CLINICAL TRIAL / NCT02166463
Brentuximab Vedotin and Combination Chemotherapy in Treating Children and Young Adults With Stage IIB, Stage IIIB, IVA, or IVB Hodgkin Lymphoma
- Interventional
- Recruiting
- NCT02166463
Contact Information
A Randomized Phase 3 Study of Brentuximab Vedotin (SGN-35) for Newly Diagnosed High-Risk Classical Hodgkin Lymphoma (cHL) in Children and Young Adults
This phase III trial studies brentuximab vedotin and combination chemotherapy to see how well they work compared to combination chemotherapy alone in treating children and young adults with stage IIB with bulk, stage IIIB, IVA, or IVB Hodgkin lymphoma. Combinations of biological substances in brentuximab vedotin may be able to carry cancer-killing substances directly to Hodgkin lymphoma cells. Chemotherapy drugs, such as doxorubicin hydrochloride, bleomycin sulfate, vincristine sulfate, etoposide, prednisone, and cyclophosphamide, 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 if combination chemotherapy is more effective with or without brentuximab vedotin in treating children with high-risk Hodgkin lymphoma.
PRIMARY OBJECTIVE:
I. To assess the event free survival (EFS) of a novel regimen incorporating brentuximab
vedotin (Bv; Adcetris) in the chemotherapy backbone of doxorubicin hydrochloride
(doxorubicin) (Adriamycin), vincristine sulfate (vincristine), etoposide, prednisone and
cyclophosphamide (Bv-AVEPC) in newly diagnosed high-risk classical Hodgkin lymphoma (cHL)
compared to those treated with Adriamycin, bleomycin sulfate, vincristine sulfate, etoposide,
prednisone, and cyclophosphamide (ABVE-PC).
SECONDARY OBJECTIVES:
I. To determine whether children/young adults with high-risk cHL treated with Bv-AVEPC have a
higher rate of early response (determined by fludeoxyglucose F 18 [FDG]-positron emission
tomography [PET]) and a reduction in protocol directed radiation therapy (RT) compared to
those treated with ABVE-PC.
II. To compare the rate of neuropathy (>= grade 3) among patients treated on the Bv-AVEPC
(experimental arm) to patients treated on the ABVE-PC (standard arm).
EXPLORATORY OBJECTIVES:
I. To validate and compare the Childhood Hodgkin International Prognostic Score (CHIPS) to
conventional Ann Arbor stage (stages II B with bulk, III B, IV A or B) in predicting outcome
in high-risk childhood cHL.
II. To determine the incidence of preferentially expressed antigen in melanoma (PRAME) and
testis-specific antigens in Epstein-Barr virus (EBV)- cHL tumors and the incidence of EBV
antigens (Epstein-Barr nuclear antigen 1 [EBNA1], Epstein-Barr virus latent membrane protein
1 [LMP1], large multifunctional peptidase 2 [LMP2]) in EBV+ cHL tumors, with the goal of
developing strategies to integrate cellular therapy into treatment for newly diagnosed
high-risk cHL. (Biology) III. To incorporate qualitative visual FDG-PET into
response-directed treatment algorithms and explore quantitative FDG-PET and computed
tomography (CT) definitions of tumor burden and response for incorporation into next
generation pediatric cHL risk-stratification schemes, exploring the extension of these
algorithms to young adults. (Imaging) IV. To evaluate the reduction in normal tissue
irradiation associated with the current treatment approach compared to the volume of historic
involved field radiation therapy (IFRT) fields. (Radiation Therapy) V. To evaluate EFS and
patterns of relapse following protocol-specified RT utilization and treatment volumes.
(Radiation Therapy) VI. To characterize the extent of chemotherapy induced peripheral
neuropathy (CIPN), as reported by patients and parent proxies, through serial administration
of the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group-Neurotoxicity
(FACT-GOG-NTX). (Patient Reported Outcomes [PRO] of Peripheral Neuropathy and Health-Related
Quality of Life) VII. To describe the Health-Related Quality of Life (HRQL) consequences of
peripheral neuropathy over time by correlating total neuropathy scale scores with the
individual items with the Child Health Ratings Inventories (CHRIs)-Global scale (e.g.,
physical health, pain, emotional functioning). (PRO of Peripheral Neuropathy and
Health-Related Quality of Life) VIII. To perform a cross validation of the FACT-GOG-NTX with
the Total Neuropathy Score-Pediatric Vincristine (TNS-PV) to determine the performance of
both measures with the use of brentuximab vedotin in a limited institutional approach in
children and adolescents with cHL. (PRO of Peripheral Neuropathy and Health-Related Quality
of Life) IX. To assess the resource use and cost implications of Bv in combination with
chemotherapy and radiotherapy (RT) for newly diagnosed high-risk cHL in children and young
adults. (Economic) X. To estimate the risk of relapse among rapidly responding lesions (RRL)
subjects that have at least one lesion that is Deauville 3 at PET 2. (Follow-up of Deauville
score 3 lesions on FDG-PET imaging [confirmed by central imaging review]) XI. To characterize
the pharmacokinetics of brentuximab vedotin in children < 13 years of age.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I (ABVE-PC): Patients receive doxorubicin hydrochloride intravenously (IV) over on days
1-2, bleomycin sulfate IV or subcutaneously (SC) on days 1 and 8, vincristine sulfate IV on
days 1 and 8, etoposide IV on days 1-3, prednisone orally (PO) twice daily (BID) or
methylprednisolone IV on days 1-7, and cyclophosphamide IV on days 1 and 2.
ARM II (Bv-AVEPC): Patients receive brentuximab vedotin IV on day 1. Patients also receive
doxorubicin hydrochloride, etoposide, prednisone or methylprednisolone, and cyclophosphamide
as in Arm I and vincristine sulfate IV on day 8.
In both arms, treatment repeats every 21 days for 5 cycles in the absence of disease
progression or unacceptable toxicity. Granulocyte simulating factor (GCSF) or equivalent is
given on both arms.
After completion of study treatment, patients are followed up at 3, 6, 9, 12, 18, 24, 30, 36,
and 48 months.
Gender
All
Age Group
2 Years to 22 Years
Accepting Healthy Volunteers
No
Inclusion Criteria:
- Patients with newly diagnosed, pathologically confirmed cHL meeting one of the
following Ann Arbor stages are eligible:
- Stage IIB with bulk
- Stage IIIB
- Stage IVA
- Stage IVB
- If study eligibility by staging is uncertain, consultation with Imaging and
Radiation Oncology Core (IROC) Rhode Island (RI) may be obtained prior to
study enrollment
- 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 (performed within
14 days prior to enrollment):
- 2 to < 6 years: male 0.8 mg/dL, female 0.8 mg/dL
- 6 to < 10 years: male 1 mg/dL, female 1 mg/dL
- 10 to < 13 years: male 1.2 mg/dL, female 1.2 mg/dL
- 13 to < 16 years: male 1.5 mg/dL, female 1.4 mg/dL
- >= 16 years: male 1.7 mg/dL, female 1.4 mg/dL
- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (performed within 14 days
prior to enrollment)
- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate transaminase [AST]) or serum
glutamate pyruvate transaminase (SGPT) (alanine transaminase [ALT]) < 2.5 x upper
limit of normal (ULN) for age (performed within 14 days prior to enrollment)
- Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by
radionuclide angiogram
- Forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) > 60% by
pulmonary function test (PFT), unless due to large mediastinal mass from Hodgkin
lymphoma (HL)
- For children who are unable to cooperate for PFTs, the criteria are: no evidence of
dyspnea at rest, no exercise intolerance, and a pulse oximetry reading of > 92% on
room air
- 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
Exclusion Criteria:
- Patients with nodular lymphocyte-predominant HL
- 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 who are pregnant; (since fetal toxicities and teratogenic effects have been
noted for several of the study drugs, a negative pregnancy test is required for female
patients of childbearing potential)
- Lactating females who plan to breastfeed
- Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation and for
30 days after the last dose of chemotherapy
- Patients known to be positive for human immunodeficiency virus (HIV) are not eligible
- Patients who have received any previous chemotherapy or radiation therapy are not
eligible
- Patients who received systemic corticosteroids within 28 days of enrollment on this
protocol, except as specified, are not eligible