Multicentre Placebo-controlled Double-blinded Phase II Study of Lenvatinib Efficacy in Patients With Locally Advanced or Metastatic GIST (Gastrointestinal Stromal Tumor) After Imatinib/Sunitinib Failure
Multicentre Placebo-controlled Double-blinded Phase II Study of Lenvatinib Efficacy in Patients With Locally Advanced or Metastatic GIST (Gastrointestinal Stromal Tumor) After Imatinib/Sunitinib Failure
The primary objective is to compare the efficacy of lenvatinib plus Best Supportive Care
 versus Placebo plus Best Supportive Care in the treatment of patients with advanced GIST,
 after failure of imatinib and sunitinib.
Even though the prognosis of advanced GIST has been tremendously improved by the introduction
 of tyrosine kinase inhibitors, the vast majority of patients will develop secondary
 resistance to these agents.

 The therapeutic options of patients with advanced GIST with resistance (or intolerance) to
 imatinib and sunitinib remain then very limited and prognosis of patients are very poor.

 Nilotinib has an inferior activity in first line setting as compared to imatinib. Sorafenib
 has been evaluated in off-label and compassionate use studies with a median PFS close to 3 to
 4 months, and a median overall survival close to 9 months with few prolonged tumor control
 and limited availability.

 Regorafenib was tested in a phase II and a randomized phase III trial (GRID) in this setting
 , and provided a significant PFS advantage with no significant improvement in OS.

 There are no recognized standard options in patients whose tumors progress after 3 or more
 TKIs. The recently updated guidelines from ESMO in 2014, included the reintroduction of
 imatinib in an attempt to control the progression of the sensitive cell clones, and on the
 basis of the results of the RIGHT study.

 This is therefore a situation with a clear unmet medical need.

 Lenvatinib is a broad spectrum TKI targeting oncogenes KIT and RET and receptor tyrosine
 kinases, PDGFRA, VEGFR 1-3 and FGFR 1-4. It has demonstrated activity in iodine resistant
 metastatic thyroid cancers. Whether lenvatinib would be a useful agent in patients with GIST
 is not known but there is a rationale to investigate its activity in patients with advanced
 GIST.

 In the present study, we propose to analyze the antitumor activity of lenvatinib in patients
 with GIST failing to at least imatinib and sunitinib in a randomized setting, vs placebo.
Inclusion Criteria:

 I1. Male or female ≥ 18 years at the day of consenting to the study.

 I2. Patient must have histologically confirmed diagnosis of GIST.

 I3. Disease must be locally advanced or metastatic.

 I4. Patient who failed (disease progression and/or intolerance) previously at least to
 imatinib and sunitinib.

 Nota Bene: patients with more than 2 previous anticancer treatments are eligible.

 I5. Patient must have evidence of measurable disease as per the RECIST version 1.1
 (Appendix 2).

 I6. Patient must have documented disease progression. I7. ECOG performance status 0, 1 or 2
 (Appendix 3).

 I8. Patient must have normal organ and bone marrow function as defined below:

 -  Hematologic

 -  Absolute neutrophil count (ANC) ≥ 1.5 Gi/L

 -  Haemoglobin ≥ 9 g/dl (5.6 mmol/l) (subjects may not have had a transfusion within
 7 days of screening assessment)

 -  Platelets ≥ 100 Gi/l

 -  Coagulation panel

 -  Prothrombin time (PT) or international normalized ratio (INR) ≤ 1.2 X upper limit
 of normal (ULN)

 -  Partial thromboplastin time (PTT) ≤ 1.2 X ULN Subjects receiving anticoagulant
 therapy are eligible if their INR is stable and within the recommended range for
 the desired level of anticoagulation.

 -  Hepatic

 -  Total bilirubin ≤ 1.5 X ULN

 -  AST and ALT ≤ 2.5 X ULN

 -  Renal

 -  Serum creatinine ≤ 1.5 mg/dl (133 µmol/l) Or, if greater than 1.5 mg/dl:
 calculated creatinine clearance ≥ 50 ml/min

 -  Urine Protein to Creatinine ratio (UPC) < 1; If UPC > 1, then a 24-hour urine
 protein must be assessed. Subjects must have a 24-hour urine protein value <1g.

 I9. Patient and his/her partner using an effective contraception as defined in Appendix 1.

 I10. Patient able to understand and willingness for follow-up visits. I11. Patient covered
 by a medical insurance. I12. Signed and dated informed consent document indicating that the
 patient has been informed of all the pertinent aspects of the trial prior to any
 study-specific procedure.

 Exclusion Criteria:

 E1. Patient with a documented mutation in PDGFRA exon 18 (D842V substitution).

 E2. Clinically significant gastrointestinal abnormalities that may increase the risk for
 gastrointestinal bleeding including, but not limited to:

 -  Active peptic ulcer disease

 -  Known intraluminal metastatic lesions with risk of bleeding

 -  Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other
 gastrointestinal conditions with increased risk of perforation

 -  History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
 within 28 days prior to beginning study treatment

 -  Clinically significant gastrointestinal abnormalities that may affect absorption of
 investigational product including, but not limited to:

 -  Malabsorption syndrome

 -  Major resection of the stomach or small bowel.

 E3. Any active/uncontrolled infection, including known infection with HIV, Hepatitis B or
 Hepatitis C.

 E4. Corrected QT interval (QTc) > 480 msecs using Bazett's formula

 E5. History of any one or more of the following cardiovascular conditions within the past 6
 months prior to the first dose of study drug:

 -  Cardiac angioplasty or stenting

 -  Myocardial infarction

 -  Unstable angina

 -  Coronary artery bypass graft surgery

 -  Symptomatic peripheral vascular disease

 -  Class III or IV congestive heart failure, as defined by the New York Heart Association
 (NYHA) classification.

 E6. Poorly controlled arterial hypertension (Systolic blood pressure: 150mmHg / Diastolic
 blood pressure: 90mmHg).

 Note: Patients with high blood pressure can be enrolled provided that the hypertension is
 well controlled at a stable dose of antihypertensive therapy for at least 1 week prior to
 lenvatinib start).

 E7. Prior major surgery or trauma within 28 days prior to first dose of study drug and/or
 presence of any non-healing wound, fracture, or ulcer (procedures such as catheter
 placement not considered to be major).

 E8. Evidence of active bleeding or bleeding diathesis. E9. Known endobronchial lesions
 and/or lesions infiltrating major pulmonary vessels.

 E10. Clinically significant haemoptysis within 8 weeks of first dose of study drug.

 E11. Any serious and/or unstable pre-existing medical, psychiatric, or other condition
 (geographic, social…) that could interfere with subject's safety, provision of informed
 consent, or compliance to study procedures.

 E12. Unable or unwilling to discontinue use of prohibited medications list in Section 6.3
 for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first
 dose of study drug and for the duration of the study.

 E13. Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is
 progressing in severity, except alopecia.

 E14. Inability to swallow E15. Any contraindication to Lenvima®, according to its Summary
 of Product Characteristics E16. History of hypersensitivity or allergic reactions
 attributed to compounds of similar chemical or biologic composition of lenvatinib E17.
 Clinically significant unrelated systemic illness (e.g., serious infection or significant
 cardiac, pulmonary, hepatic, or other organ dysfunction) that would compromise the
 patient's ability to tolerate study treatment or would likely interfere with study
 procedures or results.

 E18. Pregnant or breastfeeding women. Women of childbearing potential (Appendix 1) are
 required to have a negative serum pregnancy test within 72 hours prior to study treatment
 start. A positive urine test must be confirmed by a serum pregnancy test Note: Female if
 applicable, subjects should discontinue breast-feeding prior to the first dose of study
 drug and should refrain from breastfeeding throughout the treatment period and for 14 days
 following the last dose of study drug.

 E19. Patient under tutorship or curatorship.