Clinical trial NCT02867384
Conditions: Graft vs. Host Disease
Keywords: Graft vs. Host Disease
Sponsor: Dana-Farber Cancer Institute
Start date: 2016-11-29; Completion date: 2024-11-14
Enrollment: 181 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This research study is studying a drug called obinutuzumab as a means of preventing chronic Graft vs. Host Disease (cGVHD).

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease.

The FDA (the U.S. Food and Drug Administration) has not approved Obinutuzumab for prevention of chronic Graft-vs.-Host Disease (cGVHD), but it has been approved for other uses.

In this research study, the investigators are aiming to determine the effect of Obinutuzumab on the incidence of corticosteroid-requiring cGVHD after allogeneic Hematopoetic Cell Transplant (aHCT).

Chronic GVHD is a medical condition that can occur after bone marrow or stem cells are transplanted from one individual to another. After the transplant, the donor immune system may recognize the recipient body as foreign and may attempt to 'reject' the body. This process is referred to as Graft-vs. -Host Disease and may occur at any time, although generally not earlier than one hundred days after transplantation.

The immune system produces two types of lymphocytes (white blood cells), B cells and T cells. B cells are part of the 'memory' for the immune system, and they make antibodies (proteins) when bacteria, viruses or other potentially harmful materials enter the body. Obinutuzumab is an antibody, a molecule that targets certain cells by binding to specific parts of the target cell. In this case, Obinutuzumab will bind to a component of B cells called CD20, resulting in the B cell getting killed. It is thought that reducing the number of B cells will reduce the chances of developing cGVHD after transplant. Previous studies with another antibody targeting CD20 on B cells suggests that there may be a reduced chance of developing cGVHD and the need to prescribe Corticosteroids to treat cGVHD when B cells are killed.

This is a randomized, placebo controlled trial. This means that approximately half of the study participants will receive Obinutuzumab, and the other half will receive a placebo (saline solution). A computer will decide which participants will receive Obinutuzumab or placebo, and neither the participant or the study doctor will know which the participant has received until the study is completed. It is important to note that the current standard is to receive no therapy specifically to prevent cGVHD.

Arms: arm 1: Obinutuzumab or will be administered at a pre- determine dose, intravenously, at 3, 6, 9 and 12 months from transplantation.

* Premedication with histamine blockers and acetaminophen will be provided
* All subjects will undergo allogeneic stem cell transplantation according to locally approved clinical trials arm 2: Placebo will be administered at a pre- determine dose, intravenously, at 3, 6, 9 and 12 months from transplantation.

* Premedication with histamine blockers and acetaminophen will be provided
* All subjects will undergo allogeneic stem cell transplantation according to locally approved clinical trials
Interventions: intervention 1: Obinutuzumab intervention 2: Placebo
Intervention descriptions: intervention 1: B cell depletion intervention 2: Placebo

Protocol documents:
Prot_SAP_000.pdf: 
A Randomized Phase 2 Study of Obinutuzumab for Prevention of Chronic Graft-vs.-Host Disease After 
Allogeneic Peripheral Blood Stem Cell Transplantation 
 
NCT Number: NCT02867384 
IRB Approval Date: Version 2.6 Protocol Version Date 10/06/2021 


1
DF/HCC Protocol #: 16-256
A Randomized Phase 2 Study of Obinutuzumab for Prevention of Chronic Graft- 
vs.-Host Disease After Allogeneic Peripheral Blood Stem Cell Transplantation
Coordinating Center:
Dana-Farber Cancer Institute
Principal Investigator (PI):
Corey Cutler, MD MPH FRCP(C)
Dana-Farber Cancer Institute
Site Investigators:
 
Massachusetts General Hospital
Stanford University School of Medicine
University of Minnesota
Huntsman Cancer Institute
Statistician:
Regulatory Study Coordinator:
Dana-Farber Cancer Institute
Dana-Farber Cancer Institute
Responsible Research Nurse:
Responsible Data Manager:
Hassan El Banna
Dana-Farber Cancer Institute
Dana-Farber Cancer Institute
Study Agent: Obinutuzumab (Gazyva, Genentech, Inc)
Study Exempt from IND Requirements per 21 CFR 312.2(b)
Protocol Type: Original
Version # 2.6
Version Date: October 6, 2021


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TABLE OF CONTENTS
SCHEMA.........................................................................................................................................2
1.
OBJECTIVES......................................................................................................................5
1.1
Study Design............................................................................................................5
1.2
Primary Objectives...................................................................................................5
1.3
Secondary Objectives...............................................................................................5
2.
BACKGROUND .................................................................................................................5
2.1
Chronic GVHD and B Cells ....................................................................................5
2.2
Study Agent .............................................................................................................6
2.3
Rationale ..................................................................................................................7
2.4
Correlative Studies Background ..............................................................................7
3.
PARTICIPANT SELECTION.............................................................................................9
3.1
Eligibility Criteria ....................................................................................................9
3.2
Exclusion Criteria ..................................................................................................10
3.3
Inclusion of Women and Minorities ......................................................................11
4.
REGISTRATION PROCEDURES ...................................................................................11
4.1
General Guidelines for DF/HCC and DF/PCC Institutions...................................11
4.2
Registration Process for DF/HCC and DF/PCC Institutions .................................11
4.3
General Guidelines for Other Investigative Sites ..................................................11
4.4
Registration Process for Other Investigative Sites.................................................11
5.
TREATMENT PLAN........................................................................................................11
5.1
Stem Cell Transplantation......................................................................................11
5.2
Trial Screening and Entry ......................................................................................12
5.3
Treatment Regimen................................................................................................12
5.4
Pre-Treatment Criteria for Doses 2, 3 and 4 ..........................................................12
5.5
Agent Administration.............................................................................................12
5.6
Management of Infusion Reactions .......................................................................13
5.7
Immunosuppressive Medication Tapering.............................................................14
5.8
Concomitant Medication Use ................................................................................14
5.9
Criteria for Taking a Participant Off Protocol Therapy.........................................14
5.10
Duration of Follow Up...........................................................................................15
5.11
Criteria for Taking a Participant Off Study ...........................................................15
6.
DOSING DELAYS/DOSE MODIFICATIONS. ..............................................................15
7.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .............................15
7.1
Expected Toxicities of Obinutuzumab...................................................................16
7.2
Adverse Event Characteristics...............................................................................16
7.3
Expedited Adverse Event Reporting......................................................................17
7.4
Serious Adverse Events for Genentech Reporting.................................................18
7.5
Adverse Events of Special Interest (AESIs) for Genentech ..................................19


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7.6
Serious Adverse Event Reporting to Roche/Genentech.........................................20
7.7
Expedited Reporting to Hospital Risk Management..............................................21
8.
PHARMACEUTICAL INFORMATION..........................................................................21
8.1
Obinutuzumab........................................................................................................21
8.2
Placebo...................................................................................................................24
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES.........................................24
10.
STUDY CALENDAR .......................................................................................................26
11.
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................27
11.1
Data Reporting.......................................................................................................27
11.2
Data Safety Monitoring..........................................................................................27
11.3
Multicenter Guidelines...........................................................................................27
12.
STATISTICAL CONSIDERATIONS...............................................................................28
12.1
Study Design/Endpoints.........................................................................................28
12.2
Sample Size, Accrual Rate and Study Duration.....................................................28
12.3
Stratification Factors..............................................................................................29
12.4
Blinding..................................................................................................................29
12.5
Interim Monitoring Plan.........................................................................................29
12.6
Analysis of Primary Endpoints ..............................................................................29
12.7
Analysis of Secondary Endpoints ..........................................................................30
12.8
Analysis of Correlative Studies
12.9
Reporting and Exclusions ......................................................................................30
13.
PUBLICATION PLAN .....................................................................................................31
14.
REFERENCES ..................................................................................................................31
APPENDIX A
PERFORMANCE STATUS CRITERIA...................................................34
APPENDIX B
MEDWATCH 3500 Reporting form .........................................................35
APPENDIX C
Safety Reporting Fax Cover Sheet.............................................................36
APPENDIX D
Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety 
Monitoring Plan .................................................................................................................37
APPENDIX E             Patient GVHD Survey…………………………………………………...51
APPENDIX F             Provider GVHD Survey…………………………………………………53


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1.
OBJECTIVES
1.1
Study Design
This is a prospective, multicenter, randomized phase II trial of prophylactic obinutuzumab vs. placebo for 
prevention of chronic Graft vs. Host Disease (cGVHD) after Hematopoietic Cell Transplantation (HCT). A 
single dose of obinutuzumab or placebo will be administered prophylactically at 3, 6, 9 and 12 months after 
HCT. Clinical and immunological endpoints are measured sequentially. 200 subjects will be randomized 
and analyzed in a modified intention-to-treat fashion.
1.2
Primary Objectives
The primary objective is to determine the effect of obinutuzumab prophylaxis on the incidence of 
corticosteroid-requiring cGVHD after allogeneic HCT. The primary endpoint of this phase II trial is the 
rate of corticosteroid-requiring cGVHD one year after HCT.
1.3
Secondary Objectives
Secondary objectives are to determine the overall rate of cGVHD after HCT, the rate of NIH moderate- 
severe cGVHD after HCT, the cumulative incidence of non-relapse mortality and relapse, adverse 
hematologic events and infections, immunosuppression-free survival (IFS) at 1 and 2 years from 
transplantation, progression-free and overall survival at 1 and 2 years from transplantation, and 
immunologic correlates of B cell depletion.
2.
BACKGROUND
2.1
Chronic GVHD and B Cells
cGVHD involves inflammatory T- and B-cell responses against allogeneic and autologous antigens and is 
the most important late complication of allogeneic HCT.1 With the increasing use of mobilized peripheral 
blood progenitor cells, and a gradual reduction in early HCT-related mortality,2 a steady increase in the 
incidence of cGVHD has occurred. As a result, cGVHD is the leading cause of late morbidity, impaired 
quality of life, and mortality after allogeneic HCT.1;3;4
The mainstay of treatment of cGVHD is systemic corticosteroids, which are associated with incomplete 
responses and considerable toxicity. Aside from corticosteroids, there are no standards for the treatment of 
cGVHD, and management of these patients is challenging. There is a desperate need for effective 
therapeutics in cGVHD, but a preventative approach would be more fruitful. Graft manipulation (through 
in vivo or ex vivo T cell depletion or CD34+ selection) can prevent cGVHD,5;6 but graft manipulation has 
not been associated with an improvement in overall survival due to excess mortality associated with 
opportunistic infections and possibly relapse. Allogeneic tolerance induction with post-HCT 
cyclophosphamide may prevent cGVHD, but long-term outcomes have not been compared with traditional 
GVHD prevention strategies.7
Based on our initial association between the development of anti-H-Y antibodies in sex-mismatched HCT 
and the occurence of cGVHD,8 we and other groups have reported on the use of B cell depletion with 
rituximab as therapy for established cGVHD.9;10 Common to all reported studies, rituximab administration 
is safe with a low incidence of adverse events. The response rate to a 4 week course of therapy in steroid- 
refractory settings (375 mg/m2/week in most series), has been as high as 83%,11 although response rates in


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the 65% range are more commonly reported.10 Cutaneous and myofascial disease were the most responsive 
in most series.
Several novel strategies have been attempted in cGVHD therapy using rituximab. Miklos et al have 
performed a pilot study of rituximab in combination with corticosteroids as initial therapy of cGVHD. 35 
subjects with new-onset cGVHD that required corticosteroid treatment received rituximab (375 
mg/m2/week x 4) in combination with prednisone (1 mg/kg/day). A second course was allowed for 
incomplete responses. Response, defined as a complete or partial response with a prednisone dose of <0.25 
mg/kg/day, was noted in 40% of subjects at 6 and 12 months, suggesting promising but incomplete activity. 
While there were 6 deaths from cGVHD within 12 months of rituximab therapy, only 2 subjects suffered a 
relapse of their malignancy.12
Given the promising activity of rituximab in the treatment of established cGVHD, and reports of cGVHD 
prevention with peri-HCT B cell depletion,13;14 we explored the role of rituximab as prevention of 
cGVHD.15 In this phase II trial (DFCI 05-377), rituximab (375 mg/m2) was administered at 100 days, 6, 9 
and 12 months after HCT (n=65). The cumulative incidence of cGVHD and systemic corticosteroid- 
requiring cGVHD at 2 years from HCT were 48% and 31% respectively, lower than rates in a concurrent 
control cohort (60%, p=0.1 and 48.5%, p=0.015, respectively). In related donors, the incidence of cGVHD 
and corticosteroid-requiring cGVHD at 2 years was 35% and 23%, whereas the corresponding figures in 
unrelated donors was 59% and 38% (Figures 1, 2). Rituximab was safe, with no severe infusional events 
and a 2 year cumulative incidence of grade 3-5 infections of 15%. There was no difference in relapse 
incidence (34% vs. 28%, p=0.79), but treatment-related mortality at 4 years from HCT was significantly 
lower in treated subjects when compared with controls (5.1% vs. 19.0%, p=0.02), and overall survival was 
superior at 4 years (71% vs. 56%, p=0.05). In a multivariable regression model, only rituximab use (HR 
0.56, 95% CI 0.31-1.00, p=0.048) and high/very high disease risk index (HR 1.90, 95% CI 1.02-3.53, 
p=0.04) were significantly associated with overall survival.
In a similar experience, Miklos and colleagues also tested the role of rituximab as prevention of cGVHD, 
and reported similar outcomes using a TLI/ATG preparative regimen.16 In this experience involving 35 
subjects, Rituximab (375 mg/m2) was infused weekly (days +56, 63, 70, 77). The cumulative incidence of 
cGVHD was 20%, which is lower than the published rates of cGVHD using this regimen.17
2.2
Study Agent
Figure 1 (left): Incidence of cGVHD with rituximab cGVHD prophylaxis, stratified by donor type. Figure 
2 (right):100 Day Landmark Survival Analysis.


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Obinutuzumab (also known as RO5072759, GA101, Gazyva) is a humanized glycoengineered type II anti- 
CD20 monoclonal antibody (mAb). Obinutuzumab was derived by humanization of the parental B-Ly1 
mouse antibody and subsequent glycoengineering leading to the following characteristics: high-affinity 
binding to the CD20 antigen, high antibody-dependent cellular cytotoxicity (ADCC), and antibody- 
dependent cellular phagocytosis (ADCP); low complement-dependent cytotoxicity (CDC) activity; and 
high direct cell death induction. These nonclinical features of obinutuzumab may translate into an anti- 
CD20 monoclonal antibody with superior clinical efficacy compared to other anti-CD20-mAb.
Obinutuzumab is FDA-approved for use in combination with chlorambucil for the treatment of individuals 
with previously untreated chronic lymphocytic leukemia.
Obinutuzumab will be provided by Roche/Genentech Inc.
2.3
Rationale
In both the preliminary experiences of prevention of cGVHD with rituximab, prevention of cGVHD was 
incomplete. While it is understood that B cells are not entirely responsible for the pathogenesis of cGVHD, 
it is hypothesized that a more potent anti-B cell agent could be a more effective prophylaxis agent, since it 
is known that rituximab-unresponsive cGVHD patients have B cells with a CD20Lo phenotype and 
persistent elevations in BAFF,18 rendering them more resistant to apoptosis via activation of the BCR 
pathway.19
We therefore propose a randomized, placebo-controlled Phase II trial of obinutuzumab. The size and 
randomized nature of this multicenter study has the potential to change the field of allogeneic HCT, and 
could result in improved patient outcomes across multiple tumor types, and across all conditioning 
intensities.
2.4
Correlative Studies Background
While many mHA are likely involved in cGVHD, the F→M 
HCT model provides a convenient set of known mHA whose 
antibody responses can be tracked. The Miklos lab has identified 
a series of 9 highly immunogenic minor histocompatibility 
(mHA) proteins on the Y chromosome (H-Y proteins). Subjects 
who underwent F→M HCT, were found to have significantly 
higher levels of anti-H-Y IgG antibodies, which correlated with 
a higher rate of cGVHD after HCT. As shown in Figure 3, H-Y 
antibodies are associated with a higher probability of cGVHD 
but lower levels of relapse, displaying both the GVHD and GVL
Figure 3: Association between anti-H-Y 
antibodies with cGVHD and protection 
from relapse
effects of the allo-immune response.8 While antibody responses in humans are correlated with cGVHD, it 
is important to note that in the mouse, deposition of IgG is involved in the pathology of cGVHD.
The DBY-2 peptide (KNDPERLDQQLANLDLNSEK) contains the DBY-2 epitope, frequently recognized 
in allogeneic F→M antibody responses that occur following HCT. Miklos was able to demonstrate the 
presence of circulating B cells expressing immunoglobulin receptors that specifically bind DBY-2. In a 
retrospective analysis of 28 subjects undergoing F→M HCT without prior cGVHD, DBY-2–binding B cells 
were detected in 16 subjects (57%) 6 months after HCT, with appropriate negative controls, including 
healthy female donors or male donor PBMC incubated with high-titer anti–DBY-2 IgG (Figure 4).20 
Importantly, 15 of these 16 developed cGVHD, including 6 who were diagnosed at the time of the anti- 
DBY-2 analysis. The absolute and relative number of DBY-2–specific B cells was significantly higher 6


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months after HCT in patients who developed NIH moderate or severe cGVHD compared with those with 
NIH mild cGVHD or no cGVHD at all (P = 0.02; Figure 5). It is important to note that none of the patients 
with detectable anti-DBY-2 B cells yet had detectable circulating anti-DBY-2 IgG, suggesting that the 
detection of the B cell is a more relevant marker of impending cGVHD than identification of the circulating 
antibody. If the anti-DBY-2 antibody is pathogenic then it also argues that intervention prior to the 
elaboration of the anti-DBY-2 antibody may be fruitful in cGVHD prevention. The phenotype of the DBY- 
2 specific B cells corresponds to the commonly accepted phenotype for naïve or transitional B cells 
(CD19+IgM+IgD+CD27−CD38+CD5−), which allows more precise identification of the target B cell for 
further interventional strategies.
Figure 4 (left): DBY-2–binding B cells are detected in some F→M 
patients after HCT but not in healthy male and female donors (left 
column). Data for the X chromosome homologue DBX-2 are shown in 
right column. Data for 1 representative F→M HCT patient, 6 months 
after HCT (top) and for healthy controls (2nd through 4th panels). 
(Adapted from Sahaf et al, 2013).
Figure 5 (below): HY-specific B-cells predict cGVHD severity.
In the study cited above of primary therapy of cGVHD using corticosteroids and rituximab, cGVHD clinical
response was predicted by a naïve (CD19+CD38-IgD+CD27-) B cell phenotype (p=0.03).12 15 cGVHD 
subjects underwent had F→M HCT, and 6 (38%) were H-Y IgM positive while 9 (56%) were IgG positive 
at cGVHD diagnosis. Among 15 F→M HCT recipients with cGVHD treated with rituximab, 11 responded, 
and both H-Y IgM and IgG became undetectable for at least 6 months following rituximab. In contrast, the 
4 F→M subjects who did not respond remained H-Y IgG positive. Moreover, 2 subjects that redeveloped 
H-Y IgG later had recurrent cGVHD. H-Y antigen-specific B cells depleted after rituximab recovered in 6 
of the 11 F→M assayed, suggesting that alternative anti-B cell strategies are required.
In the Stanford trial of primary prevention of cGVHD with rituximab, rituximab administration significantly 
reduced B cell allogeneic immunity. In 10 F→M recipients enrolled in this trial, there was complete 
prevention of alloreactive H-Y antibody development, and none of these subjects developed cGVHD. In 
comparison, among 25 F→M HCT patients who used the same TLI-ATG conditioning regimen but without 
prophylactic rituximab during this time period, 14 of the 25 (56%) developed H-Y antibodies, with 13 of 
the 25 (52%) developing cGVHD (p=0.01).16 Similarly, in our trial of primary cGVHD prevention with 
rituximab (DFCI 05-377), of 13 F→M recipients, none developed anti-DBY antibodies between 6 months 
and 1 year from HCT, whereas 4 of 10 F→M control recipients developed anti-DBY antibodies in the same 
time period (p=0.02).


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In this clinical trial, samples from all F→M recipients will be collected and analyzed for the presence of 
pathogenic alloreactive H-Y antibodies as well as pathogenic anti H-Y B cells. Samples will also be 
analyzed for non H-Y restricted antibodies (preliminary data not shown).
3.
PARTICIPANT SELECTION
3.1
Eligibility Criteria
3.1.1
Subjects deemed potentially eligible by their treating physicians will be screened for enrollment 
after d+60 from transplantation
3.1.2
Patients who have undergone either ablative or non-myeloablative allogeneic stem cell 
transplantation are eligible.
3.1.3
Peripheral blood stem cells must have been used as the stem cell source.
3.1.4
Patients must have received transplantation from donors (both related and unrelated) who are 
identical at 8 HLA loci (A, B, C and DR1), or mismatched at no more than 1 locus (7/8). Among 
related donors, HLA C typing is not required (6/6 HLA matches). Class I typing is to be performed 
by PCR-SSP techniques and CDC techniques. Class II typing is performed by PCR-RFLP +/- PCR-
SSP techniques.
3.1.5
No evidence of relapsed or residual malignancy within 30 days of trial entry. All patients must 
undergo appropriate staging for their malignancy (i.e. bone marrow aspiration for the leukemias 
and PET-CT scanning for the lymphomas). Evidence of a persistent cytogenetic abnormality will 
constitute evidence of residual or relapsed disease in the leukemias, where present. Individuals with 
CLL are eligible if there is no more than 20% residual leukemia in the bone marrow at the time of 
study entry.
3.1.6
Patients who have undergone a non-myeloablative stem cell transplant must have > 80% donor 
hematopoiesis within 30 days of study enrollment. Chimerism within 30 days of study entry must 
be greater than, equal to, or no more than 5% less than the chimerism measured at approximately 
day+30 (if performed).
3.1.7
Age ≥ 18.0
3.1.8
ECOG performance status ≤2 (Karnofsky ≥60%) (See Appendix A)
3.1.9
Participants must have normal marrow function as defined by:

WBC
≥ 2,500/μL

Absolute Neutrophil Count
≥ 1,000/μL

Platelets
≥ 50,000/μL
3.1.10 Ability to understand and the willingness to sign a written informed consent document.


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3.1.11
The effects of obinutuzumab on the developing human fetus are unknown. For this reason, 
women of child-bearing potential and men must agree to use adequate contraception (hormonal or 
barrier method of birth control; abstinence) prior to study entry and for the duration of study 
participation. Should a woman become pregnant or suspect she is pregnant while she or her 
partner is participating in this study, she should inform her treating physician immediately. Men 
treated or enrolled on this protocol must also agree to use adequate contraception prior to the 
study, for the duration of study participation, and 4 months after completion of obinutuzumab 
administration.
3.2
Exclusion Criteria
3.2.1
Allogeneic stem cell transplantation using a single or multiple umbilical cord blood units or using 
bone marrow.
3.2.2
Allogeneic stem cell transplantation using in vivo or ex vivo T cell depletion, either by cell 
manipulation or with T cell depleting antibodies (Any anti-thymocyte globulin preparation or 
alemtuzumab given within 30 days of transplantation)
3.2.3
Participation in a clinical trial evaluating another preventative strategy for chronic GVHD, or 
ongoing participation in a clinical trial for therapy of acute GVHD. Prior completion of 
experimental therapy for acute GVHD is permissible if the experimental agent was used > 30 days 
prior to enrollment.
3.2.4
Any evidence of ongoing gastrointestinal or hepatic acute GVHD, or evidence of greater than 
ongoing Stage I cutaneous acute GVHD. Ongoing, tapering therapy for resolved acute GVHD is 
permissible.
3.2.5
Any evidence of prior active or resolved chronic GVHD.
3.2.6
Any evidence of cGVHD or late aGVHD between enrollment and first dose of obinutuzumab.
3.2.7
History of severe allergic reaction to obinutuzumab
3.2.8
No Donor Lymphocyte Infusion (DLI) prior to day 100, and no plans for a DLI in the upcoming 
30 days.
3.2.9
Evidence of any active uncontrolled infection (bacterial, viral or fungal) or evidence of natural 
exposure to Hepatitis B, Hepatitis C or HIV. Evidence of Hepatitis B exposure includes the 
presence of Hepatitis B surface antigenemia, a positive serological test for Hepatitis B core 
antibody or nucleic acid testing (NAT testing) that is positive for Hepatitis B. Vaccination to 
Hepatitis B is not an exclusion criteria. Testing done in the pre-transplant setting is sufficient to 
rule out infection.
3.2.10 Pregnancy or lactation. Negative pregnancy test is required within the screening window for 
women of child bearing potential.
3.2.11 Active use of any other investigational agents.


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3.3
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.
4.
REGISTRATION PROCEDURES
4.1
General Guidelines for DF/HCC and DF/PCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) OnCore. 
Registrations must occur prior to the initiation of protocol therapy. Any participant not registered to the 
protocol before protocol therapy begins will be considered ineligible and registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Following registration, participants may begin protocol therapy. Issues that would cause treatment delays 
should be discussed with the Overall Principal Investigator (PI). If a participant does not receive protocol 
therapy following registration, the participant’s registration on the study must be canceled. Registration 
cancellations must be made in OnCore as soon as possible.
4.2
Registration Process for DF/HCC and DF/PCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol Registration
(SOP #: REGIST-101) must be followed.
4.3
General Guidelines for Other Investigative Sites
Eligible participants will be entered on study centrally at the DFCI by the Study Coordinator.
Following registration, participants should begin protocol therapy within 14 days. Issues that would cause 
treatment delays should be discussed with the Overall PI. If a participant does not receive protocol 
therapy following registration, the participant’s registration on the study must be canceled. The Study 
Coordinator should be notified of cancellations as soon as possible.
4.4
Registration Process for Other Investigative Sites
For information regarding the registration process, please refer to section 3.7 of the DSMP located in 
appendix D.
5.
TREATMENT PLAN
5.1
Stem Cell Transplantation
All subjects will undergo allogeneic stem cell transplantation according to locally approved clinical trials 
or treatment plans. No specific conditioning regimen or GVHD prophylaxis regimen is mandated. The stem 
cell source must have been peripheral blood stem cells. No in vitro or in vivo T cell depletion is permitted. 
Participation in a clinical trial evaluating novel approaches to acute GVHD prophylaxis is not


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allowed, but participation in a trial evaluating novel agents for therapy of acute GVHD is allowed, as long 
as the experimental agent was discontinued > 30 days prior to trial entry.
5.2
Trial Screening and Entry
Subjects deemed potentially eligible by their treating physicians will be screened for enrollment after day
+60 from transplantation. Once screened, deemed eligible and registered, the subject will be randomized in 
a 1:1 to the active treatment (obinutuzumab) or placebo arm. Stratification will be by center, conditioning 
intensity and donor type, using a permuted block algorithm within strata. Blinding will be maintained at the 
level of the Research Pharmacy.
5.3
Treatment Regimen
Obinutuzumab or placebo will be administered at a dose of 1000 mg, intravenously, at 3, 6, 9 and 12 months 
from transplantation. The first dose is administered at day +90 (+/- 10 days), followed by doses at days
+180 (+/- 10 days), 270 (+/- 10 days) and +365 (+/- 10 days).
Premedication with histamine blockers and acetaminophen will be provided (see Section 5.5 below), but 
corticosteroids at the time of obinutuzumab infusion are not permitted. Placebo will be administered with 
the same premedications and precautions.
No dose modifications are permitted, although doses may be skipped based on unresolved toxicity (see 
Section 6: Dosing Delays/Dose Modifications). If a dose is missed, the investigator may choose to continue 
with protocol-specified treatments within the next dosing time period.
5.4
Pre-Treatment Criteria for Doses 1, 2, 3 and 4
There are no criteria for treatment at dose 1. Dose 1 will be administered at the discretion of the 
provider.
Criteria for treatment at doses 2, 3 and 4 are:

WBC
≥ 2,500/μL

Absolute Neutrophil Count
≥ 1,000/μL

Platelets
≥ 50,000/μL
The occurrence of acute GVHD prior to doses 2, 3, 4 is allowed as long as all GVHD symptoms are 
resolved to Gr 0 for hepatic and gastrointestinal disease and Gr I for cutaneous disease, per section 
3.2.43.2.4
5.5
Agent Administration
Initial Dose
Research subjects should be premedicated with Acetaminophen (650 – 1000 mg oral) and 
Diphenhydramine (25-50 mg intravenous).
Obinutuzumab or placebo is administered initially at 50 mg/h. In the absence of infusional reactions, the 
rate can be increased in increments of 50 mg/h every 30 minutes to a maximum of 400 mg/h. With this 
schedule, a 1000 mg dose of Obinutuzumab will be infused over 4.25 hours. See Table 1.
Second and Subsequent Doses


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Doses and schedules are adapted from Phase I and Phase II studies in non-CLL patient populations.21-24
Research subjects should be premedicated with Acetaminophen (650 – 1000 mg, oral) and 
Diphenhydramine (25-50 mg, intravenous).
In the absence of severe infusional reactions with the initial dose, Obinutuzumab can be administered 
initially at 100 mg/h. In the absence of infusional reactions, the rate can be increased in increments of 100 
mg/h every 30 minutes to a maximum of 400 mg/h. With this schedule, a 1000 mg dose of Obinutuzumab 
will be infused over 3.25 hours. See Table 1.
Placebo will administered at the same rate with the same pre-medications as obinutuzumab.
Table 1. Administration of Obinutuzumab
1st Dose 
Rate
Duration
Dose Delivered
Total Time
Cumulative Dose
50 mg/hr
30 minutes
25 mg
0.5 hours
25 mg
100 mg/hr
30 minutes
50 mg
1 hour
75 mg
150 mg/hr
30 minutes
75 mg
1.5 hours
150 mg
200 mg/hr
30 minutes
100 mg
2 hours
250 mg
250 mg/hr
30 minutes
125 mg
2.5 hours
375 mg
300 mg/hr
30 minutes
150 mg
3 hours
525 mg
350 mg/hr
30 minutes
175 mg
3.5 hours
700 mg
400 mg/hr
45 minutes
300 mg
4.25 hours
1000 mg
2nd and Subsequent Doses
Rate
Duration
Dose Delivered
Total Time
Cumulative Dose
100 mg/hr
30 minutes
50 mg
0.5 hour
50 mg
200 mg/hr
30 minutes
100 mg
1 hours
150 mg
300 mg/hr
30 minutes
150 mg
1.5 hours
300 mg
400 mg/hr
1.75 hours
700 mg
3.25 hours
1000 mg
5.6
Management of Infusion Reactions
Infusion reactions are noted in the presence of high tumor burden in the treatment, and as a result are more 
frequent in the treatment of CLL in comparison with NHL. Stem cell transplant recipients are leukopenic 
and are anticipated to have an even lower likelihood of infusion reactions than B cell malignancy patients.
Infusion reactions should be managed according to the grade of the reaction. For Grade 4 reactions, the 
infusion must be stopped and permanently discontinued. For Grade 3 reactions, the infusion should be 
temporarily interrupted and appropriate medication administered to treat the symptoms. For Grade 1–2 
reactions, the infusion should be slowed down and symptoms treated as appropriate. Upon resolution of 
symptoms, infusion can be restarted, except following Grade 4 IRR, at no more than half the previous rate 
and, if the patient does not experience the same adverse event with the same severity, infusion rate 
escalation may resume at the increments and intervals as appropriate for the treatment dose.


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For infusion reactions, additional doses of H1- and H2-blocking antihistamine agents are administered. 
Corticosteroids may be administered but only for Grade 3 or 4 reactions when deemed necessary by the 
treating physician.
5.7
Immunosuppressive Medication Tapering
Immunosuppressive medications should be tapered according to the treating physicians’ discretion with 
careful attention to the clinical trial or treatment plan to which the participating subject is already enrolled. 
The date of discontinuation of all immunosuppressive medications will be recorded.
5.8
Concomitant Medication Use
5.8.1
Growth Factors: Growth factors to promote WBC or RBC numbers are allowed as dictated by the 
clinical situation. They should not be used simply to meet eligibility requirements for subsequent 
obinutuzumab doses.
5.8.2
Immunoglobulin Repletion: ASBMT guidelines for the repletion of IgG levels should be 
followed. Prolonged hypogammaglobulinemia is anticipated after B cell depleting therapy.
5.9
Criteria for Taking a Participant Off Protocol Therapy
The following are criteria for removing a participant from active study:

The development of steroid-requiring cGVHD

Malignant disease progression

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s)

Participant demonstrates an inability or unwillingness to comply with the treatment regimen

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant unacceptable 
for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply. The reason for 
removal from protocol therapy, and the date the participant was removed, must be documented in the case 
report form (CRF). Patients with steroid-requiring cGVHD, unacceptable AEs or intercurrent illness 
preventing further drug administration who come off treatment should continue to have laboratory studies 
and clinical assessments performed at the appropriate timepoints. Patients with malignant disease 
progression do not require laboratory or clinical follow-up. Alternative care options will be discussed 
with the participant.
An ODQ/CTRIO Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the ODQ/CTRIO website or obtained from the ODQ/CTRIO 
registration staff.


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In the event of unusual or life-threatening complications, treating investigators must immediately notify 
the Overall PI, Corey Cutler at 617 632-3000 pager #41115.
5.10
Duration of Follow Up
Research subjects will be followed until 2 years from the time of transplantation, or until death, whichever 
occurs first. Participants removed from protocol therapy for unacceptable adverse events will be followed 
closely until resolution or stabilization of the adverse event, and then until 2 years from the time of 
transplantation, or until death, whichever occurs first. Participants who withdraw consent will be followed 
until that time.
5.11
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Death
The reason for taking a participant off study, and the date the participant was removed, must be documented 
in the case report form.
For Centralized Subject Registrations, the research team submits a completed Off Treatment/Off Study 
form to ODQ when a participant comes off study. This form can be found on the ODQ website or 
obtained from the ODQ registration staff.
For Decentralized Subject Registrations, the research team updates the relevant Off Treatment/Off Study 
information in OnCore.
6.
DOSING DELAYS/DOSE MODIFICATIONS
No dose modifications are permitted.
Dose delays are permitted only within the window of administration for that specific dose (+/- 10 days). 
Investigators are discouraged from using exogenous colony stimulating factors purely to attain hematologic 
thresholds acceptable for dosing of obinutuzumab. Criteria for the administration of doses 2, 3 and 4 are 
found in Section 5.4.
7.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following list of 
reported and/or potential AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting in addition to routine reporting. Safety 
assessments will consist of monitoring and reporting adverse events (AEs) and serious adverse events 
(SAEs) that are considered related to obinutuzumab per protocol, all events of death, and any study 
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7.1
Expected Toxicities of Obinutuzumab
7.1.1
Infusion-Related Reactions
Infusion-related reactions (IRRs) were observed consistently in all obinutuzumab trials; the highest 
incidence of IRR was at the first infusion with the incidence decreasing rapidly with subsequent infusions. 
The incidence of IRR observed with combination therapy (FC and CHOP) appears similar to that observed 
with monotherapy. Furthermore, the incidence of IRR appears to be higher in CLL compared to NHL 
patients and higher in obinutuzumab- compared to rituximab-exposed patients based on evidence from 
studies BO21003 and BO21999. There is no clear relationship between obinutuzumab dose and the 
incidence of IRR based on data from study GAO4768g. In Stage 2 of the pivotal Phase III study, BO21004/ 
CLL 11, investigating GClb vs RClb in patients with CLL, the incidence of IRR, Grade 3/4 IRR and IRR 
leading to discontinuation was higher in GClb arm compared to RClb. This study investigated several 
measures to minimize the risk of IRRs including: use of corticosteroids, withdrawal of antihypertensive 
treatments, slow infusion, and split dosing and the evidence suggests that these risk minimization measures 
decreased the risk of IRRs (all grades); however, the impact on the incidence of Grade 3-4 events and 
treatment discontinuations due to IRR was limited.
7.1.2
Thrombocytopenia
The main risk associated with thrombocytopenia is hemorrhage. In trial BO21004/CLL11, the overall 
incidence of hemorrhagic AEs was comparable between the treatment arms (8% GClb; 7% RClb) with the 
majority of events being of Grade 1 or 2 severity. However, and importantly, all fatal hemorrhagic events 
in the GClb arm occurred in Cycle 1 in contrast to such events in the RClb arm which occurred later (beyond 
1 year after first administration of study drug).
7.1.3
Other AEs
Other AEs of particular interest include neutropenia, infections including progressive multifocal 
leukoencephalopathy (PML), and hepatitis B virus (HBV) reactivation.
7.2
Adverse Event Characteristics

CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web 
site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

For expedited reporting purposes only:
-
AEs for the agent(s) that are listed above should be reported only if the adverse event varies 
in nature, intensity or frequency from the expected toxicity information which is provided.
-
Other AEs for the protocol that do not require expedited reporting are outlined in the next 
section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-Specific 
Expedited Adverse Event Reporting Exclusions.

Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.


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-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
7.3
Expedited Adverse Event Reporting
7.3.1
Investigators must report to the Overall PI any serious adverse event (SAE) that occurs after the 
initial dose of study treatment, during treatment, or within 30 days of the last dose of treatment on 
the local institutional SAE form.
7.3.2
For multi-institution studies where a DF/HCC investigator is serving as the Overall Principal 
Investigator, each participating institution must abide by the reporting requirements set by the 
DF/HCC. This applies to any medical event equivalent to an unexpected grade 2 or 3 with a 
possible, probable or definite attribution, unexpected grade 4 toxicities, and grade 5 (death) 
regardless of study phase or attribution.
7.3.3
DF/HCC Expedited Reporting Guidelines
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy.
Other investigative sites will report AEs to their respective IRB according to the local IRB’s 
policies and procedures in reporting adverse events. A copy of the submitted institutional AE 
form should be forwarded to the Overall PI within the timeframes detailed in the table below.
DF/HCC Reportable AEs
Attribution
Gr. 2 & 3 AE
Expected
Gr. 2 & 3 AE
Unexpected
Gr. 4 AE Expected
Gr. 4 AE
Unexpected
Gr. 5 AE Expected 
or Unexpected
Unrelated 
Unlikely
Not required
Not required
5 calendar days#
5 calendar days
24 hours*
Possible 
Probable 
Definite
Not required
5 calendar days
5 calendar days#
5 calendar days
24 hours*
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported.
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last intervention, 
the AE should be reported within 1 business day of learning of the event.
The Overall PI will submit AE reports from outside institutions to the DFCI OHRS according to 
DFCI IRB policies and procedures in reporting adverse events.
7.3.4
Protocol-Specific Expedited Adverse Event Reporting Exclusions
For this protocol only, the AEs/grades listed below do not require expedited reporting to the 
Overall PI or the DFCI IRB. However, they still must be reported through the routine reporting 
mechanism (i.e. case report form).
The appearance of signs or symptoms known to be associated with acute or chronic GVHD are specifically 
exempt from AE or SAE reporting, regardless of their severity.


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Similarly, infectious complications following stem cell transplantation are common, and will not be 
reported as AEs unless the clinical investigator deems the infection to be very atypical for the post- 
transplant setting, or the infection results in death.
Relapse of the original malignancy will not be reported as an AE, but will be monitored, as detailed in 
section 12.7
7.4
Serious Adverse Events for Genentech Reporting
An AE should be classified as an SAE if the following criteria are met:

It results in death (i.e., the AE actually causes or leads to death).

It is life threatening (i.e., the AE, in the view of the investigator, places the patient at immediate 
risk of death. It does not include an AE that, had it occurred in a more severe form, might have 
caused death.).

It requires or prolongs inpatient hospitalization.

It results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the patient’s ability to conduct normal life functions).

It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
obinutuzumab.

It is considered a significant medical event by the investigator based on medical judgment (e.g., 
may jeopardize the patient or may require medical/surgical intervention to prevent one of the 
outcomes listed above).
7.4.1
Deaths
All deaths that occur during the protocol-specified AE reporting period, regardless of attribution, will be 
reported to the appropriate parties. When recording a death, the event or condition that caused or contributed 
to the fatal outcome should be reported as the single medical concept. If the cause of death is unknown and 
cannot be ascertained at the time of reporting, report “Unexplained Death”.
7.4.2
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the start of the study. Such conditions should be 
reported as medical and surgical history. A preexisting medical condition should be re-assessed throughout 
the trial and reported as an AE or SAE only if the frequency, severity, or character of the condition worsens 
during the study. When reporting such events, it is important to convey the concept that the preexisting 
condition has changed by including applicable descriptors (e.g., “more frequent headaches”).
7.4.3
Hospitalizations for Medical or Surgical Procedures
Any AE that results in hospitalization or prolonged hospitalization should be documented and reported as 
an SAE. If a patient is hospitalized to undergo a medical or surgical procedure as a result of an AE, the 
event responsible for the procedure, not the procedure itself, should be reported as the SAE. For example, 
if a patient is hospitalized to undergo coronary bypass surgery, record the heart condition that necessitated 
the bypass as the SAE.
Hospitalizations for the following reasons do not require reporting:


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
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for 
preexisting conditions

Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study 
or

Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of the 
study.
7.4.4
Pregnancy
If a female patient becomes pregnant while receiving obinutuzumab or within one year after the last dose 
of obinutuzumab, or the partner of a male patient becomes pregnant while receiving therapy or within three 
months of completing therapy, a report should be completed and expeditiously submitted to the 
Roche/Genentech, Inc. Follow-up to obtain the outcome of the pregnancy should also occur. Abortion, 
whether accidental, therapeutic, or spontaneous, should always be classified as serious, and expeditiously 
reported as an SAE. Similarly, any congenital anomaly/birth defect in a child born to a female patient 
exposed to obinutuzumab should be reported as an SAE.
7.4.5
GVHD
Neither acute or chronic GVHD require reporting to Genentech.
7.4.6
Post-Study Adverse Events
The investigator should expeditiously report any SAE occurring after a patient has completed or 
discontinued study participation if attributed to prior obinutuzumab exposure. If the investigator should 
become aware of the development of cancer or a congenital anomaly in a subsequently conceived offspring 
of a female patient who participated in the study, this should be reported as an SAE.
7.5
Adverse Events of Special Interest (AESIs) for Genentech
AEs of special interest (AESIs) are defined as a potential safety problem, identified as a result of safety 
monitoring of Obinutuzumab. Adverse events of special interest (AESI) in clinical trials are sent to 
Genentech within 24 hours, even when they are considered non-serious by the investigator.
The following AESIs must be reported to the Sponsor expeditiously irrespective of regulatory seriousness 
criteria:
–
Tumor Lysis Syndrome (serious and non- serious events)
The following events can be reported as AESI only when considered SERIOUS by the investigator:
-
Serious neutropenia
-
Serious infection
-
Serious Infusion Related Reaction (IRR)
Other selected events can be considered for reporting as AESIs:

infections (including PML)


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
neutropenia (including late onset neutropenia - defined as neutrophil count < 1000 cells/mm3, 
occurring 28 days or more after obinutuzumab treatment has been completed or stopped; prolonged 
neutropenia - defined as neutrophil count < 1000 cells/mm3, which does not resolve after 28 days 
(without obinutuzumab treatment),

thrombocytopenia (including acute thrombocytopenia - events occurring during and within 24 
hours post obinutuzumab infusion)

Hepatitis B reactivation

cardiac events

second malignancies

GI perforation.
7.6
Serious Adverse Event Reporting to Roche/Genentech
Investigators must report all AESIs and SAEs to Roche/Genentech within the timelines described below. 
The completed MedWatch/case report (Appendix B) should be faxed/emailed immediately upon 
completion to Genentech at the following contacts:
All protocol-defined AEs, SAEs, AESIs, Special Situation Reports (including pregnancy reports) and 
Product Complaints with an AE should be sent to: 
Fax: (650) 238-6067
Email: usds_aereporting-d@gene.com 
All Product Complaints without an AE should be sent to:
Email: kaiseraugst.global_impcomplaint_management@roche.com 
A cover sheet for faxes to Roche/Genentech is found in Appendix C
A copy of the submitted institutional AESIs,SAEs, Special Situation Reports (including pregnancy reports) and Product 
Complaints (with or without an AE) should be forwarded to the Overall PI.
Relevant follow-up information should be submitted to Roche/Genentech Drug Safety as soon as it becomes 
available.
Serious AE reports that are related to obinutuzumab will be transmitted to Roche/Genentech within 15 
calendar days of the Awareness Date.
The Principal Investigator will periodically forward listings of non-serious AEs originating from the Study 
to Roche/Genentech.
In addition to SAEs and pregnancy reports, the following Special Situations Reports should be collected 
and transmitted to Roche/Genentech even in the absence of an Adverse Event within thirty (30) calendar 
days:

Data related to product usage during pregnancy or breastfeeding

Data related to overdose, abuse, misuse, inadvertent/erroneous administration, medication error or 
occupational exposure, with or without association with an AE/SAE unless otherwise specified in the 
protocol
Product Complaints: 
All Product Complaints (with or without an AE) shall be forwarded to Genentech within fifteen (15) 
calendar days of the awareness date.
A Product Complaint is defined as any written or oral information received from a complainant that alleges 


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deficiencies related to identity, quality, safety, strength, purity, reliability, durability, effectiveness, or 
performance of a product after it has been released and distributed to the commercial market or clinical 
trial.
Investigators should also report events to their IRB as required.
7.6.1
MedWatch 3500A Reporting Guidelines
In addition to completing appropriate patient demographic and suspect medication information, the report 
should include the following information within the Event Description (item 5) of the MedWatch 3500A 
form:

Protocol description (and number, if assigned)


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
Description of event, severity, treatment, and outcome if known

Supportive laboratory results and diagnostics

Investigator’s assessment of the relationship of the to each investigational product and suspect 
medication
Additional information may be added to a previously submitted report by any of the following methods:

Adding to the original MedWatch 3500A report and submitting it as follow-up

Adding supplemental summary information and submitting it as follow-up with the original 
MedWatch 3500A form

Summarizing new information and faxing it with a cover letter including patient identifiers (i.e.,
D.O.B. initial, patient number), protocol description and number, if assigned, brief AE description, 
and notation that additional or follow-up information is being submitted (The patient identifiers are 
important so that the new information is added to the correct initial report)
Occasionally Roche/Genentech may contact the reporter for additional information, clarification, or current 
status of the patient for whom and AE was reported. For questions regarding SAE reporting, you may 
contact the Roche/Genentech Drug Safety representative noted above or the MSL assigned to the study. 
Relevant follow-up information should be submitted to Roche/Genentech Drug Safety as soon as it becomes 
available and/or upon request.
MedWatch 3500A form is available at 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm
7.7
Expedited Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant safety reports 
or sentinel events that require reporting according to institutional policy.
8.
PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational agent administered in 
this study can be found in Section 7.1.
8.1
Obinutuzumab
8.1.1
Description
Obinutuzumab is a humanized and glycoengineered type II anti-CD20 monoclonal antibody of the 
IgG1 subclass. It recognizes a specific epitope of the CD20 molecule found on B-cells. The 
molecular mass of the antibody is approximately 150 kDa.
An antibody-producing cell line was established from the CHO K1 cell line. 
INN:
Obinutuzumab
Code Number:
Drug substance: RO5072759
Drug product: Ro 5072759/F06-01 (1000 mg/vial)
Chemical Name:
Humanized glycoengineered type II anti-CD20 monoclonal
antibody


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Other Names:
GAZYVA®, GAZYVARO™, huMAb<CD20>, GA101
Chemical Structure:
H2L2 polypeptide structure consisting of two light chains and two
heavy chains held together by disulfide bonds.
Molecular Weight:
Approximately 150 kDa
Description:
The drug substance is a clear, colorless to slightly brownish liquid.
The drug product is a colorless to slightly brownish liquid 
concentrate.
8.1.2
Form
Obinutuzumab is provided as a single 1000 mg dose liquid concentrate with a strength of 25 
mg/mL. It is supplied in 50 mL glass vials containing 40 mL of the 25 mg/mL liquid concentrate. 
In addition to the antibody, the liquid also contains histidine/histidine-HCl, trehalose, poloxamer 
188 and HPW. HPW meets the specified limits for highly purified water according to Ph.Eur. and 
for WFI according to USP.
8.1.3
Storage and Stability
The recommended storage conditions for obinutuzumab drug product are between 2°C and 8°C, 
protected from light.
For microbiological stability, the diluted obinutuzumab infusion solution should be used 
immediately.
8.1.4
Compatibility
Do not mix obinutuzumab with other drugs.
No incompatibilities between obinutuzumab and polyvinylchloride (PVC) or non-PVC 
polyolefin bags and administration sets have been observed.
8.1.5
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the 
environment, should undertake the preparation, handling, and safe disposal of the chemotherapeutic 
agent in a self-contained and protective environment.
8.1.6
Availability
Obinutuzumab will be distributed to the Study Sites directly from Genentech, Inc.
8.1.7
Preparation
Prepare the solution for infusion, using aseptic technique, as follows:
Inspect visually for any particulate matter and discoloration prior to administration.
Dilute into a 0.9% sodium chloride PVC or non-PVC polyolefin infusion bag. Do not use other 
diluents such as dextrose (5%).
Remove 20 ml overfill from 0.9% sodium chloride 250 ml bag. Remove an additional 40 ml from 
the 0.9% sodium chloride 250 ml bag.
Withdraw 40 mL (1000 mg) of obinutuzumab and inject into the 0.9% sodium chloride bag.


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Mix diluted solution by gentle inversion. Do not shake. 
Total volume for administration is 250 ml.
Final concentration is 4 mg/ml.
The prepared infusion solution should be used immediately or may be stored at 2 to 8 degrees C 
(36 to 46 degrees F) for up to 24 hours.
8.1.8
Administration
Initial Dose
Research subjects should be premedicated with Acetaminophen (650 – 1000 mg oral) and 
Diphenhydramine (25-50 mg intravenous).
Obinutuzumab is administered initially at 50 mg/h. In the absence of infusional reactions, the rate 
can be increased in increments of 50 mg/h every 30 minutes to a maximum of 400 mg/h. With this 
schedule, a 1000 mg dose of Obinutuzumab will be infused over 4.25 hours.
Second and Subsequent Doses
Research subjects should be premedicated with Acetaminophen (650 – 1000 mg oral) and 
Diphenhydramine (25-50 mg intravenous).
In the absence of severe infusional reactions with the initial dose, Obinutuzumab can be 
administered initially at 100 mg/h. In the absence of infusional reactions, the rate can be increased 
in increments of 100 mg/h every 30 minutes to a maximum of 400 mg/h. With this schedule, a 1000 
mg dose of Obinutuzumab will be infused over 3.25 hours.
Doses and schedules are adapted from Phase I and Phase II studies in non-CLL patient 
populations.21-24
Placebo will administered at the same rate with the same pre-medications as obinutuzumab.
8.1.9
Ordering
Obinutuzumab will be ordered directly from Genentech, Inc by each study site.
8.1.10 Accountability
Each research Pharmacy will maintain a careful record of the inventory and disposition of the 
agent using locally approved drug accountability forms.
8.1.11 Reconciliation
The Sponsor agrees to conduct reconciliation for the product. Roche/Genentech and the Sponsor 
will agree to the reconciliation periodicity and format, but agree at minimum to exchange 
quarterly (no less frequently than monthly) line listings of cases received by the other party. If 
discrepancies are identified, the Sponsor and Roche/Genentech will cooperate in resolving the 
discrepancies. The responsible individuals for each party shall handle the matter on a case-by- 
case basis until satisfactory resolution. The sponsor shall receive reconciliation guidance 
documents within the ‘Activation Package’.


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8.1.12 Destruction and Return
All unused obinutuzumab will be destroyed and disposed by the Research Pharmacy at the 
conclusion of the trial according to local pharmacy practices.
8.2
Placebo
Placebo compound will be prepared by each research pharmacy to physically resemble the active 
treatment agent. Placebo will be 0.9% sodium chloride 250 ml bag. Remove 20 ml overfill from the bag 
for a total volume 250 ml
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
Approximately 40-50 subjects enrolled in this clinical trial will be F→M subjects, 50% of who will receive 
obinutuzumab prophylaxis. Comparing obinutuzumab and placebo recipients, we will examine whether 
effective prevention of alloreactive B cells development, H-Y antibody development or a reduction in H-Y 
antibody titers correlate with prevention of clinical cGVHD or subsequent severity of cGVHD. We will 
determine if H-Y antibodies that predate the initial administration of obinutuzumab are predictive of 
eventual cGVHD development. This latter observation will inform future studies, which may examine 
earlier administration of obinutuzumab after HCT. All subjects will undergo routine immunophenotyping 
to monitor the kinetics of BAFF and B cell recovery after obinutuzumab/placebo administration.
Samples will be collected in conjunction with study visits, and no additional study visits are required to 
fulfill the correlative study objectives.
Peripheral Blood Samples:
Peripheral blood samples will be collected at 3 months, 3.5 months, 6 months, 9 months, 12 months, 18 
months, and 24 months from the time of transplantation.
The volume and frequency will not exceed the recommended blood amounts. (It will not exceed 200 
mL/day and a maximum of 275 mL in a four week period).
Processing and Shipping Samples:
This is optional for non-DFHCC centers. 
Samples will be processed as follows.
1.
Blood from the first tube will be used for immune cell subset analysis by flow cytometry.
2.
The remainder of the tube will be used for DNA extraction.
3.
If the non-DFHCC centers prefer to process the samples on-site, the 1st tube of would be frozen as 
whole blood, and the DNA would later be extracted at Dana-Farber.
4.
The 2nd tube will be centrifuged, and 4 mls of plasma will be frozen in vials of 1 ml each.
5.
The remaining blood from the 2nd tube and the 3rd tube will be used for Ficoll-Paque density 
gradient sedimentation, and the isolated mononuclear cells frozen in aliquots of approximately 20 
million cells per 1ml-vial in 10% DMSO.
6.
All samples should be stored in 1.8cc Nunc vials.
7.
Frozen plasma should be stored at -70° C to -20° C. Cryopreserved mononuclear cells should be 
stored in vapor phase liquid nitrogen.
8.
Samples older than 48 hours are too old to bank, except for DNA.
Domestic samples will be shipped on dry ice priority overnight to Dana-Farber for banking. It is 
recommended that World Courier be used for shipping if possible. Samples will be labeled with a de-


27
DF/HCC Protocol #16-256
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identified number, date blood drawn, sample type, cell count and DF/HCC protocol number. The key for 
identification should be sent to the study chair (Corey Cutler).
The shipping address for the samples is: 
Attn Doreen Hearsey
Cell Manipulation Core Facility
Pasquarello Tissue Lab, Jimmy Fund building, J604 
Dana-Farber Cancer Institute
44 Binney St
Boston, MA 02115
Lab telephone: 617-632-3087
The samples should only be shipped on Sunday-Thursday, for Monday through Friday delivery. The 
laboratory cannot receive samples after 4pm on Friday or on the week-end.
Samples (whole blood, serum, and cells) will be banked to be used at a future date for correlative studies
Sample storage:
Samples (cells and plasma) will be eventually stored at the Pasquarello Tissue Bank (under the 
supervision of Jerome Ritz, MD) for up to 5 years following the end of the study. Corey Cutler, MD, will 
be the administrator. All samples will be de-identified prior to being sent out for testing. The key will be 
stored securely by and accessible only to the administrator. Requests for samples from non-study 
investigators will be granted only if they fall within the scope of this study. If they do not, the samples 
will not be released without IRB approval.
Staff from the Pasquarello Tissue Bank will coordinate sample collection, processing and storage.


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10. STUDY CALENDAR
Month
Pre- 
transplant
Screening2
33
3.5
63
6.5
93
9.5
123
12.5
1810 2410
Obinutuzumab




Placebo




Medical 
History
●
●
●
●
●
●
●
●
Physical
Examination
●
●
●
●
●
●
●
●
CBC with 
differential
●
●
●4
●
●4
●
●4
●
●4
●
●
Pulmonary
Function Test
●
●
●
Pregnancy 
Test
●
Informed
Consent
●
Chimerism 
analysis5
●
●
●
●
●
●
Tumor
Staging
●
Immunology6
●
●
●
●
●
●
●
Chronic 
GVHD
Assessment9
●
●
●
●
●
Toxicity 
Assessment
●
●
●
●
●
●
●
Infectious 
Disease
Testing7
●
Patient 
Survey8
●
●
●
●
●
1As measured from the time of transplantation.
2Screening can begin 60 days from transplantation
3The administration of Obinutuzumab at month 3, 6, 9 and 12 can be +/- 10 days. Similarly, the required follow-up 
after the first administration of Obinutuzumab occurs +/-4 days 14 days after the administration of Obinutuzumab.
4CBC after obinutuzumab should be 14 +/-4 days from the administration of obinutuzumab. CBCs can be 
performed at local providers, except after the first infusion.
5Chimerism studies are required at screening for only subjects who have undergone non-myeolablative 
transplantation. Chimerism analysis will be performed by single locus microsatellite DNA probes. Total and T 
cell chimerism measurements should be performed at all evaluation timepoints for all patients regardless of 


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DF/HCC Protocol #16-256
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conditioning regimen.
6Quantitative immunoglobulin measurement; Lymphocyte subset analysis for B cells, T cells; ELISA for minor  
histocompatibility antigens DBY, DBX under the appropriate clinical conditions (sex-mismatch); Plasma banking, 
and storage of additional mononuclear cells. See Section 9 for additional details.
7Testing done in the pre-transplant setting is sufficient to rule out active Hepatitis A, Hepatitis B, Hepatitis C, and 
HIV infection.
8Patient GVHD will be administered to patients during the Month 6, 9, 12, 18, and 24 appointments. Continue to 
administer at follow-up visits even if patient has been taken off treatment. Survey is located in Appendix E.
9Provider cGVHD survey administered at the month 6, 9, 12, 18, and 24 appointments.
10There is a +/- 21 day window for month 18 and month 24 appointments.
11. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.
11.1
Data Reporting
11.1.1 Method
The ODQ/CTRIO will collect, manage, and perform quality checks on the data for this study.
11.1.2 Responsibility for Data Submission
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data 
forms to the ODQ/CTRIO according to the schedule set by the ODQ/CTRIO.
11.2
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Board (DSMB) will review and monitor study progress, toxicity, 
safety and other data from this study. The board is chaired by a medical oncologist from outside of DF/HCC 
and has external and internal representation. Information that raises any questions about participant safety 
or protocol performance will be addressed by the Overall PI, statistician and study team. Should any major 
concerns arise, the DSMB will offer recommendations regarding whether or not to suspend the study.
The DSMB will meet twice a year to review accrual, toxicity, response and reporting information. 
Information to be provided to the DSMB may include: participant accrual; treatment regimen information; 
adverse events and serious adverse events reported by category; summary of any deaths on study; audit 
results; and a summary provided by the study team. Other information (e.g. scans, laboratory values) will 
be provided upon request.
11.3
Multicenter Guidelines
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and Safety 
Monitoring Plan. The specific responsibilities of the Overall PI, Coordinating Center, and Participating 
Institutions and the procedures for auditing are presented in Appendix D.

The Overall PI/Coordinating Center is responsible for distributing all IND Action Letters or 


30
DF/HCC Protocol #16-256
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Safety Reports to all participating institutions for submission to their individual IRBs for action 
as required.

Mechanisms will be in place to ensure quality assurance, protocol compliance, and adverse event 
reporting at each site.


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DF/HCC Protocol #16-256
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
Except in very unusual circumstances, each participating institution will order the study agent(s) 
directly from supplier. A participating site may order the agent(s) only after the initial IRB 
approval for the site has been forwarded to the Coordinating Center.
12. STATISTICAL CONSIDERATIONS
This is a prospective, multicenter, randomized phase II trial of prophylactic obinutuzumab vs. placebo for 
prevention of cGVHD after HCT. The primary objective is to determine the effect of obinutuzumab 
prophylaxis on the incidence of corticosteroid-requiring cGVHD after allogeneic HCT. A single dose of 
obinutuzumab or placebo will be administered prophylactically at 3, 6, 9, and 12 months after HCT.
12.1
Study Design/Endpoints
This is a randomized, Phase II trial. The primary objective is to determine the rate of corticosteroid- 
requiring cGVHD when obinutuzumab is used as cGVHD prophylaxis.
The primary endpoint of this phase II trial is the rate of corticosteroid-requiring cGVHD at one year from 
HCT.
Secondary objectives are to determine the overall cGVHD rate after HCT, NIH moderate-severe cGVHD 
rate after HCT, cumulative incidence of non-relapse mortality and relapse, adverse hematologic events and 
infections, immunosuppression-free survival (IFS) at 1 and 2 years from transplantation, progression-free 
and overall survival at 1 and 2 years from transplantation, and immunologic correlates of B cell depletion. 
IFS is defined as time from randomization to relapse, institution of systemic immune suppression, or death, 
whichever occurs first.
12.2
Sample Size, Accrual Rate and Study Duration
The sample size is 200 eligible patients, based on event rates from DFCI 05-377. In this study, 65 patients 
who received rituximab as cGVHD prophylaxis were compared to a contemporaneous control group and 
the 1-year corticosteroid-requiring cGVHD rate was 21% in the rituximab group and 38% in the control 
group. Based on this information, we assume that the 1-year corticosteroid-requiring cGVHD rate will be 
38% in the control group and hypothesize that there will be at least a 45% reduction in the obinutuzumab 
group to a 1-year corticosteroid-requiring cGVHD rate of 21%. With 200 eligible patients, the study will 
have 80% power to detect a 45% reduction in the obinutuzumab arm using a two-sided test at a significance 
level of 0.1. This power calculation is based on Fisher’s exact test.
Accrual from 3 participating clinical sites (DFCI, MGH, Stanford) is projected to be approximately 100 
patients/year, given competing trials and relapse or death prior to 3 months from HCT. Based on this 
projection, we anticipate that the study will complete its accrual in 2 years.
Patients who initially join the study but are later deemed ineligible due to exclusion criteria 3.2.6 will not 
be counted toward the overall accrual goal.
All surviving patients will be followed at least for 1 year after HCT for the evaluation of the primary 
endpoint
Special attention will be paid to the recruitment of women and minorites per NIH guidelines.


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12.3
Randomization and Stratification Factors
Randomization will be 1:1, stratified by center, conditioning intensity (myeloablative vs. reduced 
intensity) and donor type (matched related vs. matched unrelated) using permuted block algorithm within 
strata.
QACT will notify the research pharmacy of the randomization status of the patient by fax and via 
email (DFCIPharmacyIDS@partners.org) . The remainder of the study team will be blinded to 
which arm the patient will receive.
12.4
Blinding
Blinding will be performed at the level of the Research Pharmacy. Obinutuzumab or placebo will be 
issued from the Research Pharmacy without identifying labels to prevent unblinding at the bedside.
The research pharmacy will not be blinded. Unblinding will occur when knowledge of the treatment is 
essential for the emergency management of adverse events. Unblinding may also occur at the request of the 
Principal Investigator when all patients have come off study treatment. In case of an emergency, the treating 
physician or study investigator has the sole responsibility for determining if unblinding of a patient’s 
treatment assignment is warranted for medical management of the event. In these events the primary and 
backup unblinded study members will be the Clinical Research Manager Daniel Surette, and Regulatory 
Coordinator Jennifer Sherwill, and these members will not otherwise be accessing patient data. 
12.5
Interim Monitoring Plan
The study will be monitored using standard procedures and processes by an independent Data and Safety 
Monitoring Board (DSMB) of the Dana-Farber Harvard Cancer Center (DF/HCC).
Monitoring of key safety endpoints (relapse, grade 3 or higher treatment related toxicity, grade III-IV acute 
GVHD after study enrollment) will be conducted in accordance with the DF/HCC DSMB meeting. Since a 
concern for excess relapse exists, even though our preliminary studies do not support this, we will compare 
the relapse rate along with other key safety endpoints between two arms at each interim analysis. If, at any 
interim analysis, this difference is significant at the two-sided level of 0.05, this would trigger a consultation 
with the DF/HCC DSMB for additional review of early stopping. However, this will not be a formal 
stopping rule that would mandate automatic closure of study enrollment.
Interim analyses for efficacy will be performed every six months in conjunction with semi-annual DF/HCC 
DSMB meeting, beginning at the 25% information time, which is anticipated to occur approximately 1.5 
years after the start of the trial. The interim results will be reported to the DF/HCC DSMB. However, these 
interim analyses will not have an effect in terms of stopping accrual to the study and terminate the study 
early in favor of alternative (superiority) or null hypothesis (futility). This is because i) due to a small sample 
size at the first interim analysis, stopping early for futility would result in substantially wide confidence 
intervals, larger Type II error, and thus leading to greater uncertainty about the magnitude of the steroid 
requiring cGVHD difference, ii) by the time of the second interim analysis, the study is anticipated to 
complete accrual, iii) even if the steroid requiring cGVHD difference is not as large as targeted, 
investigators are interested in learning the magnitude of the difference for further investigation,
iv) stopping early for superiority would provide less safety data than planned and potential difficulty with 
the efficacy analysis and its interpretation.
12.6
Analysis of Primary Endpoints


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DF/HCC Protocol #16-256
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The primary endpoint of this phase II trial is one year corticosteroid-requiring cGVHD rate.
The primary analysis will be a modified intent-to-treat analysis (mITT) fo with all randomized patients who 
receive any amount of the study drug, either obinutuzumab or placebo. Patients who are randomized but do 
not receive the study drug and off the study will not be included in mITT and be replaced (Section 5.11). 
The primary analysis will be performed using i) a Chi-square test for comparison of crude proportions, ii) 
comparison of cumulative incidence rates of corticosteroid-requiring cGVHD in the context of competing 
risks framework. In this analysis, death or relapse without developing a corticosteroid-requiring cGVHD 
will be considered as a competing event and cumulative incidence of death or relapse without developing 
cGVHD will also be reported, iii) multivariable competing risks regression analysis using the Fine and Gray 
model25.
12.7
Analysis of Secondary Endpoints
Secondary objectives include to determine the overall cGVHD rate after HCT, NIH moderate-severe 
cGVHD rate after HCT, cumulative incidence of non-relapse mortality and relapse, adverse hematologic 
events and infections, immunosuppression-free survival (IFS) at 1 and 2 years from transplantation, 
progression-free and overall survival at 1 and 2 years from transplantation, and immunologic correlates of 
B cell depletion.
For the comparison of GVHD, NRM and relapse, competing risks data analysis will be performed using 
Gray test26 and Fine and Gray competing risks regression analysis25. For PFS, OS, and IFS, standard 
survival analysis will be performed. Adverse hematologic events will be compared by cumulative incidence 
measures. All analysis will be repeated by disease group (myeloid vs. lymphoid).
12.8
Analysis of Correlative Studies
The primary analysis for the correlative studies is concerns male recipients with female donors (F→M) 
and H-Y minor histocompatibility antigens (mHA). The analysis will be exploratory without adjustment 
for multiple testing. Based on the recent report from the Miklos lab27, we hypothesize that patients with 
multiple anti-H-Y antibodies (defined as >=2 antibodies out of 6) at study entry are more likely to 
develop corticosteroid-requiring cGVHD at one year after HCT. Assuming 50 patients (from both arms) 
will undergo F→M HCT, if the one-year corticosteroid-requiring cGVHD rate is 55% and 15% for 
patients with and without multiple anti-H-Y antibodies, respectively, there will be 84% power to detect 
this difference. This power calculation is based on Fisher’s exact test at the two-sided significance level 
of 0.1 assuming 18 patients in F→M 27 will have multiple anti-H-Y antibodies at the study entry.
Using the H-Y protein arrays developed in the Miklos lab, we measured IgG antibodies specific for DBY 
(one of HY mHA proteins) in 13 F→M who received rituximab prophylaxis (DFCI#05-377) and 10 
F→M who did not receive rituximab. After 6 months post HCT, no one in the rituximab group developed 
anti-DBY reactivity whereas 4 out of 10 in the control group developed the anti-DBY reactivity (p=0.02). 
Extrapolating this result to this randomized phase II trial, if the anti-DBY response rates are 5% and 40% 
in the obinutuzumab and placebo group, respectively, in F→M, there will be 88% power to detect this 
difference (Table). This power calculation is based on Fisher’s exact test at the two-sided significance 
level of 0.1 assuming 25 patients will undergo F→M HCT in each treatment group.
Table. Power for various levels of responses between obinutuzumab and placebo arm
anti-DBY reactivity
(10%, 35%)
(5%, 35%)
(5%, 40%)
Power
57%
79%
88%


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DF/HCC Protocol #16-256
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When data are available, we will repeat a similar analysis for multiple antibodies and investigate whether 
a combination of antibody responses is more discriminatory. We will also investigate whether H-Y 
antibodies measured prior to the initial administration of treatment are predictive of eventual cGVHD 
using ROC (receiver operating characteristic) curve analysis and multivariable regression analysis after 
adjusting for treatment arm. In addition, an appropriate statistical analysis will be applied for routine 
immunophenotype data analysis including BAFF and B cell recovery as well as for new or existing 
autosomal mHA that may be associated with development of cGVHD across all recipient and donor sex 
combinations.
12.9
Reporting and Exclusions
12.9.1 Evaluation of Toxicity
All participants will be evaluable for toxicity as long as a single infusion of obinutuzumab or 
placebo is initiated.
12.9.2 Evaluation of the Primary Efficacy Endpoint
The primary analysis will be an intent-to-treat analysis with all randomized patients included for 
evaluation of the primary endpoint.
13. PUBLICATION PLAN
The results of this study will be submitted to a peer-reviewed journal for consideration of publication 
within 24 months of the end of follow-up. Submission of an abstract to a scientific meeting may occur 
prior to completion of the study follow-up period.
Results will be made publicly available on www.clinicaltrials.gov in accordance to the requirements 
posted on that website.
Any literature articles that are a result of the study will be sent to Roche/Genentech. Copies of such 
reports should be mailed to the assigned Clinical Operations contact for the study:
Email: ga101-gsur@gene.com 
Fax: 866-706-3927
14. REFERENCES
1.
Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow 
Transplant 2003;9:215-233.
2.
Gooley TA, Chien JW, Pergam SA et al. Reduced mortality after allogeneic hematopoietic-cell 
transplantation. N Engl J Med 2010;363:2091-2101.
3.
Fraser CJ, Bhatia S, Ness K et al. Impact of chronic graft-versus-host disease on the health status of 
hematopoietic cell transplantation survivors: a report from the Bone Marrow Transplant Survivor 
Study. Blood 2006;108:2867-2873.
4.
Pidala J, Kurland B, Chai X et al. Patient-reported quality of life is associated with severity of 
chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the


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Chronic GVHD Consortium. Blood 2011;117:4651-4657.
5.
Soiffer RJ, Weller E, Alyea EP et al. CD6+ donor marrow T-cell depletion as the sole form of graft- 
versus-host disease prophylaxis in patients undergoing allogeneic bone marrow transplant from 
unrelated donors. J Clin Oncol 2001;19:1152-1159.
6.
Ho VT, Soiffer RJ. The history and future of T-cell depletion as graft-versus-host disease 
prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood 2001;98:3192-3204.
7.
Luznik L, O'Donnell PV, Symons HJ et al. HLA-haploidentical bone marrow transplantation for 
hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation 
cyclophosphamide. Biol Blood Marrow Transplant 2008;14:641-650.
8.
Miklos DB, Kim HT, Miller KH et al. Antibody responses to H-Y minor histocompatibility 
antigens correlate with chronic graft-versus-host disease and disease remission. Blood 
2005;105:2973-2978.
9.
Cutler C, Miklos D, Kim HT et al. Rituximab for steroid-refractory chronic graft-vs.-host disease. 
Blood 2006;108:756-762.
10.
Kharfan-Dabaja MA, Mhaskar AR, Djulbegovic B et al. Efficacy of rituximab in the setting of 
steroid-refractory chronic graft-versus-host disease: a systematic review and meta-analysis. 
Biol.Blood Marrow Transplant 2009;15:1005-1013.
11.
Canninga-van Dijk MR, van der Straaten HM, Fijnheer R et al. Anti-CD20 monoclonal antibody 
treatment in 6 patients with therapy-refractory chronic graft-versus-host disease. Blood 
2004;104:2603-2606.
12.
Sahaf B, Arai S, Otani J et al. Rituximab Provides Steroid-Sparing Therapy in New-Onset Chronic 
Graft-Versus-Host Disease [abstract]. Biology of blood and marrow transplantation : journal of the 
American Society for Blood and Marrow Transplantation 2013;19:S140.
13.
Ratanatharathorn V, Horowitz M, Logan B et al. Prior Therapy with Rituximab Correlates with 
Less Acute Graft-Versus-Host Disease and Better Survival in B-Cell Lymphoma Patients Who 
Received Allogeneic Peripheral Blood Stem Cell Transplantation (PBSCT). Blood 2007;110:
14.
Bornhaeuser M, Schwerdtfeger R, Kroschinsky F et al. Pretreatment with rituximab reduces the 
incidence of chronic graft-versus-host disease after allogeneic stem cell transplantation in patients 
with B cell lymphoma. Blood 2004;104:348a [Abstr.].
15.
Cutler C, Kim HT, Bindra B et al. Rituximab prophylaxis prevents corticosteroid-requiring chronic 
GVHD after allogeneic peripheral blood stem cell transplantation: results of a phase II trial. Blood 
2013
16.
Arai S, Sahaf B, Narasimhan B et al. Prophylactic rituximab after allogeneic transplantation 
decreases B-cell alloimmunity with low chronic GVHD incidence. Blood 2012;119:6145-6154.
17.
Kohrt HE, Turnbull BB, Heydari K et al. TLI and ATG conditioning with low risk of graft-versus- 
host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from 
related and unrelated donors. Blood 2009;114:1099-1109.
18.
Sarantopoulos S, Stevenson KE, Kim HT et al. Recovery of B-cell homeostasis after rituximab in 
chronic graft-versus-host disease. Blood 2011;117:2275-2283.
19.
Allen JL, Tata PVW, Wooten J et al. BCR Hyper-Responsiveness In B Cells From Patients With 
Chronic Gvhd Is Blocked With The Syk Inhibitor R406. Blood 2013;122:910.
20.
Sahaf B, Yang Y, Arai S et al. H-Y antigen-binding B cells develop in male recipients of female 
hematopoietic cells and associate with chronic graft vs. host disease. Proc.Natl.Acad.Sci.U.S.A 
2013;110:3005-3010.
21.
Radford J, Davies A, Cartron G et al. Obinutuzumab (GA101) plus CHOP or FC in 
relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000). Blood 
2013;122:1137-1143.
22.
Morschhauser FA, Cartron G, Thieblemont C et al. Obinutuzumab (GA101) monotherapy in 
relapsed/refractory diffuse large b-cell lymphoma or mantle-cell lymphoma: results from the phase 
II GAUGUIN study. J Clin.Oncol. 2013;31:2912-2919.
23.
Salles GA, Morschhauser F, Solal-Celigny P et al. Obinutuzumab (GA101) in patients with


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relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study. J 
Clin.Oncol. 2013;31:2920-2926.
24.
Salles G, Morschhauser F, Lamy T et al. Phase 1 study results of the type II glycoengineered 
humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. 
Blood 2012;119:5126-5132.
25.
Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am 
Stat Assoc 1999;94:509.
26.
Gray R. A class of K-sample tests for comparing the cumulative incidence of a competing risk. 
Annals of Statistics 1988;16:1140-1154.
27. Nakasone H, Tian L, Sahaf B, et al. Allogeneic HY antibodies detected 3 months after female- 
to-male HCT predict chronic GVHD and nonrelapse mortality in humans. Blood. 2015 May 
14;125(20):3193-201.


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APPENDIX A
PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
15. Normal activity. Fully active, 
able to carry on all pre- 
disease performance without 
restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
2
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization
indicated. Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.


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APPENDIX B
MEDWATCH 3500 REPORTING FORM
HTTP://WWW.FDA.GOV/ABOUTFDA/REPORTSMANUALSFORMS/FORMS/DEFAULT.HTM


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DF/HCC Protocol #16-256
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APPENDIX C
SAFETY REPORTING FAX COVER SHEET
ROCHE/GENENTECH SUPPORTED RESEARCH
AE/SAE FAX No: (650) 238-6067
Page 1 of  
Roche/Genentech Study Number
Principal Investigator
Site Name
Reporter name
Reporter Telephone #
Reporter Fax #
Initial Report Date
 
/
/
 dd 
/ mmm / yyyy
Follow-up Report Date
Patient Initials
(Please enter a dash if the patient has 
no middle name)
 
 - 
- 
SAE or Safety Reporting questions, contact Roche/Genentech Safety: (888) 835-2555
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET


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DF/HCC Protocol #16-256
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APPENDIX D
DANA-FARBER/HARVARD CANCER CENTER MULTI-CENTER DATA AND 
SAFETY MONITORING PLAN
TABLE OF CONTENTS
1.
INTRODUCTION .............................................................................................................38
1.1
Purpose...................................................................................................................38
1.2
Multi-Center Data and Safety Monitoring Plan Definitions..................................38
2.
GENERAL ROLES AND RESPONSIBILITIES .............................................................39
2.1
DF/HCC Sponsor...................................................................................................39
2.2
Coordinating Center...............................................................................................39
2.3
Participating Institution..........................................................................................40
3.
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS..............................40
3.1
Protocol Distribution..............................................................................................40
3.2
Protocol Revisions and Closures ...........................................................................41
3.3
Informed Consent Requirements ...........................................................................41
3.4
IRB Documentation ...............................................................................................41
3.5
IRB Re-Approval...................................................................................................42
3.6
Participant Confidentiality and Authorization Statement......................................42
3.7
DF/HCC Multi-Center Protocol Registration Policy.............................................42
3.8
DF/HCC Protocol Case Number............................................................................43
3.9
Safety Assessments and Toxicity Monitoring .......................................................44
3.10
Data Management..................................................................................................45
4.
REQUISITIONING INVESTIGATIONAL DRUG..........................................................45
5.
MONITORING: QUALITY CONTROL..........................................................................45
5.1
Ongoing Monitoring of Protocol Compliance .......................................................46
5.2
Monitoring Reports................................................................................................46
5.3
Accrual Monitoring................................................................................................46
6.
AUDITING: QUALITY ASSURANCE ...........................................................................46
6.1
Audit Plan: DF/HCC Sponsored Trials..................................................................47
6.2
Audit Notification..................................................................................................47
6.3
Audit Reports.........................................................................................................47
6.4
Participating Institution Performance ....................................................................47


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DF/HCC Protocol #16-256
Protocol Version Date: October 6, 2021
1.
INTRODUCTION
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (DF/HCC 
DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research protocol. The 
DF/HCC DSMP should serve as a reference for any sites external to DF/HCC that will be 
participating in the research protocol.
1.1
Purpose
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center 
protocol will comply with Federal Regulations, Health Insurance Portability and Accountability Act 
(HIPAA) requirements and applicable DF/HCC Standard Operating Procedures.
1.2
Multi-Center Data and Safety Monitoring Plan Definitions
DF/HCC Multi-Center Protocol: A research protocol in which one or more outside institutions are 
collaborating with Dana-Farber/Harvard Cancer Center where a DF/HCC investigator is the sponsor. 
DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial Affiliates.
Lead Institution: One of the Dana-Farber/Harvard Cancer Center consortium members (Dana- 
Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel Deaconess 
Medical Center (BIDMC), Boston Children’s Hospital (BCH), Brigham and Women’s Hospital 
(BWH)) responsible for the coordination, development, submission, and approval of a protocol as 
well as its subsequent amendments per the DFCI IRB and applicable regulatory guidelines (CTEP, 
Food and Drug Administration (FDA), Office of Biotechnology Activities (OBA) etc.). The Lead 
Institution is typically the home of the DF/HCC Sponsor. The Lead Institution also typically serves 
as the Coordinating Center for the DF/HCC Multi-Center Protocol.
DF/HCC Sponsor: The person sponsoring the submitted Multi-Center protocol. Within DF/HCC, 
this person is the Overall Principal Investigator who takes responsibility for initiation, management 
and conduct of the protocol at all research locations. In applicable protocols, the DF/HCC Sponsor 
will serve as the single liaison with any regulatory agencies (ie FDA). The DF/HCC Sponsor has 
ultimate authority over the protocol and is responsible for the conduct of the study at DF/HCC and 
all Participating Institutions. In most cases the DF/HCC Sponsor is the same person as the DF/HCC 
Overall Principal Investigator; however, both roles can be filled by two different people.
Participating Institution: An institution that is outside the DF/HCC and DF/PCC consortium that 
is collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC Investigator. The 
Participating Institution acknowledges the DF/HCC Sponsor as having the ultimate authority and 
responsibility for the overall conduct of the study.
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract Research 
Organization (CRO), etc) that provides administrative support to the DF/HCC Sponsor in order that 
he/she may fulfill the responsibilities outlined in the protocol document and DSMP, and as specified 
in applicable regulatory guidelines (i.e. CTEP Multi-Center Guidelines). In general, the Lead 
Institution is the Coordinating Center for the DF/HCC Multi-Center Protocol. Should the DF/HCC 
Sponsor decide to use a CRO, the CRO will be deemed the Coordinating Center.


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DF/HCC Protocol #16-256
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DF/HCC Office of Data Quality: A group within DF/HCC responsible for registering human 
subjects for trials, ensuring high-quality standards are used for data collection and the ongoing 
management of clinical trials, auditing, and data and safety monitoring. ODQ/CTRIO also 
coordinates quality assurance efforts related to multi-center clinical research.
2.
GENERAL ROLES AND RESPONSIBILITIES
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and the 
Participating Institutions are expected to adhere to the following general responsibilities:
2.1
DF/HCC Sponsor
The DF/HCC Sponsor, Corey Cutler, MD will accept responsibility for all aspects of conducting a 
DF/HCC Multi-Center protocol which includes but is not limited to:

Oversee the coordination, development, submission, and approval of the protocol as well as 
subsequent amendments.

Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol.

Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the protocol.

Ensure all Participating Institutions are using the correct version of the protocol.

Ensure that each participating investigator and study team member receives adequate 
protocol training and/or a Site Initiation Visit prior to enrolling participants and throughout 
trial’s conduct as needed.

Ensure the protocol will be provided to each participating site in a language understandable 
to all applicable site personnel when English is not the primary language.

Monitor progress and overall conduct of the study at all Participating Institutions.

Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable reporting 
requirements are met.

Review data and maintain timely submission of data for study analysis.

Ensure compliance with all requirements as set forth in the Code of Federal Regulations, 
applicable DF/HCC requirements, HIPAA requirements, and the approved protocol.

Commit to the provision that the protocol will not be rewritten or modified by anyone other 
than the DF/HCC Sponsor.

Identify and qualify Participating Institutions and obtain accrual commitments prior to 
extending the protocol to that site.

Monitor accrual and address Participating Institutions that are not meeting their accrual 
requirements.
2.2
Coordinating Center
The general responsibilities of the Coordinating Center may include but are not limited to:

Assist in protocol development.

Review registration materials for eligibility and register participants from Participating 
Institutions with DF/HCC ODQ/CTRIO.

Distribute protocol and informed consent document updates to Participating Institutions as 
needed.

Oversee the data collection process from Participating Institutions.

Maintain documentation of Serious Adverse Event (SAE) reports and deviations/violation 
submitted by Participating Institutions and provide to the DF/HCC Sponsor for timely 
review.


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DF/HCC Protocol #16-256
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
Distribute serious adverse events reported to the DF/HCC Sponsor that fall under the DFCI 
IRB Adverse Event Reporting Policy to all Participating Institutions.

Provide Participating Institutions with information regarding DF/HCC requirements that 
they will be expected to comply with.

Carry out plan to monitor Participating Institutions either by on-site or remote monitoring.

Maintain Regulatory documents of all Participating Institutions which includes but is not 
limited to the following: local IRB approvals/notifications from all Participating 
Institutions, confirmation of Federalwide Assurances (FWAs) for all sites, all SAE 
submissions, Screening Logs for all sites, IRB approved consents for all sites

Conduct regular communications with all Participating Institutions (conference calls, 
emails, etc) and maintain documentation all relevant communications.
2.3
Participating Institution
Each Participating Institution is expected to comply with all applicable federal regulations and 
DF/HCC requirements, the protocol and HIPAA requirements.
The general responsibilities for each Participating Institution may include but are not limited to:

Document the delegation of research specific activities to study personnel.

Commit to the accrual of participants to the protocol.

Submit protocol and/or amendments to their local IRB.

Maintain regulatory files as per sponsor requirements.

Provide the Coordinating Center with regulatory documents or source documents as 
requested.

Participate in protocol training prior to enrolling participants and throughout the trial as 
required (i.e. teleconferences).

Update Coordinating Center with research staff changes on a timely basis.

Register participants through the Coordinating Center prior to beginning research related 
activities.

Submit Serious Adverse Event (SAE) reports to local IRB per local requirements and to the 
Coordinating Center, in accordance with DF/HCC requirements.

Submit protocol deviations and violations to local IRB per local requirements and to the 
DF/HCC Sponsor in accordance with DF/HCC requirements.

Order, store and dispense investigational agents and/or other protocol mandated drugs per 
federal guidelines and protocol requirements.

Have office space, office equipment, and internet access that meet HIPAA standards.

Participate in any quality assurance activities and meet with monitors or auditors at the 
conclusion of a visit to review findings.

Promptly provide follow-up and/or corrective action plans for any monitoring queries or 
audit findings.
3.
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS
The following section will clarify DF/HCC Requirements and further detail the expectations for 
participating in a DF/HCC Multi-Center protocol.
3.1
Protocol Distribution
The Coordinating Center will distribute the final DFCI IRB approved protocol and any subsequent 
amended protocols to all Participating Institutions.


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DF/HCC Protocol #16-256
Protocol Version Date: October 6, 2021
3.2
Protocol Revisions and Closures
The Participating Institutions will receive notification of protocol revisions and closures from the 
Coordinating Center. It is the individual Participating Institution’s responsibility to notify its IRB of 
these revisions.

Non life-threatening revisions: Participating Institutions will receive written notification 
of protocol revisions regarding non life-threatening events from the Coordinating Center. 
Non-life-threatening protocol revisions must be IRB approved and implemented within 90 
days from receipt of the notification.

Revisions for life-threatening causes: Participating Institutions will receive immediate 
notification from the Coordinating Center concerning protocol revisions required to protect 
lives with follow-up by fax, mail, e-mail, etc. Life-threatening protocol revisions will be 
implemented immediately followed by IRB request for approval.

Protocol closures and temporary holds: Participating Institutions will receive notification 
of protocol closures and temporary holds from the Coordinating Center. Closures and holds 
will be effective immediately. In addition, the Coordinating Center, will update the 
Participating Institutions on an ongoing basis about protocol accrual data so that they will 
be aware of imminent protocol closures.
3.3
Informed Consent Requirements
The DF/HCC approved informed consent document will serve as a template for the informed consent 
for Participating Institutions. The Participating Institution consent form must follow the consent 
template as closely as possible and should adhere to specifications outlined in the DF/HCC Guidance 
Document on Model Consent Language for PI-Initiated Multi-Center Protocols. This document will 
be provided separately to each Participating Institution.
Participating Institutions are to send their version of the informed consent document and HIPAA 
authorization, if a separate document, to the Coordinating Center for review and approval prior to 
submission to their local IRB. The approved consent form must also be submitted to the 
Coordinating Center after approval by the local IRB for all consent versions.
The Principal Investigator (PI) at each Participating Institution will identify the physician members 
of the study team who will be obtaining consent and signing the consent form for therapeutic 
protocols. Participating institutions must follow the DF/HCC requirement that only attending 
physicians obtain informed consent and re-consent to interventional trials (i.e. drug and/or device 
trials).
3.4
IRB Documentation
The following must be on file with the Coordinating Center:

Initial approval letter of the Participating Institution's IRB.

Copy of the Informed Consent Form(s) approved by the Participating Institution’s IRB.

Participating Institution’s IRB approval for all amendments.

Annual approval letters by the Participating Institution's IRB.


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DF/HCC Protocol #16-256
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3.5
IRB Re-Approval
Verification of IRB re-approval from the Participating Institutions is required in order to continue 
research activities. There is no grace period for continuing approvals.
The Coordinating Center will not register participants if a re-approval letter is not received from the 
Participating Institution on or before the anniversary of the previous approval date.
3.6
Participant Confidentiality and Authorization Statement
In 1996, congress passed the first federal law covering the privacy of health information known as 
the Health Insurance Portability and Accountability Act (HIPPA). Any information, related to the 
physical or mental health of an individual is called Protected Health Information (PHI). HIPAA 
outlines how and under what circumstances PHI can be used or disclosed.
In order for covered entities to use or disclose protected health information during the course of a 
study, the study participant must sign an authorization statement. This authorization statement may 
or may not be separate from the informed consent document. The Coordinating Center, with the 
approval from the DFCI IRB, will provide a consent template, with information regarding 
authorization for the disclosure of protected health information.
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in its trials. 
However, because of the nature of these trials, certain protected health information must be 
collected. DF/HCC has chosen to use authorizations, signed by the participant in the trial, rather than 
limited data sets with data use agreements.
3.6.1
DF/HCC Multi-Center Protocol Confidentiality
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology Reports, 
MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center should be de-identified. 
It is recommended that the assigned DF/HCC ODQ/CTRIO case number (as described below) be 
used for all participant specific documents. Participant initials may be included or retained for cross 
verification of identification.
3.7 DF/HCC Multi-Center Protocol Registration Policy
3.7.1
Participant Registration and Randomization
To register a participant, the following documents should be completed by the Participating 
Institution and faxed to the Coordinating Center at 617-582-9103.

Copy of Eligibility Checklist

Signed participant consent form

HIPAA authorization form

Source documentation confirming eligibility criteria
The Coordinating Center will review the submitted documents in order to verify eligibility and 
consent. To complete the registration process, the Coordinating Center will:

Register the participant on the study with the DF/HCC ODQ/CTRIO


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DF/HCC Protocol #16-256
Protocol Version Date: October 6, 2021

Upon receiving confirmation of registration by the ODQ/CTRIO, the Coordinating Center 
will inform the Participating Institution and provide the study specific participant case 
number, and if applicable the dose level.
Treatment may not begin without confirmation from the Coordinating Center that 
the participant has been registered.
Randomization can only occur during ODQ/CTRIO’s normal business hours, Monday through 
Friday from 8:00 AM to 5:00 PM Eastern Time.
3.7.2
Initiation of Therapy
Participants must be registered with the DF/HCC ODQ/CTRIO before receiving treatment. 
Treatment may not be initiated until the Participating Institution receives confirmation of the 
participant’s registration from the Coordinating Center. The DF/HCC Sponsor and DFCI IRB must 
be notified of any violations to this policy.
3.7.3
Eligibility Exceptions
The DF/HCC ODQ/CTRIO will make no exceptions to the eligibility requirements for a protocol 
without DFCI IRB approval. The DF/HCC ODQ/CTRIO requires each institution to fully comply 
with this requirement.
3.8 DF/HCC Protocol Case Number
At the time of registration, ODQ/CTRIO requires the following identifiers for all subjects: initials, 
date of birth, gender, race and ethnicity. Once eligibility has been established and the participant 
successfully registered, the participant is assigned a unique protocol case number. Participating 
Institutions should submit all de-identified subsequent communication and documents to the 
Coordinating Center, using this case number to identify the subject.
3.8.1
Protocol Deviations, Exceptions and Violations
Federal Regulations require an IRB to review proposed changes in a research activity to ensure that 
researchers do not initiate changes in approved research without IRB review and approval, except 
when necessary to eliminate apparent immediate hazards to the participant. DF/HCC requires all 
departures from the defined procedures set forth in the IRB approved protocol to be reported to the 
DF/HCC Sponsor, who in turn is responsible for reporting to the DFCI IRB.
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” to 
describe departures from a protocol. All Participating Institutions must adhere to these requirements 
for reporting to the DF/HCC Sponsor and will follow their institutional policy for reporting to their 
local IRB.
3.8.2
Definitions
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-approved 
protocol which is prospectively approved prior to its implementation.


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DF/HCC Protocol #16-256
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Protocol Exception: Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria.
Protocol Violation: Any protocol deviation that was not prospectively approved by the IRB prior to 
its initiation or implementation.
3.8.3
Reporting Procedures
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the medical 
record and/or regulatory documents to describe all protocol exceptions, deviations and violations. 
The DF/HCC Sponsor will also be responsible for ensuring that all protocol violations/deviations 
are promptly reported per DFCI IRB guidelines.
Participating Institutions: Protocol deviations require prospective approval from the DFCI IRB. The 
Participating Institution must submit the deviation request to the Coordinating Center who will then 
submit the deviation request to the DFCI IRB. Upon DFCI IRB approval the deviation is submitted 
to the Participating Institution IRB, per institutional policy. A copy of the Participating Institution’s 
IRB report and determination will be forwarded to the Coordinating Center within 10 business days 
after the original submission.
All protocol violations must be sent to the Coordinating Center in a timely manner.
Coordinating Center: Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for review. 
Subsequently, the Participating Institution’s IRB violation/deviation report will be submitted to the 
DFCI IRB for review per DFCI IRB reporting guidelines. DF/HCC will forward all violation reports 
to CTEP via an internal DF/HCC process, as applicable.
3.9
Safety Assessments and Toxicity Monitoring
The study teams at all participating institutions are responsible for protecting the safety, rights and 
well-being of study participants. Recording and reporting of adverse events that occur during the 
course of a study help ensure the continuing safety of study participants.
All participants receiving investigational agents and/or other protocol mandated treatment will be 
evaluated for safety. The safety parameters include all laboratory tests and hematological 
abnormalities, physical examination findings, and spontaneous reports of adverse events reported 
by participants. All toxicities encountered during the study will be evaluated according to the NCI 
criteria specified in the protocol. Life-threatening toxicities must be reported immediately to the 
DF/HCC Sponsor via the Coordinating Center.
Additional safety assessments and toxicity monitoring will be outlined in the protocol.
3.9.1
Guidelines for Reporting Serious Adverse Events
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are detailed in 
protocol section 7 of the main protocol document.
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the Coordinating Center 
following the DFCI IRB Adverse Event Reporting Policy


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DF/HCC Protocol #16-256
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The Coordinating Center will maintain documentation of all Participating Institution Adverse Event 
reports and be responsible for communicating to all participating investigators, any observations 
reportable under the DFCI IRB Reporting Requirements. Participating Institutions will review and 
submit to their IRB according to their institutional policies and procedures
3.9.2
Guidelines for Processing IND Safety Reports
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety Reports 
are distributed to the Participating Institutions. Participating Institutions will review and submit to 
their IRB according to their institutional policies and procedures.
3.10 Data Management
The DF/HCC ODQ/CTRIO develops case report forms (CRF/eCRFs), for use with the protocol. 
These forms are designed to collect data for each study. The DF/HCC ODQ/CTRIO provides a web 
based training for eCRF users.
3.10.1 Data Forms Review
Data submissions are monitored for timeliness and completeness of submission. Participating 
Institutions are notified of their data submission delinquencies in accordance with the following:
Incomplete or Questionable Data
If study forms are received with missing or questionable data, the submitting institution will receive 
a written or electronic query from the DF/HCC ODQ/CTRIO Data Analyst, Coordinating Center or 
designee. Responses to all queries should be completed and submitted within 14 calendar days. 
Responses may be returned on the written query or on an amended paper case report form, or in the 
case of electronic queries, within the electronic data capture (eDC) system. In the case of a written 
query for data submitted on a paper case report form, the query must be attached to the specific data 
being re-submitted in response.
Missing Forms
If study forms are not submitted on schedule, the Participating Institution will receive a Missing 
Form Report from the Coordinating Center noting the missing forms. These reports are compiled by 
the DF/HCC ODQ/CTRIO and distributed on a monthly basis.
4.
REQUISITIONING INVESTIGATIONAL DRUG
The ordering of investigational agent is specified in the protocol section 8. 
Participating Institutions should order their own agent.
Each site must ensure that the pharmacy will be able to receive and store the agent according to state 
and federal requirements. The local IRB should be kept informed of who will supply the agent (i.e., 
NCI or a pharmaceutical company) so that any regulatory responsibilities can be met in a timely 
fashion.
5.
MONITORING: QUALITY CONTROL


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DF/HCC Protocol #16-256
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The quality control process for a clinical trial requires verification of protocol compliance and data 
accuracy. The Coordinating Center, with the aid of the DF/HCC internal monitor will provide quality 
control oversight for the protocol.
5.1
Ongoing Monitoring of Protocol Compliance
The Participating Institutions may be required to submit participant source documents to the 
Coordinating Center for monitoring. Participating Institution may also be subject to on-site 
monitoring conducted by the Coordinating Center.
The Coordinating Center will implement ongoing monitoring activities to ensure that Participating 
Institutions are complying with regulatory and protocol requirements, data quality, and participant 
safety. Monitoring will occur before the clinical phase of the protocol begins, continue during 
protocol performance and through study completion. Additional monitoring practices may include 
but are not limited to; source verification, review and analysis of the following: eligibility 
requirements of all participants, informed consent procedures, adverse events and all associated 
documentation, study drug administration/treatment, regulatory files, protocol departures, pharmacy 
records, response assessments, and data management.
Participating institutions will be required to participate in Coordinating Center initiated 
teleconferences. A schedule of these calls is forthcoming.
Remote Monitoring
Participating Institutions will be required to forward de-identified copies of participants’ medical 
record and source documents to the Coordinating Center to aid in source data verification. Random 
study subjects will be chosen for intermittent remote monitoring.
5.2
Monitoring Reports
The DF/HCC Sponsor will review all monitoring reports for on-site and remote monitoring of 
Participating Institutions to ensure protocol compliance. The DF/HCC Sponsor may increase the 
monitoring activities at Participating Institutions that are unable to comply with the protocol, 
DF/HCC Sponsor requirements or federal and local regulations. Participating Institutions may also 
be subject to an audit as determined by the DF/HCC Sponsor.
5.3
Accrual Monitoring
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual 
requirements for each participating institution. Accrual will be monitored for each participating 
institution by the DF/HCC Sponsor or designee. Sites that are not meeting their accrual 
expectations may be subject to termination.
The accrual expectation for Stanford University School of Medicine is approximately 15 
participants per year.
6.
AUDITING: QUALITY ASSURANCE
Auditing is a method of Quality Assurance. Its main focus is to measure whether standards and 
procedures were followed. Auditing is the systematic and independent examination of all trial related 
activities and documents. Audits determine if evaluated activities were appropriately conducted and


50
DF/HCC Protocol #16-256
Protocol Version Date: October 6, 2021
whether data was generated, recorded and analyzed, and accurately reported per the protocol, 
Standard Operating Procedures (SOPs), and the Code of Federal Regulations (CFR).
6.1
Audit Plan: DF/HCC Sponsored Trials
One on-site audit will be scheduled by the ODQ/CTRIO, assuming at least three participants have 
been treated on protocol at the site. Approximately 3-4 participants would be audited at the site over 
a 2 day period. If violations which impact participant safety or the integrity of the study are found, 
more participant records may be audited.
6.2
Audit Notification
It is the Participating Institution’s responsibility to notify the Coordinating Center of all scheduled 
audit dates (internal or NCI) and re-audit dates (if applicable), which involve this protocol. All 
institutions will forward a copy of final audit and/or re-audit reports and corrective action plans (if 
applicable) to the Coordinating Center, within 12 weeks after the audit date.
6.3
Audit Reports
The DF/HCC Sponsor will review all final audit reports and corrective action plans if applicable. 
The Coordinating Center, must forward these reports to the DF/HCC ODQ/CTRIO per DF/HCC 
policy for review by the DF/HCC Audit Committee. Based upon the audit assessments the DF/HCC 
Audit Committee could accept or conditionally accept the audit rating and final report. Conditional 
approval could require the DF/HCC Sponsor to implement recommendations or require further 
follow-up. For unacceptable audits, the DF/HCC Audit Committee would forward the final audit 
report and corrective action plan to the DFCI IRB as applicable.
6.4
Participating Institution Performance
The DF/HCC Sponsor, DFCI IRB, is charged with considering the totality of an institution’s 
performance in considering institutional participation in the protocol.
6.4.1
Corrective Actions
Participating Institutions that fail to meet the performance goals of accrual, submission of timely 
and accurate data, adherence to protocol requirements, and compliance with state and federal 
regulations, may be recommended for a six-month probation period. Such institutions must respond 
with a corrective action plan and must demonstrate during the probation period that deficiencies 
have been corrected, as evidenced by the improved performance measures. Participating Institutions 
that fail to demonstrate significant improvement will be considered by the DF/HCC Sponsor for 
revocation of participation. A DF/HCC Sponsor and/or the DFCI IRB may terminate a site’s 
participation if it is determined that a site is not fulfilling its responsibilities as described above.






EATING AND DIGESTION:
Not at
all
Slightly
Moderately
Quite a 
bit
Extremely
17.
Difficulty swallowing solid foods….
0
1
2
3
4
18.
Difficulty swallowing liquids……….
0
1
2
3
4
19.
Vomiting…………………………….
0
1
2
3
4
20.
Weight loss…………………………
0
1
2
3
4
MUSCLES AND JOINTS:
Not at
all
Slightly
Moderately
Quite a 
bit
Extremely
21.
Joint and muscle aches…………...
0
1
2
3
4
22.
Limited joint movement……………
0
1
2
3
4
23.
Muscle cramps……………………..
0
1
2
3
4
24.
Weak muscles……………………...
0
1
2
3
4
ENERGY:
Not at
all
Slightly
Moderately
Quite a 
bit
Extremely
25.
Loss of energy…………………….
0
1
2
3
4
26.
Need to sleep more/take naps…..
0
1
2
3
4
27.
Fevers………………………………
0
1
2
3
4
MENTAL AND EMOTIONAL:
Not at
all
Slightly
Moderately
Quite a 
bit
Extremely
28.
Depression…………………………
0
1
2
3
4
29.
Anxiety……………………………...
0
1
2
3
4
30.
Difficulty sleeping………………….
0
1
2
3
4


APPENDIX F – Provider GVHD Survey 
Provider Assessment
Patient:
MRN:
Provider Name:
Date of Visit:
Study Timepoint:
At this study timepoint, the patient has:
   Documented aGVHD 
(Proceed to assessment)
   Documented cGVHD 
(Proceed to assessment)
   No Documented aGVHD or cGVHD 
(Do not complete assessment)