E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-small cell lung cancer (NLCLC) |
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E.1.1.1 | Medical condition in easily understood language |
Non-small cell lung cancer (NLCLC) |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061873 |
E.1.2 | Term | Non-small cell lung cancer |
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 determine if patients with a high tumour mutational burden, TMB (>8.5 mutations per megabase) have a hazard ratio equal to or less than 0.55 as compared to patients with low TMB. |
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E.2.2 | Secondary objectives of the trial |
1. To investigate different levels of TMB in tumour tissue compared to blood samples, as predictors for development of clinical response 2. To characterise the transcriptome (RNA seq) 3. To investigate urine for predictive biomarkers (ctDNA, miRNA) 4. To evaluate if selected biomarkers correlate to progression-free survival and overall survival in PDL1 negative and positive patients receiving the PD-L1-inhibitor durvalumab after chemoradiation 5. To investigate the immunological response, tumour development (if present) and dynamics in the tumour micro-environment 6. To investigate if chemoradiation upregulates / changes PDL1 expression in the PDL1 negative / positive patients 7. To evaluate if biomarkers predict toxicity of this treatment in lung cancer patients |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
For inclusion in the study patients must fulfill all of the following criteria: 1. Locally-advanced, unresectable, stage 3 NSCLC (including PET-CT and MRI-brain in the diagnostic work-up). 2. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations. 3. Diagnostic biopsy with PDL1 <1% in 50 patients PDL1 ≥1% in 50 patients 4. Adequate core or excisional biopsy 5. Age ≥ 18 years at time of study entry 6. Eastern Cooperative Oncology Group (ECOG performance status of 0, 1 or 2 7. Life expectancy of at least 12 weeks 8. Body weight >30 kg 9. Adequate normal organ and marrow function as defined below: Hemoglobin ≥9.0 g/dL Absolute neutrophil count (ANC) 1.5 (or 1.0) x (> 1500 per mm3) Platelet count ≥100 (or 75) x 109/L (>75,000 per mm3) Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance 10. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. 11. Women of childbearing potential should have a negative urine or serum pregnancy test within 7 days prior to receiccing first dose of study medication. if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. A woman is considered WOCBP, i.e. fertile, following menarche and untill becoming post-menopausal unkess permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 12. WOCBP should use an adequate method to avoid pregnancy 13.Males who are sexually active with women of childbearing potential must agree to follow instructions for method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo five half-lives 14.Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
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E.4 | Principal exclusion criteria |
1. Non-small cell lung cancer disease suitable for curative surgery 2. Significant cardiac, pulmonary or other medical illness that would limit activity or survival 3. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study during the last 2 weeks. 4. Any concurrent chemotherapy, Investigational product (IP), biologic- or homonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer related conditions (e.g. hormone replacement therapy) is acceptable. 5. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable. 6. History of allogenic organ transplantation. 7. Active or prior documented autoimmune or inflammatory disorders 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 8. 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/social situations 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 9. History of other active cancer disease 10. History of active primary immunodeficiency or medical condition requiring high doses (>30 mg prednisolone daily) of systemic steroids or other forms of immunosuppressive therapy 11. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), and hepatitis C. 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 hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 12. 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) 13. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP. 14. Female patients who are pregnant or breastfeeding 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. 15. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients. 16. Prior randomisation or treatment in a previous durvalumab clinical study regardless of treatment arm assignment. 17. Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements. 18. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. 19. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician.
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E.5 End points |
E.5.1 | Primary end point(s) |
Patients with high Tumour Mutational Burden, TMB (> 8.5 mutations per megabase) have a hazard ratio equal to or less than 0.55 as compared to patients with low TMB. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluation is planned when all included patients are followed-up for two years after start of treatment. |
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E.5.2 | Secondary end point(s) |
1. Tumour Mutational Burden, TMB in tumor tissue and blood samples are associated and are predictive of clinical response 2. Specific RNA profiles predict response to treatment 3. Molecular profiles in urine predict response to treatment 4. Analysis of pre-treatment and under-treatment samples may identify biomarkers for predicting which patients will benefit from treatment with durvalumab after chemoratiation 5. The durvalumab treatment following chemoradiatio will induce T cell responses against antigens expressed in each patient´s tumor 6. A possible change in PDL1 status will be explored 7. The durvalumab treatment following chemoradiation has acceptable safety and tolerability in NSCLC patients, as assessed by Patient Reported Outcome measurements. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Evaluation is planned when all included patients are followed-up for two years after start of 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 | No |
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 | No |
E.8.1.1 | Randomised | No |
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 | No |
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 | No |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 | No |
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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All subjects will be followed for survival until the end of the study defined as the last expected visit of the last subject on study, approximately 10 years after the last subject discontinue treatment with investigational product or when the sponsor stops the study, whichever occurs earlier. |
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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 | 10 |
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 | 10 |