E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Lung cancer called “small cell lung cancer (SCLC)” limited to the thorax and not spread into other tissues. |
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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 evaluate whether patients treated with chemo-radiotherapy and prophylactic cranial irradiation followed by consolidation treatment (nivolumab plus ipilimumab) have a better outcome in terms of progression-free survival and overall survival, compared to patients treated with chemo-radiotherapy and prophylactic cranial irradiation without consolidation treatment. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate secondary measures of clinical efficacy including, objective response rate (ORR) and time to treatment failure.
- To assess the safety and the tolerability of the treatment in both arms.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
For enrolment:
- Histologically or cytologically confirmed small cell lung carcinoma
- Untreated limited stage disease (with the exception of one cycle of chemotherapy given prior to enrolment) as defined by stage I-IIIB based on 7th TNM classification (IASLC classification for SCLC proposal). M0 proven by
- Whole body FDG-PET CT including a contrast-enhanced CT of thorax and upper abdomen (incl. liver, kidney, adrenals);
OR contrast-enhanced CT of thorax and upper abdomen (incl. liver, kidney, adrenals) and bone scan;
AND
- brain MRI (or contrast enhanced CT of the brain)
within 28 days before start of chemotherapy
- Age ≥ 18 years
- ECOG performance status 0-1
- Adequate haematological function:
haemoglobin >9 g/dL
neutrophils count >1.5×109/L
platelet count >100 × 109/L
- Adequate liver function:
Total bilirubin <2.5 × ULN
ALT and/or AST <2.5 × ULN
alkaline phosphatase <5 × ULN.
- Adequate renal function: Calculated creatinine clearance ≥30 mL/min (Cockroft-Gault).
- Pulmonary function FEV1 of 1.0L or >40% predicted value and DLCO >40% predicted value.
- Patient capable of proper therapeutic compliance, and accessible for correct follow-up.
- Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 7 days before beginning of chemotherapy. The test has to be repeated within 7 days before randomisation and then every 6 weeks during consolidation treatment. Pregnancy tests should be repeated at approximately 30 days and approximately 70 days after consolidation treatment stop.
- All sexually active men and women of childbearing potential must use an effective contraceptive method (two barrier methods or a barrier method plus a hormonal method) during the study treatment and for a period of at least 12 months following the last administration of trial drugs.
- Measurable or evaluable disease (according to RECIST 1.1 criteria). Not eligible: patients with only one measurable or evaluable tumour lesion which was resected or irradiated prior to enrolment.
- Written Informed Consent (IC) must be signed and dated by the patient and the investigator prior to any trial-related intervention for
a) Chemo-radiotherapy treatment, PCI, and subsequent randomisation, including mandatory biological samples
b) Optional biological material collection, long-term storage and future use of biological material for translational research
For randomization:
- Chemo-radiotherapy completed per protocol: 4 cycles of chemotherapy, ≥85% of PTV of thoracic radiotherapy, as well as completed, mandatory PCI
- Non-PD after chemo-radiotherapy and PCI
- Recovery of all adverse events to a Grade ≤1, except for fatigue, appetite, oesophagitis and renal impairment (where ≤2 is allowed) and alopecia (any grade)
- Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 7 days before randomisation. |
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E.4 | Principal exclusion criteria |
For enrolment:
-Patients with mixed small-cell and non-small-cell histologic features
-Patients with pleural or pericardial effusions proven to be malignant
- Patients who have had in the past 5 years any previous or concomitant malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ ductal carcinoma of the breast (if no RT was involved).
- Patients with other serious diseases or clinical conditions, including but not limited to uncontrolled active infection and any other serious underlying medical processes that could affect the patient’s capacity to participate in the study.
- Ongoing clinically serious infections requiring systemic antibiotic or antiviral, antimicrobial, or antifungal therapy.
- Known or suspected hypersensitivity to nivolumab or ipilimumab or any of their excipients.
- Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results.
- Documented history of severe autoimmune or immune mediated symptomatic disease that required prolonged (more than 2 months) systemic immunosuppressive treatment (e.g. steroids), such as but not limited to ulcerative colitis and Crohn´s disease, rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, or autoimmune vasculitis (e.g. Wegener’s granulomatosis).
- Subjects with an autoimmune paraneoplastic syndrome requiring concurrent immunosuppressive treatment.
- Interstitial lung disease or pulmonary fibrosis.
- Women who are pregnant or in the period of lactation.
- Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the study.
- Patients with any concurrent anticancer systemic therapy (except for chemotherapy cycle 1).
- HIV, active Hepatitis B or Hepatitis C infection
- Previous radiotherapy to the thorax (prior to inclusion), including RT for breast cancer
- Planned radiotherapy to lung of mean dose >20 Gy or V20 >35%
- Patients who received treatment with an investigational drug agent during the 3 weeks before enrolment in the study.
- Prior chemotherapy or radiotherapy for SCLC. Exception: one cycle of chemotherapy (as specified to section 10.2) may be administered prior to enrolment.
For randomization:
- Less than 4 cycles of chemotherapy administered, less than 85% PTV of thoracic radiotherapy delivered, or PCI not completed
- Progressive disease after chemo-radiotherapy and PCI |
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E.5 End points |
E.5.1 | Primary end point(s) |
-Progression-free survival (PFS) by RECIST 1.1Overall survival
- Overall survival |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Time from the date of randomisation until death from any cause.
- PFS: time from the date of randomisation until documented progression or death, if progression is not documented.
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E.5.2 | Secondary end point(s) |
- Objective Response (ORR) determined by RECIST 1.1
- Time to treatment failure
- Adverse events graded according to CTCAE V4.0
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- ORR: best overall response (CR or PR) across all assessment time-points during the period from randomisation to termination of trial treatment. Objective response to chemo-radiotherapy determined by tumour assessment around week 15
- Time to treatment failure: from the date of randomisation to discontinuation of treatment for any reason
- AEs: day of enrolment until 150 days after final dose of IMP or within 150 days after the last visit in the observation arm. |
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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 |
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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
| 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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 49 |
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 |
Belgium |
France |
Germany |
Netherlands |
Spain |
Switzerland |
United Kingdom |
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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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Patient accrual is expected to be completed within 3 years. Patients will be followed until death – thus follow-up is estimated up to last up to 4,5 years following the enrolment of the last patient. The trial will end with the preparation of the final report, scheduled for 7.5 years after the inclusion of first patient. |
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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 | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |