Brentuximab Vedotin and Combination Chemotherapy in Treating Older Patients With Previously Untreated Stage II-IV Hodgkin Lymphoma

LEAD IN: Patients receive brentuximab vedotin intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity.

AVD CHEMOTHERAPY: Patients then receive doxorubicin hydrochloride IV, vinblastine IV, and dacarbazine IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients achieving CR receive brentuximab vedotin IV over 30 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

• brentuximab vedotin (Drug), also known as anti-CD30 ADC SGN-35, anti-CD30 antibody-drug conjugate SGN-35, antibody-drug conjugate SGN-35, SGN-35: Given IV
• doxorubicin hydrochloride (Drug), also known as ADM, ADR, Adria, Adriamycin PFS, Adriamycin RDF: Given IV
• vinblastine (Drug), also known as Velban, Velsar, VLB: Given IV
• dacarbazine (Drug), also known as DIC, DTIC, DTIC-Dome: Given IV
• quality-of-life assessment (Procedure), also known as quality of life assessment: Ancillary studies
• DNA analysis (Genetic): Optional correlative studies
• RNA analysis (Genetic): Optional correlative studies
• fludeoxyglucose F 18 (Radiation), also known as 18FDG, FDG: Correlative studies
• positron emission tomography (Procedure), also known as FDG-PET, PET, PET scan, tomography, emission computed: Correlative studies
• laboratory biomarker analysis (Other): Optional correlative studies
• immunohistochemistry staining method (Other), also known as immunohistochemistry: Optional correlative studies
• polymorphism analysis (Genetic): Optional correlative studies

Primary outcomes

• Complete Remission Rate After Chemotherapy [after completion of AVD chemotherapy and prior to SGN-35 consolidation, approximately 9 months]: The primary objective of this study is to evaluate the complete remission rate among older patients with HL receiving sequential brentuximab vedotin therapy with AVD chemotherapy

Secondary outcomes

• Overall Response Rate After 2 Cycles of SGN-35 [2 cycles of SGN-35 lead-in therapy, approximately 42 days]: The incidence of overall response rate to induction SGN-35 will be reported for the initial 22 patients where PET is being employed.
• Complete Remission Rate Following 2 Cycles of SGN-35 [2 cycles of lead-in SGN-35, approximately 42 days]: The incidence of CR rate to induction SGN-35 will be reported for the initial 22 patients where PET is being employed
• Safety of Sequential SGN-35/AVD/SGN-35 Therapy [From time of treatment to 30 days after discontinuation of study treatment]: Detailed examination of Averse Events, laboratory test results, vital signs or other physical findings. Below we have summarized the top 10 most common Grade 3 and Grade 4 related adverse events. Please see the Adverse Events section of this record for a full listing of Adverse Events.
• 2-year Progression Free Survival [2 years from time of registration to study]: Progression Free Survival (PFS) is defined as lymphoma progression or death from any cause. This outcome measure is the percentage of patients that have not progressed at 2 years from time of registration.
• Overall Survival Following SGN-35/AVD Sequential Therapy [up to 2 years from the time of registration]: Defined as the percentage of patients that are alive 2 years after registration.
• 2 Year Event-Free Survival [From registration until treatment failure, up to 2 years]: An event is defined as treatment failure including discontinuation of treatment for any reason, such as disease progression, toxicity, patient preference, initiation of new treatment without documented progression, or death. This outcome measure is reported as the percentage of patient that did not have an event at 2 years from registration.
• Freedom From Progression [from baseline to end of study, approximately 4 years]: Measured from the time of study entry to progression of disease. Other causes of treatment failure are not include in freedom from progression.
• Patient Reported Outcomes for Symptoms and Quality of Life [Baseline and AVD Cycle 1, a total of 6 weeks]: Evaluate patient reported outcomes at baseline and during treatment to determine potential symptom palliation, treatment-related symptoms, and overall health-related quality of life. The Function Assessment of Cancer Therapy for Lymphoma (FACT-Lym) scale has a range of 0(minimum score) to 168 (maximum score). Higher scores indicate a better outcome. The mean scores for each timepoint are reported below.
• Association Between Cumulative Illness Rating Scale (CIRS) With Outcomes [approximately 2 years from treatment start]: Number of co-morbidities collected for each patient at baseline and at the end of completion of all therapy utilizing the Cumulative Illness Rating Scare (CIRS). For binary outcomes such as CR, logistic regression will be used to assess the relationship with CIRS score; for time-to-event outcomes, the method of Kalan Meier and the log rank test will be used. The minimum score of the CIRS is 0 and the maximum score is 56. High Scores on the CIRS scale indicate that the patient has more severe comorbidities

Sex: All, ages: 60 Years to any

Inclusion Criteria:

* Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care
* Previously untreated classical Hodgkin lymphoma (i.e., nodular sclerosis, mixed cellularity, lymphocyte depleted, lymphocyte-rich, and not otherwise specified \[NOS\]); nodular lymphocyte predominant Hodgkin lymphoma is not eligible
* Stage II, III, and IV disease by Ann Arbor classification
* Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
* Patients must have bi-dimensional measurable disease documented in the lymphoma baseline tumor assessment form within 30 days prior to registration (at least 1.5 cm); patients with non-measurable disease in addition to measurable disease must have been assessed within 60 days prior to registration
* Patients must have a bone marrow biopsy (bilateral preferred, unilateral acceptable) within 60 days prior to registration
* Patients must have a multi gated acquisition scan (MUGA) or echocardiogram within 60 days prior to study registration and the ejection fraction must be >= 45%
* Absolute neutrophil count (ANC) > 1000/mm\^3
* Platelet count > 75,000/mm\^3
* Creatinine < 2.5 mg/dl
* Bilirubin < 3.0 mg/dl
* Patients with documented marrow involvement by lymphoma at the time of registration are not required to meet the above hematologic parameters
* Patients must not have received prior chemotherapy or radiation therapy for the treatment of Hodgkin lymphoma
* Both females and males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug
* Patients must sign the informed consent form before registration

Exclusion Criteria:

* Previous treatment with brentuximab vedotin or any other prior anti-CD30-based antibody therapy
* History of another primary malignancy that has not been in remission for at least 3 years; (the following are exempt from the 3-year limit: early stage \[stage I or II\] breast cancer treated with surgery and radiation +/- hormones \[without adjuvant chemotherapy\], non-melanoma skin cancer, fully excised melanoma in situ \[stage 0\], curatively treated localized prostate cancer, and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Papanicolaou test \[PAP smear\])
* Known cerebral/meningeal disease
* Any active systemic viral, bacterial, or fungal infection requiring treatment with antimicrobial therapy within 1 week prior to first dose
* Patients with hepatitis B surface antigen (HBsAg) positive hepatitis B virus (HBV) infection; patients with prior history of hepatitis B infection, but immune, with only Immunoglobulin G (IgG) hepatitis core antibody + (HBcAb +) must receive anti-viral prophylaxis (e.g., lamivudine 100mg orally \[po\] daily) for at least 1 week prior to cycle 1 and throughout induction and continuation therapy and for at least 6 months after the last brentuximab vedotin dose; in addition, consultation with a hepatologist is recommended
* Patients with a known hypersensitivity to any excipient contained in the drug formulation
* Patients with dementia or an altered mental state that would preclude the understanding and rendering of informed consent

Participant flow

Outcome results

• Complete Remission Rate After Chemotherapy (Primary), Count of participants, Participants: Treatment (Antibody-drug Conjugate and Combination Chemo) 38
• Overall Response Rate After 2 Cycles of SGN-35 (Secondary), Count of participants, Participants: Treatment (Antibody-drug Conjugate and Combination Chemo) 18
• Complete Remission Rate Following 2 Cycles of SGN-35 (Secondary), Count of participants, Participants: Treatment (Antibody-drug Conjugate and Combination Chemo) 8
• Safety of Sequential SGN-35/AVD/SGN-35 Therapy (Secondary), Number, participants: Treatment (Antibody-drug Conjugate and Combination Chemo) 21
• 2-year Progression Free Survival (Secondary), Number, percentage of patients: Treatment (Antibody-drug Conjugate and Combination Chemo) 84 (69 to 92)
• Overall Survival Following SGN-35/AVD Sequential Therapy (Secondary), Number, percentage of patients: Treatment (Antibody-drug Conjugate and Combination Chemo) 93 (80 to 98)
• 2 Year Event-Free Survival (Secondary), Number, percentage of patients: Treatment (Antibody-drug Conjugate and Combination Chemo) 80 (65 to 89)
• Freedom From Progression (Secondary)
• Patient Reported Outcomes for Symptoms and Quality of Life (Secondary), Mean, score on a scale: Treatment (Antibody-drug Conjugate and Combination Chemo) 128.29 +/- 25.45
• Association Between Cumulative Illness Rating Scale (CIRS) With Outcomes (Secondary), Number, percentage of participants: Treatment (Antibody-drug Conjugate and Combination Chemo) 38 (13 to 63)

Adverse events

Time frame: 7 years, 9 months

Serious adverse events by term

Other adverse events by term

146 more terms not shown.

• Results publication: Evens AM, Advani RH, Helenowski IB, Fanale M, Smith SM, Jovanovic BD, Bociek GR, Klein AK, Winter JN, Gordon LI, Hamlin PA. Multicenter Phase II Study of Sequential Brentuximab Vedotin and Doxorubicin, Vinblastine, and Dacarbazine Chemotherapy for Older Patients With Untreated Classical Hodgkin Lymphoma. J Clin Oncol. 2018 Oct 20;36(30):3015-3022. doi: 10.1200/JCO.2018.79.0139. Epub 2018 Sep 4. PMID 30179569

• Study Protocol and Statistical Analysis Plan (PDF, 2022-10-04)

• Leo Gordon, MD, Principal investigator, Northwestern University