| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Neoadjuvant/Adjuvant treatment for participants with Resectable Stage II or IIIA-B (N2) NSCLC |
|
| E.1.1.1 | Medical condition in easily understood language |
| Newly diagnosed early stage non small cell lung 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029518 |
| E.1.2 | Term | Non-small cell lung cancer stage II |
| 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 | 10029520 |
| E.1.2 | Term | Non-small cell lung cancer stage IIIA |
| 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 | 10029521 |
| E.1.2 | Term | Non-small cell lung cancer stage IIIB |
| 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 evaluate event-free survival (EFS) by biopsy assessed by a local pathologist or by investigator-assessed imaging using RECIST 1.1
2. To evaluate the overall survival (OS). |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the rate of major pathological response (mPR) assessed by blinded central laboratory pathologist following NAC +/- pembrolizumab.
2. To evaluate the rate of pathological complete response (pCR) in the resected primary tumor and lymph nodes assessed by blinded central laboratory pathologist following NAC +/- pembrolizumab.
3. To evaluate mean change from baseline in the neoadjuvant phase and in the adjuvant phase in global health status/quality of life (QoL) using the European Organization for Research and Treatment of Cancer (EORTC) QoL questionnaire (QLQ)-C30.
4. To evaluate the safety and tolerability of NAC plus pembrolizumab followed by surgery and adjuvant pembrolizumab. |
|
| E.2.3 | Trial contains a sub-study | No |
| 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 and pathologically confirmed resectable Stage II, IIIA, or IIIB (N2) NSCLC. Lymph node disease requires pathologic confirmation, while T3 (rib destruction) disease requires only radiographic documentation. A PET scan may be utilized as a surrogate for pathologic staging of N1 lymph nodes for participants with T2b and T4 tumors (the presence or absence of tumor in the N1 lymph nodes will not change the actual stage by which the participant is stratified). Similarly, biopsy confirmation of N2 disease is not required for pathologically confirmed T3N1 tumors and T4N0-1 tumors, as knowledge of the N2 status will not change the stage.
2. Be able to undergo protocol therapy, including necessary surgery.
3. 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:
- Chemotherapy: 95 days
• Refrains from donating sperm
PLUS either:
• Abstains from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) 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. .
* Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed
4. 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 (abstinent on a long-term and persistent basis), 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:
- Chemotherapy: 180 days
- MK-3475: 120 days
The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
- 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 the first dose of study intervention. If a urine
test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
5. The participant (or legally acceptable representative) has provided documented informed consent/assent for the trial. The participant may also provide consent for Future Biomedical Research. However, the participant may participate in the study without participating in Future Biomedical Research.
6. Have available formalin-fixed paraffin embedded (FFPE) tumor tissue sample blocks for submission. If blocks are not available, have unstained slides for submission for central PD-L1 testing. See Procedures Manual for further details.
7. Have an ECOG performance status of 0 to 1 within 10 days of randomization.
8. Have adequate organ function as defined in the protocol. Specimens must be collected within 10 days prior to the start of trial treatment. |
|
| E.4 | Principal exclusion criteria |
1. Has one of the following tumor locations/types:
- NSCLC involving the superior sulcus
- Large cell neuro-endocrine cancer (LCNEC)
- Sarcomatoid tumor
2. Has a history of (non-infectious) pneumonitis /interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease that requires steroids.
3. Has an active infection requiring systemic therapy.
4. Has had an allogenic tissue/solid organ transplant.
5. Has a known severe hypersensitivity (≥ Grade 3) to pembrolizumab, its active substance and/or any of its excipients.
(Refer to the respective Investigator’sBrochure for a list of excipients.)
6. Has a known severe hypersensitivity (≥ Grade 3) to any of the study chemotherapy agents and/or to any of their excipients.
7. 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.
8. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority.
9. 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.
10. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
11. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant’s participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
12. Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the trial.
13. 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).
14. Has received prior systemic anticancer therapy including investigational agents for the current malignancy prior to randomization/allocation.
15. Has received prior radiotherapy within 2 weeks of start of trial treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
16. Has received a live or live attenuated vaccine within 30 days prior to the first dose of trial 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 (eg, FluMist®) are live attenuated vaccines and are not allowed.
17. Is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of trial treatment.
18. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (dose exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of trial drug.
19. Has a known additional malignancy that is progressing or requires active treatment within the past (5 years).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Event-free survival (EFS)
- Overall survival (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| EFS at IA2 and OS at Final Analysis |
|
| E.5.2 | Secondary end point(s) |
- Major pathological response (mPR) rate
- Pathological complete response (pCR) rate
- PRO outcome
- Safety and tolerability |
|
| 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 | 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 | 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| 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
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 86 |
| 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 |
| Brazil |
| Canada |
| China |
| Japan |
| Korea, Republic of |
| South Africa |
| Taiwan |
| United States |
| Estonia |
| France |
| Latvia |
| Lithuania |
| Poland |
| Romania |
| Spain |
| Germany |
| Italy |
| Belgium |
| Ireland |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| 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 | 7 |
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