Clinical trial NCT05724602: Radiotherapy Plus Xevinapant in Older Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma
Official title: Radiotherapy Plus Xevinapant or Placebo in Older Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma: a Randomized Phase II Study RAVINA
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE2
Conditions: Locally Advanced Head and Neck Squamous Cell Carcinoma
Keywords: Older adults (≥ 70 years)
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2023-02-13
Enrollment: 230
Sex: ALL
Minimum age (years): 70
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a multicenter, randomized, placebo-controlled, triple blind, phase II study to determine the efficacy and safety of xevinapant with radiotherapy in older patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) of oral cavity, oropharynx, hypopharynx, or larynx.

Upon confirmation of eligibility, subjects will be enrolled and randomized in a 1:1 ratio to:

* Arm A: 3 cycles of xevinapant (200 mg/day from Day 1 to 14, per cycle) + intensive modulated radiotherapy (IMRT) followed by 3 cycles of xevinapant in monotherapy phase (200 mg/day from Day 1 to 14, per cycle)
* Arm B: 3 cycles of placebo (from Day 1 to 14, per cycle) + IMRT followed by 3 cycles of placebo in monotherapy phase (from Day 1 to 14, per cycle).

Patients will be stratified by institution, disease location/p16 status (p16 positive oropharyngeal cancer, versus others), G8 score. Three strata for the G8 will be used (\>14, versus 11-14 versus \<11).

Patients will undergo imaging in week 20 and upon clinical suspicion of progression/recurrence. Clinical examination will take place every 12 weeks in the first 3 years.


Eligibility criteria: Main Inclusion Criteria:

* Age ≥ 70 years.
* Pathologically proven new diagnosis of HNSCC of oral cavity, oropharynx, hypopharynx and larynx tumor.
* cT3-4 cN0 cM0 or cT1-4 cN1-3 cM0 except for T1-2N1 p16 positive oropharyngeal cancer (AJCC 8th edition).
* HPV status using p16 immunohistochemistry (IHC) available for oropharyngeal squamous cell carcinoma.
* Measurable disease per RECIST 1.1.
* Eastern Coperative Oncology Group Performance Status (ECOG PS) ≤ 1.
* Intention to treat with curative intent primary radiotherapy alone.
* Able to swallow liquids or has an adequately functioning feeding tube, gastrostomy or jejunostomy placed.
* Adequate hematologic, renal, and hepatic function as indicated by:
* Creatinine clearance ≥ 30 mL/min, measured with the Cockroft and Gault formula.
* Absolute neutrophil count ≥ 1 500 cells/μL.
* Platelets ≥ 100 000 cells/μL.
* Hemoglobin ≥ 9.0 g/dL or ≥5.6 mmol/L (blood transfusions during screening are permitted).
* AST and ALT ≤ 3.0 × upper limit of normal (ULN).
* Total bilirubin ≤ 1.5 × ULN (up to 2.0 × ULN is allowed if the direct bilirubin level is normal and the elevation is limited to indirect bilirubin).
* Written informed consent must be signed according to ICH/GCP, and national/local regulations.

Main Exclusion Criteria:

* Unknown primary, primary nasopharynx and paranasal sinus.
* Two primaries.
* Any previous or current treatment for invasive head and neck cancer, including induction chemotherapy, surgery, concomitant chemotherapy and cetuximab.
* Gastrointestinal disorders that could affect drug absorption.
* Another malignancy in the previous 3 years with exception of curatively treated disease with no evidence of recurrence.
* Known allergy to xevinapant or any excipient known to be present in active or placebo formulation.
* Active gastrointestinal bleeding, or any other uncontrolled bleeding requiring more than 2 red blood cell transfusions or 4 units of packed red blood cells within 4 weeks prior to enrolment
* Non-Decompensated or symptomatic liver cirrhosis (Child-Pugh score: B or C).
* Impaired cardiovascular function or clinically significant cardiovascular diseases
* Any uncontrolled, intercurrent illness or clinical situation that would in the judgment of investigator, limit compliance with study requirements. This includes but is not limited to uncontrolled active infections, defined as any infection requiring IV antibiotics within 7 days prior to enrolment.

Primary outcomes:
measure: Locoregional event-free survival (LREFS)
timeFrame: 5 years after first patient in
Secondary outcomes:
measure: Response to treatment by RECIST 1.1
timeFrame: 5 years after first patient in
measure: Progression Free Survival as assessed by the local investigator
timeFrame: 5 years after first patient in
measure: Overall Survival
timeFrame: 5 years after first patient in
measure: Safety according to the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0 for toxicity and Serious Adverse Event reporting
timeFrame: 5 years after first patient in
measure: HRQOL as assessed by global health/QoL and physical functioning scales at week 20 (Fatigue scale from the Quality of Life Core-30 (QLQ-C30) and pain in the head and neck scale from Item List-225 (IL225)).
timeFrame: 5 years after first patient in
Other outcomes:
Locations:
city: Aalst
country: Belgium
facility: Onze Lieve Vrouw Ziekenhuis
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Woluwe-Saint-Lambert
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Lille
country: France
facility: Centre Oscar Lambret
city: Nancy
country: France
facility: Institut de Cancerologie de Lorraine
city: Paris
country: France
facility: Assistance Publique Hopitaux Paris- APHP - APHP Sorbonne Univ - Hopital la Pitie-Salpetriere
city: Paris
country: France
facility: Assistance Publique Hopitaux Paris- APHP - APHP Sorbonne Univ - Hopital Tenon
city: Berlin
country: Germany
facility: Charite - Universitaetsmedizin Berlin - Campus Virchow-Klinikum
city: Essen
country: Germany
facility: Universitaetsklinikum - Essen
city: Hamburg
country: Germany
facility: Universitaets Krankenhaus Eppendorf - Universitaetsklinikum Hamburg-Eppendorf KE - University Cancer Center
city: Galway
country: Ireland
facility: University Hospital Galway
city: Rathgar
country: Ireland
facility: St Luke Hospital & SLRON - SLRON - St. Luke'S Hospital Rathgar
city: Bologna
country: Italy
facility: IRCCS--Ospedale Bellaria-Bologna
city: Florence
country: Italy
facility: Univ. of Florence -Azienda Ospedaliero-Universitaria Careggi
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC - locatie VUMC
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen - University Medical Center Groningen
city: Maastricht
country: Netherlands
facility: Academisch Ziekenhuis Maastricht
city: Bergen
country: Norway
facility: Helse Bergen HF -Haukeland Hospital - Univ. Hosp
city: Oslo
country: Norway
facility: Oslo University Hospital - Radiumhospitalet
city: Ljubljana
country: Slovenia
facility: The Institute Of Oncology
city: Barcelona
country: Spain
facility: Institut Catala d'Oncologia - ICO L'Hospitalet - Hospital Duran i Reynals
city: Barcelona
country: Spain
facility: Vall D Hebron - Hospital Universitari Vall d'Hebron
city: Birkenhead
country: United Kingdom
facility: The Clatterbridge cancer Center NHS foundation Trust - Clatterbridge Cancer Center - Wirral
city: Bristol
country: United Kingdom
facility: University Hospitals Bristol NHS Foundation Trust - Bristol Haematology And Oncology Centre
city: Glasgow
country: United Kingdom
facility: NHS Greater Glasgow and Clyde - Beatson West of Scotland Cancer Centre - Gartnavel General Hospital
Study officials:
affiliation: University Medical Center Groningen
name: Sjoukje Oosting, Dr
role: STUDY_CHAIR
affiliation: Azienda Ospedaliero-Universitaria Careggi
name: Pierluigi Bonomo, Dr
role: STUDY_CHAIR
References: