E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locoregionally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN): Pathologically (histologically or cytologically) proven diagnosis of squamous cell carcinoma of the head and neck (SCCHN) of the oropharynx, larynx, hypopharynx, or p16-positive unknown primary. |
|
E.1.1.1 | Medical condition in easily understood language |
Advanced head and neck cancer. |
|
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 | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10041823 |
E.1.2 | Term | Squamous cell carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 |
Phase II: > To determine whether radiation with cisplatin weekly is superior in terms of acute toxicity, as measured by the T-scores (TAME method), to radiation with cisplatin every 3 weeks for patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN).
Phase III: > To determine whether radiation with cisplatin weekly is non-inferior to radiation with cisplatin every 3 weeks in terms of overall survival (OS) for patients with locoregionally advanced SCCHN. > To determine whether radiation with cisplatin weekly is superior in terms of acute toxicity, as measured by the T-scores (TAME method), to radiation with cisplatin every 3 weeks for patients with locoregionally advanced SCCHN.
|
|
E.2.2 | Secondary objectives of the trial |
> To assess and compare progression-free survival (PFS) between arms. > To assess and compare locoregional failure and distant metastasis between arms. > To assess acute and late toxicity (CTCAE v5.0). > To assess patient-reported outcomes quality of life (PRO/QOL), as measured by the Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N) (primary PRO), between arms. > To assess hearing loss, as measured by audiograms and the modified TUNE grading scale between arms. > To assess hearing loss, as measured by speech audiometry Consonant-Nucleus-Consonant word scores and tympanometry. > To assess hearing-related QOL as measured by the Hearing Handicap Inventory-Screening (HHIA-S) (secondary PRO), between arms. > To assess long-term PFS, OS, and toxicity between arms. > To assess 3-year restricted-mean survival time for OS & PFS between arms (if long-term update is warranted).
Refer to protocol for additional Exploratory Objectives.
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Pathologically (histologically or cytologically) proven diagnosis of squamous cell carcinoma of the head and neck (SCCHN) of the oropharynx, larynx, hypopharynx, or p16-positive unknown primary.
2. Patients must have clinically or radiographically evident measurable disease at the primary site or at nodal stations.
3. Clinical stage (AJCC, 8th ed.) as indicated in the trial protocol, including no distant metastases based diagnostic workup.
4. Age ≥ 18;
5. Zubrod (ECOG) performance status of 0-1 within 14 days prior to registration;
6. Adequate hematologic function within 30 days prior to registration defined in the trial protocol.
7. Adequate renal function within 30 days prior to registration (per protocol definition).
8. Adequate hepatic function within 30 days prior to registration defined as follows: • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (not applicable to patients with known Gilbert’s syndrome); • AST and ALT ≤ 1.5 x institutional ULN.
9. Known human immunodeficiency virus (HIV) infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months and CD4 T Cell count > 200 cells/mm3 are eligible for this trial. Testing is not required for entry into protocol.
10. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
11. Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to registration.
12. Willing to use highly effective contraceptives for participants of childbearing potential (participants who may become pregnant or who may impregnate a partner) during therapy and for 14 months (females); for 11 months (males) following last dose of cisplatin.
13. The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.
|
|
E.4 | Principal exclusion criteria |
1. Patients with oral cavity cancer, nasopharynx cancer, or p16-negative cancer of unknown primary (CUP);
2. Recurrence of the study cancer;
3. Definitive clinical or radiologic evidence of distant metastatic disease;
4. Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable, however, any prior exposure to cisplatin is excluded;
5. Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields;
6. Severe, active co-morbidity defined as follows: • Unstable angina requiring hospitalization in the last 6 months; • Myocardial infarction within the last 6 months; • New York Heart Association Functional Classification III/IV (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.); • Persistent Grade 3-4 (CTCAE version 5.0) electrolyte abnormalities that cannot be reversed despite replacement as indicated by repeat testing; • Patient must not have an active infection requiring IV antibiotics prior to registration; • Other chronic renal disease like nephrotic syndrome, that could be worsened by cisplatin therapy; • History of allogenic organ transplantation; • Any symptomatic peripheral sensory neuropathy Grade ≥ 2 (CTCAE version 5.0);
7. Pregnancy and individuals unwilling to discontinue nursing.
8. History of hypersensitivity to cisplatin or platinum-containing compounds.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Phase II Primary Endpoint: Acute toxicity, as measured by the T-scores. Phase III Primary Endpoints: • Primary: Overall Survival (OS). • Co-primary: Acute toxicity, as measured by the T-scores.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
At the end of Phase II. End of trial. |
|
E.5.2 | Secondary end point(s) |
Secondary Endpoints: • Locoregional failure. • Distant metastasis. • Progression-Free Survival (PFS). • 3-year restricted mean survival time (RMST) for OS and PFS (if long-term update is warranted). • Acute toxicity, as measured by CTCAE v5.0. • Late toxicity, as measured by CTCAE v5.0. • Late toxicity, as measure by the A-scores. • Quality of life, as measured by FACT-H&N. • Hearing loss, as measured by HHIA-S. • Hearing loss (cochleotoxicity), as measured by audiograms and the modified TUNE grading scale. • Speech audiometry Consonant-Nucleus-Consonant word scores and tympanometry (subject to the modified TUNE grading scale testing results; otherwise, it will be an exploratory endpoint). |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
At the end of Phase II. End of trial. |
|
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 | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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) | Yes |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | No |
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 |
|
E.8.7 | Trial has a data monitoring committee | No |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 11 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 14 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |