E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
ALK-rearranged non-small cell lung cancer (NSCLC) after disease progression on prior ALK inhibitor therapy |
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E.1.1.1 | Medical condition in easily understood language |
ALK+ NSCLC is a type of cancer that forms in tissues of the lung, and has an alteration in the ALK gene |
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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 | 10029522 |
E.1.2 | Term | Non-small cell lung cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10029521 |
E.1.2 | Term | Non-small cell lung cancer stage IIIB |
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 estimate Objective Response Rate (ORR) in all patients with measurable disease at baseline |
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E.2.2 | Secondary objectives of the trial |
Central Nervous System Objective Response Rate (C-ORR) in all patients with measurable CNS metastases at baseline.
Progression-Free Survival (PFS) in all patients.
Time to Progression in all patients.
Disease Control Rate (DCR) in all patients with measurable disease.
Duration Of Response (DOR) in all patients with measurable disease.
CNS Duration Of Response (C-DOR) in all patients with measurable CNS metastases at baseline.
Overall Survival (OS) rate at two-years in all patients.
Time to CNS progression in all patients.
Quality of life (QLQ-C30, LC13, BN20 questionnaires for patients with CNS metastases and EQ-5D-5L). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Patients with histologically or cytologically confirmed locally advanced or metastatic NSCLC (Stage IIIB or IV accordingly to American Joint Committee on Cancer [AJCC] classification)
- Male or female ≥ 18 years old
- Life expectancy of at least 12 weeks, in the opinion of the Investigator
- Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 2
- Patients having:
a) contributive biopsy performed on fresh tissue (FFPE blocks required) taken after progression on previous therapy showing:
- presence of anaplastic lymphoma kinase (ALK) rearrangement, assessed by IHC and confirmed by FISH,
- absence of resistance mechanism to alectinib assessed by the Biomarkers Board:
1. ALK I1151Tins I1171N/S, V1180L and G1202R mutations (known to induce a resistance to alectinib),
2. epidermal growth factor receptor (EGFR) exon 19 deletions, L858R mutation or Kirsten rat sarcoma viral oncogene homolog (KRAS) codon 12, 13 or 61 mutations,
3. High level of MET amplification,
4. tumor histologic transformation into small cell lung cancer.
b) disease progression, limited to CNS without possibility of tissue biopsy,
c) non-contributive molecular analyses (no enough tumor cells or DNA amount or failure of analyses for technical reasons): inclusion is at investigator discretion (his decision taken upon Biomarker Board recommendation)
- History of crizotinib exposure
- Adequate hematologic function
- Adequate renal function
- For all females of childbearing potential, a negative pregnancy test must be obtained within three days before starting study drug
- For women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use two adequate methods of contraception, including at least one method with a failure rate of < 1% per year, during the treatment period and for at least 90 days after the last dose of study drug
- For men: agreement to remain abstinent or use a barrier method of contraception (e.g., condom) during the treatment period and for at least 90 days after the last dose of study drug and agreement to refrain from donating sperm during this same period
- Patient has national health insurance coverage |
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E.4 | Principal exclusion criteria |
- Prior therapy with other ALK inhibitors than crizotinib (including alectinib)
- Patients with symptomatic CNS metastases who are neurologically unstable or require increasing doses of steroids within one week prior to Day 0 to manage CNS symptoms (Patients with brain or leptomeningeal metastases are allowed, symptomatic disease is allowed as long as symptoms are controlled and stable and prior treatment with whole brain radiation or gamma knife must have been completed at least 14 days prior to Day 0 and patients must be clinically stable)
- Patients with progression limited to CNS and eligible to a focal treatment (surgery or stereotaxic radiotherapy)
- Liver disease characterized by: Alanine transaminase (ALT) or aspartate aminotransferase (AST) > 3 × upper limit of normal (ULN) (≥ 5×ULN for patients with concurrent liver metastasis) confirmed on two consecutive measurements
OR Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or other conditions of decompensated liver disease such as coagulopathy, hepatic encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices.
OR Acute viral or active autoimmune, alcoholic, or other types of hepatitis
- Patients with baseline QTc > 470 ms or patients with symptomatic bradycardia.
- Pregnant or lactating women
- Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the patient before trial entry
- Serious, uncontrolled infections or current known infection with human immunodeficiency virus (HIV) |
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E.5 End points |
E.5.1 | Primary end point(s) |
ORR, defined as the percentage of patients who achieve complete response (CR) or partial response (PR) as determined by Investigators using Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v.1.1) |
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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) |
C-ORR in all patients with measurable CNS metastases at baseline
PFS in all patients
TTP in all patients
DCR in all patients
DOR in all patients
C-DOR in all patients
Two-year OS
Time to CNS progression |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
C-ORR: 12 months
PFS: 24 months
TTP: 24 months
DCR: 12 months
DOR: 24 months
C-DOR: 24 months
OS: 24 months
Time to CNS progression: 24 months |
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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 | 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 |
To assess exploratory biomarkers |
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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) | 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 | Yes |
E.8.1.7.1 | Other trial design description |
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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 | 21 |
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
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |