| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-small cell lung cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| 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 | LLT |
| E.1.2 | Classification code | 10029514 |
| E.1.2 | Term | Non-small cell lung cancer NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 estimate the objective response rate (ORR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) |
|
| E.2.2 | Secondary objectives of the trial |
1. To estimate Progression-Free Survival (PFS) as assessed by the investigator according to RECIST 1.1
2. To evaluate the safety and tolerability of investigational treatment combinations based on proportion of adverse events
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participant has histologically- or cytologically-confirmed diagnosis of Stage IV (M1a, M1b, or M1c per current AJCC criteria) squamous or nonsquamous NSCLC
2. Participant with nonsquamous NSCLC who is not eligible for an approved targeted therapy
3. Have confirmation that EGFR-, ALK-, or ROS1-directed therapy is not indicated as primary therapy (documentation of absence of tumor activating EGFR AND absence of ALK or ROS1 gene rearrangements). If participant’s tumor is known to have a predominantly squamous histology, molecular testing for EGFR mutation and ALK and ROS1 translocations will not be required, as this is not part of current diagnostic guidelines
4. Participant has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology assessment. Lesions situated in a previously irradiated area are considered measurable if progression has been known in such lesions
5. Participant is able to provide archival tumor tissue sample collected either within 5 years or within the interval from completion of last treatment but before entering the screening period; or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated obtained within 90 days of treatment initiation. FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. Biopsies obtained before receipt of adjuvant/neoadjuvant chemotherapy will be permitted if recent biopsy is not feasible.
6. Participant 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 before the development of metastatic disease
7. Participants with PD-L1 TPS ≥1%
8. Participant is Male or Female who is at least 18 years of age at the time of providing documented informed consent
9. Participant has an ECOG performance status of either 0 or 1 as assessed within 7 days before initiation of study intervention
10. Participant is able to complete all screening procedures within the 35-day screening window. A participant may be rescreened after sponsor consultation
11. Participant has adequate organ function; all screening laboratory tests should be performed within 10 days of initiation of study intervention
12. A male participant must agree to use contraception and should refrain from donating sperm for at least 120 days after study interventions
13. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:
a. Not a WOCBP,
OR
b. A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after study intervention
14. The participant (or legally acceptable representative if applicable) has provided 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 |
|
| E.4 | Principal exclusion criteria |
1. Has a diagnosis of small cell lung cancer. For mixed tumors, if small cell elements are present, the patient is ineligible
2. 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 before the first dose of study drug. Participants with asthma that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study
3. Has a known additional malignancy that is progressing or has required active treatment within the past 2 years
4. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable (ie, without evidence of progression) for at least 2 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable, and without requirement of steroid treatment for at least 14 days before first dose of study intervention. Patients having untreated brain metastases will require treatment of the metastases to be eligible to enter the study
5. Has an active autoimmune disease that has required systemic treatment in the 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
6. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. Lymphangitic spread of the NSCLC is not exclusionary.
7. Has an active infection requiring systemic therapy
8. Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, or New York Heart Association Class III or IV congestive heart failure. Medically controlled arrhythmia stable on medication is permitted
9. Has a known history of HIV infection (known HIV 1/2 antibodies positive)
10. 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
11. Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study
12. Has had major surgery (<3 weeks before first dose)
13. Is expected to require any other form of antineoplastic therapy while on study
14. Has received prior radiation therapy to the lung that is >30 Gy within 6 months of the first dose of study intervention. Participants must have recovered from all radiationrelated toxicities, not require corticosteroids, and not have radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy to CNS disease)
15. Has received a live vaccine within 30 days before the first dose of study intervention.
16. Has received any prior immunotherapy and was discontinued from that treatment due to a Grade 3 or higher irAE
17. Has had chemotherapy or biological cancer therapy within 4 weeks before the first dose of study treatment, or has not recovered to CTCAE Grade 1 or better from the AEs due to cancer therapeutics administered more than 4 weeks before the first dose of study treatment (including participants who had previous immunomodulatory therapy with residual irAEs). a)Participants receiving ongoing hormone replacement therapy for endocrine irAEs will not be excluded from participation in this trial. b)Participants with Grade 2 or lower neuropathy may be eligible
18. Has received prior systemic cytotoxic chemotherapy or other targeted or biological antineoplastic therapy for metastatic disease
19. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or prior therapy targeting other immuno-regulatory receptors or mechanisms
20. 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
21. Previously had a severe hypersensitivity (≥Grade 3) reaction to treatment with monoclonal antibodies (including pembrolizumab) and/or any of their excipients
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 120 days after the last dose of study intervention
23. Has had an allogenic tissue/solid organ transplant |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Up to approximately 24 months |
|
| E.5.2 | Secondary end point(s) |
1. Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
2. Number of Participants Who Experience One or More Adverse Events (AEs)
3. Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 24 months
2. Up to approximately 27 months
3. Up to approximately 24 months |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| rolling arm, adaptive design |
|
| 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 |
| Israel |
| Korea, Republic of |
| United States |
| Germany |
| Hungary |
| Italy |
| Poland |
| Spain |
|
| 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 | 0 |
| 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 | 6 |
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