E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally advanced squamous cell carcinoma of the head and neck (SCCHN) |
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E.1.1.1 | Medical condition in easily understood language |
Locally advanced head and neck cancer |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 26.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10060121 |
E.1.2 | Term | Squamous cell carcinoma of head and neck |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate superior efficacy of Xevinapant vs placebo when added to CRT in locally advanced SCCHN. |
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E.2.2 | Secondary objectives of the trial |
- To assess the efficacy of Xevinapant compared to placebo when added to CRT according to additional efficacy endpoints.
- To compare safety, tolerability and treatment compliance of Xevinapant vs placebo, when added to CRT.
- To compare the health-related quality of life of Xevinapant vs placebo when added to CRT using patient-reported outcome questionnaires. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Willing and able to sign written informed consent prior to study screening.
2. Male or female ≥ 18 years of age (or based on the country legal age limit for adults) on day of signing the ICF.
3. Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1.
4. Histologically confirmed diagnosis in previously untreated LA-SCCHN patient (stage III, IVA or IVB according to the American Joint Committee on Cancer [AJCC]/TNM Staging System, 8th Ed.) suitable for definitive CRT as defined in the protocol.
5. Evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by computed tomography scan (CT-scan) or magnetic resonance imaging (MRI), based on RECIST v 1.1.
6. For OPC patients, primary tumors must be HPV-negative as determined by p16 expression using immunohistochemistry (IHC). For OPC participants, p16 cutoff for determination of HPV status is defined in the protocol.
7. Able to swallow liquids or has an adequately functioning feeding tube, gastrostomy or jejunostomy in place.
8. No hearing loss by clinical assessment or ≤Grade 2 hearing
impairment (according to NCI- CTCAE v.5).
9. Peripheral neuropathy < grade 2
10. Adequate hematologic, renal and hepatic function as defined in the protocol.
11. Women of childbearing potential (according to recommendations of the Clinical Trial Facilitation Group) must have a negative serum pregnancy test at screening and must not be breastfeeding. Non-sterilized males who are sexually active with a female partner of childbearing potential must agree to use adequate birth control as defined in the protocol from ICF signature to 6 months after the last administration of chemotherapy or 3 months after the last dose of Xevinapant / matched placebo, whichever is the latest.
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E.4 | Principal exclusion criteria |
1. Primary tumor of nasopharyngeal, paranasal sinuses, nasal or oral cavity, salivary, thyroid or parathyroid gland pathologies, skin or unknown primary site.
2. Metastatic disease (stage IVC as per AJCC/TNM, 8th Ed.).
3. Prior definitive or adjuvant RT and/or radical surgery to the head and neck region which may jeopardize the primary tumor irradiation plan, or any other prior SCCHN systemic treatment, including investigational agents.
4. Use within 14 days prior to randomization or requirement for ongoing treatment with any drug(s) on the prohibited medication list.
5. Treatment with an investigational agent or use of an investigational device within 4 weeks of the first dose of study treatment.
6. Known history of infection with HIV. If unknown history of HIV, an HIV screening test is to be performed and participants with positive serology for HIV-1/2 must be excluded.
7. Known chronically active HBV or HCV infection. If unknown status, see further details in the protocol.
8. Other infections (viral and/or bacterial and/or mycotic) requiring systemic treatment.
9. Live-attenuated vaccinations within 30 days prior to first investigational treatment administration.
10. Ongoing uncontrolled infection requiring intravenous antibiotic therapy within 1 week prior to randomization.
11. Known gastrointestinal disorder with clinically established malabsorption syndrome and major gastrointestinal surgery that may limit oral absorption.
12. Documented weight loss of >10% during the last 4 weeks prior to randomization (unless adequate measures are undertaken for nutritional support), OR plasmatic albumin <3.0 g/dL.No albumin transfusions are
allowed within 2 weeks before randomization.
13. 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 randomization.
14. Active uncontrolled inflammatory disease (including rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, severe extensive psoriasisand other autoimmune diseases) requiring ongoing treatment with anti-TNF medication.
15. Any concomitant medication known to prolong the QT interval that cannot be discontinued or replaced by safe alternative medication within 7 days prior to start of treatment.
16. Impaired cardiovascular function or clinically significant cardiovascular diseases, see further details in the protocol.
17. Symptomatic pulmonary disease requiring continuous or intermittent oxygen supply.
18. History of another malignancy within the last 3 years prior to randomization, with the exception of completely resected non-melanoma cell skin cancer outside the head and neck area or completely resected stage I breast cancer, or completely resected in-situ non-muscular invasive bladder, cervix and/or uterine carcinomas, or T1a squamous cell carcinoma of the esophagus.
19. Known contraindication to undergoing positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro-D-glucose (18F-FDG-PET) scans, and/ or both contrast-enhanced MRI and contrast-enhanced CT scans.
20. Known allergy to Xevinapant, cisplatin, carboplatin, other platinum-based agent or any excipient known to be present in any of these products or in the placebo formulation.
21. Non-compensated or symptomatic liver cirrhosis (Child-Pugh score: B or C).
22. Any ongoing condition or disorder, before randomization, including drug(s) or alcohol abuse, which in the judgment of the Investigator would make the patient inappropriate for entry into the study or precluding his/her ability to comply with study procedures. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Event- Free Survival (EFS) as defined in the protocol. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Endpoints will be evaluated in the timepoints listed in the protocol |
|
E.5.2 | Secondary end point(s) |
- Overall survival (OS)
- Progression-free survival (PFS)
- Locoregional control (LRC) as defined in the protocol
- Overall response rate (ORR)
- CR rate (CRR)
- Duration of response as defined in the protocol
- Proportion of participants with radical salvage surgery
- Time to subsequent systemic cancer treatments
- Incidence and severity of adverse events, serious adverse events and
adverse events of special interest, changes in laboratory values, vital
signs, and electrocardiograms
- Extent of exposure of the different treatment agents
- Changes from baseline in QOLevents and
adverse events of special interest, changes in laboratory values, vital
signs, and electrocardiograms
- Extent of exposure of the different treatment agents
- Changes from baseline in QOL |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Endpoints will be evaluated in the timepoints listed in the protocol |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 138 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Switzerland |
Ukraine |
Taiwan |
Australia |
Brazil |
Canada |
China |
Georgia |
Israel |
Japan |
Korea, Republic of |
Russian Federation |
United Kingdom |
United States |
Austria |
Belgium |
Czechia |
France |
Germany |
Greece |
Hungary |
Italy |
Poland |
Portugal |
Spain |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The EOS will be triggered once 386 OS events are observed or the last
on-study participant has reached his/her 60-months post-randomization
visit. At this timepoint (±2 months), all participants who
have not previously discontinued from the study prematurely will
undergo the EOS assessments and will be considered as having
completed the study. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 4 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 9 |