| 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 |
| Stage III lung cancer condition |
|
| 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 | 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. To compare pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab plus olaparib to concurrent chemoradiation therapy followed by durvalumab with respect to progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR).
2. To compare pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab to concurrent chemoradiation therapy followed by durvalumab with respect to PFS per RECIST 1.1 as assessed by BICR.
3. To compare pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab plus olaparib to concurrent chemoradiation therapy followed by durvalumab with respect to Overall Survival (OS).
4. To compare pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab to concurrent chemoradiation therapy followed by durvalumab with respect to OS.
|
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the safety and tolerability of pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab alone or with olaparib compared to concurrent chemoradiation therapy followed by durvalumab.
2. To compare pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab alone or with olaparib to concurrent chemoradiation therapy followed by durvalumab with respect to Objective Response Rate (ORR) and Duration of Response (DOR) per RECIST 1.1 as assessed by BICR.
3. To evaluate the change from baseline (at Cycle 1) and the time to deterioration (TTD) in global health status/quality of life (QoL), cough, chest pain, dyspnea, physical functioning and, role functioning following treatment with pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab alone or with olaparib compared to concurrent chemoradiation therapy followed by durvalumab.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has pathologically (histologically or cytologically) confirmed diagnosis of NSCLC.
2. Has Stage IIIA, IIIB, or IIIC NSCLC by American Joint Committee on Cancer Version 8.
3. Is unable to undergo surgery with curative intent for 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 fluorodeoxyglucose (FDG)-PET 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 one lesion being appropriate for selection as a target lesion, as determined by local site investigator/radiology review.
6. Has not received prior treatment (chemotherapy, targeted therapy or radiotherapy) for their Stage III NSCLC.
7. Has provided tumor tissue sample (tissue biopsy [core, incisional, or excisional]). FFPE blocks are preferred to slides. Newly obtained tumor sample is highly preferred over archival tissue and should be obtained prior to the thoracic imaging at screening.
8. Has a performance status of 0 or 1 on the ECOG Performance Status 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. Has adequate organ function; all screening laboratory tests should be performed within 10 days prior to initiation of study intervention.
12. Participants are at least 18 years of age on the day of providing informed consent.
13.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:
-Olaparib and platinum doublet: 90 days
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 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.
14. 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 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:
•Pembrolizumab: 120 days
•Olaparib, platinum doublet, and radiotherapy: 180 days
The investigator should evaluate the potential for contraceptive method failure (ie,
noncompliance, recently initiated) in relationship to the first dose of study intervention.
•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.
•Has had her medical history, menstrual history, and recent sexual activity reviewed by the investigator to decrease the risk for inclusion of a woman with an early undetected pregnancy.
15. Has (or legally acceptable representative if applicable) provided documented informed consent/assent for the study. The participant may also provide consent/assent for FBR. However, the participant may participate in the main trial without participating in FBR. |
|
| E.4 | Principal exclusion criteria |
1. Has SCLC or a mixed tumor with presence of small cell elements.
2. Has MDS)/ (AML) or has features suggestive of MDS/AML.
3. Has had documented weight loss >10% (from baseline) in the preceding 3 months.
4. Is likely to have a radiation treatment plan that will encompass a volume of whole lung (total lung V20-GTV) receiving > 20 Gy in total (V20) of more than 34% of lung volume.
5. Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus,mediastinum, 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 prior therapy with olaparib or with any other PARP inhibitor.
8. Had major surgery <4 weeks prior to the first dose of study medication (except for placement of vascular access).
9. Is expected to require any other form of antineoplastic therapy, while on study.
10.Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
11. 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.
12. Is currently receiving either strong or moderate inducers of CYP3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 5 weeks for pentobarbital and 3 weeks for other agents.
13. Is currently receiving either strong or moderate inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 2 weeks.
14. Pemetrexed-specific: 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.
15. Pemetrexed-specific: Is unable/unwilling to take folic acid, vitamin B12, and dexamethasone.
16.Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
17. The presence of uncontrolled, potentially reversible cardiac conditions, as judged by the investigator or participant has congenital long QT syndrome.
18. 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.
19. Has a known additional malignancy that is progressing or has required active treatment within the past 5 years.
20. Has severe hypersensitivity (≥ Grade 3) to study intervention and/or any of its excipients
21. 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.
22. 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.
23. Has an active infection requiring systemic therapy.
24. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority.
25. 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.
26. Has active tuberculosis and is receiving treatment.
27. 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.
28. In the opinion of the treating investigator, is considered a poor medical risk due to a serious, uncontrolled medical disorder or nonmalignant systemic disease.
29. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
30. Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption .
31.Participants who have not adequately recovered from major surgery or have ongoing surgical complications.
32. Has had an allogenic tissue/solid organ transplant. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)as Assessed by Blinded Independent Central Review (BICR)
2. Overall Survival (OS)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 48 months
2. Up to approximately 72 months
|
|
| E.5.2 | Secondary end point(s) |
1. Incidence of Adverse Events (AE)
2. Discontinuation Rate of Study Intervention Due to an Adverse Event
(AE)
3. 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)
4. Duration of Response (DOR) Per Response Evaluation Criteria in Solid
Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent
Central Review (BICR)
5. Change from Baseline in EORTC Quality of Life Questionnaire-Core 30
(QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Scale
Score
6. Change From Baseline in Cough Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer Module 13 (EORTC QLQ-LC13) Item 1 Score
7. Change From Baseline in Chest Pain Using the EORTC QLQ-LC13 Item 10 Score
8. Change From Baseline in Dyspnea Using the EORTC QLQ-C30 Item 8 Score
9. Change From Baseline in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score
10.Change From Baseline in Role Functioning Using the EORTC QLQ-C30 Items 6-7 Score
11. Time to Deterioration (TTD) in HRQoL Using the EORTC QLQ-C30 Items 29 and 30 Score
12. TTD in Cough Using the EORTC QLQ-LC13 Item 1 Score
13. TTD in Chest Pain Using the EORTC QLQ-LC13 Item 10 Score
14. TTD in Dyspnea Using the EORTC QLQ-C30 Item 8 Score
15. TTD in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score
16.TTD in Role Functioning Using the EORTC QLQ-C30 Items 6-7 Score
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. to 4. Up to approximately 72 months
5. to 9. Baseline (at randomization) and at the end of study
(approximately 72 months post randomization)
10.Baseline (at randomization) and at the end of study (approximately 72 months post randomization)
11.to 16. Up to approximately 72 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Group A and B: double-blind; Group C: open-label |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 71 |
| 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 |
| Canada |
| Chile |
| China |
| Japan |
| Korea, Republic of |
| Mexico |
| Peru |
| Thailand |
| United States |
| Estonia |
| France |
| Latvia |
| Poland |
| Romania |
| Spain |
| Czechia |
| Germany |
| Italy |
| Hungary |
| Norway |
| Russian Federation |
| Turkey |
| 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 | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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