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Phase I/Ib Dose Escalation & Biomarker Study of Ceritinib (LDK378) + Everolimus for Locally Advanced or Metastatic Solid Tumors With an Expansion in Non-Small Cell Lung Cancer (NSCLC) Characterized by Abnormalities in Anaplastic Lymphoma Kinase (ALK) Expression

NCT02321501

Description:

The goal of this clinical research study is to find the highest tolerable dose of ceritinib (LDK378) and everolimus that can be given to patients with NSCLC or head and neck cancer. The safety of the drug combination will also be tested. This is an investigational study. LDK 378 is FDA approved and commercially available for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic lung cancer (NSCLC) who have progressed on or intolerant to crizotinib. Everolimus is also FDA approved or commercially available for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer, advanced neuroendocrine tumors of pancreatic origin (PNET), advanced renal cell carcinoma (RCC), renal angiomyolipoma and tuberous sclerosis complex (TSC), and subependymal giant cell astrocytoma (SEGA) with Tuberous Sclerosis Complex (TSC). The combination of the drugs is being used for research purposes only. Up to 66 participants will be enrolled in this study. All will take part at MD Anderson.

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Phase I/Ib Dose Escalation & Biomarker Study of <span class="go-doc-concept go-doc-intervention">Ceritinib (LDK378)</span> + <span class="go-doc-concept go-doc-intervention">Everolimus</span> for Locally Advanced or Metastatic Solid Tumors With an Expansion in Non-<span class="go-doc-concept go-doc-disease">Small Cell Lung Cancer </span>(<span class="go-doc-concept go-doc-disease">NSCLC</span>) Characterized by Abnormalities in Anaplastic Lymphoma Kinase (<span class="go-doc-concept go-doc-biomarker">ALK</span>) Expression

Title

  • Brief Title: Phase I/Ib Dose Escalation & Biomarker Study of Ceritinib (LDK378) + Everolimus for Locally Advanced or Metastatic Solid Tumors With an Expansion in Non-Small Cell Lung Cancer (NSCLC) Characterized by Abnormalities in Anaplastic Lymphoma Kinase (ALK) Expression
  • Official Title: A Phase I/Ib Dose Escalation and Biomarker Study of Ceritinib (LDK378) in Combination With Everolimus in Patients With Locally Advanced or Metastatic Solid Tumors With an Expansion in Non-Small Cell Lung Cancer (NSCLC) Characterized by Abnormalities in Anaplastic Lymphoma Kinase (ALK) Expression
  • Clinical Trial IDs

    NCT ID: NCT02321501

    ORG ID: 2014-0890

    NCI ID: NCI-2015-00062

    Trial Conditions

    Head and Neck Cancer

    Lung Cancer

    Trial Interventions

    Drug Synonyms Arms
    Ceritinib (LDK378) Zykadia Dose Escalation of Ceritinib (LDK378) + Everolimus, Dose Expansion of Ceritinib (LDK378) + Everolimus, Ceritinib (LDK378) + Everolimus - Progression
    Ceritinib (LDK378) 750 mg Zykadia Dose Expansion of Ceritinib (LDK378) - NSCLC + ALK+
    Everolimus Afinitor, Zortress, RAD001 Dose Escalation of Ceritinib (LDK378) + Everolimus, Dose Expansion of Ceritinib (LDK378) + Everolimus, Ceritinib (LDK378) + Everolimus - Progression

    Trial Purpose

    The goal of this clinical research study is to find the highest tolerable dose of ceritinib
    (LDK378) and everolimus that can be given to patients with NSCLC or head and neck cancer.
    The safety of the drug combination will also be tested.

    Detailed Description

    Study Groups and Study Drug Administration:

    If you are found to be eligible to part in this study, the dose of LDK378 you receive will
    depend on when you join this study. The first group of participants will receive the lowest
    dose level of LDK 378 and everolimus. Each new group will receive either higher dose of LDK
    378 or a higher dose of everolimus than the group before it, if no intolerable side effects
    were seen. This will continue until the highest tolerable dose of LDK 378 and everolimus is
    found.

    Once the high tolerable dose is found, up to 30 participants will receive the drug at this
    dose level.

    You will take 2 to 4 capsules (depending on the dose) of LDK 378 by mouth 1 time each day
    for each 28-day study cycle.

    LDK 378 should be taken in the morning right after (within 30 minutes) a low-fat meal (about
    1.5 to 9 grams of fat [no more than 15 grams] and about 100 to 330 total calories [no more
    than 500 total calories]). You should swallow the capsule whole with a cup of water (about
    8 ounces) over as short a time as possible (not slower than 1 capsule every 2 minutes). Do
    not chew or open the capsules.

    If you vomit or miss a dose, do not take another dose to make it up. That day's dose should
    be skipped, and you should take your next dose on the following day.

    You will take 1 or 2 capsules of everolimus (depending on the dose) tablets by mouth 1 time
    each day for each 28-day cycle. Everolimus should be taken at about the same time every day
    with a glass of water, either consistently with or without food

    Study Visits:

    On Day 1 of Cycle 1:

    - You will have a physical exam, including a check of your blood oxygen level.

    - Blood (about 2 teaspoons) will be drawn for routine tests and to check your cholesterol
    levels. You must fast for at least 12 hours before the draw.

    - Blood (about 2 teaspoons at each draw) will be drawn for pharmacokinetic (PK) and
    biomarker testing before your dose of LDK378 and then 6 more times over the next 24
    hours after the dose. PK testing measures the amount of study drug in the body at
    different time points.

    On Days 8, 15, and 21 of Cycle 1:

    - You will have a physical exam.

    - Blood (about 2 teaspoons) will be drawn for routine tests and to check your cholesterol
    levels. You must fast for at least 12 hours before the draw.

    - On Days 15 and 21 only, blood (about 2 teaspoons) will be drawn for PK and biomarker
    testing.

    On Day 1 of Cycle 2:

    - You will have a physical exam, including a check of your blood oxygen level.

    - Blood (about 2 teaspoons) will be drawn for routine tests and to check your cholesterol
    levels. You must fast for at least 12 hours before the draw.

    - You will have an EKG before you take the study drug.

    - Blood (about 2 teaspoons at each draw) will be drawn for PK testing before and 6 more
    times between 1-24 hours after your dose of study drugs.

    - If you can become pregnant, blood (about teaspoon) or urine will be collected for a
    pregnancy test.

    On Day 1 of Cycle 3:

    - You will have a physical exam, including a check of your blood oxygen level.

    - Blood (about 2 teaspoons) will be drawn for routine tests and to check your cholesterol
    levels. You must fast for at least 12 hours before the draw.

    - You will have an EKG before you take the study drug.

    - Blood (about 2 teaspoons) will be drawn for PK and biomarker testing.

    - If you can become pregnant, blood (about teaspoon) or urine will be collected for a
    pregnancy test.

    On Day 1 of Cycles 3 and every other cycle after that (Cycles 5, 7 and so on), you will have
    a CT scan or MRI of your chest, abdomen, and brain to check the status of the disease.

    On Day 1 of Cycles 4 and beyond:

    - You will have a physical exam, including a check of your blood oxygen level.

    - Blood (about 2 teaspoons) will be drawn for routine tests and to check your cholesterol
    levels. You must fast for at least 12 hours before the draw.

    - You will have an EKG before you take the study drug.

    - If you can become pregnant, blood (about teaspoon) or urine will be collected for a
    pregnancy test.

    Length of Study:

    You may continue taking the study drugs as long as the doctor thinks it is in your best
    interest. You will no longer be able to take the study drug if the disease gets worse, if
    intolerable side effects occur, or if you are unable to follow study directions.

    Your participation in this study will be over after the end-of-study visit.

    End-of-Study Visit:

    Within 28 days of your last dose of study drugs:

    - You will have a physical exam, including a check of your blood oxygen level.

    - Blood (about 2 teaspoons) will be drawn for routine tests and to check your cholesterol
    levels. You must fast for at least 12 hours before the draw.

    - Blood (about 2 teaspoons) will be drawn for PD testing.

    - If you can become pregnant, blood (about teaspoon) or urine will be collected for a
    pregnancy test.

    This is an investigational study. LDK 378 is FDA approved and commercially available for
    the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic lung
    cancer (NSCLC) who have progressed on or intolerant to crizotinib.

    Everolimus is also FDA approved or commercially available for the treatment of advanced
    hormone receptor-positive, HER2-negative breast cancer, advanced neuroendocrine tumors of
    pancreatic origin (PNET), advanced renal cell carcinoma (RCC), renal angiomyolipoma and
    tuberous sclerosis complex (TSC), and subependymal giant cell astrocytoma (SEGA) with
    Tuberous Sclerosis Complex (TSC).

    The combination of the drugs is being used for research purposes only.

    Up to 66 participants will be enrolled in this study. All will take part at MD Anderson.

    Trial Arms

    Name Type Description Interventions
    Dose Escalation of Ceritinib (LDK378) + Everolimus Experimental First group of participants receive the lowest dose level of Ceritinib (LDK 378) and Everolimus. Each new group receives either higher dose of Ceritinib (LDK 378) or a higher dose of everolimus than the group before it, if no intolerable side effects were seen. This continues until highest tolerable dose of Ceritinib (LDK 378) and Everolimus is found. Dose Escalation Phase Starting Dose of Ceritinib (LDK378): 450 mg by mouth once a day in a 28 day cycle. Dose Escalation Phase Starting Dose of Everolimus: 5 mg by mouth once a day in a 28 day cycle. Ceritinib (LDK378), Everolimus
    Dose Expansion of Ceritinib (LDK378) + Everolimus Experimental Non small cell lung cancer participants (NSCLC) with anaplastic lymphoma kinase (ALK+) expression on IHC treated with combination of Ceritinib (LDK378) and Everolimus at maximum tolerated dose (MTD) from Dose Escalation Phase. Dose Expansion Phase Starting Dose of Ceritinib (LDK378): MTD from Dose Escalation Phase. Dose Expansion Phase Starting Dose of Everolimus: MTD from Dose Escalation Phase. Ceritinib (LDK378), Everolimus
    Dose Expansion of Ceritinib (LDK378) - NSCLC + ALK+ Experimental Non small cell lung cancer (NSCLC) participants with anaplastic lymphoma kinase (ALK+) expression on IHC receive single agent Ceritinib (LDK378) at 750 mg by mouth once a day for a 28 day cycle. Ceritinib (LDK378) 750 mg
    Ceritinib (LDK378) + Everolimus - Progression Experimental Dose Expansion Phase participants with non small cell lung cancer (NSCLC), with anaplastic lymphoma kinase (ALK+) expression on IHC who have progressed, treated with Ceritinib (LDK378) and Everolimus at MTD from Dose Escalation Phase. Ceritinib (LDK378), Everolimus

    Eligibility Criteria

    Inclusion Criteria:

    1. For dose escalation cohort: Patients with histologically or cytologically confirmed
    locally advanced or metastatic solid tumors who have failed at least one line of
    therapy.

    2. For dose expansion cohort: Patients with Stage IIIB or IV ALK + NSCLC who have failed
    at least one line of therapy and are progressing on an ALK inhibitor.

    3. Patient must have adequate organ function as determined by the following laboratory
    values: Absolute Neutrophil Count (ANC) >/= 1,500/microliter; Platelets >/=
    100,000/microliter; Hemoglobin (Hgb) >/= 9 g/dL; Creatinine </= 1.5 X upper limit of
    normal (ULN); Prothrombin Time (PT), Partial Thromboplastin Time(PTT) </= 1.5 X ULN;
    Total bilirubin </= 1.5X ULN; Alanine Transaminase (ALT) and Aspartate
    Aminotransferase (AST) < 1.5 X ULN (< 5 X ULN if patient has liver metastasis)

    4. Patient will have a tumor suitable for fine needle aspirates (FNA) or core biopsy for
    research purposes (2 or more FNAs if core is not feasible)

    5. 18 years of age or older

    6. Able to swallow oral medications

    7. Patient must have performance status </=2 on the ECOG Performance Scale.

    8. Measurable disease by RECIST or evaluable disease (e.g., bone metastasis, or lesions
    which do not fulfill RECIST criteria for metastatic disease).

    9. ALK-positive NSCLC patients with asymptomatic central nervous system (CNS) metastases
    who are neurologically stable or have not required increasing doses of steroids
    within the 2 week prior to study entry to manage CNS symptoms.

    10. Non-ALK-positive NSCLC patients with CNS metastasis should have completed a course of
    therapy would be eligible for the study provided they are clinically stable for 1
    month prior to entry as defined as: (1) no evidence of new or enlarging CNS
    metastasis (2) off steroids.

    11. Negative serum or urine pregnancy test beta-Human Chorionic Gonadotropin (beta hCG)
    within 2 weeks prior to receiving the first dose of study medication for women of
    childbearing age.

    12. Patient must have completed any systemic therapy regimens (except an ALK inhibitor)
    and therapeutic radiation a minimum of 21 days prior to initiation of study therapy.

    13. Fasting serum cholesterol </= 300 mg/dL OR </= 7.75 mmol/L AND fasting triglycerides
    </= 2.5x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient
    can only be included after initiation of appropriate lipid lowering medication;

    14. Signed informed consent obtained prior to any screening procedures.

    Exclusion Criteria:

    1. Patients who have received prior everolimus or ceritinib

    2. Patients with known history of extensive disseminated bilateral interstitial fibrosis
    or interstitial lung disease, including a history of pneumonitis, hypersensitivity
    pneumonitis, interstitial pneumonia, obliterative bronchiolitis, and clinically
    significant radiation pneumonitis (i.e. affecting activities of daily living or
    requiring therapeutic intervention).

    3. Patients currently receiving anticancer therapies or who have received anticancer
    therapies within 4 weeks including chemotherapy, radiation therapy, antibody based
    therapy, etc.;

    4. Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g.
    sirolimus, temsirolimus);

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

    6. Known impairment of gastrointestinal (GI) function or GI disease that may
    significantly alter the absorption of oral everolimus;

    7. Uncontrolled diabetes mellitus as defined by hemoglobin A1c (HbA1c) >8% despite
    adequate therapy. Patients with a known history of impaired fasting glucose or
    diabetes mellitus (DM) may be included, however blood glucose and antidiabetic
    treatment must be monitored closely throughout the trial and adjusted as necessary;

    8. Patient has clinically significant, uncontrolled heart disease and/or recent cardiac
    event (within 6 months), such as: a. unstable angina within 6 months prior to
    screening; b. myocardial infarction within 6 months prior to screening; c. history of
    documented congestive heart failure (New York Heart Association functional
    classification III-IV); d. 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; e. ventricular
    arrhythmias; supraventricular and nodal arrhythmias not controlled with medication;
    f. other cardiac arrhythmia not controlled with medication; g. corrected QTc > 450
    msec using Frederica correction on the screening electrocardiogram (ECG)

    9. Patients who have any severe and/or uncontrolled medical conditions such as: a.
    active (acute or chronic) or uncontrolled severe infection, liver disease such as
    cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable
    hepatitis B virus test [HBV-DNA] and/or positive hepatitis B surface antigen [HbsAg],
    quantifiable hepatitis C virus test [HCV-RNA]), b. known severely impaired lung
    function (spirometry and carbon monoxide diffusing capacity [DLCO] 50% or less of
    normal and oxygen [O2] saturation 88% or less at rest on room air), c. active,
    bleeding diathesis;

    10. Chronic treatment with high dose corticosteroids or other immunosuppressive agents.
    Topical, inhaled, and low dose oral corticosteroids are allowed provided stable
    dosing for at least 2 weeks;

    11. 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 the study participation: a. Medication with a known risk of
    prolonging the QT interval or inducing Torsades de Pointes b. Strong inhibitors or
    strong inducers of CYP3A4/5 c. Medications with a low therapeutic index that are
    primarily metabolized by CYP3A4/5, CYP2C8 and/or CYP2C9 d. Therapeutic doses of
    warfarin sodium (Coumadin) or any other coumadin-derived anti-coagulant.
    Anticoagulants not derived from warfarin are allowed (eg, dabigatran, rivaroxaban,
    apixaban). e. Unstable or increasing doses of corticosteroids f. enzyme-inducing
    anticonvulsive agents g. herbal supplements

    12. Known history of HIV seropositivity;

    13. Patients who have received live attenuated vaccines within 1 week of start of
    everolimus and during the study. Patient should also avoid close contact with others
    who have received live attenuated vaccines. Examples of live attenuated vaccines
    include intranasal influenza, measles, mumps, rubella, oral polio, Bacillus
    Calmette-Gurin (BCG), yellow fever, varicella and TY21a typhoid vaccines;

    14. Patients who have a history of another primary malignancy unless the patient has been
    disease free for >/= 3 years;

    15. Patients with a history of non-compliance to medical regimens or who are considered
    potentially unreliable or will not be able to complete the entire study;

    16. Patients who are currently part of or have participated in any clinical investigation
    with an investigational drug within 1 month prior to dosing (except ALK inhibitors);

    17. 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 hCG laboratory test.

    18. Women of child-bearing potential (WOCBP), 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: a. 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. b. 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. Exclusion criteria continued in #19.

    19. Exclusion criteria #18 continued: c. 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. d. Combination of any two of the
    following (i+ii or i+iii or ii+iii): i. 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. ii. Placement of an intrauterine device (IUD) or
    intrauterine system (IUS). iii. Barrier methods of contraception: Condom or Occlusive
    cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
    suppository. Exclusion criteria continued in #20.

    20. Exclusion criteria # 18 continued from #19: 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.

    21. 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. Also
    male patients whose sexual partner(s) are WOCBP who are not willing to use adequate
    contraception during the study and for 8 weeks after the end of enrollment.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Maximum Tolerated Dose (MTD) of Ceritinib plus Everolimus

    Secondary Outcome Measures

    Progression-Free Survival (PFS)

    Trial Keywords

    Head and Neck Cancer

    Lung Cancer

    Non small cell lung

    NSCLC

    Metastatic

    Locally advanced

    Metastatic solid tumors

    Anaplastic lymphoma kinase

    ALK

    Ceritinib

    LDK378

    Zykadia

    Everolimus

    Afinitor

    Zortress

    RAD001

    Pharmacokinetic

    PK

    Biomarker testing