Clinical trial NCT02169505
Conditions: Lymphoma
Keywords: Lymphoma Hodgkin lymphoma HL CD30 positive Hodgkin Lymphoma Anaplastic large cell lymphoma ALCL Allogeneic Stem Cell Transplantation ASCT Graft-versus-host disease GVHD Brentuximab Vedotin SGN-35 Adcetris
Sponsor: M.D. Anderson Cancer Center
Start date: 2015-05-22; Completion date: 2017-08-14
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to study the safety of ADCETRISTM (brentuximab vedotin) in patients with Hodgkin lymphoma or ALCL who have had an allogeneic or haploidentical stem cell transplant. Another goal of this study is to learn if brentuximab vedotin can help to prevent the disease from coming back.

Detailed description:
Study Drug Administration:

If you agree to take part in this study, about 35-60 days after the transplant, you will receive brentuximab vedotin by vein over about 30 minutes on Day 1 of each 21-day study cycle. You may receive up to 6 cycles of brentuximab vedotin.

At Cycles 3 and beyond, you will receive a higher dose of the study drug than you received during Cycles 1 and 2.

Study Visits:

About 5 days before Day 1 of Cycle 1:

* You will have a physical exam. As part of the physical exam, you will be checked for graft-versus-host disease (GVHD -- when transplanted donor tissue attacks the tissues of the recipient's body). You may have an additional blood draw to check for GVHD as part of your standard of care.
* Blood (about 2 tablespoons) will be drawn for routine tests and to check how the transplant has taken.
* Blood (about 2 teaspoons each time) will be drawn before and after your dose of study drug to check the immune system.

On Days 3 and 5 of Cycle 1, blood (about 2 teaspoons) will be drawn to check the immune system.

About 5 days before Day 1 of Cycles 2-6:

* You will have a physical exam.
* Blood (about 2 tablespoons) will be drawn for routine tests and to check the immune system.

If your doctor thinks it is needed, you may have a skin biopsy or endoscopy to check for GVHD and/or graft failure. You will sign a separate consent form that explains the procedures and risks.

Length of Study:

You will be taken off study 1 year after the transplant. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, if you develop an infection (such as cytomegalovirus \[CMV\] that does not respond to treatment), or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visits.

Follow-Up Visits:

About 1, 3, 6, and 12 months after the transplant, you will have follow-up visits as part of your standard of care after your transplant. At these visits:

* You will have a physical exam
* Blood (about 4 tablespoons) will be drawn for routine tests, to learn how the transplant has taken, and to check the status of the disease.
* You will have a computed tomography (CT) scan to check the status of the disease.
* You will have a bone marrow biopsy and aspiration to check the status of the disease and for cytogenetic testing. To collect a bone marrow biopsy/aspirate, an area of the hip or other site is numbed with anesthetic, and a small amount of bone marrow and bone is withdrawn through a large needle. Cytogenetic testing looks at how genetic changes to cells may affect how the disease may react to the study drug.

This is an investigational study. Brentuximab vedotin is FDA approved and commercially available for the treatment of Hodgkin lymphoma and ALCL. It is investigational to give brentuximab vedotin at an earlier time after a transplant.

Up to 20 participants will be enrolled in this study. All will take part at MD Anderson.

Arms: arm 1: Brentuximab by vein over 30 minutes every 3 weeks for a total of 6 cycles starting between days 30 and 60 post allogeneic stem cell transplant (SCT).

Brentuximab dose based on actual body weight starting with an initial dose of 1.2 mg/kg for the first 2 cycles and dose increased to 1.8 mg/kg after the second cycle for all subsequent cycles.
Interventions: intervention 1: Brentuximab Vedotin
Intervention descriptions: intervention 1: Starting dose: 1.2 mg/kg by vein on Day 1 for the first 2, 21 day cycles. Dose increased to 1.8 mg/kg by vein after the second cycle for all subsequent cycles.

Protocol documents:
Prot_SAP_000.pdf: 
2013-0351 
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Protocol Page
Safety and Efficacy of Brentuximab Vedotin Maintenance After Allogeneic and 
Haploidentical Stem Cell Transplantation in High Risk CD30+ Lymphoma (Hodgkin 
Lymphoma and ALCL)
2013-0351
Core Protocol Information
Short Title 
Brentuximab Vedotin in High-Risk CD30+ Lymphoma Post Allo and Haplo SCT
Study Chair: 
Additional Contact:
Department:
Stem Cell Transplantation and Cellular Therapy
Phone:
Unit:
Full Title: 
Safety and Efficacy of Brentuximab Vedotin Maintenance After Allogeneic and Haploidentical 
Stem Cell Transplantation in High Risk CD30+ Lymphoma (Hodgkin Lymphoma and ALCL)
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 08/14/2017
Version:
08
Submitted by:
-11/30/2016 10:59:50 AM
OPR Action:
Accepted by:  
 -- 12/5/2016 8:55:37 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


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Protocol Body
1.0 Objectives
1.1
Primary Objective:
1.1.1  
To determine the incidence of secondary graft failure with brentuximab maintenance post 
allogeneic or haploidentical stem cell transplant.
 
1.2
Secondary Objectives:
1.2.1
To evaluate the hematologic toxicity of brentuximab maintenance after an allogeneic 
stem cell transplant.
1.2.1
To determine the response rates in patients who start post transplant brentuximab with 
measurable disease. 
1.2.2
To determine the relapse rate in this patient population
1.2.3
To determine the incidence of cytomegalovirus (CMV) reactivation and/or CMV disease.
1.2.4
To determine the incidence of acute graft-versus-host disease (GVHD). 
1.2.5
To describe the effect of brentuximab on central and effector memory and naïve CD4 and 
CD8 cell subpopulations.
1.2.6
To describe the effect of brentuximab on serum CD30 levels both in patient subsets with 
and without GVHD.
1.2.7
To determine the progression free survival and overall survival of patients on 
brentuximab maintenance.
2.0 Background
2.1
Allogeneic hematopoietic stem cell transplants for Hodgkin lymphoma:
Hodgkin’s lymphoma (HL) is primarily treated with conventional chemotherapy to which it is highly 
responsive(1).  After relapse the standard of care is an autologous stem cell transplant (SCT) (2).  The 
results of auto SCT are variable with recurrence of HL ensuing in 50% of patients after autologous 
SCT(3).   Prognosis of patients who relapse following an auto SCT is generally poor, although allogeneic 
SCT can induce long-term remissions through a graft-vs.-lymphoma (GVL) effect. The use of 
myeloablative regimens for allogeneic SCT results in prohibitively high treatment related mortality (TRM), 
upward of 22% in the first 100 days(4).  Reduced intensity conditioning (RIC) treatments have been 
shown to significantly reduce TRM, although relapse remains a significant problem.  Anderlini and 
colleagues at our institution (5) have demonstrated decreased TRM using fludarabine/melphalan as 
conditioning with rates of TRM of 7% at day 100 and 15% at 2 years. Their data reveals an overall 
survival (OS) rate of 64% and progression free survival (PFS) of 32% at 2 years, with a 2-year rate of 
disease progression or relapse at 55%.  In an EBMT analysis of 250 patients who received a reduced 
intensity allo SCT for found that chemorefractory disease was associated with PFS and OS of 8% and 
25% respectively at 2 years. Patients in CR at time of transplant PFS had a 3-year PFS of 42%(6). 
Sureda et al.(3) reported on RIC allo SCT using fludarabine and melphalan and observed a TRM of 8% at 
100 days and 15% at 1 year.  The estimated PFS for the entire allografted population was 24% at 4 years 
and patients allografted in CR had PFS of 50% at 4 years. Alvarez et al.(8) found that patients allografted 
with chemosensitive disease (including CR patients) at time of transplantation had a PFS at 2 years of 


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55% ± 16%. These studies illuminate that although patients in CR and with chemosensitive disease have 
better outcomes, disease progression is still in the range of 50% 2-4 years post transplant.  Reduced 
intensity allogeneic transplant can lead to long term disease free survival, however relapse after allo SCT 
has very poor outcomes with less than 50% of patients surviving past 3 years(7). Beyond allogeneic 
transplant there are limited effective therapeutic options. 
This is an extremely high risk patient population for progression of disease and brentuximab vedotin has 
been shown to induce partial and complete responses in patients who relapse post allogeneic transplant 
with acceptable toxicity.(7) Decreasing the relapse rate will be a substantial factor in improving overall 
survival for these patients, which is the rationale for using brentuximab vedotin as a maintenance therapy 
early post-allogeneic transplant.  
2.2
Allogeneic hematopoietic stem cell transplantation in anaplastic large cell lymphoma:
Systemic anaplastic large cell lymphoma (ALCL) is a rare, mature T-cell non-Hodgkin lymphoma (NHL) 
This disease accounts for approximately 3% of adult NHLs, 10-15% of pediatric NHLs and 25% of newly 
diagnosed peripheral T cell lymphomas in North America(9). ALCLs that do not express anaplastic 
lymphoma kinase (ALK) have a particularly poor prognosis with fewer than 30% of patients achieving 
long term disease free survival(10).  Patients with relapsed or refractory disease are considered incurable 
with chemotherapy alone, and often proceed to high dose chemotherapy followed by autologous 
transplant or allogeneic SCT.  Allogeneic transplant may benefit a subset of patients who relapse if they 
have a good performance status and matched related or unrelated donors. Corradini et al. (10) reported 
on a phase II study of RIC allogeneic stem cell transplantation in 17 patients with relapsed or refractory 
peripheral T-cell lymphoma (PTCL) and after a median follow-up time of 28 months, the estimated 3-year 
OS and PFS rates were 81% and 64%, respectively. The TRM at 2 years was considered acceptable at 
only 6%10. Two of 13 patients in CR relapsed after transplant while overall 3 of the total 17 patients had 
progressive disease.   
2.3
Haploidentical hematopoietic stem cell transplantation in Hodgkin Lymphoma:
One of the limitations with an allogeneic stem cell transplant is that the majority of patients lack an 
identical sibling and no more than 50% of patients, searching the Registries for unrelated donors or cord 
blood units, undergo an allo-SCT (World Marrow Donor Association data, 2012 unpublished). Recently, 
encouraging results have been obtained with HLA haploidentical-related donor, following an NMA 
regimen, unfractionated BM and post-transplantation CY (PT-CY) (11).
Twenty-six patients with advanced Hodgkin’s disease received a related HLA haploidentical 
unmanipulated BMT, following a non-myeloablative conditioning with low-dose TBI and GVHD 
prophylaxis consisted of high-dose post-transplantation CY (PT-CY), mycophenolate and a calcineurin 
inhibitor. The incidence of grade II–IV acute GVHD and of chronic GVHD was 24% and 8%, respectively. 
With a median follow-up of 24 months (range 18–44) 21 patients are alive, 20 disease free. The 
cumulative incidence of TRM and relapse was 4% and 31%, respectively. The actuarial 3-year survival is 
77%, the actuarial 3-year PFS is 63%. (12).
Haploidentical transplant has been tested by multiple centers for Hodgkin lymphoma and found to 
preserve graft versus lymphoma effect without significant additive toxicity.
2.4
CD30 Expression:
Hodgkin Reed-Sternberg cells express the CD30 antigen almost universally (11). Systemic ALCL tumors 
present with large blastic CD30-expressing cells and the CD30 antigen is also expressed in some 
cutaneous T-cell lymphomas (CTCLs), other natural killer (NK) and T-cell neoplasms, a subset of B-cell 
lymphomas and embryonal carcinoma.(13,14) CD30 is a transmembrane glycoprotein receptor member 
of the tumor necrosis factor (TNF) receptor superfamily 8 (TNFRSF8). The functions of CD30 are not fully 
understood. Its distribution on normal cells is restricted to activated T and B cells and 
macrophages(12,15), and it seems to be an activator of the canonical and alternative nuclear factor-kB 
(NF-kB) pathways, transducing a cell survival signal. (6, 16,18)


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Brentuximab vedotin is a CD30-directed antibody-drug conjugate consisting of 3 components:  the 
monoclonal chimeric antibody cAC10 that is specific for human CD30 the potent antimicrotubule agent 
monomethyl auristatin E (MMAE) a protease-cleavable linker that covalently attaches MMAE to cAC10. 
The biologic activity of brentuximab vedotin results from a multi-step process. Binding of the 
antibody-drug conjugate (ADC) to CD30 on the cell surface commences internalization of the ADC-CD30 
complex, which then traffics to the lysosomal compartment where MMAE is released via proteolytic 
cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, induces the mitotic 
spindle cell cycle checkpoint and results in growth arrest and apoptotic death of the CD30-expressing 
tumor cells. (16) 
Younes and colleagues reported the initial data in a phase I dose escalation trial that enrolled 45 patients 
with relapsed or refractory CD30+ hematologic malignancies. They showed 20 objective responses, 
including 11 complete remissions (CRs), in 17 patients and tumor regression was observed in 86% of 
evaluable patients. Seventy-three percent of patients in that trial had undergone autoSCT.(19) 
Subsequently this group presented a phase 2 study using Brentuximab vedotin (1.8 mg/kg intravenously 
every 3 weeks) after auto SCT for 102 patients with relapsed/refractory CD30+ HL and revealed objective 
responses in 75% of patients, with CRs observed in 34% of patients.(20) The estimated 12-month 
survival was 89% and the median PFS was 5.6 months. Adverse events associated with brentuximab 
vedotin were typically grade 1 or 2 and able to be managed through standard supportive care. 
Cumulative peripheral neuropathy, the most clinically meaningful adverse event, improved or resolved 
completely in 80% of patients during the study. Patients who had previously received an alloSCT were 
excluded from both of these trials.
Pro et al.(18), demonstrated an objective response of 86% and complete remission of 57% in 58 patients 
with relapsed or refractory systemic anaplastic large cell lymphoma (ALCL) treated at the dose of 1.8 
mg/kg every 3 weeks. The median durations of overall response and CR were 12.6 and 13.2 months, 
respectively. Grade 3 or 4 adverse events in >10% of patients were neutropenia (21%), 
thrombocytopenia (14%), and peripheral sensory neuropathy (12%).
2.5
Transplantation and use of Brentuximab Vedotin:
More recently Gopal et al.,(7) published their experience with 25 HL patients treated with brentuximab at  
1.8 mg/kg every 21 days after relapse post allogeneic  SCT. Overall and complete response rates were 
50% and 38% respectively, median OS not reached. In their study, the drug was very well tolerated with 
most common grade >/-3 side effects being: neutropenia (24%), anemia (20%), hyperglycemia (12%) of 
which all were reversible.  CMV was detected in 5 patients and was clinically significant in 1 patient. 
Sixteen patients (64%) had an objective response after allo SCT, including 14 CRs and 2 PRs. The 
median interval between allo SCT and first dose of brentuximab vedotin was 42 months (range, 
6-116).(7) Adverse events most frequently reported as being related to study drug were peripheral 
sensory neuropathy (n/12, 48%), nausea (n/ 7, 28%), alopecia and neutropenia (n/6, 24% each), and 
fatigue and vomiting (n/5, 20% each). Between transplant and brentuximab initiation 17 pts (68%) were 
reported to have acute/and or chronic GVHD. On brentuximab 9 pts (36%) received transient steroids for 
non-GVHD indications (B symptoms or infusion reactions). No GVHD was reported after initiation of 
brentuximab vedotin therapy.
2.6
CD30 expression and Graft versus Host Disease:
CD30 expression on CD8+ T cells may be a potential biomarker for acute GVHD.(20) Chen and 
colleagues recently published data analyzing CD30 expression on peripheral blood T-cell subsets and 
soluble CD30 levels in 26 patients at the time of onset of acute GVHD (aGVHD) treatment and then 
compared them to transplant patients without aGVHD.(22) Analysis by flow cytometry showed that 
patients with aGVHD had a greater percentage of CD30 expressing CD8+ T cells with the difference 
especially pronounced in the central memory subset (CD30+CD8+ CD45RO+ CD62L+). Levels of central 
memory CD30+CD8+ CD45RO+ CD62L+ cells were 6 times higher among patients with acute GVHD 
than among those without aGVHD. There were similar levels of CD30 expression in naive T cells, CD4+ 


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T cells, and regulatory (CD4+CD127lowCD25+) T cells.1(10)
Plasma levels of soluble CD30 were significantly greater in patients with GVHD and 
immunohistochemical analysis of affected intestinal tissue showed many CD30+ infiltrating lymphocytes 
present. These results suggest that CD30 expression on CD8+T-cell subsets or plasma levels of soluble 
CD30 may be a potential biomarker for aGVHD. 
In this study we will evaluate the safety of brentuximab early after allogeneic stem cell transplant and 
haploidentical allogeneic transplantant and observe if there is a decrease in the risk of relapse.
3.0 Patient Eligibility
3.1
Inclusion Criteria:
3.1.1 Patients with CD30 positive Hodgkin Lymphoma (HL) or anaplastic large cell lymphoma 
(ALCL) that have undergone allogeneic or haploidentical SCT in the past 60 days (matched 
related or matched unrelated donors only).  
3.1.2 Age 18 to 65 years. 
3.1.3 Performance status: Zubrod 0-1 or Karnofsky 80-100.  
3.1.4 Serum creatinine < 1.5 mg/dL or creatinine clearance greater than or equal to 40 cc/min as 
defined by MDRD method from National Kidney Disease Education Program (NKDEP). 
3.1.5
Serum direct bilirubin < 1.5 mg/dL (unless Gilbert's syndrome).
3.1.6
SGPT < 200 IU/L unless related to patient's malignancy.
3.1.7
Evidence of neutrophil and platelet engraftment, defined as platelet count equal or greater 
than 50,000 mm
3 independent of platelet transfusion or thrombopoietin factor and ANC 
equal or greater to 1000 without growth factor support for at least 5 days.
3.1.8
Patients with previous exposure to brentuximab pre-transplant are eligible for the study.
3.2
Exclusion Criteria: 
3.2.1
Pregnancy or breast-feeding (women of childbearing potential, any female who has 
experienced menarche and who has not undergone surgical sterilization or is 
post-menopausal with a positive serum pregnancy test. 
3.2.2
Presence of steroid-refractory acute graft-versus-host disease (GVHD).
3.2.3
Patients that underwent allogeneic transplantation as a treatment of graft failure.
3.2.4 Dual refractory CMV reactivation to foscarnet and ganciclovir or evidence of CMV disease.
4.0 Treatment Plan
4.1 Treatment Initiation:
Brentuximab will be given as an IV infusion over 30 minutes every 3 weeks for a total of 6 cycles.
starting between days 35 and 60 post allogeneic SCT. 
Brentuximab dose will be based on actual body weight starting with an initial dose of 1.2 mg/kg for 
the first 2 cycles and then the dose will be increased to 1.8 mg/kg after the second cycle for all 
subsequent cycles. Brentuximab dose will be based on actual body weight except for patients 
weighing more than 100 kg, then dose will be calculated based on 100 kg.
Patients must meet the following criteria to start any cycle of brentuximab:
1. Absolute neutrophil count > 1,000/mm3 not requiring daily growth factor support on the day of 
the brentuximab infusion.
2. Platelet count greater than 50,000/mm3 independent of platelet transfusions or thrombopoietin 
factor  for at least 5 days.
3. No clinical evidence of life-threatening infection. 


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4. No active bleeding. 
5. No uncontrolled acute GVHD (steroid refractory).
6. No CMV re-activation that is dual-refractory to foscarnet and ganciclovir/ No active CMV 
disease.
7.   Creatinine< 1.5 mg/dL or creatinine clearance greater than or equal to 40 cc/min as defined by 
MDRD method from National Kidney Disease Education Program (NKDEP) 
8. Serum bilirubin <1.5 mg/dL 
9.
SGPT < 200 IU/L unless related to patient's malignancy
Vital sign monitoring, observation, and treatment of hypersensitivity reactions during and after 
infusion will be performed per standard of care. 
4.2 Dose Modification:
Dose will be reduced from 1.8 mg/kg  to 1.2 mg/kg or from 1.2 mg/kg to 1 mg/kg or from 1 mg/kg to 
stop treatment if:
1. Neutropenia grade 3-4 unresponsive to G-CSF or grade 4 thrombocytopenia are observed.
2. Peripheral neuropathy, new or worsening grade 2 or 3. Withhold treatment until improvement or 
return to grade 1 or baseline; then resume with a dose reduction. 
Dose will be reduced to 1 mg/kg if:
1.   Creatinine clearance < 30 cc/min as defined by MDRD method from NKDEP.  
http://nkdep.nih.gov/lab-evaluation/gfr/estimating.shtml
2.
Hepatic impairment defined as bilirubin > 2 mg/dL. 
If the patient develops grade 3-4 neutropenia unresponsive to G-CSF: Hold until resolution to grade 
</= 1 and restart at lower dose. 
4.3 Treatment will be discontinued if: 
1. If the dose that was administered was 1 mg/kg and the patient develops grade 4 hematological 
toxicity as described above.
2. If the patient develops both foscarnet and ganciclovir-resistant CMV viremia or histologic CMV 
end-organ disease.
3. If an anaphylactic reaction is observed.
4. If peripheral neuropathy, grade 4 is observed.
5. If progressive multifocal leukoencephalopathy (PML) is confirmed. Treatment must be withheld 
until PML is confirmed.
6. If the patient develops Stevens-Johnson syndrome. 
4.4 Treatment will not be dose reduced or stopped for:
1. New onset GVHD.
2. An infusion reaction, in which case the infusion will be interrupted and appropriate medical 
intervention will be administered. Pre-medicate subsequent infusions with acetaminophen, an 
antihistamine, and/or a corticosteroid.
5.0 Evaluation During Treatment
5.1
Prior to the first cycle (within 5 days prior to receiving first dose of brentuximab):
1. Physical exam including GvHD assessment.
2. CBC with diff and platelets, chemistries.
3. Correlative studies: blood sample for immunophenotyping studies prior to 1st dose, and 1, 3, 


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and 5 days after first brentuximab dose. 
4. Chimerism studies in peripheral blood.
5.2
At each subsequent cycle (within 5 days prior to receiving first dose of brentuximab in 
each cycle):  
1. Physical exam including toxicity and GVHD assessment.
2. CBC with diff and platelets, chemistries.
3. Correlative studies: blood sample prior to the brentuximab dose.
5.3 
If patient has a biopsy (skin, GI or liver) at any time for GVHD diagnosis, a blood sample (10 mL) 
will be taken at that time for correlative studies.
5.4       To be performed at approximately 1, 3, 6 and 12 months post-transplant.
These evaluations follow our standard practice and are done to monitor engraftment and disease 
status. If clinically indicated these studies may be done at other time points which can replace the 
nearest planned timepoint. 
1.  Chimerism studies from peripheral blood performed on separated T-cells and myeloid cells.
2.  At each visit, physical examination and adverse event documentation including GvHD 
assessment. 
3.  Disease specific assessment with bone marrow aspirate with cytogenetics, serum 
immunoglobulins in peripheral blood and CT for lymphoma staging as indicated.
5.5
Correlative Studies to be performed by Dr. K Rezvani in her laboratory (no cost to the 
patients): 
5.5.1  T cell immunophenotyping to define:
    
a. “naïve”(CD45RO-CCR7+) T cells.
b. “effector memory” (CD45RO+CCR7-) T cells.
c. “central memory” (CD45RO+CCR7+) T cells.
d. “terminally differentiated effector memory” (CD45RO-CCR7-) T cells.
e. “regulatory” T cells (CD4+CD25+CD127loFoxp3+).
5.5.2  
Functional T cell studies to assess impact of brentuximab on T cell function and recovery 
including regulatory T cell subsets; will co-stain with CD30.  CD30 is also expressed on 
NK cells and can assess impact of brentuximab on NK cells.
5.5.3  
Functional studies of antigen-specific T cell responses to pathogens (CMV and EBV), 
and if impact on pathogen-specific T cell recovery. 
5.5.4  
Determine impact of brentuximab on diversity of reconstituting T cell repertoire by flow 
cytometric analysis. 
5.6 
To be done with collaboration with pathology department - Assess tissue biopsies from 
GVHD sites for CD30 expression. Tissue biopsies with matched disease and site specific GvHD 
will be collected and sued for controls to evaluate CD30 expression in brentuximab treatement 
patients. (if done  for CD30+CD8+ or CD30+CD4+ T cell infiltration)
6.0 Study Criteria
Off Study Criteria:
6.1 
Patient withdraws consent.
6.2 
Patient can not tolerate treatment.
6.3 
Unexpected pattern of toxicity.
6.4 
Presence of both steroid and 2nd line treatment refractory GvHD while on treatment with 
brentuximab.
6.5 
Presence of dual-refractory CMV reactivation to foscarnet and ganciclovir or CMV end-organ 
disease while on treatment with brentuximab.


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6.6
Patient's inability of unwillingness to have follow-up visits and/or laboratory tests required by this 
protocol. 
6.7    One year after treatment completion.
Steroid refractory GVHD is defined as: absence of any response 7 days after the initiation of 
corticosteroids for skin GVHD or 10-14 days after its initiation for GI and liver GVHD. Patients who are 
steroid refractory are not eligible to be enrolled on protocol, however if a patient develops GVHD while on 
protocol, brentuximab will not be held.
Secondary graft failure is defined as a sustained declined of ANC <0.5 x 10
9/L for 3 consecutive days 
after initial documented engraftment with no evidence of disease progression and is not associated with 
concomitant medication that is known to cause cytopenias.
7.0 Expected Adverse Events and Reporting Requirements
Reporting requirements will adhere with the IRB policy 15.001. The adverse events (AEs) known to be 
related to brentuximab are listed in section 9.0 of this protocol.
Assessment of the Adverse Events Severity. 
The severity of the AEs will be graded according to the Common Terminology Criteria v4.0 (CTCAE). 
Events not included in the CTCAE chart will be scored as follows:
General grading:
Grade 1: Mild: discomfort present with no disruption of daily activity, no treatment required beyond 
prophylaxis.
Grade 2: Moderate: discomfort present with some disruption of daily activity, require treatment.
Grade 3: Severe: discomfort that interrupts normal daily activity, not responding to first line treatment. 
Grade 4: Life Threatening: discomfort that represents immediate risk of death.
Casualty Assessment. 
For the purpose of this study adverse events known to be caused by brentuximab and its direct 
consequences will be scored as definitive related.  When the relationship of the adverse event cannot be 
ruled out with certainty the AE may be considered probable or possible related. Adverse events known to 
be related to drugs used for supportive treatment will be scored as unrelated.
The principal investigator will be the final arbiter in determining the casualty assessment. 
When possible, signs and symptoms indicating a common adverse event will be noted as 1
comprehensive event.
Events not to be considered AEs in this study are those related to original disease; changes in laboratory 
parameters such as electrolyte, magnesium and metabolic imbalances, uric acid changes, elevations of 
GPT, GOT, LDH and alkaline phosphatase. These would not be monitored.
8.0 Statistical Considerations
Study Design 
8.1 This is a phase II study in which brentuximab will be initiated after transplant (approximately day 
35-60) post engraftment and restaging at day 30 (+10 days) and continued every 21 days for 6 
cycles. Dose initiation will be at 1.2 mg/kg for 2 cycles and escalated to 1.8 mg/kg on subsequent 4 
cycles. If  greater than grade 3 toxicity seen at 1.2 mg/kg dose level then dose will be decreased to 1 
mg/kg for all patients at initiation with subsequent cycles at 1.2 mg/kg dose.  We will allow intrapatient 
dose modification based on toxicity. 
  


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8.2  Determination of graft failure rate
Based on literature the standard graft failure rate for reduced intensity transplants is higher than that 
of myeloablative regimens(23), and in the range of 10%(24).  With 20 patients, a two-sided 95% 
confidence interval for a 5% incidence of graft failure would be 0-14.6%. The primary objective of this 
study will be to assess the safety of brentuximab as a preventative measure after allogeneic MUD or 
MRD transplant in high risk CD30+ lymphoma patients. Safety is defined by no more than two 
secondary graft failures within 6 months of transplant (Day 0), based on an observed graft failure rate 
of <10% using standard of care treatment.  If at any time more than two of these events are observed 
during the specified time frame, the study will be stopped and no further patients will be accrued.
8.3 Determination of hematologic toxicity and CMV disease 
The most common grade > 3 side effects on brentuximab after allogeneic transplant(7) are 
neutropenia (24%), and thrombocytopenia (20%) which were reversible.  CMV was detected in 5 
patients and was clinically significant in 1 patient.
Brentuximab will be discontinued if patient develops dual foscarnet and ganciclovir-resistant CMV 
viremia or histologic CMV end-organ disease. In addition, the study drug will be reduced in all 
future patients if at any time there is >25% grade IV neutropenia rate or >10% CMV disease rate 
attributable to treatment observed within Day 45- Day 180. 
These rates will be monitored in a continuous fashion. 
8.4 Determination of incidence of GVHD and assessment of the effects of brentuximab on T cell 
populations (central and effector memory and naïve CD4 and CD8 cells) and serum CD30 levels both 
in subsets with and without GVHD
Based on data published by Chen et al., (reviewed above) we hypothesize that down-regulation of 
CD30 may decrease the incidence of GVHD.  We will perform immunological correlative studies on 
peripheral blood mononuclear cells (PBMC) and serum collected from patients at baseline (prior to 
initiation of brentuximab therapy) and on days 1, 3, and 5 after initiation of brentuximab and every 21 
days thereafter to assess the effect on T cell subsets and their effector function as well as other 
immune subsets. We will also test both tissue and serum in patients who develop clinically significant 
GVHD.
8.5 Determination of the response and complete response rates in patients with measurable disease 
after day +30 restaging and progression free and overall survival of this regimen
Kaplan-Meier (1958) survival curves will be used to estimate overall survival and progression-free 
survival.  Cox proportional hazards regression analysis may be used to model the association 
between overall survival and progression-free survival and disease and demographic covariates of 
interest.  
9.0 Background Drug Information
9.1  Mechanism of Action 
Brentuximab vedotin is an antibody drug conjugate (ADC) directed at CD30 consisting of 3 components: 
1) a CD30-specific chimeric IgG1 antibody cAC10; 2) a microtubule-disrupting agent, 
monomethylauristatin E (MMAE); and 3) a protease cleavable dipeptide linker (which covalently 
conjugates 
MMAE to cAC10). The conjugate binds to cells which express CD30, and forms a complex which is 
internalized within the cell and releases MMAE. MMAE binds to the tubules and disrupts the cellular 
microtubule network, inducing cell cycle arrest (G2/M phase) and apoptosis.
9.2 Pharmacodynamics/Kinetics
Distribution: Mean steady state volume of distribution of approximately 6-10 L for ADC.
Metabolism: MMAE: Minimal, primarily via oxidation by CYP3A4/5
Half-life elimination: Terminal: ADC: ~4-6 days
Time to peak: ADC: At end of infusion; MMAE: ~1-3 days


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Excretion: MMAE: Feces (~72%, primarily unchanged); urine
9.3 Current Indications:
9.3.1
Hodgkin Lymphoma
Brentuximab vedotin is indicated for treatment of patients with Hodgkin lymphoma after 
failure of autologous stem cell transplant (ASCT) or after failure of at least two prior 
multi-agent chemotherapy regimens in patients who are not ASCT candidates.
9.3.2
Systemic Anaplastic Large Cell Lymphoma
Brentuximab is indicated for treatment of patients with systemic anaplastic large cell 
lymphoma after failure of at least one prior multi-agent chemotherapy regimen.
9.4  Preparation and Storage:
9.4.1
Reconstitution:  Reconstitute each 50mg vial of brentuximab with 10.5ml Sterile Water for 
Injection, USP, to yield a single-use solution containing 5mg/ml brentuximab vedotin.  Direct 
the stream toward the wall of the vial and not directly at the cake or powder.  Gently swirl the 
vial to aid dissolution.  DO NOT SHAKE. The reconstituted solution should be clear to slightly 
opalescent, colorless, and free of visible particulates.  Following reconstitution, dilute 
immediately into an infusion bag, or store the solution at 2-8· C (36-46·F) and use within 24 
hours of reconstitution.  DO NOT FREEZE.  Discard any unused portion left in the vial.
9.4.2
Dilution:  Calculate the required volume of 5mg/ml reconstituted brentuximab solution needed 
and withdraw this amount from the vials.  Immediately add the reconstituted solution to an 
infusion bag containing a minimum volume of 100ml to achieve a final concentration of 
0.4mg/ml to 1.8mg/ml brentuximab vedotin.  The drug can be diluted into 0.9% Sodium 
Chloride Injection, 5% Dextrose Injection or Lactated Ringer’s Injection.  Following dilution, 
infuse the solution immediately.
9.4.3
Storage:   The brentuximab vedotin solution may be stored at 2-8·C (36-46·F).  DO NOT 
FREEZE.  The solution must be used within 24 hours of reconstitution.  The single-use vials 
should be stored in the original carton to protect from light at 2-8·C (36-46·F)
9.5  Administration
9.5.1
Administer only as an intravenous infusion over 30 minutes every 3 weeks
9.5.2
Do not mix brentuximab with, or administer as an infusion with, other medicinal products
9.6  Dosage form and strength
9.6.1
Brentuximab vedotin  is available as single-use vials containing 50mg of brentuximab vedotin 
as a sterile, white to off-white lyophilized, preservative-free cake or powder.
9.7  Adverse Events
9.7.1
The most common adverse reactions (seen in > 20% of patients) include neutropenia, 
anemia, thrombocytopenia, peripheral sensory neuropathy, fatigue, nausea, vomiting, 
diarrhea, pyrexia, rash, cough and upper respiratory tract infection
9.7.2
Serious but less common adverse reactions include serious infections and opportunistic 
infections, tumor lysis syndrome, progressive multifocal leukoencephalopathy (PML), 
Stevens-Johnson syndrome, and embryo-fetal toxicity.


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