Clinical Trials /

Ceritinib + Trametinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer (NSCLC)

NCT03087448

Description:

This is a phase I/II study of ceritinib and trametinib in Stage IIIB or IV anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC). The Phase I portion will investigate the safety and tolerability of the combination of ceritinib and trametinib in ALK or ROS-1 rearranged NSCLC. The Phase II portion will investigate the clinical efficiency of the combination of ceritinib and trametinib in 3 single arm cohorts: ALKi (ALK inhibitor) naïve patients; post-crizotinib progressed disease (PD) patients; and PD second line ALK tyrosine kinase inhibitor (TKI) patients.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ceritinib + Trametinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer (NSCLC)
  • Official Title: A Phase I/II Study of Ceritinib + Trametinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer (NSCLC)

Clinical Trial IDs

  • ORG STUDY ID: CC# 166512
  • NCT ID: NCT03087448

Conditions

  • Non-small Cell Lung Cancer

Interventions

DrugSynonymsArms
CeritinibZykadiaCeritinib + Trametinib
TrametinibMekinistCeritinib + Trametinib

Purpose

This is a phase I/II study of ceritinib and trametinib in Stage IIIB or IV anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC). The Phase I portion will investigate the safety and tolerability of the combination of ceritinib and trametinib in ALK or ROS-1 rearranged NSCLC. The Phase II portion will investigate the clinical efficiency of the combination of ceritinib and trametinib in 3 single arm cohorts: ALKi (ALK inhibitor) naïve patients; post-crizotinib progressed disease (PD) patients; and PD second line ALK tyrosine kinase inhibitor (TKI) patients.

Detailed Description

      This is a phase I/II study of ceritinib and trametinib in Stage IIIB or IV ALK rearranged
      NSCLC.

      The phase I portion is a standard 3+3 dose escalation study starting at dose level 1 and will
      be open to any patient with ALK-rearranged, or ROS-1 rearranged NSCLC.

      The phase II portion will consist of 3 single arm cohorts in ALK-rearranged NSCLC:

        -  Cohort A (ALKi Naïve): 20 evaluable patients

        -  Cohort B (Post-crizotinib PD): 21 evaluable patients

        -  Cohort C (PD second line ALK TKI (e.g., alectinib, ceritinib, PF-06463922 or - AP21163):
           10 evaluable patients.

      The aim will be to enroll up to 69 patients. Patients may continue treatment for up to 24
      months from the time of study entry, and will receive 12 months of follow-up following
      completion of the drugs.
    

Trial Arms

NameTypeDescriptionInterventions
Ceritinib + TrametinibExperimentalPHASE 1 Standard 3+3 dose escalation starting at dose level 1. Patients with ALK-rearranged, or ROS-1 rearranged NSCLC. 6-18 patients will be enrolled. Ceritinib dose: 300-450mg orally, once daily over 28 day cycles. Trametinib dose: 1.5mg-2.0mg orally, once daily over 28 day cycles. PHASE II Cohort A (ALKi Naïve): those who have had no prior ALK inhibitor therapy (prior chemotherapy or immunotherapy is allowed). Aim 20 evaluable patients. Cohort B (Post-crizotinib PD): those who have received prior treatment with crizotinib and documented disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Aim 21 evaluable patients. Cohort C (PD on 2nd generation ALKi): those who have received prior treatment with 2nd generation ALKi (e.g. ceritinib, alectinib, loratinib, or brigatinib) and documented disease progression by RECIST 1.1 criteria. Aim 10 evaluable patients. The Phase II doses will be determined by Phase I dose escalation study
  • Ceritinib
  • Trametinib

Eligibility Criteria

        Inclusion Criteria:

          1. Age 18 years old or older.

          2. Able to swallow and retain orally administered medication and does not have any
             clinically significant gastrointestinal abnormalities that may alter absorption such
             as malabsorption syndrome or major resection of the stomach or bowels.

          3. Women of childbearing potential must have a negative serum pregnancy test within 14
             days prior to randomization and agree to use effective contraception, throughout the
             treatment period, and for 4 months after the last dose of study treatment.

          4. Patients must have histologically or cytological confirmed stage IIIB or IV non-small
             cell lung cancer.

          5. Documented ALK-rearrangement (or ROS1 rearrangement for phase I only) break-apart
             fluorescence in situ hybridization (FISH) (in at least 15% of tumor cells), or next
             generation sequencing assay performed on tumor sample or cell-free DNA in Clinical
             Laboratory Improvement Amendments (CLIA)-approved laboratory.

          6. Measurable disease defined by RECIST 1.1 criteria

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

          8. Life expectancy of at least 3 months.

          9. Resolution of all acute toxic effects of prior chemotherapy, immunotherapy,
             radiotherapy or surgical procedures to ≤ grade 2 (CTCAE v 4.0). Exception to this
             criterion: patients with any grade of alopecia are allowed to enter the treatment.

         10. The following laboratory criteria have been met:

               -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

               -  Hemoglobin (Hgb) ≥ 9 g/dL

               -  Platelets ≥ 75 x 109/L

               -  Prothrombin time (PT) / international normalized ratio (INR) and Partial
                  thromboplastin time (PTT) ≤1.5 x upper limit of normal (ULN)

               -  Serum creatinine ≤ 1.5 mg/dL and /or calculated creatinine clearance (using
                  Cockcroft-Gault formula) ≥ 30 mL/min

               -  Albumin 2.5 g/dL

               -  Total bilirubin ≤ 1.5 x ULN, except for patients with Gilbert's syndrome who may
                  be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN

               -  Aspartate transaminase (AST) ≤ 2.5 x ULN; alanine transaminase (ALT) ≤ 2.5 x ULN,
                  except for patients with liver metastasis, who are only included if AST and ALT <
                  5 x ULN

               -  Alkaline phosphatase (ALP) ≤ 5.0 x ULN

               -  Fasting plasma glucose ≤ 175 mg/dL (≤ 9.8 mmol/L)

               -  Serum amylase ≤ 2 x ULN

               -  Serum lipase ≤ ULN

         11. Patient must have the following laboratory values or have the following laboratory
             values corrected with supplements to be within normal limits before the first dose of
             ceritinib + trametinib:

             • Potassium

               -  Magnesium

               -  Phosphorus

               -  Total calcium (corrected for serum albumin)

         12. Left Ventricular Ejection fraction (LVEF) ≥ lower limit of normal (LLN) by
             echocardiogram (ECHO) or multigated acquisition scan (MUGA)

         13. Patient has the ability to understand and provide signed informed consent.

         14. Willingness and ability to comply with scheduled visits, treatment plans, laboratory
             tests and other study procedure.

         15. Specific inclusion criteria for the phase II dose expansion cohorts:

        Documented ALK-rearranged stage IIIB or IV NSCLC and:

          -  Cohort A: No prior ALK inhibitor therapy (prior chemotherapy or immunotherapy is
             allowed).

          -  Cohort B: Prior treatment with crizotinib and documented disease progression by RECIST
             1.1 criteria.

          -  Cohort C: Prior treatment with 2nd generation ALKi (e.g. ceritinib, alectinib,
             loratinib, or brigatinib) and documented disease progression by RECIST 1.1 criteria.

        Exclusion Criteria:

          1. Patients with known hypersensitivity to any of the excipients of ceritinib
             (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and
             magnesium stearate).

          2. Patient has history of interstitial lung disease or interstitial pneumonitis,
             including clinically significant radiation pneumonitis (i.e., affecting activities of
             daily living or requiring therapeutic intervention).

          3. Patient who has received thoracic radiotherapy to lung fields ≤4 weeks prior to
             starting the study treatment or patients who have not recovered from
             radiotherapy-related toxicities. For all other anatomic sites (including radiotherapy
             to thoracic vertebrae and ribs) radiotherapy ≤ 2 weeks prior to starting the study
             treatment or has not recovered from radiotherapy-related toxicities. Palliative
             radiotherapy for bone lesions ≤ 2 weeks prior to starting study treatment is allowed.

          4. Prior systemic anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy,
             vaccine therapy, or investigational treatment) within the last 3 weeks, or
             chemotherapy without delayed toxicity within the last 2 weeks preceding the first dose
             of the combination. Prior systemic treatment in the adjuvant setting is allowed.

          5. Patient has clinically significant, uncontrolled heart disease and/or recent cardiac
             event (within 6 months), such as:

             • unstable angina within 6 months prior to screening;

             • myocardial infarction within 6 months prior to screening;

             • history of documented congestive heart failure (New York Heart Association
             functional classification III-IV);

             • Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg
             and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without antihypertensive
             medication

             • initiation or adjustment of antihypertensive medication(s) is allowed prior to
             screening;

             • ventricular arrhythmias

             • supraventricular and nodal arrhythmias not controlled with medication;

             • other cardiac arrhythmia not controlled with medication;

             • corrected QT (QTcF) > 470 ms using Fridericia's correction on the screening
             electrocardiogram (ECG)

          6. Patient has impairment of gastrointestinal (GI) function or GI disease that may
             significantly alter the absorption of orally administered medication (e.g., ulcerative
             diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).

          7. Receiving medications that meet one of the following criteria and that cannot be
             discontinued at least 1 week prior to the start of treatment with ceritinib and for
             the duration of participation:

               -  Medication with a known risk of prolonging the QT interval or inducing Torsades
                  de Pointes (please refer to
                  http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm)

               -  Strong inhibitors or strong inducers of CYP3A4/5 (please refer to
                  http://medicine.iupui.edu/flockhart/table.htm or
                  http://www.druginteractioninfo.org)

               -  Medications with a low therapeutic index that are primarily metabolized by
                  CYP3A4/5, and/or CYP2C9 (please refer to
                  http://medicine.iupui.edu/flockhart/table.htm or
                  http://www.druginteractioninfo.org)

               -  Therapeutic doses of warfarin sodium (Coumadin) or any other coumadin-derived
                  anti-coagulant. Anticoagulants not derived from warfarin are allowed (eg,
                  dabigatran, rivaroxaban, apixaban).

               -  Unstable or increasing doses of corticosteroids; If patients are on
                  corticosteroids for endocrine deficiencies or tumor-associated symptoms, dose
                  must have been stabilized (or decreasing) for at least 5 days before first dose
                  of study treatment.

               -  Enzyme-inducing anticonvulsive agents

               -  Herbal supplements

        10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
        female after conception and until the termination of gestation, confirmed by a positive
        human Chorionic Gonadotropin (hCG) laboratory test.

        11. Women of child-bearing potential, defined as all women physiologically capable of
        becoming pregnant, unless they are using highly effective methods of contraception during
        dosing and for 3 months after the last dose of study treatment. Highly effective
        contraception methods include:

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

          -  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.

          -  Male sterilization (at least 6 months prior to screening) with the appropriate
             post-vasectomy documentation of the absence of sperm in the ejaculate. For female
             subjects on the study the vasectomized male partner should be the sole partner for
             that subject.

          -  Combination of any two of the following (a+b or a+c or b+c):

               1. 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.

               2. Placement of an intrauterine device (IUD) or intrauterine system (IUS).

               3. 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 for a minimum of 3 months before taking study treatment.

                  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 prior to screening. 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.

                  12. Sexually active males unless they use a condom during intercourse while
                  taking drug and for 3 months after the last dose of study treatment. Male
                  patients for 3 months should not father a child in this period. A condom is
                  required to be used also by vasectomized men in order to prevent delivery of the
                  drug via seminal fluid.

                  13. Patient has a history of pancreatitis or history of increased amylase or
                  lipase that was due to pancreatic disease.

                  14. Patient has other severe, acute, or chronic medical conditions including
                  uncontrolled diabetes mellitus or psychiatric conditions or laboratory
                  abnormalities that, in the opinion of the investigator, may increase the risk
                  associated with study participation or may interfere with the interpretation of
                  study results.

                  16. Patient has had major surgery (e.g., intra-thoracic, intra-abdominal or
                  intra-pelvic) within 4 weeks prior to starting study treatment or has not
                  recovered from side effects of such procedure. Video-assisted thoracic surgery
                  (VATS) and mediastinoscopy will not be counted as major surgery and patients can
                  receive study treatment ≥ 1 week after these procedures.

                  17. History of another malignancy. Exception: Subjects who have been disease-free
                  for 3 years, or subjects with a history of completely resected non-melanoma skin
                  cancer and/or subjects with indolent (early stage breast cancer or prostate
                  cancer) second malignancies are eligible after discussion with the study
                  principle investigator (PI).

                  18. History of retinal vein occlusion (RVO)

                  19. Symptomatic brain metastases or leptomeningeal (LM) disease requiring
                  corticosteroids for symptom management. Asymptomatic brain metastases or LM will
                  be allowed on study.

                  20. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or
                  Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of cleared
                  HBV and HCV infection will be permitted).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of the combination of ceritinib and trametinib in advanced ALK-rearranged, or ROS-1 rearranged NSCLC, by number of Adverse Events (AEs)
Time Frame:Each dose level (potential for three) will be followed from baseline to 4 weeks, therefore potential total of 12 weeks.
Safety Issue:
Description:Determine the maximum tolerated dose (MTD) of ceritinib in combination with trametinib in patients with advanced ALK-rearranged, or ROS-1 rearranged NSCLC by evaluating the number and frequency of Adverse Events (AEs) as determined by National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.0 by investigator assessment, and identify a recommended phase II dose (RP2D) for phase II dose expansion cohorts.

Secondary Outcome Measures

Measure:Overall response rate (ORR) with combination ceritinib + trametinib in patients with Stage IIIB or IV ALK-rearranged NSCLC
Time Frame:From date of screening, then day 1 of every 28 day cycle, until end of treatment (an average of 1 year), then every 3 months for 12 months after end of treatment.
Safety Issue:
Description:Assess the overall response rate (ORR) of combination ceritinib + trametinib in patients with Stage IIIB or IV ALK-rearranged NSCLC in the first, second, or third line setting. The ORR is defined as the best overall response recorded from the start of the treatment until disease progression or recurrence as assessed over a 1-year period from the start of treatment. The frequency and percentages of patients with a best overall response rate of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) will be determined.
Measure:Disease control rate (DCR) with combination ceritinib + trametinib in patients with Stage IIIB or IV ALK-rearranged NSCLC
Time Frame:From date of screening, then day 1 of every 28 day cycle, until end of treatment (an average of 1 year), then every 3 months for 12 months after end of treatment.
Safety Issue:
Description:Assess the disease control rate (DCR) with combination ceritinib + trametinib in patients with Stage IIIB or IV ALK-rearranged NSCLC in the first, second, or third line setting. : DCR will be defined as the percentage of patients who have achieved CR, PR, or SD for at least 12 weeks. The DCR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).
Measure:Progression-free survival (PFS) with combination ceritinib + trametinib in patients with Stage IIIB or IV ALK-rearranged NSCLC
Time Frame:From date of screening, then day 1 of every 28 day cycle, until end of treatment (an average of 1 year), then every 3 months for 12 months after end of treatment.
Safety Issue:
Description:Assess progression-free survival (PFS) with combination ceritinib + trametinib in patients with Stage IIIB or IV ALK-rearranged NSCLC in the first, second, or third line setting. PFS will be calculated as 1+ the number of days from the first dose of study drugs to documented radiographic progression or death due to any cause over a period of 18 months. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis. The Kaplan-Meier analysis will be used to calculate the mean PFS with 95% confidence interval.
Measure:Overall survival (OS) with combination ceritinib + trametinib in patients with Stage IIIB or IV ALK-rearranged NSCLC
Time Frame:From date of screening, then day 1 of every 28 day cycle, until end of treatment (an average of 1 year), then every 3 months for 12 months after end of treatment.
Safety Issue:
Description:Assess overall survival (OS) with combination ceritinib + trametinib in patients with Stage IIIB or IV ALK-rearranged NSCLC in the first, second, or third line setting. OS will be calculated as 1+ the number of days from the first dose of study drugs to death due to any cause over a period of 18 months. The Kaplan-Meier analysis will be used to calculate the mean PFS with 95% confidence interval.
Measure:Time to central nervous system (CNS) progression with combination ceritinib + trametinib in patients with Stage IIIB or IV ALK-rearranged NSCLC
Time Frame:From date of screening, then day 1 of every 28 day cycle, until end of treatment (an average of 1 year), then every 3 months for 12 months after end of treatment.
Safety Issue:
Description:Assess time to central nervous system (CNS) progression with combination ceritinib + trametinib in patients with Stage IIIB or IV ALK-rearranged NSCLC in the first, second, or third line setting. CNS progression will be defined as development of new CNS lesions detected on Brain MRI or CT scan, or in cerebrospinal fluid (CSF).
Measure:Peak plasma concentration (Cmax) of ceritinib + trametinib
Time Frame:Day 1 of every 28 day cycle until end of treatment (an average of 1 year) (last test 30 days after last dose of study drug). Time points: Prior to drug administration, then between 30-60 minutes after drug administration.
Safety Issue:
Description:Measure peak plasma concentration (Cmax) of combination treatment ceritinib + trametinib

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of California, San Francisco

Trial Keywords

  • ALK rearranged
  • Stage IIIB NSCLC
  • Stage IV NSCLC
  • ROS-1 rearranged NSCLC

Last Updated

September 29, 2017