study.

Exclusion Criteria:

1. Patients who are candidates for surgery with curative intent are not eligible.
2. Less than two weeks from surgical resection or other major surgical procedure at start of treatment. Planned surgery for other diseases.
3. Previous treatment with EGFR small molecule inhibitors, EGFR inhibitory antibodies and / or any investigational agents for the treatment of HNSCC within 4 weeks prior to the selection was not allowed.

   Note: Previous treatment with chemotherapy and/or radiotherapy is allowed.

4. Patient must have recovered from any previous treatment toxicity to Grade ≤ 2.
5. Existence of any other intercurrent malignant disease is not allowed within the previous 2 years to inclusion.

   Note: Patients with non melanoma skin cancer, curatively treated localized prostate cancer, or carcinoma in situ of any type (if complete resection was performed) are allowed.

6. Active severe Severe infectious disease in the 4 weeks prior to the initiation of study treatment, including . Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.
7. Patient has documented history of a cerebral vascular event (stroke or transient ischemic attack), or the following criteria for cardiac disease:
   1. Myocardial infarction or unstable angina pectoris within 6 months of enrollment.
   2. History of serious ventricular arrhythmia (ie, ventricular tachycardia or ventricular fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias requiring antiarrhythmic medications (except for atrial fibrillation that is well controlled with antiarrhythmic medication); history of QT interval prolongation.
   3. New York Heart Association (NYHA) class III or greater congestive heart failure or left ventricular ejection fraction of < 40%.
8. Participants with QTc interval (corrected) > 470 msec at screening.
9. History of interstitial lung disease requiring corticosteroids or pneumonitis.
10. Gastrointestinal disorders that may interfere with the absorption of the study drug or chronic diarrhea.
11. Patient has known hypersensitivity to afatinib or to any excipient contained in the drug formulation.
12. Female patients who are or intend to be pregnant or breastfeeding during their participation in the study or 1 month after the final study drug administration.
13. Patients unable to comply with the protocol as determined by the investigator.
14. The patient is currently participating in another clinical trial that would interfere with the radiological imaging schedule or any other determinations required in this protocol.
15. Patient has other underlying medical conditions that, in the opinion of the investigator, would impair the ability of the patient to receive or tolerate the planned treatment and follow-up.
16. Patients with psychiatric disorders that may interfere with monitoring.