A single-arm phase II study of cetuximab plus platinum and taxane-based chemotherapy followed by AVElumab and Cetuximab as first-line therapy for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients with PD-L1 combined positive score (CPS)≥1≤19: the immunotherapy sequence reversal

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione GONO Plus

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

5 Dec 2024 → ongoing

Decision date (initial)

2024-10-09

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Merck Serono S.p.A.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate if TPE followed by avelumab and cetuximab maintenance is able to increase the 6-months (6m)-PFS from 40% to 55% of PD-L1 CPS≥1≤19 R/M HNSCC patients.

Secondary objectives 5

1. To evaluate the Overall Survival (OS) of TPE followed by avelumab and cetuximab in PD-L1 CPS≥1≤19 R/M HNSCC patients
2. To evaluate the Overall Response Rate (ORR) of TPE followed by avelumab and cetuximab in PD-L1 CPS≥1≤19 R/M HNSCC patients
3. To determine the safety and tolerability of TPE followed by avelumab and cetuximab in PD-L1 CPS≥1≤19 R/M HNSCC patients
4. To evaluate the Duration of Response (DOR) of TPE followed by avelumab and cetuximab in PD-L1 CPS≥1≤19 R/M HNSCC patients
5. The activation of immune properties following the anti-EGFR based poly-chemotherapy (TPE, including taxanes) will lead to an increased sensitivity upon ICIs-based therapy (AVEC).

Conditions and MedDRA coding

recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Subjects able to sign the informed consent and ≥18 y-old.
2. Histologically or cytologically confirmed diagnosis of HNSCC
3. Confirmed R/M HNSCC (i.e. oral cavity, oropharynx, larynx, hypopharynx) not suitable for curative loco-regional therapy.
4. PD-L1 CPS≥1≤19 (assessment allowed either on primary and/or recurrent/metastatic site of disease).
5. Measurable disease according to RECIST Criteria 1.1.
6. Subjects should not have had prior systemic therapy administered in the R/M HNSCC setting.
7. Systemic therapy that was completed more than 6 months prior to signing consent, if given as a part of multimodal curative treatment for locally advanced disease, is allowed.
8. ECOG Performance Status (PS) 0-1.
9. Adequate bone marrow function: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, hemoglobin ≥ 9 g/dL.
10. Adequate liver function: total bilirubin level < 1.5 X Upper Limit of Normal (ULN) (except from known medical reason not interfering with liver function, such as Gilbert syndrome), AP, GGT <3 x ULN and AST and ALT levels ≤ 2.5 × ULN.
11. Adequate renal function: calculated or analyzed creatinine clearance ≥ 30 mL/min. For patients with a CrCl between ≥30 and <60 mL/min, carboplatin will be administered at a dose of AUC 5 every 21 days. If CrCl is ≥60 mL/min, cisplatin can be used instead of carboplatin. (Note: Symptomatic peripheral neuropathy NCI-CTC v5.0 grade ≥2 and / or ototoxicity grade ≥2 (except for cases in which ototoxicity is due to trauma or tumor-related mechanical impairment) and/or creatinine clearance < 60 mL/min are acceptable and they must be approached with carboplatin (instead of cisplatin) since the trial start.)
12. All patients deemed eligible by the investigator to receive first-line TPE regardless of their participation in the clinical study, will be considered for inclusion
13. Archival or fresh tissue of primary disease (i.e. T and/or N and/or M) OR recurrent/metastatic disease available at baseline (before starting TPE) (available as Formalin-Fixed Paraffin-Embedded - FFPE - or as unstained 10-20 slices).
14. Participants have to provide peripheral blood samples (at least 8-10 mL stored in EDTA) according the timing described in the translational part of thef Thecurrent
15. Palliative radiotherapy and/or surgery within 4 weeks before the study entry are allowed.

Exclusion criteria 17

1. Nasopharyngeal, salivary gland, nasal sinus, and non-melanoma skin cancers are not allowed.
2. Life expectancy lower than 3 months according to the judgement of trial investigator is not allowed.
3. Previous chemotherapy, or biological therapy (i.e. Cetuximab), or immunotherapy administered for R/M setting of HNSCC is not allowed.
4. Diagnosis of immunodeficiency or subjects receiving systemic steroid therapy (> 10 mg/day of prednisone or equivalent) or any other form of immunosuppressive therapy within 30 days prior to start of study treatment which cannot be interrupted.
5. Known allergic/hypersensitivity reaction to investigational products or any component in their formulations.
6. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
7. Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with type I diabetes, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
8. Any diagnosed and/or treated additional malignancy within 5 years before the study entry with the exception of: curatively treated basal cell carcinoma of the skin, curatively treated squamous cell carcinoma of the skin, curatively treated prostate cancer, curatively resected in situ cervical cancer, and curatively resected in situ breast cancer.
9. Subjects with a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subjects’ participation for the full duration of the trial, or is not in the best interest of the subject to participate, according to the opinion of the treating investigator.
10. Significant neurologic or known psychiatric or substance abuse disorders that would interfere with cooperation and the requirements of the trial.
11. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (≤6 months prior to enrollment), myocardial infarction (≤6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
12. Prior organ transplantation including allogenic stem-cell transplantation
13. Active uncontrolled infection requiring systemic therapy (i.e. IV antibiotics).
14. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) are NOT ELIGIBLE.
15. Hepatitis B virus (HBV) Participants with active infectious diseases (a, b): a) Active hepatitis B infection (1, 2) (i.e. Positive test for hepatitis B virus (HBV) DNA) (1) Participants who are HBsAg positive with NEGATIVE HBV-DNA viral load before trial inclusion are ELIGIBLE. Negativization of HBV DNA viral load can be occurred spontaneously or after antiviral treatment (2) Participants with antecedents of hepatitis B (i.e., anti-hepatitis B core [HBc] positive, HBsAg and hepatitis B virus [HBV]-deoxyribonucleic acid [DNA] NEGATIVE) are ELIGIBLE. b) Active hepatitis C infection (3) (i.e. Positive test for hepatitis C virus (HCV) RNA). (3) Participants who have positive anti-HCV antibodies with NEGATIVE HCV-RNA viral load before trial inclusion are ELIGIBLE. Negativization of HCV RNA viral load can be occurred spontaneously or after antiviral treatment
16. Live vaccination within 30 days of planned start of study treatment (inactivated vaccines are allowed).
17. Pregnancy (absence of pregnancy must be confirmed by negative serum or urine pregnancy test - ß-HCG - for women of childbearing potential) and/or breastfeeding are not allowed. Subjects of childbearing potential willing to use effective contraceptive method [Pearl Index < 1; e.g. oral contraceptive (pill), hormone spiral, hormone implant, transdermal patch, a combination of two barrier methods (condom and diaphragm), sterilization, sexual abstinence] for the entire study duration and 30 days post-dosing.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. To assess 6m-progression free survival (PFS) of cetuximab plus platinum and taxane-based chemotherapy followed by avelumab and cetuximab maintenance

Secondary endpoints 16

1. To assess overall survival (OS) of cetuximab plus platinum and taxane-based chemotherapy followed by avelumab and cetuximab maintenance
2. To assess overall response rate (ORR) of cetuximab plus platinum and taxane-based chemotherapy followed by avelumab and cetuximab maintenance
3. To assess safety of cetuximab plus platinum and taxane-based chemotherapy followed by avelumab and cetuximab maintenance
4. To assess duration of response (DOR) of cetuximab plus platinum and taxane-based chemotherapy followed by avelumab and cetuximab maintenance
5. Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
6. Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with type I diabetes, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
7. Any diagnosed and/or treated additional malignancy within 5 years before the study entry with the exception of: curatively treated basal cell carcinoma of the skin, curatively treated squamous cell carcinoma of the skin, curatively treated prostate cancer, curatively resected in situ cervical cancer, and curatively resected in situ breast cancer.
8. Subjects with a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subjects’ participation for the full duration of the trial, or is not in the best interest of the subject to participate, according to the opinion of the treating investigator.
9. Significant neurologic or known psychiatric or substance abuse disorders that would interfere with cooperation and the requirements of the trial.
10. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (≤6 months prior to enrollment), myocardial infarction (≤6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
11. Prior organ transplantation including allogenic stem-cell transplantation.
12. Active uncontrolled infection requiring systemic therapy (i.e. I.V. antibiotics).
13. Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
14. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive).
15. Live vaccination within 30 days of planned start of study treatment (inactivated vaccines are allowed).
16. Pregnancy (absence of pregnancy must be confirmed by negative serum or urine pregnancy test-ß-HCG-for women of childbearing potential) and/or breast-feeding are not allowed. Subjects of childbearing potential willing to use effective contraceptive method [PI<1; e.g. oral contraceptive (pill), hormone spiral, hormone implant, transdermal patch, a combination of two barrier methods (condom and diaphragm), sterilization, sexual abstinence] for the entire study duration and 30 days post-dosing

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione GONO Plus

Sponsor organisation

Fondazione GONO Plus

Address

Interno 11, Via Cesarea 8 Via Cesarea 8

City

Genoa

Postcode

16121

Country

Italy

Scientific contact point

Organisation

Gruppo Oncologico Del Nord Ovest

Contact name

Salvatore Alfieri

Public contact point

Organisation

Gruppo Oncologico Del Nord Ovest

Contact name

Salvatore Alfieri

Locations

1 EU/EEA country · 19 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

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