Clinical Trial Details
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NCT02321501 : 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
PhasePhase 1
AgesMin: 18 Years Max: N/A
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

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 normal (ULN); Prothrombin Time (PT), Partial Thromboplastin Time(PTT) Total bilirubin 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
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 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

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

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
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