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Patients receive doxorubicin hydrochloride IV, vinblastine sulfate IV, and dacarbazine IV on days 1 and 15. Patients also receive brentuximab vedotin IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Doxorubicin Hydrochloride

Pharmacological Study

Paul G Rubinstein

This pilot phase I/II trial studies the side effects and the best dose of brentuximab vedotin when given together with combination chemotherapy and to see how well they work in treating patients with stage II-IV human immunodeficiency virus (HIV)-associated Hodgkin lymphoma. Brentuximab vedotin is a monoclonal antibody, called brentuximab, linked to a chemotherapy drug called vedotin. Brentuximab attaches to CD30-positive cancer cells in a targeted way and delivers vedotin to kill them. Drugs used in chemotherapy, such as doxorubicin hydrochloride, vinblastine sulfate, and dacarbazine, 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. Giving brentuximab vedotin together with combination chemotherapy may kill more cancer cells.

PRIMARY OBJECTIVES I. To identify the maximum tolerated dose (MTD) of brentuximab vedotin when combined with the doxorubicin hydrochloride, vinblastine sulfate, and dacarbazine (AVD) chemotherapy regimen in the treatment of HIV-associated stage II-IV Hodgkin lymphoma. (Phase I) II. Establish an estimate of the two-year progression-free survival (PFS) for participants with HIV-associated stage II-IV Hodgkin lymphoma when treated using brentuximab vedotin plus the AVD chemotherapy regimen. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the toxicity of AVD and brentuximab vedotin with highly active antiretroviral therapy (HAART).

II. To estimate the partial response (PR) rate, complete response (CR) rate, overall survival (OS), and event free survival (EFS) at 2 and 5 years.

III. To evaluate the effect of AVD and brentuximab vedotin on cluster of differentiation (CD)4 and CD8 counts after cycle 1, 4, at the end of therapy, and every 3 months after treatment completion for one year.

IV. To investigate the prognostic value of fludeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) scans at baseline, after cycle 2, and at treatment completion, with respect to 2-year progression free survival.

V. To evaluate HAART status at baseline and to correlate this with tumor response to therapy and OS and PFS.

VI. To characterize the histologic subtypes in HIV-Hodgkin lymphoma (HL) in the highly active antiretroviral therapy (HAART) era.

VII. To assess the neurotoxicity of HAART in combination with AVD and brentuximab vedotin.

VIII. To evaluate effect of AVD and brentuximab vedotin on viral load after cycles 1, 4, at the completion of therapy, and every 3 months after treatment completion for one year.

IX. To perform pharmacokinetic and immunogenicity studies to determine drug levels during therapy.

X. To perform micro ribonucleic acid (miRNA) profile analysis on the HIV-HL tumor specimens and to correlate miRNA expression with OS, PFS, tumor response to therapy, histologic subtype of HIV-HL, and HIV disease characteristics.

XI. To perform tissue microarray analysis on HIV-HL tumor specimens and to correlate the markers studied with OS, PFS, and tumor response to therapy.

XII. To identify Epstein-Barr virus (EBV)-associated tumor derived deoxyribonucleic acid (DNA) in the plasma of study participants and to correlate these levels during therapy with disease response and OS. (Phase II) XIII. To identify cytokines in the plasma of participants during therapy that can be used as tumor and prognostic markers. (Phase II) XIV. To assess latent and expressed HIV reservoirs before, during, and post chemotherapy. To understand how cytotoxic chemotherapeutic agents affect HIV expression.

OUTLINE: This is a phase I, dose-escalation study of brentuximab vedotin followed by a phase II study.

Patients receive doxorubicin hydrochloride intravenously (IV), vinblastine sulfate IV, and dacarbazine IV on days 1 and 15. Patients also receive brentuximab vedotin IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Brentuximab Vedotin and Combination Chemotherapy in Treating Patients With Stage II-IV HIV-Associated Hodgkin Lymphoma

A Pilot Trial of AVD and Brentuximab Vedotin (SGN-35) in the Treatment of Stage II-IV HIV-Associated Hodgkin Lymphoma

Defined as the dose level at which =\< 1 of 6 subjects experience dose limiting toxicity.

2-year PFS is determined based on the Kaplan-Meier estimates and corresponding 95% confidence intervals based on standard errors using Greenwood's formula.

Number of Participants who had one or more adverse events

Number of participants who achieved a partial response per RECIST v1.0 criteria

Number of participants who experienced a complete response per RECIST v1.0 criteria

Number of participants who achieved a complete response per RECIST v1.0 criteria

Proportion of study participants who are alive at 2 years estimated using the Kaplan-Meier survival function

Proportion of participants who are alive at 5 years using a Kaplan-Meier estimate

Proportion of participants who are alive and progression-free at 2 years

Binomial probabilities and their 95% confidence intervals will be used to estimate the response rates (i.e., partial response rate, complete response rate, overall response rate) and event free survival at 2 and 5 years of AVD and brentuximab vedotin for a treatment of patients with stage III/IV HIV-associated Hodgkin lymphoma.

CD4 counts (absolute) at visit 4 (cycle 5)

Log-rank analysis will be used to investigate the prognostic value of FDG-PET scans at baseline, after 2 courses and post-therapy in patients with HIV and HL with respect to progression free survival.

Log-rank analysis will be used to evaluate HAART status at baseline for difference in outcome in terms of overall survival and progression free survival.

Participants with mixed cellularity histologic subtype

Number of participants who experience neurotoxicity at cycle 5 (visit 4)

The Lymphoma Academic Research Organisation

National Cancer Institute (NCI)

Patients receive doxorubicin hydrochloride IV, vinblastine sulfate IV, and dacarbazine IV on days 1 and 15. Patients also receive brentuximab vedotin IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Brentuximab Vedotin: Given IV

Dacarbazine: Given IV

Doxorubicin Hydrochloride: Given IV

Pharmacological Study: Correlative studies

Vinblastine: Given IV

Phase I - Brentuximab 1.2 mg/kg

Phase II - Brentuximab 1.2 mg/kg

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

France

Region of Enrollment

Kimberly Mosby-Griffin

Treatment (Brentuximab and Combination Chemotherapy)

Participants entered into the phase I portion of the study

Maximal Tolerated Dose of Brentuximab Vedotin (Phase I)

2-year Progression-free Survival (PFS)

Participants who were treated with brentuximab and combination chemotherapy

Frequency of Adverse Events

Partial Response Rate

Complete Response Rate

2-year Overall Survival

Overall Survival

Phase II Brentuximab 1.2 mg/kg

Event-free Survival

Participants with absolute cd4 counts at cycle 5

CD4 Counts

Participants with absolute CD8 counts at cycle 5

CD8 Counts

Viral Load

Prognostic Value of Fludeoxyglucose F-18 (FDG)-Positron Emission Tomography (PET) in Patient With HIV and Hodgkin Lymphoma (HL) With Respect to 2 Year Progression Free Survival

Prognostic Value of FDG-PET in Patient With HIV and HL With Respect to 2 Year Progression Free Survival

HAART Status

Characterization of Histologic Subtypes in HIV-HL in the HAART Era

Participants who had neurotoxicity evaluated at cycle 5

Incidence of Neurotoxicity

Patients receive doxorubicin hydrochloride IV, vinblastine sulfate IV, and dacarbazine IV on days 1 and 15. Patients also receive brentuximab vedotin IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Brentuximab Vedotin: Given IV

Phase II - Brentuximab 1.2 m/kg

Overall Study

Antirheumatic Agents

Anti-Inflammatory Agents

Dermatologic Agents

Antiemetics

Neuroprotective Agents

Gastrointestinal Agents

Etoposide

Cyclophosphamide

Prednisone

Vincristine

Prednisolone

Etoposide phosphate

Podophyllotoxin

Methylprednisolone

Bleomycin

Cortisone

Methylprednisolone Acetate

Methylprednisolone Hemisuccinate

Prednisolone acetate

Prednisolone hemisuccinate

Prednisolone phosphate

Immunosuppressive Agents

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Protective Agents

Keratolytic Agents

Patients receive doxorubicin hydrochloride IV over on days 1-2, bleomycin sulfate IV or SC on days 1 and 8, vincristine sulfate IV on days 1 and 8, etoposide IV on days 1-3, prednisone orally PO BID or methylprednisolone IV on days 1-7, and cyclophosphamide IV on days 1 and 2. Treatment repeats every 21 days for 5 cycles in the absence of disease progression or unacceptable toxicity.

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. Treatment repeats every 21 days for 5 cycles in the absence of disease progression or unacceptable toxicity.

Bleomycin Sulfate

Laboratory Biomarker Analysis

Quality-of-Life Assessment

Questionnaire Administration

Vincristine Sulfate

Sharon M Castellino

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.

Brentuximab Vedotin and Combination Chemotherapy in Treating Children and Young Adults With Stage IIB, Stage IIIB, IVA, or IVB Hodgkin Lymphoma

A Randomized Phase 3 Study of Brentuximab Vedotin (SGN-35) for Newly Diagnosed High-Risk Classical Hodgkin Lymphoma (cHL) in Children and Young Adults

CHIPS will be computed for all patients and summarized by descriptive statistics. Will examine the association between CHIPS and early response by cross-tabulations and Chi-square tests within each arm separately, as well as logistic regression model where early response is the outcome variable and CHIPS the predictor variable combining the 2 arms with adjustment for randomized chemotherapy.

Descriptive statistics will be used to summarize RT doses received by normal tissues on this study. Two-sample t-test will be used to compare the doses received on this study to those on prior studies.

EFS for patients on each arm as well as those receiving ISRT or those with slow early response (SER) on each arm will be estimated. One-sample log rank test will be used to compare the observed EFS to the assumed baseline of 82% at 3 years to see if the observed EFS is significantly lower than the projection in these subsets.

The risk of relapse for cases that are RRL, but have Deauville 3 lesions, will be compared to those that are classified as complete metabolic response at PET2 with solely Deauville 1 or 2 lesions with K-sample test.

PK concentration time profile will be evaluated.

Primary analysis will be based 1-sided log rank test comparison of EFS curves between the 2 randomized arms per intention-to-treat principle. Progression is defined as an ≥50% increase of in the product of the perpendicular diameters of any of the involved nodes or nodal masses or focal organ lesions in sites that were persistently PET positive; or recurrent PET positive lesions (Deauville 4, 5) in sites that had previously been PET negative regardless of change of size, as was the development of new PET avid measurable lesion(s) \>1.5cm in any axis, or new sites of assessable disease. Relapse is defined in patients who achieved a prior CR but subsequently has an increase of ≥50% of the PPD in prior nodal or extranodal sites in a recurrently PET positive lesion(s), or the development of new measurable lesion(s) \>1.5cm in any axis, or new sites of assessable disease. Second malignancy is defined based on report of a cancer that is not considered to be classic Hodgkin Lymphoma.

The percentages of patients (with available PET scan) with no SRL and no PD will be compared between the two randomized arms to see if brentuximab vedotin in the chemotherapy backbone of doxorubicin hydrochloride, vincristine sulfate, etoposide, prednisone and cyclophosphamide (Bv-AVEPC) arm has a higher rate of early response compared to doxorubicin hydrochloride, bleomycin sulfate, vincristine sulfate, etoposide, prednisone, and cyclophosphamide (ABVE-PC) arm. Two-sample Z test of proportions at 1-sided alpha level of 0.05 will be used for these comparisons.

The percentages of patients experiencing grade 3+ peripheral neuropathy assessed by the treating clinician using the modified Balis scale. The "Modified Balis scale of Pediatric Neuropathy" allows clinicians to assign a score for sensory or motor neuropathy symptoms separately. Scores range from 1 to 4 with 1 being the least symptomatic state and 4 indicating a severe debility. The percentages of patients (with a score \>/=3) will be compared between the 2 arms by two-sample Z test at 1-sided alpha level of 0.05.

Adverse Events are collected using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). Per the protocol, SAE reporting requirements and expedited reporting of AEs did differ for the Bv-AVEPC arm, given that Bv was under IND. All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table.

Arm I (ABVE-PC)

ARM II (Bv-AVEPC)

Age, Categorical

Canada

Results Reporting Coordinator

Assuming a 3-year EFS of 82% (5-year EFS of 78.4%, long term EFS of 76%) for standard arm, the study will have approximately 86% power for detecting an 8% improvement in 3-year EFS in the Bv-AVEPC arm (3-year EFS of 90%, 5-year EFS of 88.0%, long term EFS of 86.7%) in log rank test.

All the eligible patients who had undergone randomization

Event Free Survival (EFS), Where Events Include Disease Progression or Relapse, Second Malignancy, or Death

All the eligible patients who had undergone randomization and had PET result by central review after completed cycle 2

Percentages of Patients With Early Response Defined as no Slow Responding Lesions (SRL) and no Progressive Disease (PD) at Any Disease Sites Determined by Positron Emission Tomography (PET) Per Deauville Criteria Through Central Review

Percentages of Patients Experiencing Grade 3+ Peripheral Neuropathy Assessed by Modified Balis Scale

Childhood International Prognostic Score (CHIPS) Score

Dose of Radiation Received by Normal Tissues Following Chemotherapy on Either Study Arm

Efficacy of Involved Site Radiotherapy (ISRT) by Analyzing the Event-free Survival of Patients Treated With Response-adapted ISRT and by Evaluating Patterns of Relapse Following ISRT

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Brentuximab Vedotin and Combination Chemotherapy in Treating Patients With Stage II-IV HIV-Associated Hodgkin Lymphoma	NCT01771107	AIDS-Related Ho... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Classic Hodgkin... HIV Infection	Brentuximab Ved... Dacarbazine Doxorubicin Hyd... Pharmacological... Vinblastine	18 Years -	National Cancer Institute (NCI)
Brentuximab Vedotin and Combination Chemotherapy in Treating Children and Young Adults With Stage IIB, Stage IIIB, IVA, or IVB Hodgkin Lymphoma	NCT02166463	Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Childhood Hodgk... Classic Hodgkin...	Bleomycin Sulfa... Brentuximab Ved... Cyclophosphamid... Doxorubicin Hyd... Etoposide Laboratory Biom... Methylprednisol... Pharmacological... Prednisone Quality-of-Life... Questionnaire A... Vincristine Sul...	2 Years - 22 Years	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for ann arbor stage iiib hodgkin lymphoma