| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| FGFR1-amplified squamous non-small cell lung cancer (NSCLC) |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 16.1 |
| 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the objective response rate (ORR) of lucitanib in patients with FGFR1 amplified squamous non-small cell lung cancer (NSCLC) |
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| E.2.2 | Secondary objectives of the trial |
- To determine the Clinical Benefit Rate (CBR), Progression-Free Survival (PFS) and duration of the response
- To evaluate the kinetic of tumour size change prior to and after lucitanib exposure.
- To evaluate the safety profile of lucitanib.
- To collect additional information on the pharmacokinetic profile of lucitanib.
- To perform a pharmacogenomic analysis of inter-patients variation in genes encoding for proteins involved in absorption/distribution/ metabolism/excretion (ADME).
- To evaluate the pharmacodynamics profile of lucitanib by characterizing its biological activity and by exploring biomarkers potentially predictive for benefit from 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 confirmed stage IV squamous NSCLC.
3. FGFR1-amplification determined on the most recent archive sample available or on a newly performed biopsy.
a. FGFR1 amplification may be determined through a study-specific screening or may be known already through a molecular screening program.
b. Patients can be included based on local assessment by Fluorescence In Situ Hybridization [FISH], Comparative Genomic Hybridization [CGH] or Chromogenic In Situ Hybridization [CISH].
c. Confirmatory central reading with FISH is required for determination of the FGFR1 amplification status. The screening status is considered as FGFR1-amplified under at least one of the following conditions:
i. the gene-to-centromere (FGFR1/CEN8) ratio is ≥ 2.0,
ii. the average number of FGFR1 signals per tumour cell nucleus is ≥ 6,
iii. the percentage of tumour cells containing ≥ 15 FGFR1 signals or large clusters is ≥ 10%,
iv. the percentage of tumour cells containing ≥ 5 FGFR1 signals is ≥ 50%
Amplification is deemed to be of low level if (iv) is the sole condition met.
d. Patients in whom the central reading does not confirm amplification can continue the study at the discretion of the treating physician if clinical benefit is observed but have to be replaced.
4. Availability of a tissue sample suitable for the central confirmation by FISH of FGFR1 amplification.
5. Documented progressive extra CNS disease at the time of inclusion.
6. At least one measurable lesion extra CNS according to RECIST 1.1 (with the last objective assessment no more than 4 weeks before the first lucitanib intake).
a. In addition, one prior scan of the measurable lesion(s) performed within maximum 3 months, if available, should be collected to assess tumour kinetics.
7. At least one prior treatment line in the advanced-metastatic setting (including chemotherapy and/or targeted therapy).
8. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
9. Ability to take oral medication.
10. Adequate bone marrow function: ANC ≥ 1.0 x 10E9/L, platelet counts ≥ 100 x 10E9/L and haemoglobin ≥ 9 g/dL.
11. Adequate renal function defined as: calculated clearance ≥ 60 mL/min (assessed with MDRD formula), proteinuria dipstick < 1+. If proteinuria dipstick ≥ 1+, urinary protein over 24 hours should be < 1.0 g/24hrs.
12. Adequate hepatic function defined as: AST, ALT ≤ 3 x UNL (≤ 5 x UNL in case of liver metastasis); bilirubin < 1.5 x UNL; ALP ≤ 2.5 x UNL (≤ 5 x UNL in case of bone metastasis).
13. Left ventricular ejection fraction (LVEF) ≥ 50% evaluated by cardiac ultrasound (ECHO) or Multi Gated Acquisition Scan (MUGA).
14. Full recovery (to Grade ≤ 1) from any prior surgical procedure(s) and from reversible side effects of prior therapy for cancer including radiation therapy, chemotherapy, and immunotherapy.
15. Negative serum pregnancy test during screening for women with childbearing potential within 7 days prior to the first lucitanib intake.
16. For men and women of child-bearing potential, use of a medically accepted method of contraception for the duration of the study and for 6 months after participation in the study.
17. Willingness and ability to give written informed consent and to comply with study procedures as described in section 13.3 of the protocol. |
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| E.4 | Principal exclusion criteria |
1. Known symptomatic central nervous system (CNS) metastases not controlled by prior surgery or radiotherapy and/or low dose steroids.
2. Active second malignancy or history of another malignancy within 2 years, with the exception of non-melanoma skin cancers or carcinoma in situ (CIS) of the breast or cervix or controlled, superficial carcinoma of the bladder.
3. Cyclical chemotherapy within a period of time that is shorter than the cycle length used for that treatment (e.g. 3 weeks for pemetrexed, cisplatin, navelbine, gemcitabine, docetaxel) before the first dose of lucitanib.
4. Biologic therapy within a period of time that is ≤ 5 T1/2 or ≤ 4 weeks (whichever is shorter) before the first dose of lucitanib.
5. Treatment with a small molecule therapeutics on a continuous or intermittent schedule within a period of time that is ≤ 5 T1/2 or ≤ 4 weeks (whichever is shorter) before the first dose of lucitanib.
6. Involvement in another therapeutic clinical trial at the same time or within 4 weeks prior to consent.
7. Wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks before the first dose of lucitanib.
8. Tumours that are invading or abutting a major vessel and/or tumours that are cavitary as assessed by CT or MRI.
9. History of major surgical procedure, open biopsy, or significant trauma within 28 days prior to consent.
10. A prior history of hemoptysis ≥ ½ teaspoon (2.5mL) of blood per day for a day or more within 1 week of study treatment.
11. History of gross hemoptysis within 3 months prior to enrolment.
12. History of coagulopathy or haemorrhagic disorders.
13. History of abdominal fistula, GI perforation, or intra-abdominal abscess within 3 month prior to enrolment.
14. Serious non-healing wound, ulcer, or bone fracture.
15. Uncontrolled hypertension (defined as supine systolic blood pressure ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg) despite optimized antihypertensive therapy.
16. Cardiovascular disease or conditions, including:
- Congestive heart failure (New York Heart Association functional classification ≥ 2) or requiring therapy.
- 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.
- Ventricular and/or supra-ventricular arrhythmia requiring therapy.
- Conduction disturbance including QTc prolongation (defined as a QTc interval > 450 ms according to Fridericia’s correction as observed by the investigator) or other significant ECG abnormalities including 2nd degree AV block type II, 3rd degree AV block or bradycardia (HR < 50 bpm); history of severe arrhythmia, or history of familial arrhythmia [e.g., Wolff-Parkinson-White syndrome]).
- Risk factors or unavoidable concomitant treatment with medications known to prolong QTc interval and that may be associated with Torsades de Pointes (see Appendix 4).
17. Patients with thromboembolic events < 12 months prior to treatment start or at high risk of such events.
18. Ongoing treatment with Warfarin or drugs highly bound to plasma protein (see Appendix 5).
19. Significant gastrointestinal abnormalities, including active ulcerative colitis, chronic diarrhoea associated with intestinal malabsorption, Crohn's disease, and/or prior surgical procedures affecting absorption or requirement for intravenous (IV) alimentation.
20. Serious/active bacterial, viral or fungal infection (including known active human immunodeficiency virus [HIV] infection) requiring systemic treatment.
21. 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.
22. Psychiatric disorder or altered mental status that would preclude understanding of the informed consent process and/or completion of the necessary study procedures.
23. Known hypersensitivity to gelatin or lactose monohydrate.
24. Pregnant or lactating women.
25. Men and women of child-bearing potential unable or unwilling to employ effective contraception during the study and for 6 months thereafter. Male patients whose sexual partners are women of child-bearing potential willing to use effective contraception during the study and for 6 months after the end of the study treatment are eligible. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective Response Rate (ORR): Proportion of patients in whom a confirmed Complete Response (CR) or a confirmed Partial Response (PR), as best overall response according to RECIST criteria, will be observed. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline and every 8 weeks (every 2 cycles) |
|
| E.5.2 | Secondary end point(s) |
- Efficacy:
● Clinical Benefit Rate (CBR): Proportion of patients in whom a confirmed CR or confirmed PR or a prolonged Stable Disease (SD) (> 6 months), as best overall response according to RECIST, will be observed.
● Progression Free Survival (PFS): Progression free survival will be calculated from the date of first drug intake until the date of progression or death due to any cause, whichever occurs first.
● Duration of response: Duration of response will be calculated among the responders (i.e. with best overall response CR or PR) from the time that measurement criteria are first met for complete or partial response until the date of progression or death due to any cause, whichever occurs first.
● Duration of clinical benefit: for responders and patients with SD as best overall response, time from the first drug intake until the date of progression or death for any cause.
● Overall Survival: from the date of first drug intake to the date of death for any cause.
● Tumour growth kinetics.
- Safety:
● Adverse events.
● Laboratory examinations (biochemistry, haematology and urinalysis).
● Physical examination and performance status (ECOG).
● Vital signs (blood pressure, heart rate, temperature and body weight).
● ECG parameters.
● LVEF by MUGA or cardiac ultrasound (ECHO).
- PK parameters of lucitanib.
- Pharmacogenomic approach of inter-patients variation in gene encoding ADME involved proteins.
-PD: soluble growth factors and other biomarkers, including circulating tumour DNA. |
|
| 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 Day 1 (pre-dose), Day 14, Day 28, Day 56, every 4 weeks thereafter and at end of study.
ECG - Screening or Day 1 (pre-dose), Day 14 (pre-dose, 2h and 3h after lucitanib intake), Day 28, Day 56, every 8 weeks thereafter and at end of study visit
LVEF - Screening or Day 1 (pre-dose), Day 28, Day 56, every 8 weeks thereafter and at end of study visit
PK - Day 14 (pre-dose, 1h , 2h and 3h after lucitanib intake) and Day 28 (pre-dose)
PG - Day 1 (pre-dose)
PD - Day 1 (pre-dose) and Day 14 (pre-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 | 2 |
| 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 | 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 Kingdom |
| United States |
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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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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