Clinical Trials /

Ceritinib and Everolimus in Treating Patients With Locally Advanced or Metastatic Solid Tumors or Stage IIIB-IV Non-small Cell Lung Cancer

NCT02321501

Description:

This phase I trial studies the side effects and best dose of ceritinib and everolimus in treating patients with solid tumors that have spread from where they started to nearby tissue or lymph nodes (locally advanced) or to other places in the body (metastatic) or stage IIIB-IV non-small cell lung cancer. Ceritinib and everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

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

  • ORG STUDY ID: 2014-0890
  • SECONDARY ID: NCI-2015-00062
  • NCT ID: NCT02321501

Conditions

  • Head and Neck Cancer
  • Lung Cancer

Interventions

DrugSynonymsArms
Ceritinib (LDK378)ZykadiaDose Escalation of Ceritinib (LDK378) + Everolimus
Ceritinib (LDK378) 750 mgZykadiaDose Expansion of Ceritinib (LDK378) - NSCLC + ALK+
EverolimusAfinitor, Zortress, RAD001Dose Escalation of Ceritinib (LDK378) + Everolimus

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. 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.

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 ½ 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 ½ 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 ½ teaspoon) or urine will be collected for a
           pregnancy test.

      If at any time the disease appears to get worse while you are on study, you will have an FNA
      or core biopsy for biomarker testing.

      If the doctor thinks it is needed, you will have extra EKGs.

      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 PK and biomarker testing.

        -  If you can become pregnant, blood (about ½ teaspoon) or urine will be collected for a
           pregnancy test.
    

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation of Ceritinib (LDK378) + EverolimusExperimentalFirst 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) + EverolimusExperimentalNon 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+ExperimentalNon 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 - ProgressionExperimentalDose 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. For dose
             expansion, patients who have ROS1 rearrangement testing by either next generation
             sequencing (NGS) or fluorescence in situ hybridization (FISH) will be eligible.

          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
             Fridericia 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-Guérin (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 3 months after the end of enrollment
      
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 Ceritinib plus Everolimus
Time Frame:28 days
Safety Issue:
Description:MTD defined as the highest dose level in which 6 patients were treated with at most 1 experiencing a dose limiting toxicity (DLT). DLT defined as hematologic grade 4 neutropenia lasting > 7 days or any febrile neutropenia; Delay of treatment > 14 days due to hematologic toxicity; Platelet count < 10K; non-hematologic toxicity grade 3 or higher; however nausea/vomiting, diarrhea and electrolyte imbalances only considered DLT if they persist for 48 hours despite adequate supportive care. Toxicities defined via CTCAE v4.0, and must have possible, probable, or definite attribution to study drugs.

Secondary Outcome Measures

Measure:Progression-Free Survival (PFS)
Time Frame:6 months
Safety Issue:
Description:PFS defined as time from start of study until disease progressive or death.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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

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