Brentuximab Vedotin and Gemcitabine Hydrochloride in Treating Younger Patients With Relapsed or Refractory Hodgkin Lymphoma

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose of
brentuximab vedotin in combination with gemcitabine administered every three weeks to
children with relapsed or primary refractory Hodgkin lymphoma (HL).

II. To define and describe the toxicities of brentuximab vedotin in combination with
gemcitabine administered on this schedule.

III. To determine the complete response (CR) rate after treatment with four cycles of
gemcitabine with brentuximab vedotin among patients with relapsed or refractory HL.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of brentuximab vedotin in combination with
gemcitabine within the confines of a Phase 1 study.

II. To describe the overall response rate (ORR) after 4 cycles of therapy among patients with
relapsed or refractory HL.

III. To describe the proportion of patients with HL able to mobilize an adequate yield of
cluster of differentiation (CD) 34+ stem cells after gemcitabine with brentuximab vedotin.

IV. To describe the relationship between disease response among patients with HL and changes
in thymus and activation-regulated chemokine (TARC) during treatment, and to determine if
specific micro ribonucleic acid (miRNA) profiles correlate with response to treatment.

V. To describe the frequency of the Fc gamma receptor IIIa (FcγRIIIa)-158 valine
(V)/phenylalanine (F) polymorphism among patients who experience pulmonary toxicity on this
protocol.

OUTLINE: This is a phase I, dose-escalation study of brentuximab vedotin followed by a phase
II study. (Phase I completed as of amendment 4)

Patients receive brentuximab vedotin intravenously (IV) over 30 minutes on day 1 and
gemcitabine hydrochloride IV over 100 minutes on days 1 and 8. Treatment repeats every 21
days for up to 15 more courses in the absence of disease progression or unacceptable
toxicity. Patients with CR after any course may go off protocol therapy for stem cell
transplant.

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

Inclusion Criteria:

- Patients must have had histologic verification of the malignancy at original
diagnosis; patients must have histologic verification of recurrent Hodgkin disease at
the time of relapse; no additional biopsy is required for patients with primary
refractory disease (i.e. no prior CR)

- PARTS A AND B: Patients with Hodgkin lymphoma (HL) are eligible for both the phase 1
and 2 portions, if they are in one of the following categories:

- Primary refractory disease (i.e. no prior CR)

- Very early relapse (< 6 months from the end of initial therapy, including
chemotherapy ± radiation)

- Advanced stage (III or IV) at diagnosis who relapse less than one year from the
end of initial therapy

- Note that patients with low-stage disease (IA or IIA) at initial diagnosis, who
were treated with radiation alone or fewer than four cycles of chemotherapy will
NOT be eligible

- Patients must have measurable disease, documented by clinical and radiographic
criteria

- Patients must have a life expectancy of >= 8 weeks (>= 56 days)

- Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16
years of age; patients who are unable to walk because of paralysis, but who are up in
a wheelchair, will be considered ambulatory for the purpose of assessing the
performance score

- Patients must have fully recovered from the acute toxic effects of all prior
anti-cancer chemotherapy

- At least 14 days after the last dose of myelosuppressive chemotherapy (28 days if
prior nitrosourea); Note: cytoreduction with hydroxyurea can be initiated and
continued for up to 24 hours prior to the start of therapy

- At least 14 days after the last dose of a long-acting growth factor (e.g.
Neulasta) or 7 days for short-acting growth factor; for agents that have known
adverse events occurring beyond 7 days after administration, this period must be
extended beyond the time during which adverse events are known to occur; the
duration of this interval must be discussed with the study chair

- At least 7 days after the last dose of a biologic agent; for agents that have
known adverse events occurring beyond 7 days after administration, this period
must be extended beyond the time during which adverse events are known to occur;
the duration of this interval must be discussed with the study chair

- At least 42 days after the completion of any type of immunotherapy, e.g. tumor
vaccines

- At least 3 half-lives of the antibody after the last dose of a monoclonal
antibody

- At least 14 days after local palliative radiation therapy (XRT) (small port); at
least 150 days must have elapsed if prior total body irradiation (TBI),
craniospinal XRT or if >= 50% radiation of pelvis; at least 42 days must have
elapsed if other substantial bone marrow (BM) radiation

- Patients with prior autologous or allogeneic stem cell transplant (SCT) are
excluded from this study

- At least 28 days must have elapsed since the most recent dose of bleomycin, to
allow adequate time to detect evidence of bleomycin-related pulmonary toxicity

- PART A: FOR PATIENTS WITH KNOWN BONE MARROW INVOLVEMENT (Completed as of Amendment 4)

- Peripheral absolute neutrophil count (ANC) >= 1000/uL

- Platelet count >= 100,000/uL (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment)

- PART B: FOR PATIENTS WITHOUT KNOWN BONE MARROW INVOLVEMENT

- Peripheral absolute neutrophil count (ANC) >= 750/uL

- Platelet count >= 75,000/uL (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment)

- Patients with lymphoma metastatic to bone marrow who have granulocytopenia, anemia,
and/or thrombocytopenia will be eligible for study but not evaluable for hematologic
toxicity (in Part A, there will be a maximum of one per cohort); such patients must
meet the blood counts as in Part A (may receive transfusions provided they are not
known to be refractory to red cell or platelet transfusions); if dose-limiting
hematologic toxicity is observed, all subsequent patients enrolled in Part A must be
evaluable for hematologic toxicity

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
ml/min/1.73 m^2 OR

- A serum creatinine based on age/gender as follows:

- =< 0.6 mg/dL (for 1 to < 2 years of age)

- =< 0.8 mg/dL (for 2 to < 6 years of age)

- =< 1.0 mg/dL (for 6 to < 10 years of age)

- =< 1.2 mg/dL (for 10 to < 13 years of age)

- =< 1.4 mg/dL (for females >= 13 years of age)

- =< 1.5 mg/dL (for males 13 to < 16 years of age)

- =< 1.7 mg/dL (for males >= 16 years of age)

- Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for
age

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

- Serum albumin >= 2 g/dL

- No evidence of dyspnea at rest, no exercise intolerance due to pulmonary
insufficiency, and a pulse oximetry > 92% while breathing room air

- Forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) > 60% by
pulmonary function test (PFT), unless due to large mediastinal mass from HL; carbon
monoxide diffusion capacity (DLCO), FEV1, and forced vital capacity all > 50%
predicted value; Note: pulmonary function testing is not required for children < 8
years old, or for any child who is developmentally unable to comply with pulmonary
function testing

- Patients with seizure disorder may be enrolled if on anticonvulsants and well
controlled

- Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE]
version [v] 4) resulting from prior therapy must be < grade 2

Exclusion Criteria:

- Pregnant or breast-feeding women will not be entered on this study; pregnancy tests
must be obtained in girls who are post-menarchal; males or females of reproductive
potential may not participate unless they have agreed to use an effective
contraceptive method during protocol therapy and for at least 30 days after the last
dose of brentuximab vedotin; abstinence is an acceptable method of birth control

- Concomitant medications

- Patients receiving stable or decreasing corticosteroids are not eligible for
other concurrent conditions (e.g. asthma, autoimmune diseases, rash, documented
adrenal insufficiency) are eligible for this study

- Patients who are currently receiving another investigational drug are not
eligible

- Patients who are currently receiving other anti-cancer agents are not eligible

- Patients who have an uncontrolled infection are not eligible

- Patients with an immunodeficiency that existed prior to diagnosis, such as primary
immunodeficiency syndromes, organ transplant recipients and children on current
systemic immunosuppressive agents are not eligible

- Patients known to be positive for human immunodeficiency virus (HIV) are not eligible

- Prior therapy

- Patients with prior exposure to brentuximab vedotin are not eligible; NOTE: prior
exposure to gemcitabine is NOT an exclusion criterion

- Patients who have undergone prior autologous or allogeneic SCT are not eligible

- Patients with HL who were stage IA or IIA at initial diagnosis and treated with
either radiation alone or < 4 cycles of chemotherapy are not eligible

- Patients who have received a prior solid organ transplantation are not eligible

- Patients with known hypersensitivity to Escherichia coli (E.coli)-derived proteins,
filgrastim, or any component of filgrastim are not eligible

- Patients who in the opinion of the investigator may not be able to comply with the
safety monitoring requirements of the study are not eligible

- All patients and/or their parents or legal guardians must sign a written informed
consent

- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met