Brentuximab Vedotin Before Autologous Stem Cell Transplant in Treating Patients With Hodgkin Lymphoma

Study Overview
=================
Brief Summary
-----------------
This phase II trial studies how well brentuximab vedotin before autologous (taken from an individual's own cells) stem cell transplant works in treating patients with Hodgkin lymphoma. Monoclonal antibody-drug conjugates, such as brentuximab vedotin, can block cancer growth in different ways by targeting certain cells.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. The primary objective of this study is to determine the activity of salvage brentuximab vedotin in Hodgkin lymphoma prior to autologous hematopoietic stem cell transplantation, as measured by overall response rate (ORR). SECONDARY OBJECTIVES: I. To describe the safety, toxicity, and tolerability of brentuximab vedotin as a salvage regimen. II. To summarize the stem cell mobilization results of patients receiving brentuximab vedotin as salvage therapy (e.g., total cluster of differentiation (CD)34+ cell yield, number of apheresis days, proportion of patients who achieve >= 3 x 10^6 CD34+ cells/kg). III. To evaluate potential changes in Hodgkin lymphoma biological markers of patients treated with brentuximab vedotin as first line salvage therapy. IV. To examine and characterize the outcomes of patients who receive brentuximab vedotin as first line salvage followed by autologous hematopoietic stem cell transplantation (AHCT) (e.g., toxicity, 2-year progression free survival [PFS], overall survival [OS], relapse-progression incidence and non-relapse mortality rate [NRM]) OUTLINE: Patients receive brentuximab vedotin intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 courses. Patients in the new cohort receive regular study dose of brentuximab vedotin for courses 1 and 2. Patients not achieving complete remission (CR) after 2 courses receive higher-dose brentuximab vedotin IV over 60 minutes on day 1 for 2 additional courses. After completion of study treatment, patients are followed up at 21 days.

Official Title
-----------------
A Phase II Study of Brentuximab Vedotin as Salvage Therapy for Hodgkin Lymphoma Prior to Autologous Hematopoietic Stem Cell Transplantation

Conditions
-----------------
Recurrent Hodgkin Lymphoma, Refractory Hodgkin Lymphoma

Intervention / Treatment
-----------------
* Drug: brentuximab vedotin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have histologically documented or cytologically confirmed Hodgkin lymphoma with CD 30 expression Patients must have absolute neutrophil count (ANC) >= 1000/uL; neupogen (filgrastim) can be given prior to start of SGN-35 (brentuximab vedotin) and during SGN-35 treatment to achieve target ANC >= 1000/uL Patients must have platelets (Plts) >= 50,000/uL; platelet transfusion can be given prior to the start of SGN-35 and during SGN-35 treatment to achieve a target plt >= 50,000/uL Patients must have measurable disease > 1.5 cm evidenced by computed tomography (CT) scan of the neck/chest/abdomen(abd)/pelvis or CT/positron emission tomography (PET) scans Patient must be either primary refractory to one frontline induction therapy or relapsed after one frontline induction therapy; patients who do not achieve complete remission after induction therapy are also eligible Patients cannot have had a second line salvage treatment (chemotherapy, biologic agents, investigational drugs, or radiation) or have had an autologous or allogeneic hematopoietic stem cell transplantation; patients can have had mixed frontline therapy such as 2-4 cycles of ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) followed by 2-4 cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) as long as the induction chemotherapy is not more than 8 cycles in total length Radiation use as part of induction regimen or consolidation (within 90 days after completion of induction chemotherapy) is allowed 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 Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study Male subject agrees to use an acceptable method of contraception for the duration of the study Life expectancy of greater than 3 months Karnofsky performance status of > 60% ANC >= 1000/uL Plts >= 50,000/uL Total bilirubin within 1.5 x of the upper limit of normal (ULN) institutional limits, patients with elevation of unconjugated bilirubin alone, as in Gilbert's disease, are eligible Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 2.5 X institutional ULN (unless demonstrated Hodgkin lymphoma involvement of the liver) Calculated creatinine clearance >30 ml/min (unless demonstrated Hodgkin lymphoma involvement of the kidney) ELIGIBILITY FOR 2.4 MG/KG DOSING IN THE NEW COHORT: - In addition to the inclusion/exclusion criteria outlined, to be eligible for treatment with the higher 2.4 mg/kg dose of brentuximab vedotin in the new cohort of 20 additional patients, best response after 2 cycles of brentuximab vedotin administered at the 1.8 mg/kg dose, must be partial remission (PR) or stable disease (SD) as determined by radiographic imaging Exclusion Criteria: Patient has > 1.5 x ULN total bilirubin, unless history of Gilbert's syndrome Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevant Patient has hypersensitivity to brentuximab vedotin Female subject is pregnant or breast-feeding; confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening; pregnancy testing is not required for post-menopausal or surgically sterilized women Patient has received other investigational drugs within 14 days before treatment of treatment with brentuximab vedotin Serious medical or psychiatric illness likely to interfere with participation in this clinical study Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy Patients with other active malignancies (no evidence of other cancer or life expectancy greater than 5 years) are ineligible for this study Patients with active central nervous system (CNS) disease or history of brain metastases (mets) are excluded from study Patients may be on steroids prior to initiation of treatment as long as by cycle 1 day 1 steroids use was tapered down less than or equal to 20 mg of prednisone.

Ages Eligible for Study
-----------------
Minimum Age: 11 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (brentuximab vedotin)<br>Patients receive brentuximab vedotin IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 courses. Patients in the new cohort receive regular study dose of brentuximab vedotin for courses 1 and 2. Patients not achieving CR after 2 courses receive higher-dose brentuximab vedotin IV over 60 minutes on day 1 for 2 additional courses. | Drug: brentuximab vedotin<br>* Given IV<br>* Other names: Adcetris;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate Among Patients With Salvage Brentuximab Vedotin (BV) | The overall response rate is calculated as the percent of evaluable patients that have confirmed CR or PR by radiographic imaging, and the exact 95% confidence interval is calculated for this estimate. Per Revised Response Criteria for Malignant Lymphoma (Cheson et al. 2007) for target lesions and assessed by CT/PET scans: Complete Response (CR), complete disappearance of all detectable clinical and radiographic evidence of disease; Partial Response (PR), ≥50% decrease in the sum of the product of the diameters of up to six of the largest dominant nodes or nodal masses. | 21 days after completion of last course of study treatment, up to 5 years | 
| Complete Response (CR) Rate Among Patients With Salvage Brentuximab Vedotin (BV) | The CR rate is calculated as the percent of evaluable patients that have confirmed CR by radiographic imaging, and the exact 95% confidence interval is calculated for this estimate. Per Revised Response Criteria for Malignant Lymphoma (Cheson et al. 2007) for target lesions and assessed by CT/PET scans: Complete Response (CR), complete disappearance of all detectable clinical and radiographic evidence of disease. | 21 days after completion of last course of study treatment, up to 5 years | 
| Overall Response Rate in Cohort #2 | The overall response rate is calculated as the percent of evaluable patients that have confirmed CR or PR by radiographic imaging, and the exact 95% confidence interval is calculated for this estimate. Per Revised Response Criteria for Malignant Lymphoma (Cheson et al. 2007) for target lesions and assessed by CT/PET scans: Complete Response (CR), complete disappearance of all detectable clinical and radiographic evidence of disease; Partial Response (PR), ≥50% decrease in the sum of the product of the diameters of up to six of the largest dominant nodes or nodal masses. | 21 days after completion of last course of study treatment, up to 5 years | 
| Complete Response (CR) Rate in Cohort #2 | The CR rate is calculated as the percent of evaluable patients that have confirmed CR by radiographic imaging, and the exact 95% confidence interval is calculated for this estimate. Per Revised Response Criteria for Malignant Lymphoma (Cheson et al. 2007) for target lesions and assessed by CT/PET scans: Complete Response (CR), complete disappearance of all detectable clinical and radiographic evidence of disease. | 21 days after completion of last course of study treatment, up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total CD34+ Cell Dose Among Patients Receiving Brentuximab Vedotin Followed by Autologous Hematopoietic Stem Cell Transplantation | Among the patients receiving salvage Brentuximab Vedotin (BV) followed by Autologous Hematopoietic Stem Cell Transplantation (AutoHCT), their total CD34+ cell yield by stem cell mobilization. | 60 days after completion of last course of study treatment, up to conditioning regimens | 
| Progression Free Survival at Year Two Among AutoHCT Patients With BV | Progression Free Survival (PFS) defined as the time from first treatment day (post AHCT) until objective or symptomatic relapse or death as a result of lymphoma or acute toxicity of treatment. Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formula. | Assessed for up to 5 years, at least half of the surviving participants followed 2+ years | 
| Overall Survival at Year Two Among AutoHCT Patients With BV | Overall Survival (OS) defined as the time from first treatment day (post AHCT) until death. Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formula. | Assessed for up to 5 years, at least half of the surviving participants followed 2+ years |