Patient case: 32-year-old female with inflammatory myofibroblastic tumor; genetic feature: RANBP2-ALK fusion

Clinical trial: 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

Summary: 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.

Eligibility: 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

Relevance to patient case: not relevant