This is an, open-label, two-cohort protocol designed to evaluate the activity of targeted
therapy and SABR in ALK positive lung adenocarcinoma.
Cohort A will evaluate the combination in ALK-inhibitor naïve patients. Cohort B will
evaluate the combination in patients who have received treatment with one prior ALK
inhibitor.
Ceritinib will be administered to the patient until disease progression by RECIST 1.1,
unacceptable toxicity, withdrawal of consent, or discontinuation of the trial for any other
reason including death.
The primary focus of this protocol is identifying response in ALK+ lung cancer patients.
Patients with Ventana assay and Vysis FISH probe positive tumors will be treated. Evidence of
ALK gene rearrangement will also be considered eligible for the trial.
Primary Objective:
Cohort A: Superiority of ceritinib + SABR median PFS compared to historical control of 10
months (expected to be 20 months)
Endpoint:
Cohort A Median PFS defined as time from initiation of ceritinib until disease progression by
RECIST 1.1, unacceptable toxicity, withdrawal of consent, or discontinuation of the trial for
any other reason including death.
Primary:
Cohort B: Superiority of ceritinib + SABR median PFS compared to historical control of 7
months.
Endpoint:
Cohort B: Median PFS defined as time from initiation of ceritinib until disease progression
by RECIST 1.1, unacceptable toxicity, withdrawal of consent, or discontinuation of the trial
for any other reason including death.
Secondary:
- Report Overall survival Overall survival
- Report Time to 2nd SABR Time from start of systemic therapy to first day of second
course of SABR
- Report Time to 3rd SABR Time from start of therapy to first day of third course of SABR
- Report proportion of patients CR/PR/stable disease at 6 and12 months Number of patients
with CR/PR/stable disease for 6 and 12 months after initiation
Safety:
-Demonstrate safety of ceritinib followed by SABR Describe toxicity and adverse events (CTCAE
v.4) compared to historical controls.
Inclusion Criteria:
1. Histologically or cytologically confirmed diagnosis of lung adenocarcinoma that
demonstrates ALK rearrangement as detected by the approved FISH test (Abbott Molecular
Inc), using Vysis breakapart probes (defined as 15% or more positive tumor cells); or
the Ventana IHC test. Evidence of rearrangement by gene sequencing tests such as
FoundationOne or Caris will also be seen as evidence of ALK abnormality and meeting
eligibility requirement.
2. Patients with no prior ALK-inhibitor therapy will be placed in cohort A, those treated
with one prior line of ALK-inhibitor (at any time) will enter cohort B.
3. Patients will not have any other curative therapeutic option, such as radiation or
surgery.
4. WHO performance status 0-2.
5. Age ≥18 years.
6. Patients must have recovered from all toxicities related to any prior anticancer
therapies to ≤ Grade 2 (CTCAE v 4.03), provided that any concomitant medication is
given prior to initiation of treatment with ceritinib. Exception to this criterion:
patients with any grade of alopecia are allowed to enter the treatment.
7. Adequate organ function: the following laboratory criteria have been met:
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- Hemoglobin (Hgb) ≥ 8 g/dL
- Platelets ≥ 75 x 109/L
- Serum creatinine <1.5 mg/dL and /or calculated creatinine clearance (using
Cockcroft-Gault formula) ≥30 mL/min
- Total bilirubin ≤ 1.5 x upper limit of normal (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) < 2.0 x ULN, except for patients with liver
metastasis, who are only included if AST < 3 x ULN; alanine transaminase (ALT) <
2.0 x ULN, except for patients with liver metastasis, who are only included if
ALT < 3 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
8. 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:
- Potassium
- Magnesium
- Phosphorus
- Total calcium (corrected for serum albumin)
9. Written informed consent for the protocol must be obtained prior to any screening
procedures.
10. Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests and other procedures.
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. History of carcinomatous meningitis.
3. Prior therapy with ceritinib.
4. Presence or history of a malignant disease other than lung adenocarcinoma that has
been diagnosed and/or required therapy within the past year and is undergoing active
anticancer treatment. Exceptions to this exclusion include the following: completely
resected basal cell and squamous cell skin cancers, and completely resected carcinoma
in situ of any type.
5. 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).
6. 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.
7. 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 ECG
8. Impaired GI function or GI disease that may alter absorption of ceritinib or inability
to swallow up to five ceritinib capsules daily. Although, patients unable to swallow
capsules will be allowed to participate in this study, by following the specific
instructions on making a slurry of the medication.
9. Patient has impairment of GI function or GI disease that may significantly alter the
absorption of ceritinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting,
diarrhea, or malabsorption syndrome).
10. 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 (see Appendix 1 Tables):
- 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, CYP2C8 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
(non-CNS), dose must have been stabilized (or decreasing) for at least 5 days
before first dose of study treatment.
- Enzyme-inducing anticonvulsive agents
- Herbal supplements
11. 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.
12. 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 agree to continue 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.
13. Sexually active males unless they agree to use a condom during intercourse while
taking drug and agree to continue 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.
14. Patient has a history of pancreatitis or history of increased amylase or lipase that
was due to pancreatic disease.
15. 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.
