| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Limited-Stage Small Cell Lung Cancer (LS-SCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Limited-Stage Small Cell Lung Cancer (LS-SCLC) |
|
| 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 | 10041071 |
| E.1.2 | Term | Small cell lung cancer stage unspecified |
| 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 progression free survival (PFS) per RECIST 1.1 as assessed by BICR
2. To compare overall survival (OS)
|
|
| E.2.2 | Secondary objectives of the trial |
1.To evaluate the safety and tolerability (ST) of concurrent chemoradiation therapy (CCT) with pembrolizumab (pembro) followed by pembro plus olaparib (Gp B) compared to CCT alone (Gp C)
2.To evaluate ST of CCT with pembro followed by pembro (Gp A) compared to Gp C
3.To compare Gp B to Gp C with respect to objective response rate (ORR) as assessed by BICR per RECIST 1.1
4.To compare Gp A to Gp C with respect to ORR as assessed by BICR per RECIST 1.1
5.To compare Gp B to Gp C with respect to duration of response (DOR) as assessed by BICR per RECIST 1.1
6.To compare Gp A to Gp C with respect to DOR as assessed by BICR per RECIST 1.1
7.To evaluate change from baseline (CFB) (at Cycle 1) and time to true deterioration (TTD) in global health status/quality of life (QoL) in Gp B compared to Gp C
8.To evaluate CFB (at Cycle 1) and the TTD in QoL in Gp A compared to Gp C
9.To evaluate the effect of programmed cell death ligand 1 (PD-L1) expression levels on OR, DOR, PFS, and OS. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Has pathologically (histologically or cytologically) confirmed SCLC.
2.Has LS-SCLC (Stage I-III, by AJCC 8th Edition Cancer Staging), and can be safely treated with definitive radiation doses.
3.Has no evidence of metastatic disease by whole body PET/CT scan, CT or MRI scans of diagnostic quality of chest, abdomen, pelvis and brain.
4.Has at least 1 lesion that meets the criteria for being measurable, as defined by RECIST 1.1, and is appropriate for selection as a target lesion, as determined by local site investigator/radiology review.
5.Has not received prior treatment (chemotherapy or radiotherapy or
surgery resection) of LS-SCLC.
6.Is not expected to require tumor resection during the course of the
study.
7.Must submit a pretreatment tumor tissue sample. Any available tumor tissue sample can be submitted: histologic (ie, core, incisional, or excisional biopsy) or cytologic sample (if tissue sample unavailable). The sample should be submitted before or within 4 weeks after randomization; however, participants may be enrolled into the study before the pretreatment tissue sample is submitted.
8.Has ECOG Performance score 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 an FEV1 >50% (of predicted normal
volume) or ≥ 1.2 L/Sec and a 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) ≥90% room air.
11.Has adequate organ function; all screening laboratory tests should be performed within 10 days prior to initiation of study intervention.
12. Male and female participants who are at least 18 years of age at the time of signing the informed consent.
13. 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:
- 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
• Uses contraception unless confirmed to be azoospermic (vasectomized
or secondary to medical cause) as detailed below:
o 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. Note: Men with a pregnant or
breastfeeding partner must agree to remain abstinent from penilevaginal intercourse or use a male condom during each episode of penilevaginal penetration.
14. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Not 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:
- Pembrolizumab: 120 days
- Olaparib and platinum doublet: 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 (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.
• Abstains from breastfeeding during the study intervention period and for at least the following period after the last study intervention:
- Pembrolizumab: 120 days
- Olaparib: 7 days
•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.The participant (or legally acceptable representative) has 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 study without participating in FBR |
|
| E.4 | Principal exclusion criteria |
1.Has extensive stage disease, defined as stage IV (T any, N any M1a/b), or T3-4 due to multiple lung nodules that are too extensive or have tumor/nodal volume that is too large to be encompassed in a tolerable radiation plan.
2.Has history, current diagnosis, or 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 the volume of the (Total Lung-GTV) receiving at least 20 Gy is more than 34% of the (Total Lung-GTV) for the once-daily regimen and is more than 28% for the twice-daily regimen.
5.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.
6.Has received prior therapy with olaparib or with any other PARP inhibitor.
7.Had major surgery <4 weeks prior to the first dose of study intervention (except for placement of vascular access).
8.Is expected to require any other form of antineoplastic therapy, while on study.
9.Has received a live or live attenuated vaccine within 30 days prior to the first dose of study intervention.
10.Has received colony-stimulating factors within 28 days prior to the first dose of study intervention.
11.Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) 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 phenobarbital and 3 weeks for other agents.
12.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.
13. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention.
14.Has uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg, unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500 millisecond, electrolyte disturbances, etc.), or participants with congenital long QT syndrome.
15.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.
16.Has a known additional malignancy that is progressing or has required active treatment within the past 5 years.
17.Has severe hypersensitivity (≥ Grade 3) to study intervention and/or any of its excipients.
18.Active autoimmune disease that has required systemic treatment in past 2 years. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid ) is allowed.
19.Has a known history of, or active, neurologic paraneoplastic syndrome.
20.Has a history of (noninfectious) pneumonitis/interstitial lung disease that requires steroids or has current pneumonitis/interstitial lung disease. Lymphangitic spread of the LS-SCLC is not exclusionary.
21.Has an active infection requiring systemic therapy.
22.Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority.
23.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.
24.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.
25.In the opinion of the treating Investigator, is considered a poor medical risk due to a serious, uncontrolled medical disorder or non-malignant systemic disease.
26. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
27. Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption.
28.Has had an allogenic tissue/solid organ transplant.
29 Participant, in the judgement of the Investigator, is unlikely to comply with the study procedures, restrictions, and requirements of the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1): the time from randomization to progression or death due to any cause, whichever occurs first
2. Overall Survival (OS): the time from randomization to death due to any cause |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 59 months
2. Up to approximately 82 months |
|
| E.5.2 | Secondary end point(s) |
1. Number of Participants Experiencing an Adverse Events (AEs)
2. Number of Participants Discontinuing Study Treatment Due to Adverse Events (AEs)
3. Objective Response (OR): complete response (CR) or partial response (PR)
4. Duration of Response (DOR): the time from the earliest date of first documented evidence of confirmed CR or PR until the earliest date of disease progression or death from any cause, whichever comes first
5. Change from Baseline at Cycle 1 in European Organization for Research and Treatment (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status / Quality of Life (Items 29 & 30) Scale Score
6. Change from Baseline at Cycle 1 in EORTC Quality of Life Questionnaire Lung Cancer Module 13 (QLQ-LC13) Cough (Item 1) Scale Score
7. Change from Baseline at Cycle 1 in EORTC QLQ-LC13 Chest Pain (Item 10) Scale Score
8. Change from Baseline at Cycle 1 in EORTC QLQ-C30 Dyspnea (Item 8) Scale Score
9. Change from Baseline at Cycle 1 in EORTC QLQ-C30 Physical Functioning (Items 1 to 5) Scale Score
10. Time to True Deterioration (TTD) in EORTC QLQ-C30 Global Health Status / Quality of Life (Items 29 & 30) Scale Score
11. Time to True Deterioration (TTD) in Cough (LC13/Item 1) Scale Score
12. Time to True Deterioration (TTD) in Chest Pain (LC13/Item 10) Scale Score
13. Time to True Deterioration (TTD) in EORTC QLQ-C30 Dyspnea (Item 8) Scale Score
14. Time to True Deterioration (TTD) in EORTC QLQ-C30 Physical Functioning (Items 1 to 5) Scale Score
15. Objective Response (OR, according to RECIST 1.1 by BICR) assessed by programmed cell death ligand 1 (PD-L1) expression levels
16. Duration of Response (DOR, according to RECIST 1.1 by BICR) assessed by programmed cell death ligand 1 (PD-L1) expression levels
17. Progression-free Survival (PFS, according to RECIST 1.1 by BICR) assessed by programmed cell death ligand 1 (PD-L1) expression levels
18. Overall Survival (OS) assessed by programmed cell death ligand 1 (PD-L1) expression levels |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 82 months
2. Up to approximately 82 months
3. Up to approximately 82 months
4. Up to approximately 82 months
5. Baseline and 82 months post randomization
6. Baseline and 82 months post randomization
7. Baseline and 82 months post randomization
8. Baseline and 82 months post randomization
9. Baseline and 82 months post randomization
10. Up to 82 months post randomization
11. Up to 82 months post randomization
12. Up to 82 months post randomization
13. Up to 82 months post randomization
14. Up to 82 months post randomization
15. Up to approximately 82 months
16. Up to approximately 82 months
17. Up to approximately 59 months
18. Up to approximately 82 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 | 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 | 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| 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 |
| Canada |
| China |
| Japan |
| Mexico |
| United States |
| Russian Federation |
| Turkey |
| Ukraine |
| Belgium |
| Bulgaria |
| Estonia |
| France |
| Greece |
| Hungary |
| Italy |
| Lithuania |
| Portugal |
| Romania |
| Spain |
| Korea, Republic of |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 82 |
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