Phase II Trial of Ceritinib in Combination With Stereotactic Ablative Radiation in ALK-rearranged Metastatic Lung Adenocarcinoma
Phase II Trial of Ceritinib in Combination With Stereotactic Ablative Radiation in ALK-rearranged Metastatic Lung Adenocarcinoma
The purpose of this study is to see if Ceritinib can target ALK in non-small cell lung cancer and slow down cancer growth and prevent it from spreading.
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:
Safety:
-Demonstrate safety of ceritinib followed by SABR Describe toxicity and adverse events (CTCAE v.4) compared to historical controls.
Inclusion Criteria:
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.
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.
Patients will not have any other curative therapeutic option, such as radiation or surgery.
WHO performance status 0-2.
Age ≥18 years.
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.
Adequate organ function: the following laboratory criteria have been met:
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:
Written informed consent for the protocol must be obtained prior to any screening procedures.
Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other procedures.
Exclusion Criteria:
Patients with known hypersensitivity to any of the excipients of ceritinib (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate).
History of carcinomatous meningitis.
Prior therapy with ceritinib.
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.
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).
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.
Patient has clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 months), such as:
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.
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).
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):
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.
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):
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.
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.
Patient has a history of pancreatitis or history of increased amylase or lipase that was due to pancreatic disease.
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.
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.