Details
Title A Phase II, multi-center, open-label, five-arm study to evaluate the efficacy and safety of oral ceritinib treatment for patients with ALK-positive non-small cell lung cancer (NSCLC) metastatic to the brain and/or to leptomeninges
IRB NOVA 1515
CC 15-401
Hospital Main Campus
Phase Phase 2
Disease Lung, Lung - NSCLC (Non-small cell lung cancer)
Drug Ceritinib
Description
Primary Objective- The primary objective is to evaluate the antitumor activity of ceritinib in patients with ALK-positive NSCLC metastatic to the brain and/or to leptomeninges based on investigator assessment per RECIST 1.1
- To evaluate Disease Control Rate (DCR) in patients with ALK-positive NSCLC metastatic to the brain and/or to leptomeninges based on investigator assessment per RECIST 1.1
- To evaluate intracranial tumor-response related endpoints as assessed by investigators and Blinded Independent Review Committee (BIRC) (using modified RECIST 1.1 criteria) overall and for each of Arms 1 through 4
- To evaluate extracranial tumor-response related endpoints as assessed by investigators and BIRC (using RECIST 1.1 criteria) overall and for each of Arms 1 through 4
- To evaluate whole body tumor-response related endpoints as assessed by investigators and BIRC(using RECIST 1.1 criteria) overall and for each of Arms 1 through 4
- To evaluate overall survival (OS) overall and for each of Arms 1 through 5
- To evaluate safety overall and for each of Arms 1 through 5
- To characterize the PK of ceritinib in this patient population
- To evaluate intracranial endpoints for patients with measurable brain metastases at baseline in Arms 1 to 4 and for patients with active brain lesions at baseline in Arms 1 to 4 using the Response Assessment in Neuro-Oncology (RANO) criteria for high grade gliomas (Wen et al 2010) by investigators and BIRC.
- To assess the distribution of ceritinib in the CSF.
- To explore potential predictive or patient selection biomarkers of benefit from ceritinib treatment.
- To explore potential resistance biomarkers by measuring somatic mutations arising in the ALK gene and in other genes that interact with the ALK pathway or are thought to be important in cancer at the time of disease progression on ceritinib, and/or assessing molecular status (e.g. mutation analysis, expression, activation, inhibition) of other components of the ALK signaling pathway, or other aberrations and molecular status of other pathways known to be involved in NSCLC carcinogenesis.
- To explore ceritinib exposure/response relationships
Inclusion Criteria
- Histologically or cytologically confirmed diagnosis of metastatic NSCLC according to the 7th edition of the AJCC Cancer Staging Manual. In addition, the NSCLC must harbor an ALK rearrangement, as assessed at a Novartis designated central laboratory using the FDA approved Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) test and scoring algorithm (including positivity criteria). Patients must wait for the central result of the ALK rearrangement status before initiating treatment with ceritinib.
- All patients must have a tumor tissue sample available as an archival sample (if possible obtained after the completion of the patient's last therapeutic regimen) or as a new biopsy to send to the Novartis designated central laboratory. If that is not possible, any tumor biopsy obtained at or since the time of diagnosis can be used (a maximum of two years from biopsy excision is preferred).
- At least one extracranial measurable lesion as defined by RECIST 1.1. A previously irradiated site lesion may only be counted as a target lesion if there is clear sign of progression since the irradiation. Note: Enrollment of patients with only non-measurable brain metastases may be closed in one or more arms if it is determined that the target for patients with measurable brain metastases across study arms will not be met.
- Patient is 18 years of age or older at the time of informed consent.
- Patients may or may not have neurological symptoms but must:
- Be able to swallow and retain oral medication.
- Be neurologically stable within at least 1 week prior to the first dose of study drug. Neurologically stable is defined as improved or stable neurological examination without increased doses of steroids to manage CNS symptoms within the last 5 days.
- Patients may have received prior chemotherapy, crizotinib, biologic therapy or other investigational agents including other ALK inhibitors. Patients must have recovered from all toxicities related to prior anticancer therapies to grade = 1 (CTCAE v 4.03). Patients with any grade of alopecia are allowed to enter the study.
- Patients who have been treated with chemotherapy, with biological therapy or other investigational agent (except ALK inhibitors) must have discontinued the treatment at least 2 weeks (14 days) prior to starting study drug. In case last chemotherapy contains nitrosourea or mitomycin C, the treatment must be discontinued at least 6 weeks prior to the first dose of study drug.
- Patients, if previously treated with ALK inhibitors (including crizotinib) must discontinue treatment at least 1 week (7 days) prior to the first dose of study drug.
- Patient must meet the following laboratory values at the screening visit:
- Absolute Neutrophil Count ≥ 1.5 x 109/L
- Platelets ≥ 75 x 109/L
- Hemoglobin (Hgb) ≥ 8 g/dL
- Serum creatinine < 1.5 mg/dL and /or calculated creatinine clearance (using Cockcroft-Gault formula) ≥ 30 mL/min
- Total bilirubin ≤ 1.5 x ULN except for patients with Gilbert's syndrome who may only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN
- Aspartate transaminase (AST) ≤ 3 x ULN, except for patients with liver metastasis, who are only included if AST ≤ 5 x ULN
- Alanine transaminase (ALT) ≤ 3 x ULN, except for patients with liver metastasis, who are only included if ALT ≤ 5 x ULN
- Alkaline phosphatase (ALP) ≤ 5.0 x ULN
- Serum amylase ≤ ULN
- Serum lipase ≤ ULN
- Patient must have the following laboratory values within normal limits or corrected to within normal limits with supplements during screening:
- Potassium
- Magnesium
- Phosphorus
- Total calcium (corrected for serum albumin)
- Patient has life expectancy ≥ 6 weeks.
- Patient has a WHO performance status 0-2.
- Patient has the ability to understand and provide signed informed consent.
- Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures.
- Patients must have active brain metastases from NSCLC, confirmed by Gadoliniumenhanced MRI without concomitant leptomeningeal carcinomatosis. Dose of steroids must be stable for 5 days before the baseline brain MRI. Note: An active brain lesion is a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation). The following lesions are considered active:
- A newly diagnosed brain metastasis in a patient who has never received treatment to the brain or in a patient with previously treated brain metastases.
- A brain lesion previously treated with whole brain radiation will only be considered active when there is an unequivocal size increase in its solid component (cystic component of the lesion is not considered for progression determination) compared to the first available post-radiation radiological evaluation.
- An enlarging brain lesion previously treated with SRS will only be considered active when the nature of the enlargement is clearly attributed to the tumoral component of the lesion and not to the radiation effect.
- Patients must be diagnosed with leptomeningeal carcinomatosis. The diagnosis requires either documentation of the presence of malignant cells detected at the cytological examination of the cerebrospinal fluid or a serious suspicion of leptomeningeal carcinomatosis, supported by imaging findings typical of LC on the Gadolinium-enhanced MRI of the brain or spine (in this latter case, the determination of the presence of malignant cells in CSF cytology is strongly recommended).
Patients in Arm 1 to 4 must also meet the following inclusion criteria:
Patients in Arm 5 must also meet the following inclusion criteria:
Exclusion Criteria
- Patient with a history of treatment with ceritinib. Patient with known hypersensitivity to any of the excipients of ceritinib (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate).
- Patients who need whole brain radiation to control the brain metastases. Patients will not be eligible unless treated brain lesions are progressive or new brain lesions are observed since the post whole brain radiation therapy MRI.
- In case active brain lesions (single or not) require local treatment but other active brain lesions do not and are not treated, patients will be excluded only if the local treatment (neurosurgical treatment or Stereotactic Radiosurgery ) for the brain metastases is conducted within 2 weeks prior to starting study drug. Patients must have recovered from relevant toxicities related to these procedures to grade ≤ 1(CTCAE v 4.03) prior to receiving the first dose of study drug.
- Planning of any brain local treatment (including but not limited to surgery, stereotactic radiosurgery, whole brain radiation, intrathecal chemotherapy) following the administration of the first dose of study drug.
- 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 the first dose of study drug is allowed.
- Patient has had major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior to the first dose of study drug 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 the procedure.
- Patient with a concurrent malignancy or history of a malignant disease other than NSCLC that has been diagnosed and/or required therapy within the past 3 years. 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 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 (as mean of triplicate ECGs).
- 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).
- Patient receiving treatment with 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 (Appendix 1):
- Strong inhibitors or strong inducers of CYP3A4/5.
- Medications with a low therapeutic index that are primarily metabolized by CYP3A4/5 and/or CYP2C9.
- Medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes.
- Patient is currently receiving treatment with warfarin sodium (Coumadin®) or any other coumarin-derivative anticoagulants.
- Patient is receiving 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. Note: Dose of steroids must be stable for 5 days before the baseline brain MRI.
- Patient is receiving treatment with any enzyme-inducing anticonvulsant (Appendix 1) that cannot be discontinued at least 1 week before first dose of study treatment, and for the duration of the study. Patients on non enzyme-inducing anticonvulsants are eligible.
- Patient is pregnant or nursing (lactating) woman.
- Patient is a woman of child-bearing potential, defined as a woman physiologically capable of becoming pregnant, unless she is using highly effective contraception during the study and for 3 months after stopping ceritinib treatment. Highly effective contraception is defined as any of:
- 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 partner 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 patient].
- Use of a combination of any two of the following (a+b or a+c or b+c):
- 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 hormonal vaginal ring or transdermal hormone contraception.
- Placement of an intrauterine device (IUD) or intrauterine system (IUS).
- Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
- Sexually active males unless they use a condom during intercourse while taking the drug and for 3 months after the last dose of ceritinib treatment. Male patients should not father a child for 3 months after the last dose of ceritinib treatment. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.
- 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 that may interfere with the interpretation of study results.
- 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 has a history of pancreatitis or a history of increased amylase or lipase that was due to pancreatic disease.
- Patient has been previously enrolled in the treatment phase of any ceritinib clinical study, regardless of which treatment group the patient was allocated or randomized to.
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.