Ceritinib With Brentuximab Vedotin in Treating Patients With 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