Induction Chemo w/ABVD Followed by Brentuximab Vedotin Consolidation in Newly Diagnosed, Non-Bulky Stage I/II Hodgkin Lymphoma

Study Overview
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Brief Summary
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The standard chemotherapy for Hodgkin lymphoma is called ABVD which is a combination of 4 chemotherapy drugs (doxorubicin, bleomycin, vinblastine, and dacarbazine). The number of cycles of ABVD chemotherapy Hodgkin lymphoma patients receive is about 4-6 cycles. In addition to the ABVD chemotherapy, patients with Hodgkin lymphoma will routinely receive radiation therapy. The use of chemotherapy and radiation may cause long term treatment related side effects such as heart problems and other cancers. Researchers are trying to find if combining ABVD chemotherapy with new drugs and reducing the number of ABVD chemotherapy cycles given is just as effective as the standard Hodgkin treatment. Brentuximab vedotin is approved by the United States Food and Drug administration (FDA) for the treatment of Hodgkin lymphoma that has come back (relapsed). For this research study, the use of brentuximab vedotin in newly diagnosed Hodgkin lymphoma is considered investigational. Brentuximab vedotin is an antibody that also has a chemotherapy drug attached to it. Antibodies are proteins that are part of your immune system. They can stick to and attack specific targets on cells. The antibody part of the brentuximab vedotin sticks to a target called cluster of differentiation antigen 30 (CD30). CD30 is an important molecule on some cancer cells and some normal cells of the immune system. The purpose of this research study is to see the effects of treatment with fewer cycles of the combination chemotherapy, ABVD, followed by the study drug brentuximab vedotin has on study participants and Hodgkins lymphoma.

Detailed Description
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This study is designed as a single arm pilot feasibility trial using an induction of 2-6 cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy followed by 6 cycles of brentuximab vedotin (SGN-35) consolidation for previously untreated patients with stage I and II non-bulky Hodgkin Lymphoma (HL). Feasibility will be determined by the percentage of patients who have no clinical evidence of HL, and achieve positron emission tomograph (PET) negative disease post brentuximab consolidation. We anticipate approximately 40 patients will be eligible across participating centers (including UNC, Mayo Clinic, and the UNC Cancer Network (UNCCN)) over a 2 year period. A future phase II study evaluating progression free survival (PFS) after ABVD followed by brentuximab vedotin will be considered feasible if ≥ 13 of 15 patients enrolled in this pilot trial become PET negative after brentuximab vedotin consolidation.

Official Title
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LCCC 1115: A Pilot Feasibility Trial of Induction Chemotherapy With ABVD Followed by Brentuximab Vedotin (SGN-35) Consolidation in Patients With Previously Untreated Non-Bulky Stage I or II Hodgkin Lymphoma (HL)

Conditions
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Hodgkin Lymphoma, Adult

Intervention / Treatment
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* Drug: Brentuximab vedotin
* Drug: ABVD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously untreated stage I or II non-bulky Hodgkin lymphoma No mediastinal mass >0.33 maximum intrathoracic diameter on chest x-ray (see Appendix B) No adenopathy ≥7.5 cm in its largest diameter Measurable disease as assessed by 2 dimensional measurement by CT (>2cm or 1.5 cm if 0.5 cm slices are used, as in spiral CT scan) Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Age ≥18 years and ≤60 years of age Life expectancy of at least 3 months Adequate bone marrow function (without transfusion support within one week of screening) as demonstrated by: Hemoglobin ≥ 8 g/dL Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 Platelet count ≥ 75,000/mm3 Adequate hepatic and renal function as demonstrated by: Aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN) Total serum bilirubin ≤1.5 x ULN Serum creatinine ≤ 2.0 mg/dL Negative serum human chorionic gonadotropin (β-hCG) pregnancy test within 72 hours of day 1 of treatment with ABVD in women of child-bearing potential Females of childbearing potential, and males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 6 months following the last dose of brentuximab vedotin. Effective contraception is defined as any medically recommended method (or combination of methods) as per standard of care, including abstinence. Females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy. Signed an institutional review board (IRB)-approved informed consent document for this protocol Prior to Day 1 of brentuximab vedotin, patients must again meet the following inclusion criteria: Adequate bone marrow function (without transfusion support within one week of D1 of brentuximab vedotin) as demonstrated by: Hemoglobin ≥ 8 g/dL Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 Platelet count ≥ 75,000/mm3 Adequate hepatic and renal function as demonstrated by: Aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN) Total serum bilirubin ≤1.5 x ULN Serum creatinine ≤ 2.0 mg/dL Achieved at least a partial response (PR) (and not progressed) after ABVD therapy Exclusion Criteria: Prior therapies for treatment of HL including involved field radiation therapy or any prior treatment for any malignancy with anthracyclines. Bulky disease (defined as a mass measuring > 7.5 cm or one-third the maximal diameter of the thoracic cavity) Known central nervous system (CNS) involvement Symptomatic pulmonary disease currently requiring regular medication including but not restricted to bronchodilators Known history of human immunodeficiency virus (HIV), hepatitis B and hepatitis C (testing is not necessary if patient does not have history of these diseases, and no risk factors for acquisition of these viruses) Cardiac disease with left ventricular ejection fraction of less than 45% Known hypersensitivity to any excipient contained in the drug formulation of brentuximab vedotin or any component of ABVD Medical or other condition that would represent an inappropriate risk to the patient or would likely compromise achievement of the primary study objective Other active malignancies with the exception of: Non-melanoma skin cancer Cervical carcinoma in situ without evidence of disease Prostatic intraepithelial neoplasia without evidence of prostate cancer Pregnant or lactating women Prior to Day 1 of brentuximab vedotin, please verify the patient does not meet the criteria below: Symptomatic pulmonary disease currently requiring regular medication including but not restricted to bronchodilators

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: ABVD followed by Brentuximab vedotin<br>Single arm trial | Drug: Brentuximab vedotin<br>* IV, 1.8mg/kg, every 3 weeks for 6 cycles.<br>* Other names: Adcetris;Drug: ABVD<br>* Doxorubicin - 25mg/m2 IV over 3-5 minutes, Day 1 and 15, every 28 days, 2-6 cycles. Bleomycin - 10u/m2 IV, Day 1 and 15, every 28 days, 2-6 cycles Vinblastine - 6mg/m2 IV over 3-5 minutes, Day 1 and 15, every 28 days, 2-6 cycles. Dacarbazine - 375mg/m2 IV over 30 minutes, Day 1 and 15, every 28 days, 2-6 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Positron Emission Tomography (PET) Negative Disease | Percentage of patients who convert to PET negative disease post consolidation. This is defined by PET with Deauville <=2. The Deauville 5-point scoring system is a five-point scoring system for the Fluorodeoxyglucose (FDG) avidity of a Hodgkin's lymphoma or Non-Hodgkin's lymphoma tumor mass as seen on FDG Positron emission tomography: Score 1: No uptake above the background Score 2: Uptake ≤ mediastinum Score 3: Uptake > mediastinum but ≤ liver Score 4: Uptake moderately increased compared to the liver at any site Score 5: Uptake markedly increased compared to the liver at any site Score X: New areas of uptake unlikely to be related to lymphoma | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participant Who Achieved a Complete Response | Response criteria based on the International Workshop to standardize response criteria for malignant lymphomas. Complete Response is defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. | 12 months | 
| Conversion Rate to Complete Response. Number of Participants Who Had a Partial Response Post ABVD Who Converted to a Complete Response. | Conversion rate to Complete Response after brentuximab vedotin in patients with partial response at the end of ABVD therapy. Response criteria based on the International Workshop to standardize response criteria for malignant lymphomas. Complete Response is defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses. These nodes or masses should be selected according to all of the following: they should be clearly measurable in at least 2 perpendicular dimensions; if possible they should be from disparate regions of the body; and they should include mediastinal and retroperitoneal areas of disease whenever these sites are involved. | 12 months | 
| 3 Year Progression Free Survival Rate | Defined as the percentage of participants who did not show relapse/progression or death from any cause occurred at 3 years after the time from ABVD treatment start. Relapse/progression is measured using the Revised Response Criteria for Malignant Lymphoma and is defined as the following: appearance of any new lesion > 1.5 centimeters (cm) in any axis during or at the end of therapy; at least a 50% increase from nadir in the sum of the product of the diameters (SPD) of any previously involved nodes, or in a single involved node, or the size of other lesions; or at least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short axis. In addition, lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was positron emission tomography (PET) positive before therapy | 3 years | 
| 3 Year Time to Progression Rate | Defined as the percentage of participants who did not show relapse/progression at 3 years after the time from ABVD treatment start. Relapse/progression is measured using the Revised Response Criteria for Malignant Lymphoma and is defined as the following: appearance of any new lesion > 1.5 centimeters (cm) in any axis during or at the end of therapy; at least a 50% increase from nadir in the sum of the product of the diameters (SPD) of any previously involved nodes, or in a single involved node, or the size of other lesions; or at least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short axis. In addition, lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was positron emission tomography (PET) positive before therapy | 3 years | 
| Number of Adverse Events Attributed to Brentuximab Vedotin With a Grade 3 or Higher | Number of adverse events attributed to Brentuximab Vedotin with a grade 3 or higher. Toxicity assessed via the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI CTCAE) v. 4. The NCI Common Terminology Criteria for Adverse Events is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term.The higher the grade the more severe the adverse event. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hodgkin's lymphoma, Hodgkin lymphoma