Clinical Trials /

LEE001 and Chemoembolization In Patients With Advanced Hepatocellular Carcinoma

NCT02524119

Description:

The purpose of this study is determine whether the combination therapy with LEE011 and chemoembolization in patients with locally advanced Hepatocellular Carcinoma not amenable to curative therapies will provide greater efficacy than chemoembolization alone with a tolerable safety profile.

Related Conditions:
  • Hepatocellular Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: LEE001 and Chemoembolization In Patients With Advanced Hepatocellular Carcinoma
  • Official Title: A Phase Ib/II Study of LEE011 and Chemoembolization In Patients With Advanced Hepatocellular Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: STU 052015-073
  • NCT ID: NCT02524119

Conditions

  • Hepatocellular Carcinoma

Interventions

DrugSynonymsArms
LEE011LEE001 with Chemoembolization

Purpose

The purpose of this study is determine whether the combination therapy with LEE011 and chemoembolization in patients with locally advanced Hepatocellular Carcinoma not amenable to curative therapies will provide greater efficacy than chemoembolization alone with a tolerable safety profile.

Detailed Description

      Single-arm, single-institution, non-randomized, open-label phase II study to determine the
      efficacy and safety of treatment with LEE011 and chemoembolization in patients with advanced
      HCC (Hepatocellular Carcinoma) not amenable to curative therapies. A total of 40 patients
      will be enrolled and undergo chemoembolization. Patients will receive LEE011 (600 mg PO once
      daily, 3 weeks on/1 week off) on Day 1 with chemoembolization. Patients can receive a total
      of 4 chemoembolization treatments within 6 month following first treatment as needed to treat
      initial HCC (Hepatocellular Carcinoma) lesion.

      Progression free survival will be based on tumor assessment using RECIST 1.1 criteria
      (Response Evaluation Criteria in Solid Tumors) Patients will receive trial treatment until
      disease progression, unacceptable toxicity, death or discontinuation from the study treatment
      for any other reason. Patients will be followed for survival regardless of treatment
      discontinuation for any reason.

      The study will include men and women with locally advanced HCC (Hepatocellular Carcinoma) not
      amenable to curative therapy who have received no prior therapy for advanced disease.

      Investigational Therapy:

      LEE011 oral (3 weeks on/1 week off) in combination with chemoembolization.

      Efficacy Assessments:

        1. Dynamic contrasted abdominal computed tomography or magnetic resonance imaging will be
           done at baseline, every 8 weeks, and every 3 months thereafter following initial
           chemoembolization.

        2. Chest CT imaging as clinically indicated

        3. Survival status every 12 months (or earlier if required) regardless of treatment
           discontinuation reason

      Data Analysis:

      The primary endpoint of the trial will be progression free survival (PFS) of HCC patients.
      PFS is defined to be the time from initiation of treatment to progression or death without
      evidence of progression. For cases without documentation of progression, follow-up will be
      censored at the date of last disease assessment without progression, unless death occurs
      within 4 months following the date of last progression-free, in which case death will be
      counted as an event. The historical median PFS for TACE (Transcatheter arterial
      chemoembolization) alone is 8-10 months. This study will target a hazard ratio of 0.69 with
      an 80% power and a one-sided significance level of 10%. Assuming a 24-month accrual and an
      18-month follow-up period the study requires 38 patients initiating LEE011 treatment with the
      median PFS for TACE alone is 8 months, and 41 patients with the median PFS for
      TACE(Transcatheter arterial chemoembolization) alone is 10 months. PFS will be estimated
      using the Kaplan-Meier method, and Greenwood's formula will be used to calculate the standard
      error of the corresponding Kaplan-Meier estimate and 95% confidence interval. Survival curves
      will be estimated using Kaplan-Meier methodology.

      Secondary endpoints of efficacy are to evaluate OS (Overall Survival). The statistical
      methods used for the analysis of PFS will be used for the analysis of OS.

      Other secondary objectives will include description of toxicity of the therapy regimen. These
      data will be analyzed separately. The safety analyses will be performed on all patients who
      receive any dose of therapy. Adverse events will be described using the NCI CTCAE v 4.03
      criteria (ctep.cancer.gov/forms.CTCAEv4.pdf). Frequency and severity of adverse events
      according to the NCI CTCAE ) v 4.03 (Common Terminology Criteria for Adverse Events) body
      system and severity criteria will be described. In addition, frequency of Grade 3 or 4
      adverse events will be described separately. Causality will also be noted. Adverse events
      will be recorded for up to 1 year following discontinuation from study. Response rate and
      toxicity rate will be estimated using an exact binomial method along with the 95% confidence
      interval
    

Trial Arms

NameTypeDescriptionInterventions
LEE001 with ChemoembolizationExperimentalA total of 40 patients will be enrolled and undergo chemoembolization. Patients will receive LEE011 (600 mg PO once daily, 3 weeks on/1 week off) on Day 1 with chemoembolization. Patients can receive a total of 4 chemoembolization treatments within 6 month following first treatment as needed to treat initial HCC lesion.
  • LEE011

Eligibility Criteria

        Inclusion Criteria:

          1. Patient must have a histologically confirmed diagnosis of RB positive hepatocellular
             carcinoma

          2. Patients must have HCC limited to the liver. There must be no clinical or radiographic
             evidence of extrahepatic HCC. Portal lymphadenopathy is permitted as lymphadenopathy
             is commonly associated with cirrhosis unrelated to malignancy;

          3. Absence of occlusive main portal vein thrombus, branch venous thrombus is allowed;

          4. Patients with locally advanced HCC not eligible for curative therapies;

          5. Age ≥ 18 years;

          6. Child-Pugh Score A or B7;

          7. ECOG (Eastern Cooperative Oncology Group) Performance score of 0-2;

          8. Life expectancy greater than 6 months;

          9. Following baseline laboratory values:

         10. Total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤1.5 x ULN in patients with
             well-documented Gilbert's Syndrome;

         11. INR (international normalized ratio) ≤ 1.7;

         12. Hgb ≥ 9.0 g/dl;

         13. Alkaline Phosphatase, AST (Aspartate Aminotransferase), ALT (Alanine Aminotransferase)
             <7 times ULN;

         14. Platelet count ≥ 75,000/mm3;

         15. Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 50 mL/min;

         16. Absolute neutrophil ≥ 1,500 cells/mm3;

         17. Potassium, total calcium (corrected for serum albumin), magnesium, and phosphorus
             within normal limits for the institution or corrected to within normal limits with
             supplements before first dose of study medication

         18. Sodium >130 meq/L;

         19. Women of childbearing potential must have a negative pregnancy test;

         20. Prior therapy is allowed provided the following are met: at least 4 weeks since prior
             locoregional therapy including surgical resection, chemoembolization, radiotherapy, or
             ablation. Provided target lesion has increased in size by 25% or more or the target
             lesion was not treated with locoregional therapy;

         21. Must be able to swallow LEE011 capsules.

        Exclusion Criteria:

          1. Patient who received any CDK4/6 inhibitor (cyclin-dependent kinase 4);

          2. Patient who has received previous systemic therapy;

          3. Patients with central nervous system (CNS) involvement, unless they meet ALL of the
             following criteria:

          4. At least 4 weeks from prior therapy completion (including ration and/or surgery) to
             starting the study treatment;

          5. Clinically stable CNS tumor at the time of screening and not receiving steroids and/or
             enzyme-inducing anti-epileptic medications for brain metastases;

          6. Clinically significant, uncontrolled heart disease and/or recent events including any
             of the following:

          7. History of acute coronary syndromes (including myocardial infarction, unstable angina,
             coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic
             pericarditis within 12 months prior to screening;

          8. History of documented congestive heart failure (New York Heart Association functional
             classification III-IV);

          9. Documented cardiomyopathy;

         10. Patient has a left ventricular ejection fraction <50% as determined by MUGA (Multi
             Gated Acquisition scan) or ECHO at screening;

         11. History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal
             arrythmias, or conduction abnormality within 12 months of screening;

         12. Bradycardia (heart rate <50 at rest), by ECG or pulse, at screening;

         13. Congenital long QT syndrome or family history of long QT syndrome;

         14. Systolic Blood Pressure (SBP) >160 or <90 mm Hg;

         15. On screening inability to determine the QTcF (Fridericia Correction Formula) interval
             on the ECG (i.e.: Unreadable or Not Interpretable) or QTcF > 450 msec (using
             Fridericia's correction). All as determined by screening ECG (mean of triplicate
             ECGs);

         16. Patient is currently receiving any of the following medications and cannot be
             discontinued 7 days prior to treatment (see appendix 1 for details):

         17. Known strong inducers or inhibitors of CYP3A4/5 (a member of the cytochrome P450),
             including grapefruit, grapefruit hybrids, pomelo, star-fruit, and Seville oranges;

         18. That have a known risk to prolong the QT interval or induce Torsades de Pointes

         19. Herbal preparations/medications, dietary supplements;

         20. That have a narrow therapeutic window and are predominantly metabolized through
             CYP3A4/5;

         21. Tumor involvement > 50% of the liver;

         22. Patient has a known history of HIV infection (testing is not required);

         23. Patient has any other concurrent sever and/or uncontrolled medical condition that
             would, in the investigator's judgment, cause unacceptable safety risks, contraindicate
             patient participation in the study or compromise compliance with the protocol (e.g.
             chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled
             fungal, bacterial, or viral infections, etc.);

         24. Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks to
             starting study drug, or who have not fully recovered from side effects of such
             treatment

         25. The following uses of corticosteroids are permitted: single doses, topical
             applications (e.g.: for rash), inhaled sprays (e.g.: for obstructive airways
             diseases), eye drops or local injections (e.g.: intra-articular);

         26. Patient is currently receiving warfarin or other Coumadin-derived anticoagulant for
             treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight
             heparin (LMWH) or fondaparinux is allowed;

         27. Participation in a prior investigational study within 30 days prior to enrollment or
             within 5 half-lives of the investigational product, whichever is longer;

         28. Patient who has received radiotherapy ≤ 4 weeks or limited field radiation for
             palliation ≤ 2 weeks prior to starting study drug, and who has not recovered to grade
             1 or better from related side effects of such therapy (exceptions include alopecia)
             and/or in whom ≥ 30-25% of the bone marrow was irradiated;

         29. Patient has had major surgery within 14 days prior to starting study drug or has not
             recovered from major side effects (tumor biopsy is not considered as major surgery);

         30. Patient has not recovered from all toxicities related to prior anticancer therapies to
             NCI-CTCAE version 4.03 Grade <1 (Exception to this criterion: patients with any grade
             of alopecia are allowed to enter the study);

         31. Patient has a known hypersensitivity to any of the excipients of LEE011;

         32. Prior ablative, radiation, resection, or transplant therapies less than 4 weeks before
             study registration;

         33. Active gastrointestinal bleeding;

         34. Allergy to iodine or gadolinium contrast that cannot be safely controlled with
             premedication;

         35. Concurrent malignancy or malignancy within 3 years of study entry, with the exception
             of adequately treated basal or squamous cell carcinoma, non-melanomatous skin cancer
             or treated cervical cancer;

         36. Contraindication to angiography or chemoembolization medications;

         37. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
             female after contraception and until the termination of gestation, confirmed by a
             positive hCG (Human chorionic gonadotropin) laboratory test;

         38. Women of child-bearing potential, defined as all women physiologically capable of
             becoming pregnant, unless they are using highly effective methods of contraception
             throughout the study and for 8 weeks after study drug discontinuation. Highly effected
             contraception methods include:

         39. Total abstinence when this is in line with the preferred and usual lifestyle of the
             patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
             methods) and withdrawal are not acceptable methods of contraception

         40. Female sterilization (have had surgical bilateral oophorectomy with or without
             hysterectomy) or tubal ligation at least six weeks before taking study treatment. In
             case of oophorectomy alone, only when the reproductive status of the woman has been
             confirmed by follow up hormone level assessment

         41. Male sterilization (at least 6 months prior to screening). For female patients on the
             study, the vasectomized male partner should be the sole partner for that patient.

         42. Combination of any of the two following (a+b or a+c or b+c) 43A-Use of oral, injected
             or implanted hormonal methods of contraception or other forms of hormonal
             contraception that have comparable efficacy (failure rate <1%), for example hormone
             vaginal ring or transdermal hormone contraception; 45 B-Placement of an intrauterine
             device (IUD) or intrauterine system (IUS); 45 C-Barrier methods of contraception:
             Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal
             foam/gel/film/cream/ vaginal suppository in case of use of oral contraception, women
             should have been stable on the same pill before taking study treatment.

        Note: Oral contraceptives are allowed but should be used in conjunction with a barrier
        method of contraception due to unknown effect of drug-drug interaction. Women are
        considered post-menopausal and not of child bearing potential if they have had 12 months of
        natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age
        appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy
        (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of
        oophorectomy alone, only when the reproductive status of the woman has been confirmed by
        follow up hormone level assessment is she considered not of child bearing potential.

        46-Sexually active males, unless they use a condom during intercourse while taking the
        drug, and for 21 days after stopping treatment of LEE011 -- should not father a child in
        this period. A condom is required to be used also by vasectomized male in order to prevent
        delivery of the drug via seminal fluid.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival
Time Frame:Every 8 weeks for up to 3 years.
Safety Issue:
Description:CT Chest scans must be performed at baseline. CT-Chest/abdomen/pelvis must be performed every 8 weeks during the treatment phase (12 months). Once the patient has been discontinued from the study and enters the efficacy phase, radiological assessment (CT or MRI) will continue every 8 weeks until progression or for the first 12 months, whichever comes first. After a year, radiological (CT or MRI) assessments will be performed every 12 weeks for up to 1 year.

Secondary Outcome Measures

Measure:Survival
Time Frame:Every 12 weeks for up to 3 years.
Safety Issue:
Description:CT Chest scans must be performed at baseline. CT-Chest/abdomen/pelvis must be performed every 8 weeks during the treatment phase (12 months). Once the patient has been discontinued from the study and enters the efficacy phase, radiological assessment (CT or MRI) will continue every 8 weeks until progression or for 3 years, whichever comes first. After a year, radiological (CT or MRI) assessments will be performed every 12 weeks for up to 3year.
Measure:Safety measured by adverse events
Time Frame:Each visit for up to 3 years
Safety Issue:
Description:The safety of LEE in combination with chemoembolization will be measured by adverse events.
Measure:Tolerability measured by adverse events
Time Frame:At each patient visit while on LEE001 for up to 3 years
Safety Issue:
Description:The tolerability of LEE in combination with chemoembolization will be measured by adverse events.
Measure:Treatment Response (Tumor assessments)
Time Frame:Every 8 weeks for 3 years
Safety Issue:
Description:Tumor assessments every 8 weeks for 3 years.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Texas Southwestern Medical Center

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