A Pilot Study of Brentuximab Vedotin Combined with AVD Chemotherapy in Patients with Newly Diagnosed Early Stage, Unfavorable Risk Hodgkin Lymphoma

This phase II trial studies how well brentuximab vedotin works when given with combination chemotherapy and radiation therapy in treating patients with newly diagnosed, early stage, unfavorable-risk Hodgkin lymphoma. Brentuximab vedotin is a monoclonal antibody, called brentuximab, linked to a chemotherapy drug called vedotin. Brentuximab attached to CD30 positive cancer cells in a targeted way and delivers vedotin to kill them. Drugs used in chemotherapy, such as doxorubicin hydrochloride, vinblastine, and dacarbazine, work in different ways to stop the growth of cancer cells, either by killing them, by stopping them from dividing, or by stopping them from spreading. Involved-site radiation therapy uses high energy x rays to kill cancer cells. Giving brentuximab vedotin with combination chemotherapy and involved-site radiation therapy may kill more cancer cells and may have fewer side effects than other types of treatment.

Inclusion Criteria

• Histologic diagnosis of classical CD30 positive Hodgkin lymphoma confirmed at enrolling institution
• Fludeoxyglucose F 18 (FDG)-avid disease by FDG-PET/CT and measurable disease of at least 1.5 cm by CT
• Ann Arbor stage I or II disease
• Disease bulk defined as any lymph node mass with transverse maximal diameter > 7.0 cm OR coronal maximal diameter > 7.0 cm on CT imaging
• Females of childbearing age must be on an acceptable form of birth control per institutional standards

Exclusion Criteria

• Cardiac ejection fraction =< 50%
• Hemoglobin-adjusted diffusing capacity of carbon monoxide < 40%
• Absolute neutrophil count (ANC) =< 1000/ul
• Platelets =< 75,000/ul
• Total bilirubin >= 2.0 mg/dl in the absence of a history of Gilbert's disease
• Serum creatinine clearance of < 30 mL/min as estimated by the Cockcroft-Gault method
• Known pregnancy or breast-feeding
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Medical illness unrelated to Hodgkin lymphoma, which, in the opinion of the attending physician and/or Memorial Sloan Kettering (MSK) principal investigator, makes participation in this study inappropriate
• Peripheral neuropathy > grade 1
• Patients receiving chronic treatment with systemic steroids; however, patients can receive up to 10 days of steroid therapy prior to starting treatment with brentuximab vedotin (BV)+ doxorubicin, vinblastine, dacarbazine (AVD)

PRIMARY OBJECTIVES:

I. Evaluate the rate of development of significant pulmonary toxicity with the proposed treatment program. (Initial 30 patients)

II. Evaluate the rate of positron emission tomography (PET)-negative complete responses at the end-of-treatment. (All four cohorts)

SECONDARY OBJECTIVES:

I. Preliminarily evaluate the 1-year progression-free survival of the treatment program in cohorts 1-4.

II. Evaluate the prognostic significance (i.e. correlation with progression free survival) of interim fluorodeoxyglucose-positron emission tomography (PET) in this patient population measured by visual analysis and semi-quantitative analysis.

III. Compare the effect of the radiation therapy (RT) field and dose on pattern of progression and treatment-related toxicity.

IV. Evaluate the prognostic significance (i.e. correlation with progression free survival) of serum cytokine levels.

V. Evaluate the prognostic significance of gene-expression based predictor using NanoString technology.

OUTLINE: Patients are assigned to 1 of 4 cohorts.

COHORT I (CLOSED TO ACCRUAL): Patients receive brentuximab vedotin intravenously (IV) over 30 minutes, doxorubicin hydrochloride IV over 3-5 minutes, vinblastine sulfate IV over 3-5 minutes, and dacarbazine IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Within 12-42 days, patients whose PET scan is negative undergo higher-dose ISRT 5 days a week for 2-3 weeks.

COHORT II (CLOSED TO ACCRUAL): Patients receive brentuximab vedotin, doxorubicin hydrochloride, vinblastine sulfate, and dacarbazine as in Cohort I. Within 12-42 days, patients whose PET scan is negative undergo lower-dose ISRT 5 days a week for 2-3 weeks.

COHORT III: Patients receive brentuximab vedotin, doxorubicin hydrochloride, vinblastine sulfate, and dacarbazine as in Cohort I. After completion of cycle 4, patients whose PET scan is negative undergo consolidation volume radiation therapy (CVRT) daily for 3.5 weeks.

COHORT IV: Patients receive brentuximab vedotin, doxorubicin hydrochloride, vinblastine sulfate, and dacarbazine as in Cohort I. After completion of cycle 4, patients whose PET scan is negative undergo a consultation and PET-computed tomography (CT) simulation but receive no further treatment.

After completion of study treatment, patients are followed up at 4 and 8 weeks, and then every 6 months for up to 5 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Anita Kumar

• Primary ID 13-034
• Secondary IDs NCI-2013-01144
• Clinicaltrials.gov ID NCT01868451