| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Squamous or Nonsquamous Non-Small-Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic 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 | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| 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 Area under the curve (AUC) between pembrolizumab (MK-3475) subcutaneous (SC) vs pembrolizumab intravenous (IV)
2. To compare minimal concentration (Ctrough) between pembrolizumab SC vs pembrolizumab
|
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate pembrolizumab SC and pembrolizumab IV with respect to objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR)
2. To evaluate exposure of pembrolizumab SC compared to pembrolizumab IV
3. To evaluate the safety and tolerability of pembrolizumab SC compared to pembrolizumab IV
4. To evaluate pembrolizumab SC and pembrolizumab IV with respect to progression-free survival (PFS) per RECIST 1.1 as assessed by BICR
5. To evaluate pembrolizumab SC and pembrolizumab IV with respect to overall survival (OS)
6. To evaluate pembrolizumab SC and pembrolizumab IV with respect to duration of response (DOR) per RECIST 1.1 as assessed by BICR
7. To evaluate the development of antidrug antibodies (ADAs) following administration of pembrolizumab SC compared to pembrolizumab IV
|
|
| 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 |
| Time & Motion pharmacoeconomic sub-study |
|
| E.3 | Principal inclusion criteria |
1. Has pathologically (histologically or cytologically) confirmed diagnosis of squamous or nonsquamous NSCLC
2. Has Stage IV (T any, N any, M1a, M1b, or M1c - American Joint Committee on Cancer 8th Edition) squamous or nonsquamous NSCLC
3. Has confirmation that EGFR, ALK, or ROS1-directed therapy is not indicated (documentation of absence of tumor-activating EGFR mutations AND absence of ALK and ROS1 gene rearrangements, OR presence of a KRAS mutation) in nonsquamous NSCLC as well as mixed nonsquamous/squamous NSCLC. Participants with purely squamous NSCLC do not require testing
4. Has not received prior systemic treatment for their metastatic NSCLC. Participants who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months prior to the development of metastatic disease
5. Participants are at least 18 years of age on the day of signing the informed consent
6. Has an ECOG PS of 0 or 1 (as assessed within 7 days prior to randomization)
7. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 95 days from the last dose of chemotherapy:
• Refrain from donating sperm
PLUS either:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
OR
• Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause) as detailed below:
Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant
8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a WOCBP
OR
• Is a WOCBP and using 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 180 days after the last dose of chemotherapy or 120 days after the last dose of pembrolizumab, whichever occurs last, and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this same time period after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention
• A WOCBP must have a negative highly sensitive pregnancy test (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 is positive or not evaluable, a serum test will be required
• The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy
9. The participant (or legally acceptable representative) provides documented informed consent/assent for the study. The participant may also provide consent/assent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research
10. Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions
11. Submit an archival tumor tissue sample or newly obtained core or incisional biopsy of a tumor lesion not previously irradiated for PD-L1 status determination prior to randomization. FFPE tissue blocks are preferred to slides. Biopsies obtained prior to receipt of adjuvant/neoadjuvant chemotherapy will be permitted if recent biopsy is not feasible
12. Has adequate organ function as detailed in the protocol. Specimens must be collected within 10 days prior to the start of study intervention |
|
| E.4 | Principal exclusion criteria |
1. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
2. Has known central nervous system (ie, brain and/or spinal cord) metastases and/or carcinomatous meningitis. Participants with treated brain metastases (eg, whole brain radiation treatment [WBRT], stereotactic radiosurgery, or equivalent) may participate only if they satisfy all of the following:
• Have no evidence of new or enlarging brain metastases confirmed by post-treatment repeat brain imaging (using the same modality) performed at least 4 weeks after pretreatment brain imaging, and
• Are neurologically stable without the need for steroids for at least 14 days before first dose of trial treatment as per local site assessment
3. Has severe hypersensitivity (≥Grade 3) to study intervention and/or any of its excipients
4. 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
5. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. Lymphangitic spread of the NSCLC is not exclusionary
6. Has an active infection requiring systemic therapy
7. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority
8. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection
9. 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
10. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study
11. Has symptomatic ascites or pleural effusion. A participant who is clinically stable after treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible
12. Before the first dose of study intervention:
• Has received prior systemic cytotoxic chemotherapy for metastatic NSCLC
• Has received antineoplastic biological therapy (eg, erlotinib, crizotinib, cetuximab) for metastatic NSCLC
• Has had major surgery (<3 weeks prior to first dose)
• 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 coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)
13. Received radiation therapy to the lung that is >30 Gray within 6 months of the first dose of study intervention
14. Is expected to require any other form of antineoplastic therapy while on study
15. Is unable to interrupt aspirin or other NSAIDs, other than an aspirin dose ≤1.3 g/day, for a 5-day period (8-day period for long acting agents, such as piroxicam)
16. Is unable or unwilling to take folic acid or vitamin B12 supplementation
17. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease
18. Has received a live or live attenuated vaccine within 30 days prior to the first dose of study intervention
19. 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 intervention
20. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention
21. Has had an allogenic tissue/solid organ transplant |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Area Under the Curve From 0-3 Weeks (AUC0-3wks) of Pembrolizumab for Cycle 1
2. Minimal Concentration (Ctrough) of Pembrolizumab at the End of Cycle 6
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Pharmacokinetic (PK) collection at designated timepoints in Cycle 1 (Up to approximately 3 weeks; cycle length = 3 weeks)
2. PK collection at end of Cycle 6 (approximately at end of Week 18; cycle length = 3 weeks)
|
|
| E.5.2 | Secondary end point(s) |
1. Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
2. Ctrough of Pembrolizumab at the End of Cycle 1
3. Maximal concentration (Cmax) of Pembrolizumab for Cycle 1
4. AUC0-3wks of Pembrolizumab for Cycle 6
5. Cmax of Pembrolizumab for Cycle 6
6. Number of Participants Who Experienced an Adverse Event (AE)
7. Number of Participants Who Discontinued Study Treatment Due to an AE
8. Progression-Free Survival (PFS) per RECIST 1.1 as Assessed by BICR
9. Overall Survival (OS)
10. Duration of Response (DOR) per RECIST 1.1 as Assessed by BICR
11. Antidrug Antibodies (ADAs) Incidence After Administration of Pembrolizumab
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 5 years
2. PK collection at end of Cycle 1 (approximately at end of Week 3; cycle length = 3 weeks)
3. PK collection at designated timepoints in Cycle 1 (Up to approximately 3 weeks; cycle length = 3 weeks)
4. PK collection at designated timepoints in Cycle 6 (Up to approximately 3 weeks; cycle length = 3 weeks)
5. PK collection at designated timepoints in Cycle 6 (Up to approximately 3 weeks; cycle length = 3 weeks)
6. Up to approximately 28 months
7. Up to approximately 25 months
8. Up to approximately 5 years
9. Up to approximately 5 years
10. Up to approximately 5 years
11. Up to approximately 26 months
|
|
| 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 | No |
| 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) | 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
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 31 |
| 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 |
| Brazil |
| Guatemala |
| Japan |
| Korea, Republic of |
| Peru |
| Russian Federation |
| South Africa |
| Taiwan |
| Turkey |
| Ukraine |
| United States |
| France |
| Hungary |
| Poland |
| Romania |
| Spain |
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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