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

  • End date
    Mar 9, 2023
  • participants needed
  • sponsor
    Centre Leon Berard
Updated on 9 August 2021


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.

Condition Gastro Intestinal Stromal Tumour
Treatment Placebo, Best supportive care, Lenvatinib
Clinical Study IdentifierNCT04193553
SponsorCentre Leon Berard
Last Modified on9 August 2021


Yes No Not Sure

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
I5. Patient must have evidence of measurable disease as per the RECIST version
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
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
Total bilirubin 1.5 X ULN
AST and ALT 2.5 X ULN
Serum creatinine 1.5 mg/dl (133 mol/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
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
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
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
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