Lymphocyte-Sparing And Radio-Immunotherapy in Head and Neck Carcinoma

Official title

A Multicenter, Randomised 2*2 Factorial Design Comparing Standard to Reduced-target Volume Radiotherapy With or Without All-trans Retinoic Acid (ATRA) in Patients With Lateralised Oropharyngeal, Laryngeal and Hypopharyngeal Squamous Cell Carcinoma.

Overview

The aim of this study is to investigate the effect of ATRA (Vesanoid) and the effect of tailored radiotherapy in patients with squamous cell carcinoma of the oropharynx, larynx or hypopharynx.

Detailed description

Following validation of eligibility criteria, patients will be randomised (1:1:1:1) to receive:

* Arm A: Standard radiotherapy then follow-up * Arm B: Tailored radiotherapy and ATRA (Vesanoid) * Arm C: Standard radiotherapy and ATRA (Vesanoid) * Arm D: Tailored radiotherapy then follow-up

This randomised phase III clinical trial will provide the clinical proof-of-concept that unilateral irradiation for lateralized tumors and the addition of ATRA (Vesanoid) to radiotherapy in HNSCC prevents severe lymphopenia and immunosenescence and therefore, may foster a radiation-induced anticancer immune response sufficient to increase event-free survival at 2 years.

Interventions

• Drug Vesanoid
  Before (chemo)radiotherapy: D1 to D3: 150mg/m2/day, 1 week before radiotherapy. Post (chemo)radiotherapy: D1 to D3: 150mg/m2/day every 3 weeks for up to 4 cycles post (chemo)radiotherapy
• Radiation Standard radiotherapy
  70 Gy in 35 fractions of 2 Gy over 6 (6 fractions per week) or hyperfractionated RT with a median therapeutic dose of 80.5 Gy delivered in 70 fractions of 1.15 Gy over 7 weeks.
• Radiation Tailored radiotherapy
  70 Gy in 35 fractions of 2 Gy over 6 weeks (6 fractions per week) or hyperfractionated RT with a median therapeutic dose of 80.5 Gy delivered in 70 fractions of 1.15 Gy over 7 weeks.
• Drug Cisplatin
  Cisplatin is recommended for the following patients : Stage T1-T2/N2a-N2b and T3/N0-N1-N2a-N2b. concomitant chemotherapy is standard of care treatments and should be administered as per standard practice. Chemotherapy will include one of the two cisplatin regimens specified in this protocol at the discretion of the participating centers. The centers must however treat all their recruited patients with one of the two regimens chosen before site activation. Chemotherapy should start the first day
• Drug Cetuximab
  Cetuximab is recommended for the following patients : Stage T1-T2/N2a-N2b and T3/N0-N1-N2a-N2b. concomitant Cetuximab is standard of care treatments and should be administered as per standard practice. Cetuximab therapy will be started with an intravenous loading dose of 400 mg/m2 one week before start of RT followed by six (radiotherapy over 6 weeks) or seven (radiotherapy over 7 weeks) weekly doses of 250 mg/m2.

Primary outcome measures

• Event Free Survival (EFS) [Time frame: At 6, 9, 15, 21 and 27 months from randomisation then annually assessed up to 2 years]

Secondary outcome measures (12)

• Local relapse Free Survival [Time frame: At 6, 9, 15, 21 and 27 months from randomisation then annually assessed up to 2 years]
• Regional relapse Free survival [Time frame: At 6, 9, 15, 21 and 27 months from randomisation then annually assessed up to 2 years]
• Metastasis Free Survival [Time frame: At 6, 9, 15, 21 and 27 months from randomisation then annually assessed up to 2 years]
• Rate of pathologically positive lymph nodes [Time frame: At 4 months from the completion of (chemo)-radiotherapy]
• Event Free Survival (EFS) [Time frame: At 4 months from the completion of (chemo)-radiotherapy]
• Overall survival [Time frame: Until up to 2 years follow-up of the last patient enrolled]
• Adverse events [Time frame: From the date of first intake of study drug until 27 months after the randomisation of the last randomised patient]
• Patient quality of life (EORTC QLQ-C30) [Time frame: At randomisation, at 6, 9, 15, 21 and 27 months after randomisation and30 days after the last study treatments administration]
• Patient quality of life (EQ5-DL) [Time frame: At randomisation, at 6, 9, 15, 21 and 27 months after randomisation and30 days after the last study treatments administration]
• Patient quality of life (EORTC QLQ-H&N43) [Time frame: At randomisation, at 6, 9, 15, 21 and 27 months after randomisation and30 days after the last study treatments administration]
• Health economic analysis [Time frame: From the first patient enrolled to 2 years after treatment discontinuation of the last patient enrolled]
• Immunomonitoring [Time frame: Cycle 1 Day 1 pre-dose of Vesanoid, Day 1 of radiotherapy and end of radiotherapy (8 to 10 weeks after randomisation)]

Eligibility criteria

Inclusion criteria

I1. Male or female patients aged ≥ 18 years old at time of inform consent signature.

I2. Patients with primary head and neck tumour up to, but not crossing the midline, previously untreated with histologically-confirmed squamous cell carcinoma of:

• the oropharynx p16-, larynx or hypopharynx : T1/N2a-N2b, T2/N0-N2b, T3/N0-N2b (UICC 8th Ed.), or
• the oropharynx p16+ : T1/N1 (multiple nodes), T2-T3/N0-N1 (UICC 8th Ed.).

I3. Patients with lymph node staging assessed by an FDG-PET/CT with no contralateral nodal uptake.

I4. Patients amenable to treatment with RT or concomitant chemo-radiotherapy as decided by the treating physician as a function of tumor stage, tumor location, performance of the patients.

I5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.

I6. Adequate hematologic and end-organ function, defined by the following laboratory test results obtained within 7 days prior to randomisation :

Hematological (without transfusion within 2 weeks) :

• Neutrophils count > 1.5 × 109 /L
• Platelets count > 75 × 109 /L
• WBC≥ 3.0 × 109 /L

Hepatic function :

• Total Bilirubin < 1.5 × ULN (except for Gilbert's syndrome which will allow bilirubin ≤ 3 ULN).
• Alanine aminotransferase (ALT) ≤ 2.5 × ULN.
• Aspartate aminotransferase (AST) ≤ 2.5 × ULN.
• Albumin >3.0g/dL

Renal function :

• Serum creatinine < 1.5 ×ULN.

I7. QTcF ≤450ms for men and 470ms for women, from 3 electrocardiograms on screening ECG, within 7 days prior randomisation.

I8. Women patients of child-bearing potential are eligible, provided they have a negative serum or urine pregnancy test within 7 days prior randomisation, and agrees to use adequate contraception for up to 1 month after the end of study treatments.

I9. Fertile men must agree to use an effective method of contraception during the study and for up to 1 month after the end of study treatments.

I10. Patient should understand, sign, and date the written voluntary informed consent form prior to any protocol-specific procedures performed and should be able and willing to comply with study visits and procedures as per protocol.

I11. Patients must be covered by a medical insurance in country where applicable.

Exclusion criteria

E1. Patient with primary tumor crossing the midline or patients with bilateral primary tumors.

E2. Patients with T1-N0 (p16-), T1-N1 (p16-), T1-N0 (p16+), T4 (p16- and p16+), bilateral lymph nodes or nodal disease more than 6 cm (p16- and p16+).

E3. Patients with unknown primary tumor size as per TNM i.e. T0-N1 to T0-N3, p16- or p16+.

E4. Patients with contralateral FDG-PET/CT nodal uptake.

E5. Patient with any previous anti-cancer therapy for HNSCC (all prior treatment are forbidden: chemotherapy, radiotherapy, targeted therapy, immunotherapy or any other therapy approved or experimental).

E6. Patient with malignancies other than HNSCC within 3 years prior to randomisation with the exception of adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localised prostate cancer treated surgically with curative intent.

E7. Patient with ongoing or anticipation of need for systemic immunosuppressive medication (including, but not limited to, glucocorticoids, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alpha agents); with the exceptions of intranasal, inhaled or topical corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.

E8. Patient with ongoing or anticipation of need for systemic immunostimulatory agents (including, but not limited to, interferons and IL-2).

E9. Patient with concurrent treatment with any other anti-cancer treatment, approved or investigational agent or participation in another clinical trial with therapeutic intent.

E10. Patient with infectious diseases :

• Severe infection within 4 weeks prior to randomisation, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia,
• Active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen \[HBsAg\] test at screening),
• Active hepatitis C. Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA at screening,
• HIV infection,
• Active tuberculosis.

E11.Patient with any psychological, cognitive, familial, sociological or geographical condition potentially hampering compliance with the study protocol, completion of patient reported measures and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.

E12. Patient with known hypersensitivity to tretinoin, other retinoids, soya, peanut or to any of the excipients of vesanoid.

E13. Patient with known malabsorption syndrome and/or unable to swallow oral medication.

E14.Patient with ongoing or expected need for concomitant treatment with vitamin A, tetracyclines, other retinoids, anti-fibrinolytic agent, and strong inducers or inhibitors of CYP3A4.

E15.Pregnant or lactating woman.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Factorial

Masking

Open label

Primary purpose

Treatment

Study locations

France · 8 centers

• Centre Léon Bérard — Lyon
• Institut de Cancérologie de Lorraine — Vandœuvre-lès-Nancy
• Institut Gustave Roussy — Villejuif
• Institut de Cancérologie de l'Ouest - Paul Papin — Angers
• Centre Oscar Lambret — Lille
• Centre Antoine Lacassagne — Nice
• AP-HP - Hôpital Tenon — Paris
• Institut Godinot — Reims

Publications

• Gau M, Alfaraj FA, Huang SH, O'Sullivan B, Su J, Xu W, Hamilton SN, Maletta A, Salman O, McInerney M, Javed A, Sanz-Garcia E, Bratman S, Hahn E, Hope A, Kim JJ, Malik N, McPartlin A, Tsai CJ, Waldron J, Yao CMKL, de Almeida JR, Hosni A. Unilateral vs bilateral neck irradiation: The importance of careful patient selection in tailoring radiation therapy for lateralized palatine-tonsil and non-palati PMID 40692081

Identifiers

NCT: NCT06706401 · ET 22-156

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗