AFAN trial. Phase Ib/II study to investigate the safety and efficacy of Afatinib when administered as therapy in Fanconi anemia patients with unresectable and / or metastatic locoregionally advanced squamous cell carcinoma of the oral cavity, oropharynx or hypopharynx or larynx

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacio Institut De Recerca De L Hospital De La Santa Creu I Sant Pau

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Not possible to specify

Trial duration

8 Nov 2024 → ongoing

Decision date (initial)

2025-06-03

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

European funds of the Recovery, Transformation and Resilience Plan. Next Generation Funds · Fanconi Anemia Research Fund

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Pharmacodynamic

To investigate the efficacy of Afatinib when administered as therapy in Fanconi anemia patients with unresectable and / or metastatic locoregionally advanced squamous cell carcinoma of the oral cavity, oropharynx or hypopharynx or larynx. Primary endpoint for efficacy will be objective response rate (ORR).

Secondary objectives 4

1. To determine clinical outcomes such as disease control rate (DCR), duration of response (DoR), disease-free survival (DFS) and overall survival (OS) of afatinib for squamous cell carcinoma of the oral cavity, oropharynx or hypopharynx or larynx.
2. Quality of life
3. Exploratory Objectives: To determine the correlation between pathology-specific genetic alterations (i.e. EGFR genetic alterations) at baseline and during treatment and the efficacy of afatinib for squamous cell carcinoma of the oral cavity, oropharynx or hypopharynx or larynx.
4. Safety: To evaluate safety and tolerability of afatinib in participants with FA and HNSCC. Safety will be assessed by the frequency and severity of adverse events and Treatment-related adverse events (TRAEs) assessed by NCI CTCAE v5.0.

Conditions and MedDRA coding

Patients diagnosed with unresectable and / or metastatic locoregionally advanced squamous cell carcinoma of the oral cavity, oropharynx or hypopharynx or larynx secondary to Fanconi anemia.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

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 (See‬‭Section‬‭4.1.3.3‬‭).‬
4. Histologically‬ ‭or‬ ‭cytologically‬ ‭confirmed‬ ‭unresectable‬ ‭or‬ ‭locoregionally‬ ‭advanced‬ ‭squamous‬ ‭cell‬ ‭carcinoma‬ ‭of‬ ‭the‬ ‭oral‬ ‭cavity,‬ ‭oropharynx,‬ ‭hypopharynx,‬ ‭larynx,‬ ‭nasopharynx,‬‭paranasal‬‭sinuses‬‭or‬‭salivary‬‭glands.‬‭Patients‬‭with‬‭distal‬‭metastasis‬‭(‭M ‬ 1,‬ ‭th‬ ‭AJCC 8‬ ‭ed‬‭.) are also eligible.‬
5. ‭Tumor‬ ‭not‬ ‭a‬ ‭candidate‬ ‭for‬ ‭resection‬ ‭prior‬ ‭to‬ ‭Afatinib‬ ‭due‬ ‭to‬ ‭technical‬ ‭inability‬ ‭to‬ ‭resect‬ ‭(tumor‬ ‭fixation‬‭/‬‭invasion‬‭in‬‭the‬‭skull‬‭base,‬‭cervical‬‭vertebrae,‬‭nasopharynx‬‭or‬ ‭fixed lymph nodes) and / or low surgical cure [‬‭T3-T4, N2-N3; , AJCC 8‬‭th‬ ‭ed.‬‭]).‬
6. ‭Patients‬ ‭should‬ ‭not‬ ‭be‬ ‭candidates‬ ‭for‬ ‭other‬ ‭curative‬ ‭standard‬ ‭treatment‬ ‭options‬ ‭including radiotherapy, chemotherapy or immunotherapy.‬
7. ‭Patients ‬‭must ‬‭have ‬‭at ‬‭least‬‭ 1 ‬‭measurable ‬‭lesion ‬‭by ‬‭computed‬ ‭tomography ‬‭(CT) ‬‭scan ‬‭or‬ ‭magnetic resonance imaging (MRI) as defined by RECIST v1.1 (‬‭Appendix 4‬‭).‬
8. Previous ‬‭anticancer ‬‭treatment ‬‭is‬‭allowed‬‭ if ‬‭it‬‭ends ‬‭6‬‭weeks ‬‭or ‬‭5‬‭half-lives,‬‭whichever‬ ‭is shorter, before the expected date of start of the study treatment.‬
9. ‭Previous locorregional treatments such as radiotherapy are allowed.‬
10. Eastern‬ ‭Cooperative‬ ‭Oncology‬ ‭Group‬ ‭(ECOG)‬ ‭performance‬ ‭status‬ ‭<‬ ‭2‬ ‭at‬ ‭inclusion‬ ‭(‭A ‬ ppendix 11‬‭).‬
11. Adequate organ and bone marrow functions, as defined below:‬ a‭ .‬ ‭Neutrophils > 1000 cells / microliter.‬ ‭b.‬ ‭Platelets > 50,000 cells / microliter.‬ ‭c.‬ ‭Hemoglobin > 8 g / dL‬ ‭d.‬ ‭Creatinine < 1.5 x upper limit normal (ULN) with clearance > 50 mL / min.‬ ‭e.‬ ‭Total‬ ‭bilirubin‬ ‭<‬ ‭1.5‬ ‭x‬ ‭ULN.‬ ‭Note:‬ ‭patients‬ ‭with‬ ‭Gilbert's‬ ‭may‬ ‭be‬ ‭included‬ ‭with bilirubin <2 x ULN.‬ ‭f.‬ ‭Aspartate‬‭aminotransferase‬‭(AST)‬‭and‬‭alanine‬‭aminotransferase‬‭(ALT)‬‭<‬‭2.5‬‭x‬ ‭ULN or < 5 ULN if liver metastases are present.‬ ‭g.‬ ‭International normalized ratio (INR) and prothrombin time (PT) <1.5 x ULN.‬
12. ‭Female patients must either:‬ ‭a.‬ ‭Be of nonchildbearing potential:‬ ‭i.‬ ‭ii.‬ ‭ ostmenopausal‬‭*(defined‬‭as‬‭at‬‭least‬‭1‬‭year‬‭without‬‭any‬‭menses)‬‭prior‬ P ‭to screening , or‬ ‭Documented‬ ‭surgically‬ ‭sterile‬ ‭(e.g.hysterectomy,‬ ‭bilateral‬ ‭salpingectomy, bilateral oophorectomy, or bilateral tubal occlusion).‬ ‭*Those‬ ‭who‬ ‭are‬ ‭amenorrheic‬ ‭due‬ ‭to‬‭an‬‭alternative‬‭medical‬‭cause‬‭are‬ ‭not‬ ‭considered‬ ‭postmenopausal‬ ‭and‬ ‭must‬ ‭follow‬ ‭the‬ ‭criteria‬ ‭for‬ ‭childbearing potential subjects.‬ ‭OR‬ ‭b.‬ ‭If of childbearing potential:‬ ‭i.‬ ‭Agree‬‭not‬‭to‬‭try‬‭to‬‭become‬‭pregnant‬‭during‬‭the‬‭study‬‭and‬‭for‬‭at‬‭least‬‭1‬ ‭months after the final study drug administration,‬ ‭ii.‬ ‭And‬‭have‬‭a‬‭negative‬‭urine‬‭or‬‭serum‬‭pregnancy‬‭test‬‭within‬‭7‬‭days‬‭prior‬ ‭to‬ ‭Day‬ ‭1‬ ‭(females‬ ‭with‬ ‭false‬ ‭positive‬ ‭results‬ ‭and‬ ‭documented‬ ‭verification‬ ‭of‬ ‭negative‬ ‭pregnancy‬ ‭status‬ ‭are‬ ‭eligible‬ ‭for‬ ‭participation),‬ ‭iii.‬ ‭And‬ ‭if‬ ‭heterosexually‬ ‭active,‬ ‭agree‬ ‭to‬ ‭abstinence‬ ‭(if‬ ‭in‬‭line‬‭with‬‭the‬ ‭usual‬ ‭preferred‬ ‭lifestyle‬ ‭of‬ ‭the‬ ‭patient)‬‭or‬‭consistently‬‭use‬‭a‬‭condom‬ ‭plus‬‭1‬‭form‬‭of‬‭highly‬‭effective‬‭birth‬‭control‬‭(‬‭Appendix‬‭12‬‭)‬‭per‬‭locally‬ ‭accepted‬ ‭standards‬ ‭starting‬ ‭at‬ ‭screening‬ ‭and‬ ‭throughout‬ ‭the‬ ‭study‬ ‭period‬ ‭and‬ ‭for‬ ‭at‬ ‭least‬ ‭1‬ ‭month‬ ‭after‬ ‭the‬ ‭final‬ ‭study‬ ‭drug‬ ‭administration.‬
13. 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.‬
14. ‭Male‬ ‭patients‬ ‭must‬ ‭not‬ ‭donate‬ ‭sperm‬ ‭starting‬ ‭at‬ ‭screening‬ ‭and‬ ‭throughout‬ ‭the‬‭study‬ ‭period, and for at least 1 month after the final study drug administration.‬
15. Male‬ ‭patients‬ ‭with‬ ‭a‬ ‭partner‬ ‭with‬ ‭childbearing‬ ‭potential,‬ ‭or‬ ‭who‬ ‭is‬ ‭pregnant‬ ‭or‬ ‭breast feeding‬‭ must‬‭ agree ‬‭to ‬‭abstinence‬‭ or ‬‭use ‬‭ a ‬‭condom‬ ‭plus ‬‭1 ‬‭form ‬‭of ‬‭highly‬‭ effective b‭irth ‬‭control‬ ‭through out ‬‭the ‬‭study‬‭ period‬‭ and‬ ‭for ‬‭at ‬‭least ‬‭1‬‭month‬‭ after‬‭ the ‬‭final ‬‭study‬ ‭drug administration.‬
16. Patient‬ ‭agrees‬ ‭not ‬‭to‬‭ participate ‬‭in ‬‭another‬‭ interventional‬‭ study‬‭ while ‬‭on ‬‭treatment ‬‭in‬ ‭the present study.‬

Exclusion criteria 16

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 infectious disease in the 4 weeks prior to the initiation of study treatment, including 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: a. Myocardial infarction or unstable angina pectoris within 6 months of enrollment. b. 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. c. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Efficacy: To evaluate antitumor activity by means of: ORR according to RECIST V1.1

Secondary endpoints 7

1. Duration of response (DoR).
2. Disease control rate (DCR).
3. Disease-free survival (DFS) according to RECIST V1.1.
4. Overall survival (OS).
5. Health-related quality of life (HRQoL)
6. Pharmacodinamics
7. Safety: To evaluate safety and tolerability of afatinib in participants with FA and HNSCC. Safety will be assessed by the frequency and severity of adverse events and Treatment-related adverse events (TRAEs) assessed by NCI CTCAE v5.0

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacio Institut De Recerca De L Hospital De La Santa Creu I Sant Pau

Sponsor organisation

Fundacio Institut De Recerca De L Hospital De La Santa Creu I Sant Pau

Address

Calle De San Quintin 77-79

City

Barcelona

Postcode

08041

Country

Spain

Scientific contact point

Organisation

Fundacio Institut De Recerca De L Hospital De La Santa Creu I Sant Pau

Contact name

MFAR Clinical Research

Public contact point

Organisation

Fundacio Institut De Recerca De L Hospital De La Santa Creu I Sant Pau

Contact name

MFAR Clinical Research

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

1 submissions — initial application plus substantial / non-substantial modifications