Submitted by: John Michael Dominic Go 2017-06-29 00:00:00 Last Updated by: Jeverly Ann S. Principe 2017-07-03 09:15:12 Export to PDF

Phase I/II study of oral administration of S 49076 given in combination with gefitinib in patients with EGFR mutated advanced non-small-cell lung cancer who have progressed after treatment with EGFR tyrosine kinase inhibitor.

PHRR170703-001581

CL1-49076-003

2017-CT0402

Phase I/II study of oral administration of S 49076 given in combination with gefitinib in patients with EGFR mutated advanced non-small-cell lung cancer who have progressed after treatment with EGFR tyrosine kinase inhibitor.

This is a phase I/II international, multicenter, single arm, open-label, non-randomised and non-comparative study divided in two parts:

Phase I part: dose-finding study of S 49076 in combination with gefitinib (250mg q.d.). The purpose of the dose escalation Phase I part is to determine the Recommended Phase II Dose (RP2D) of S 49076 in combination with standard dose of gefitinib, based on the assessment of the Dose-Limiting Toxicities (DLTs).

Phase II part: activity study of S 49076 in combination with gefitinib. The purpose of this part is to evaluate the anti-tumor activity in several biomarker populations, of S 49076 given at the RP2D defined in the dose escalation phase I part with standard dose of gefitinib.

Regime Classification Priority
2010 - 2016 Health Technology Development Drug Discovery and Development
Start Date Duration in Months Target Completion Date Actual Completion Date
2017-10-01 26 2019-12-01 0000-00-00

Pending

Sites have not yet been initiated

Institution Classification Region LTO #
Servier Philippines, Inc. Private Business NCR CDRR-NCR-S-6
Institution Classification Region LTO #
INC Research Pte. Ltd. Private Business NCR CDRR-NCR-CRO-1
Institution Amount Region
Servier Philippines, Inc. N/A NCR
Name E-Mail Phone Number Postal Address
Marian Andaluz marian.andaluz@servier.com +632 8978990 loc 97 02 Orion Cor. Mercedes Sts., Bel-Air I Village, Makati City, 1209, Philippines
Name E-Mail Phone Number Postal Address
Jose Leandro L. Nuguid jose.nuguid@servier.com +65 6509 9811 67 Ubi Avenue 1, #06-08 StarHub Green, Singapore 408942
Name Expertise Affiliation
Rubi K. Li, MD Oncology St. Luke's Medical Center - Quezon City
Priscilla B. Caguioa, MD Oncology University Of Santo Tomas
Project Location Institutional Ethics Review Board
St. Luke's Medical Center - Quezon City St. Luke's Medical Center Institutional Ethics Review Committee
University Of Santo Tomas N/A

Non-Small Cell Lung Cancer

Evaluate the objective response rate (ORR) according to RECIST v1.1, in 3 subgroups of patients with locally advanced or metastatic NSCLC and treated with S 49076 and gefitinib defined according to the mechanism of acquired resistance to EGFR tyrosine kinase inhibitor (TKI):

•Subgroup 1: Moderate to high level of MET amplification and/or overexpression
•Subgroup 2: Moderate level of AXL overexpression
•Subgroup 3: High level of AXL overexpression.

An interim analysis will be performed in each subgroup to stop the recruitment early for futility if it is clear that the association S 49076 and gefitinib is unlikely to show the expected benefit.
 

• Evaluate the survival rate at 6 months, the progression-free survival (PFS), the response duration, the Clinical Benefit Rate (CBR) in the 3 subgroups of patients. Clinical benefit rate is defined as the proportion of patients who have confirmed Complete Response (CR) or Partial Response (PR) as best response, or who experience Stable Disease (SD) lasting at least 6 months in the 3 subgroups of patients.
• Characterize the safety and tolerability of the combination in assessing incidence of adverse events (AEs) according to CTCAE V4.0.
• Collect additional information on the PK profile of S 49076 in combination with gefitinib.
• Evaluate the biomarkers potentially predictive of response using archived tumour or newly performed biopsy.

Pending

  • Australia
  • Canada
  • China
  • Germany
  • Hungary
  • Italy
  • Japan
  • Philippines
  • Russia
  • Singapore
  • South Korea
  • Spain
  • Taiwan
  • Thailand
  • United Kingdom

Clinical Trial

20170329145915

2017-05-31

None

Demographic characteristics
1. Male or female patient aged  18 years old, or legal age of the majority in the country.

Disease characteristics
2. Histologically or cytologically confirmed stage IIIB/IV NSCLC (locally advanced or metastatic, noneligible for radical chemoradiotherapy or surgery with curative intention).
3. Progression will have occurred on single agent EGFR TKI treatment (erlotinib, gefitinib, icotinib, afatinib) in the 1st line setting or in the 2nd line (after a first line of chemotherapy).
4. Patients must have measurable tumour disease according to RECIST v1.1 (with at least one measurable lesion).
5. Patients must meet definition of acquired resistance based on the modified Jackman criteria as follows:
5.1 Previously received treatment with a single-agent EGFR TKI (erlotinib, gefitinib, icotinib, afatinib).
5.2 EGFR activating mutation positive (EGFRm) determined at the time of progression after EGFR TKI therapy and within 6 weeks prior to the inclusion.
5.3 Objective clinical benefit from treatment with an EGFR TKI as defined by either: documented partial response or complete response (based on RECIST v1.1 or WHO), or significant and durable (≥ 6 months) clinical benefit (stable disease as defined by RECIST v1.1 or WHO) after initiation of EGFR TKI.
5.4 Documented disease progression (based on RECIST v1.1 or WHO) while on continuous treatment with EGFR TKI within the last 30 days prior to the inclusion.
5.5 No intervening systemic therapy between EGFR TKI cessation and inclusion.
5.6 For patients treated with gefitinib, gefitinib should not be interrupted before inclusion. For patients treated with erlotinib, afatinib or icotinib, a wash-out period for at least 5 half lives
is required (not exceeding 15 days).
6. Blood samples and archival and/or fresh biopsy tissue sample after progression with EGFR TKI should be available within 6 weeks prior to the inclusion.
7. Patient must have T790M negativity and one of the following criteria as assess after central analysis:
7.1 Moderate to high MET amplification evidenced by fluorescence in situ hybridization (FISH) and/or high overexpression evidenced by immunohistochemistry (IHC), or
7.2 Moderate to high AXL overexpression evidenced by IHC.
8. Block or 9 slides of tissue sample (with a minimum of 6 slides) obtained at the time of progression should be available for the central analysis.
Medical and therapeutic criteria
9. Ability to take oral medication.
10. Estimated life expectancy > 12 weeks.
11. Eastern Cooperative Oncology Group (ECOG) (Appendix 9) performance status ≤ 1.
12. Adequate haematological, renal and hepatic functions within 7 days prior to the inclusion, defined as:
12.1 Absolute neutrophil count (ANC) 1.5 x 109/L.
12.2 Haemoglobin ≥ 9g/dL.
12.3 Platelets 100 x 109/L.
13. Creatinine clearance ≥ 50 mL/min/1.73 m² (assessed with Cockroft & Gault) based on the last assessment performed within 7 days prior to the inclusion.
14. ASAT and ALAT £ 3 x local ULN based on the last assessment performed within 7 days prior to the inclusion.
15. Total bilirubin < 1.5 x local ULN (except Gilbert disease confirmed by the UGT1A1 polymorphism analysis) based on the last assessment performed within 7 days prior to the inclusion.
16. Kaliemia within the local normal range (with or without potassium supply) based on the last assessment performed within 7 days prior to the inclusion.
17. Magnesemia within the local normal range (with or without magnesium supply) based on the last assessment performed within 7 days prior to the inclusion.
18. Any toxicity related to prior EGFR TKI must have resolved to Grade 1 or less.
19. Patients must use effective contraception:
19.1 In case patient is a woman of childbearing potential: woman must have been tested negative in a serum pregnancy test within 7 days prior to the first day of test drug administration and must use highly effective methods of birth control defined as those alone or in combination that result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectable, combined oral contraceptives, some intra-uterine devices (IUDs), or vasectomized partner during the study, starting at least 1 month prior to the first test drug administration and lasting at least 3 months after the last dose of test drug.
19.2 In case patient is a man: man must be either vasectomized or use effective contraception such as condom. In this last case, the partner of childbearing potential must use highly effective methods of birth control defined as those alone or in combination that result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly, starting at least 1 month prior to the first test drug administration and lasting at least 3 months after the last dose of test drug for both sexes.

General criteria
20. Written informed consent form should have been read and signed by patients before any trial procedures.

Non-inclusion criteria:
General criteria
21. Foreseeable poor compliance to the study procedures.
22. Legally incapacitated person under guardianship or trusteeship.
23. Pregnant or breast-feeding women.
24. Unable to undergo CT scans or MRI.
25. Involvement in another therapeutic interventional trial at the same time or within five half-life prior to the inclusion. In case of involvement in a non-interventional clinical trial (e.g. epidemiological study), inclusion in the present study is possible.

Medical and therapeutic criteria
26. Patients who have received more than 1 line of chemotherapy and more than 1 line of erlotinib, gefitinib, icotinib or afatinib.
27. Blood transfusion within 2 weeks prior to the inclusion.
28. Major surgery within 4 weeks prior to the inclusion.
29. Prior radiotherapy within 4 weeks prior to the inclusion.
30. Prior treatment with a tyrosine kinase inhibitor (TKI, including HGF or MET or AXL pathway inhibitors) except EGFR TKI.
31. Symptomatic central nervous system (CNS) metastases that are neurologically unstable or requiring increasing doses of steroids to control CNS disease within 4 weeks before inclusion.
32. Concomitant uncontrolled infection or severe systemic disease (at the discretion of the investigator).
33. In the investigator’s opinion, significant malabsorption syndrome, significant chronic digestive or gastrointestinal inflammatory syndrome, history of bleeding ulcer within 4 weeks prior to the inclusion.
34. Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study (e.g., unstable or uncompensated respiratory, cardiac, hepatic or renal disease, deep venous/arterial thrombosis and symptomatic pulmonary embolism).
35. Uncontrolled diabetes mellitus even under treatment.
36. Known positive test for HIV.
37. Cardiovascular disorders, including any of the following:
37.1 Uncontrolled high blood pressure even under treatment (SBP ≥ 160 or DBP ≥ 100 mm Hg).
37.2 Within 6 months prior to inclusion, history of: New York Heart Association (NYHA) grade 2 or greater congestive heart failure, acute coronary syndromes (including unstable angina and
myocardial infarction), uncontrolled angina, coronary angioplasty, and/or stenting, ischemic/haemorrhagic stroke, atrial fibrillation.
37.3 LVEF < 55% as assessed by echocardiogram performed within 14 days of inclusion.
37.4 QTc prolongation (defined as a QTc interval ≥ 450 ms (males) or ≥ 470 ms (females) according to Fridericia’s correction after central reading) or other significant ECG abnormalities, e.g. atrial fibrillation, 2nd degree AV block type II, 3rd degree AV block, or bradycardia (HR < 50 bpm), or any history of 2nd type II or 3rd degree block, using the analysis of an ECG performed within 7 days of inclusion.
38. Patients who are receiving medications known to prolong QTc interval and that may be associated with Torsades de Pointes within 5 half-life prior to inclusion.
39. History of congenital long QT syndrome.
40. Cardiac Troponin (cTn) I (or T if cTnI is not available) > 2 x local UNL.
41. Patients who are receiving anticoagulant oral drugs (Vitamin K antagonist), aspirin associated with clopidogrel, aspirin associated with prasugrel. Patients receiving rivaroxaban, dabigatran, apixaban or edoxaban. Low-molecular-weight heparin as well as clopidogrel or prasugrel alone are permitted.

Non-inclusion criteria related to S 49076 and gefitinib administration
42. Patients treated by strong inhibitors and/or inducers cytochrome P450 3A4 within 5 half-life before the inclusion.
46. Patients treated with rosuvastatin within 5 half-lives prior to the inclusion.

Non-inclusion criteria related to gefitinib administration
43. Known hypersensitivity to any component of gefitinib.
44. Any significant ophthalmologic abnormality.
45. Known pre-existing interstitial lung disease or idiopathic pulmonary fibrosis.

Interventional

S 49076 and Gefitinib

S 49076 and gefitinib will be given orally once daily (q.d.) on a continuous schedule of 28-day cycles, in fasting conditions.
S 49076 will be supplied as tablets of 100 mg strength for oral administration, presented as 1 small box of 1 bottle containing 30 tablets.
Gefitinib will be supplied as tablets of 250 mg strength for oral administration presented as a box containing 3 PVC/aluminium blisters of 10 film coated tablets.
 

Non-randomized

Open Label

Unspecified

Parallel

The purpose of the Phase II part is to evaluate the anti-tumor activity in several biomarker populations, of S 49076 given at the RP2D defined in the dose escalation phase I part with standard dose of gefitinib.
 

Phase I/II

6

Unspecified

Unspecified

01 Oct 2017

Utilization Utilization Info
No records found.

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