| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-small cell lung cancer stage IV |
| Nicht-kleinzelliges Bronchialkarzinom Stadium IV |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | HLT |
| E.1.2 | Classification code | 10029664 |
| E.1.2 | Term | Non-small cell neoplasms malignant of the respiratory tract cell type specified |
| 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 |
The primary endpoint is progression-free survival 1 (PFS1) using Investigator assessments according to RECIST 1.1. PFS1 is defined as the time from
randomization to disease progression and will be primarily used for the formal hypothesis test. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are as follows:
- Progression-free survival after initiation of second-line therapy (PFS2)
- Overall survival after initiation of second-line therapy (OS)
- Objective response rate (ORR) - best overall response during second line treatment
- Subgroup analysis: Objective response rate (best overall response) after randomization
- Duration of response (DoR)
- TFST (Time to first subsequent treatment): Time from initiation of second line treatment to initiation of third line treatment.
- Tolerability and adverse events
- Quality of life
- Biomarkers |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed Informed Consent Form
2. Age ≥18 years at time of study entry
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
4. Histologically or cytologically confirmed, stage IV NSCLC (per the Union Internationale contre le Cancer/American Joint Committee on Cancer staging
system).
5. Indication for standard-of-care second line platinum-based chemotherapy, using cisplatin or carboplatin in combination with pemetrexed, paclitaxel, nab-paclitaxel, vinorelbine or gemcitabine
6. Life expectancy of > 12 weeks
7. Body weight > 30 kg
8. First-line mono-immunotherapy with checkpoint inhibitors (anti-PD1/PD-L1) with a best response of stable disease (SD) or better
9. Documented tumor PD-L1 expression status of ≥50%. Any existing data can be used.
10. First-line progression-free survival of at least 12 weeks after at least two reassessments after initiation of first-line treatment.
11. Patients who have received prior neo-adjuvant or adjuvant chemotherapy, or chemoradiotherapy with curative intent for non-metastatic disease must have experienced a treatment-free interval of at least 6 months from initiation of first-line immunotherapy since the last adjuvant chemotherapy or chemoradiotherapy cycle.
12. Patients with a history of treated asymptomatic CNS metastases are eligible, provided they meet all of the following criteria:
- No ongoing requirement for corticosteroids as therapy for CNS disease
- No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to enrolment
- No evidence of interim progression between the completion of CNS-directed therapy and the screening
- Only supratentorial and cerebellar metastases allowed (i.e., no metastases to midbrain, pons, medulla or spinal cord)
13. No known sensitizing mutation in the EGFR gene or evidence of an ALK fusion oncogene.
14. Measurable disease, as defined by RECIST v1.1. Previously irradiated lesions can only be considered as measurable disease if disease progression has been unequivocally documented at that site since radiation.
15. Adequate hematologic and end organ function, defined by the following laboratory results obtained within 3 days prior to enrolment:
a. ANC 1500 cells/μL without granulocyte colony-stimulating factor support
b. Lymphocyte count ≥ 500/μL
c. Platelet count ≥ 100,000/μL without transfusion
d. Hemoglobin ≥ 9.0 g/dL. Patients may be transfused to meet this criterion. Transfusions are allowed throughout the study.
e. Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
f. 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
g. Measured creatinine clearance (CL) >60 mL/min or calculated creatinine clearance CL>60 mL/min by the Cockcroft-Gault formula (Cockcroft and
Gault 1976) or by 24-hour urine collection for determination of creatinine clearance |
|
| E.4 | Principal exclusion criteria |
1. Use of immunosuppressive medication (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 14 days prior to randomization.
2. Prior treatment with other immune-modulating agents (other than anti-PD-1/PD-L1)
3. Treatment with systemic immunostimulatory agents (including but not limited to IFNs, IL-2) within 4 weeks or five half-lives of the drug, whichever is longer, prior to randomization. Prior treatment with cancer vaccines is allowed.
4. Involvement in the planning and/or conduct of the study (applies to both sponsor staff and/or staff at the study site)
5. Concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study
6. Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 28 days prior to randomization
7. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy (including second line platinum-based chemotherapy) with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria - Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Chair.
- Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Chair.
8. Any toxicity that led to permanent discontinuation of prior immunotherapy.
9. AE ≥ grade 4 immune-related AE or an immune-related neurologic or ocular AE of any grade while receiving prior immunotherapy.
10. Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non–cancerrelated conditions (e.g., hormone replacement therapy) is acceptable.
11. History of allogenic organ transplantation.
12. 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.
13. 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:
- vitiligo or alopecia
- hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
- Any chronic skin condition that does not require systemic therapy
- without active disease in the last 5 years may be included but only after consultation with the Study Chair
- celiac disease controlled by diet alone
14. 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
15. History of another primary malignancy except
- Malignancy treated with curative intent and with no known active disease ≥3 years prior to study enrolment and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- Adequately treated carcinoma in situ without evidence of disease
16. History of leptomeningeal carcinomatosis
17. History of active primary immunodeficiency
18. Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus. Patients with a past or resolved HBV infection are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
19. Receipt of live or live attenuated vaccine within 30 days prior to the first dose of IP.
20. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
21. 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 a defined timepoint after last dose of treatment
22. A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 ms);
A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of Long QT Syndrome). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is progression-free survival 1 (PFS1) using Investigator assessments according to RECIST 1.1. PFS1 is defined as the time from
randomization to disease progression and will be primarily used for the formal hypothesis test. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PFS1 is defined as the time from randomization to disease progression. |
|
| E.5.2 | Secondary end point(s) |
- Progression-free survival after initiation of second-line therapy (PFS2)
- Overall survival after initiation of second-line therapy (OS)
- Objective response rate (ORR) - best overall response during second linetreatment
- Subgroup analysis: Objective response rate (best overall response) after randomization
- Duration of response (DoR)
- TFST (Time to first subsequent treatment): Time from initiation of second line treatment to initiation of third line treatment.
- Tolerability and adverse events
- Quality of life
- Biomarkers |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The nomenclature of the efficacy endpoint is defined in a way that the suffix “1” indicates the time from randomization, whereas the suffix “2” indicates the time from initiation of second line treatment. Both timepoints have been chosen in order to i) guarantee comparability with published data and ii) to address the question to which extent patients benefit from the experimental treatment. |
|
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 25 |
| 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 | 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
|
Global end of study is defined as
1. all randomized patients attended the EoT visit or permanently discontinued the study, and
2. the required number of PFS events has been observed or a maximum followup phase of two years after last patient EoT has been reached. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 49 |
| E.8.9.1 | In the Member State concerned days | |
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