| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced/metastatic lung cancer and FGF, VEGF, or PDGF-related genetic alterations |
|
| 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 | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10050017 |
| E.1.2 | Term | Lung cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 the objective response rate (ORR) of lucitanib in patients with advanced/metastatic lung cancer and fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), or platelet derived growth factor (PDGF) related genetic alterations |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the clinical benefit rate (CBR), progression-free survival (PFS), duration of the response (DR) and overall survival (OS).
- To evaluate the kinetics of tumor size change prior to and after lucitanib exposure.
- To evaluate the safety profile of lucitanib.
- To collect additional information on the pharmacokinetic (PK) profile of lucitanib. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patient aged ≥ 18 years.
2. Histologically or cytologically confirmed advanced/metastatic SCLC or NSCLC.
3. Documented radiographic disease progression following at least one line of therapy in the advanced/metastatic setting:
• Patient must be refractory to all appropriate and approved therapies.
4. Any of the following tumor tissue based genetic alterations known prior to screening:
• FGFR1, FGFR2, FGFR3, VEGFA, or PDGFRα amplification
• Any FGFR1, FGFR2, or FGFR3 fusion
• FGFR1, FGFR2, or FGFR3 activating mutation (see Appendix 5 for specific qualifying FGFR mutations)
5. Availability of formalin fixed paraffin embedded (FFPE) tumor tissue sample sufficient for the central confirmation of the genetic alteration and exploratory analyses
6. Documented progressive extra central nervous system (CNS) disease at the time of inclusion.
7. At least one extra CNS measurable lesion according to RECIST 1.1 (with the last objective assessment no more than 4 weeks before the first dose of lucitanib). In addition, one prior measurable evaluation within a maximum of 3 months, if available, should be collected to assess tumor kinetics.
8. At least one prior treatment line in the advanced/metastatic setting.
9. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
10. Ability to take oral medication.
11. Adequate bone marrow function: absolute neutrophil count (ANC) ≥ 1.0 × 109/L, platelet counts ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL.
12. Adequate renal function defined as: calculated clearance ≥ 60 mL/minute (assessed with modification of diet in renal disease [MDRD] formula), proteinuria dipstick < 1+. If proteinuria dipstick ≥ 1+, urinary protein over 24 hours should be < 1.0 g/24 hours.
13. Adequate hepatic function defined as: aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 3 × under normal limit (UNL) (≤ 5 × UNL in case of liver metastasis); bilirubin < 1.5 × UNL; alkaline phosphatase (ALP) ≤ 2.5 × UNL (≤ 5 × UNL in case of bone metastasis).
14. LVEF ≥ 50% evaluated by cardiac ultrasound (echocardiogram [ECHO]) or Multi Gated Acquisition Scan (MUGA).
15. Negative serum pregnancy test during screening for women of child bearing potential within 7 days prior to the first dose of lucitanib
16. For men and women of child-bearing potential, willingness to use an effective contraception method during the study and up to 6 months after the last dose is administered. Effective methods include the following: non-hormonal intrauterine device, barrier method (condoms, diaphragm) in combination with spermicidal jelly, or total abstinence. Oral, injectable, or implant hormonal contraceptives are discouraged. Male patients whose sexual partners are women of child bearing potential must be willing to use effective contraception during the study and for 6 months after the end of treatment with lucitanib.
17. Willingness and ability to give written informed consent and to comply with study procedures
|
|
| E.4 | Principal exclusion criteria |
1. Carcinoid history
2. Known symptomatic CNS metastases not controlled by prior surgery or radiotherapy and/or low dose steroids.
3. Active second malignancy; i.e., patient known to have potentially fatal cancer present for which he/she may be (but is not necessarily) currently receiving treatment .
4. Chemotherapy within 6 months or bone marrow transplant (BMT) within 2 years prior to the first dose of lucitanib in patients with a history of cancer other than SCLC or NSCLC and with no current evidence of disease.
5. Anti cancer treatment for lung cancer within 28 days or 5 half lives, whichever is longer, before the first dose of lucitanib.
6. Investigational treatment within 28 days before the first dose of lucitanib
7. Wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks before the first dose of lucitanib.
8. Tumors that are invading a major vessel
9. NSCLC tumors abutting (adjacent and proximal) to a major vessel.
10. History of major surgical procedure or significant trauma within 28 days prior to the first dose of lucitanib, or non study related minor surgical procedure within 14 days prior to the first dose of lucitanib.
11. Ongoing AEs from surgery or prior anti cancer therapies, including radiation, targeted, or cytotoxic therapies without resolution of any Grade 2 or greater side effects to Grade ≤ 1.
12. History of gross hemoptysis within 3 months prior to first dose of lucitanib or history of hemoptysis ≥ ½ teaspoon (2.5 mL) of blood per day for a day or more within 1 week prior to the first dose of lucitanib.
13. History of coagulopathy or hemorrhagic disorders.
14. History of abdominal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within 3 months prior to first dose of lucitanib
15. Clinically significant non-healing wound, ulcer, or bone fracture.
16. Uncontrolled hypertension (defined as systolic blood pressure ([SBP]) ≥ 140 mmHg and/or diastolic blood pressure ([DBP]) ≥ 90 mmHg) with optimized anti hypertensive therapy.
•The requirement for > 2 anti hypertensives to control hypertension at the time of enrolment is exclusionary.
17. Cardiovascular disease or conditions, including:
a. Congestive heart failure (New York Heart Association functional classification ≥ 2) or requiring therapy.
b. History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, and/or stenting within 6 months before the first day of study drug administration.
c. Ventricular and/or supra-ventricular arrhythmia requiring therapy.
d. Conduction disturbance including QTC prolongation (defined as a QTC interval > 470 ms according to Fridericia’s correction as observed by the investigator) or other significant ECG abnormalities including 2nd degree atrioventricular (AV) block type II, 3rd degree AV block, or bradycardia (heart rate < 50 bpm); history of severe arrhythmia;, or history of familial arrhythmia [e.g., Wolff-Parkinson-White syndrome]).
e. Risk factors for or concomitant treatment with medications known to prolong QTC interval and that are clearly associated with Torsades de Pointes (see Appendix 2).
18. Patients with history of thromboticdisorders
a. Any history of venous thrombotic events, deep vein thrombosis (with the exception of catheter related deep vein thrombosis), or pulmonary embolism within 6 months prior to the first dose of lucitanib.
b. Any history of arterial thrombotic events, cerebrovascular accident, or transient ischemic accident within 6 months prior to the first dose of lucitanib.
c. Any peripheral vascular disease or vasculitis which required treatment within 6 months prior the first dose of lucitanib.
d. Patient with hereditary risk factors of thromboembolic events (e.g., mutation of the Factor V of Leiden).
19. Uncontrolled hypothyroidism defined as serum thyroid stimulating hormone (TSH) higher than 5 mIU/mL while receiving appropriate thyroid hormone therapy.
20. Administration of strong inhibitors of CYP2C8, CYP3A4, or strong inducers of CYP3A4
≤ 7 days prior to the first dose of lucitanib or have on-going requirements for these medications (see Appendix 4).
21. Serum potassium (K+) levels below lower limit of normal (LLN)
22. Significant GI abnormalities, including active ulcerative colitis, chronic diarrhea associated with intestinal malabsorption, Crohn's disease, and/or prior surgical procedures affecting absorption or requirement for intravenous (IV) alimentation.
23. Active bacterial, viral, or fungal infection (including known active human immunodeficiency virus [HIV] infection) requiring systemic treatment.
24. Concurrent severe or uncontrolled medical disease or organ system dysfunction which, in the opinion of the investigators, would limit life expectancy to < 3 months, compromise the patient's safety, or interfere with evaluation of the safety of the investigational product.
exclusion criteria 25-27 are listed in the protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ORR Proportion of patients with a confirmed complete response (CR) or a confirmed partial response (PR), as best overall response according to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline and every 8 weeks (every 2 cycles) and at the end of the study. |
|
| E.5.2 | Secondary end point(s) |
-ORR: Proportion of patients with a confirmed Complete Response (CR) or a confirmed Partial Response (PR), as best overall response according to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 criteria
-CBR: Proportion of patients with a confirmed CR, a confirmed PR, or a prolonged stable disease (SD) (>6 months), as best overall response according to RECIST 1.1 PFS, DR, duration of clinical benefit, OS, tumor growth kinetics.
-Adverse Events, laboratory abnormalities, physical examinations including vital signs, electrocardiogram (ECG), and ventricular ejection fraction (LVEF) abnormalities.
-Population PK |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
CBR, PFS, Duration of response, Duration of clinical benefit, Overall
survival, Adverse events - monitored throughout study
Tumour growth kinetics - Baseline and every 8 weeks
Laboratory examinations, physical examination, ECOG performance
status, vital signs - Screening or D1 (pre-dose), D4 (physical
examination and vital signs only), D14, D28, D56, every 4 weeks
thereafter and at end of study
ECG and LVEF - Screening or on D1 (pre-dose), D1 (ECG only: 2 h post-dose), D14 (ECG only: pre-dose, 2h and 3h post-dose), D28, D56, every 8 weeks thereafter and at end of study
PK - D14 (pre-dose and 2h post-dose) and pre-dose on D28, D56 and
D84
PG - D1 (pre-dose)
PD - D1 (pre-dose), D14 (pre-dose) and end of study visit 24h after last dose |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| 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 |
| France |
| Germany |
| Italy |
| Spain |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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