| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Stage III-IVA Resectable Locoregionally Advanced Head and Neck Squamous Cell Carcinoma (LA HNSCC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Newly diagnosed, resectable Stage III-IVA locally advanced Head and Neck Squamous Cell Carcinoma subjects |
|
| 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 | 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) |
|
| 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 |
1: To compare pembrolizumab neoadjuvant therapy to no neoadjuvant therapy with respect to the rate of major pathological response (mPR) as assessed by the central pathologist at the time of definitive surgery in participants whose tumors express PD-L1 CPS≥1 and in all participants regardless of CPS status.
2: To compare pembrolizumab as neoadjuvant therapy and in combination with radiotherapy (RT) ± cisplatin as adjuvant therapy to only RT ± cisplatin as adjuvant therapy with respect to EFS per RECIST 1.1 as assessed by BICR in participants whose tumors express PD-L1 CPS≥1 and in all participants regardless of CPS status. |
|
| E.2.2 | Secondary objectives of the trial |
1: To compare pembrolizumab as neoadjuvant therapy and in combination with radiotherapy (RT) ± cisplatin as adjuvant therapy to only RT ± cisplatin as adjuvant therapy with respect to OS in participants whose tumors express PD-L1 CPS≥1 and in all participants regardless of CPS status.
2: To evaluate the rate of pCR as assessed by the central pathologist at the time of definitive surgery in participants whose tumors express PD-L1 CPS≥1 and in all participants regardless of CPS status.
3: To evaluate global health status/quality of life (QoL) and physical functioning scores using the EORTC QoL questionnaire (QLQ)-C30, and swallowing, speech and pain symptoms using the EORTC Head and Neck–Specific QoL questionnaire (EORTC QLQH& N35) in participants whose tumors express PD-L1 CPS≥1 and in all participants regardless of CPS status.
4: To determine the safety and tolerability of pembrolizumab as neoadjuvant therapy and in combination with RT ± cisplatin as adjuvant therapy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have histologically confirmed new diagnosis of resectable, non-metastatic, squamous cell carcinoma as assessed by the Investigator based on baseline imaging and clinical assessment that is either:
a. Stage III oropharyngeal p16 positive that is T4 (N0-N2), M0
OR
b. Stage III or IVA oropharyngeal p16 negative
OR
c. Stage III or IVA larynx/hypopharynx/oral cavity (independent of p16).
2. Be eligible for primary surgery based on investigator decision and per local practice. This decision must be validated by members of a multidisciplinary team, including the surgical oncologist, medical oncologist and radiation oncologist
3. Male/female participants who are at least 18 years of age at the time of providing informed consent.
4. If male, agrees to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is as follows:
- Pembrolizumab: no contraception requirement
- Cisplatin: 180 days
- Radiotherapy: 90 days
•Refrains from donating sperm
PLUS either:
•Abstains from heterosexual intercourse as their preferred and usual lifestyle and agrees to remain abstinent
OR
•Uses contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause, documented from the site personnel's review of the participant's medical records, medical examination, or medical history interview) as detailed below:
- Uses a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
5. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
•Not a WOCBP
OR
•A WOCBP and:
- Uses a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle, during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The length of time required to continue contraception for each study intervention is as follows:
- Pembrolizumab: 120 days
- Cisplatin: 180 days
- Radiotherapy: 180 days
•Has a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours for urine or within 72 hours for serum before randomization.
•Abstains from breastfeeding during the study intervention period and for at least 120 days after the last dose of pembrolizumab and 180 days after the last dose of cisplatin.
•Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a woman with an early undetected pregnancy.
6. The participant (or legally acceptable representative) provides documented informed consent for the study. The participant may also provide consent for Future Biomedical Research. However, the participant may participate in the main study without participating in Future Biomedical Research.
7. Have evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI), based on RECIST 1.1 as assessed by the local site investigator/radiology.
8. Have provided newly obtained core or excisional biopsy of a tumor lesion not previously irradiated for central PD-L1 biomarker analysis from a core or excisional biopsy (fine needle aspirate [FNA] is not adequate) for stratification prior to randomization. Repeat samples may be required if adequate tissue is not provided. Formalin-fixed, paraffin embedded tissue blocks are preferred to slides.
9. Have results from (local) testing of HPV status for oropharyngeal cancer defined as p16 IHC testing using CINtec® p16 Histology assay (Ventana Medical Systems Inc., Tucson AZ) using standard protocol. Positive p16 expression is defined as strong and diffuse nuclear and cytoplasmic staining in 70% or more of the tumor cells. If HPV status was previously tested using this method, no additional testing is required.
10. Have an ECOG performance status of 0 to 1 performed within 10 days of treatment randomization.
11. Have adequate organ function. Specimens must be collected within 10 days prior to randomization. |
|
| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
1. Has Stage T4B and/or N3 LA HNSCC and/or distant metastases.
2. Has cancer outside of the oropharynx, larynx, and hypopharynx or oral cavity, such as nasopharyngeal, sinus, other para-nasal, or other unknown primary HNC.
3. A WOCBP who has a positive pregnancy test within 24 hours (urine)
or within 72 hours (serum) before randomization or within 24 hours
prior to the start of RT ± cisplatin. If the urine test is positive or cannot
be confirmed as negative, a serum pregnancy test will be required. In
such cases, the participant must be excluded from participation if the
serum pregnancy result is positive.
4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
5. Has received prior radiotherapy treatment or systemic anticancer therapy including investigational agents for the HNC under study prior to randomization/allocation.
6. Has received a live vaccine within 30 days prior to randomization. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist® [Influenza Vaccine Live, AstraZeneca]) are live attenuated vaccines and are not allowed.
7. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to randomization.
8. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization.
9. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
10. Has radiographically detectable (even if asymptomatic and/or previously treated) central nervous system metastases and/or carcinomatous meningitis as assessed by local site investigator and radiology review.
11. Has Grade ≥2 audiometric hearing loss.
12. Has Grade ≥2 neuropathy.
13. Has Grade 3-4 bleeding due to the underlying malignancy.
14. If participant has received major surgery, and the participant has not recovered adequately from the toxicity and/or complications from the intervention prior to randomization.
15. Has had previous allogeneic tissue/solid organ transplant.
16. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients, RT or cisplatin or their analogs.
17. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
18. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
19. Has an active infection requiring systemic therapy.
20. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority.
21. Has a known history of or is positive for Hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C (defined as Hepatitis C virus [HCV] RNA [qualitative] is detected).
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
23. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Major pathological response - defined as having less than or equal to 10% invasive squamous cell carcinoma within the resected primary tumor specimen and all sampled regional lymph nodes
2. Event-free survival (EFS) - time from the date of randomization to the date of first record of any of the following events: radiographic disease progression, local or distant recurrence as assessed with imaging or biopsy as indicated, death due to any cause |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Overall survival - defined as time from the date of randomization to the date of death due to any cause.
2. Pathological complete response - defined as having no residual invasive squamous cell carcinoma within the resected primary tumor specimen and all sampled regional lymph nodes
3. 3.EORTC QLQ C30- global health status/QoL scales and physical functioning scales; EORTC QLQ-H&N35 swallowing multi-item scale, speech multi-item scale, and pain multi-item scale
4. Adverse events (AEs)
5. Study drug discontinuations due to AEs |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| 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) | 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Active control: no neadjuvant therapy |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 41 |
| 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 |
| Australia |
| Brazil |
| Canada |
| Chile |
| China |
| Colombia |
| Israel |
| Korea, Republic of |
| Taiwan |
| United States |
| Austria |
| France |
| Poland |
| Spain |
| Germany |
| Belgium |
| Hungary |
| Ireland |
| Portugal |
| Russian Federation |
| Ukraine |
| United Kingdom |
|
| 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 overall study ends when the last participant completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the participant is unable to be contacted by the investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the last laboratory result or at the time of final contact with the last participant, whichever comes last. |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | 23 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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