| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Histologically confirmed frail Limited Disease Small Cell Lung Cancer (ECOG PS 2, ECOG PS 0-1 and older than 70 or did not receive a concomitant thoracic CRT because of comorbidities) previously untreated
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| E.1.1.1 | Medical condition in easily understood language |
Histologically confirmed frail Limited Disease Small Cell Lung Cancer previously untreated
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy in term of the progression free survival (PFS) (according to RECIST v 1.1 per investigator) of LD-SCLC patients on durvalumab maintenance treatment or on surveillance following thoracic CRT. |
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| E.2.2 | Secondary objectives of the trial |
To evaluate in each arm of treatment the :
• Centralized Progression Free Survival (cPFS),
• Overall survival (OS),
• Safety profile,
• Health-related Quality of life (HRQoL) using EORTC QLQ-C30 and LC13. |
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| 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 |
Bio-DurvaLung: to analyse peripheral and tumoral biomarkers of clinical benefit from the durvalumab maintenance strategy.
Sarco-DurvaLung:
1. To determine the impact of sarcopenia on OS in the LD-SCLC population.
2. To assess the: a) prevalence of sarcopenia, b) impact of CRT on the muscle mass, c) impact of immunotherapy on the muscle mass, d) Impact of sarcopenia on PFS.
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| E.3 | Principal inclusion criteria |
Inclusion Screening Criteria :
1. Patient must have signed a first written informed consent form prior to screening visit and to any trial specific procedures.
2. Histological confirmation of SCLC.
3. Limited disease (T0-T4, N0-N3 and M0) according to the TNM classification 8th edition or to the VALSG 2-stage classification. As per standard guidelines a complete radiological evaluation has to be performed within 28 days before the start of induction chemotherapy including all the radiological exams below:
• Total body PET- scan.
• Contrast enhanced CT-scan of thorax and upper abdomen.
• Contrast enhanced MRI or CT-scan of brain.
4. Measurable disease according to RECIST v1.1 criteria.
5. Patients must not have been previously treated for the SCLC.
6. Patients ≥18 years old.
7. Body weight >30 kg.
8. Patients can be candidate to concomitant or sequential thoracic CRT by IMRT.
• Patients candidate to concomitant thoracic CRT have to receive at least 60 Gy (one-daily fraction of 1.8-2 Gy) or 45 Gy twice daily (1.5 Gy per fraction) combined with cisplatin-etoposide regimen.
• Patients candidate to sequential thoracic CRT have to receive at least 60 Gy (one-daily fraction of 1.8-2 Gy) or 45 Gy twice daily (1.5 Gy per fraction) along with carboplatin AUC5-6-etoposide regimen.
9. Patients that received previous thorax radiotherapy may be eligible if they can receive the CRT schedule planned in the clinical study according to previous irradiation fields and, in any case, after the medical monitor agreement.
10. Women of childbearing potential must have a negative serum beta-HCG test before the beginning of the trial, during the study treatment and for a period of at least 3 months after the last administration of the experimental drug.
11. All sexually active men and women of childbearing potential must use an effective contraception method for the duration of study treatment and for 3 months after completing treatment.
12. Patients affiliated to the social security system.
13. Patient must be willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow
Inclusion Randomization Criteria :
1. Patient must have signed a second written informed consent form prior to randomization and to any specific trial procedure.
2. Patients must have completed concomitant or sequential thoracic CRT by IMRT:
• Patients that received concomitant thoracic CRT must have received at least 60 Gy (one-daily fraction of 1.8-2 Gy) or 45 Gy twice daily (1.5 Gy per fraction) combined with cisplatin-etoposide regimen.
• Patients that received sequential thoracic CRT must have received at least 60 Gy (one-daily fraction of 1.8-2 Gy) or 45 Gy twice daily (1.5 Gy per fraction) along with carboplatin AUC5-6-etoposide regimen.
All other schedules/methods performed need to be centrally approved before the randomization.
3. Confirmation of disease control (SD, CR or PR) at radiological assessment with contrast enhanced thorax and upper abdomen CT- scan and contrast enhanced brain CT-scan or MRI after the thoracic CRT according to RECIST v1.1.
4. Use of brain MRI in case of PCI avoidance is mandatory. PCI has to be prescribed according to the investigator’s choice and the local recommendations.
5. Patients must belong to one of these groups at the screening visit after the thoracic CRT :
• ECOG PS 2.
• ECOG PS 0-1 and older than 70.
• ECOG PS 0-1 and who did not receive a concomitant thoracic CRT because of comorbidities (radiotherapy beginning before D1C3 of chemotherapy).
6. Adequate hematological function:
• Hemoglobin > 9 g/dL.
• Platelet count > 100 x 109L.
• Neutrophil count > 1.5 x 109L.
7. Adequate renal function with a creatinine clearance ≥ 50 ml/min calculated with the Cockcroft-Gault formula.
8. Adequate hepatic function:
• Total bilirubin < 1.5 ULN.
• AST and ALT < 2.5 ULN.
• Alkaline phosphatase < 2.5 ULN.
9. HRQoL questionnaire performed.
10. No grade 3 or more toxicities remaining after the end of chemoradiotherapy. |
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| E.4 | Principal exclusion criteria |
Patients are not eligible to participate in the trial if they comply with any of the following criteria:
1. History of another primary malignancy except for
a. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of durvalumab and of low potential risk for recurrence.
b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
c. Adequately treated carcinoma in situ without evidence of disease.
2. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
3. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
a. Patients with vitiligo or alopecia.
b. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement.
c. Any chronic skin condition that does not require systemic therapy.
d. Patients without active disease in the last 5 years may be included but only after consultation with the study physician.
e. Patients with celiac disease controlled by diet alone.
4. Any concurrent chemotherapy, immune checkpoint inhibitors, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
5. History of leptomeningeal carcinomatosis.
6. Major surgical procedure (as defined by the Investigator) including surgical resection of the primary disease, within 28 days prior to the first dose of IMP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
7. History of allogenic organ transplantation.
8. History of active primary immunodeficiency.
9. Known active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, or TB testing in line with local practice) and hepatitis B and hepatitis C (positive hepatitis C virus [HCV] antibody, hepatitis B virus [HBV] surface antigen [HBsAg] or HBV core antibody [anti-HBc]).Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Patients known to have been tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) are not eligible.
10. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:
a. Intranasal, inhaled, topical steroids or local steroid injections (e.g., intra articular injection).
b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent.
c. Steroids as premedication for hypersensitivity reactions (e.g., CT-scan premedication).
11. Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab.
Note: Patients randomized in experimental arm should not receive live vaccine whilst receiving durvalumab and up to 30 days after the last dose of durvalumab.
12. Patients with known or suspected hypersensitivity to durvalumab or any of its excipients.
13. Patients who participated in another therapeutic trial within the 30 days prior to the start of the trial (screening phase included).
14. Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment arm assignment.
15. Female patients who are pregnant or breast feeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy.
16. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
17. Persons deprived of their liberty or under protective custody or guardianship. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
PFS is defined by investigator as the time from randomization until disease progression (per RECIST v1.1) or death from any cause, whichever occurs first.
At the time of analysis, patients alive and without disease progression will be censored at the date of the last tumor assessment. Patients alive without disease progression who started a new anticancer therapy will be censored at the date of the last tumor assessment prior to the start of the new anticancer therapy.
For patients without any evidence of disease at randomization, the progression will be defined as an appearance of a new lesion (measurable or not measurable).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1. cPFS is defined by central review as the time from randomization until disease progression (per RECIST v1.1) or death from any cause, whichever occurs first.
At the time of analysis, patients alive and without disease progression will be censored at the date of the last tumor assessment. Patients alive without disease progression who started a new anticancer therapy will be censored at the date of the last tumor assessment prior to the start of the new anticancer therapy.
For patients without any evidence of disease at randomization, the progression will be defined as an appearance of a new lesion (measurable or not measurable).
2. Overall Survival (OS) is defined as the time from randomization to death due to any cause. Patients still alive at the time of analysis (including lost to follow-up) will be censored at the last known alive date.
3. Safety profile: occurrence of adverse events coded using NCI CTC-AE version 5.0.
4. Quality of life (QL) will be assessed by the European Organization for Research and Treatment of Cancer (EORTC) core QL questionnaire, the EORTC QLQ-C30 and LC13 questionnaires (Lung Cancer Module). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | No |
| 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) | 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 | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| surveillance as per standard of care |
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| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 30 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
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| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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