| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable, Locally Advanced Stage III Non-Small Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
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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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029519 |
| E.1.2 | Term | Non-small cell lung cancer stage III |
| 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. Within each platinum doublet chemotherapy cohort, evaluate the percentage of
participants who develop Grade 3 or higher pneumonitis
2. Within each platinum doublet chemotherapy cohort, estimate the objective response rate as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 |
|
| E.2.2 | Secondary objectives of the trial |
1. Within each platinum doublet chemotherapy cohort, evaluate the progression-free survival (PFS) assessed by BICR according to RECIST 1.1
2. Within each platinum doublet chemotherapy cohort, evaluate overall survival (OS)
3. Within each platinum doublet chemotherapy cohort, evaluate the safety and tolerability of each treatment regimen by the percentage of participants who develop AEs |
|
| 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 tissue) 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. |
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| E.3 | Principal inclusion criteria |
1. Male/female participants, who are at least 18 years of age on the day of signing informed consent with previously untreated, pathologically confirmed NSCLC and Stage IIIA, IIIB or IIIC NSCLC by American Joint Committee on Cancer Version 8.
2. No evidence of metastatic disease by whole body PET/ CT scan, diagnostic quality CT scan, and brain imaging. The process for image collection and transmission to the central imaging vendor can be found in the Site Imaging Manual.
3. Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology.
4. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archival tissue. In cases where the core or excisional biopsy is not available or cannot be obtained due to anatomical location of tumor, a cell block obtained through EUS/EBUS may be submitted after consultation with the Sponsor Clinical Director and documenting approval via a Sponsor Communication Form.
5. Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
6. Have adequate pulmonary function test (PFT) as a forced expiratory volume in 1 second (FEV1) >50% of predicted normal volume and the carbon monoxide lung diffusing capacity (DLCO) >40% of predicted normal value. Participants for whom DLCO measurements are not available will be deemed to have adequate oxygen transfer if their resting capillary/arterial blood gas on room air reveals an oxygen pressure (PO2) >60 mmHg.
7. Have adequate organ function
8. A male participant must agree to use contraception for at least 180 days after the last dose of study treatment in Cycles 1 through 3 or for 120 days after the last dose of study treatment in Cycle 4 through the end of treatment and refrain from donating sperm during this period.
9. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and if participant is a woman of childbearing potential (WOCBP), agrees to follow the contraceptive guidance during the treatment period and for at least 180 days after the last dose of study treatment in Cycles 1 through 3 or for 120 days after the last dose of study treatment in Cycle 4 through the end of treatment.
10. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial. The participant may also provide consent for Future Biomedical Research. However participant may participate in the main trial without participating in Future Biomedical Research.
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|
| E.4 | Principal exclusion criteria |
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to treatment allocation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
2. Has small cell lung cancer. Mixed tumors will be categorized by the predominant cell type: if small cell elements are present, the participant is ineligible; if non-small cell histology with any squamous element is present (example squamous, adenosquamous), the participant is not eligible for Cohort B (pemetrexed based chemotherapy).
3. Has had documented weight loss >10% in the preceding 3 months.
4. Participants whose radiation treatment plans are likely to encompass a volume of whole lung receiving >20 Gy in total (V20) of more than 31% of lung volume.
5. Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus or for breast cancer.
6. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
7. Has received a live vaccine within 30 days prior to the first dose of study drug. 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 (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
8. Has had an allogenic tissue/solid organ transplant.
9. 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 the first dose of study treatment.
10. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg prednisone daily or equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.
11. Has a known additional malignancy that is progressing or has required active treatment within the past 5 years.
12. Has severe hypersensitivity (Grade 3 or higher) to pembrolizumab and/or any of its excipients (refer to the IB for a list of excipients).
13. Has a known severe hypersensitivity (Grade 3 or higher) to any of the study chemotherapy agents and/or to any of their excipients.
14. 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.
15. Has a history of (non-infectious) pneumonitis/ interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease that requires steroids.
16. Has an active infection requiring systemic therapy.
17. Has a known history of human immunodeficiency virus (HIV) infection. HIV testing is not required unless mandated by local health authority.
18. Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
19. Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
20. 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.
21. Has a known psychiatric or substance abuse disorder that would interfere with cooperating with the requirements of the study.
22. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of study treatment in Cycles 1-3 or for 120 days after the last dose of study treatment in Cycle 4 through the end of treatment.
23. Any other specific criterion determined to be required for treatment with standard of care therapies, based on documented regional or country-specific regulatory request,
subsequently approved by the Sponsor. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Grade 3 or higher pneumonitis
-Confirmed complete response or partial response |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Tumor imaging to evaluate efficacy endpoints that include Complete Response and Partial Response will be performed every 9 weeks (± 7 days) until Week 54 and then every 12 weeks (± 14 days) until Week 150 and then every 24 weeks (± 28 days).
KN799 will use a sequential monitoring procedure based on pre-specified criteria described in the Statistical Analysis Plan in the protocol to monitor the safety and efficacy endpoints. There will likely be multiple interim analyses for each cohort of the study. The first interim analysis will be conducted when at least 36 participants have completed a minimum of 15 weeks of follow-up in each cohort.
|
|
| E.5.2 | Secondary end point(s) |
- PFS defined as the time from enrollment to the first documented disease progression or death due to any cause, whichever occurs first
- OS defined as the time from enrollment to death due to any cause
- Adverse events (AEs)
- Discontinuations due to AEs |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Tumor imaging to evaluate efficacy endpoints that include PFS will be performed every 9 weeks (± 7 days) until Week 54 and then every 12 weeks (± 14 days) until Week 150 and then every 24 weeks (± 28 days).
OS and safety endpoints will be monitored during the treatment Phase at clinic visits scheduled every 3 weeks (± 3 days), or by telephone contact conducted as needed. During the survival follow-up period, participants will be contacted every 12 weeks (± 14 days) to assess survival status.
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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 | 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 34 |
| 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 |
| France |
| Germany |
| Korea, Republic of |
| New Zealand |
| Poland |
| Russian Federation |
| Spain |
| United Kingdom |
| United States |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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