Ceritinib With Brentuximab Vedotin in Treating Patients With ALK-Positive Anaplastic Large Cell Lymphoma
Ceritinib With Brentuximab Vedotin in Treating Patients With ALK-Positive Anaplastic Large Cell Lymphoma
This phase I/II trial studies the side effects and best dose of ceritinib when given together
 with brentuximab vedotin to see how well they work in treating treatment-naive patients with
 anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma. Ceritinib may stop
 the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal
 antibodies, such as brentuximab vedotin, may interfere with the ability of tumor cells to
 grow and spread. Giving ceritinib together with brentuximab vedotin may be a better treatment
 for ALK-positive anaplastic large cell lymphoma.
PRIMARY OBJECTIVES: I. To define a dose of ceritinib administered concurrently with
 brentuximab vedotin that has an acceptable toxicity profile (based on dose-limiting toxicity
 [DLT] rate) and sufficient efficacy (based on response rate) among patients with
 treatment-naive ALK-positive anaplastic large cell lymphoma (ALCL). SECONDARY OBJECTIVES: I.
 To assess the antitumor activity of ceritinib and brentuximab vedotin combination in
 treatment-naive patients with ALK-positive ALCL. II. To assess the utility of the molecular
 marker of ALK-positive ALCL in patient's plasma before, during and after therapy for disease
 risk assessment and post-treatment monitoring. OUTLINE: This is a phase I, dose-escalation
 study of ceritinib followed by a phase II study. Patients receive brentuximab vedotin
 intravenously (IV) over 30 minutes on day 1. Patients also receive ceritinib orally (PO) once
 daily (QD) on days 8-21 of course 1 and on days 1-21 for all subsequent courses. Treatment
 repeats every 21 days for up to 17 courses in the absence of disease progression or
 unacceptable toxicity. After completion of study treatment, patients are followed up every 3
 months up to 3 years.
Inclusion Criteria:

 -  Treatment-naive systemic ALK-positive ALCL patients

 -  Histologically confirmed diagnosis of cluster of differentiation (CD)30-positive ALCL
 with documented ALK-positive status

 -  Fluorodeoxyglucose (FDG)-avid disease by positron emission tomography (PET) and
 dimensional measurable disease of at least 1.5 cm as documented by radiographic
 technique (spiral computed tomography [CT] preferred)

 -  Eastern Cooperative Oncology Group (ECOG) performance status =< 3

 -  Absolute neutrophil count (ANC) >= 1500/ul

 -  Platelet count >= 75,000/ul (unless documented bone marrow involvement with lymphoma)

 -  Hemoglobin (Hgb) >= 8 gr/dL

 -  Serum creatinine =< 1.5 x 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 or documented hepatic involvement with lymphoma who may be included
 if bilirubin =< 3.0 x ULN or direct bilirubin =< 1.5 x ULN

 -  Aspartate transaminase (AST) =< 3 x ULN, except with liver involvement by the lymphoma
 who are only included if AST =< 5 x ULN; alanine transaminase (ALT) < 3.0 x ULN,
 except with liver involvement by the lymphoma who are only included if AST =< 5 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

 -  Patients must have the following laboratory values or have the following laboratory
 values corrected to be within normal limits before the first dose of ceritinib: *
 Potassium * Magnesium * Phosphorus * Total calcium (corrected for serum albumin)

 -  Females of child bearing potential, defined as all women physiologically capable of
 becoming pregnant, must have a negative serum or urine beta human chorionic
 gonadotropin (b-hCG) pregnancy test results within 7 days prior to the first dose of
 study treatment, and must agree to use highly effective methods of contraception
 during dosing and for 3 months after the last dose of study treatment; highly
 effective methods of contraception 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 six months prior to screening) with the
 appropriate post-vasectomy documentation of absence of sperm in the ejaculate; for
 female subjects on the study the vasectomized male partner should be sole partner for
 that subject * Combination of any two of the following: ** 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 ** 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 * 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 who have had a bilateral tubal
 ligation or hysterectomy

 -  Sexually active males must agree to use a condom during intercourse while receiving
 and for 3 months after the last dose of study treatment; male patients should not
 father a child for 3 months after the last dose of study treatment; a condom is
 required to be used also by vasectomized men in order to prevent delivery of the drug
 via seminal fluid

 -  Patients or their legally authorized representative must have the ability to
 understand and provide signed informed written consent

 -  Patients must express willingness and ability to comply with scheduled visits,
 treatment plans, laboratory tests and other study procedures

 Exclusion Criteria:

 -  Known hypersensitivity to any of the excipients of ceritinib (microcrystalline
 cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate)

 -  Known prior history of interstitial pneumonitis, including clinically significant
 radiation pneumonitis (i.e. affecting activities of daily living or requiring
 therapeutic intervention)

 -  Impaired gastrointestinal (GI) function or GI disease that may significantly alter the
 absorption of ceritinib (e.g. ulcerative disease, uncontrolled nausea, vomiting,
 diarrhea, or malabsorption syndrome) or inability to swallow up to five ceritinib
 capsules daily

 -  History of pancreatitis or history of increased amylase or lipase that was due to
 pancreatitis

 -  Other severe, acute, or chronic medical condition including uncontrolled diabetes
 mellitus or psychiatric condition or laboratory abnormalities that, in the opinion of
 the investigator, may increase risk associated with study participation or may
 interfere with the interpretation of study results

 -  Major surgery (e.g. intra-abdominal, intra-thoracic or intra-pelvic) within 4 weeks
 prior to starting study treatment or lack of recovery 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

 -  History of another primary malignancy that has not been in remission for at least 3
 years (the following malignancies are exempt from the 3 year limit: non-melanoma skin
 cancer, fully-excised melanoma in situ [stage 0], curatively treated, localized
 prostate cancer, and cervical carcinoma in situ in biopsy or a squamous
 intraepithelial lesion on Papanicolau [PAP] smear)

 -  Known cerebral/meningeal disease

 -  Clinically significant, uncontrolled heart disease and/or recent cardiac event (within
 6 months), such as: * Unstable angina * Myocardial infarction * 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 * Ventricular arrhythmias, or supraventricular/nodal arrhythmias not
 controlled with medications; other cardiac arrhythmias not controlled with medications
 * Left ventricular ejection fraction < 20% corrected QT (QTcF) > 470 ms using
 Fridericia's correction on the screening electrocardiogram (ECG) * Initiation or
 adjustment of antihypertensive medication(s) is allowed prior to screening

 -  Any active grade 3 or higher (per the National Cancer Institute [NCI] Common
 Terminology Criteria for Adverse Events [CTCAE], version 4.03) viral, bacterial, or
 fungal) infection within two weeks prior to the first dose of study treatment

 -  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: * Medication with a known risk of prolonging the QT
 interval or inducing Torsades de Pointes * Strong inhibitors or strong inducers of
 cytochrome P450, family 3, subfamily A, polypeptide 4/5 (CYP3A4/5) * Medications with
 a low therapeutic index that are primarily metabolized by CYP3A4/5, and/or cytochrome
 P450, family 2, subfamily C, polypeptide 9 (CYP2C9) * Therapeutic doses of warfarin
 sodium (Coumadin) or any other Coumadin-derived anti-coagulant; anticoagulants not
 derived from warfarin are allowed (e.g., dabigatran, rivaroxaban, apixaban) * Unstable
 or increasing doses of corticosteroids; if patients are on corticosteroids for
 endocrine deficiencies or tumor-associated symptoms (non-central nervous system
 [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

 -  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 positive
 b-hCG laboratory test