Detailed Description:
This is a global, open-label, randomized, 2-arm, Investigator's choice Phase 3 (Pivotal
Stage) study to investigate the efficacy/performance and safety of NBTXR3/RT±cetuximab versus
RT±cetuximab in treatment-naïve, platinum-ineligible, elderly participants with LA-HNSCC.
Participants will undergo a screening assessment over a period of ≤28 days to determine
eligibility. One primary tumor lesion that is amenable for intratumoral injection, as
determined by the Investigator
Eligible participants will be treated by the Investigator's choice of RT alone or RT in
combination with cetuximab. Following the Investigator's choice, participants will be
randomized in a 1:1 ratio on Day:
- Arm A: NBTXR3, as an intratumoral/intranodal injection, activated by investigator's
choice of RT alone or RT in combination with cetuximab
- Arm B: Investigator's choice of RT alone or RT in combination with cetuximab
All participants (Arm A and Arm B) will receive 70 Gy in 35 fractions over a 7 week period.
An EOT visit will be performed 4 weeks after the completion of RT. Follow-up visits will
start at 12 weeks post-RT completion, and will continue every 12 weeks for 2 years, and then
every 24 weeks thereafter until death; the participant is determined to be lost to follow up;
withdrawal of consent; or the end of the study, whichever occurs first. Participants who have
received further anti-cancer therapy for the study disease and/or have had disease
progression/recurrence will be followed only for survival information
Inclusion Criteria:
- Signed informed consent form (ICF) indicating that the participant understands the
purpose of, and procedures required for the study, and is willing to participate in
the study
- Age ≥65 years
- Biopsy-confirmed squamous cell carcinoma (SCC) of the oral cavity, oropharynx,
supraglottic larynx, or hypopharynx (archived biopsies are allowed); if no biopsies
are available, a new biopsy must be obtained to provide confirmation of SCC
- For participants with oropharyngeal cancer, human papilloma virus (HPV) p16 status
must be known
- Tumor categories T3-T4 any N or T2, if ≥N2 according to the 8th edition of the
American Joint Committee on Cancer Staging Manual (AJCC v8)
- Has one primary tumor lesion that is amenable for intratumoral injection, as
determined by the Investigator
- Ineligible to receive platinum-based chemotherapy for the treatment of LA HNSCC as
defined by having at least one of the following:
1. Aged ≥75 years
2. Estimated creatinine clearance ≥30 and <50 mL/min (calculated by Cockcroft and
Gault)
3. Hearing loss or tinnitus Grade ≥2
4. Grade ≥2 peripheral neuropathy
5. ECOG = 2
6. New York Heart Association (NYHA) class III
- Must be able to tolerate RT with curative intent as determined by the study
Investigator.
- Amenable to definitive treatment with RT. Participants with an oral cavity cancer,
should not be eligible to the primary standard treatment, which is surgery, and the
decision for definitive treatment with RT requires consultation with the head and neck
surgeon and the site's multidisciplinary tumor board.
- ECOG performance status of 0 to 2
- Life expectancy ≥6 months
- Adequate organ and bone marrow function at screening as defined by:
1. Hemoglobin >9.0 g/dL
2. Platelet count >100,000 cells/mm3
3. Leukocytes >3000 cells/mm3
4. Absolute neutrophil count >1500 cells/mm3
5. Alanine aminotransferase (ALT) ≤3 x upper limit of normal (ULN)
6. Aspartate aminotransferase (AST) ≤3×ULN
7. Total bilirubin ≤1.5 mg/dL (in participants with Gilbert's syndrome, if total
bilirubin is >1.5×ULN, measure direct and indirect bilirubin and if direct
bilirubin is ≤1.5×ULN, the participant may be eligible)
8. Total serum magnesium within normal ranges (1.7-2.2 mg/dL or 0.85 to 1.10 mmol/L)
if the participant is a candidate for cetuximab treatment as per the
Investigator's choice prior to randomization
Exclusion Criteria:
- HNSCC category T1, T2N0, T2N1 or M1 according to the 8th edition of the American Joint
Committee on Cancer Staging Manual (AJCC v8)
- Has received prior antineoplastic systemic therapy or intervention (including
pharmacological - both marketed and investigational, RT, or surgery) for the treatment
of HNSCC
- Participants with known severe Grade 3 or 4 hypersensitivity reactions to cetuximab
and participants with known prior or ongoing interstitial lung disease must be
excluded as a candidate for cetuximab treatment as per the Investigator's choice
before randomization (these participants can still be eligible for the study, only if
RT alone is chosen by the Investigator before randomization)
- Known history of human immunodeficiency virus (HIV) Chronically ongoing active
hepatitis B, or chronically ongoing active hepatitis C infection as defined in AASLD
(American Association for the Study of Liver Diseases)/EASL (European Association for
the Study of the Liver) guidelines
- Local regionally recurrent HNSCC that has been previously treated with chemotherapy
and/or RT are not eligible for the study
- Ulceration or other characteristics that may, in the opinion of the Investigator,
increase the risk of severe tumor bleeding
- SCC originating in the nasopharynx or paranasal sinus, from the salivary gland, or
thyroid gland, or non-squamous histology (e.g., melanoma or neuroendocrine carcinoma),
or SCC of unknown primary origin
- Prior or concurrent malignancy whose natural history or treatment has the potential to
interfere with the safety or efficacy assessment of the investigational regimen
- Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia, ventricular
fibrillation, torsades de pointes, second- or third-degree atrioventricular heart
block without a permanent pacemaker in place)
- Class IV congestive heart failure as defined by the New York Heart Association
functional classification system <6 months prior to screening
- A pregnant or nursing woman, or women of childbearing potential and men who are
sexually active and not willing/able to use medically acceptable forms of
contraception starting from signed ICF through 150 days after the last cetuximab
dose/RT fraction. A woman who is ≥1 year postmenopausal or surgically sterile is not
considered to be of childbearing potential.
- Ongoing areca nut (betel nut) consumption within 6 months prior to randomization
- Any condition for that, in the opinion of the Investigator, participation would not be
in the best interest of the individual (e.g., compromises the participant's
well-being) or that could prevent, limit, or confound the protocol/CIP specified
assessments, including subjects under legal protection
- Subject participating in another clinical study at the time of signature of the
informed consent form
Primary outcome:
1. Progression-free Survival (PFS) (Time Frame - 30 months following first randomized participant):
Time from randomization to local-regional recurrence, local-regional progression, distant progression, or death from any cause, whichever occurs first
Secondary outcome:
1. Overall Survival (OS) (Time Frame - 48 months following first randomized participant):
Time from randomization to death from any cause
2. Local-regional control (Time Frame - 48 months following first randomized participant):
Time to local regional progression: time from Randomization to local-regional progression or death, whichever occurs first
3. Distant control (Time Frame - 48 months following first randomized participant):
Time to distant progression: time from Randomization to distant progression or death, whichever occurs first
4. Objective Response Rate (ORR) (Time Frame - 48 months following first randomized participant):
Rate of complete response (CR)+partial response (PR) [RESIST 1.1]
5. Duration of Overall Response (Time Frame - 48 months following first randomized participant):
Time from CR or PR to progression of disease, unequivocal clinical progression, or death, whichever occurs first
6. Quality of Life over time - QLQ H&N35 (Time Frame - 48 months following first randomized participant):
Change from baseline over time in symptoms, function, and health related QOL using the European Organisation for Research and Treatment of Cancer (EORTC) questionnaire-Head and Neck Cancer Module (QLQ H&N35)
7. Quality of Life over time - EQ 5D 5L (Time Frame - 48 months following first randomized participant):
Change from baseline over time in symptoms, function, and health related QOL using the 5 level EuroQol 5 dimension (EQ 5D 5L) instrument
8. Safety across duration of study - AEs (Time Frame - 48 months following first randomized participant):
Adverse events (AEs)
- Experimental: Arm A
NBTXR3, as an intratumoral/intranodal injection, activated by investigator's choice of RT alone or RT in combination with cetuximab. NBTXR3 is given as a single intratumoral injection as a dose of 33% of the Gross Tumor Volume - Active Comparator: Arm B
Investigator's choice of RT alone or RT in combination with cetuximab
- NBTXR3 (Functionalized hafnium oxide nanoparticles):
Suspension of inert, crystalline hafnium oxide particles, designed to generate oxygen free radicals to destroy cancer cells after activation by ionizing radiation. - Cetuximab (Erbitux):
Solution for infusion - Radiation Therapy:
Intensity-modulated radiation therapy (IMRT): 70 Gray in 35 fractions over a 7-week period.
Quelle: ClinicalTrials.gov
