| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent/metastatic head and neck squamous cell carcinoma. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Recurrent/metastatic head and neck squamous cell carcinoma. |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10071540 |
| E.1.2 | Term | Head and neck cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067821 |
| E.1.2 | Term | Head and neck cancer |
| 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 the Progression Free Survival (PFS) per RECIST 1.1 as assessed by blinded independent central review (BICR) in first line recurrent/ metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) subjects, treated with pembrolizumab monotherapy versus
standard treatment
2) To compare PFS per RECIST 1.1 as assessed by BICR in first line R/M
HNSCC subjects, treated with pembrolizumab in combination with chemotherapy versus standard treatment.
3) To evaluate the overall survival (OS) in first line R/M HNSCC subjects,
treated with pembrolizumab monotherapy versus standard treatment.
4) To evaluate OS in first line R/M HNSCC subjects, treated with
pembrolizumab in combination with chemotherapy versus standard
treatment. |
|
| E.2.2 | Secondary objectives of the trial |
1) To evaluate the safety and tolerability profile of pembrolizumab
monotherapy or a combination of pembrolizumab with chemotherapy in all first line R/M HNSCC subjects
2) To evaluate proportion progression free at 6 and 12 months per RECIST 1.1 by BICR of first line R/M HNSCC subjects
3) To evaluate ORR per RECIST 1.1 by BICR in first line R/M HNSCC subjects
4) To evaluate mean change from baseline in global health
status/quality of life in first line R/M HNSCC subjects.
5) To evaluate time to deterioration (TTD) in global health status/quality
of life, pain and swallowing in first line R/M HNSCC subjects. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have histologically or cytologically-confirmed R/M HNSCC that is considered incurable by local therapies.
2. Be willing and able to provide documented informed consent for the trial. The subject may also provide consent for FBR. However, the subject may participate in the main trial without participating in FBR.
3. Be 18 years of age on day of signing informed consent.
4. Have measurable disease based on RECIST 1.1 as determined by the site. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such
lesions.
5. Have a performance status of 0 or 1 on the ECOG Performance Scale.
6. Demonstrate adequate organ function
7. Have results from testing of HPV status for oropharyngeal cancer defined as p16 IHC testing using CINtec® p16 Histology assay and a 70% cutoff point (please see Section 7.1.2.7 for details). If HPV status was previously tested using this method, no additional testing is required.
8. Have provided tissue for PD-L1 biomarker analysis from a core or excisional biopsy (FNA is not adequate).
9. Female subjects of childbearing potential should have a negative blood pregnancy test within 72 hours prior to receiving the first dose of study medication. A urine test can be considered if a blood test is not appropriate.
10. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 180 days after the last dose of study medication Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for >1 year.
11. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 180 days after the last dose of study therapy. |
|
| E.4 | Principal exclusion criteria |
1. Has disease that is suitable for local therapy administered with curative intent.
2. Has PD within 6 months of completion of curatively intended systemic treatment for locoregionally advanced HNSCC.
3. Has had radiation therapy (or other nonsystemic therapy) within 2 weeks prior to randomization or subject has not fully recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to a previously administered treatment.
4. Is currently participating and receiving study therapy, or has participated in a study of an investigational agent and received study therapy, or used an investigational device, any of which occurred within 4 weeks of the first dose of treatment.
5. Has a life expectancy of less than 3 months and/or has rapidly progressing disease (e.g. tumor bleeding, uncontrolled tumor pain) in the opinion of the treating investigator.
6. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Corticosteroid use as premedication for allergic reactions (e.g. IV contrast), or as a prophylactic management of AEs related to the chemotherapies specified in the protocol is allowed. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
7. Has a diagnosed and/or treated additional malignancy within 5 years prior to randomization with the exception of: curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, curatively resected in situ cervical cancer, and curatively resected in situ breast cancer. Other exceptions may be considered with Sponsor consultation.
8. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
9. Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
10. Has had an allogeneic tissue/solid organ transplant.
11. Has a history of (noninfectious) pneumonitis that required steroids or current pneumonitis.
12. Has an active infection requiring systemic therapy.
13. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion
of the treating investigator.
14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
15. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 180 days after the last dose of trial treatment.
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or if the patient has previously participated in Merck MK-3475 clinical trials.
17. Has a known history of HIV (HIV 1/2 antibodies).
18. Has known active Hepatitis B or Hepatitis C .
19. Has received a live vaccine within 30 days of planned start of study therapy. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Progression-free survival (PFS) - RECIST 1.1 by BICR
- Overall Survival |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Progression-free-survival (PFS) is defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on BICR or death due to any cause, whichever occurs first.
2. Overall Survival is defined as the time from randomization to death due to any cause. Subjects without documented death at the time of the final Analysis will be censored at the date of the last follow-up. |
|
| E.5.2 | Secondary end point(s) |
- Objective Response Rate (ORR) - RECIST 1.1 by BICR
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Objective response rate is defined as the proportion of the subjects in the analysis population who have a complete response (CR) or partial response (PR). Responses are based upon BICR per RECIST 1.1.
|
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | 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) | 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 | 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 | 3 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 56 |
| 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 |
| Colombia |
| Hong Kong |
| Israel |
| Japan |
| Malaysia |
| Mexico |
| Peru |
| Philippines |
| Singapore |
| South Africa |
| Taiwan |
| Thailand |
| United States |
| Austria |
| Estonia |
| Finland |
| France |
| Latvia |
| Poland |
| Sweden |
| Netherlands |
| Romania |
| Spain |
| Switzerland |
| Czechia |
| Germany |
| Greece |
| Italy |
| Denmark |
| Hungary |
| Norway |
| Russian Federation |
| Turkey |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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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