FIVE PRIME FIGHT

Étude de phase III ; double aveugle, contrôlée contre placebo évaluant FPA144 et le FOLFOX-6 modifié chez des patients atteints d'un cancer gastrique ou gastro-œsophagien avancé n'ayant reçu aucun traitement antérieur .

Critères d'inclusion :

1. Disease that is unresectable, locally advanced, or metastatic documented with radiographic imaging (preferred CT scan, MRI acceptable) of chest, abdomen and pelvis ≤ 28 days of enrollment

2. Understand and sign an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved informed consent form (ICF) prior to any study-specific evaluation

3. Life expectancy of at least 3 months in the opinion of the Investigator

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

5. Age 18 years at the time the ICF is signed

6. Negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test ≤ 72 hours prior to enrollment (women of childbearing potential only)

7. In sexually active patients (women of child bearing potential and males), willingness to use 2 effective methods of contraception, of which 1 must be a physical barrier method (condom, diaphragm, or cervical/vault cap) until 6 months after the last dose of FPA144. Other effective forms of contraception include:

 Permanent sterilization (hysterectomy and/or bilateral oophorectomy, or bilateral tubal ligation with surgery, or vasectomy) at least 6 months prior to Screening

 Women of childbearing potential who are on stable oral contraceptive therapy or intrauterine or implant device for at least 90 days prior to the study, or abstain from sexual intercourse as a way of living

8. Adequate hematological and biological function, confirmed by the following laboratory values: Bone Marrow Function  Absolute neutrophil count (ANC)  1.5 × 109 /L  Platelets > 100 × 109 /L  Hemoglobin  9 g/dL Hepatic Function  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 × upper limit of normal (ULN); if liver metastases, then < 5 × ULN

 Bilirubin< 1.5 × ULN Renal Function

 Calculated creatinine clearance  50 mL/min

9. Patients on full-dose anticoagulants must be on a stable dose of warfarin and have an international normalised ratio (INR) within the therapeutic range for the patient’s condition or be on a stable dose of low molecular weight heparin

10. Measurable or non-measurable disease

11. Tumor tissue for determination of FGFR2 status Patients enrolling into Phase 1 of the study must also meet the following inclusion criteria:

12. Histologically or cytologically confirmed GI malignancy for which mFOLFOX6 is considered an appropriate treatment (e.g., GC, colorectal carcinoma, pancreatic adenocarcinoma)

13. Patient must be a candidate to receive at least 2 doses of mFOLFOX6 chemotherapy Patients enrolling into Phase 3 of the study must also meet the following inclusion criteria:

14. Histologically documented gastric or gastroesophageal junction adenocarcinoma

15. FGFR2 overexpression as determined by IHC and/or FGFR2 amplification as determined by ctDNA blood assay

16. Patient must be a candidate for mFOLFOX6 chemotherapy

17. No prior chemotherapy for metastatic or unresectable disease (except a maximum of 1 dose of a platinum and fluoropyrimidine combination may have been administered while awaiting results of FGFR2 testing)

18. No prior platinum-based chemotherapy (except as noted in the Inclusion Criterion #17)

19. If prior adjuvant or neo-adjuvant therapy (chemotherapy and/or chemoradiation) has been received, more than 6 months must have elapsed between the end of adjuvant therapy and enrollment

Critères de non inclusion :

1. Untreated or symptomatic central nervous system (CNS) metastases. Patients with asymptomatic CNS metastases are eligible provided they have been clinically stable for at least 4 weeks and do not require intervention such as surgery, radiation, or any corticosteroid therapy for management of symptoms related to CNS disease

2. Impaired cardiac function or clinically significant cardiac disease, including any of the following:

 Unstable angina pectoris

6 months prior to enrollment

 Acute myocardial infarction

6 months prior to enrollment

 New York Heart Association class II-IV congestive heart failure

 Uncontrolled hypertension (as defined as ≥ 160/90 despite optimal medical management)

 Cardiac arrhythmia requiring anti-arrhythmic therapy other than beta blockers or digoxin

 Active coronary artery disease

 QTcF > 450 msec for males or > 470 msec for women

3. Peripheral sensory neuropathy

 Common Terminology Criteria for Adverse Events (CTCAE) grade 2

4. Active infection requiring systemic treatment or any uncontrolled infection

 14 days prior to enrollment

5. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, or known active or chronic hepatitis B or C infection

6. History of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis)

7. Evidence or history of bleeding diathesis or coagulopathy

8. Radiotherapy

 28 days of enrollment. Patients must be recovered from all radiotherapy-related toxicities. No radiopharmaceuticals (strontium, samarium) within 8 weeks of enrollment

9. Prior treatment with any selective inhibitor (e.g., AZD4547, BGJ398, JNJ-42756493, BAY1179470) of the FGF-FGFR pathway

10. Ongoing adverse effects from prior treatment > NCI CTCAE Grade 1 (with the exception of Grade 2 alopecia)

11. Participation in another therapeutic clinical study or receiving any investigational agent within 28 days of enrollment or during this clinical study

12. Corneal defects, corneal ulcerations, keratitis, keratoconus, history of corneal transplant, or other known abnormalities of the cornea that may pose a risk with FPA144 treatment

13. Positive HER2 status (as defined by a positive IHC test of 3+ or IHC of 2+ with positive FISH).

14. Major surgical procedures are not allowed 28 days prior to enrollment. Surgery requiring local/epidural anesthesia must be completed at least 72 hours before enrollment. In all cases the patient must be sufficiently recovered and stable before treatment administration

15. Women who are pregnant or breastfeeding (unless the patient is willing to interrupt breastfeeding during study treatment administration and then resume 6 months after study discontinuation); women of childbearing potential must not consider getting pregnant during the study

16. Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study (e.g., substance abuse, psychiatric disturbance, or uncontrolled intercurrent illness including, arterial thrombosis, and symptomatic pulmonary embolism)

17. Presence of any other condition that may increase the risk associated with study participation () or may interfere with the interpretation of study results, and, in the opinion of the Investigator, would make the patient inappropriate for entry into the study

18. Known allergy or hypersensitivity to components of the FPA144 formulation including polysorbate or to platinum-containing medications, fluorouracil, or leucovorin

19. History of prior malignancy except another malignancy that, in the Investigator’s opinion, would not affect the determination of study treatment effect No waivers of these inclusion or exclusion criteria will be granted.