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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

Sclerosis

Nivolumab

Immunomodulating Agents

Lenograstim

Immune Checkpoint Inhibitors

Adjuvants, Immunologic

Patients receive doxorubicin hydrochloride IV, vinblastine sulfate IV, dacarbazine IV, and nivolumab IV over 30 minutes on days 1 and 15. Patients may receive pegfilgrastim SC on days 2 and 16, or filgrastim SC or IV on days 6-10 and 21-25. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. After completion of cycle 6, patients may receive radiation therapy 5 days per week for approximately 4 weeks at the discretion of the treating physician. Patients also undergo peripheral blood specimen collection and CT, PET/CT and MRI on study.

Patients receive doxorubicin hydrochloride IV, vinblastine sulfate IV, dacarbazine IV, and brentuximab vedotin IV over 30 minutes on days 1 and 15. Patients may receive pegfilgrastim SC on days 2 and 16, or filgrastim SC or IV on days 6-10 and 21-25. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. After completion of cycle 6, patients may receive radiation therapy 5 days per week for approximately 4 weeks at the discretion of the treating physician. Patients also undergo peripheral blood specimen collection and CT, PET/CT and MRI on study.

Biospecimen Collection

Computed Tomography

Filgrastim

Magnetic Resonance Imaging

Pegfilgrastim

Positron Emission Tomography

Quality-of-Life Assessment

Questionnaire Administration

Radiation Therapy

Vinblastine Sulfate

Alex F Herrera

This phase III trial compares immunotherapy drugs (nivolumab or brentuximab vedotin) when given with combination chemotherapy in treating patients with newly diagnosed stage III or IV classic Hodgkin lymphoma. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Brentuximab vedotin is a monoclonal antibody, brentuximab, linked to a toxic agent called vedotin. Brentuximab attaches to cancer cells in a targeted way and delivers vedotin to kill them. Chemotherapy drugs, such as doxorubicin, vinblastine, 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. The addition of nivolumab or brentuximab vedotin to combination chemotherapy may shrink the cancer or extend the time without disease symptoms coming back.

PRIMARY OBJECTIVE:

I. To compare the progression-free survival (PFS) in patients with newly diagnosed advanced stage classical Hodgkin lymphoma randomized to N-AVD (nivolumab, doxorubicin hydrochloride \[doxorubicin\], vinblastine sulfate \[vinblastine\], dacarbazine) versus that obtained with BV-AVD (brentuximab vedotin, doxorubicin, vinblastine, dacarbazine).

SECONDARY OBJECTIVES:

I. To compare overall survival (OS) in patients randomized to N-AVD versus BV-AVD.

II. To compare event-free survival (EFS) in patients randomized to N-AVD versus BV-AVD.

III. To compare the metabolic complete response (CR) rate at the end of treatment in patients randomized to N-AVD versus BV-AVD.

IV. To compare the physician-reported treatment-related adverse event rates between arms stratified by age groups.

V. To compare patient-reported symptoms using selected Patient Reported Outcome Common Toxicity Criteria for Adverse Events (PRO-CTCAE) items between arms stratified by age groups.

VI. To compare the safety and tolerability of N-AVD versus that of BV-AVD.

QUALITY OF LIFE OBJECTIVE:

I. To compare between arms patient-reported fatigue, neuropathy and health-related quality of life over time (baseline, beginning of cycle 3, 4-8 weeks after the last dose of protocol therapy \[following last dose of study drug or radiation therapy, whichever is later\], and 1 and 3 years after randomization) using the Patient Reported Outcomes Measurement Information System (PROMIS)-Fatigue, the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx), and the PROMIS Global, respectively.

BANKING OBJECTIVES:

I. To bank specimens for future correlative studies. II. To bank positron emission tomography (PET)-computed tomography (CT) images for future correlative studies.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive doxorubicin hydrochloride intravenously (IV), vinblastine sulfate IV, dacarbazine IV, and nivolumab IV over 30 minutes on days 1 and 15. Patients may receive pegfilgrastim subcutaneously (SC) on days 2 and 16, or filgrastim SC or IV on days 6-10 and 21-25. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. After completion of cycle 6, patients may receive radiation therapy 5 days per week for approximately 4 weeks at the discretion of the treating physician. Patients also undergo peripheral blood specimen collection and CT, PET/CT and/or magnetic resonance imaging (MRI) on study.

ARM II: Patients receive doxorubicin hydrochloride IV, vinblastine sulfate IV, dacarbazine IV, and brentuximab vedotin IV over 30 minutes on days 1 and 15. Patients may receive pegfilgrastim SC on days 2 and 16, or filgrastim SC or IV on days 6-10 and 21-25. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. After completion of cycle 6, patients may receive radiation therapy 5 days per week for approximately 4 weeks at the discretion of the treating physician. Patients also undergo peripheral blood specimen collection and CT, PET/CT and MRI on study.

After completion of study treatment and prior to disease progression, patients are followed up every 3 months for the first year, every 6 months for years 2 and 3, then annually until 10 years after registration. Patients are followed up at the time of progression and then annually until 10 years after registration. Patients who receive radiation therapy are followed up at 8-12 weeks after completion of radiation therapy.

Immunotherapy (Nivolumab or Brentuximab Vedotin) Plus Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage III-IV Classic Hodgkin Lymphoma

A Phase III, Randomized Study of Nivolumab (Opdivo) Plus AVD or Brentuximab Vedotin (Adcetris) Plus AVD in Patients (Age &gt;/= 12 Years) With Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

Will test the null hypothesis (HR=1) for PFS using stratified log-rank test with a one-sided alpha of 0.021. The analysis will be based on modified intent-to-treat and will include all eligible patients as randomized regardless of treatment received. The one-sided alpha of .021 will control of the overall type-one error of the study (including the 2 interim superiority analyses) to be less than .025.

Will be estimated using Kaplan-Meier method and compared between treatment arms using cox regression model.

Defined using 2014 Lugano classification.

Toxicity will be evaluated using Common Terminology Criteria of Adverse Events (CTCAE) version 5 items. Treatment-related toxicities between arms will be compared using Fisher's exact test stratified by age groups. Targeted patient-reported toxicities also will be collected at each time point using the Patient Reported Outcome (PRO)-CTCAE for patients 18 years and older and from youth 12-17 years, using the Pediatric PRO-CTCAE.

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)
Immunotherapy (Nivolumab or Brentuximab Vedotin) Plus Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage III-IV Classic Hodgkin Lymphoma	NCT03907488	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... Lymphocyte-Rich...	Biospecimen Col... Brentuximab Ved... Computed Tomogr... Dacarbazine Doxorubicin Hyd... Filgrastim Magnetic Resona... Nivolumab Pegfilgrastim Positron Emissi... Quality-of-Life... Questionnaire A... Radiation Thera... Vinblastine Sul...	12 Years -	National Cancer Institute (NCI)

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