Clinical Trials /

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

NCT04193553

Description:

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.

Related Conditions:
  • Gastrointestinal Stromal Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: A Multicentre, Comparative, Placebo-controlled, Double-blinded, Phase II Study of the Efficacy of Lenvatinib in Patients With Locally Advanced or Metastatic GIST After Failure of Imatinib and Sunitinib

Clinical Trial IDs

  • ORG STUDY ID: ET18-291 - LENVAGIST
  • NCT ID: NCT04193553

Conditions

  • Gastro Intestinal Stromal Tumour

Interventions

DrugSynonymsArms
LenvatinibLenvatinib + Best Supportive Care
PlaceboPlacebo + Best Supportive Care

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Lenvatinib + Best Supportive CareExperimental
  • Lenvatinib
Placebo + Best Supportive CarePlacebo Comparator
  • Placebo

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-Free Survival (PFS)
Time Frame:Up to 30 months
Safety Issue:
Description:PFS, defined as the time from the date of randomisation to the date of the first documented radiological progression (RECIST 1.1) or death due to any cause. PFS will be estimated using the Kaplan-Meier method and will be described in terms of median PFS per arm, and hazard ratio for progression between the 2 arms. Associated 2-sided 95% CI for the estimates will be provided.

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:Up to 30 months
Safety Issue:
Description:OS, is defined as the time from the date of randomisation until the date of death due to any cause. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive.
Measure:Objective Response Rate (ORR) for patient in the blinded part of the study
Time Frame:Up to 30 months
Safety Issue:
Description:ORR, is the proportion of patients with a Complete Response or Partial Response as Best Overall Response.
Measure:Best Overall Response (BOR) for patient in the blinded part of the study
Time Frame:Up to 30 months
Safety Issue:
Description:BOR, is described as the proportion of patients with a best overall response of Complete Response, Partial Response, Stable Disease or Progressive Disease.
Measure:Quality of Life (QoL) for patient in the blinded part of the study
Time Frame:Up to 30 months
Safety Issue:
Description:QoL, will be assessed using the EORTC QLQ-C30. Scores will be calculated at each time point according to the scoring manuals. Descriptive statistics will be used to evaluate baseline scores and evolution of scores from baseline to each time point. Data will be compared between arms using the Student's t-test.
Measure:Patient's tolerance to treatment
Time Frame:Up to 30 months
Safety Issue:
Description:The safety will be described mainly on the frequency of adverse events coded using the common toxicity criteria (NCI-CTCAE v5.0) grade. Descriptive statistics will be provided for characterizing and assessing patient tolerance to treatment. Adverse events will be coded according to the MedDRA®.
Measure:Progression-Free Survival (PFS) In patients from the placebo arm who switched into the active treatment group
Time Frame:Up to 30 months
Safety Issue:
Description:OS, is defined as the time from the date of randomisation until the date of death due to any cause. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Centre Leon Berard

Trial Keywords

  • Gastro Intestinal Stromal Tumour
  • Locally advanced or metastatic
  • Tyrosine kinase inhibitors

Last Updated

April 15, 2020