| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma |
|
| 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 | 19.1 |
| 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 |
All Subjects
Objective: To compare the overall survival (OS) in subjects with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with pembrolizumab compared to standard treatment.
|
|
| E.2.2 | Secondary objectives of the trial |
All Subjects
Compare PFS per RECIST 1.1 in subjects with R/M HNSCC treated with MK-3475 compared to standard treatment
To compare ORR per RECIST 1.1 in subjects with R/M HNSCC treated with MK-3475 compared to standard treatment
Subjects With Positive PD-L1 Expression, defined by >/= 1% Combined Positive Score, henceforth abbreviated as PD-L1 1% CPS:
Compare PFS per RECIST 1.1 in subjects with R/M HNSCC treated with MK-3475 compared to standard treatment
Compare OS in subjects with R/M HNSCC treated with MK-3475 compared to standard treatment
Compare ORR per RECIST 1.1 in subjects with R/M HNSCC treated with MK-3475 compared to standard treatment
Evaluated separately among 1. Subjects with PD-L1 1% CPS, 2. All Subjects regardless of PD-L1 expression
Evaluate the safety and tolerability profile of MK-3475
Evaluate TTP per RECIST 1.1 and DOR per RECIST 1.1 in subjects with R/M HNSCC treated with MK-3475 compared to standard treatment |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Merck will conduct Future Biomedical Research on DNA (blood and tumor) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
|
| E.3 | Principal inclusion criteria |
Be willing and able to provide written informed consent for the trial. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
2. Be > 18 years of age on day of signing informed consent.
3. Have histologically or cytologically-confirmed R/M HNSCC of the oral cavity, oropharynx, hypopharynx, and larynx that is considered incurable by local therapies. Subjects may not have any other primary tumor site (e.g. nasopharynx).
4. Prior platinum failure as defined by, either:
a. Disease progression after treatment with a platinum-containing regimen for recurrent/metastatic disease
Note: Disease progression may occur at any time during or after a platinum-containing regimen (e.g. carboplatin or cisplatin) which was administered in either 1L or 2L in the recurrent/metastatic setting.
OR
b. Recurrence/progression within 6 months of prior multimodal therapy using platinum (e.g. locally advanced setting)
5. Have results from local testing of HPV positivity for oropharyngeal cancer defined as p16 IHC testing using CINtec® p16 Histology assay and a 70% cut-off point. If HPV status has previously been tested using this procedure, no retesting is required.
Note: HPV stratification in this trial will be performed using local or central testing of HPV status in patients with oropharynx cancer. Oral cavity, hypopharynx, and larynx cancer are not required to undergo HPV testing by p16 IHC as by convention assumed to be HPV negative.
6. Have provided tissue for PD-L1 biomarker analysis - and received PD-L1 results (PD-L1 analysis will be blinded to both site and Sponsor) from a newly obtained core or excisional biopsy. Repeat samples may be required if adequate tissue is not provided.
Note: Patients for whom newly obtained samples cannot be obtained (e.g. inaccessible or patient safety concern) may submit an archived specimen only upon agreement from the Sponsor.
Note: If emerging data indicate a high concordance in PD-L1 expression scores between newly obtained and archival samples, archived samples may be acceptable.
7. Have radiographically 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.
8. Have a performance status of 0 or 1 on the ECOG Performance Scale, as assessed within 10 days of treatment initiation.
9. Demonstrate adequate organ function as defined in Table 1 of the protocol, all screening labs should be performed within 10 days of treatment initiation.
10. Female subjects of childbearing potential should have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication. A urine test can be considered if a serum test is not appropriate.
11.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 120 days after the last dose of pembrolizumab (Reference Section 5.7.2) or through 120-180 days after the last dose of docetaxel, methotrexate or cetuximab, according to local standard of care. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
Note: Abstinence is acceptable if this is the established and preferred contraception for the subject.
12.Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of pembrolizumab or through 120-180 days after the last dose of docetaxel, methotrexate or cetuximab, according to local standard of care.
Note: Abstinence is acceptable if this is the established and preferred contraception for the subject
|
|
| E.4 | Principal exclusion criteria |
1. Has disease that is suitable for local therapy administered with curative intent.
2. Had progressive disease within three months of completion of curatively intended treatment for locoregionally advanced or recurrent HNSCC.
Note: this exclusion criteria is only applicable for subjects who have not had treatment in the recurrent/metastatic setting
3. Is currently participating in and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to randomization.
Note: Subjects who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks since the last dose of trial treatmentthe previous investigational agent or device
4. Was previously treated with 3 or more systemic regimens given for recurrent and/or metastatic disease.
5. Patients previously treated or resistant to one of the 3 standard of care agents in this trial (i.e. docetaxel, methotrexate, or cetuximab) may not receive the same agent if randomized to the standard treatment arm (see Section 5.2 for details).
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. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
7. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
8. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
Note: Subjects with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this criterion and may qualify for the study.
Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
9. 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 and/or curatively resected in situ cervical and/or breast cancers.
10. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
11. Has 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 (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is permitted.
12. Has active, non-infectious pneumonitis;
13. Has an active infection requiring systemic therapy.
14. 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.
15. Has a known psychiatric or substance abuse disorders that would interfere with co- operation with the requirements of the trial.
16. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
17. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or has previously participated in Merck MK-3475 clinical trials.
18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).;
19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
20. 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) |
The primary efficacy endpoint is:
• Overall survival (OS) (i.e., time from randomization to death due to any cause). Subjects with documented death at the time of the final analysis will be censored at the date of the last follow-up
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The final OS analysis will be conducted after ~288 deaths have occurred between the MK-3475 arm and the standard treatment arm, if the trial is not stopped early for efficacy or futility.
|
|
| E.5.2 | Secondary end point(s) |
Key secondary efficacy endpoints:
• OS in subjects with PD-L1 1% CPS
• ORR per RECIST 1.1 in all subjects
• ORR per RECIST 1.1 in subjects with PD-L1 1% CPS
• Progression-free-survival (PFS) per RECIST 1.1 in all subjects
• PFS per RECIST 1.1 in subjects with PD-L1 1% CPS
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The timing of the evaluation of the secondary endpoints will be driven by and the same as the timing and evaluation of the primary endpoint |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 |
| Australia |
| Belgium |
| Canada |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Korea, Republic of |
| Lithuania |
| Mexico |
| Netherlands |
| Poland |
| Portugal |
| Puerto Rico |
| Russian Federation |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| United States |
|
| 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 trial begins when the first subject signs the informed consent form. The overall trial ends when the last subject completes the last trial visit, discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by the investigator). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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