| 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 (NSCLC) |
|
| 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 compare PFS per RECIST 1.1 as assessed by BICR.
2. To compare OS.
|
|
| E.2.2 | Secondary objectives of the trial |
1.To compare MK-7684A with cCRT followed by MK7684A to cCRT followed by durvalumab with respect to ORR per RECIST 1.1 as assessed by BICR in participants with TPS ≥1% and PD-LI all-comers
2.To evaluate the safety and tolerability of MK-7684A with cCRT followed by MK7684A compared to cCRT followed by durvalumab.
3.To compare MK-7684A with cCRT followed by MK-7684A to cCRT followed by durvalumab with respect to DOR per RECIST 1.1 as assessed by BICR in participants with TPS ≥1% and PD-LI all-comers
4.To evaluate the change from baseline in GHS/QoL, cough, chest pain, dyspnea and physical functioning following treatment with MK-7684A with cCRT followed by MK-7684A compared to cCRT followed by durvalumab in participants with TPS ≥1% & PD-L1 all-comers
5.To evaluate the TTD in GHS/QoL, cough, chest pain, dyspnea and physical functioning following treatment with MK-7684A with cCRT followed by MK-7684A compared to cCRT followed by durvalumab in participants with TPS ≥1% & PD-L1 all-comers |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has pathologically confirmed diagnosis of NSCLC
2. Has Stage IIIA, IIIB, or IIIC NSCLC by American Joint Committee on Cancer Version 8
3. Is determined to have unresectable, Stage III NSCLC as documented by a multidisciplinary tumor board or by the treating physician in consultation with a thoracic surgeon
4. Has no evidence of metastatic disease, indicating Stage IV NSCLC, in whole-body FDGPET or FDG-PET/CT and CT or MRI scans of diagnostic quality of chest, abdomen, pelvis and brain
5. Has measurable disease as defined by RECIST 1.1, with at least 1 lesion being appropriate for selection as a target lesion, as determined by local site investigator/radiology review
6. Has not received prior treatment for their Stage III NSCLC
7. Has provided tumor tissue sample. FFPE blocks are preferred to slides
8. Has an ECOG Performance Status of 0 or 1 assessed within 7 days prior to the first administration of study intervention
9. Has a life expectancy of at least 6 months
10. Has adequate PFT defined as a 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 pulse oximetry (O2 saturation) is determined to be ≥90% on room air
11. Is male or female, at least 18 years of age inclusive, at the time of providing informed consent
12. Male participants are eligible to participate if they agree 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 platinum doublet: 95 days
- Radiotherapy: 90 days
• Refrain from donating sperm
PLUS either:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent
OR
• Must agree to use contraception unless confirmed to be azoospermic 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
- 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
13. 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:
- Uses a contraceptive method that is highly effective, with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle, 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 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 platinum doublet: 180 days
◦Radiotherapy: 180 days
◦MK-7684A: 120 days
◦Durvalumab: 90 days
The investigator should evaluate the potential for contraceptive method failure 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 within 24 hours for urine and within 72 hours for serum before the first dose of study intervention. If a urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive
- Abstains from breastfeeding during the study intervention period and for at least 120 days after study intervention MK-7684A, 90 days after the last dose of durvalumab, and 180 days after the last dose of chemotherapy platinum doublet or radiotherapy
- Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a woman with an early undetected pregnancy
14. The participant has provided documented informed consent for the study. The participant may also provide consent/assent for FBR
15. Has adequate organ function |
|
| E.4 | Principal exclusion criteria |
1. Has SCLC or tumors with the presence of small cell elements. Mixed squamous/nonsquamous tumors are eligible
2. Is likely to have a radiation treatment plan that will encompass a volume of whole lung (total lung-GTV) receiving ≥20 Gy in total (lung V20) of more than 34% of whole lung volume
3. Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus, mediastinum, or for breast cancer
4. Has received prior therapy with an anti-TIGIT, 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)
5. Has received major surgery (with the exception of replacement of vascular access) within 4 weeks before randomization
6. Is expected to require any other form of antineoplastic therapy, while on study
7. Has received colony-stimulating factors (e.g., G-CSF, GM-CSF, or recombinant erythropoietin) within 28 days prior to the first dose of study intervention
8. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed
Pemetrexed-specific Criteria
9. Is unable to interrupt aspirin or other NSAIDs, other than an aspirin dose ≤1.3 grams per day, for at least 2 days (5 days for long-acting agents [for example, piroxicam]) before, during, and for at least 2 days after administration of pemetrexed
10. Is unable/unwilling to take folic acid, vitamin B12, and dexamethasone
11. Has received an investigational agent or has used an investigational
device within 4 weeks prior to study intervention
12. 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 medication
13. Has a known additional malignancy that is progressing or has required active treatment within the past 5 years
14. Has severe hypersensitivity (≥ Grade 3) to MK-7684A, platinum doublet components, durvalumab and/or any of its excipients
15. Active autoimmune disease that has required systemic treatment in past 2 years, except replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid))
16. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
17. Has an active infection requiring systemic therapy
18. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority
19. 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
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 the participant’s ability to cooperate with the requirements of the study
22. In the opinion of the treating investigator, is considered a poor medical risk due to a serious, uncontrolled medical disorder or nonmalignant systemic disease. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, or superior vena cava syndrome
23. Has had an allogenic tissue/solid organ transplant |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Progression-Free Survival (PFS))For All Participants
2. Progression-Free Survival (PFS) For Participants With Programmed
Cell Death Ligand 1 (PD-L1) Tumor Proportion Score (TPS) ≥1%
3. Overall Survival (OS) For All Participants
4. Overall Survival (OS) For Participants With Programmed Cell Death
Ligand 1 (PD-L1) Tumor Proportion Score (TPS) ≥1%
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to ~55 months
2. Up to ~55 months
3. Up to ~ 75 months
4. Up to approximately 75 months |
|
| E.5.2 | Secondary end point(s) |
1. Objective response rate (ORR) For All Participants
2. Objective Response Rate (ORR) For Participants With Programmed
Cell Death Ligand 1 (PD-L1) Tumor Proportion Score (TPS) ≥1%
3. Number of Participants Who Experience at Least One Adverse Event
(AE)
4. Number of Participants Who Discontinue Study Treatment Due to an
Adverse Event (AE)
5. Duration of response (DOR) For All Participants
6. Duration of Response (DOR) For Participants With Programmed Cell
Death Ligand 1 (PD-L1) Tumor Proportion Score (TPS) ≥1%
7. Change from Baseline in the Global Health Status /Quality of Life
Items 29 and 30 Combined Score on the European Organization for
Research and Treatment of Cancer Quality of Life Questionnaire Core 30
(EORTC QLQ-C30) For All Participants
8. Change from Baseline in the Global Health Status/Quality of Life
Items 29 and 30 Combined Score on the EORTC QLQ-C30 For Participants
With PD-L1 TPS ≥1%
9. Change from Baseline in Physical Functioning (Items 1-5) Combined
Score on the EORTC QLQ-C30 For All Participants
10. Change from Baseline in Physical Functioning (Items 1-5) Combined
Score on the EORTC QLQ-C30 For Participants With PD-L1 TPS ≥1%
11. Change from Baseline in Cough Score (Item 31) on the European
Organization for Research and Treatment of Cancer Quality of Life
Questionnaire Lung Cancer 13 (EORTC QLQ-LC13) For All Participants
12. Change from Baseline in Cough Score (Item 31) on the EORTC QLQLC13
For Participants With PD-L1 TPS ≥1%
13. Change from Baseline in Chest Pain Score (Item 40) on the EORTC
QLQ-LC13 For All Participants
14. Change from Baseline in Chest Pain Score (Item 40) on the EORTC
QLQ-LC13 For Participants With PD-L1 TPS ≥1%
15. Change from Baseline in Dyspnea (Item 8) Score on the EORTC QLQC30
For All Participants
16. Change from Baseline in Dyspnea (Item 8) Score on the EORTC QLQC30
For Participants With PD-L1 TPS ≥1%
17. Time to True Deterioration (TTD) in the Global Health Status/Quality
of Life Items 29 and 30 Combined Score on the EORTC QLQ-C30 For All
Participants
18. Time to True Deterioration (TTD) in the Global Health Status/Quality
of Life Items 29 and 30 Combined Score on the EORTC QLQ-C30 For
Participants With PD-L1 TPS ≥1%
19. Time to True Deterioration (TTD) in Physical Functioning (Items 1-5)
Combined Score on the EORTC QLQ-C30 For All Participants
20. Time to True Deterioration (TTD) in Physical Functioning (Items 1-5)
Combined Score on the EORTC QLQ-C30 For Participants With PD-L1 TPS
≥1%
21. Time to True Deterioration (TTD) in Cough Score (Item 31) on the
EORTC QLQ-LC13 For All Participants
22. Time to True Deterioration (TTD) in Cough Score (Item 31) on the
EORTC QLQ-LC13 For Participants With PD-L1 TPS ≥1%
23. Time to True Deterioration (TTD) in Chest Pain Score (Item 40) on
the EORTC QLQ-LC13 For All Participants
24. Time to True Deterioration (TTD) in Chest Pain Score (Item 40) on
the EORTC QLQ-LC13 For Participants With PD-L1 TPS ≥1%
25. Time to True Deterioration (TTD) in Dyspnea (Item 8) Score on the
EORTC QLQ-C30 For All Participants
26. Time to True Deterioration (TTD) in Dyspnea (Item 8) Score on the
EORTC QLQ-C30 For Participants With PD-L1 TPS ≥1% |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-6. Up to ~75 months
7-16. Baseline (at randomization) and at the end of study
(approximately 75 months post randomization)
17-26. Up to approximately 75 months post randomization |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| 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 |
| Brazil |
| Chile |
| China |
| Costa Rica |
| Guatemala |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| United States |
| Romania |
| Spain |
| Germany |
| Greece |
| Italy |
| Portugal |
| Russian Federation |
| Turkey |
| Ukraine |
|
| 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 | |
| E.8.9.1 | In the Member State concerned months | 88 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 88 |
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