Brentuximab Vedotin or Crizotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage II-IV Anaplastic Large Cell Lymphoma

Study ID
NCI-2013-02167

Cancer Related
Yes

Healthy Volunteers
No

Study Sites

  • Children’s Medical Center (Dallas, Plano, Southlake)

Contact
AMANDA RICHARDS
214-456-6300
amanda.richards@childrens.com

Principal Investigator
Martha Stegner, M.D.

Official Title

A Randomized Phase II Trial of Brentuximab Vedotin (SGN35, NSC# 749710), or Crizotinib (NSC#749005, Commercially Labeled) in Combination With Chemotherapy for Newly Diagnosed Patients With Anaplastic Large Cell Lymphoma (ALCL)

Brief Overview


This partially randomized phase II trial studies how well brentuximab vedotin or crizotinib
and combination chemotherapy works in treating patients with newly diagnosed stage II-IV
anaplastic large cell lymphoma. Monoclonal antibody-drug conjugates, such as brentuximab
vedotin, can block cancer growth in different ways by targeting certain cells. Crizotinib
and methotrexate may stop the growth of cancer cells by blocking some of the enzymes needed
for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of
cancer cells, either by killing the cells, by stopping them from dividing, or by stopping
them from spreading. It is not yet known whether brentuximab vedotin and combination
chemotherapy is more effective than crizotinib and combination chemotherapy in treating
anaplastic large cell lymphoma.

Summary


PRIMARY OBJECTIVES:

I. To determine the tolerability of brentuximab vedotin given in combination with standard
chemotherapy (anaplastic large cell lymphoma [ALCL]99) and to determine the tolerability of
crizotinib given in combination with chemotherapy (ALCL99).

II. To estimate the event free survival (EFS) of Arm brentuximab vedotin (BV) and Arm
crizotinib (CZ) and contrast these to historical control data.

SECONDARY OBJECTIVES:

I. To determine the prognostic significance of minimal disseminated disease (MDD) at
diagnosis and minimal residual disease (MRD) as measured by real-time (RT)-polymerase chain
reaction (PCR) in peripheral blood.

OUTLINE: Patients are randomized into 1 of 2 treatment arms.

ARM BV:

COURSE A (COURSES 1, 3, AND 5): Patients receive brentuximab vedotin intravenously (IV) over
30 minutes on day 1, dexamethasone orally (PO) twice daily (BID) or IV on days 1-5,
ifosfamide IV over 60 minutes on days 1-5, methotrexate IV over 3 hours on day 1, cytarabine
IV over 1-30 minutes every 12 hours for 4 doses on days 4 and 5, and etoposide IV over 2
hours on days 4 and 5.

COURSE B (COURSES 2, 4, AND 6): Patients receive brentuximab vedotin, dexamethasone, and
methotrexate as in Arm BV, Course A. Patients also receive cyclophosphamide IV over 15-30
minutes on days 1-5 and doxorubicin hydrochloride IV over 1-15 minutes on days 4 and 5.

ARM CZ:

COURSE A (COURSES 1, 3, AND 5): Patients receive crizotinib PO BID on days 1-21 and
dexamethasone, ifosfamide, methotrexate, cytarabine, and etoposide as in Arm BV, Course A.

COURSE B (COURSES 2, 4, AND 6): Patients receive crizotinib as in Arm CZ, Course A and
dexamethasone, cyclophosphamide, methotrexate, and doxorubicin hydrochloride as in Arm BV,
Course B.

In all arms, treatment repeats every 21 days for 6 courses in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3, 6, 9, 12, 18, 24, 36,
48, and 60 months.

Participant Eligibility


Inclusion Criteria:

- Newly diagnosed patients with histologically proven ALCL (International
Classification of Diseases for Oncology [ICD-0] code: 9714/3)

- Disease must be cluster of differentiation (CD)30 positive

- Disease must be anaplastic lymphoma kinase (ALK) positive (defined by local
institutional standards)

- Patients must have stage II, III, or IV disease

- Patients must have a life expectancy of >= 8 weeks

- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age

- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x
upper limit of normal (ULN) for age; for the purpose of this study, the ULN for ALT
is 45 U/L

- If the lab abnormality is thought to be due to the lymphoma the patient is eligible
and dose adjustments should be made

- Shortening fraction of >= 27% by echocardiogram, or

- Ejection fraction of >= 50% by radionuclide angiogram

- Patients with a history of pulmonary dysfunction must have no evidence of dyspnea at
rest, no exercise intolerance due to pulmonary insufficiency, and a pulse oximetry >
92% while breathing room air unless current dysfunction is due to the lymphoma in
which case the patient is eligible

Exclusion Criteria:

- Patients with central nervous system (CNS) disease are not eligible

- Patients with disease limited to the skin are not eligible, regardless of how
wide-spread

- Patients with stage I disease are not eligible

- Patients who have received any prior cytotoxic chemotherapy for the current diagnosis
of ALCL or any cancer diagnosed previously are not eligible

- Previous steroid treatment and/or radiation treatment is not allowed unless it is for
the emergent management of a mediastinal mass; emergent steroid treatment and/or
radiation treatment should stop once protocol therapy is initiated

- Intrathecal chemotherapy prior to enrollment is allowed for the current diagnosis of
ALCL as long as adequate cerebrospinal fluid (CSF) is obtained prior to
administration of the intrathecal chemotherapy and subsequently demonstrated to be
negative for ALCL

- Female patients who are pregnant are not eligible; pregnancy tests must be obtained
in girls who are post menarchal

- Lactating females are not eligible unless they have agreed not to breastfeed their
infants

- Sexually active patients of reproductive potential are not eligible unless they agree
to use an effective contraceptive method for the duration of treatment and for 3
months after stopping treatment

- Patients with Down syndrome are not eligible

- Patients with an immunodeficiency that existed prior to diagnosis such as primary
immunodeficiency syndromes or organ transplant recipients are not eligible

- Cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) substrates with narrow
therapeutic indices: Patients chronically receiving medications known to be
metabolized by CYP3A4 and with narrow therapeutic indices including pimozide,
aripiprazole, triazolam, ergotamine and halofantrine are not eligible; the topical
use of these medications (if applicable) is allowed

- CYP3A4 inhibitors: patients chronically receiving drugs that are known potent CYP3A4
inhibitors within 7 days prior to study enrollment, including but not limited to
ketoconazole, itraconazole, clarithromycin, erythromycin, ritonavir, indinavir,
nelfinavir, saquinavir, delavirdine, nefazodone, diltiazem, verapamil, and grapefruit
juice are not eligible; the topical use of these medications (if applicable), e.g. 2%
ketoconazole cream, is allowed

- CYP3A4 inducers: patients chronically receiving drugs that are known potent CYP3A4
inducers within 12 days prior to study enrollment, including but not limited to
carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, ritonavir, and St.
John's wort are not eligible; the topical use of these medications (if applicable) is
allowed

- Patients that are known to be positive for human immunodeficiency virus (HIV) are not
eligible; note: inclusion of HIV positive patients will be considered at a later date

- Patients who weigh < 10 kg are not eligible