E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with Stage I-III Limited Disease Small-Cell Lung Cancer (LD-SCLC) |
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E.1.1.1 | Medical condition in easily understood language |
Specific type of lung cancer called "Small Cell Lung Cancer" (SCLC) |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10041069 |
E.1.2 | Term | Small cell lung cancer limited stage |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
- To assess the efficacy of durvalumab monotherapy as well as durvalumab in combination with tremelimumab therapy compared to placebo in terms of PFS.
- To assess the efficacy of durvalumab in combination with tremelimumab therapy compared to placebo in terms of OS. |
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E.2.2 | Secondary objectives of the trial |
To Assess :
- the efficacy of durvalumab compared to placebo in terms of OS.
- the efficacy of durvalumab and durvalumab and tremelimumab compared to placebo in terms of ORR, PFS18a, PFS24a, TTDM, OS24, OS36, and PFS2.
- the efficacy of durvalumab and tremelimumab compared to durvalumab in terms of PFS, OS and ORR,,
- disease-related symptoms and HRQoL in patients treated with durvalumab or durvalumab and tremelimumab compared to placebo using the EORTC QLQ-C30 v3 and QLQ-LC13.
- the PK of durvalumab and durvalumab and tremelimumab.
To Investigate:
- the immunogenicity of durvalumab and durvalumab and tremelimumab.
- the relationship between a patient’s tumor mutational burden (TMB) measured in tumor and/or blood and efficacy outcomes with mono and combination therapy.
- safety and tolerability of durvalumab and durvalumab and tremelimumab compared to placebo |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Histologically or cytologically documented limited-stage SCLC (Stage I-III SCLC [T any, N any, M0] i.e., patients whose disease can be encompassed within a radical radiation portal - Patients with Stage I to IIA disease must be medically inoperable.
- Received 4 cycles of platinum-based chemotherapy concurrent with RT, which must be completed within 1 to 42 days prior to first dose of IP. The chemotherapy regimen must contain platinum and etoposide, as per local standard-of-care regimens.
- The radiotherapy must have commenced no later than the end of Cycle 2 of chemotherapy and patients must have received a total dose of radiation of 60 to 66 Gy for standard QD radiation schedules or 45 Gy for hyperfractionated BID radiation schedules.
- Patients must have achieved CR, PR, or SD and not have progressed following definitive, platinum-based, concurrent CRT.
- World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at enrolment and randomization.
- Provision of an archived tumour tissue block (or at least 15 newly cut unstained slides, where available) ≤3 years old, where such samples exist in a quantity sufficient to allow for analysis (refer to the Laboratory Manual for details).
- A recent (≤3 months) tumour biopsy* (taken following completion of the most recent therapy) is an optional requirement, provided that a biopsy procedure is technically feasible and the procedure is not associated with unacceptable clinical risk. |
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E.4 | Principal exclusion criteria |
- Extensive-stage SCLC.
- Mixed SCLC and NSCLC histology.
- Brain metastases or spinal cord compression. All patients will have an MRI (preferred) or CT, preferably with IV contrast of the brain, prior to study entry.
- Patients who received sequential chemoradiation therapy for LD-SCLC (no overlap of RT with chemotherapy).
- Receipt of consolidation chemotherapy after radiation. (Treatment with etoposide and platinum after radiation is acceptable as 1 regimen for 1 to 2 cycles; chemotherapy regimens other than etoposide and platinum as consolidation are not permitted.)
- Patients with Grade ≥2 pneumonitis from prior CRT
- Active or prior documented autoimmune/inflammatory disorders, uncontrolled intercurrent illness or active infections
- Prior exposure to immune-mediated therapy. |
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E.5 End points |
E.5.1 | Primary end point(s) |
- PFS using BICR assessments according to RECIST 1.1
- OS |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- PFS: On-study tumor assessments begin at baseline, then occur q8w ± 1w for the first 72 weeks (relative to the date of randomization), followed by q12w ±1w until up to 96 weeks relative to the date of randomization, and then q24w ±1w thereafter until RECIST 1.1-defined radiological progression, plus one follow-up scan
- OS: every 4 weeks during treatment period at least every 8 weeks (±2 weeks) following treatment discontinuation
- OS and PFS will be made periodically until end of study. |
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E.5.2 | Secondary end point(s) |
- OS
- ORR, PFS18, PFS24, and TTDM using BICR assessments according to RECIST 1.1, OS24 and OS36, PFS2
- PFS and ORR using BICR assessments according to RECIST 1.1, OS
- EORTC QLQ-C30 and QLQ-LC13: change in symptoms, functioning, and global health status/QoL
- Concentration of durvalumab and tremelimumab in serum (such as peak concentration and trough; sparse sampling)
- Presence of ADA for durvalumab and tremelimumab (confirmatory results: positive or negative)
- TMB relative to response/efficacy outcomes (ORR, PFS, and OS)
- Safety assessment: AEs; laboratory findings including clinical chemistry, hematology, urinalysis; physical examinations; vital signs including blood pressure and pulse; and electrocardiograms |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- ORR, PFS18, PFS24, TTDM, PFS. ORR: tumor assessments begin at baseline, then q8w±1w for the first 72 weeks (relative to the date of randomization), followed by q12w±1w until up to 96 weeks , and then q24w±1w thereafter until RECIST 1.1 radiological progression, plus one follow-up scan.
- OS: Every 4 weeks during treatment, at least every 8 weeks (±2 weeks) following IP discontinuation
- EORTC QLQ-C30, QLQ-LC13: Every 4 weeks (±3 days) relative to randomization until study termination or death
- PK at C1 (post dose) and C2, C5, C26 (pre dose) and week 12 post IP discontinuation
- ADA at C1, C5, C26 (pre dose) and week 12 and 24 post IP discontinut
- TMB at screening (tumor) and C1, C2, C3, C4, C5 (blood)
- Safety: screening and each treatment vist and up to 12 weeks post treatment. |
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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 | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability
Healthcare resource utilization
Quality of life |
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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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 48 |
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 |
Argentina |
Belgium |
Canada |
China |
Czech Republic |
Germany |
India |
Italy |
Japan |
Korea, Republic of |
Netherlands |
Russian Federation |
Spain |
Taiwan |
Turkey |
United States |
Vietnam |
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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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The end of study is defined as the last expected visit/contact of the last patient undergoing the study.
A patient is considered to have completed the study when he/she has completed his/her last scheduled visit or last scheduled procedure. |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |