Conditions: Follicular Lymphoma Marginal Zone Lymphoma Mantle Cell Lymphoma Chronic Lymphocytic Lymphoma B-Cell Lymphoma
Keywords: CD47 Monoclonal Anti-CD20 Antibody Follicular Lymphoma Marginal Zone Lymphoma
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 11
Healthy volunteers: no

Brief summary:
Background:

B-cell lymphoma is a cancer of certain white blood cells (called lymphocytes). These cells are found in lymph nodes. The cancer can cause enlargement of the lymph nodes leading to pain and discomfort. Swollen lymph nodes can also press on nearby organs such as liver and kidneys which can affect normal functioning of the organs. Researchers think that a new combination of drugs may be able to help.

Objective:

To find out if it is safe to give the combination of Magrolimab, Obinutuzumab and Venetoclax to people with B-cell lymphomas.

Eligibility:

Adults age 18 and older with an indolent B-cell lymphoma whose disease has returned or progressed after other treatment. Indolent B-cell lymphoma for this protocol is defined as having either follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma or marginal zone lymphoma.

Design:

Participants will be screened under a separate protocol.

Participants will have 28-day 'cycles' of treatment. They will take Venetoclax by mouth daily. They will get Obinutuzumab and Magrolimab by intravenous (IV) infusion. Treatment will last for about 8 months. They may be able to have more cycles of treatment if their cancer is responding well.

Participants will have physical exams, medical histories, and medicine reviews. Data about how they function in their daily activities will be obtained. They will have blood and urine tests. They may have bone marrow tests.

Participants will have imaging scans. These will include computed tomography (CT) and/or magnetic resonance imaging (MRI) scans and positron emission tomography (PET) scans.

Participants may give a cheek swab or saliva sample. They may give tumor tissue and bone marrow samples. These samples may be used for gene testing.

Participants will have a follow-up visit about 30 days after treatment ends. Then they will have visits every 3 months for the first 2 years, every 6 months for the next 3 years, and then yearly after that.

Detailed description:
Background:

* Indolent B-cell malignancies are associated with frequent disease relapse
* Standard frontline therapy includes a monoclonal anti-cluster of differentiation 20 (CD20) antibody with or without chemotherapy; novel targeted therapies have changed the treatment landscape and are preferred therapy for some patients with high-risk molecular features
* Targeted therapies given indefinitely add to drug resistance, treatment-emergent toxicities, and non-compliance
* Cluster of differentiation 47 (CD47) is a rational target for indolent B-cell malignancies; CD47 expression is higher in tumor cells than normal B-cells, and blocking CD47 results in phagocytosis of tumor cells
* Magrolimab is an anti-CD47 monoclonal antibody with activity in refractory indolent lymphomas when combined with rituximab (a first generation anti-CD20 monoclonal antibody)
* Obinutuzumab is a novel anti-CD20 monoclonal antibody with enhanced binding to the Fc receptor that may improve antibody-dependent cell-mediated cytotoxicity (ADCC), and phagocytosis, when combined with magrolimab
* We aim to test the safety and efficacy of venetoclax when added to the backbone of magrolimab and obinutuzumab in patients with relapsed or refractory indolent B-cell malignancies
* Treatment duration will be response-adapted and time-limited in all patients

Objective:

-To determine the safety of the triplet combination of venetoclax, magrolimab and obinutuzumab in relapsed and refractory indolent B-cell malignancies

Eligibility:

* Follicular lymphoma (FL) (grades 1-2, or 3a), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) with greater than or equal to 2 prior therapies, with at least one of those therapies containing an anti-CD20 monoclonal antibody
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Adequate bone marrow and organ function

Design:

* Phase 1 study with expansion cohorts of up to 76 patients with relapsed or refractory FL, MZL, MCL or CLL
* The safety profile of magrolimab, venetoclax, and obinutuzumab will first be determined in a dose-finding phase of up to 24 patients (6-12 patients with FL and 6-12 patients with MZL, MCL or CLL). Patients without dose-limiting toxicity (DLT) will receive an additional 5 cycles (total 6 cycles) of the triplet combination.
* After dose-finding is completed, expansion cohorts of each histology will first receive magrolimab and obinutuzumab for 2 cycles in a window for translational research. After the window, venetoclax will be added and patients will receive 6 cycles (total 8 cycles) of the triplet combination.
* Patients who achieve a complete response (CR) (after a total of 6 cycles of the triplet combination) will stop treatment and initiate active monitoring with radiologic imaging and assays for circulating tumor DNA (ctDNA); if these patients relapse, they can be retreated with 6 additional cycles. Patients who achieve partial response (PR) after 6 cycles of the triplet will continue for an additional 6 cycles; then, will initiate active monitoring.

Arms:
arm 1: Window of magrolimab intravenous (IV) with a 1 mg/kg priming dose followed by 30mg/kg loading and maintenance doses + obinutuzumab IV 1000mg combination for two (2) cycles (28-days each, Cycles -2 and -1), then venetoclax will be added at target dose (dose determined from Arm 1). Triplet combination treatment with magrolimab + obinutuzumab + venetoclax will be 6 cycles (28-days each, Cycles 1-6); further treatment will be response-adapted. arm 2: Magrolimab intravenous (IV) with a 1 mg/kg priming dose followed by 30mg/kg loading and maintenance doses + obinutuzumab IV 1000mg + venetoclax 800mg by mouth (PO) combination administered to 6 patients for six (6) cycles (28-days each, Cycles 1-6); further treatment with additional cycles will be response-adapted. Note: Dose-limiting toxicity (DLT) assessment of the magrolimab + obinutuzumab + venetoclax triplet will take place during Cycle 1. If =2 patients experience DLT, an additional 6 patients will be enrolled at Dose level (DL (-1) of venetoclax 600mg with magrolimab and obinutuzumab. arm 3: Magrolimab intravenous (IV) with a 1 mg/kg priming dose followed by 30mg/kg loading and maintenance doses + obinutuzumab IV 1000mg + venetoclax ramp-up to target dose of 400mg over 5 weeks (35 days, Cycle 1) administered to 6 patients. Triplet combination of magrolimab + obinutuzumab + venetoclax (target dose, no ramp-up) will continue for five (5) additional cycles (28-days each, Cycles 2-6); further treatment with additional cycles will be response-adapted. Note: Dose-limiting toxicity (DLT) assessment of the magrolimab + obinutuzumab + venetoclax triplet will take place during Cycle 1. If =2 patients experience DLT, an additional 6 patients will be enrolled at Dose level (DL (-1) of venetoclax 200mg with magrolimab and obinutuzumab. arm 4: Window of magrolimab intravenous (IV) with a 1 mg/kg priming dose followed by 30mg/kg loading and maintenance doses + obinutuzumab IV 1000mg combination for two (2) cycles (28-day cycles, Cycles -2 and -1), then venetoclax safety ramp-up to target dose (dose determined from Arm 2) over 5 weeks (35-days, Cycle 1). Triplet combination treatment with magrolimab + obinutuzumab + venetoclax (target dose, no ramp-up) will continue for 5 additional cycles (28-days each, Cycles 2-6); further treatment will be response-adapted.

Interventions: intervention 1: Obinutuzumab intervention 2: Venetoclax intervention 3: Magrolimab intervention 4: Acetaminophen intervention 5: Diphenhydramine intervention 6: Prednisone/prednisolone intervention 7: Methylprednisolone intervention 8: CT Scan chest/abdomen/pelvis intervention 9: MRI intervention 10: 18-FDG-PET intervention 11: Bone Marrow Biopsy intervention 12: Bone Marrow Aspiration
Intervention descriptions: intervention 1: Administered intravenously, on Days 1, 2, 8 and 15 of Cycle 1 at doses escalating from 100mg - 1000mg then on the first day for all subsequent cycles at 1000mg for dose finding phase. For expansion phase, administered on Days 1, 2, 8 and 15 of Cycle 2 at doses escalating from 100mg - 1000mg then on the first day for all subsequent cycles at 1000mg. intervention 2: For follicular lymphoma (FL) patients in dose finding phase, administered orally at a dose of 600mg or 800mg depending on tolerance, daily, cycles 1-12. For MZL (Marginal Zone Lymphoma), MCL (Mantle Cell Lymphoma) or CLL (Chronic Lymphocytic Leukemia) patients in dose finding phase administered at an escalating dose from 20mg-400mg Cycle 1 on days 1-35, and at a dose of 400mg per day for Cycles 2-12. Patients in expansion phase will receive target dose established from dose finding cohorts daily for all 12 cycles. intervention 3: Administered intravenously, starting at 1 mg/kg on second day of first cycle then 30mg/kg on days 8, 15 and 22 of cycle 1 and days 1 and 15 of cycles 2-12 for patients in both the dose finding and expansion phases. intervention 4: Premedication with 650mg acetaminophen 30-60 minutes prior to obinutuzumab doses. intervention 5: Premedication with 25-50mg diphenhydramine 30-60 minutes prior to obinutuzumab doses. intervention 6: Premedication with 100mg intravenous prednisone/prednisolone 30-60 minutes before obinutuzumab infusion. intervention 7: Premedication with intravenous methylprednisolone 80mg 30-60 minutes before obinutuzumab infusion. intervention 8: Screening, baseline, window Cycle -1/pre cycle 1, cycles 6-12; cycles 3-9, end of treatment and follow-up. intervention 9: Screening, baseline, window Cycle -1/pre cycle 1, cycles 6-12; cycles 3-9, end of treatment and follow-up. intervention 10: Baseline, Cycle -1, Day 1, window Cycle -1/pre cycle 1, cycles 6-12, end of treatment and follow-up. intervention 11: Screening, Cycle 7-12, Day 1 and end of treatment. intervention 12: Screening, Cycle 7-12, Day 1 and end of treatment.

Protocol document:
ICF_002.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 12/08/2023
Page 1 of 29
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:
Mark Roschewski, M.D.
STUDY TITLE:
A Phase 1 Study of Venetoclax added to Magrolimab and 
Obinutuzumab for Relapsed and Refractory Indolent B-
cell Malignancies
STUDY SITE:
NIH Clinical Center
Cohort: 
Affected patient
Consent Version:
12/08/2023 
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator:               Mark Roschewski, M.D. 
Phone:  240-760-6183
Email:  mark.roschewski@nih.gov
KEY INFORMATION ABOUT THIS RESEARCH 
This consent form describes a research study and is designed to help you decide if you would 
like to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
This section provides the information we believe is most helpful and important to you in making 
your decision about participating in this study. Additional information that may help you decide 
can be found in other sections of the document. Taking part in research at the NIH is your choice.
You are being asked to take part in this study because you have an indolent B-cell lymphoma 
and your disease has returned or progressed after other treatment. You have completed screening 
for this study and the test results show that you are able to take part in this treatment part of the 
study.
The main purpose of this study is to find out if it is safe to give the combination of three drugs 
– magrolimab, obinutuzumab, venetoclax – to patients with B-cell lymphomas. Specifically, we 
will look at patients with follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle 
cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL).  
Although obinutuzumab (GAZYVA®) and venetoclax (VENCLEXTATM) have been approved 
and used either alone or in combination to treat types of lymphoma, magrolimab has not. The 
use of magrolimab in this research study is experimental, which means that the FDA has 
not approved its use for cancer treatment or treatment of any other disease. In addition, 
the combination of magrolimab, obinutuzumab, venetoclax in this study is experimental, 
which means that while the FDA has approved obinutuzumab and venetoclax for cancer 
treatment, they have not approved the combination of obinutuzumab and venetoclax with 
magrolimab. 
IRB NUMBER: 20C0162
IRB EFFECTIVE DATE: 1/23/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 12/08/2023
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
We want to study the side effects of these drugs when given together. We also want to see if the 
combination of these three drugs is an effective treatment for your disease, and hope to learn 
about how they work together to treat B-cell lymphomas.  
There are other drugs and treatments that may be used for your disease, and these can be 
prescribed by your regular cancer doctor, should you decide to not be on this study. If you would 
prefer other drugs or treatments, you should consider not joining this study. The side effects of 
other treatments may be similar to those that you might have in this study. 
If you decide to join this study, here are some of the most important things that you should know 
that will happen:
•
Treatment will last for about 8 months and will require you to come in for check-ups about 
every 4 weeks. You will be assigned to an experimental treatment group based on your 
specific type of lymphoma.
•
In the first part of the study (dose finding phase), we want to find the highest dose of 
venetoclax that is safe to use with magrolimab and obinutuzumab. We will test the highest 
dose of venetoclax in small groups of patients and see what side effects the combination of 
these medications might cause. We will decrease the dose of venetoclax in the next small 
group of patients if needed. After the first part is done, we will enroll additional patients in 
a second part of the study (dose expansion phase) to learn more about whether these study 
medications can effectively treat your cancer.
•
If you are part of the dose-finding phase of the study, and are tolerating the combination of 
drugs well, you will receive 6 cycles of treatment, 28-days each (except for the first cycle 
for MZL, MCL and CLL participants which will be 35 days). After that, you may be able to 
receive more cycles of treatments if your cancer is responding well.
•
If you are part of the dose expansion phase of the study, you will receive 8 cycles of 
treatment- the first 2 cycles (28-days each) with magrolimab and obinutuzumab alone 
(“window” period), and the next 6 cycles of all three study drugs together (triplet 
combination therapy), each cycle lasting 28 days (except for the first cycle of the triplet 
combination for MZL, MCL and CLL participants, which will be 35 days). After that, you 
may be able to receive more cycles of treatments if your cancer is responding well.
•
You may have side effects from the treatment.  Some can be mild or very serious, temporary, 
long-lasting, or permanent, and  may include death.  Examples of some of the side effects 
that you may have include:  changes in blood counts (such as low red or white cells), 
gastrointestinal (such diarrhea, nausea, vomiting), fatigue, bleeding and bruising, rash, and 
infections. Some side effects may affect your ability to have children.  You may also have 
side effects from some of the procedures (such as lymph node biopsies) and bone marrow 
tests. All of the possible side effects are described in more detail later in the consent form.
•
You will be seen regularly during the study. You will have clinical, laboratory, and imaging 
tests to see how you are doing and to assess your disease. We will also collect required 
samples from you (including blood, bone marrow, and tumor biopsies) for both clinical and 
research purposes.  We may also collect saliva or cheek swabs for research that involves 
genetic testing to better understand the disease and how it responds to the drug.  
IRB NUMBER: 20C0162
IRB EFFECTIVE DATE: 1/23/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 12/08/2023
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
•
After the study treatment has ended, we will need to see you about 30 days after the last dose 
of study drugs at the NIH Clinical Center. We will continue to see you about every 3-6 
months for about 5 years after treatment, and then at least yearly to see how you are doing 
and if your cancer gets worse (or comes back). After this time, we may contact you to see 
how you are doing for the rest of your life or until the study ends.
Just as we do not know what side-effects you might have; we cannot know if you may benefit 
from taking part in this study. If you do not benefit, this study and the results from our research 
will help others in the future.
You are free to stop participating in the trial at any time.  If you decide to stop, the study doctor 
may ask you to agree to certain tests to make sure it is safe for you to stop.
The remaining document will now describe the research study in more detail.  This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information in this document. Some people have personal, religious, or ethical beliefs 
that may limit the kinds of medical or research treatments they would want to receive (such as 
blood transfusions). Take the time you need to ask any questions and discuss this study with NIH 
staff, and with your family, friends, and personal health care providers.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
B-cell lymphoma is a cancer of certain white blood cells (called lymphocytes) that are found in 
lymph nodes and the cancer affects the lymphatic system. The lymphatic system helps to fight 
infections and disease. The purpose of this research study is to see if the combination of 
magrolimab, obinutuzumab, and venetoclax is safe and effective at treating different types of B-
cell lymphoma. We are asking you to join this research study because you have either follicular 
lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL) or chronic 
lymphocytic leukemia (CLL) and your disease has returned or progressed. You have already taken 
part in the screening portion of this study and are able to participate.
Additional information is provided about each of the drugs being combined for the purposes of 
this study: 

Venetoclax (VENCLEXTATM) is a drug that targets a specific protein in the body called 
BCL-2.  When normal cells are damaged or old, your body tells them to self-destruct. This 
natural process is called apoptosis. In some lymphomas, BCL-2 may build up and prevent 
cancer cells from self-destructing naturally. By targeting BCL-2 with venetoclax, the 
process of apoptosis may be restored, allowing your body to destroy cancer cells.  

Obinutuzumab (GAZYVA®) is a type of drug called a “monoclonal antibody”. It is 
believed that obinutuzumab works by targeting a specific protein in the body called CD20.  
IRB NUMBER: 20C0162
IRB EFFECTIVE DATE: 1/23/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
CD20 is found on the surface of B-cells in the body, often in high amounts in some types 
of lymphoma. By using obinutuzumab to target CD20 and attach to it, it may work by 
causing the cell to die or by signaling your immune system to destroy the cancer cells.  

Magrolimab is also a “monoclonal antibody”. It is believed that magrolimab works by 
targeting a specific protein in the body called CD47. CD47 is a protein on the surface of 
cancer cell that sends a “do not eat me” signal to the body’s immune system. Blocking this 
protein with an anti-CD47 antibody such as magrolimab may allow the body’s immune 
system to recognize and kill these cancer cells. 
Although obinutuzumab (GAZYVA®) and venetoclax (VENCLEXTATM) have been approved and 
used either alone or in combination to treat types of lymphoma, magrolimab has not. The use of 
magrolimab in this research study is experimental, which means that the FDA has not 
approved its use for cancer treatment or treatment of any other disease. In addition, the 
combination of magrolimab, obinutuzumab, venetoclax in this study is experimental, which 
means that while the FDA has approved obinutuzumab and venetoclax for cancer treatment, they 
have not approved the combination of obinutuzumab and venetoclax with magrolimab. However, 
the FDA has given us permission to use these drugs together in this study. 
We want to study the side effects of these drugs when given together. We also want to see if the 
combination of these drugs is effective treatment for your disease and hope to learn about how 
these drug work together to treat B-cell lymphomas. 
WHAT WILL HAPPEN DURING THE STUDY?
Study Treatment
The screening process showed that you are eligible to participate in the study, and if you choose 
to be in it, you may need to have a few additional standard tests completed if not done recently. 
You will also have additional samples collected for research tests. You may then begin treatment 
on the study. You will be seen in the clinic at least every 4 weeks while on the study, with more 
frequent scheduled visits during some cycles.  This is described in detail below.  
You will be assigned to a treatment arm depending on your specific type of lymphoma. The study 
has two parts in terms of patient enrollment, and your length of treatment will depend on how well 
you are tolerating the treatment, what part of the study you are in, and how well your disease is 
responding to treatment.
You will receive “cycles” of treatment; each cycle is around 4 weeks (28 days)  – see exceptions 
below. The treatment is expected to last at least 6 dosing cycles if you are in the dose-finding phase 
of the study (1 cycle of venetoclax dose-finding together with magrolimab and obinutuzumab, and 
another 5 cycles of the triplet combination after that) but may continue for up to 12 dosing cycles. 
If you are part of the dose expansion phase treatment is expected to last at least 8 dosing cycles (2 
cycles of obinutuzumab and magrolimab alone [Window period],  and another 6 cycles of the 
triplet combination after that) but may continue for up to 14 dosing cycles. 
Dose-finding phase: We do this portion of the study because we want to find the safe dose of 
venetoclax, when given together with magrolimab and obinutuzumab. First a group of 6 patients 
will receive venetoclax at the highest dose with magrolimab and obinutuzumab. All patients will 
receive the same doses of magrolimab and obinutuzumab. This group of patients will be watched 
IRB NUMBER: 20C0162
IRB EFFECTIVE DATE: 1/23/2024


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Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
for serious side effects from the combination of venetoclax, magrolimab and obinutuzumab during 
the first cycle. The first cycle for patients with FL will be 28 days long, with venetoclax given at 
the desired dose. The first cycle for patients with MCL, MZL and CLL will be 35 days long with 
venetoclax given in a “ramp-up” schedule- which means that these patients will start venetoclax 
at a lower dose and have the dose gradually increased every week until the desired dose is reached.  
If no serious side effects are found, all future patients will receive that dose of venetoclax . If 
however, there are serious side effects, the dose of venetoclax will be lowered in the next group of 
6 patients.
If tolerated, patients will continue on to receive 5 more cycles of magrolimab, obinutuzumab and 
venetoclax (28-days cycles), meaning they will receive 6 cycles in total. An additional 6 cycles of 
treatment will be available if patients do not achieve a complete response to treatment and the 
investigator thinks it is in the best interest of the patient.   
Dose expansion phase: Once the safe dose of venetoclax, when given together with magrolimab 
and obinutuzumab, is determined, then the next part of the study will begin. In this part of the 
study, patients will receive the safest dose of venetoclax, as determined in the dose-finding phase, 
together with the same doses of magrolimab and obinutuzumab to learn more about effectiveness 
of the triplet drug combination in treating B-cell lymphoma.
Patients enrolled onto the Expansion phase of the study will receive treatment as follows: 

Window period: For the first 2 cycles (Cycle -1 and -2, 28-days each), obinutuzumab and 
magrolimab will be given without venetoclax to see the early clinical activity and response to 
these drugs alone.

Triplet combination therapy period: After completing the window, venetoclax will be added 
at the dose determined in the dose-finding phase of the study. During Cycle 1 of triplet 
combination therapy, patients with FL will receive venetoclax at the target dose for a 28-day 
cycle. Patients with MZL, MCL and CLL will be given venetoclax in a “ramp-up” schedule as 
described above for Cycle 1 (35-days long),  which means venetoclax will start at a lower dose 
and doses will be increased weekly to attain a desired dose during the first cycle of triplet 
combination therapy. 
After completion of Cycle 1, all patients in the dose-expansion phase will be treated with an 
additional 5, 28-day- cycles of venetoclax, magrolimab and obinutuzumab. An additional 6 cycles 
(i.e., 14 cycles total) of treatment will be available to patients whose disease is stable or if they do 
not achieve a complete response to treatment and they relapse and the investigator thinks it is in 
the best interest of the patient.   
The treatment drugs and schedule for each study drug is described in more detail here:

Venetoclax: This is an oral drug, taken by mouth daily on Days 1-28 or Day 1-35 of every 
cycle, except for the first 2 cycles of the Window Period for patients in dose-expansion 
phase of the study. Do not break or chew the tablets. Venetoclax tablets should be taken 
with a glass of water and should be taken with food. You will receive a supply of venetoclax 
to take at home on the days you are not seen in the clinic.  You should take the tablets at 
about the same time each day. If you do not remember to take all or any of the medications, 
do not make-up the dose or take extra the following day to make-up for the missed dose. 
IRB NUMBER: 20C0162
IRB EFFECTIVE DATE: 1/23/2024


PATIENT IDENTIFICATION
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NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
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MEDICAL RECORD
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You should store the medicine at room temperature . You will be given a drug diary to help 
you remember the schedule and to record each dose that you take, if you choose to do so.  
We will ask you to bring this diary and any leftover supply of study medications to each 
clinic visit.  
When venetoclax is started in patients with MZL, MCL and CLL (Cycle 1) it will be given 
in a “ramp-up” schedule as mentioned above. Starting with the second cycle that  of 
venetoclax, you will take the same dose each day. The study staff will review the doses 
and schedule with you. Venetoclax will be given from the start at a fixed dose in patients 
with FL without safety ramp-up.  

Obinutuzumab:  Obinutuzumab will be administered by intravenous (IV) infusion for about 
4 hours on Days 1, 2, 8, and 15 of the first cycle for all patients (Cycle 1 for patients in the 
dose-finding phase of the study, and Cycle -2 of the Window: Period for patients in the 
dose-expansion phase of the study.  Obinutuzumab will be administered by intravenous 
(IV) infusion for about 4 hours on Day 1 of all subsequent cycles. Before each infusion 
you will receive premedications to help lessen or prevent some side effects. On days when 
obinutuzumab and magrolimab are administered on the same day, obinutuzumab will be 
administered approximately 1 hour after magrolimab.

Magrolimab: Magrolimab will be administered by IV infusion on Days 2, 8, 15 and 22 on 
of the first cycle for all patients (Cycle 1 for patients in the dose-finding phase of the study, 
and Cycle -2 of the Window: Period for patients in the dose-expansion phase of the study. 
After that, magrolimab will be administered on Days 1 and 15 of all subsequent cycles. 
Your first infusion of magrolimab will take approximately 3 hours. After that all infusions 
will take approximately 2 hours. Before the first two infusions, you will receive 
premedications to help lessen or prevent some side effects. We will check your complete 
blood count (CBC) within 6 hours of the first and second dose of magrolimib (Cycle 1 on 
Days 2 and 8 for patients in the dose-finding phase of the study; and Cycle -2 on Days 2 
and 8 for patients in the dose-expansion phase of the study). We will also check the CBC 
twice weekly for the first cycle during both the dose-finding and dose-expansion phases of 
the study.
Additional Information
During the study, you may not receive any live vaccines, and may need to avoid certain 
medications. Examples of live vaccines include but are not limited to: the intranasal influenza 
vaccine known as Flu-Mist, measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, 
and typhoid vaccine Before, you start taking any new medicines, including medicines you can buy 
‘over-the-counter’, please talk to the study doctor to make sure they are allowed on this study. 
In addition, avoid eating grapefruit, Seville oranges (bitter oranges) and star fruit while on this 
study as they interfere with venetoclax. Please be aware that these fruits can be processed into 
preserves (e.g., marmalade), juice drinks and food supplements; these should also be avoided.
Assessments during treatment
Similar to the tests done at the beginning of the study, many of the same tests will be repeated 
during the study to see how you are doing and how the cancer may be responding to treatment. 
IRB NUMBER: 20C0162
IRB EFFECTIVE DATE: 1/23/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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Some of these tests may be performed more often if felt to be needed clinically for your care by 
your doctor:
Before starting treatment and before the start of every cycle and at the end of treatment or when 
your disease progresses:

Review of medical history, and a physical exam (check weight and vitals), including 
obtaining information about how you function in your daily activities, side effects and 
symptoms, and review of medications

Routine blood and urine tests (Approximately 2.9 tablespoons will be collected at each 
timepoint):
o
Tests to measure your blood counts and organ function (such as liver and kidneys), 
and blood electrolytes.  
o
Tests to measure how well your blood clots
o
If you are a woman able to get pregnant and you are not already known to be 
pregnant, you will also have a pregnancy test done (this may be done by blood or 
urine test)
o
Tests routinely done in patients with your type of cancer to confirm the status of 
your disease
At the time of disease evaluation:

Bone marrow testing will be repeated if the previous test result was positive to confirm 
response to treatment.   

Imaging to show all sites of disease, including CT and/or MRI scans (if your doctor thinks 
they are necessary), and PET scans .
o
CT and/or MRI scans will be done before starting treatment, at the end of the 
Window period (dose expansion patients only) or before Cycle 1, and then every 3 
cycles (after Cycle 3, 6, 9 and 12 -if you have that many cycles of treatment).
o
PET scans will be done before starting treatment, at the end of the Window period 
(dose expansion patients only) or before Cycle 1, and then every 6 cycles (after 
Cycle 6 and 12- if you have that many cycles of treatment). 
Additional research testing
In addition to the tests that we will conduct to determine whether you are having side effects or if 
you are responding to the study therapy, we will also collect samples from you for purposes of 
research only.  The samples are being done to look at the effects of therapy on your immune system 
and markers of tumor activity, including collecting and testing tumor cells. We will also collect 
samples to perform genetic analysis on your tumor tissue, to determine which genes are expressed 
both before and after treatment. Gene expression is when the information stored in our DNA is 
converted into instructions for making proteins or other molecules. This process allows a cell to 
respond to its environment. We are interested to know if the study therapy changes the environment 
around the tumor.
Research samples for this study include the following.  These samples are required unless 
otherwise noted:
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

Blood Samples for Research: Samples will be drawn to learn more about how the study 
drugs affect your body, and your cancer, blood samples will be collected on Days 1, 8 and 
15 of the first cycle of the Window period and after the first and second cycles of the 
Window period (for patients in the dose expansion phase), and for all patients after Cycles 
3,6,9, and 12, and once you are finished treatment in follow-up (see below). Approximately  
2.7 tablespoons will be collected at each timepoint.

Blood Samples for Pharmacokinetics (PK) and Anti-Drug Antibody (ADA):  To check 
how much of the drug magrolimab is in your blood and the presence of anti-magrolimab 
antibodies, blood samples will be collected on Day 1 of the first Cycle of the Window 
period and Day 1 of Cycles 1, 3, 7 and 11 for patients in the dose expansion phase, and on 
Day 1 of Cycles 1, 3 , 5 and 9 and after Cycle 12 for patients in the dose-finding phase. 
Approximately 0.5 tablespoons will be collected at each timepoint.

Bone Marrow Samples:  These will be done before starting treatment, during the first cycle 
of the Window period (optional-only for those patients in the dose expansion phase), at the 
time of response (improvement or progression), and after 6 cycles of triplet combination 
treatment. Any bone marrow samples will be collected in the same way as those routinely 
done to monitor your disease and we will try to collect at the same time, whenever possible.

Cheek Swab or Saliva Samples: A required cheek swab and/or saliva sample to collect 
normal tissue will be done, before starting treatment. To obtain a cheek swab, a small brush 
is rubbed against the inside of the cheek to wipe off some cells. To obtain saliva, a special 
collection tube will be used and it may take a few minutes to collect the saliva.

Tumor Tissue and Biopsies:  A portion of the biopsies done in the past for your cancer will 
be collected and are required. We will ask you to undergo a tumor biopsy before starting 
treatment (if there is not enough tissue from prior biopsies for research), and during Cycle 
1 of the Window period (optional-only for patients in the dose expansion phase), and if 
your disease should progress/ at the end of treatment, only if it is safe to do so. The biopsies 
are being collected for special research tests.  Your decision if to have the biopsies will be 
documented in the medical record. You may agree to biopsies now and change your mind 
later. If at any time you do not want to have a biopsy done, please tell us.
Usually tissue can be obtained safely and comfortably with local anesthesia. However, in 
some cases, we may need to use conscious sedation which is usually given during minor 
surgical procedures to relax participants and minimize discomfort.  It can be given as a pill, 
a shot, an IV or even inhaled. You may have to wait up to an hour to start feel the effects 
depending on how it is given. Once it takes effect, you will be mostly awake, though 
relaxed or drowsy. You will be monitored throughout the procedure for any changes to 
your breathing and blood pressure. If you require conscious sedation before undergoing a 
biopsy, you will be informed of the risks and you will be asked to sign an additional consent 
prior to undergoing the procedure. Biopsies will NOT be done on this study if they require 
general anesthesia. We may ask that you have ultrasound or CT scan to help clearly locate 
your tumor when doing a biopsy.  
All of your samples collected for research purposes on this study (such as the tumor and normal 
tissue) may be used to look for specific changes in the DNA in tumors that could be used to develop 
new ways of diagnosing and treating cancer. DNA (also called deoxyribonucleic acid) in the cells 
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carries genetic information and passes it from one generation of cells to the next – like an 
instruction manual. Normal tissue contains the DNA (instructions) that you were born with, DNA 
in tumor cells has changed – or mutated – and we think that change in the DNA is what causes 
tumors to form and to grow. 
To look at your DNA, we may use do what is called “whole genome sequencing.”  This where we 
will do special tests in the lab to look at the entire sequence, or order, of how your DNA is put 
together.  This is what makes you unique.  
To determine which parts of the DNA have mutated, we will compare the DNA in your tumor cells 
to DNA from your normal cells. We will then analyze the results from similar tumors to see if 
there are any changes in the DNA that are common to a particular type of tumor. To examine the 
tumor and normal tissue we may use several different techniques depending on the type of tissue 
we collect. These could include growing cell lines (cells which keep dividing and growing in the 
laboratory, sometimes for years allowing us to continually study those cells), xenograft studies 
(placing or growing cells in another animal, such as mice), and looking in detail at the parts of the 
genes that produce specific proteins.
However, you should know that the analyses that we perform in our laboratory are for research 
purposes only; they are not nearly as sensitive as the tests that are performed in a laboratory that 
is certified to perform genetic testing or testing for routine clinical care. For these reasons, we will 
not give you the results of the research tests done on your research samples in most cases.  There 
may be exceptions to what we share with you and this is described later in this consent form in the 
section for “Return of research results.” 
When you are finished taking the drugs (treatment)
When you are finished the study treatment, we will ask you to come to the clinic for follow-up 
visits and assessments at about the following times:  about 30 days after the last treatment, every 
3 months for the first 2 years,  every 6 months for the next 3 years, and then about yearly after that 
for as long as your doctor thinks it is necessary or beneficial, unless your disease comes back (or 
worsens) or you need other treatment not in this study.
These clinic visits will include having physical exams, routine laboratory tests and other 
procedures, as needed, to see how you are doing, and may also include imaging to check the status 
of your cancer.  At most of these visits, research blood samples will also be collected.  If at any 
time your disease comes back or worsens, we will ask to collect blood and tissue samples (biopsy) 
for the study. 
If your disease worsens, or you need to start a new anti-cancer treatment not in this study, we will 
continue to follow-up with you by phone every 3-6 months to see how you are doing, for the rest 
of your life. 
HOW LONG WILL THE STUDY TAKE?
If you agree to take part in this study, your involvement is expected to last for the rest of your life. 
You will be seen several times during treatment (at least 10 visits) and then in follow-up every 3-
6 months for about 5 years after treatment (about 14 visits).  During follow-up after the treatment, 
the number of visits will depend on how you are doing and if your cancer gets worse. The 
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outpatient visits during and after treatment usually take about 3 hours but should not take longer 
than 8 hours.
HOW MANY PEOPLE WILL PARTICIPATE IN THIS STUDY?
We plan to have approximately 76 people participate in this study at the NIH.
WHAT ARE THE RISKS AND DISCOMFORTS OF BEING IN THE STUDY?
You should talk to your study doctor about any symptoms that you experience while taking part 
in the study.
What side effects or risks can I expect from being in this study? 
If you choose to take part in this study, there is a risk that:

you may lose time at work or home and spend more time in the hospital or doctor’s office 
than usual

you may also be asked sensitive or private questions which you normally do not discuss
Here are important points about side effects:

The study doctors do not know who will or will not have side effects.

Some side effects may go away soon, some may last a long time, or some may never go 
away.

Some side effects may interfere with your ability to have children.

Some side effects may be serious and may even result in death.
Here are important points about how you and the study doctor can make side effects less of a 
problem:

Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect.

The study doctor may be able to treat some side effects.

The study doctor may adjust the study drugs to try to reduce side effects.

The study doctor will provide you with information about other drugs you may need to 
avoid while receiving the study drug.
The tables below show the most common and the most serious side effects that researchers know 
about. There might be other side effects that researchers do not yet know about. If important new 
side effects are found, the study doctor will discuss these with you.
Let your study doctor know of any questions you have about possible side effects. You can ask the 
study doctor questions about side effects at any time.
You should report and discuss with the study doctor any other medication(s) you are taking while 
you are treated with the study drug, so that he/she can take action to prevent any potential drug 
interactions.
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Risks from the study drugs
Venetoclax (VENCLEXTATM)
Likely:

Low white blood cell count (cells that help fight infection) (neutropenia)

Low red blood cell count (anemia)

Low platelet count (cells that help blood to clot) (thrombocytopenia)

Diarrhea

Nausea

Fatigue (feeling tired)

Upper respiratory tract infection
Less Likely:

Low white blood cell counts with fever (febrile neutropenia)

Vomiting

Constipation

Fever (pyrexia)

Swelling of the hands and feet (peripheral edema)

Pneumonia

Chemical imbalance in blood (including low potassium, high potassium, high phosphate, 
high levels of uric acid, lactate dehydrogenase)

Back pain

Headache

Cough

Dizziness (syncope)

Infection (including lower respiratory infection and urinary tract infection)

Low levels of oxygen in the blood (hypoxia)
Rare but Serious:

Unusual levels of chemicals in the blood caused by the fast breakdown of cancer cells, 
which may lead to changes in kidney function, abnormal heartbeat, or seizures (Tumor 
Lysis Syndrome)

Liver failure (hepatic failure)

Infertility in males

Severe infection throughout the body (sepsis)
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Obinutuzumab (GAZYVA®)
Likely:

Low white blood cell count (cells that help fight infection) (neutropenia)

Low platelet count (cells that help blood to clot) (thrombocytopenia)

Low red blood cell count (anemia)

Low white blood cell counts with fever (febrile neutropenia)

Fatigue 

Infusion reactions (see additional information below)

Fever (pyrexia)

Nausea

Vomiting

Diarrhea

Constipation

Decreased appetite

Cough

Infections, the most common include:  upper respiratory tract infection, sinusitis, urinary 
tract infection

General weakness (asthenia) 

Joint or muscle pain (arthralgia or musculoskeletal pain)
Less Likely:

Low number of other white blood cells, cells that help fight infection; with or without fever 
(including granulocytopenia, leukopenia, lymphopenia)

Heartburn or indigestion (dyspepsia)

Sore throat (nasopharyngitis, pharyngitis)

Joint aches (arthralgia)

Pain in extremity

Nasal congestion

Itching (pruritus)

Chemical imbalance in blood (including low albumin calcium, phosphate, potassium and 
sodium, and high levels of liver enzymes)

Abnormal blood clotting (Disseminated Intravascular Coagulation)

Intestinal perforation

Basal Cell Carcinoma

Squamous Cell Carcinoma

Cytokine Release Syndrome
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Rare but Serious:

Effects on the heart (see additional information below)
More information:
Allergic and infusion reactions:  Sometimes people have allergic reactions to drugs.  Serious 
allergic reactions can be life-threatening.  If you have an allergic reaction, you might develop a 
rash, difficulty breathing, wheezing when you breathe, sudden low blood pressure with light-
headedness, swelling around the mouth, throat or eyes, a racing heartbeat, and/or sweating.  Before 
starting the study drug, you must tell your study doctor about any drug allergies.  You should tell 
a member of the study team right away if you have any allergy symptoms listed above.
Bleeding effects:  You may experience bruising or nose bleeds during dosing.  Rarely, serious 
internal bleeding, such as bleeding in your stomach, intestine, or brain may occur sometimes 
resulting in death.  If you take medicines or supplements that increase your risk of bleeding, such 
as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) or medicines used to prevent or treat 
blood clots or stroke, some medications, including ibrutinib and obinutuzumab, may increase this 
risk.  Blood thinners such as warfarin or other vitamin K antagonists should not be taken together 
with ibrutinib and obinutuzumab.  If you have signs or symptoms of severe bleeding in or around 
the brain (such as sudden severe headaches, weakness in the arms or legs, difficulty speaking or 
understanding speech, or loss of balance) or if you have signs or symptoms of serious bleeding 
(such as blood in your stools or urine or bleeding that lasts for a long time or that you cannot 
control), please call the study team right away.  
Effects on the heart:  Abnormal heartbeats (atrial fibrillation and/or atrial flutter) and worsening 
of heart conditions have been reported in patients treated with ibrutinib and obinutuzumab, 
especially when they also have a history of these and other heart conditions, including increased 
blood pressure, infections, or had abnormal heartbeat in the past.  Atrial fibrillation/flutter is a 
common type of abnormal heartbeat.  The heartbeat may be fast or irregular causing symptoms 
such as a pounding or racing heart, dizziness, weakness, feeling light-headed or shortness of 
breath.  If you develop any of these symptoms while on the study drug, you should tell your study 
doctor immediately.
Hepatitis B Reactivation:  In patients with a history of hepatitis B infection, taking obinutuzumab 
could cause it to return.  You should not receive obinutuzumab or any of the study medications if 
you have active hepatitis B or C liver disease.  We will screen you at baseline for hepatitis and 
monitor you during the study.  You should tell your study doctor immediately if you have any of 
these symptoms which may suggest hepatitis:  worsening of fatigue and yellow discoloration of 
the skin or eyes.
Infection: 
o
A rare and usually fatal viral disease in the brain, Progressive Multifocal 
Leukoencephalopathy (PML), has been reported in patients treated with obinutuzumab.  If 
you experience symptoms such as weakness, paralysis, vision loss and/or impaired speech, 
you should tell the study team immediately.
o
Patients with MZL who receive obinutuzimab are at a higher risk for developing a fungal 
infection of the lungs that can cause pneumonia (Pneumocystis Jiroveci pneumonia). For 
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this reason, all patients with MZL will receive medication from the start of therapy until 
completion to prevent this infection.
Magrolimab
The following events have been observed in at least 1 out of 10 patients treated with magrolimab 
(taken alone or with another anti-cancer drug):

Red blood cell agglutination (red blood cells sticking together when viewed on a glass 
slide under the microscope)

Thrombocytopenia (abnormally low platelets in the blood)

Nausea

Diarrhea

Vomiting

Constipation

Abdominal pain

Fatigue

Fever

Chills

Infusion- related reaction (allergic reaction to drugs while it is being given into your vein 
or shortly thereafter)

Blood bilirubin increased (increase of orange-yellow pigment that occurs normally when 
part of your red blood cells break down)

Decreased appetite 

Back Pain

Headache

Cough

Shortness of breath

Dizziness (lightheadedness)

Joint aches (arthralgia)

Low white blood cell counts with fever (febrile neutropenia)

Low white blood cell count (cells that help fight infection) (neutropenia)

Difficulty breathing (dyspnea)
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
Hypophosphatemia (low phosphorus in your blood) 

Hypokalemia (decrease of potassium in the blood) 

Hypotension (low blood pressure) 

Peripheral edema (swelling and fluid retention in the arms and legs) 

Pneumonia (lung infection) 

Pruritus (itchy skin) 

Severe infection throughout the body (sepsis)

Anemia (abnormally low number of red blood cells) and hemolysis (destruction of red 
blood cells): The study drug, magrolimab, attaches to red blood cells. When it attaches to 
old red blood cells, some of the old red blood cells may die, causing anemia, especially at 
the beginning of the treatment. Anemia is detected by a blood test counting the red blood 
cells, and can cause pale skin, fatigue and loss of energy, shortness of breath, low blood 
pressure and/or rapid heartbeats. In a few patients treated with magrolimab, anemia or the 
effects of anemia have been life-threatening or fatal. Sudden deaths have occurred during 
or shortly after initial treatment doses. Your study doctor will test your blood for anemia 
before each magrolimab infusion during the study, and a few hours after you start the first 
and second doses of magrolimab. Your blood may also be tested more often if your study 
doctor is concerned about anemia. If anemia is severe, your doctor may recommend a blood 
transfusion to increase the number of your red blood cells and/or stop or delay treatment 
altogether with magrolimab. It is important that you inform the study doctor about any past 
known or suspected cardiovascular (heart) disease and any related symptoms, including 
but not limited to: chest pain, difficulty breathing, and swelling of the lower limbs before 
participating in the study. These conditions may increase your risk of side effects from 
anemia.

Pneumonitis and respiratory distress: Cases of lung inflammation (pneumonitis) and 
respiratory distress have been reported with magrolimab use. All reported patients were 
also receiving other medications that are known to cause lung toxicity and respiratory 
distress. Common symptoms of pneumonitis are cough and shortness of breath. 
Pneumonitis is diagnosed by imaging (chest X-ray or CT scan). If detected, your study 
doctor may delay, or stop treatment with magrolimab. Your study doctor may also give 
you oxygen and some drugs to treat the symptoms. In some cases, hospitalization may be 
required. For your safety, the study doctor will monitor you for these events. For example, 
respiratory rate and oxygen saturation will be checked at every follow-up visit. You will 
be asked for respiratory symptoms during follow-up visits as well. Patients with known 
lung and heart conditions will be monitored closely. 

Infusion Reactions: Magrolimab may cause side effects similar to an allergic reaction, 
called an infusion reaction, while it is being given into your vein or shortly after it is given, 
especially during/after the 2 first doses. These reactions could include symptoms such as 
fever, chills, back pain, nausea, vomiting, and shortness of breath.  To-date, these reactions 
were observed to be mild to severe. Before each administration of the first 2 doses of 
magrolimab, you will receive medications in an attempt to minimize the risk of occurrence 
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of infusion reaction.  If you experience these symptoms, your study doctor may slow down, 
interrupt, or even stop the delivery of magrolimab into your vein. Your study doctor may 
also give you some drugs to treat these symptoms. In some cases, you might be admitted 
to the hospital for treatment and monitoring.  You will receive medications before your 
initial treatments of magrolimab in an attempt to minimize the risk of occurrence of these 
signs/symptoms.  If you have experienced infusion reactions, your study doctor may 
prescribe premedication prior to your next treatment with magrolimab or discontinue 
treatment with magrolimab permanently. For your safety, the study doctor will monitor 
you for these events. For example, you will have your blood pressure, pulse, body 
temperature, and respiratory rate monitored before and for 1 hour after the magrolimab  
infusions for the first four weeks. If you are receiving magrolimab  and experience a 
reaction that could be related to magrolimab, we may stop the infusion, and you may be 
withdrawn from the study if the reaction is severe or it recurs.

Hemagglutination: Studies in test tubes have shown that the study drug can make the red 
blood cells sticky – this is known as hemagglutination.  This may be a potential concern 
because sticky red blood cells can cause tiny clots, which may obstruct normal blood flow 
in the smallest blood vessels and cause ischemia (restriction of blood and oxygen supply 
to tissues), including blood vessels in the eyes.  Patients treated with magrolimab have been 
found to have clumping of red blood cells on a glass slide under the microscope; however, 
most of these patients did not have side effects that could be directly linked to that 
observation.   In earlier studies, the sponsor checked blood smears and performed vision 
tests during each treatment cycle and did not observe clinically significant 
hemagglutination.  These tests will continue to be done as part of this study.

Anti-drug Antibody Reactions: In some patients, treatment with magrolimab causes the 
body’s immune system to develop special antibodies directed at magrolimab. These 
antibodies can affect how magrolimab is handled by your body.  Antibodies are proteins 
made in the body that respond to a substance that is foreign to the body.  If you develop 
these special antibodies, it may affect your body’s ability to respond to magrolimab in the 
future and might produce side effects including infusion reactions or problems with your 
kidneys.  Blood samples will be drawn to monitor for the development of these antibodies 
during study treatment and 30 days after your last infusion of study drug.

Other Laboratory Abnormalities: Thrombocytopenia (abnormally low platelets in the 
blood) was observed in at least 1 out of 10 patients treated with magrolimab.  Platelets are 
colorless blood cells that help blood to clot.  Low platelets could lead to bleeding. If your 
platelets go too low, your doctor may prescribe appropriate treatment. Other laboratory 
abnormalities experienced by at least one out of 10 patients included low neutrophils which 
can lead to increased risk of infection, hyperbilirubinemia (increase of orange-yellow 
pigment that occurs normally when part of your red blood cells break down, also known 
as jaundice) and hypokalemia (decrease of potassium in the blood).

Thromboembolic events: Blood clots forming in blood vessels such as large veins or 
arteries have been reported in some patients receiving magrolimab, sometimes early in 
therapy. These clots have mostly been found in the lung arteries and in deep veins. Clots 
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in the lung arteries can lead to difficulty breathing and heart issues. Clots in the leg deep 
veins can cause leg swelling and pain. It is currently unknown if magrolimab increases 
your risk of getting blood clots. Your study doctor will monitor you carefully for potential 
clots and take proper medical action including possibly having you take anti-clotting 
medications if any such situations arise. Please contact your doctor immediately if you 
experience shortness of breath, weakness or chest pain.

Interactions with Other Drugs:  magrolimab may have some side effects that may overlap 
with some of the side effects caused by other medications that also stimulate the immune 
system.  It may be dangerous to take both/all of these drugs at the same time.  It is important 
to inform your doctor the last time you took any medication or nutritional supplements that 
stimulate the immune system. Your study doctor will discuss this with you further. 

Risks Related to Blood Type and Cross-Match Testing:  Based on studies in the laboratory 
using human blood samples, magrolimab may interfere with some of the tests used to 
determine your blood type. This may require that special additional testing be performed 
on your blood if you were to need a blood transfusion for any reason.  For any non-
emergency blood transfusion, you will be required to go to a site, or come back to our 
clinic, where the appropriate testing can be performed.  In the event of an emergency and 
you are taken to another hospital, the emergency doctors should contact the magrolimab 
study doctor immediately. The primary risk of interference of the blood type and cross 
match results is that you could receive blood that is the wrong type, resulting in a serious 
and life-threatening reaction or death.
Other General Risks
Tumor Lysis Syndrome: You may experience a large release of tumor cell chemicals in the blood 
after treatment, which could lead to kidney failure and possibly death. This may lead to changes 
in kidney function, abnormal heartbeat, or seizures. Your study doctor may do blood tests to check 
for TLS, and treat you for it as needed. This may include possible inpatient admission in the 
hospital.
Risks from tests and procedures
The risks of taking part may include the following:  

Blood draws:
o
Likely: discomfort, swelling, bruising, and/or bleeding at the site of the needle 
insertion. 
o
Less likely: dizziness or feeling faint. 
o
Rare: infection (symptoms may include fever, shaking, chills, fatigue, confusion, 
joint aches, or rapid pulse). 
Up to about 7 tablespoons of blood may be collected at any day, up to about 27 tablespoons 
may be collected within 8 weeks.

Bone marrow testing: A numbing agent that can cause a stinging or burning sensation may 
be injected at the site of your bone marrow biopsy. The biopsy needle will go through the 
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skin into the bone and may produce a brief, sharp pain. As the bone marrow liquid is taken 
from the bone, there may be a brief, sharp pain. Since the inside of the bone cannot be 
numbed, this procedure may cause some discomfort, however not all people experience 
discomfort. The possible side effects associated with a bone marrow biopsy include pain, 
bleeding, bruising, and infection, as well as a reaction to the numbing agent.

Biopsy: 
o
Likely: discomfort or pain, redness, swelling, and/or bruising at the site of the needle 
insertion.
o
Less likely: Bleeding from the site of the needle insertion
o
Rare: significant infection or bleeding from this procedure, allergic reaction to the 
local anesthetic, or formation of a scar at the site of needle entry. 
You will be asked to sign a separate consent form prior to any biopsy procedure.

Conscious Sedation:  The common side effects of conscious sedation include drowsiness, 
delayed reflexes, hypotension, headache, and nausea. These are generally mild and last no 
more than a few hours. You will be monitored throughout the procedure.

Imaging:  The following may be done as directed by your doctor based on your disease:  
o
CT Scan (computerized tomography):  There is a slight risk of developing an 
allergic reaction to the iodine contrast material.  The reaction can be mild (itching, 
rash) or severe (difficulty breathing or sudden shock).  Death resulting from an 
allergic reaction in this setting is rare.  Most reactions can be controlled using drugs.  
Be sure to tell your doctor if you have allergies of any kind (such as hay fever, 
iodine allergy, eczema, hives, or food allergies).
The contrast material used during CT scanning can cause water loss or damage to 
the kidneys that may lead to kidney failure.  This is a concern if you have poor 
kidney function, dehydration, or diabetes, especially if you take Metformin® 
(Glucophage) to control diabetes.
You may also experience discomfort related to lying still in an enclosed space for 
a prolonged period of time.
o
MRI Risks: MRI uses a strong magnetic field and radio waves to take pictures of 
the body.  We may obtain pictures of your brain or other parts of your body for this 
study.  The MRI scanner is a metal cylinder surrounded by a strong magnetic field.  
During the MRI, you will lie on a table that can slide in and out of the cylinder.  We 
will place soft padding or a coil around your head. You will be in the scanner about 
45 minutes. You may be asked to lie still for up to 15 minutes at a time. While in 
the scanner you will hear loud knocking noises, and you will be fitted with earplugs 
or earmuffs to muffle the sound. You will be able to communicate with the MRI 
staff at all times during your scan, and you may ask to be moved out of the machine 
at anytime.
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It is very important for the experiment that you do not move your head or body 
inside the scanner. We will use padding around your head to help keep it in place. 
We may place a bar in your mouth to help keep your head still. 
People are at risk for injury from the MRI magnet if they have some kinds of metal 
in their body. It may be unsafe for you to have an MRI scan if you have pacemakers 
or other implanted electrical devices, brain stimulators, some types of dental 
implants, aneurysm clips (metal clips on the wall of a large artery), metal prostheses 
(including metal pins and rods, heart valves, and cochlear implants), permanent 
eyeliner, tattoos, an implanted delivery pump, or shrapnel fragments. Welders and 
metal workers may have small metal fragments in the eye. You will be screened for 
these conditions before having any MRI scan. If you have a question about metal 
in your body, you should inform the staff. You will be asked to complete an MRI 
screening form before each MRI scan you have. 
In addition, all magnetic objects (like watches, coins, jewelry, and credit cards) 
must be removed before entering the MRI scan room.
People with fear of confined spaces may become anxious during an MRI. Those 
with back problems may have back pain or discomfort from lying in the scanner.  
The noise from the scanner is loud enough to damage hearing, especially in people 
who already have hearing loss. Everyone having a research MRI scan will be fitted 
with hearing protection. If the hearing protection comes loose during the scan, you 
should let us know right away.
There are no known long-term risks of MRI scans.
Risks for gadolinium enhanced MRI scans:
Procedure:  During part of the MRI you may receive gadolinium, a contrast agent, 
through an intravenous (IV) catheter. It will be done for medical purposes.
It is not known if MRI with contrast is completely safe for a developing fetus. 
Therefore, all women of childbearing potential will have a pregnancy test 
performed no more than 24 hours before each MRI scan with contrast. The scan 
will not be done if the pregnancy test is positive.
Risks: The risks of an IV catheter include bleeding, infection, or inflammation of 
the skin and vein with pain and swelling.  
Mild symptoms from gadolinium infusion occur in fewer than 1% of those who 
receive it and usually go away quickly.  Mild symptoms may include coldness in 
the arm during the injection, a metallic taste, headache, and nausea.  In an extremely 
small number, fewer than one in 300,000 people, more severe symptoms have been 
reported including shortness of breath, wheezing, hives, and lowering of blood 
pressure. You should not receive gadolinium if you previously had an allergic 
reaction to it.  You will be asked about such allergic reactions before gadolinium is 
given.   
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People with kidney disease are at risk for a serious reaction to gadolinium contrast 
called “nephrogenic systemic fibrosis” which has resulted in a very small number 
of deaths.  A blood test of your kidney function may be done within the month 
before an MRI scan with gadolinium contrast. You will not receive gadolinium for 
a research MRI scan if your kidney function is not normal or if you received 
gadolinium within the previous month. 
Most of the gadolinium contrast leaves the body in the urine.  However, the FDA 
has issued a safety alert that indicates small amounts of gadolinium may remain in 
the body for months to years.  The effects of the retained gadolinium are not clear. 
At this time, retained gadolinium has not been linked to health risks in people whose 
kidneys work well.
Some types of gadolinium contrast drugs are less likely to remain in the body than 
others.  In this study, we will use the gadolinium contrast drugs that are less likely 
to remain in the body. 
Please tell your research team if you have had any MRI scans in the past 12 
months. We will also give you additional information called a “Medication Guide.”  
Upon request, we will give you individual information about retained gadolinium 
we see on your studies.
What are the risks related to pregnancy? 
If you are capable of becoming pregnant, we will ask you to have a pregnancy test before beginning 
this study. You will need to practice an effective form of birth control before starting study 
treatment, during study treatment, and for 90 days after the last dose of magrolimab, 30 days after 
the last dose of venetoclax, and 18 months after the last dose of obinutuzumab for women and 6 
months after the last dose of obinutuzumab for men, whichever is later (the restricted period). If 
you become pregnant, there may be unknown risks to the fetus or unborn child, or risks that we 
did not anticipate. There may be long-term effects of the treatment being studied that could 
increase the risk of harm to a fetus. You must tell the study doctor if your birth control method 
fails during the restricted period. If you think or know you have become pregnant during the 
restricted period, please contact the research team member identified at the top of this document 
as soon as possible. 
If you are a sexually active person with a partner capable of becoming pregnant, it is important 
that your partner not become pregnant during the restricted period. There may be unknown risks 
to a fetus or risks we did not anticipate. You and your partner must agree to use birth control if 
you want to take part in this study. If you think your partner has become pregnant during the 
restricted period, please contact the research team member identified at the top of this document 
as soon as possible.  If you and your partner plan for your partner to become pregnant after the 
restricted period, please discuss this with the study team.
What are the risks of radiation from being in the study?
During your participation in this research study, you will be exposed to radiation from CT scans 
of the chest, abdomen and pelvis, 18F-FDG PET/CTs of the torso and the extremities, and CT-
guided biopsies (including screening and treatment). The amount of radiation exposure you will 
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receive from these procedures is equal to approximately 14.1 rem. A rem is a unit of absorbed 
radiation. Every day, people are exposed to low levels of radiation that come  from the sun and the 
environment around them. The average person in the United States receives a  radiation exposure 
of 0.3 rem per  year from these sources.  This type of radiation is called “background radiation.” 
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of  radiation is harmful to your 
body. The CT scans, 18F-FDG PET/CT, and CT-guided biopsies, that you get in this study will 
expose you to roughly the same amount of radiation as 35.7 years’ worth of background radiation. 
Being exposed to too much radiation can cause harmful side effects such as an increase in the risk 
of cancer.  The risk depends on how much radiation you are exposed to. Please be aware that  about 
40 out  of 100 people (40%) will get cancer during their lifetime, and 20 out of 100 (20%) will die 
from cancer. The risk of getting cancer from the radiation exposure in this  study is 1.1 out of 100 
(1.1%) and of getting a fatal cancer is 0.5 out of 100 (0.5%). 
You may not participate in this study if you are pregnant. If you are  able to become pregnant, we 
will perform a pregnancy test before exposing you to radiation. You must tell us if you may have 
become pregnant within the previous 14 days because the pregnancy test is unreliable during that 
time.
Psychological or Social Risks Associated with Loss of Privacy
As part of the research study, it is possible that you could learn that you have genetic risks for 
another disease or disability. This may be upsetting and, depending on what you learn, might create 
a need to make challenging decisions about how to respond. 
Although your genomic information is unique to you, you share some genomic similarities with 
your children, parents, brothers, sisters, and other blood relatives. Therefore, learning your 
research results could mean something about your family members and might cause you or your 
family distress. Before joining the study, it may be beneficial to talk with your family members 
about whether and how they want you to share your results with them. 
Privacy Risks Associated with Return of Incidental or Secondary Findings
As part of the research study, it is possible that you could learn that you have genetic risks for 
another disease or disability. This may be upsetting and, depending on what you learn, might create 
a need to make challenging decisions about how to respond. 
Although your genomic information is unique to you, you share some genomic similarities with 
your children, parents, brothers, sisters, and other blood relatives. Therefore, learning your 
research results could mean something about your family members and might cause you or your 
family distress. Before joining the study, it may be beneficial to talk with your family members 
about whether and how they want you to share your results with them. 
Protections against misuse of genetic information 
This study involves genetic testing on samples.  Some genetic information can help predict future 
health problems of you and your family and this information might be of interest to your employers 
or insurers. The Genetic Information Nondiscrimination Act (GINA) is a federal law that prohibits 
plans and health insurers from requesting genetic information or using genetic information. It also 
prohibits employment discrimination based on your health information. However, GINA does not 
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address discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. GINA also does not protect you against discrimination based on an already-diagnosed 
condition or disease that has a genetic component.
WHAT ARE THE BENEFITS OF BEING IN THE STUDY?
You might not benefit from being in this study. 
However, the potential benefit to you might be the shrinking of your tumor or lessening of your 
symptoms, such as pain, that are caused by the cancer.
Are there any potential benefits to others that might result from the study?
In the future, other people might benefit from this study because of the knowledge gained from 
the study drug combination or the results of the research studies. 
WHAT OTHER OPTIONS ARE THERE FOR YOU?
Before you decide whether or not to be in this study, we will discuss other options that are 
available to you. Instead of being in this study, you could:

choose to be treated with surgery, radiation or with drugs already approved by the FDA for 
your disease

choose to take part in a different study, if one is available

choose not to be treated for cancer but you may want to receive comfort care to relieve 
symptoms.
You should discuss with your doctor your other choices and their risks and benefits.
DISCUSSION OF FINDINGS
New information about the study
If we find out any new information that may affect your choice to participate in this study, we 
will get in touch with you to explain what we have learned. This may be information we have 
learned while doing this study here at the NIH or information we have learned from other 
scientists doing similar research in other places.
Return of research results
When we are examining your DNA, it is possible that we could identify possible changes in other 
parts of your DNA that are not related to this research. These are known as “incidental medical 
findings”. 
These include: 

Changes in genes that are related to diseases other than cancer 

Changes in genes that are not known to cause any disease. These are known as normal 
variations. 

Changes in genes that are new and of uncertain clinical importance. This means that we do 
not know if they could cause or contribute to a disease or if they are normal variations. 
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Since the analyses that we perform in our laboratory are not nearly as sensitive as the tests that are 
performed in a laboratory that is certified to perform genetic testing, the genetic changes that we 
find may or may not be valid.  Therefore, we do not plan to inform you of all of the genetic results 
of testing on your tissue and blood that is performed in our research lab. However, in the unlikely 
event that we discover a finding believed to be clinically important based on medical standards at 
the time we first analyze your results, we will contact you. This could be many years in the future. 
We will ask you to provide another sample to verify the findings we have seen in our lab. If the 
results are verified, you will be re-contacted and offered a referral to a genetic Healthcare Provider 
to discuss the results.
EARLY WITHDRAWAL FROM THE STUDY 
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if your disease worsens or comes back during treatment

if you have side effects from the treatment that your doctor thinks are too severe

if you become pregnant

if the study drugs may become unavailable

if new information shows that another treatment would be better for you

if you do not follow the study rules

if the study is stopped for any reason
In this case, you will be informed of the reason therapy is being stopped.  
After therapy is stopped we would like to see you for a safety visit 30 days after your last dose.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to the Gilead Sciences Inc., 
AbbVie, Inc., Genentech, Inc., or designated representatives.
STORAGE, SHARING AND FUTURE RESEARCH USING YOUR SPECIMENS AND 
DATA
Will your specimens or data be saved for use in other research studies?
As part of this study, we are obtaining specimens and data from you. We will remove all the 
identifiers, such as your name, date of birth, address, or medical record number and label your 
specimens and data with a code so that you cannot easily be identified. However, the code will 
be linked through a key to information that can identify you. We plan to store and use these 
specimens and data for studies other than the ones described in this consent form that are going 
on right now, as well as studies that may be conducted in the future. These studies may provide 
additional information that will be helpful in understanding lymphoma, or other diseases or 
conditions. This could include studies to develop other research tests, treatments, drugs, or 
devices, that may lead to the development of a commercial product by the NIH and/or its research 
or commercial partners. There are no plans to provide financial compensation to you if this 
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happens. Also, it is unlikely that we will learn anything from these studies that may directly 
benefit you.
I give permission for my coded specimens and data to be stored and used for future research as 
described above.
_____ Yes
_____ No
Initials
Initials
Will your specimens or data be shared for use in other research studies?
We may share your coded specimens and data with other researchers.  If we do, while we will 
maintain the code key, we will not share it, so the other researchers will not be able to identify 
you.  They may be doing research in areas that are similar to this study or in other unrelated 
areas. These researchers may be at NIH, other research centers and institutions, or commercial 
entities.
I give permission for my coded specimens and data to be shared with other researchers and used 
by these researchers for future research as described above.
_____ Yes 
_____ No
Initials
Initials
If you change your mind and do not want us to store and use your specimens and data for future 
research, you should contact the research team member identified at the top of this document. 
We will do our best to comply with your request but cannot guarantee that we will always be 
able to destroy your specimens and data. For example, if some research with your specimens and 
data has already been completed, the information from that research may still be used. Also, for 
example, if the specimens and data have been shared already with other researchers, it might not 
be possible to withdraw them. 
In addition to the planned use and sharing described above, we might remove all identifiers and 
codes from your specimens and data and use or share them with other researchers for future 
research at the NIH or other places.  When we or the other researchers access your anonymized 
data, there will be no way to link the specimens or data back to you.  We will not contact you to 
ask your permission or otherwise inform you before we do this.  We might do this even if you 
answered "no" to the above questions.  If we do this, we would not be able to remove your 
specimens or data to prevent their use in future research studies, even if you asked, because we 
will not be able to tell which are your specimens or data.
NIH policies require that your clinical and other study data be placed in an internal NIH database 
that is accessible to other NIH researchers for future research. Usually, these researchers will not 
have access to any of your identifiers, such as your name, date of birth, address, or medical 
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record number; and your data will be labeled with only a code. We cannot offer you a choice of 
whether your data to be placed in this database or not.  If you do not wish to have your data 
placed in this database, you should not enroll in this study.  
Will your genomic data be shared outside of this study? 
As part of this research study, we will put your genomic data in a large database for broad sharing 
with the research community. These databases are commonly called data repositories. The 
information in this database will include but is not limited to genetic information, race and 
ethnicity, and sex.  If your individual data are placed in one of these repositories, they will be 
labeled with a code and not with your name or other information that could be used to easily 
identify you, and only qualified researchers will be able to access them. These researchers must 
receive prior approval from individuals or committees with authority to determine whether these 
researchers can access the data.
Summary information about all of the participants included in this study (including you) is being 
placed in a database and will be available through open access. That means that researchers and 
non-researchers will be able to access summary information about all the participants included in 
the study, or summary information combined from multiple studies, without applying for 
permission. The risk of anyone identifying you with this information is very low.
in a repository for sharing. Therefore, we cannot offer you a choice of whether your data will be 
shared.  If you do not wish to have your data placed in a repository, you should not enroll in this 
study.  
How long will your specimens and data be stored by the NIH?
Your specimens and data may be stored by the NIH for as long as the study is open.  When this 
study is closed, we will keep the samples for future research indefinitely.
Risks of storage and sharing of specimens and data
When we store your specimens and data, we take precautions to protect your information from 
others that should not have access to it. When we share your specimens and data, we will do 
everything we can to protect your identity, for example, when appropriate, we remove information 
that can identify you. Even with the safeguards we put in place, we cannot guarantee that your 
identity will never become known or someone may gain unauthorized access to your information. 
New methods may be created in the future that could make it possible to re-identify your specimens 
and data.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
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Will you receive reimbursement or direct payment by NIH as part of your participation?
On this study, the NCI will cover the cost for some of your expenses.  Some of these costs may be 
paid directly by the NIH and some may be reimbursed after you have paid. The amount and form 
of these payments are determined by the NCI Travel and Lodging Reimbursement Policy.   You 
will be given a summary of the policy which provides more information.
If your travel to the NIH Clinical Center (e.g., flight, hotel) is arranged and paid for by the NIH, 
the agency making the reservations and their representatives will have access to your identifiable 
information.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. .  

If some tests and procedures are performed outside the NIH Clinical Center, 
you may have to pay for these costs if they are not covered by your insurance 
company.

Medicines that are not part of the study treatment will not be provided or paid 
for by the NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be 
provided by the NIH Clinical Center.
CONFLICT OF INTEREST (COI) 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for 
conflicts of interest.  This process is detailed in a COI Guide.  You may ask your research 
team for a copy of the COI Guide or for more information.  Members of the research team 
who do not work for NIH are expected to follow these guidelines or the guidelines of their 
home institution, but they do not need to report their personal finances to the NIH. 
The following pharmaceutical collaborators are providing the following drugs for this 
study to NIH without charge:

Gilead Sciences, Inc. is providing magrolimab 

AbbVie, Inc. manufactures venetoclax 

Genentech, Inc., is providing ventoclax and obinutuzumab
No NIH investigator involved in this study receives payments or other benefits from any 
company whose drug, product or device is being tested. However, there are some research 
partners not associated with the NIH working on this study who may receive payments or 
benefits, limited by the rules of their workplace. 
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
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CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Some of your health information, and/or information about your specimen, from this study will 
be kept in a central database for research. Your name or contact information will not be put in 
the database. Your test results will be identified by a unique code and the list that links the code 
to your name will be kept separate from your sample and health information. Your information 
may be given out if required by law. For example, certain states require doctors to report to health 
boards if they find a disease like tuberculosis. However, the researchers will do their best to 
make sure that any information that is released will not identify you.
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

Qualified representatives from Gilead Sciences, Inc., the pharmaceutical company who 
provides magrolimab.

Qualified representatives from AbbVie, Inc., the pharmaceutical company who produces 
venetoclax.

Qualified representatives from Genentech, Inc., the pharmaceutical company who provides 
venetoclax and obinutuzumab.
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons.
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.  However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections.  
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
IRB NUMBER: 20C0162
IRB EFFECTIVE DATE: 1/23/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 12/08/2023
Page 28 of 29
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
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3. is for other research;
4. is disclosed with your consent. 
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POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
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PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Mark 
Roschewski, M.D., Building 10, Room 4N115, Telephone:  240-760-6183. You may also call the 
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CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 20C0162
IRB EFFECTIVE DATE: 1/23/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 12/08/2023
Page 29 of 29
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
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Prot_SAP_000.pdf: 
Abbreviated Title:  VENOM in R/R B-Cell NHL 
Version Date: 12/18/2023
1
Abbreviated Title: VENOM in R/R B-Cell NHL 
NIH Protocol #: 20C0162
         Version Date:   12/18/2023
NCT Number: NCT04599634
A Phase 1 Study of Venetoclax with Obinutuzumab and Magrolimab (VENOM) in 
Relapsed and Refractory Indolent B-cell Malignancies
NCI Principal Investigator: Mark Roschewski, M.D.
Lymphoid Malignancies Branch (LYMB)
Center for Cancer Research (CCR)
National Cancer Institute (NCI)
Building 10, Room 4N115
National Institutes of Health
9000 Rockville Pike
Bethesda, MD  20892
Phone:  240-760-6183 
Email:  mark.roschewski@nih.gov
Drug Name:
Magrolimab 
Venetoclax (Venclexta)
Obinutuzumab (Gazyva®)
IND Number:
148205
Sponsor:
Center for Cancer Research
Manufacturer:
Gilead Sciences, 
Inc. 
AbbVie
Genentech
Supplier:
Gilead Sciences, 
Inc. 
Genentech
Genentech


Abbreviated Title:  VENOM in R/R B-Cell NHL 
Version Date: 12/18/2023
2
PRÉCIS
Background:

Indolent B-cell malignancies are associated with frequent disease relapse

Standard frontline therapy includes a monoclonal anti-CD20 antibody with or without 
chemotherapy; novel targeted therapies have changed the treatment landscape and are 
preferred therapy for some patients with high-risk molecular features

Targeted therapies given indefinitely add to drug resistance, treatment-emergent toxicities, 
and non-compliance

CD47 is a rational target for indolent B-cell malignancies; CD47 expression is higher in 
tumor cells than normal B-cells, and blocking CD47 results in phagocytosis of tumor cells

Magrolimab is an anti-CD47 monoclonal antibody with activity in refractory indolent 
lymphomas when combined with rituximab (a first generation anti-CD20 monoclonal 
antibody)

Obinutuzumab is a novel anti-CD20 monoclonal antibody with enhanced binding to the Fc 
receptor that may improve antibody-dependent cell-mediated cytotoxicity (ADCC), and 
phagocytosis, when combined with magrolimab

We aim to test the safety and efficacy of venetoclax when added to the backbone of 
magrolimab and obinutuzumab in patients with relapsed or refractory indolent B-cell 
malignancies

Treatment duration will be response-adapted and time-limited in all patients
Objective:

To determine the safety of the triplet combination of venetoclax, magrolimab and 
obinutuzumab in relapsed and refractory indolent B-cell malignancies 
Eligibility:

Follicular lymphoma (FL) (grades 1-2, or 3a), marginal zone lymphoma (MZL), mantle 
cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) with 2 prior therapies, 
with at least one of those therapies containing an anti-CD20 monoclonal antibody 

ECOG performance status 0-2

Adequate bone marrow and organ function
Design:

Phase 1 study with expansion cohorts of up to 76 patients with relapsed or refractory FL, 
MZL, MCL or CLL 

The safety profile of magrolimab, venetoclax, and obinutuzumab will first be determined 
in a dose-finding phase of up to 24 patients (6-12 patients with FL and 6-12 patients with 
MZL, MCL or CLL). Patients without dose-limiting toxicity (DLT) will receive an 
additional 5 cycles (total 6 cycles) of the triplet combination.

After dose-finding is completed, expansion cohorts of each histology will first receive 
magrolimab and obinutuzumab for 2 cycles in a window for translational research. After 
the window, venetoclax will be added and patients will receive 6 cycles (total 8 cycles) of 
the triplet combination.


Abbreviated Title:  VENOM in R/R B-Cell NHL 
Version Date: 12/18/2023
3

Patients who achieve a complete response (CR) (after a total of 6 cycles of the triplet 
combination) will stop treatment and initiate active monitoring with radiologic imaging 
and assays for circulating tumor DNA (ctDNA); if these patients relapse, they can be 
retreated with an 6 additional cycles. Patients who achieve partial response (PR) after 6 
cycles of the triplet will continue for an additional 6 cycles; then, will initiate active 
monitoring.


Abbreviated Title:  VENOM in R/R B-Cell NHL 
Version Date: 12/18/2023
4
TABLE OF CONTENTS
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................4
STATEMENT OF COMPLIANCE ................................................................................................7
1
INTRODUCTION ...................................................................................................................7
1.1
Study Objectives............................................................................................................7
1.2
Background and Rationale ............................................................................................8
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................31
2.1
Eligibility Criteria........................................................................................................31
2.2
Screening Evaluation...................................................................................................35
2.3
Participant Registration and Status Update Procedures ..............................................36
2.4
Baseline Evaluation.....................................................................................................38
3
STUDY IMPLEMENTATION .............................................................................................38
3.1
Study Design ...............................................................................................................38
3.2
Drug Administration....................................................................................................43
3.3
Dose Modifications .....................................................................................................49
3.4
Safety Management Guidelines for Other Common Toxicities..................................54
3.5
On Study Evaluations..................................................................................................57
3.6
Treatment Considerations/Exceptions.........................................................................57
3.7
Post-Treatment/Follow-Up Evaluations......................................................................58
3.8
Study Calendar ............................................................................................................59
3.9
Cost and Compensation...............................................................................................59
3.10
Criteria for Removal from Protocol Therapy and Off Study Criteria .........................59
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................60
4.1
Permitted Therapy .......................................................................................................60
4.2
Prohibited Food and Medications................................................................................64
5
CORRELATIVE STUDIES FOR RESARCH......................................................................65
5.1
BIOSPECIMEN COLLECTION ................................................................................65
5.2
Sample Collection and Processing ..............................................................................69
5.3
Biomarker and Research Methods ..............................................................................72
5.4
Sample Storage, Tracking and Disposition .................................................................74
5.5
Samples for Genetic/Genomic Analysis......................................................................76
6
DATA COLLECTION AND EVALUATION .....................................................................77


Abbreviated Title:  VENOM in R/R B-Cell NHL 
Version Date: 12/18/2023
5
6.1
Data Collection............................................................................................................77
6.2
Data Sharing Plans ......................................................................................................78
6.3
Response Criteria ........................................................................................................78
6.4
Toxicity Criteria ..........................................................................................................85
7
NIH REPORTING REQUIREMENTS / DATA SAFETY MONITORING PLAN ............85
7.1
Definitions...................................................................................................................85
7.2
OHSRP Office of Compliance and Training/IRB reporting .......................................85
7.3
NCI Clinical Director Reporting .................................................................................85
7.4
NIH Required Data and Safety Monitoring Plan ........................................................85
8
SPONSOR PROTOCOL/SAFETY REPORTING................................................................86
8.1
Definitions...................................................................................................................86
8.2
Assessment of Safety Events.......................................................................................88
8.3
Reporting of Serious Adverse Events .........................................................................88
8.4
Waiver of Expedited Reporting to CCR......................................................................89
8.5
Safety Reporting Criteria to the Pharmaceutical Collaborators ..................................89
8.6
Reporting Pregnancy ...................................................................................................89
8.7
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND ...............89
8.8
Sponsor Protocol Deviation Reporting........................................................................90
9
CLINICAL MONITORING..................................................................................................90
10
STATISTICAL CONSIDERATIONS ..................................................................................91
10.1
Statistical Hypothesis ..................................................................................................91
10.2
Sample Size Determination and Statistical Plan .........................................................91
10.3
Populations for Analyses.............................................................................................92
10.4
Statistical Analyses......................................................................................................93
11
COLLABORATIVE AGREEMENTS..................................................................................94
11.1
Clinical Trial Agreement (CTA) .................................................................................94
12
HUMAN SUBJECTS PROTECTIONS................................................................................94
12.1
Rationale For Patient Selection ...................................................................................94
12.2
Participation of Children .............................................................................................95
12.3
Risk/Benefit Assessment.............................................................................................95
12.4
Consent Process and Documentation ..........................................................................96
13
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................97
13.1
Study Discontinuation and Closure.............................................................................97


Abbreviated Title:  VENOM in R/R B-Cell NHL 
Version Date: 12/18/2023
6
13.2
Quality Assurance and Quality Control ......................................................................98
13.3
Conflict of Interest Policy ...........................................................................................98
13.4
Confidentiality and Privacy.........................................................................................98
14
PHARMACEUTICAL INFORMATION .............................................................................99
14.1
Magrolimab .................................................................................................................99
14.2
Venetoclax (VENCLEXTA®)...................................................................................100
14.3
Obinutuzumab ...........................................................................................................102
15
REFERENCES ....................................................................................................................103
16
APPENDICES .....................................................................................................................112
Appendix A:  Performance Status Criteria ..............................................................................112
Appendix B:  Guidelines for Pregnancy and Nursing .............................................................113
Appendix C:  Inhibitors and Inducers of CYP3A and P-gp ....................................................115
Appendix D:  Study Drug Diary (Optional) ............................................................................116
Appendix E:  Cairo-Bishop Definition for TLS ......................................................................118
Appendix F:  Magrolimab PK and ADA Sample Collection, Processing, and Shipping 
Instruction................................................................................................................................119
Appendix G:  Study Calendar..................................................................................................122
 


Abbreviated Title:  VENOM in R/R B-Cell NHL 
Version Date: 12/18/2023
7
STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective
To determine the safety of the triplet combination of magrolimab, venetoclax, and obinutuzumab 
in relapsed and refractory indolent B-cell malignancies
1.1.2
Secondary Objectives

To determine the best overall response rate (CR + PR) of triplet combination therapy with 
magrolimab, obinutuzumab, and venetoclax

To determine the rate of complete molecular remission (MRD negativity) by flow 
cytometry or similar assays as they become available in patients after triplet combination 
therapy with magrolimab, obinutuzumab, and venetoclax (in CLL patients only)

To determine the duration of response (DOR) of triplet combination therapy with 
magrolimab, obinutuzumab, and venetoclax

To estimate progression-free survival (PFS), event-free survival (EFS), and overall 
survival (OS) of triplet combination therapy with magrolimab, obinutuzumab, and 
venetoclax
1.1.3
Exploratory Objectives

To determine the best overall response rate (CR + PR) of 2 cycles of doublet combination 
therapy with magrolimab and obinutuzumab (‘Window Treatment’)

To determine the rate of complete molecular remission (MRD negativity) by circulating 
tumor DNA (ctDNA) assay or similar assays as they become available after doublet-
combination therapy with magrolimab and obinutuzumab and/or triplet combination 
therapy with magrolimab, obinutuzumab, and venetoclax

To identify a mutational or gene-expression signature that predicts response to magrolimab 
and obinutuzumab


Abbreviated Title:  VENOM in R/R B-Cell NHL 
Version Date: 12/18/2023
8

To identify a mutational or gene-expression signature associated with intrinsic resistance 
to magrolimab and obinutuzumab

To explore immunologic correlates of response and mechanisms of resistance to 
magrolimab and obinutuzumab

To determine if ctDNA assays identify molecular relapse prior to clinical progression

To test immunogenicity of magrolimab and to assess the effect of anti-drug antibodies 
(ADA) on the pharmacokinetics, pharmacodynamic markers, efficacy, and safety of 
magrolimab
1.2
BACKGROUND AND RATIONALE
1.2.1
Trial Design Summary
This study will evaluate the safety and efficacy of magrolimab added to venetoclax and 
obinutuzumab in patients with relapsed and/or refractory indolent B-cell malignancies.  The first 
portion of the study will determine the dose of venetoclax to be used during expansion.  The triplet 
combination will use a 5-week safety ramp-up of venetoclax in patients with mantle cell lymphoma 
(MCL), marginal zone lymphoma (MZL), and chronic lymphocytic leukemia (CLL).  Patients with 
follicular lymphoma (FL) will have venetoclax started at the target dose without a ramp-up. 
Patients without DLT in the dose-finding portion will be treated with an additional 5 cycles of 
triplet combination therapy.  
After the dose finding portion is complete and the dose of venetoclax is known, further expansion 
cohorts will test the efficacy of the triplet combination within individual histologies. In the 
expansion phase of the study, patients will first receive a “window” of two cycles of magrolimab 
and obinutuzumab in order to define the early indicators of efficacy of this combination in indolent 
B-cell malignancies.  The primary translational endpoints will occur during this window, including 
the molecular and immunologic correlates of response and mechanisms of resistance.  After the 
window, venetoclax will be added. Patients who achieve CR after 6 cycles of the triplet 
combination will stop therapy and initiate active surveillance with periodic standard imaging and 
research assays for ctDNA. Patients with PR after the initial 6 cycles of the triplet combination 
will continue for an additional 6 cycles before stopping therapy and initiating active surveillance. 
Patients who do not achieve at least PR after the initial 6 cycles of the triplet combination or those 
who discontinue treatment before 6 cycles will stop therapy and initiate active surveillance.  
1.2.2
Indolent B-cell Lymphomas: Follicular Lymphoma and Marginal Zone Lymphoma
Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL)(1), 
accounting for ~25% of cases with an estimated incidence of 74,680 new cases diagnosed in 2018.  
The clinical course of FL is highly variable; many patients have indolent disease that is slowly 
progressive and defined by a perpetually relapsing and remitting course, while other patients 
experience rapid growth of lymph nodes and aggressive clinical behavior that requires therapy 
shortly after diagnosis(2, 3). FL is generally not curable with standard frontline systemic 
chemotherapy, so most patients require multiple sequential treatment regimens throughout their 
disease course.  Further, a subset of FL patients who relapse within 2 years from frontline therapy 
have a poor overall prognosis with standard treatment.  A retrospective analysis of 588 patients 
with FL in the National LymphoCare database demonstrated that approximately 20% of patients 
experience progression of disease within 2 years of diagnosis (POD24) despite therapy with 
rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone with (R-CHOP)(4).  


Abbreviated Title:  VENOM in R/R B-Cell NHL 
Version Date: 12/18/2023
9
The patients with POD24 had significantly worse overall survival including a hazard ratio for early 
death of 7.17 (95% CI, 4.83 to 10.65) compared with the reference group. 5-year survival of 
patients with POD24 was ~50%, compared with a 5-year survival rate of 90% for the remaining 
patients(4).  Early disease progression after therapy was further validated as a surrogate marker of 
poor overall survival with a pooled analysis of 13 randomized studies in FL and >5,000 patients 
known as the Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) dataset(5). In the 
FLASH dataset, POD24 was confirmed to be associated with poor subsequent overall survival 
(OS) (hazard ratio (HR) = 5.24; (4.63 - 5.93); p < .01).  Current research focuses on understanding 
the molecular biology of FL patients with POD24 after standard frontline chemotherapy, so these 
patients can be prioritized for treatment with novel combinations designed to overcome intrinsic 
chemotherapy resistance(6).  FL patients who relapse beyond 2 years from initial chemotherapy 
may also benefit from novel combinations, particularly regimens that are not administered 
indefinitely.  In particular, patients who have become refractory to rituximab-based regimens have 
limited treatment options and should be considered for novel treatment combinations.  Most trials 
incorporating novel agents for FL have continued treatment until disease progression, death or 
unacceptable toxicity. Given that many FL patients have a long life expectancy, there is a need for 
time-limited treatment regimens that provide deep, durable responses, and avoid cumulative 
toxicities. 
Marginal zone lymphoma (MZL) is an indolent B-cell lymphoma that includes three (3) subtypes: 
nodal marginal zone lymphoma (NMZL), extranodal marginal zone lymphoma of mucosa-
associated lymphoid tissue (MALT), and splenic B-cell marginal zone lymphoma (SMZL).  
Together, these MZLs account for ~12% of cases of NHL(1).  The average age at diagnosis is 60 
years.  Marginal zone lymphomas arise from a post-germinal center marginal zone B cell and may 
present in the lymph nodes, spleen, or extranodal tissues.  The treatment approach to MZL is not 
standardized and ranges from watchful waiting, localized radiation, or systemic treatment with 
chemotherapy and/or anti-CD20 monoclonal antibodies(7, 8).  Similar to FL, MZL is generally 
incurable with standard frontline systemic chemotherapy, and patients often require multiple 
sequential treatments throughout their disease course.  Although many patients with MZL will 
have an indolent disease course, some cases of MZL are associated with resistance to 
chemotherapy and/or rituximab.  Patients with MZL with short remission durations and those who 
are refractory to rituximab should be prioritized for novel treatment combinations.  
Recently, the FDA granted accelerated approval for the use of ibrutinib monotherapy in patients 
with MZL who require systemic therapy and have received at least one prior anti-CD20-based 
therapy.  This approval was based on a phase 2 study of ibrutinib in 63 patients with 
relapsed/refractory MZL(9).  In this study, the overall response rate was 46% (95% CI: 33.4-59.1), 
but only 3% were complete responses.  Efficacy was observed across all three MZL types.  
However, the treatment with ibrutinib was administered indefinitely.  The treatment experience in 
CLL has demonstrated that many patients do not tolerate prolonged ibrutinib monotherapy, and 
treatment-emergent toxicities include hemorrhage, infections, cytopenias, and atrial 
fibrillation(10). 
Recommendations for clinical trial development in FL and related indolent B-cell lymphomas 
emphasize the importance of effective treatment combinations with a good safety profile able to 
provide durable clinical benefit for patients(11).  The ultimate therapeutic goal for indolent B-cell 
lymphomas is time-limited combination regimens of novel targeted agents that offer the potential 
for cure. 


Abbreviated Title:  VENOM in R/R B-Cell NHL 
Version Date: 12/18/2023
10
1.2.3
Indolent B-cell Leukemias:  Chronic Lymphocytic Leukemia and Mantle Cell 
Lymphoma
Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) (henceforth called 
CLL) and mantle cell lymphoma (MCL) are also incurable B-cell malignancies that are considered 
separately in this protocol because they are frequently associated with a leukemic component that 
manifests with high levels of circulating tumor cells.  These patients may be more susceptible to 
specific toxicities such as tumor lysis syndrome (TLS), and hence, will receive a lower target dose 
of venetoclax on this protocol. 
CLL is the most common B-cell malignancy in developed countries and is estimated to result in 
approximately 21,000 new cases in the United States in 2018.  Similar to the other B-cell 
malignancies included in this protocol, CLL predominantly affects older patients with a median 
age at diagnosis of 72 years(12).  Furthermore, treatment of CLL is generally not curative and 
patients with resistant disease or multiple disease relapses need novel combinations.  The 
combination of chemotherapy with anti-CD20 monoclonal antibodies has been the mainstay of 
therapy for decades, but most patients will not have durable remissions with this approach beyond 
3-4 years. Moreover, a subset of patients with CLL, such as those with TP53 aberration, either 
because of deletion of chromosome 17p or TP53 mutation, relapse very early after frontline 
chemoimmunotherapy(13).  Another important consideration is that the toxicity associated with 
chemotherapy can be challenging in patients over the age of 65 years.  For all of these reasons, the 
treatment landscape has changed dramatically over the last few years towards novel targeted small 
molecule inhibitors of BTK and Bcl-2(14).  One significant advantage of these small molecule 
inhibitors is their activity in patients with high-risk features such as a TP53 aberration(15, 16).  As 
single agents, however, these targeted therapies do not achieve deep remissions, are not curative, 
and must be taken indefinitely.  A recent 5-year follow-up study of ibrutinib monotherapy at the 
NIH in patients with both treatment-naïve and relapsed CLL demonstrated an overall 5-year PFS 
of 58.2% in patients with TP53 aberrations(17).  However, patients with relapsed/refractory CLL 
had a 5-year PFS of only 19.4% (95% CI, 6.3%-60%).  Venetoclax is a small molecule inhibitor 
of Bcl-2 that has also shown significant single agent activity in patients with relapsed CLL.  In a 
phase 1b study, the 15 month PFS of venetoclax in patients treated with the maximum dose was 
estimated at 69% and similar activity in patients with or without chromosome 17p deletions(18).  
Notably, venetoclax has demonstrated an overall response rate of 59% in patients who have 
progressed after ibrutinib(19). 
Although the treatment of CLL has been improved with the use of small molecule inhibitors, new 
challenges have arisen due to the extended durations of treatment which lead to long-term 
toxicities, noncompliance, and a significant financial burden.  A recent population-based study of 
616 patients who started on ibrutinib monotherapy for CLL showed that after only 17 months, an 
estimated 41% of patients had discontinued ibrutinib with a median time of only 7 months on 
treatment prior to discontinuation(10). The most common reason for discontinuation was 
intolerance rather than disease progression.  These data highlight the potential benefit of time-
limited treatment strategies with adequate safety profiles.  Another potential limitation of small 
molecule inhibitors as monotherapy is the infrequent achievement of complete response or 
achievement of minimal residual disease (MRD) negativity. For this reason, novel treatment 
combinations have been explored that are capable of clearing MRD.  A recent study of venetoclax-
rituximab in relapsed CLL demonstrated a superior PFS compared to bendamustine-rituximab and 
this benefit was observed across all clinical and biological subgroups(20).  The improved PFS was 


Abbreviated Title:  VENOM in R/R B-Cell NHL 
Version Date: 12/18/2023
11
due to the ability of venetoclax-rituximab to attain deep remissions since the landmark analysis at 
9 months showed 62.4% of patients were negative for MRD while only 13.3% of patients were 
MRD negative in the bendamustine-rituximab arm.  These data support the notion that novel 
combinations are more likely to achieve deep remissions that translate to durable clinical benefit.
Mantle cell lymphoma (MCL) is a distinct B-cell lymphoma that represents about 6% of all B-cell 
NHLs.  It is characterized by the t(11;14) translocation that results in aberrant expression of cyclin 
D1(21).  Despite this unifying genetic event, MCL is biologically and clinically heterogeneous.  A 
subset of patients with MCL have an indolent disease course and can safely have their initial 
therapy deferred without an impact on survival(22, 23).  In contrast, other patients with MCL will 
have rapid disease progression and relapse quickly after frontline therapy despite the use of highly 
intensive immunochemotherapy and consolidation with autologous stem cell transplant 
(ASCT)(24, 25).  Importantly, MCL is not curable with highly intensive chemotherapy and long-
term follow-up has demonstrated a continuous incidence of disease relapse(26).  MCL has worse 
prognosis than most indolent B-cell malignancies, partly because it occurs in older men.  The 
median age at diagnosis of MCL is ~65 years which limits the broad use of highly intensive 
therapies such as ASCT.  Hence, both those patients who have relapsed after intensive therapies 
as well as those who are not candidates for highly intensive treatments can potentially benefit from 
effective treatment combinations with a good safety profile.
Over the last decade, numerous targeted agents have been FDA-approved for use in patients with 
relapsed MCL including the proteasome inhibitor, bortezomib, the immunomodulatory agent, 
lenalidomide, and the inhibitors of Bruton’s tyrosine kinase (BTK), ibrutinib and acalabrutinib(27-
31).  The use of these novel targeted agents with anti-CD20 antibodies and chemotherapy has led 
to improvements in overall survival for all ages of MCL patients according to a recent analysis of 
the SEER database(32).  One particularly challenging clinical problem, however, is that patients 
who progress after ibrutinib often have a very aggressive disease course associated with poor 
outcomes.  In an international, multicenter, retrospective cohort study involving 114 patients with 
a median of 3 prior treatments, the median OS following cessation of ibrutinib was 2.9 months 
(95% CI 1.6-4.9 months)(33).  Patients with ibrutinib resistance or intolerance do not have good 
treatment choices and represent a population that needs effective novel combinations with an 
acceptable safety profile. 
1.2.4
Magrolimab 
1.2.4.1
Background and Pre-Clinical Studies 
Magrolimab is a monoclonal antibody that targets CD47 and is being developed in combination 
with rituximab for the treatment of both indolent and aggressive B-cell malignancies(34).  CD47 
was discovered by Stanford researchers to play a key role in the ability of cancer cells to evade 
phagocytosis by the innate immune system(35).  Cancer cells are able to overcome intrinsic 
phagocytic (“eat me”) signals via the binding of CD47 to its ligand, signal regulatory protein alpha 
(SIRP), that is expressed on phagocytic cells, including macrophages, monocytes, and dendritic 
cells (Figure 1).  The binding of SIRP on phagocytic cells to CD47 on lymphoma cells initiates 
recruitment of the src homology-2 domain containing protein tyrosine phosphatases SHP-1 and 
SHP-2 resulting in inhibition of phagocytosis.  CD47 expression is higher in tumor cells than in 
normal peripheral blood and germinal center B cells across a variety of B-cell NHL subtypes 
including FL, CLL, and MCL, and is associated with a worse clinical prognosis(36).  Blocking of 
the SIRP-CD47 pathway (“don’t eat me” signal) with magrolimab leads to phagocytosis of the 


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lymphoma cell.  As tested in Raji cell lines, there was a positive correlation between CD47 
expression and degree of anti-CD47 antibody-mediated phagocytosis with both mouse and human 
macrophage effector cells.  Beyond the postulated effect on the innate immune system, 
magrolimab may also activate the adaptive immune system against the tumor.  Phagocytosis of 
tumor cells by macrophages leads to cross-presentation of tumor antigens, and xenograft models 
have shown that blocking anti-CD47 primed CD8+ T-cells for cytotoxic effects producing 
sustained responses(37).  Through these immunologic mechanisms, blocking CD47 with 
magrolimab is a promising immune checkpoint inhibitor therapy across a variety of 
malignancies(38, 39).
Figure 1:  CD47 antibody (yellow) binds to its antigen on the cancer cell, preventing its 
interaction with SIRP (“don’t eat me signal”) leading to phagocytosis of the cancer cell 
mediated through the intrinsic phagocytic (“eat me”) signals. 
In a pre-clinical study using cell lines, blocking anti-CD47 resulted in phagocytosis of tumor cells 
without an effect on normal peripheral blood cells(36).  The selective targeting of tumor cells 
compared to normal cells was postulated to be due to the presence of pro-phagocytic (“eat me”) 
signals that are not found on normal cell counterparts.  One exception to this selectivity is aging 
red blood cells (RBCs) since CD47 expression protects them from elimination.  As RBCs age, 
they accumulate prophagocytic changes in their cell membrane, which ultimately renders them 
susceptible to CD47 blockade. Thus, depletion of older CD47+ RBCs is an expected on-target 
clinical effect of magrolimab.
Magrolimab binding to RBCs may cause interference with cross-matching of units for 
transfusion.  This observation is supported by multiple lines of data.  First, pre-clinical and clinical 
studies have shown that the initial magrolimab priming dose leads to a pruning or cleaving of 
CD47 antigen off from RBCs, in which the remaining RBCs are found to be CD47 negative.(40) 
Given that RBCs are negative for CD47 after the initial magrolimab priming dose, RBC 
transfusion interference as well as on target RBC effects caused by magrolimab are significantly 
mitigated.  Second, while crossmatch interference is occasionally observed with magrolimab, 
these events are less frequently observed after the initial several doses of magrolimab.  Third, 


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patients have been able to successfully be typed and crossmatched and have had no significant 
adverse safety findings during RBC transfusions while on magrolimab therapy. 
In-vitro phagocytosis assays have demonstrated a synergistic action between magrolimab and 
rituximab – a monoclonal anti-CD20 antibody(36). In primary NHL cells incubated with either 
anti-CD47 antibody or rituximab alone, or both in combination at half of the single agent dose, 
NHL cells exhibited a significant increase in phagocytosis when incubated with the combination 
compared to either antibody alone. No phagocytosis of normal peripheral blood cells was 
observed.  When a similar experiment was performed in NSG mice deficient in T, B and NK cells, 
combination therapy eliminated disseminated lymphoma (Raji cells) in 60% of mice and localized 
lymphoma (Raji cells) in 86% of mice treated with combination treatment.  All showed no 
evidence of tumor growth, remained relapsed free, and were alive at over 197 days after tumor 
engraftment.  This is in comparison with mice treated with anti-CD47 antibody alone, which 
demonstrated a decrease in the rate of lymphoma growth but eventually had to be sacrificed due 
to enlarging tumors.
1.2.4.2
Magrolimab Clinical Efficacy 
Our NCI lymphoma team has been participating in a multicenter phase 1b/2 study of magrolimab 
with rituximab in relapsed and refractory FL, MZL and diffuse large B-cell lymphoma (DLBCL) 
(NCT02953509).   The interim results of the phase 1 component were published, and the updated 
results of phase 1b and phase 2 components were recently presented(41, 42).  A total of 35 patients 
with relapsed or refractory FL (with 3 median prior therapies and 85% refractory to prior 
obinutuzumab-containing regimen) have been treated on this study. Results of all patients with 
indolent lymphomas (28 FL and 1 MZL evaluable patients) were presented together – ORR was 
66% and CR rate was 24% as of February 2019. Survival data has been reported for Phase 1b FL 
patients (N=7). With median follow up of 18 months, the median duration of response had not 
been reached (range: 6.2 – 22.6+ months), including some durable CRs for > 20 months. Based on 
these results, magrolimab has achieved "Fast Track Designation" designation by the FDA for FL. 
These early clinical results of magrolimab with rituximab demonstrate a potentially highly 
effective immunotherapy for FL with a safety profile that is tolerable across all age groups.  The 
achievement of CR with a novel immunotherapy platform is a promising sign that this could serve 
as the therapeutic backbone for a potentially curative regimen.  
Further development of magrolimab-based combinations is justified, but important clinical and 
translational questions remain.  First, use of magrolimab combinations should be broadened to 
related indolent B-cell malignancies included on this protocol: CLL, MCL, and MZL.  In order to 
fully maximize the potential of this therapy, a nuanced understanding of the molecular and 
immunologic correlates of clinical response is critical.  Equally important will be the identification 
of potential immune subsets that confer resistance to magrolimab-based therapy.  Lastly, the 
favorable safety profile of magrolimab allows for the addition of other active agents such as 
venetoclax with non-overlapping toxicities in indolent B-cell malignancies.  
1.2.4.3
Pharmacokinetics (PK) and toxicokinetics (TK)
1.2.4.3.1 Pharmacokinetics and product metabolism in humans
Data from a first-in-human Phase I study in 58 patients with advanced solid tumors and lymphomas 
was presented as a poster in ASCO 2018 (NCT02216409)(43). Multiple intravenous (IV) doses in 
the range 0.1 – 30 mg/kg were given at once or twice weekly frequencies. The PK parameters were 


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consistent with the presence of a CD47 antigen sink (receptor binding in the blood cells and normal 
tissues), which was saturated at doses ≥ 10 mg/kg. Above this dose level, increases in Cmax and 
AUC were dose proportional and the half-life of the antibody was ~14 days – typical of human 
IgG4. Similar parameters were observed in another ongoing study of magrolimab monotherapy or 
in combination with azacytidine in patients with hematological malignancies (NCT03248479). 
Simulations with the model from the solid tumor study predicted that a maintenance dosing 
regimen of 30 mg/kg every other week from cycle 2 onwards would result in serum concentrations 
≥200 µg/mL, a level where full CD47 receptor occupancy on blood cells was observed in this 
study and where preclinical efficacy has also been previously reported. Based on these PK results, 
every other week dosing of 30 mg/kg will provide adequate drug exposure for maintenance(44). 
1.2.4.4
Toxicity
Safety data in relapsed and refractory NHL is available from an ongoing Phase 1b/2 study of 
magrolimab and rituximab (NCT02953509). Toxicity data for 22 patients were published(41); and 
updated safety data in 115 patients were recently presented at European Hematology Association 
(EHA) annual meeting (Figure 2)(42). Overall, the treatment has been well-tolerated.  
Figure 2: Treatment-related adverse events >10% for patients treated with magrolimab
In the phase 1b portion of the study, no maximum tolerated dose was reached. Three (3) DLTs 
were observed across 10, 20 and 30 mg/kg dose levels – neutropenia (1), immune 
thrombocytopenic purpura (1), and pulmonary embolism (1).  The pulmonary embolism occurred 
after infusion of rituximab and during infusion of magrolimab on treatment Day 8.  The patient 
was found to have a deep venous thrombosis (DVT) in a lower extremity in the setting of 
lymphoma disease at this site.  No evidence of hemagglutination was observed. The patient was 
restarted on treatment with a 50% dose reduction in magrolimab and did not experience further 
thrombotic events. 
Across 115 patients on the study, magrolimab was well-tolerated with the most common treatment-
related AEs were infusion-related reactions, headache, anemia, and nausea. Drug-related toxicities 
occur mostly during the first infusion, with anemia improving despite repeated infusions. 


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Pharmacokinetic and pharmacodynamic studies show that a priming dose of 1mg/kg is effective 
at preventing on target anemia and limits the effect of hemolysis during the first cycle of infusion.  
Reduction in hemoglobin levels observed was mild (average hemoglobin drop 0.8 g/dL), transient 
and reversible despite continuation of therapy at higher doses (30 or 45 mg/kg). The incidence of 
other G3 toxicities was 7%.  Treatment discontinuation due to AE occurred in only 8/115 (7%) 
of patients.  No autoimmune toxicities were observed. 
1.2.5
Venetoclax
1.2.5.1
Background and Clinical Studies
The Bcl-2 family of proteins are key regulatory mediators of the intrinsic mitochondrial apoptotic 
pathway.  The specific protein, Bcl-2, is an antiapoptotic protein that promotes cell survival.  The 
B-cell malignancies included on this protocol frequently overexpress Bcl-2 through a variety of 
mechanisms including a translocation involving BCL2 to the immunoglobulin heavy chain 
promoter [t(14;18)], chromosome 18q21 amplification, and from loss of the endogenous 
microRNAs, miR-15 and miR-16, that act as negative regulators of Bcl-2(45-48).  Overexpression 
of Bcl-2 has been demonstrated in all of the included indolent B-cell malignancies and has been 
implicated as a resistance factor for certain therapeutic agents(49). 
Venetoclax is a selective, orally bioavailable, small-molecule Bcl-2 family protein inhibitor 
being developed by AbbVie and Roche/Genentech(50). Venetoclax helps restore the process of 
apoptosis in NHL cells by binding directly to the Bcl-2 protein, displacing pro-apoptotic proteins 
like BIM, and triggering mitochondrial outer membrane permeabilization and the activation of 
caspases resulting in apoptosis via intrinsic pathway, without measurable binding to other Bcl-2 
proteins, such as MCL-1.  As monotherapy, venetoclax has demonstrated clinical activity in all 
of the indolent B-cell malignancies included on this protocol(18, 51).  In a phase I dose-
escalation study of venetoclax in relapsed/refractory CLL, 116 patients (56 in dose-escalation 
and 60 in safety expansion cohort) were treated. Patients received a median of 3 prior therapies, 
including 86% patients who received previous therapy with fludarabine.  92/116 (79%) patients 
had an objective response including a 20% complete response rate (5% without MRD on flow 
cytometry)(18).   Responses occurred at every dose level, the toxicity profile was manageable 
and a maximum tolerated dose (MTD) was not identified.  The most notable adverse events 
included upper respiratory tract infection (48%), nausea (47%), and grade 3 or 4 neutropenia 
(41%).  An important toxicity associated with venetoclax was TLS which occurred in 10/56 
(18%) patients in dose-escalation cohort.  The first three patients had laboratory evidence of TLS 
that necessitated an extended intrapatient ramp-up schedule to mitigate the risk of TLS. TLS, 
either laboratory (7/56) or clinical (3/56), occurred either after the administration of the first dose 
or immediately after ramping-up of the dose.  Of the 3 patients with clinical tumor lysis 
syndrome, 2 had severe sequelae: acute renal failure requiring dialysis and hospitalization in one 
patient and sudden death in another patient. The third patient had a transient elevation in serum 
creatinine, which resolved within 2 days. After resolution of the tumor lysis syndrome, 9 of 10 
patients resumed taking venetoclax. Of these patients, 8 had no recurrence of TLS at subsequent 
doses. Additional toxic effects reported in all 116 patients are reported in Table 1 below.


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Table 1: Adverse events in >20% patients or any grade 3/4 adverse events in 116 CLL 
patients receiving venetoclax monotherapy(18)
Event
Any Grade
N (%)
Grade 3 or 4
N (%)
Adverse event
Diarrhea
60 (52)
2 (2)
Upper respiratory tract infection
56 (48)
1 (1)
Nausea
55 (47)
2 (2)
Neutropenia
52 (45)
48 (41)
Fatigue 
46 (40)
4 (3)
Anemia
29 (25)
14 (12)
Thrombocytopenia
24 (21)
14 (12)
Serious adverse events
Any                                                52 (45)
Febrile neutropenia                        7 (6)
Pneumonia                                     5 (4)
Upper respiratory tract infection   4 (3)
Immune thrombocytopenia           3 (3)
TLS                                               3 (3)
Diarrhea                                        2 (2)
Fluid overload                               2 (2)
Hyperglycemia                              2 (2)
Prostate cancer                              2 (2)
Pyrexia                                          2 (2)
Venetoclax monotherapy has also been studied in patients with relapsed or refractory MCL, FL, 
and MZL. In a phase 1 study, 106 patients with relapsed and refractory NHL were treated with 
escalating doses of venetoclax(51). The study population included 28 MCL, 29 FL and 3 MZL 
patients.  Risk of TLS was managed mostly as outpatients with hydration, allopurinol and 
occasional rasburicase. All patients were given escalating doses of venetoclax in a ramp-up fashion 
to minimize the risk of TLS.  Laboratory monitoring of TLS was performed at 8 and 24 hours on 
day 1 and higher doses were administered with no evidence of TLS.  Doses were further escalated 
once per week until target dosing was attained. 
No MTD of venetoclax was defined and the mean duration of treatment was 5.3 months (range, 
0.2-46).  Two DLTs occurred, both in the 600-mg dose-escalation cohort: one grade 4 neutropenia 
and one grade 3 febrile neutropenia that both resolved after dose delay and growth factor support. 
Grade 3 and 4 adverse events occurred in 59 (56%) patients and across all doses of venetoclax. 
Most common grade 3/4 AEs were anemia (15%), neutropenia (11%), fatigue (7%), and diarrhea 
(3%). No cumulative toxicity was apparent with prolonged dosing. Fifteen patients required dose 
reductions, including nine of the 51 patients treated at 1,200 mg dose (five for nausea, four for 
diarrhea); clinical TLS was not observed. Three patients with bulky disease (maximal lymph node 
diameter > 10 cm) had laboratory changes meeting Cairo-Bishop criteria for laboratory TLS within 


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24 hours of initial dosing. All three patients received TLS treatment and continued venetoclax as 
scheduled without dose interruption. 
ORR of 44% was observed with responses in all subgroups with 21/28 (75%) MCL, 11/29 (38%) 
FL and 2/3 (66.7%) MZL patients having an overall response. Complete responses were achieved 
in 6/28 (21%) MCL, 4/29 (14%) FL and 0/3 (0%) MZL patients.  Patients with MCL or FL who 
achieved CRs had more durable responses than those who achieved PRs as best response. For 
MCL, responses were seen even at doses ≤800 mg (ORR, 76%, including CR rate of 24%) and not 
at a higher rate at doses higher than this. In FL, objective responses were more frequent at doses 
higher than 600 mg. A summary of adverse events in ≥20% patients is presented in Table 2.
Table 2: Adverse events reported in 106 NHL patients treated with venetoclax
Adverse Event
Any Grade
N (%)
Grade 3/4
N (%)
Any event
103 (97)
59 (56)
Nausea
51 (48)
0 (0)
Diarrhea
48 (45)
3 (3)
Fatigue
44 (42)
7 (7)
Decreased appetite
23 (22)
1 (1)
Vomiting
23 (22)
0 (0)
Constipation
22 (21)
2 (2)
Serious adverse events
Any                      
27 (25)
Hyponatremia
               3 (3)
Inﬂuenza
               3 (3)
Lower RTI
               3 (3)
Dehydration
               2 (2)
Diarrhea                              2 (2)
Febrile neutropenia
 2 (2)
Hypotension
               2 (2)
Pleural effusion
               2 (2)
Viral infection
               2 (2)
Viral RTI
               2 (2)
 
Venetoclax has also been studied in combination with an anti-CD20 agent, rituximab, in recurrent 
FL.  In a phase II study of 164 patients, this combination was safely administered at a target dose 
of 800 mg with most common grade 3-4 toxicities being hematologic with 27% neutropenia and 
8% thrombocytopenia, and only 1 patient experiencing grade 3 tumor lysis syndrome. Further, 17 
(33%) patients achieved an overall response, with 14 % CR.(52) 
1.2.5.2
Venetoclax Approvals
Venetoclax is currently approved for the treatment of adult patients with relapsed/refractory (R/R) 
CLL either as monotherapy or in combination with rituximab. In 2019, venetoclax was also 
approved by the FDA for the treatment of previously untreated CLL or SLL patients in 
combination with obinutuzumab. In addition, it is approved in combination with azacytidine or 


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decitabine or low-dose cytarabine (LDAC) for the treatment of newly diagnosed AML in adults 
who are age 75 years or older, or who have comorbidities that preclude use of intensive induction 
chemotherapy.  
A summary of Serious Adverse Drug Reactions (ADRs) Considered Expected in Adult Subjects 
for Safety Reporting Purposes for Venetoclax (Safety Analysis Set – Adult Subjects [≥ 18 Years 
of Age]) is presented in Table 3.
Table 3: Serious Adverse Reactions From Multiple Clinical Trials
All SARs
N = 4858
ADVERSE REACTIONS
n (%)
Fatal
Life Threatening
Blood and lymphatic system disorders
Anaemia
46 (0.95%)
NA
NA
Febrile neutropenia
354 (7.29%)
NA
NA
Neutropenia
68 (1.40%)
NA
NA
Infections and infestations
Bacteraemia
14 (0.29%)
NA
NA
Pneumonia
187 (3.85%)
NA
NA
Sepsis
46 (0.95%)
Septic shock
10 (0.21%)
Upper respiratory tract infection
21 (0.43%) 
NA
NA
Urinary tract infection
12 (0.25%)
NA
NA
Investigations
Blood potassium increased
8 (0.16%)
NA
NA
Neutrophil count decreased
6 (0.12%)
NA
NA
Metabolism and nutrition disorders 
Hyperkalaemia
15 (0.31%)
NA
NA
Hyperphosphataemia
20 (0.41%)
NA
NA
Tumor lysis syndrome
42 (0.86%)
NA
NA
1.2.6
Obinutuzumab
CD20 receptor is universally expressed by normal B cells in all stages of development, from the 
pre-B cell up to the mature plasma cell. It is also widely expressed on cell surface by most B-cell 
malignancies(53). Rituximab is a type I CD20 mAb which was first approved by the FDA in 1997 
for the treatment of relapsed and refractory non-Hodgkin lymphoma(54). It has now demonstrated 
impressive clinical activity across the majority of B-cell neoplasms and is routinely used in all 
phases of NHL treatment, including first-line therapy, maintenance, and salvage therapy. 
However, the effectiveness of rituximab is ultimately limited in part by the development of 
treatment resistance. Obinutuzumab is a novel type II, humanized, CD20 monoclonal Ab (mAb) 
that was developed in an attempt to overcome several postulated mechanisms of rituximab-
resistance. Obinutuzumab has been glycoengineered to reduce core fucosylation, conferring 
enhanced affinity for the human FcGamma receptor 3A (FCGRIIIa) on effector cells and, hence, 
enhanced antibody-dependent cell-mediated cytotoxicity (ADCC)(55, 56). Compared to type I 
mAbs (i.e., rituximab and ofatumumab), obinutuzumab has lower capacity to relocalize CD20 into 


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lipid rafts upon binding compared with type I antibodies and is a less potent in inducing 
complement-dependent cytotoxicity (CDC), but more potent in mediating homotypic cell adhesion 
and direct cell death (DCD), primarily by caspase-independent mechanisms(57). Enhancing DCD 
by mechanisms independent of caspase activation was thought to be desirable, as certain B-cell 
malignancies upregulate anti-apoptotic proteins that inhibit caspase-dependent suicidal 
pathway(54).
1.2.6.1
Summary of Pharmacokinetics and Product Metabolism in Humans
The clinical pharmacology properties of obinutuzumab have been characterized in a number of 
clinical studies, in patients with CLL and indolent NHL, including FL and non-FL, and aggressive 
NHL (DLBCL). 
Important observations in both NHL and CLL patients were as follows:

Increased doses of obinutuzumab led to increases in serum obinutuzumab concentrations, 
Cmax and AUC parameters for 50-200 mg doses of obinutuzumab were less than dose 
proportional. 

For 400-2000 mg doses of obinutuzumab, there was a trend towards dose proportionality. 
However, due to low patient numbers and disease heterogeneity no meaningful conclusions 
could be made regarding dose proportionality.

At low doses of obinutuzumab (50-200 mg), administered once every three weeks over 8 
cycles, little or no accumulation in serum concentrations (Cmax and Ctrough) or exposure 
were observed over the treatment cycles. Therefore, Cmax and Ctrough values were similar 
in Cycle 8 to Cycle 1. In contrast, when doses of 400-2000 mg were administered there 
were increases in serum concentration (Cmax and Ctrough) and exposure over the 
treatment cycles such that Cycle 8 values were higher than Cycle 1 values(58).

In order to provide a robust description of the PK of obinutuzumab, pooled PK data from 
1454 patients (343 CLL, 961 iNHL [814 with FL and 119 with MZL], 130 DLBCL and 20 
MCL) were analyzed together. The differences in steady-state exposure due to differences 
in body weight and gender were limited (<30%) and therefore do not warrant any dose 
adjustment for the recommended dose and regimen for obinutuzumab of 1000 mg based 
on body weight and gender. Please refer to investigator’s brochure for more details. 

Regimens with different loading and maintenance doses (from 50*2000 mg) have been 
compared to fixed-dose regimen using 1000 mg (D1, D8 and D15, C1; D1, C2 
onwards)(58). Fixed dose 1000 mg regimen resulted in similar serum concentrations to 
loading dose of 1600 mg on D1, D8 and D15 of C1 followed by maintenance 800 mg 
(1600/800 regimen) on D1, C2 onwards. 
1.2.6.2
Clinical Safety and Toxicity
Safety data is available for obinutuzumab as monotherapy in CLL and indolent NHLs; and in 
combination with venetoclax in CLL. Overall the safety profile across indications is similar with 
the following exceptions:

A higher incidence of Grade 3-5 infections was observed in patients with indolent NHL, 
particularly MZL 

A higher incidence of infusion-related reactions was observed in CLL 


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
A higher incidence of TLS was observed in CLL 
1.2.6.2.1 Monotherapy Studies
1.2.6.2.1.1 Obinutuzumab monotherapy in relapsed/refractory CLL 
The safety of obinutuzumab monotherapy has been established in patients with relapsed and 
refractory CLL.  In a phase 1-2 study of 33 patients with relapsed and refractory CLL, 13 patients 
received obinutuzumab 400 to 1200 mg (days 1 and 8 of cycle 1; day 1 of cycles 2-8) during the 
phase 1 part, and 20 patients received a fixed dose of 1000 mg (days 1, 8, and 15 of cycle 1; day 1 
of cycles 2-8) during the phase 2 expansion(59).  During phase 1, all patients experienced infusion-
related reactions (IRRs) and 10/13 (77%) patients experienced  grade 3 AEs.  Seven (54%) 
patients had at least 1 episode of grade  3 neutropenia with a median duration of 10 days (range, 
7-62 days).  No patient required dose reduction, no toxicities led to withdrawal, and no deaths.  In 
phase 2, IRRs were reported in 19/20 (95%) patients and   grade 3 neutropenia was reported in 
4/20 (20%) patients.  
Table 4: Summary of AEs occurring in ≥10%, and grade 3/4 AEs in CLL patients receiving 
obinutuzumab monotherapy(59, 60)
Salles, et al
Phase 1
(N=13)
Salles, et al
Phase 2
(N=20)
Leblond, et al 
(N=126)
All grades
13 (100)
20 (100)
123 (97.6)
IRR
13 (100)
19 (95)
Not reported
Neutropenia
7 (54)
4 (20)
50 (39.7)
Thrombocytopenia
4 (31)
3 (15)
28 (22.2)
Pyrexia 
3 (23)
4 (20)
29 (23)
Anemia
1 (8)
5 (25)
20 (15.9)
Febrile neutropenia
1 (8)
2 (10)
8 (6.3)
Grade 3 or higher AEs
8 (62)
13 (65)
95 (75.4)
IRR
2 (15)
5 (25)
31 (24.6)
Neutropenia
7 (54)
4 (20)
42 (33.3)
Febrile neutropenia 
1(8)
1(5)
8 (6.3)
Thrombocytopenia 
2 (15)
3 (15)
15 (11.9)
Anemia
0 (0)
2 (10)
7 (5.6)
1.2.6.2.1.2 Obinutuzumab monotherapy in indolent NHL 
Safety data will be discussed from two phase 2 studies in relapsed/refractory indolent NHL. In the 
phase 2 part of a Phase 1/2 study, indolent NHL patients (34 FL, 3 MZL, 2 LPL, 1 Waldenstrom’s 
macroglobulinemia) were randomly assigned 1:1 to receive eight cycles of obinutuzumab as a flat 
dose of 400/400 mg or 1,600/800 mg. Obinutuzumab was given on days 1 and 8 of cycle 1, and 
day 1 of subsequent cycles (every 21 days) for a total of nine infusions(61). The most common 
AEs were IRRs, which were experienced by 13 /18 (72% ) of patients in the 400/400-mg arm and 
16/22 (73% ) in the 1,600/800-mg arm.  The majority of IRRs were grade 1 or 2 and were 
associated with the first infusion.  Only 2 patients experienced grade 3 or 4 IRRs, both in the 


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1,600/800mg arm.  No IRRs were considered SAEs, and no patient withdrew.  Other grade 3 to 4 
AEs occurring in more than one patient were infection (1 in the 400/400-mg arm, grade 4; 1 
infection in three patients in the 1,600/800-mg arm, all grade 3), lymphopenia (1 in the 400/400-
mg arm; 2 in the 1,600/800-mg arm), and neutropenia (3 in the 1,600/800-mg arm).  Twelve SAEs 
occurred during treatment: three (17%) in the 400/400-mg arm and six (27%) in the 1,600/ 800-
mg arm. 
In another phase 2 study, FL patients received obinutuzumab – four (4) once-per-week IV 
infusions of 1000 mg during cycle 1, followed by once every 2 months for up to 2 years. Safety 
analysis included 87 patients (Table 5)(62).  Sixty-four (74%) patients experienced IRR with 10 
(11%) grade 3 or 4 events.  Twelve (14%) SAEs were reported, and treatment was discontinued 
because of AEs in 8% of patients in the obinutuzumab group. 
Table 5: Summary of AEs Occurring in ≥10%, and Grade 3/4 AEs in Indolent NHL 
Patients Receiving Obinutuzumab Monotherapy 
 
Salles, et al
400/400 mg Cohort
(N=18)
Salles, et al 
1600/800 mg   Cohort
(N=22)
Sehn, et al
1000 mg
(N=87)
IRR
13 (72)
16 (72)
64 (74)
Neutropenia
0 (0)
3 (14)
3 (3)
Infection
6 (33)
11 (50)
--
Pyrexia 
1 (6)
3 (14)
6 (7)
Fatigue
5 (28)
8 (36)
23 (26)
≥ grade 3 AEs
4 (22)
9 (41)
IRR
0 (0)
2 (9)
10 (11)
Neutropenia
0 (0)
3 (14)
3 (3)
Febrile neutropenia 
0 90)
1 (5)
0 (0)
Thrombocytopenia 
0 (0)
1 (5)
0 (0)
Recent data suggests that patients with MZL may be more susceptible to infections from 
obinutuzumab combinations than combinations including rituximab(63).  In a recent Phase 3 
study, obinutuzumab was evaluated in combination with CHOP (cyclophosphamide, 
doxorubicin, vincristine, and prednisone); bendamustine; or cyclophosphamide (C), vincristine 
(V), and prednisone (P) in patients with previously untreated advanced FL and chemo-naïve 
advanced MZL.(64) The MZL cohort included a higher percentage of patients in the G-chemo 
arm, compared with the R-chemo arm who experienced fatal AEs, Grade 3-5 AEs, SAEs and 
AEs leading to dose interruption and that the higher rate was due to a higher incidence of AEs 
with fatal outcome in the G-chemo MZL population (11.9%, compared with 4.0% for the FL 
population). The higher number of AEs primarily reflected significantly higher rate of infections.  
It is currently unknown if obinutuzumab is associated with a higher rate of infections, including 
opportunistic infections, in chemotherapy-free combinations.  However, to maximize safety 
monitoring, all MZL patients will receive prophylaxis to prevent pneumocystis jiroveci 
pneumonia and will include early stopping rules for this cohort (see Section 10.4). 


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1.2.6.3
Clinical Efficacy of Obinutuzumab
A Phase 1 study of obinutuzumab in dose-escalating fashion (range 50/100-1200/2000 mg) in 
patients with relapsed/refractory NHL demonstrated an ORR of 43%.  Lymphoma subtypes were 
FL (n = 13), MCL (n = 4), and SLL/CLL (n = 1).  No DLTs were observed.  Responses were 
observed in patients who  underwent prior ASCT and also in patients who were rituximab 
refractory(65).  Another phase 1 study testing obinutuzumab induction and maintenance in 
relapsed/refractory NHL showed similar results (23% ORR at the end of induction and 32% ORR 
at during maintenance therapy including 1 CR) in this group of heavily pretreated patients(66).  
Phase II enrolled 40 patients, including 34 FL patients and 1 MZL. Median number of prior 
therapies was 3 and 55% (22/40) patients were rituximab refractory. Two doses were tested – 
400/400 and 1600/800. ORR was 55% in 1600/800 mg group with 9% complete responses. 
However, the response rate and duration of response appeared lower at lower doses of 
obinutuzumab.  At a median follow-up of 33.7 months, the median PFS was 11.9 months in the 
1600/800 mg group (1.8-33.9+ months) and 6.0 months in the 400/400 mg group (1.0-33.9+ 
months). Median response duration in 9 previously rituximab refractory who responded to therapy 
was 8.8 months (0.7-30.8+), with three responses lasting more than 18 months(61). In 15 MCL 
patients enrolled, 4 received 1600/800 mg dose and 11 received 400/400 mg dose. ORR was 27% 
(2/4 patients in the 1600/800 mg dose group and 2/11 in 400/400 mg dose group) with 2 CRs in 
the 400/400 mg group.  One (1) of 7 rituximab-refractory patients had a response at end-of-
treatment.  Overall median PFS for MCL patients was 2.7 months (0.3-36.1) in the 1600/800 mg 
group and 2.6 months (0.2-32.7) in the 400/400 mg group. One patient with MCL had an ongoing 
response for 30.5+ months. The remaining three patients with MCL whose disease showed 
response had response durations of 29.8, 11.2 and 5.5 months(67). 
As tested in comparison to rituximab, obinutuzumab showed trend towards a higher ORR (44.6% 
[33/74] vs 33.3% [25/75], P=0.08) than rituximab in 149 patients with relapsed indolent NHL. A 
blinded independent review panel measured a significantly higher ORR for obinutuzumab (44.6% 
[33/74] vs 26.7% [20/75], P=0.01) with an overall similar safety profile(68). 
1.2.7
Combination Studies 
1.2.7.1
Obinutuzumab and Venetoclax in Patients with CLL 
Venetoclax has been tested in combination with obinutuzumab in patients with previously 
untreated CLL and coexisting conditions(69).  Obinutuzumab was administered for 6 cycles 
starting with 100 mg on day 1 and 900 mg on day 2 (or 1000 mg on day 1), 1000 mg on day 8 and 
1000 mg on day 15 of cycle 1, and subsequently 1000 mg on day 1 of cycles 2 through 6. The 
daily oral venetoclax regimen was initiated on day 22 of cycle 1, starting with a 5-week dose ramp-
up from 20 mg to 400 mg, thereafter continuing at 400 mg daily until completion of cycle 12(69).  
At least one adverse event of any grade occurred in 200/212 (94%) of patients. Adverse events 
leading to drug discontinuation occurred in 34/212 (16%) of the patients. The most common grade 
3 or 4 adverse event was neutropenia. Grade 3 or 4 febrile neutropenia and grade 3 or 4 infections 
were reported in 11/212 (5.2%) and 35/212 (17.5%) of patients, respectively. Tumor lysis 
syndrome was reported in 3 patients (all cases occurred during treatment with obinutuzumab and 
before treatment with venetoclax); while 5 patients had fatal AEs during treatment with infection 
being the cause of death in 4 patients, and MDS in 1 patient. 


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Table 6: Summary of AEs Occurring in ≥10%, and Grade 3/4 AEs in 212 CLL Patients 
Receiving Venetoclax and Obinutuzumab(69)
 
All Grades 
N (%)
Grade 3/4 
N (%)
Any
200 (94)
167 (78)
Neutropenia
122 (58)
112 (53)
Thrombocytopenia
51 (24)
29 (14)
Anemia 
35 (17)
17 (8)
IRR
95 (45)
19 (9)
Diarrhea
59 (28)
9 (4.2)
Nausea
40 (19)
0 (0)
Infections
Not reported
10 (4.7)
Fatigue
48 (23)
0 (0)
Serious adverse events
104 (49)
Pneumonia                         10 (5)
Sepsis                                 6 (3)
IRR          
9 (4)
Febrile neutropenia
11 (5)
Cardiac failure
3 (1)
Tumor lysis
1 (0.5)
In terms of efficacy, venetoclax-obinutuzumab group had longer 24-month PFS, when compared 
to chlorambucil-obinutuzumab group (88.2% [83.7-92.6] vs 64.1[57.4-70.8]) with consistent 
advantage in patients with TP53 deletion, mutation, or both, and in patients with unmutated 
immunoglobulin heavy-chain genes(69). The percentages of patients with both a complete 
response and minimal residual disease negativity in peripheral blood or bone marrow were 
significantly higher with venetoclax–obinutuzumab than with chlorambucil-obinutuzumab 
(peripheral blood, 42.1% vs. 14.4% [P<0.001]; bone marrow, 33.8% vs. 10.6% [P<0.001]). 
Another recent study utilized venetoclax-obinutuzumab combination for 6 cycles, followed by 
venetoclax monotherapy for fixed 1-year treatment in relapsed/refractory CLL patients.(70) 
Combination achieved responses in 95% (41/43) patients with 37% (16/43) CR/CRi. 64% (27/42) 
patients had undetectable MRD on peripheral blood ≥3 months after last obinutuzumab dose with 
sustained MRD negativity (63% [25/40]) at 12 months from the last obinutuzumab dose.
1.2.7.2
Venetoclax and Obinutuzumab with Other Novel Agents 
Venetoclax has been safely combined with obinutuzumab and other novel agents in relapsed or 
refractory NHL patients. A Phase 1 study tested three dose levels of venetoclax (200mg, 400mg 
and 800mg) in MCL patients with median 2 prior lines of therapy(71). No DLT was reported at 
any dose levels. During the first 3 months of therapy, there were no clinically relevant Grade 3-4 
non-hematological AEs. 7 patients had 29 Grade 3-4 hematological AEs including 1 febrile 
neutropenia, 4 neutropenia and 4 thrombocytopenia. Among 9 evaluable patients after 6 cycles, 5 
were in CR. 
Another Phase 1 trial of 22 patients with relapsed or refractory NHL treated with venetoclax, 
lenalidomide and obinutuzumab included 5 patients with FL and 1 with MZL(72). The study 


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incorporated 4 dose-levels with different combinations of lenalidomide and venetoclax doses. 
Three doses of venetoclax were evaluated (400mg, 600mg and 800mg). Patients commenced 
venetoclax at full target dose without a safety ramp-up. No clinically relevant TLS was observed.   
One patient had a DLT - neutropenic fever at DL1 (venetoclax 400mg, lenalidomide 15mg), but 
with expansion of DL1 and from DL2-4, no further DLTs were seen. Hematologic Grade 3-4 AEs 
included neutropenia in 20 (91%), thrombocytopenia in 5 (23%) and anemia in 3 (14%) patients. 
DL4 (venetoclax 800mg, lenalidomide 20mg) was determined to be the maximum tolerated dose. 
4 of 5 patients with FL achieved responses (2 CR and 2PR) and the 1 MZL patient went into CR. 
An ongoing Phase 1 study in our branch utilizes a combination of venetoclax and obinutuzumab 
with ibrutinib, prednisone and lenalidomide in relapsed or refractory NHL and early results were 
been presented at American Society of Hematology annual meeting in 2019(73). A total of 31 
patients were enrolled with 11 FL and 2 MZL. Median number of prior therapies was 3 (range, 
1-8) and 19 (70%) pts were refractory to last therapy. 1 DLT was reported – Grade 3 intracranial 
hemorrhage at DL1 of venetoclax (200mg). Patient was receiving comcomitant enoxaparin and 
aspirin. ≥G3 neutropenia, thrombocytopenia and anemia were reported in 16 (52%), 11 (35)% and 
6 (19%) patients. Recommended Phase 2 dose of venetoclax was 800mg. In 13 total evaluable 
patients with FL and MZL, responses were observed in 12 (92%) patients, with CR in 7 (54%). 
Phase 2 testing in FL and Phase 1 testing in MCL is currently ongoing. 
1.2.8
Scientific Rationale 
1.2.8.1
Triplet Combination of Magrolimab, Obinutuzumab and Venetoclax 
The primary purpose of our study is to test the safety and efficacy of the triplet combination of 
magrolimab, obinutuzumab, and venetoclax.  The safety profile of venetoclax with obinutuzumab 
has already been established, and we will determine if adding magrolimab to this combination is 
safe and can further deepen clinical responses(69). The safety profile of magrolimab with 
rituximab has already been established, but no studies with obinutuzumab and magrolimab have 
been conducted(41). Both agents have a risk of infusional reactions, and the risk of neutropenia is 
higher with obinutuzumab than rituximab(74). These potential safety concerns, however, are likely 
manageable and direct comparisons of obinutuzumab with rituximab in both CLL and FL have 
suggested that it is more effective(74, 75). Further, we anticipate that the majority of patients with  
relapsed or refractory non Hodgkin Lymphoma would have already received rituximab as part of 
frontline therapy, and obinutuzumab has demonstrated clinical activity in patients who have 
relapsed after rituximab(76, 77).   
A unifying biologic feature of the indolent B-cell malignancies included in this protocol is the 
frequent overexpression of Bcl-2 through a variety of mechanisms. Up to 85% of cases of FL will 
be associated with a balanced translocation involving BCL2 to the immunoglobulin heavy chain 
promoter [t(14;18)]. It is widely appreciated that Bcl-2 overexpression occurs in the majority of 
CLL from loss of endogenous microRNAs, miR-15 and miR-16, that act as negative regulators of 
Bcl-2(45, 46). Many cases of MCL overexpress Bcl-2 with a major mechanism being the 
amplification of chromosome 18q21(47). Although the mechanism is unknown, Bcl-2 is also 
frequently overexpressed in most cases of MZL(49).  
As a Bcl-2 mimetic, venetoclax has established itself as an agent that can induce deep remissions 
when given in combination with other targeted agents or anti-CD20 agent as discussed in earlier 
sections(20, 78). Synergy may exist between anti-CD47 antibodies and venetoclax. Mateo et al. 
published initial report of caspase-independent cell death in CLL cells using immobilized 


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monoclonal antibody against CD47(79).  After 18 hours of CD47 ligation by the antibody, features 
typical of apoptosis were seen including cell shrinkage and loss in mitochondria membrane 
potential. Valentin et al. reported that in primary CLL cells, ex vivo treatment with SRF231 (anti-
CD47 antibody) in combination with rituximab not only induced phagocytosis, but also induced 
cell death of non-phagocytosed target tumor cells via a mechanism that is partially mediated by 
phospholipase C(80). Based on these studies, combination of these two agents can induce cell-
death via two independent pathways. Moreover, venetoclax as an anti-apoptotic inhibitor has the 
potential to induce prophagocytic signals on tumor cells, leading to potential enhanced activity 
when combined with magrolimab and obinutuzumab. In a xenograft mouse model of B-cell 
lymphoma, SRF231 displayed profound antitumor activity and led to complete and durable tumor 
regression in combination with venetoclax.
Magrolimab with rituximab has already demonstrated clinical activity in relapsed/refractory FL 
with minimal toxicity. Moreover, venetoclax with rituximab has been effective in producing deep 
responses in both CLL and FL(20, 52). Obinutuzumab is a newer anti-CD20 antibody, and was 
derived by humanization of the parental B Ly1 mouse antibody and subsequent glycoengineering.  
It has the following characteristics, compared to type I monoclonal antibodies such as rituximab: 
high-affinity binding to the CD20 antigen, lower complement-dependent cytotoxicity activity, 
higher direct cell death induction, higher antibody-dependent cellular cytotoxicity, and antibody-
dependent cellular phagocytosis(55, 81, 82). In head-to-head comparison studies, it has shown a 
higher response rate than rituximab in relapsed indolent NHL patients(62). Additionally, its 
combination with venetoclax has been well-tolerated and effective in relapsed or refractory MCL, 
MZL, FL and CLL(70-73). Increased direct cell death induction and antibody dependent 
phagocytosis makes it the most rational anti-CD20 agent to combine with venetoclax and 
magrolimab. 
An important objective of this trial is to define the complete molecular remission rate after 
combination therapy with magrolimab, obinutuzumab, and venetoclax. Based on the ability of 
venetoclax to achieve MRD negativity when used in combination with other targeted agents, and 
the above discussed data on potential synergy between Bcl-2 inhibitor, anti-CD47 antibody and 
type II anti-CD20 antibody; we believe the next logical step is to combine these active agents. We 
hypothesize that the novel-novel triplet combination in this study will leverage the efficacy of 
these targeted agents in indolent B-cell malignancies and produce deep and durable remissions 
without the need for indefinite therapy. This combination will have additive, if not synergistic, 
effects and the anticipated toxicities will be manageable.
1.2.8.2
Rationale for Dose Selection
We will be using fixed doses of magrolimab and obinutuzumab throughout this study as no 
significant dose-dependent increase in toxicity has been demonstrated with both of these agents.  
Magrolimab at 10, 20 and 30mg/kg dose was tested in combination with rituximab 375mg/m2 in 
relapsed and refractory NHL and had minimal toxicity. A priming dose of 1mg with maintenance 
doses of 30mg/kg showed ~100% CD47-receptor occupancy – this was the recommended phase 2 
dose and will be used in this study. Although rituximab was used in this study with magrolimab, 
both rituximab 375mg/m2 and obinutuzumab 1000mg have largely similar toxicity profiles as 
compared head-to-head in a Phase 2 study, with the exception of grade 3 or 4 infusion-related 
reactions (IRR) which were seen in 11% patients receiving obinutuzumab and 5% patients 
receiving rituximab(62). IRRs are most common and most severe with first infusion, and hence 


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we will separate out the first doses of infusional medications on this study. All patients will receive 
the first dose of obinutuzumab on Day 1, and first dose of magrolimab on Day 2 of the first cycle. 
In indolent NHL, an apparent improvement in ORR has been observed for the higher doses versus 
lower doses of obinutuzumab. For patients receiving a loading dose of 1600 mg on Day 1, Day 8 
and Day 15 of Cycle 1 followed by maintenance doses of 800mg (1600/800mg regimen) on Day 
1, Cycle 2 and  onwards, ORR was 55% (95%CI: 32-76) and 2 patients (9%) had a CR; whereas, 
for the 400/400mg regimen, ORR was 17% (95%CI: 4-41) and no patient had a CR(58). A simpler 
fixed-dose regimen of 1000mg (D1, D8 and D15, C1; D1, C2 onwards) results in similar serum 
concentrations when compared with the 1600/800mg regimen, and will be used in this study(58). 
As described in Section 1.2.7.2, venetoclax 800mg was the recommended phase 2 dose in 
combination with other targeted agents for indolent NHL patients.  This will be DL1 for eligible 
FL patients on this study(71, 73). When used in combination with other agents, there is a trend 
towards higher incidence of neutropenia with higher dose levels of venetoclax(73). Therefore, a 
DL-1 of 600mg venetoclax will be available. 
In patients with relapsed or refractory CLL, venetoclax is approved at a dose of 400mg, and the 
same dose has been used in combination studies with obinutuzumab for CLL and MCL with a 
tolerable safety profile as discussed in Sections 1.2.7.1 and 1.2.5.1 (69-73). The dose of 400mg 
once daily will be used as  dose level 1 (DL1) for CLL and MCL patients on this protocol, with an 
available DL-1 of 200mg should DLT occur. Even though the 800mg dose has been utilized in 
prior studies with MZL, very few MZL patients were enrolled on these trials(71, 73). Considering 
limited safety data is available (see Section 1.2.7.2), DL1 will be 400mg and DL-1 200mg for 
MZL patients enrolled on this protocol. 
1.2.8.3
Rationale for Use of MRD to Guide Duration of Therapy in CLL
Eradication of MRD usually results in improved clinical outcomes in CLL independent of the 
choice of therapy. (83-85) Specifically, with venetoclax monotherapy, a comprehensive MRD 
analysis of the two large phase II trials in relapsed/refractory CLL patients showed peripheral 
blood MRD <10-4 by flow cytometry in 26% of the 174 patients. (86) Among MRD-positive 
patients, 23% showed intermediate (≥10-4 to <10-2) MRD levels and 51% had high MRD (≥10-2). 
24-month PFS rates were 92.8%, 84.3%, and 63.2% for MRD <10-4, intermediate MRD, and high 
MRD patients (p<0.0001).
The rates of undetectable MRD (uMRD) increase substantially when venetoclax is combined with 
obinutuzumab. In a study, an optional debulking with bendamustine was followed by an induction 
and MRD-guided maintenance treatment of venetoclax and obinutuzumab in patients with 
treatment-naïve or relapsed/refractory CLL. (87) After induction, 87% patients had uMRD, with 
the majority of patients completing maintenance treatment at the earliest possible time point due 
to conﬁrmed uMRD. In the phase III CLL14 trial, a higher rate of undetectable MRD in peripheral 
blood (via ASO-PCR) less than 10-⁴, was observed in patients given venetoclax plus obinutuzumab 
than in patients given chlorambucil plus obinutuzumab (76% vs 35%, p<0·0001). In a landmark 
analysis from last treatment exposure (ie, after 12 cycles) patients with undetectable MRD after 
the end of either treatment regimen had longer PFS compared with patients with low MRD or high 
MRD (HR 0·10, 95% CI 0·06–0·15, p<0.0001). In a post-hoc analysis, OS was also longer in 
patients who had undetectable MRD at the end of treatment (p<0.0001). (69, 88) Another phase II 
study used the same combination with a different treatment scheme: after 2 months of 
obinutuzumab, induction with 6 months of combined venetoclax and obinutuzumab followed by 


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6 additional months of venetoclax.(89) After that, patients who were at least in partial remission 
were randomly assigned to receive either maintenance treatment with 12 additional cycles of 
venetoclax irrespective of MRD, or MRD-guided (by flow cytometry) venetoclax maintenance. 
26/28 (92.9%) patients had uMRD after induction. Follow-up is ongoing for patients randomized 
to the two maintenance groups. Of note, there was 92.3% concordance between bone marrow and 
peripheral blood MRD results at end of induction. 
Based on these and other prospective studies, the 2018 iwCLL guidelines recommend that clinical 
trials aimed at maximizing the depth of remissions should include at least 1 test to assess for MRD 
- six-color ﬂow cytometry, ASO PCR, or high-throughput sequencing using the ClonoSEQ assay. 
(90) Six-color peripheral blood ﬂow cytometry (i.e., CD19, CD20, CD5, CD43, CD79b, and 
CD81) is reliably sensitive down to a level of <1 CLL cell in 10000 leukocytes. (91) Given >10-4 
sensitivity, real time availability at our institution and high concordance between peripheral blood 
and bone marrow MRD, we will be utilizing peripheral blood flow cytometry in this study as a 
marker of MRD assessment at the end of first 6 cycles of triplet combination therapy to guide 
further duration of treatment. (88, 92, 93) See Section 3.1.1. 
1.2.8.4
Molecular and Immunologic Profiling of Tumors  
A critical translational component of this trial will be the comprehensive assessment of molecular 
and immunologic correlates that predict response to magrolimab in tissue and peripheral blood.  
Accurate identification of patients most likely to respond to treatment will be paramount for the 
success of our precision medicine trial.  Similarly, the identification of both intrinsic and acquired 
resistance mechanisms to magrolimab will enhance further drug development. To reach these 
goals, we aim to study the molecular and immunologic correlates of response with a 
comprehensive molecular analysis of baseline biopsies. Further, the study design will utilize a 
“window of opportunity” in which patients will receive magrolimab and obinutuzumab for 2 cycles 
prior to the triplet combination. This study design will allow us to characterize predictive 
biomarkers from on-treatment tissue biopsies taken during the window and at disease progression.  
We will assess changes in RNA expression, clonal evolution and mechanisms of resistance.
The National Cancer Institute’s (NCI) Center for Cancer Research (CCR) is uniquely positioned 
to execute the strong translational emphasis of this proposal.  The Staudt lab will perform 
comprehensive molecular characterization of the tumors at baseline on FFPE blocks, including 
whole-exome sequencing, transcriptome profiling, AffySNP6.0 and arrays for copy number 
abnormalities, and will explore emerging technologies such as single cell RNA sequencing.  Given 
the influence of cells in the tumor microenvironment (TME) to tumor behavior, we aim to study 
the molecular evolution of both the tumor and the TME during therapy(94).  Recent advances in 
genomic technologies enable the gene expression profiling at the single cell level, a distinct 
advantage over conventional GEP which cannot always distinguish tumor vs. non-tumor gene 
expression(95, 96).  Single-cell approaches allow identification of the evolution of rare populations 
of tumor cells, prone to distant spread or therapy resistance, as well as identification of TME cells 
that may be critical for the survival of the tumor and/or those immune populations that can be 
harnessed to attack the malignancy.  The NCI-CCR operates a single cell analysis core facility 
with expert staff headed by Dr. Michael Kelly within the CCR Genomics Core.  This facility can 
take purified viably frozen cells banked from patient biopsies and prepare them, using well-
validated 10X Genomics technology, for single-cell RNA sequencing.  This core is directly 
integrated with the NCI Sequencing core facility to provide high-quality, deep-sequencing of the 
single cell RNA-SEQ samples, as well as ‘first-pass’ data processing and analysis.  Data can then 


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be transferred to scientists and bio-informaticians in the Staudt lab for further analysis of gene 
expression patterns and cellular population dynamics.
The TME within indolent lymphomas influences both response and resistance to targeted therapy.  
FL is a proliferation of malignant germinal center B-cells admixed with a varying proportion of 
nonmalignant immune cells such as T-cells, follicular dendritic cells and stromal cells.  FL tumor 
cells in nodes retain a substantial dependence with the nonmalignant cells and other stromal 
elements from the TME in a pattern described as “re-education”(97). Interactions of FL cells with 
dendritic cells and macrophages allow them to survive in the germinal center environment even in 
the absence of an attached antigen(98, 99).  Moreover, in some models of carcinogenesis, 
progression is associated with a macrophage phenotype switch with low IL-12 expression, high 
IL-10 expression, and low tumoricidal activity and promotion of tissue remodeling and 
angiogenesis(100).  Increased number of lymphoma-associated macrophages has been associated 
with worsened OS in patients treated with chemotherapy, but in patients receiving rituximab with 
chemotherapy, it was associated with improved survival(101, 102).  Other studies have found no 
association of tumor-associated macrophages on prognosis(103).  Neoplastic follicles also contain 
T cells, primarily CD4+, with a higher CD4:CD8 ratio in low-grade (Grade 1-2) than in Grade 3 
FL(104).  Multiple studies have associated Treg and TFH cells with clinical outcomes, but the 
results are inconsistent with some studies finding high Treg or high CD8+ cell numbers to be 
associated with favorable prognosis, and others non-significant(105-107). 
These studies involved different patient populations and treatment regimens, and that may have 
contributed to discordant results. Moreover, most of these studies utilized immunohistochemistry 
for detecting the types of cells and the results are subject to difference between pathologists in 
interpreting the results.  The cell types initially believed to represent a single lineage are actually 
many distinct subsets with distinct functions.  Optical tissue imaging has revealed specialized 
localization of a few of these cellular subsets in FL such as lack of naïve B cells (mantle zone), 
presence of follicular dendritic cells in extranodal sites and absence of FDCs in diffuse areas of 
FL; and high prevalence of Tregs in follicular areas and absence in areas transformed to 
DLBCL(98, 104, 108).  The spatial arrangement of the TME in FL varies across patients and 
depends on the genetic aberrations within the tumor cells as well as dependence on external stimuli 
for survival, proliferation, and immune escape.  Conventional microscopy provides spatial 
information, but typically identifies cells by one or a very few markers.  Hence, visualization and 
quantification of cellular subsets defined by complex phenotypic marker combinations is 
challenging.  In contrast, flow cytometry provides more robust phenotypic data, but no information 
about spatial distribution of the various cell subsets.  A combination of both these modalities would 
be ideal to study tumor microenvironment in indolent lymphomas.
In collaboration with Dr. Ronald N. Germain, in the Center for Advanced Tissue Imaging (CAT-
I), we have developed a lymphoma-specific antigen panel that can be assessed by a tissue imaging 
method called “histo-cytometry.” This strategy combines multiparameter 3D confocal imaging, 
spillover and deconvolution correction, identification and 3D reconstruction of specific cells of 
interest, and graphical data display.  Histo-cytometry allows visualization, quantification, and 
positional analysis of diverse cell populations characterized by multiple markers directly in tissue 
sections.  In initial studies, the histo-cytometry based cell positioning was consistent with normal 
biological localization of cell types in murine lymph nodes(109).  When tissue quantitative cells 
subset discrimination by this method was compared with flow-cytometry based quantitation of 
contralateral lymph nodes in the animals, the correspondence was close to 1:1.  Moreover, histo-


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cytometry reliably tracked the phenotypic changes associated with T-cell activation and 
proliferation and was able to identify intranodal spatial distribution of all conventional dendritic 
cell subsets.  This novel imaging technology will enable highly multiplexed, quantitative image 
analysis of lymph node samples and can be performed serially.  We plan to explore the three-
dimensional relationship of immune cells and stromal cells of interest in all indolent lymphomas 
using this technique.  This is of particular interest to our study, as the mechanism of action of 
magrolimab depends on activation of innate immune system by enabling macrophage induced 
phagocytosis of NHL cells, and also activation of adaptive immunity by dendritic cell mediated 
priming of CD8+ T-cells(36, 37).  Patients will have tumor biopsies at baseline (if required, based 
on inadequate existing tissue), during the “window” treatment period with magrolimab and 
obinutuzumab, and at the time of progression.  Dense phenotypic and spatial data made available 
by histo-cytometry at these timepoints will enable us to better understand immunological 
correlates of response, and resistance to treatment with anti-CD47 antibody and obinutuzumab.  
The diverse mechanism of action of immune checkpoint inhibitors (including magrolimab) in 
modulating the tumor microenvironment requires a careful assessment of the end points, such as 
while using functional imaging (18FDG-PET).  Because the TME is responsible for a significant 
amount of 18FDG uptake, agents causing immune activation may also cause an initial increase in 
PET activity, similarly to effects of anti-PD1/anti-CTLA4 antibodies observed in solid 
tumors(110).  Histo-cytometry will also provide additional information to distinguish immune 
reaction from tumor progression.
1.2.8.5
Use of Circulating Tumor DNA
Measurement of minimal residual disease (MRD) is not part of the standardized criteria for disease 
response or disease monitoring in indolent lymphomas, but many research applications are 
currently being developed. Multiple methods have been tested for detecting MRD in B-cell 
malignancies with limitations.  Multiparameter flow cytometry (MFC) can easily be performed on 
peripheral blood or bone marrow as a marker of MRD, but this method may not be sensitive enough 
in diseases that do not routinely circulate(111).   Even in CLL, where MFC reliably quantitates 
CLL cells to the level of 10-5, NGS-based approaches appear to have a lower limit of detection and 
can assess clonal evolution(112). 
The tumor-specific component of cell-free DNA, known as circulating tumor DNA (ctDNA), is a 
highly sensitive and specific marker of all B-cell malignancies and is an emerging technology 
designed to overcome the fundamental limitations of response assessment based on imaging scans.  
A secondary objective of this trial is to utilize ctDNA as a marker of MRD and compare the results 
to the standard assessment of disease response and monitoring for disease recurrence after therapy 
stops.  Many patients who achieve a CR based on conventional criteria will have the persistence 
of MRD below the detection limit of imaging scans highlighting the need for more sensitive 
measures(113, 114).  As a measure of the depth of response, we will define the complete molecular 
remission rate after triplet combination therapy.  Further, we will analyze the predictive ability of 
ctDNA for predicting disease relapse when measured at pre-planned timepoints after therapy stops.
Various technologies exist for the detection and analysis of ctDNA.  Malignant B cells possess a 
unique DNA sequence that encodes its rearranged immunoglobulin variable, diversity, and joining 
(VDJ) genes.  Using universal primers in combination with next-generation sequencing (NGS), 
this unique VDJ sequence can be utilized as a quantitative biomarker of disease(114). This 
technique requires identification of rearrangements in tumor tissue (a clonotype), which can then 
be followed in peripheral blood. In a study comparing NGS-based method with RQ-PCR in MCL, 


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49 out of 55 (89%) patients had a clonotype detected by NGS compared to 45 out of 55 (82%) by 
RQ-PCR(115).  Clonotypes identified by both techniques were identical in 96% of the cases. NGS 
demonstrated at least the same level of sensitivity as RQ-PCR, without the need for patient-specific 
reagents.  Technologies have since evolved, and in a more recent study, tumor clonotypes were 
successfully detected at baseline and followed serially in 96% of patients with MCL(116). Of note, 
in all patients who had baseline formalin-fixed paraffin embedded (FFPE) tissue available, one or 
more clonotypes were detected. A linear association was demonstrated between baseline 
quantitative ctDNA levels and tumor burden as measured by total metabolic tumor volume 
(TMTV). More importantly, ctDNA was able to provide an early readout of sensitivity to therapy 
as decrease in levels as early as after 1 cycle of treatment with chemotherapy and targeted agents 
(EPOCH-R plus bortezomib) was shown to associated with improved PFS. The utility of this assay 
has also been preliminarily tested in FL(117). In a randomized study of FL patients, a subset of 
patients had tumor and plasma samples available for analysis for VDJ sequences.  At least one 
tumor clonotype could be detected in 29 patients (85%) in the diagnostic tumor sample. ctDNA 
corresponding to the clonotypes were detected in 25/29 (86%) of the matched plasma samples. 
We will use a modern ctDNA platform that combines universal PCR primers for the variable-
diversity-joining (VDJ) region of the immunoglobulin receptor with next-generation sequencing 
(NGS) technologies (i.e., clonoSEQ)(118).  This ctDNA assay is highly tumor-specific and can 
be used as a method for disease detection at the molecular level in a variety of B-cell 
malignancies(115, 117, 119).  Since the clinical utility of achieving complete molecular remission 
is unknown, this will be an exploratory endpoint.  Lastly, we aim to study the utility in using 
ctDNA as an active surveillance tool after therapy has been completed to determine the kinetic 
relationship between ctDNA reappearance and clinical relapse.  These data could inform future 
studies that initiate intervention on the basis of molecular relapse.  Altogether, ctDNA will be used 
in this study as a non-invasive method to monitor tumor response kinetics during therapy, define 
the depth of response, and as a surveillance tool for early disease detection after therapy cessation. 


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2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Patients must have a confirmed histologic diagnosis of an indolent CD20 positive B-cell 
lymphoma according to the criteria established by the 2016 version of the World Health 
Organization (WHO) classification system. Lymphomas with any prior CD20 expression 
(by immunohistochemistry or flow cytometry) will be considered eligible. Diagnosis 
must be confirmed by Laboratory of Pathology, NCI and the following indolent B-cell 
lymphomas are included:

Follicular lymphoma (FL): must be grade 1-2 or 3a 

Marginal zone lymphoma (MZL) 

Mantle cell lymphoma (MCL) 

Chronic lymphocytic leukemia (CLL)
2.1.1.2
Participant must have relapsed and/or refractory disease, as defined below: 

FL: relapsed after and/or refractory to at least two (2) prior lines of therapy with at least 
one of those therapies containing an anti-CD20 monoclonal antibody. 
NOTE: Participants with FL may be eligible after one (1) prior line of therapy if 
they have either:
-
Follicular lymphoma international prognostic index (FLIPI) ≥2 (120)
-
Disease progression within 24 months of the end of last therapy (POD24) 

MZL: relapsed after and/or refractory to at least two (2) prior lines of therapy, with at 
least one containing an anti-CD20 monoclonal antibody.

MCL: relapsed after and/or refractory to at least two (2) prior lines of therapy, with at 
least one containing an anti-CD20 monoclonal antibody. 
NOTE: Participants with MCL may be eligible after one (1) prior line of therapy 
if they have either:
-
Blastoid or pleomorphic histology
-
17p deletion
-
TP53 mutation or deletion
-
Ki67 ≥30%
-
Received a BTK inhibitor as first line therapy

CLL: relapsed after and/or refractory to at least two (2) prior lines of therapy. Participants 
with CLL are not required to have had therapy containing anti-CD20.
NOTE: Participants with CLL may be eligible after one (1) prior line of therapy 
if they have either: 
-
17p deletion
-
TP53 mutation or deletion
-
Received both a Bruton’s Tyrosine Kinase (BTK) inhibitor AND a B-cell 


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lymphoma 2 (BCL2) inhibitor as first line therapy
NOTE: Participants must not have received prior treatment with a CD47 or SIRP 
targeting agent.
2.1.1.3
Adequate tissue from diagnostic biopsy (archival or fresh) must be available for 
performance of correlative studies
NOTE:  Tumor tissue may be from any previously collected tissue and adequacy is at the 
discretion of the Principal Investigator. If prior tissue is not available, patient must be 
willing to undergo baseline tissue biopsy (for patients with known or suspected bone 
marrow involvement, bone marrow may be acceptable tissue per discretion of the 
investigator). 
2.1.1.4
Patients must have at least evaluable disease as assessed by clinical exam (i.e., palpable 
lymphadenopathy, measurable skin lesions, etc.), laboratory assessment (i.e., lymphoma 
involvement of bone marrow or peripheral blood by morphology, cytology or flow 
cytometry), and/or imaging (measurable lymph nodes or masses on CT or MRI and/or 
evaluable FDG-avid lesions on PET).  Patients may also have measurable disease.  
NOTE:  Patients with known active CNS lymphoma are not eligible.
2.1.1.5
Age 18 years 
NOTE:  Because no dosing or adverse event data are currently available on the use of 
magrolimab in patients <18 years of age, children are excluded from this study
2.1.1.6
ECOG performance status < 2 (see Appendix A)
2.1.1.7
Adequate organ function as evidenced by the following laboratory parameters:  
Absolute neutrophil count 
(ANC)
≥ 1,000 /mm3 
Platelets
≥ 50,000 / mcL (transfusions permitted) 
Hemoglobin
≥ 9 g/dL (transfusions permitted). NOTE:  Patients must have 
required fewer than 2 units of RBC transfusion in the 4 weeks prior 
to screening.  Additional transfusions after screening and prior to 
enrollment are acceptable. 
Renal function 
Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 as 
estimated by the Modification of Diet in Renal Disease (MDRD) 
abbreviated formula. If not on target, a 24-hour urine creatinine 
clearance can be used to directly measure.
Aspartate 
aminotransferase (AST) 
and alanine 
aminotransferase (ALT)
≤ 3.0 x the upper ULN
NOTE: Patients with liver involvement with lymphoma
≤ 5.0 x ULN
Bilirubin
≤ 1.5 × ULN 
NOTE:  Patients with Gilbert's syndrome may have a bilirubin 
level > 1.5 × ULN, per discretion of the investigator 
2.1.1.8
The effects of the study drugs on the developing human fetus are unknown.  For this 


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reason, women of childbearing potential (WOCBP) and men must agree to use effective 
contraception when sexually active. This applies for the time period between signing of 
the informed consent form and for the following time frames after the last dose of drug, 
whichever is later: 90 days after the last dose of magrolimab, 30 days after the last dose 
of venetoclax, and 18 months after the last dose of obinutuzumab for women and 6 
months after the last dose of obinutuzumab for men. Men should refrain also from 
donating sperm for these same timeframes, and women must also refrain from donating 
eggs. 
NOTE: WOCBP is defined as any female who has experienced menarche and who has 
not undergone successful surgical sterilization or who is not postmenopausal (i.e., 
amenorrheic for >12 months without alternative medical cause; post-menopausal status 
in females under 55 years of age should be confirmed with a serum follicle-stimulating 
hormone [FSH] level within applicable local laboratory reference range for 
postmenopausal women). Permanent sterilization methods include but are not limited to 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. The investigator or a 
designated associate is requested to advise the patient how to achieve highly effective 
birth control (failure rate of less than 1%), e.g., intrauterine device (IUD), intrauterine 
hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner and 
sexual abstinence. The use of condoms by male patients is required unless the female 
partner is permanently sterile. See Appendix B for complete details of acceptable 
contraceptive methods.
2.1.1.9
Ability of patient to understand and the willingness to sign a written informed consent 
document
2.1.1.10 Patients with prior autologous or allogeneic stem cell transplantation are potentially 
eligible if transplanted > 6 months ago, and no active graft-vs-host disease requiring 
immunosuppressants.
2.1.2
Exclusion Criteria
2.1.2.1
Concomitant use of any investigational anti-lymphoma treatment 
2.1.2.2
Known primary or acquired immunodeficiency syndrome (e.g., HIV) or known infection 
with human T-cell leukemia virus 1 (HTLV1). NOTE: HIV-positive patients on 
combination antiretroviral therapy are ineligible because of the potential for 
pharmacokinetic interactions with the study drugs. In addition, these patients are at 
increased risk of lethal infections when treated with marrow-suppressive therapy. In the 
future, appropriate studies will be undertaken in patients receiving combination 
antiretroviral therapy when indicated.
2.1.2.3
History of hemolytic anemia or autoimmune thrombocytopenia in the 3 months prior to 
enrollment. Patients with positive Direct Agglutination Test (DAT) but no evidence of 
clinically active hemolysis are eligible.
2.1.2.4
Hepatitis B surface antigen or hepatitis B DNA PCR positive. NOTE:  Subjects who are 
hepatitis B core antibody positive will need to have a negative HBV DNA PCR result 
before enrollment.  Those with a positive PCR for hepatitis B are excluded.
2.1.2.5
Pregnant or breastfeeding patients. NOTE:  Pregnant women are excluded in this study 
because of the potential for teratogenic or abortifacient effects. Because there is an 


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unknown but potential risk for adverse events in nursing infants secondary to treatment 
of the mother with the study drugs, breastfeeding should be discontinued. 
2.1.2.6
Requirement to continue on any of the medications that have significant potential for 
drug-drug interactions with the study regimen, as indicated in Section 4.2  For example, 
the following:  

Use of strong CYP3A inhibitors 7 days prior to or at initiation of venetoclax, and 
during ramp-up phase is contraindicated in patients with MZL, CLL and MCL 
(see Sections 4.2.1, 4.2.1.2, and Appendix C, also see Section 4). For FL patients, 
use of strong CYP3A inhibitors is contraindicated 7 days prior to and during the 
first two weeks of venetoclax treatment. 

Consumption of one or more of the following within 3 days prior to the first dose 
of any study drug:
o
Grapefruit or grapefruit products
o
Seville oranges including marmalade containing Seville oranges
o
Star fruit
2.1.2.7
Uncontrolled intercurrent illness including, but not limited to the following that may limit 
interpretation of results or that could increase risk to the patient at the discretion of the 
investigator:

Active hepatitis C infection. NOTE:  Subjects who are hepatitis C antibody positive 
will need to have a negative HCV PCR result before enrollment.  Those with a 
positive PCR for hepatitis C are excluded.

Any second malignancy that requires active systemic therapy

Known mental or physical illness that would interfere with cooperation with the 
requirements of the trial or confound the results or interpretation of the results of 
the trial and, in the opinion of the treating investigator, would make the patient 
inappropriate for entry into the study

Known active infection, or any major infection requiring treatment with IV 
antibiotics or hospitalization within 4 weeks prior to commencement of the study 
treatment. 
2.1.2.8
Vaccination with a live vaccine ≤28 days prior to commencement of the study 
treatment. 
2.1.2.9
Inability or unwillingness to swallow a large number of tablets. 
2.1.2.10 Known hypersensitivity to any of the study medications or their excipients. 
2.1.2.11 History of inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis).
2.1.2.12 History of malabsorption syndrome felt to be significant enough to interfere with enteral 
absorption at the discretion of the investigator.
2.1.3
Recruitment Strategies
Study participants will be recruited from the population of patients screened in the lymphoid 
malignancies’ clinic of the National Institutes of Health.  Our research team currently has an active 
protocol to study the clonal evolution in FL that enrolls patients with untreated FL who are 


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appropriate for observation as well as those who require immediate treatment.  In addition, we 
participate in a locoregional consortium of eight academic institutions within the Mid-Atlantic 
region (Mid-Atlantic Lymphoma Research Consortium) that shares information regarding active 
clinical protocols and aims to enhance patient recruitment across the region. Our patients for this 
study will therefore consist of those from the FL clonal evolution study, referrals from outside 
physicians, and patient self-referrals.
This protocol may also be abstracted into a plain language announcement posted on NIH websites 
(ccr.cancer.gov/ Lymphoid-Malignancies-Branch, ClinicalTrials.gov) and on NIH social media 
platforms. 
2.2
SCREENING EVALUATION
2.2.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following:

Email, written, in person or telephone communications with prospective subjects

Review of existing medical records to include H&P, laboratory studies, etc.  

Review of existing MRI, x-ray, or CT images

Review of existing photographs or videos

Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes
2.2.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the study consent OR 
the consent for study 01C0129 (provided the procedure is permitted on that study), on which 
screening activities will be performed. Assessments performed at outside facilities or on another 
NIH protocol within the timeframes below may also be used to determine eligibility once a patient 
has signed the consent, unless otherwise noted.
NOTE:  Assessments and procedures to confirm study eligibility should be completed within 28 
days prior to the start of treatment (unless otherwise noted).  See also the Study Calendar 
(Appendix G).  
2.2.3
Clinical Evaluations

Disease history, including:  diagnosis, prior chemotherapy and/or radiation treatment 
(if applicable), and significant prior/ongoing side effects and symptoms

Complete medical history, including: all active conditions considered to be clinically 
significant by the treating investigator

Physical examination, including: height (screening only), weight, vital signs (i.e., 
temperature, pulse, respiratory rate, and blood pressure); review of concomitant 
medications and symptoms/side effects; and, assessment of performance status using 
the ECOG scale 
2.2.4
Laboratory Evaluations 
NOTE:  Results from outside NIH are accepted.


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
CBC with differential

Chemistry panels (as noted) or specific analyte required for eligibility, including:  
Creatinine (i.e., or Acute Care Panel/Basic Metabolic Panel); ALT, AST, total and 
direct (if required) bilirubin (i.e., or Hepatic Panel/Liver Function Panel); and 24-hour 
urine creatinine clearance (if needed to measure CrCl)

Coagulation panel:  PT/INR and aPTT

LDH

Urinalysis 

Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody, Hepatitis C antibody 
(HCV) [qualitative]) (within 3 months allowed)

HIV antibody (within 3 months allowed)

Urine and/or serum HCG in women of childbearing potential (within 7 days prior to 
initiation of study therapy)

Direct Anti-Globulin Test (DAT)

Assessment of 17p deletion by karyotyping of blood, bone marrow, or tissue sample 
(results from outside of NIH and/or prior to the 28-day screening window are accepted)
2.2.5
Imaging Studies 
NOTE:  Results from NIH only.

CT chest, abdomen and pelvis or MRI
2.2.6
Other Procedures to be performed/samples to be collected 

Pathologic review/confirmation of diagnosis by Laboratory of Pathology, NCI (no time 
limit).  A tissue sample is required for this evaluation; if archival sample is not 
available, a fresh tumor or bone marrow biopsy will be obtained.

Bone marrow aspiration with flow cytometry and biopsy within 12 months prior to 
starting treatment, unless repeat at screening/baseline felt to be clinically indicated in 
the opinion of the investigator (results from outside NIH are accepted; flow cytometry 
not required in these cases). 

Flow cytometry will be performed on peripheral blood for both diagnostic and staging 
purposes (only NIH results accepted; NCI Laboratory of Pathology)
2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found at:
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
2.3.1
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 


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respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE).
2.3.2
Treatment Assignment Procedures
NOTE:  For NCI CCR registration purposes only.   
2.3.2.1
Cohorts
Number
Name
Description
1
Dose-finding:
Relapsed/refractory FL
Patients with relapsed or refractory FL 
(a minimum of 6 patients; up to 12 patients) 
2
Dose-finding:  
Relapsed/refractory MZL, 
MCL, and CLL
Patients with relapsed or refractory MZL, MCL and CLL 
(a minimum of 6 patients; up to 12 patients)
3
Dose-expansion:
Relapsed/refractory FL
Patients with relapsed or refractory FL 
(up to 18 patients)
4
Dose-expansion:
Relapsed/refractory MZL
Patients with relapsed or refractory MZL 
(up to 6 patients)
5
Dose-expansion:
Relapsed/refractory MCL
Patients with relapsed or refractory MCL 
(up to 12 patients)
6
Dose-expansion:
Relapsed/refractory CLL
Patients with relapsed or refractory CLL 
(up to 6 patients)
2.3.2.2
Arms
Number
Name
Description
1
Experimental 
treatment: 
FL Dose-finding
Magrolimab IV with a 1 mg/kg priming dose followed by 30mg/kg 
loading and maintenance doses + obinutuzumab IV 1000mg + 
venetoclax 800mg PO combination administered to 6 patients for six 
(6) cycles (28-days each, Cycles 1-6); further treatment with additional 
cycles will be response-adapted.  Note: DLT assessment of the 
magrolimab + obinutuzumab + venetoclax triplet will take place during 
Cycle 1. If ≥2 patients experience DLT, an additional 6 patients will be 
enrolled at DL(-1) of venetoclax 600mg with magrolimab and 
obinutuzumab.  
2
Experimental 
treatment: 
MZL, MCL, and 
CLL Dose-finding
Magrolimab IV with a 1 mg/kg priming dose followed by 30mg/kg 
loading and maintenance doses + obinutuzumab IV 1000mg + 
venetoclax ramp-up to target dose of 400mg over 5 weeks (35 days, 
Cycle 1) administered to 6 patients. Triplet combination of magrolimab 
+ obinutuzumab + venetoclax (target dose, no ramp-up) will continue 
for five (5) additional cycles (28-days each, Cycles 2-6); further 
treatment with additional cycles will be response-adapted. Note: DLT 
assessment of the magrolimab + obinutuzumab + venetoclax triplet will 
take place during Cycle 1. If ≥2 patients experience DLT, an additional 
6 patients will be enrolled at DL(-1) of venetoclax 200mg with 
magrolimab and obinutuzumab.


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Number
Name
Description
3
Experimental 
treatment: 
FL Dose 
expansion
Window of magrolimab IV with a 1 mg/kg priming dose followed by 
30mg/kg loading and maintenance doses + obinutuzumab IV 1000mg 
combination for two (2) cycles (28-days each, Cycles -2 and -1), then 
venetoclax will be added at target dose (dose determined from Arm 1). 
Triplet combination treatment with magrolimab + obinutuzumab + 
venetoclax will be 6 cycles (28-days each, Cycles 1-6); further 
treatment will be response-adapted.
4
Experimental 
treatment: 
MZL, MCL, CLL 
Dose expansion
Window of magrolimab IV with a 1 mg/kg priming dose followed by 
30mg/kg loading and maintenance doses + obinutuzumab IV 1000mg 
combination for two (2) cycles (28-day cycles, Cycles -2 and -1), then 
venetoclax safety ramp-up to target dose (dose determined from Arm 2) 
over 5 weeks (35-days, Cycle 1). Triplet combination treatment with 
magrolimab + obinutuzumab + venetoclax (target dose, no ramp-up) 
will continue for 5 additional cycles (28-days each, Cycles 2-6); further 
treatment will be response-adapted. 
2.3.2.3
Arm Assignment
This is a four arm, non-randomized study. All patients will receive experimental treatment.  During 
the dose-finding portion, patients in Cohort 1 will be assigned to Arm 1; patients in Cohort 2 will 
be assigned to Arm 2.
During the dose-expansion portion, patients in Cohort 3 will be assigned to Arm 3; Cohorts 4, 5 
and 6 will be assigned to Arm 4. 
2.4
BASELINE EVALUATION
The baseline evaluations should be performed within 28 days prior to the first dose of magrolimab, 
unless otherwise noted; tests performed as part of screening do not need to be repeated if they were 
performed within the specified window.  See the Study Calendar (Appendix G) for details.
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN 
This is a non-randomized, open-label, four arm, single institution phase 1 study of magrolimab, 
obinutuzumab, and venetoclax for patients with relapsed/refractory indolent B-cell malignancies.  
The study involves a novel design that includes a treatment window with a doublet in order to 
maximize the potential for translational research as well as a safety period to assess the safety of 
the triplet combination of venetoclax added to magrolimab with obinutuzumab in different disease 
sub-types. 
Research biopsies of lymph nodes and/or bone marrow will be collected at baseline, during the 
window period treatment with magrolimab + obinutuzumab, and at the time of disease progression.
3.1.1
Dose-Finding Phase 
The dose-finding phase will assess the safety of venetoclax when added to obinutuzumab and 
magrolimab. Up to 6 FL patients in Arm 1 will be treated and undergo DLT assessment during the 
first 4 weeks (Cycle 1) of triplet combination therapy with magrolimab, obinutuzumab and 
venetoclax. Venetoclax will be administered at DL1 without a safety ramp-up (Figure 3). If ≥2 


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patients experience DLT at DL1, up to 6 additional patients will be enrolled (Cohort 1, Arm 1) and 
treated at DL(-1) of venetoclax. Dose-finding will follow the rules mentioned in Table 8. 
Up to 6 MZL, MCL or CLL patients treated in Arm 2 will undergo DLT assessment during the 
first 5 weeks of triplet combination therapy (Cycle 1). Venetoclax will be administered with a 
safety ramp-up to target dose (dose level 1) (Table 10, Figure 4). If ≥2 patients experience a DLT 
at DL1, up to 6 additional patients will be enrolled (Cohort 2, Arm 2) and treated at DL (-1) of 
venetoclax (Figure 3). Dose-finding will follow the rules mentioned in Table 8. 
No more than 2 patients can be in a DLT assessment period at any given time. If a DLT has 
occurred, only 1 patient can be in the respective DLT assessment period at a given time. Patients 
who withdraw before completing DLT assessment for reasons other than a DLT, will not be 
evaluable for assessment of DLT for dose review decisions, and will be replaced. 
After completion of the DLT evaluation as above, all patients will be treated with an additional 5, 
4-week cycles of triplet combination therapy (magrolimab and obinutuzumab and venetoclax). 
Final duration of therapy will be based on response to the first 6 cycles of triplet combination 
therapy. FL, MZL and MCL patients who achieve a CR and CLL patients who achieve a CR with 
undetectable peripheral blood MRD by flow cytometry after 6 cycles of triplet combination 
therapy will stop treatment but remain potentially eligible for an additional 6 cycles upon disease 
relapse provided that they still meet re-treatment criteria and the duration of CR is  6 months. 
Disease relapse is defined by conventional criteria for clinical relapse that is associated with 
radiographic progression. Additionally, for CLL patients, positive flow cytometry during follow-
up will be considered relapsed for re-treatment.  Reappearance of ctDNA is not considered disease 
relapse on this protocol. Patients who achieve a PR after 6 cycles of triplet combination therapy 
will be eligible for an immediate additional 6 cycles, and then will stop treatment.
Table 7: Venetoclax Dose Levels 
Cohort
Dose Level
Target Dose of Venetoclax*
Level 1
800 mg by mouth daily
Arm 1, Cohort 1 
(FL)
Level (-1)
600 mg by mouth daily
Level 1
400 mg by mouth daily
Arm 2, Cohort 2 
(MZL, MCL and CLL)
Level (-1)
200 mg by mouth daily
*Stated dose of venetoclax is the target (maximum) dose.
Table 8:Venetoclax dose-finding rules for Arms 1 and 2
Number of Patients with 
DLT at a Given Dose Level
Dose-Finding/Dose Decision Rules
<2 out of 6
This target dose will be used in expansion phase
≥2 out of 6 at DL1
Six (6) patients will be entered at dose level (-1).
≥2 out of 6 at DL (-1)
Further enrollment will be stopped, and a safety analysis will be 
performed to determine further course of action.


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3.1.2
Dose-Expansion Phase 
Once safety is confirmed, expansion cohorts (Cohorts 3 and 4 and Arms 3 and 4) will be enrolled 
to collect additional safety information as well as disease response (Figure 5). During the dose 
expansion portion of the study, all patients will receive magrolimab with obinutuzumab for 2 
cycles during the “window” period (i.e., Cycle -2 and Cycle -1) designed to assess for early clinical 
activity and correlates of response to magrolimab and obinutuzumab. The purpose of the window 
is to study the molecular and immunologic correlates of response to magrolimab-based therapy. It 
is not intended to provide complete information regarding the clinical activity of this doublet. 
After completing the window, venetoclax will be added with the dose determined from the dose-
finding cohorts as described above. Patients must fulfill the clinical and laboratory criteria 
mentioned in Table 9 below prior to addition of venetoclax. Patients with unequivocal PD during 
the treatment window who are tolerating therapy will be allowed to be moved immediately to the 
next phase (i.e., addition of venetoclax). After completion of Cycle 1, all patients will be treated 
with an additional five (5), 4-week cycles of triplet combination therapy (magrolimab and 
obinutuzumab and venetoclax). Final duration of therapy will be based on response to the first 6 
cycles of triplet combination therapy. FL, MZL and MCL patients who achieve a CR and CLL 
patients who achieve a CR with undetectable peripheral blood MRD by flow cytometry after 6 
cycles of triplet therapy will stop treatment but remain potentially eligible for an additional 6 cycles 
upon disease relapse provided that they still meet re-treatment criteria and the duration of CR is  
6 months.  Disease relapse is defined by conventional criteria for clinical relapse that is associated 
with radiographic progression. Additionally, for CLL patients, positive flow cytometry during 
follow-up will be considered relapsed for re-treatment. Reappearance of ctDNA is not considered 
disease relapse on this protocol.  Patients who achieve a PR after 6 cycles of triplet combination 
therapy will be eligible to receive an additional 6 cycles and then will stop treatment. 
Table 9: Criteria for commencing treatment with triplet combination therapy 
Parameter
Value
ECOG PS
0-2
Absolute neutrophil count (ANC)
≥ 1,000 /mm3 
Platelets
≥ 50,000 / mcL (transfusions permitted) 
Hemoglobin
≥ 9.0 g/dL (transfusions permitted) 
Renal function 
Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 
m2 as estimated by the Modification of Diet in Renal 
Disease (MDRD) abbreviated formula. If not on 
target, a 24 hour urine creatinine clearance can be 
used to directly measure.
Aspartate aminotransferase (AST) 
and alanine aminotransferase 
(ALT)
Patients without liver involvement with lymphoma
≤ 3.0 x the upper limit of normal (ULN)
Patients with liver involvement with lymphoma
≤ 5.0 x the upper limit of normal (ULN)


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3.1.3
Study Schemas
Figure 3: Arm 1: FL Dose-finding
Figure 4: Arm 2: MZL, MCL and CLL Dose-finding
Figure 5: Arms 3 and 4 – Dose Expansion 
3.1.4
Dose-Limiting Toxicity 
Dose limiting toxicities (DLTs) will be assessed during the venetoclax dose-finding for Arms 1 
and 2 as follows:  

the first 4 weeks of triplet combination therapy for patients enrolled in Arm 1, Cohort 1 
(C1D1 to C1D28) 


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
the first 5 weeks after starting venetoclax in Arm 2, Cohort 2 (C1D1 to C1D35). 
Dose reductions of magrolimab and obinutuzumab are not permitted during DLT assessment 
period. 
A DLT for this study is defined as any grade 3 or higher adverse event that is clinically relevant 
and deemed probably or definitely related to any of the study drugs or to the combination therapy, 
in the opinion of the Principal Investigator and occurs during the venetoclax dose-finding period 
with the exception of following: 
3.1.4.1
Non-hematologic AEs

Grade 3 nausea, vomiting, or diarrhea that persist ≤ 7 days with supportive care  

Grade 3 fatigue with improvement to ≤ grade 2 within 7 days

Grade 3 infection that improves to ≤ grade 2 after initiation of antimicrobials

Grade 3 electrolyte disturbances that improve to ≤ grade 2 within 72 hours with 
appropriate medical management and are not associated with other clinically 
significant consequences.

Grade 3 magrolimab- or obinutuzumab-infusion reactions that resolve to ≤ grade 1 
within 24 hours.  NOTE:   In a patient, if it is not clear if the AE is an infusion-related 
reaction (IRR), the patient may be replaced.  

Other grade 3 laboratory abnormality that is asymptomatic and deemed by the 
investigator to be not clinically significant 
3.1.4.2
Hematologic AEs 

Grade 3 neutropenia not associated with clinical sequelae 

Grade 3 thrombocytopenia not associated with  grade 2 bleeding  

Grade 3 anemia that lasts less than 3 days and responds to blood transfusion.  NOTE:  
Grade 3 hemolytic anemia that requires hospitalization or prolongation of existing 
hospitalization, is disabling, or limits self-care activities of daily life (ADLs) will be 
considered a DLT.

Grade 3 or 4 lymphopenia
3.1.5
Safety Ramp-Up of Venetoclax 
Patients with FL (Arms 1 and 3; Cohorts 1 and 3) will start venetoclax at target dose for that 
particular dose level. 
Intra-patient dose escalation of venetoclax will be performed with fixed doses of magrolimab and 
obinutuzumab for patients with MZL, MCL and CLL (Arms 2 and 4; Cohorts 2, 4, 5 and 6) during 
Cycle 1 (Table 10). If tolerated, venetoclax will be administered at the target dose level once daily 
for all subsequent cycles. 
NOTE: During safety ramp-up, an individual patient who experiences a DLT or toxicity that meets 
DLT criteria during dose expansion (serious toxicity) can have venetoclax dose reduced to the 
dose of venetoclax that was tolerated and continue treatment (Table 10), if felt to be in the best 
interests of the patient. Once DLT assessment is complete, all dose modifications during safety 
ramp-up will be conducted per Sections 3.3.2 and 3.3.3. DLT rules apply to all arms.  


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Table 10: Intrapatient ramped-up dose-escalation schedule for venetoclax in MZL, MCL 
and CLL patients
Patients with MZL, MCL and CLL 
(Arms 2 and 4)
Week of safety 
ramp-up period
DL(-1): 
200 mg
DL1: 
400 mg
1
20 mg
20 mg
2
50 mg
50 mg
3
100 mg
100 mg
4
200 mg
200 mg
5
200 mg
400 mg
3.2
DRUG ADMINISTRATION 
Treatment schedule from Cycles 1 to 12 is provided below (Table 11 and Table 12 for dose-
finding and dose-expansion respectively). A flexibility window between cycles of -3/+7 days is 
allowed due to scheduling or other administrative reasons; additional delays may apply based on 
toxicities.
Magrolimab doses will be calculated based on actual body weight measured at the most recent 
clinical assessment prior to administration. Patients will be encouraged to complete and return an 
optional drug diary as a memory aid to help document the date and time of all self-administered 
study drugs (Appendix D).  This drug diary as well as study drug containers and any unused study 
drug should be returned to the research team at the end of each cycle of therapy. 


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Table 11: Drug administration schedule for study medications for dose-finding cohorts 
Arm
Druga,b,c
Cycle 1
Arm 1: 28 days
Arm 2: 35 days
Cycles 2-12
Arms 1 and 2: 28 days
Magrolimab
D2: 1mg/kg
D8,15,22: 30mg/kg
D1,15: 30mg/kg
Obinutuzumab
D1: 100mg
D2: 900mg 
D8,15: 1000mg
D1: 1000mg
1
Venetoclax
D1-28: 
DL1: 800mg
DL(-1): 600mg
D1-28: 
DL1 800mg
DL(-1) 600mg
Magrolimab
D2: 1mg/kg
D8,15,22: 30mg/kg
D1,15: 30mg/kg
Obinutuzumab
D1: 100mg
D2: 900mg
D8,15: 1000mg
D1: 1000mg
2
Venetoclax
DL1:
D1-7: 20mg
D8-14: 50mg
D15-21: 100mg
D22-28: 200mg
D29-35: 400mg
DL(-1):
D1-7: 20mg
D8-14: 50mg
D15-21: 100mg
D22-28: 200mg
D29-35: 200mg
D1-28: 
DL1 400mg
DL (-1) 200mg
a When both magrolimab and obinutuzumab are given on the same visit day, obinutuzumab will be 
administered at least 1 hour after the completion of magrolimab administration.
b Premedication with acetaminophen 650 mg and diphenhydramine 25-50mg (or comparable regimen) 
will be administered 30-60 minutes prior to all obinutuzumab doses. Similar premedication will also be 
given prior to priming dose and first loading dose of magrolimab. Additional premedication with 
dexamethasone 4 to 20 mg or comparable regimen will be given before the priming dose and first loading 
dose of magrolimab. Premedication is not required for subsequent doses of magrolimab. 
c    Obinutuzumab and magrolimab are administered as intravenous infusions.


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Table 12: Drug administration schedule for study medications for expansion cohorts
Window
Triplet Combination
Cohort
Druga,b,c
Cycle-2
Cohorts 3, 4, 5, 
and 6: 28 days 
a,b,c
Cycle-1
Cohorts 3, 4, 5, 
and 6: 28 days 
a,b,c
Cycle 1
Cohort 3: 28 days
Cohort 4/5/6: 35 days 
a,b,c
Cycles 2-12
Cohorts 3, 4, 5, 
and 6: 28 days 
a,b,c
Magrolimab
D2: 1mg/kg 
priming dose
D8,15,22: 
30mg/kg
D1,15: 
30mg/kg
D1,15: 30mg/kg
D1,15: 30mg/kg
Obinutuzumab
D1: 100mg
D2: 900mg
D8,15: 1000mg
D1: 1000mg
D1: 1000mg
D1: 1000mg
3 
Venetoclax
N/A
N/A
D1-28: 
at target dose (dose 
established from dose-
finding cohorts)
D1-28: 
at target dose 
(dose established 
from dose-
finding cohorts)
Magrolimab
D2: 1mg/kg 
priming dose
D8,15,22: 
30mg/kg
D1,15: 
30mg/kg
D1,15: 30mg/kg
D1,15: 30mg/kg
Obinutuzumab
D1: 100mg
D2: 900mg
D8,15: 1000mg
D1: 1000mg
D1: 1000mg
D1: 1000mg
4, 5,6
Venetoclax
N/A
N/A
D1-35:
ramp-up to target 
dose (dose 
determined from 
dose-finding cohorts) 
D1-28: 
at target dose 
(dose established 
from dose-
finding cohorts)
a When both magrolimab and obinutuzumab are given on the same visit day, obinutuzumab will be administered at 
least 1 hour after the completion of magrolimab administration.
b Premedication with acetaminophen 650 mg and diphenhydramine 25-50mg (or comparable regimen) will be 
administered 30-60 minutes prior to all obinutuzumab doses. Similar premedication will also be given prior to 
priming dose and first loading dose of magrolimab. Additional premedication with dexamethasone 4 to 20 mg, or 
comparable regimen will be given before the priming dose and first loading dose of magrolimab. Premedication is 
not required for subsequent doses of magrolimab. 
c    Obinutuzumab and magrolimab are administered as intravenous infusions.
3.2.1
Magrolimab Administration
All patients will receive a magrolimab priming dose of 1 mg/kg on Day 2 of the first cycle of 
treatment. The duration of infusion of the priming dose will be 3 hours (±30 minutes). Use of an 
inline filter is required. All subsequent loading or maintenance doses of magrolimab will be infused 
over a duration of 2 hours (±10 minutes). When both obinutuzumab and magrolimab are given on 
the same visit day, obinutuzumab will be administered at least 1 hour after the completion of 


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magrolimab administration. All patients should be monitored for 1 hour post-infusion for all doses 
during Cycle -2. Post-infusion monitoring should begin after the last study drug is given. Post-
infusion monitoring is not required for doses after Cycle 1, Day 22 for Arms 1 and 2 (dose-finding 
arms), and Cycle -2, Day 22 for Arms 3 and 4 (dose expansion arms). Patients who experience any 
treatment-related AEs during the observation period should be further monitored, as clinically 
appropriate. 
Complete Blood Count with Differential will be performed prior to each dose, and 3-6 hours after 
the first and second doses of magrolimab - Cycle 1, Days 2 and 8 for dose-finding arms (Arms 1 and 
2), and Cycle -2, Days 2 and 8 for dose-escalation arms (Arms 3 and 4). Complete Blood Count with 
Differential will also be performed twice weekly for the first cycle (Cycle 1 for dose-finding arms 
[Arms 1 and 2], and Cycle -2 for dose-escalation arms [Arms 3 and 4]).
3.2.1.1
Premedication for magrolimab
The optimal pretreatment regimen is defined as acetaminophen 650 mg (or a comparable non-
steroidal anti-inflammatory agent) and oral or IV diphenhydramine 25 to 50 mg (or comparable 
regimen) for the priming dose and the first loading dose. Additional premedication with 
dexamethasone 4 to 20 mg will be given before the priming dose and first loading dose of 
magrolimab. Premedication is required before administration of the first 2 doses of magrolimab. 
Premedication is not required for subsequent doses unless the patient has experienced a prior grade 
3 infusion reaction; however, premedication for subsequent magrolimab treatments may be 
continued based on the treating physician’s clinical judgement and the presence/severity of prior 
infusion reactions. Intravenous corticosteroid (e.g., 100mg prednisone/prednisolone or 4 to 20mg 
dexamethasone or 80mg methylprednisolone) may be administered if a patient has experienced a 
prior grade 3 infusion reaction, or at investigator’s discretion. 
3.2.2
Obinutuzumab Administration
Table 13: Dose and infusion rate of obinutuzumab for all patients 
Day of treatment cycle
Dose of 
obinutuzumab
Rate of infusion
Day 1
100 mg
Administer at 25 mg/hr over 4 hours. Do not 
increase the infusion rate. 
Day 2
900 mg
If no IRR occurred during the previous infusion, 
administer at 50 mg/hr.
The rate of the infusion can be escalated in 
increments of 50 mg/hr every 30 minutes to a 
maximum rate of 400 mg/hr.
If the patient experienced an IRR during the 
previous infusion, start administration at 25 mg/hr. 
The rate of infusion can be escalated in increments 
of up to 50 mg/hr every 30 minutes to a maximum 
rate of 400 mg/hr.
Day 8
Cycle 1 
(Dose-finding, 
Arms 1 and 2)
Cycle -2 
(Dose expansion, 
Arms 3 and 4)
Day 15
1000 mg
If no IRR occurred during the previous infusion 
where the final infusion rate was ≥100 mg/hr, 


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Day of treatment cycle
Dose of 
obinutuzumab
Rate of infusion
Day 1
100 mg
Administer at 25 mg/hr over 4 hours. Do not 
increase the infusion rate. 
Day 2
900 mg
If no IRR occurred during the previous infusion, 
administer at 50 mg/hr.
The rate of the infusion can be escalated in 
increments of 50 mg/hr every 30 minutes to a 
maximum rate of 400 mg/hr.
If the patient experienced an IRR during the 
previous infusion, start administration at 25 mg/hr. 
The rate of infusion can be escalated in increments 
of up to 50 mg/hr every 30 minutes to a maximum 
rate of 400 mg/hr.
Cycle 1 
(Dose-finding, 
Arms 1 and 2)
Cycle -2 
(Dose expansion, 
Arms 3 and 4)
Day 8
1000 mg
If no IRR occurred during the previous infusion 
All subsequent 
cycles (all arms)
Day 1
1000 mg
infusions can be started at a rate of 100 mg/hr and 
increased by 100 mg/hr increments every 30  
minutes to a maximum of 400 mg/hr. 
If the patient experienced an IRR during the 
previous infusion administer at 50 mg/hr. The rate 
of the infusion can be escalated in increments of 
50mg/hr every 30 minutes to a maximum rate of 
400 mg/hr.
3.2.2.1
Premedication for Obinutuzumab 
Detailed guidance for the optimal pretreatment regimen is provided below (Table 14). 


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Table 14:Premedication recommendations for obinutuzumab
Day of 
treatment cycle
Patients requiring 
premedication
Premedication
Administration
Intravenous 
corticosteroid1
Acetaminophen 650 mg or 
equivalent NSAID 
Cycle 1, Days 1 and 2 
(Dose-finding, Arms 1 
and 2)
Cycle -2, Days 1 and 
2 (Dose expansion, 
Arms 3 and 4)
All patients
Anti-histaminic2 
Administered 30-60 
minutes before 
obinutuzumab infusion
Acetaminophen 650 mg or 
equivalent NSAID
All subsequent 
infusions3
All patients
Anti-histaminic2
Administered 30-60 
minutes before 
obinutuzumab infusion
1 100 mg prednisone/prednisolone or 20mg dexamethasone or 80mg methylprednisolone. Hydrocortisone should 
not be used as it has not been effective in reducing rates of IRR. 
2 For example:  25 or 50 mg diphenhydramine or equivalent 
3 Additional premedications may be given based on PI discretion and nature of previous infusion reactions
3.2.3
Venetoclax administration 
Venetoclax should be taken with a meal. If vomiting occurs within 15 minutes after taking 
venetoclax and all expelled tablets are still intact, another dose may be given.  Otherwise, no 
replacement dose is to be given.  In cases where a dose of venetoclax is missed or forgotten, the 
patient should take the dose as soon as possible and ensure that the minimal interval between the 
current dose and the next dose is at least 16 hours in order to avoid excessive drug accumulation 
after the next dose.
Venetoclax will be dispensed to patients in bottles. All doses of venetoclax taken in the clinic or 
day hospital should be taken from the bottle dispensed to the subject. Unused venetoclax tablets 
dispensed during previous visits must be returned. Returned tablets must not be re-dispensed to 
anyone. 
Patients will be encouraged to complete and return an optional drug diary as a memory aid to help 
document the date and time of all self-administered study drugs (Appendix D).  


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3.3
DOSE MODIFICATIONS 
The following sections detail dose modifications/delay guidelines for each individual drug of the 
window or triplet combination regimen based on documented toxicity. It is the responsibility of 
the investigator to determine the most likely agent responsible for the observed toxicity and follow 
dose modification/delay guidelines in the appropriate section listed below. Dose reductions or 
delay for multiple study agents based on the same toxicity is not necessary and dosing should be 
modified or delayed only for the most likely offending agent identified by the investigator.
Dose adjustments are to be made according to the system showing the greatest toxicity. If a patient 
experiences several toxicities and there are conflicting recommendations, the recommended dose 
adjustment that reduces the dose to the lowest level will be used. 
Dose modifications of magrolimab and obinutuzumab are not allowed throughout the study 
treatment, only dose delays can be considered per investigator’s discretion. If AEs occur that are 
related to either of these infusional agents, then dose delays of up to 2 weeks during the window 
period, and up to 4 weeks during the triplet therapy, are permitted until the investigator feels it is 
safe to resume. If, after the delay the investigator does not feel it is safe to re-initiate therapy with 
magrolimab or obinutuzumab, then the patient should be taken off study treatment.  
3.3.1
Exceptions to Dose Modifications/Delays during DLT Evaluation Windows
3.3.1.1
During venetoclax dose-finding (addition of venetoclax to magrolimab and 
obinutuzumab)
Dose delays of magrolimab and obinutuzumab should be avoided during the DLT assessment (i.e., 
Cycle 1 of triplet combination therapy in Arms 1 and 2) to allow for identification of toxicities. If 
a patient experiences a DLT to triplet combination therapy, then all study therapy should be held 
for up to 2 weeks per the investigator. If DLT resolves and it is deemed safe to re-initiate therapy, 
then magrolimab and obinutuzumab should be re-started at the prior dose, and venetoclax should 
be re-started at one dose level lower. Dose levels for venetoclax dose modifications are mentioned 
in the table below (Table 15).
Table 15: Venetoclax dose levels for dose-modifications
Dose level
Cohorts 1,3
(FL)
Cohorts 2, 4, 5, 6
(MZL, MCL, CLL)
DL-3
200 mg
50 mg
DL-2
400 mg
100 mg
DL-1
600 mg
200 mg
DL1 
800 mg
400 mg
3.3.2
Modifications for Hematologic Toxicity
Dose modifications for hematologic toxicities must be done according to the guidelines below 
(Table 16). The investigator may judge a more conservative dose modification if appropriate.  
Therefore, if these guidelines are not followed, the rationale for other measures is to be 
documented in detail in the patient’s medical record. Use of growth factors (filgrastim, 
pegfilgrastim, etc.) and transfusion support is permitted per investigator’s discretion. 


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Table 16: Dose modifications for hematologic toxicity 
Event(s)
Dose Delay or Modification
CTCAE Grade 3 or 
4 neutropenia, 
without infection or 
fever
CTCAE Grade 3 or 
4 thrombocytopenia
Febrile neutropeniaa,
CTCAE Grade 3 or 
4 anemia
During window period
Delay next magrolimab and obinutuzumab infusion until toxicity recovers to ≤ 
Grade 2. Upon recovery to ≤ Grade 2, resume previous doses of magrolimab 
and obinutuzumab. Dose delays of longer than 2 weeks are not permitted. 
During triplet therapy after DLT assessment (Cycle 1, Arms 1 and 2)
Hold venetoclax and delay next magrolimab and obinutuzumab infusions until 
toxicity recovers to ≤ Grade 2. 
If toxicity recovers to ≤ Grade 2, patient may be treated at one venetoclax dose 
level lower.b Dose delays of longer than 4 weeks are not permitted. 
CTCAE = Common Terminology Criteria of Adverse Events; 
a. These patients should recover from neutropenia, without fever
b. If subsequent treatment with venetoclax at lower dose levels does not result in recurrent Grade 3 or higher 
hematologic toxicity, the dose of venetoclax can be increased to the original dose level during later cycles.
3.3.3
Modifications for Non-hematologic Toxicity (for all toxicities except as specified 
below)
Dose modifications for non-hematologic toxicities are outlined below (Table 17). The investigator 
may judge a more conservative dose modification appropriate; therefore, if these guidelines are 
not followed, the rationale for other measures is to be documented in detail in the patient’s medical 
record.


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Table 17: Dose modifications for non-hematologic toxicity
Event(s)
Dose Delay or Modification
Grade 1-2a 
No dose reduction or delay is necessary. Symptomatic management per 
investigator’s discretion. 
Grade 3a 
During window period 
Delay next magrolimab and/or obinutuzumab infusion for a maximum of 2 
weeks. If improvement to Grade ≤ 2 or baseline, resume previous doses of 
magrolimab and obinutuzumab. Dose delays of longer than 2 weeks are not 
permitted.
During triplet therapy after DLT assessment (Cycle 1, Arms 1 and 2)
Per investigator’s discretion, venetoclax, magrolimab and obinutuzumab can be 
delayed for a maximum of 4 weeks. 
First episode: If improvement to Grade ≤ 2 or baseline, resume previous doses 
of venetoclax, magrolimab and/or obinutuzumab.
For subsequent episodes: If improvement to Grade ≤ 2 or baseline, venetoclax 
can be restarted at one dose level lower.b 
≥3 episodes: Consider permanent discontinuation of the offending agent. 
Permanent discontinuation of all study treatment may be considered per 
investigator’s discretion.  
Grade 4a 
Permanently discontinue all study treatment
Toxicity requiring 
delay for >4 weeks
Permanently discontinue all study treatment
a.
Appropriate supportive care may be provided per investigator’s judgement.
b.
If subsequent treatment with venetoclax at lower dose levels does not result in recurrent Grade 3 or 
higher hematologic toxicity, the dose of venetoclax can be increased to the original dose level during 
later cycles.
3.3.4
Infusion Reactions to Magrolimab 
Infusion-related reactions are defined by the NCI CTCAE Version 5.0 under “Injury, poisoning 
and procedural complications” as follows: “a disorder characterized by adverse reaction to the 
infusion of pharmacological or biological substances.” The time frame for infusion reaction 
assessment is the 24-hour period beginning from the start of the magrolimab infusion. Re-
challenge of patients has not resulted in worsening of any adverse reaction and patients who 
continue on therapy following an initial infusion reaction have tolerated subsequent treatments 
without incident. There have been no late hypersensitivity reactions. 
3.3.4.1
Grade 1
For Grade 1 symptoms (mild transient reaction; infusion interruption not indicated; intervention 
not indicated):

Monitor patient until recovery from symptoms.


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
Patients who experience IRRs with the first 2 doses of magrolimab should continue 
premedication with corticosteroids prior to subsequent doses at the Principal Investigator’s 
discretion.
3.3.4.2
Grade 2
For Grade 2 IRR, described as requiring symptomatic treatment and prophylactic medications 
(e.g. antihistamines, non-steroidal anti-inflammatory drugs, narcotics, corticosteroids, IV fluids) 
for ≤ 24 hours, infusion interruption is indicated:

Stop the magrolimab infusion, begin an IV infusion of normal saline, and treat the patient 
with diphenhydramine 50 mg IV (or equivalent) and/or 500 to 750 mg oral 
paracetamol/acetaminophen.

Monitor patient until resolution of symptoms.

Corticosteroid therapy may also be administered.

If the infusion is interrupted, wait until symptoms resolve, then restart the infusion at 50% 
of the original infusion rate when symptoms resolve.

If no further complications ensue after 60 minutes, the rate may be increased to 100% of 
the original infusion rate. Monitor the patient closely.

If symptoms recur, then stop infusion and disconnect the patient from the infusion 
apparatus; no further magrolimab will be administered at that visit. 

Patients who experience IRR with the first 2 doses of magrolimab should continue 
premedication with corticosteroids prior to subsequent doses at the Principal Investigator’s 
discretion.

Patients who experience an infusion reaction of Grade 2 during the 4-hour post-infusion 
observation period that does not resolve during that time should be observed for 24 hours 
or until the adverse event resolves, with vital sign measurements every 4 hours and 
additional evaluations as medically indicated for the management of the adverse event.
3.3.4.3
Grade 3 or 4
For Grade 3 IRR described as prolonged reactions or recurrence of symptoms following initial 
improvement, or where hospitalization indicated for other clinical sequelae (e.g., renal impairment, 
pulmonary infiltrates), or Grade 4 IRR described as having life-threatening consequences, where 
urgent intervention is indicated:

Immediately discontinue infusion of magrolimab.

Begin an IV infusion of normal saline. Systemic steroids, bronchodilators and/or 
epinephrine may be used as per institutional guidelines.

The patient should be monitored until the investigator is comfortable that the symptoms
will not recur.

Patients who have Grade 3 infusion reactions with the first dose can be offered the 
opportunity to stay on study and must be given premedication prior to subsequent doses. 
In this setting, premedication with acetaminophen (650 mg PO), diphenhydramine (25-50 
mg PO or IV) and dexamethasone (4-20 mg IV), or a comparable regimen, is recommended 
for the subsequent 2 doses. Long-term premedication can be discontinued if clinically 
indicated, for example if the patient does not demonstrate further infusion reactions after 
multiple doses.


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
In patients who receive premedication and still experience a recurrent Grade 3 infusion 
reaction, or patients who experience a Grade 4 IRR at any time should be permanently 
discontinued from the study treatment. 

All patients with Grade 3 or greater infusion related reactions will be observed for an 
additional 24 hours or longer until the adverse event resolves, with vital sign measurements 
every 4 hours and additional evaluations as medically indicated for the management of the 
AE.

In the case of late-occurring hypersensitivity symptoms (e.g., appearance of localized or 
generalized pruritus after Day 1 but within 1 week after treatment), symptomatic treatment 
may be given (e.g., oral antihistamine or corticosteroids).
3.3.5
Infusion Reactions to Obinutuzumab
The most frequently observed adverse drug reactions (ADRs) in patients receiving obinutuzumab 
were IRRs which occurred predominantly during infusion of the first 1000 mg. In patients with 
CLL who received the combined measures for prevention of IRRs (adequate corticosteroid, oral 
analgesic/anti-histamine, omission of antihypertensive medication), a decreased incidence of IRRs 
of all grades was observed. The rates of Grade 3-4 IRRs (which were based on a relatively small 
number of patients) were similar before and after mitigation measures were implemented. The 
incidence and severity of infusion-related symptoms decreased substantially after the first 1000 
mg was infused, with most patients having no IRRs during subsequent administrations of 
obinutuzumab.
In the majority of patients, irrespective of indication, IRRs were mild to moderate and could be 
managed by the slowing or temporary halting of the first infusion, but severe and life-threatening 
IRRs requiring symptomatic treatment have also been reported. IRRs may be clinically 
indistinguishable from IgE-mediated allergic reactions (e.g., anaphylaxis). Patients with a high 
tumor burden and/or high circulating lymphocyte count in CLL [> 25 x 109/L] may be at increased 
risk of severe IRR. Rate modifications depending on the severity of IRRs are provided in the table 
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Table 18: Obinutuzumab infusion rate modifications for infusion-related reactions
Grade
Intervention
Grade 1-2 
(mild and 
moderate)
Reduce infusion rate and treat symptoms.
Upon resolution of symptoms, continue infusion.
If patient does not experience any IRR symptoms, infusion rate escalation may 
resume at the increments and intervals as appropriate for the treatment dose (see 
Table 13 and Table 14).
For CLL patients receiving the Cycle -2, Day 1 dose split over 2 days, the Day 1 
infusion rate may be increased back up to 25 mg/hr after 1 hour, but not increased 
further.
Grade 3 
(severe)
Temporarily interrupt infusion and treat symptoms.
Upon resolution of symptoms, restart infusion at no more than half the previous rate 
(the rate being used at the time that the IRR occurred). If patient does not experience 
any further IRR symptoms, infusion rate escalation may resume at the increments 
and intervals as appropriate for the treatment dose (see Table 13 and Table 14:).
For CLL patients receiving the Cycle -2, Day 1 dose split over 2 days, the Day 1 
infusion rate may be increased back up to 25 mg/hr after 1 hour, but not increased 
further.
If the patient experiences a second occurrence of a Grade 3 IRR, stop infusion and 
permanently discontinue therapy.
Grade 4 
(life-threatening)
Stop infusion and permanently discontinue therapy.
3.4
SAFETY MANAGEMENT GUIDELINES FOR OTHER COMMON TOXICITIES
Guidelines for management of other common anticipated toxicities from study medications will 
be discussed in this section. It is emphasized that these are general guidelines and may or may not 
be followed depending on the patient’s clinical situation and investigator’s judgement. Other 
supportive measures which the investigator deems appropriate for the clinical situation, may be 
utilized. Therefore, if other measures are used, it must be documented appropriately. 
3.4.1
Tumor Lysis Syndrome (Venetoclax and Obinutuzumab)
See Section 4.1.2
3.4.2
Magrolimab
3.4.2.1
Anemia 
Treatment with a priming dose of 1 mg/kg followed by higher weekly maintenance dosing is 
associated with an early, transient, acute decline in hemoglobin levels of about 2 g/dL, with nadirs 
occurring in most patients within the first 2 weeks of starting therapy. In most patients with 
adequate bone marrow reserve, hemoglobin levels gradually recovery to baseline by Week 4 or 
later, despite continued treatment with magrolimab. Based on these data, all patients must have a 
documented hemoglobin ≥ 9 g/dL within 24 hours prior to each of the first 2 doses of magrolimab 
infusion during initial treatment. Patients who do not meet these criteria must be transfused and 
have their hemoglobin rechecked to meet ≥ 9 g/dL prior to each of the first 2 doses of magrolimab. 
For patients after exposure to magrolimab, hemoglobin will be monitored frequently for response 


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and/or toxicity prior to each dose, and 3 to 6 hours after the initiation of the first and second doses 
of magrolimab. The patient should be transfused as clinically appropriate.
Magrolimab binds to RBCs and may cause transient interference with cross-matching of units for 
transfusion. During the screening period, red blood cell typing per NIH CC guidelines will be 
performed for each patient. For all elective red cell transfusions, leukocyte-reduced units matched 
for the phenotype of the patients will be used. Where exact matching for all the specified blood 
groups proves impractical (e.g., for MNS blood group), local sites will decide on the best matched 
donor units to be used. Cytomegalovirus (CMV) matching (i.e., CMV-seronegative units for 
CMV-seronegative patients) will not be required for this study because it will limit the inventory 
for antigen matching.  
If the crossmatch is incompatible, the RBC units that are Coombs crossmatch-incompatible will 
be selected (e.g., phenotype-matched or least incompatible) for issue at the discretion of the local 
site’s Transfusion Service Medical Director or equivalent person, where available. For emergency 
transfusions, the transfusion laboratory may consider using emergency Group O Rhesus negative 
units if phenotyped units are not available. Blood plasma therapy will be blood-type specific. 
Platelets will be blood type compatible whenever possible, and if not, will have been tested and 
found not to have high titer anti-A or anti-B. 
3.4.2.2
Pneumonitis
Pneumonitis has been infrequently observed in patients receiving magrolimab. Generally,
immune-related AEs have not been observed in clinical use with magrolimab. In contrast to
T-cell checkpoint inhibitors, magrolimab primarily exerts its antitumor efficacy through
macrophage-mediated phagocytosis of tumor cells. Nonspecific T-cell or other host immune
responses that are seen with T-cell checkpoint inhibitors have not been observed with
magrolimab in nonclinical studies. Additionally, no events of macrophage activation syndrome
or hemophagocytic lymphohistiocytosis have been reported in clinical studies. In instances of 
suspected pneumonitis, first rule out noninflammatory causes (e.g. infections). If a
noninflammatory cause is identified, treat accordingly and continue therapy per protocol. Evaluate 
with imaging (e.g. chest x-ray or CT) and pulmonary consultation. Management of potential 
pneumonitis follows ASCO guidelines for immune-related AEs. Patients who experience Grade 3 
to 4 pneumonitis will be permanently discontinued from study treatment.
3.4.2.3
Thromboembolic Events
Thromboembolic events, including deep vein thromboses and pulmonary embolisms, have been
reported in some patients receiving magrolimab, sometimes early in therapy. Available data for
magrolimab do not support a clear or consistent relationship between clinical thromboembolic 
events and magrolimab use. Patients should be closely monitored for the symptoms of
thromboembolic events and treated accordingly.
3.4.2.4
Severe Neutropenia Prophylaxis
Severe neutropenia and febrile neutropenia were reported in patients treated with magrolimab in
combination with chemotherapy. Close monitoring of hematologic parameters including 
neutrophils is required for all patients treated with
magrolimab. For patients with high risk of developing Grade 4 neutropenia and febrile
neutropenia, primary and secondary prophylaxis with G-CSF is highly recommended.
Prophylactic use of antimicrobials may be considered at the discretion of the treating physician. 
Management of neutropenia and dose modifications will be per Section 3.3.2.


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3.4.2.5
Serious Infections
Patients (with or without neutropenia) should be regularly monitored for signs and symptoms of
infection. For patients with prolonged neutropenia or patients at risk, consider infection
prophylaxis including antibiotics (eg. fluoroquinolone) or antifungal agents (eg. oral triazoles or
parenteral echinocandin) in accordance with current guidelines.

For patients being treated for serious infections, hold the next dose of magrolimab until 
the infection has resolved clinically.

For serious infections that remain active for ≥ 14 days, consider discontinuation of 
magrolimab.
3.4.3
Obinutuzumab
3.4.3.1
Hypersensitivity Reactions 
Hypersensitivity reactions with immediate (e.g., anaphylaxis) and delayed onset (e.g., serum 
sickness), have been reported in patients treated with obinutuzumab. If a hypersensitivity reaction 
is suspected during or after an infusion (e.g., symptoms typically occurring after previous exposure 
and very rarely with the first infusion), the infusion should be stopped, and treatment permanently 
discontinued. Patients with known hypersensitivity to obinutuzumab must not be treated. 
Hypersensitivity may be clinically difficult to distinguish from infusion related reactions.
3.4.3.2
Worsening of Pre-existing Cardiac Conditions
In patients with underlying cardiac disease, arrhythmias (such as atrial fibrillation and 
tachyarrhythmia), angina pectoris, acute coronary syndrome, myocardial infarction and heart 
failure have occurred when treated with obinutuzumab. These events may occur as part of an IRR 
and can be fatal. Therefore, patients with a history of cardiac disease should be monitored closely. 
In addition, these patients should be hydrated with caution in order to prevent a potential fluid 
overload.
3.4.3.3
Hepatitis B Reactivation 
HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can 
occur in patients treated with anti-CD20 antibodies including obinutuzumab. HBV screening 
should be performed in all patients before initiation of treatment with obinutuzumab. At minimum 
this should include HBsAg-status and HBcAb-status. These can be complemented with other 
appropriate markers as per local guidelines. Patients with active Hepatitis B disease should not be 
treated with obinutuzumab. Patients with positive hepatitis B serology should consult liver disease 
experts before start of treatment and should be monitored and managed following local medical 
standards to prevent hepatitis reactivation. 
3.4.3.4
Progressive Multifocal Leukoencephalopathy (PML)
PML has been reported in patients treated with obinutuzumab. The diagnosis of PML should be 
considered in any patient presenting with new-onset or changes to preexisting neurologic 
manifestations. The symptoms of PML are nonspecific and can vary depending on the affected 
region of the brain. Motor symptoms with corticospinal tract findings (e.g., muscular weakness, 
paralysis, and sensory disturbances), sensory abnormalities, cerebellar symptoms, and visual field 
defects are common. Some signs/symptoms regarded as “cortical” (e.g., aphasia or visual-spatial 
disorientation) may occur. Evaluation of PML includes, but is not limited to, consultation with a 
neurologist, brain MRI, and lumbar puncture (cerebrospinal fluid testing for JCV DNA). Therapy 
with obinutuzumab should be withheld during the investigation of potential PML and permanently 


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discontinued in case of confirmed PML. Discontinuation or reduction of any concomitant 
immunosuppressive therapy should also be considered. The patient should be referred to a 
neurologist for the evaluation and treatment of PML.
3.5
ON STUDY EVALUATIONS
Upon successful enrollment, and following completion of the Screening/Baseline visits, patients 
will begin treatment as outlined in Section 3.1. The results from all procedures/tests must be 
reviewed prior to initiation of each cycle of treatment for consideration of dose modifications.  
Treatment with magrolimab, obinutuzumab, and venetoclax will continue until discontinuation per 
study protocol (Section 3.1), disease progression, unacceptable treatment-related toxicity, or other 
reasons outlined in Section 3.9. Refer to the Study Calendar (Appendix G) for additional 
information for all tests and procedures to be performed prior to each visit and in follow-up. 
3.6
TREATMENT CONSIDERATIONS/EXCEPTIONS
3.6.1
Treatment Beyond Progression (“Pseudo-progression”)
A minority of patients treated with immunotherapy such a magrolimab may derive clinical benefit 
despite initial evidence of progressive (PD). Patients suspected to have PD by response criteria 
will be permitted to continue study treatment beyond confirmed PD as measured by the appropriate 
evaluation criteria as long as they meet all of the following criteria as determined by the 
investigator:

Investigator assessed clinical benefit such as improvement in disease-related symptoms

Subject is tolerating therapy

Stable performance status

Absence of other signs and symptoms indicating disease progression 

Absence of evidence to suggest that other or alternative medical intervention or treatment 
is needed to treat the disease
Patients that meet the above criteria should have repeat radiographic evaluation within 6 weeks of 
initial investigator-assessed progression to determine whether there has been a decrease in the 
tumor size or continued PD.
3.7
POST-TREATMENT/FOLLOW-UP EVALUATIONS
Please see the Study Calendar (Appendix G) for all applicable windows and complete 
information.  
3.7.1
30-Day Safety Follow-Up visit
The mandatory Safety Follow-Up visit should be performed approximately 30 days following the 
last dose of study drug or before the first dose of new anti-cancer therapy, whichever comes first. 
Refer to the Study Calendar (Appendix G) for all tests and procedures to be conducted upon 
discontinuation of treatment and during follow-up. All AEs that occur prior to the safety follow-
up visit should be recorded. See section 6.1.1 for documentation of AEs after study treatment has 
ended. The investigator or qualified designee will collect information about the new anti-neoplastic 
therapy initiated after the last dose of trial treatment. Once new anti-cancer therapy has been 
initiated the subject will move into survival follow-up.


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3.7.2
Follow-Up Visits – Prior to Disease Progression
Patients who discontinue trial treatment for a reason other than disease progression will move into 
the Follow-Up Phase and should be assessed approximately as follows:  every 3 months for two 
years after completion of study therapy, every 6 months for years 3-5, and then annually thereafter 
at the discretion of the investigator. Any other evaluations and tests should be performed as 
clinically indicated. After 5 years of monitoring without disease progression the decision to 
continue further surveillance imaging, including any assessments and procedures, will be left to 
the discretion of the investigator.  
3.7.3
Follow-Up Evaluations – Survival/Post Disease Progression 
Upon disease progression or initiation of other anti-cancer therapy, the subject moves into the 
survival follow-up phase and should be contacted about every 3 to 6 months for survival status 
until death, withdrawal of consent, or the end of the study, whichever occurs first; unless otherwise 
clinically indicated.  


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3.8
STUDY CALENDAR
See Appendix G.
3.9
COST AND COMPENSATION
3.9.1
Costs 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center. If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs if they are 
not covered by their insurance company.  Medicines that are not part of the study treatment will 
not be provided or paid for by the NIH Clinical Center.    
3.9.2
Compensation
No compensation will be provided to patients for participating in this study. 
3.9.3
Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate. The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy.   
3.10
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
A safety visit will occur 30 days post last dose of study drug. Prior to removal from study, effort 
must be made to have all patients complete an additional safety visit 18 months after the last dose 
of obinutuzumab as obinutuzumab has the longest half-life out of the experimental drugs for this 
study.  Details of additional safety visits and follow-up will continue as per Section 3.7.
3.10.1 Criteria for Removal from Protocol Therapy

Disease progression
-
A patient may be granted an exception to continue on study treatment with initial 
radiographic progression if they meet the criteria outlined in Section 3.6
-
Patient who progresses prior to initiation of venetoclax will not be removed from 
the protocol, but will move on immediately to the triplet therapy or safety ramp-up 
phase

Completion of protocol therapy 

Intercurrent illness that prevents further administration of treatment

Requirement for use of prohibited therapies as listed in Section 4.2

Pregnancy

Patient requests to be withdrawn from protocol therapy

Noncompliance with trial treatment or procedure requirements in the opinion of the 
investigator; such a decision/rationale will be clearly noted in the medical record

Investigator’s decision to withdraw the patient if felt to be in the best interest of the 
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
Unacceptable adverse event(s) (see Section 3.3), unless it is felt by the Principal 
Investigator to be in the patient’s best interests to remain on study in exceptional 
circumstances (e.g., discontinue offending study agents while continuing others).
All subjects, regardless of reason for discontinuation of study treatment (with the exception of 
withdrawal of consent; unless consent to follow-up activities is documented) will be followed for 
progression and survival.
3.10.2 Off-Study Criteria
Patients who meet the following criteria should be discontinued from the study: 

Screen failure

Subject requests to be withdrawn from study

Subject is lost to follow-up

Death

Study is cancelled for any reason

Permanent loss of capacity to consent
3.10.3 Lost to Follow-up 
A participant will be considered lost to follow-up if he or she fails to return for 3 consecutive 
scheduled visits and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:

The site will attempt to contact the participant and reschedule the missed visit as soon as 
is possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, an IRB approved certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record or study file. 

Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
4
CONCOMITANT MEDICATIONS/MEASURES
4.1
PERMITTED THERAPY
All treatments that the investigator considers necessary for a subject’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care. 
Palliative and supportive care for the other disease-related symptoms and for toxicity associated 
with treatment will be offered to all patients in this trial. All concomitant medication will be 
recorded on the case report form (CRF) including all prescription, over-the-counter (OTC), herbal 
supplements, and IV medications and fluids.  If changes occur during the trial period, 
documentation of drug dosage, frequency, route, and date may also be included on the CRF.


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All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  
4.1.1
Growth factors
The use of hematopoietic growth factors filgrastim and pegfilgrastim are allowed. 
4.1.2
Tumor Lysis Syndrome (TLS)
4.1.2.1
TLS and Venetoclax
TLS is a risk for patients with NHL who are treated with high cell-killing agents, including 
venetoclax.  Changes in blood chemistries consistent with TLS that require prompt management 
can occur as early as 6 to 8 hours following the first dose of venetoclax.  The risk of TLS is a 
continuum based on multiple factors, including tumor burden and comorbidities.  Risk is highest 
for those with bulky disease, elevated leukocyte count, elevated pretreatment LDH levels, 
compromised renal function, and dehydration. We will perform tumor burden assessments, 
including radiographic evaluation (e.g., CT scan), assess blood chemistry (potassium, uric acid, 
phosphorus, calcium, and creatinine) in all patients and correct pre-existing abnormalities prior to 
initiation of treatment with venetoclax. 
Patients with MCL and CLL are at higher risk of TLS than FL. The risk is highest during the first 
5 weeks of ramp-up. A low starting dose followed by gradual dose ramp-up allows for the tumor 
size to be gradually reduced and has been effective in reducing the risk of TLS.  Hence, in our 
study, patients with MCL and CLL will undergo venetoclax dose ramped-up over 5 weeks, and 
the target dose will be lower than patients with FL. Limited data is available in patients with MZL 
and hence, as a safety measure, patients with MZL will also have venetoclax dose ramped-up over 
5 weeks. Also, we believe that use of magrolimab+obinutuzumab in the window period in our 
study may decrease bulk of disease in most of the patients resulting in reduced risk of TLS when 
venetoclax is commenced. 
The Cairo-Bishop Definition of TLS (clinical and laboratory) will be used in this study. See 
Appendix E for details. We will assess the risk for TLS based on clinical and radiological 
assessment (e.g., CT scan) prior to initiation of venetoclax treatment. For subjects at risk of TLS:

Guidelines for monitoring of clinical chemistries and administration of prophylaxis for the 
safety ramp-up period or period of risk are delineated in Table 19.  

Investigator may modify the management as s/he deems appropriate for patient’s clinical 
condition.


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Table 19: Recommended TLS prophylaxis and monitoring during Cycle 1 of venetoclax 
Blood Chemistry Monitoring
Tumor Burden
Prophylaxis
Setting and Frequency of Assessments
Low:
All LN <5 cm 
AND  
ALC <25 x109/L 
Hydration:
Oral (1.5-2 L)
Anti-hyperuricemics:
Allopurinola
CLL, MZL and MCL:

Pre-dose, 6 to 8 hours, and 24 hours after the first dose of the 
first two weeks of safety ramp-up during C1

Pre-dose at subsequent ramp-up doses
FL: 

Pre-dose, and 24 hours after the first dose of the first week 
venetoclax treatment

Pre-dose, on C1D8
Medium:
Any LN 
5 cm to <10 cm 
OR 
ALC ≥25 x109/L 
Hydration:
Oral (1.5-2 L) and 
consider additional 
intravenous fluids as 
tolerated
Anti-hyperuricemics:
Allopurinol
CLL, MZL and MCL:

Pre-dose, 6 to 8 hours, 24 hours after the first dose of the first 
two weeks of safety ramp-up during C1

Pre-dose at subsequent ramp-up doses 

Consider hospitalization for patients with CrCl <80ml/min at 
first two ramp-up doses; see below for monitoring in hospital 
FL: 

Pre-dose, and 24 hours after the first dose of venetoclax 
treatment

Pre-dose, on C1D8 and C1D15
High:
Any LN 
≥10 cm 
OR 
ALC ≥25 x109/L 
AND 
any LN ≥5 cm
Hydration:
Oral (1.5-2 L) or 
intravenous (150-200 
mL/hr as tolerated)c
Anti-hyperuricemics:
Allopurinol; consider 
rasburicaseb if baseline 
uric acid is elevated
CLL, MZL and MCL:
In hospital at first dose of the first two weeks of safety ramp-up 
during C1. 

Pre-dose, 4, 8, 12 and 24 hours 
Subsequent ramp-up doses 

Pre-dose, 6-8 hours, and 24 hours 
FL: 

Pre-dose, 6 to 8 hours, 24 hours at the first dose of 
venetoclax treatment

Pre-dose, weekly on D1 of each subsequent week during 
Cycle 1
* Hospitalization for high risk FL and MZL patients per 
investigator’s discretion.
a. Allopurinol 600 mg 24 hours prior to first dose of venetoclax, followed by 200 mg/m2 (maximum daily dose of 600 mg) in 
divided doses daily for a minimum of first 28 days of therapy. 
b. Rasburicase 0.2 mg/kg IV 24 hours prior to the first venetoclax dose. The dose may be repeated based on laboratory or 
clinical abnormalities, or per discretion of the investigator.
c. Intravenous fluids should be initiated at a rate of at least 1 mL/kg/hr (target 150-200 cc/hr; not <). Modification of fluid rate 
should also be considered for individuals with specific medical needs.
4.1.2.2
Recommendations for Initial Management and TLS Prevention 
4.1.2.2.1 First Dose of Venetoclax or Dose Escalation 
Within the first 24 hours after either the first dose or dose escalation, if laboratory criteria for TLS 
(Table 21) are met, the patient should be hospitalized for monitoring and the investigator notified. 
No additional venetoclax doses should be administered until resolution. 
-
Availability of emergency dialysis should be ensured 


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-
Intravenous (IV) fluids should be initiated at a rate of at least 1 mL/kg/h rounded to the 
nearest 10 mL (target 150-200 mL/hr; < 50 mL/hr). Modification of fluid rate should also 
be considered for individuals with specific medical needs.
The management recommendations below focus on the minimum initial responses required. If a 
diagnosis of TLS is established, ongoing intensive monitoring and multidisciplinary management 
will be as per institutional protocols.
4.1.2.3
For any occurrence of laboratory TLS:
-
Withhold the next day’s venetoclax dose. If resolved within 24 to 48 hours of last dose, 
resume at the same dose.
-
For any blood chemistry changes requiring more than 48 hours to resolve, resume at a 
reduced dose. 
-
For any events of clinical TLS, resume at a reduced dose following resolution
In addition to the above, additional recommendations for patients with chronic lymphocytic 
leukemia/ small lymphocytic lymphoma receiving first dose of venetoclax:
-
For potassium increase ≥ 0.5 mmol/L from baseline, AND > 5.0 mmol/L, recheck 
potassium, phosphorus, uric acid, calcium, and creatinine and follow guidelines per Section 
4.1.2.2.1
-
For phosphorus increase of > 0.5 mg/dL AND > 4.5 mg/dL, administer phosphate binder 
and recheck potassium, phosphorus, uric acid, calcium, and creatinine.
4.1.2.4
Tumor Lysis Syndrome from Obinutuzumab (Precautions During Cycle -2 of Dose-
Expansion)
TLS, including fatal TLS, has been reported with obinutuzumab. Patients with CLL or MCL who 
are treated with the combination of obinutuzumab and magrolimab are considered at risk of TLS 
if they have lymph nodes ≥ 5 cm or ALC ≥ 25 × 109/L, splenomegaly, renal dysfunction (Cr. Cl. 
< 70 mL/min) or baseline clinical chemistry abnormalities consistent with TLS as per Table 21. 
Patients during dose-finding portion of the study will commence obinutuzumab in combination 
with venetoclax, and the guidelines outlined in Section 4.1.2 must be followed. During dose-
expansion phase, however, patients will commence obinutuzumab in combination with 
magrolimab during Cycle -2 of the window period. CLL and MCL patients considered at risk of 
TLS when treated with obinutuzumab in combination with magrolimab must be treated and 
monitored as follows: 

Patients should receive IV or oral hydration (approximately 3 L per day recommended) 
starting 1 day before the first dose of obinutuzumab and should continue until and including 
D8 (approximately 3 L per day recommended).

Patients should be treated with uricostatics (such as allopurinol) or urate oxidase (such as 
rasburicase) as per label or local guidance. 

Patients should undergo laboratory assessments for TLS (uric acid, calcium, phosphate,  
potassium, and creatinine) and the results must be known on the same day the sample was 
taken.

D1 of Cycle -2

D2 of Cycle -2

D3 of Cycle -2


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
D8 of Cycle -2
4.1.3
Infectious prophylaxis for Pneumocystis Jiroveci
As mentioned in Section 1.2.6.2.1.2, patients with MZL who received obinutuzumab based therapy 
had a higher rate of Grade 3-5 AEs compared to patients with FL, including a higher rate of 
infections. All adult subjects with MZL will receive prophylaxis for Pneumocystis Jiroveci during 
study therapy administration. Trimethoprim/sulfamethoxazole 1 DS tablet by mouth on Monday, 
Wednesday, and Friday is the preferred schedule. Subjects allergic to either component may 
receive inhaled pentamidine 300 mg once a month or other standard treatments.
Prophylaxis will begin with initiation of treatment (Cycle 1, Day 1 of dose-finding or Cycle -2, 
Day 1 of dose expansion) and will be stopped upon completion of therapy unless continued 
administration beyond this point is deemed necessary based on inadequate immune reconstitution. 
The use of antibiotics and/or anti-viral prophylaxis according to institutional guidelines is also 
allowed.
4.2
PROHIBITED FOOD AND MEDICATIONS
Patients are prohibited from receiving the following therapies during treatment on this trial: 

Any therapies intended for the treatment of lymphoma/leukemia whether FDA approved 
or experimental (outside of this study)

Immunosuppressive therapy

Radiation therapy. NOTE: Radiation therapy to a symptomatic solitary lesion may be 
allowed at the investigator’s discretion.

Steroid treatment with doses higher than 20 mg of prednisone or equivalent for prolonged 
duration is not allowed. Short term treatment with high dose steroids for non-neoplastic 
intent (e.g., COPD) is allowed.  If a patient is on chronic corticosteroid therapy, 
corticosteroids should be de-escalated to the maximum allowed dose after the patient has 
signed the IC. Patients may be using topical or inhaled corticosteroids.

Strong CYP3A4 inhibitors around initiation of venetoclax as mentioned below in Section 
4.2.1.1.

Strong CYP3A inducers with venetoclax (Section 4.2.1.2)

Prohibited food:  Use of the following foods is prohibited for at least 3 days prior to 
initiation of venetoclax treatment and throughout venetoclax administration. Constituents 
of these foods have been shown to inhibit CYP3A4, the major enzyme responsible for the 
metabolism of venetoclax. Consumption of these foods could lead to increased venetoclax 
exposure:
o
Grapefruit 
o
Grapefruit products 
o
Seville oranges (included marmalade containing Seville oranges) 
o
Star fruit
It is not possible to produce an exhaustive list of medications that fall into these categories, so if 
in question, refer to the appropriate product label.


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4.2.1
Venetoclax and CYP3A and P-gp Inhibitors/Inducers
4.2.1.1
Venetoclax Use with CYP3A and P-gp Inhibitors
Concomitant use of venetoclax with moderate to strong CYP3A inhibitors during the ramp-up 
phase in MZL, MCL and CLL patients is contraindicated. Concomitant use of venetoclax with 
CYP3A inhibitors increases venetoclax exposure and may increase the risk for TLS at initiation 
and during ramp-up phase. For FL patients, moderate to strong CYP3A inhibitors are 
contraindicated for up to 2 weeks after initiation of venetoclax. At stable doses of venetoclax, 
attempts must be made to avoid concomitant use of strong or moderate CYP3A or P-gp inhibitors. 
However, the inhibitor may be used if needed per investigator discretion, with dose modifications 
as outlined in Table 20:.
Table 20: Management of potential venetoclax interactions with CYP3A and P-gp 
inhibitors 
Inhibitors
Ramp-Up Phase
Patients Receiving Stable Dose of Venetoclax
Strong CYP3A inhibitor
Contraindicated
Avoid inhibitor use or reduce the venetoclax dose by at 
least 75%
Moderate CYP3A inhibitor
P-gp inhibitor
Contraindicated
Avoid inhibitor use or reduce the venetoclax dose by at 
least 50%
NOTE:  Common CYP3A and P-gp inhibitors are mentioned in Appendix C. 
4.2.1.2
Venetoclax Use with CYP3A Inducers
Avoid concomitant use of venetoclax with strong CYP3A inducers (e.g., carbamazepine, 
phenytoin, rifampin, St. John’s wort). Moderate CYP3A inducers (e.g., bosentan, efavirenz, 
etravirine, modafinil, nafcillin) may be used per investigator’s discretion. Consider alternative 
treatments with less CYP3A induction.
5
CORRELATIVE STUDIES FOR RESARCH
5.1
BIOSPECIMEN COLLECTION
SUMMARY
One of the important exploratory aims of this study is to utilize multiplatform genomic analyses 
of tumor biopsies to identify biomarkers that predict response and/or resistance to magrolimab, 
both individually and in combination with venetoclax. To achieve this goal, tumor biopsies will 
be collected in all patients prior to therapy and optional biopsies will be obtained on patients with 
accessible sites of lymphoma involvement during the window period and at progression of disease. 
The Staudt lab will perform comprehensive molecular characterization of the tumors at baseline 
on FFPE blocks, and this evaluation will include whole-exome sequencing, transcriptome 
profiling, AffySNP6.0 arrays for copy number abnormalities, and emerging technologies such as 
single cell RNA sequencing. Single cell RNA sequencing will be repeated on tumor biopsies 
obtained during the window period, and upon progression. We also plan to analyze the tumor 
biopsies obtained at baseline, during window period, and upon progression with histo-cytometry 
in Dr. Germain’s lab.
Blood and bone marrow samples will be collected for exploratory objectives to evaluate 
biomarkers of sensitivity or resistance.  In blood, circulating tumor DNA (ctDNA) response and 


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correlation with molecular tumor analysis, is planned. We will use a modern ctDNA platform that 
combines universal PCR primers for the variable-dense-joining (VDJ) region of the 
immunoglobulin receptor with next-generation sequencing (NGS) technologies (i.e., 
clonoSEQ)(118). 


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Research Samples Calendar – Bloods:  
Time Points#
Window†
Triplet Combination 
Therapy
Post-
Treatment
Sample
Collection Details*
Baseline
Cycle 
-2 D1
Cycle 
-2 D8
Cycle 
-2 D15
Post-
Cycle
-2
Post-
Cycle
-1
D1 of 
Cycles 
1, 3, 7 
& 11∆
D1 of 
Cycles 1, 
3, 5 & 9; 
Post-
Cycle 12∂
Post-
Cycles
3, 6, 9 
& 12
Years 
1-2=
q3mos; 
Years 2-5=
q6mos
PD
Supervising 
Laboratory/ 
Investigator
cfDNA/ctDNA, 
Mutational panels (liquid 
biopsy), Plasma banking
1 x 10 mL Streck 
tubes 
X
X
X
X
X
X
X
X
Immune subsets, Protein, 
Immune Markers
2 x 8-10 mL CPTs 
(sodium citrate) 
X
X
X
X
X
X
X
X
Cytokine analysis, 
Serum banking
1 x 10 mL in SST 
tube
X
X
X
X
X
X
X
X
Figg
Flow cytometry
Peripheral blood 
per SOC
X
X
X
X
X
X
X
X
NCI LP
Magrolimab 
pharmacokinetics 
1 x 3.5mL in red 
SST
X
X
X
Figg/ PPD 
Richmond
Magrolimab ADA
1 x 3.5mL in red 
SST
X
X
X
Figg/ PPD 
Richmond
* Tubes/media may be adjusted at the time of collection based upon materials available or to ensure the best samples are collected for planned analyses.
# All timeframes may be adjusted to similar windows as the Study Calendar (Appendix G).  
† Samples from the window period will be available only for patients enrolled in dose-expansion cohorts (Cohorts 3, 4, 5 and 6).   
∆ For patients in dose-expansion cohorts (Cohorts 3, 4, 5 and 6).
∂ For patients in dose-finding cohorts (Cohorts 1 and 2).
NOTE:  
All blood samples/tubes should remain at ambient temperature after collection and processed on the day of collection; do not place samples on ice unless otherwise 
instructed.
Subjects who discontinue treatment for a reason other than disease progression and who do not start new treatment should continue to have samples collected at the 
scheduled time points.


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Research Samples Calendar – Tissue/Other:  
Sample
Collection Details*
Time Points
Supervising 
Laboratory/ 
Investigator
Tissue Samples
Archival and/or 
Fresh Tissue Biopsy
FFPE (block or slides); biopsy is required if 
archival is not adequate or unavailable
Excision (single or multiple nodes) or core 
(6 passes); placed in formalin/FFPE and 
media, as appropriate
Baseline; if required for adequate tissue 
During 1st cycle (Cycle -2; preferably day 8) of doublet therapy 
with magrolimab + obinutuzumab in window period (optional)†
At disease progression/end of treatment  
Staudt, Germain, 
NCI LP
Tissue/Imaging 
Analyses 
No additional tissues or imaging will be performed for these analyses, only use of already collected samples 
and/or imaging, as described in Section 5.3.6
Ahlman
Other Samples
Germline DNA
Blood, Buccal swab, or Saliva (preferred)
Baseline
Figg
Bone marrow 
aspirate (± flow 
cytometry) and 
biopsy
Aspirate (± flow cytometry) (SOC; 
heparinized tubes or EDTA/sodium heparin 
or formalin, as appropriate)
Biopsy (SOC; formalin or no media, as 
appropriate)
Baseline
During 1st cycle of doublet therapy with magrolimab + 
obinutuzumab (Cycle -2; preferably day 8) in window period 
(optional)† 
At disease progression or suspicion of CR 
After Cycle 6 of triplet therapy (magrolimab + obinutuzumab + 
venetoclax) in patients with involvement at baseline. For 
patients with no baseline bone marrow involvement, biopsy 
may be performed per investigator’s discretion.
Figg, 
NCI LP\
*Tubes/media may be adjusted at the time of collection based upon materials available or to ensure the best samples are collected for planned analyses.
†Samples from the window period will be available only for patients enrolled in dose-expansion cohorts (Cohorts 3, 4, 5 and 6)
NOTE:  
All samples/tubes should remain at ambient temperature after collection and processed on the day of collection; do not place samples on ice unless 
otherwise instructed.
Subjects who discontinue treatment for a reason other than disease progression and who do not start new treatment should continue to have samples 
collected at the scheduled time points.


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5.2
SAMPLE COLLECTION AND PROCESSING
5.2.1
Summary
The planned analyses described below may be done on leftover and/or shared sample portions 
from the respective laboratories, as needed.  In addition to the prospectively collected samples 
below, leftover portions of samples sent for routine laboratory testing (e.g., plasma from 
CBC/other hematology labs) may also be retrieved for research tests prior to being discarded.  The 
planned prospective analyses are identified below; laboratories may share resources or collaborate 
on analyses, if appropriate (e.g., isolation/analysis of DNA not prospectively planned by one lab 
may be incorporated if needed during the planned analyses).
Portions of all samples may be banked for future research analyses; prospective consent will be 
obtained during the informed consent process.  
5.2.2
Blood Samples – Figg Lab
For questions, please contact Dr. Figg’s Clinical Pharmacology Program (CPP) at 240-760-6180 
(main blood processing core number) or, if no answer, 240-760-6190 (main clinical pharmacology 
lab number).  Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting 
samples (the Friday before is preferred).  For sample pickup, page 102-11964.  For questions 
regarding sample processing, contact NCIBloodcore@mail.nih.gov.  The samples will be 
processed, barcoded, and stored in Dr. Figg’s lab until requested by the investigator. 
5.2.2.1
Cell-free DNA (cfDNA)/Circulating Tumor DNA (ctDNA), Mutational Panels, and 
Plasma Banking 

Collect blood in cell-free DNA (e.g., Streck BCT/collection tubes); gently invert the tubes 
8-10 times immediately after collection.

Plasma will be isolated and frozen at -80ºC until analysis (e.g., centrifuged at 1800 x g for 
10 minutes at room temperature; plasma transferred/frozen in aliquots of 1.5-2mL each). 
5.2.2.2
Immune Subsets/Markers and Peripheral Blood Mononuclear Cells (PBMCs)

Collect blood in Cell Preparation Tubes with sodium citrate (e.g., blue/black speckled top); 
gently invert tubes 8-10 times immediately after collection.  

PBMCs will be isolated per routine laboratory techniques
5.2.2.3
Cytokines and Serum Banking 

Collect blood in Serum Separator Tubes (e.g., red/gray or red/yellow top); gently invert the 
tubes 8-10 times immediately after collection and allow the blood to clot at room 
temperature for approximately 30 minutes.

Serum will be isolated and frozen at -80ºC until analysis (e.g., centrifuged at 1200 xg for 
5 minutes at 4ºC; serum transferred/frozen in aliquots of 1.5-2 mL each).
5.2.2.4
Magrolimab Pharmacokinetics (PK) and Anti-Drug Antibody (ADA) Samples
See Appendix F for additional details.

Fill Red Top Serum Separator Tubes COMPLETELY, as far as the vacuum will allow.

Mix immediately by gently inverting the tube 5 times.

Allow blood to clot undisturbed for 30 minutes (max. 60 minutes), tube standing upright.


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
Centrifuge tube within 1 hour of collection for 10-15 minutes at 1800 g until clot and serum 
are separated by a well –formed polymer barrier. If serum and cells have not completely 
separated, re-centrifuge the specimen for an additional 6-8 minutes.

Transfer serum, using a transfer pipette, into the Transport Tube (s).

Allow enough space between serum and tube caps to account for expansion during 
freezing. Do not overfill.

Record the subject ID number on the specimen label.

Wrap a small piece of parafilm around the cap of the transport tube. See parafilm 
instructions below.

Store serum samples for a minimum of 8 hours at -80°C until shipment to PPD Richmond.
5.2.3
Blood Samples – NCI Laboratory of Pathology
The blood samples for flow cytometry should be sent to the NCI Laboratory of Pathology; please 
contact NCI Laboratory of Pathology (LP) for questions and for notification of samples.
5.2.3.1
Flow cytometry

Collect blood, bone marrow, and/or lymph node samples in appropriate tubes (e.g., 
NaHep/sodium heparin, EDTA, etc.) tubes; gently invert the tubes 8-10 times immediately 
after collection.  

Send samples to the NCI LP for specialized flow cytometry processing and analysis.  

Studies to be performed on these samples include multi-parameter flow cytometry to 
determine the percentage of aberrant lymphoma cells.  Reagents to be used include but are 
not limited to characteristic B-cell markers including: CD10, CD19, CD20, CD21, CD22, 
CD23, Bcl-2, Bcl-6, CD79B, kappa and lambda light chain as well as various T-cell 
markers including: CD3, CD5, CD4 and CD8.
5.2.4
Tissue Samples
5.2.4.1
Archival tissue
Archival block(s) or slides (i.e., at least 15 unstained slides, 5-microns) is required at baseline; 
these may also be required in follow-up in case of future routine procedures or in case additional 
tissue is needed even in the event of optional tumor biopsy.  
5.2.4.2
Lymph node excision or core needle biopsy 
Lymph node excision or core needle biopsy will be performed per routine standard of care, by 
Surgery Consultants or Interventional Radiology, as appropriate.  A procedure-specific consent 
form will be signed by the patient prior to the procedure.  Every attempt will be made to perform 
excisional lymph node biopsies to obtain the best quality tissue for translational investigation.  
Consideration of alternative biopsy methods (e.g., core needle biopsy) will only be made if follow-
up excisional biopsy is not possible/safe or patient is unwilling to undergo repeat excisional lymph 
node biopsy.
In the event that a surgical biopsy procedure is performed, more than one lymph node and at more 
than one anatomic site may be collected, provided the additional procedures are not unacceptable 
risk to the patient.  In the event of core needle biopsy, these are obtained typically by using a 16-
18G needle at the discretion of the provider performing the procedure.  Conscious sedation may 
be used, if warranted, and the use and risks are acceptable to the patient. General anesthesia will 


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not be performed to obtain biopsies for research purposes. The type of procedure to be done and 
manner in which it will proceed (e.g., excision/core, single vs. multiple sites of biopsy) will be 
discussed with the patient prior to the biopsy procedure; if CT guidance will be used for a research 
biopsy procedure, research radiation exposure will be discussed with the patient. Similar procedure 
may be followed for extranodal disease/masses. The patient will be reminded that all sampling for 
research is voluntary. 
5.2.4.3
Sample handling/processing
When performed, excisions or core biopsies will be placed in sterile collection/core cylinder tubes 
(e.g., formalin); gently invert/inspect tubes with media 8-10 times immediately after collection to 
ensure the core(s) is completed immersed in the media.
Tissue samples will be handled/processed as below prior to planned analyses, as appropriate:

Any required routine review for histopathologic confirmation of diagnosis and/or grade 
will occur per standard of care (e.g., H&E, immunohistochemistry), if required.  

Formalin samples will be fixed and paraffin-embedded per routine techniques.  
5.2.5
Other Samples
5.2.5.1
Germline DNA
Germline DNA will be collected by blood, buccal swab, and/or saliva samples (preferred).  These 
will ideally be collected at baseline; however, may be collected at any point on study based on 
supplies.  Standardized, commercial collection kits or tubes will be used (e.g., 1, 5-10 mL K2EDTA 
tube for blood; Isohelix SK-1 for buccal swabs; Salviette/Oragene® for saliva).  In the case of 
buccal swabs, two (2) samples may be collected in order to ensure adequate DNA collection.    
The samples will be processed and DNA extracted/isolated per kit instructions and established 
techniques.  These will be handled by Dr. Figg’s lab (see Section 5.2.2 for contact information).
5.2.5.2
Bone marrow aspiration (± flow cytometry) and core biopsy
Bone marrow collection will be performed per routine standard of care. A procedure-specific 
consent form will be signed by the patient prior to the procedure. Attempt will be made to collect 
both bone marrow aspirate and core biopsy. If required, the procedure may be performed under 
conscious sedation per the discretion of the investigator. 

Bone marrow aspirate and flow cytometry samples will be placed in sterile collection tubes 
(e.g., heparinized tubes or containing EDTA/sodium heparin or formalin, as appropriate); 
gently invert tubes 8-10 times immediately after collection.  

Core biopsies will be placed in sterile collection/core cylinder tubes (e.g., formalin or no 
media); gently invert/inspect tubes with media 8-10 times immediately after collection to 
ensure the core(s) is completely immersed in the media.  

Studies to be performed on these samples include  cell analysis and histological (e.g., 
H&E), 
immunohistochemical 
(IHC)/fluorescence 
in 
situ 
hybridization 
(FISH) 
review/testing, and other analyses per established techniques (e.g., PD-1/PD-L1, BCL2, 
MUM1, Ki67, etc.).


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5.3
BIOMARKER AND RESEARCH METHODS
The technology platforms that are able to interrogate genomic structure and function are constantly 
in flux; therefore, the exact nature of the methodologies that will be employed will be assessed at 
the time that the samples are collected and ready for analysis. 
The following are technologies that are currently in use for each planned analysis:  
5.3.1
Tumor Profiling 
Immunohistochemical (IHC) analyses, including FISH for BCL2 will be performed on every FL 
sample. For all patients with MCL, IGH-CCND1 will be performed. D6Z1/MYB, D12Z3/MDM2, 
D11Z1/ATM, D13S319/LAMP1 and TP53/D17Z1 will be done on every patient’s baseline CLL 
tumor biopsy, if available.  The routine IHC panel for diagnosis of indolent lymphomas will be 
performed on tumor tissue samples, including but not necessarily limited to CD3, CD5, CD10, 
CD20, CD21, CD23, BCL2, BCL6, MUM1 and MIB-1.
5.3.2
Microenvironment Tissue Profiling
Immunohistochemical (IHC) analyses will take to assess for contribution of the tumor 
microenvironment.  IHC that will be performed may include, but are not necessarily limited to:  
CD3, CD4, CD8, CD20, CD45RO, CD57, CD68, FOXP3, Granzyme B, LAG3, PD-1/PD-L1 (H-
score), SIRP CD14, CD33, CD47, CD163 and/or CD206.
5.3.3
Immune Subset Analysis
Peripheral blood mononuclear cells (PBMC) will be assessed using multiparameter flow cytometry 
for immune subsets including but not necessarily limited to CD8+ T-cells, CD4+Foxp3- T-cells, 
Tregs, Tex, Th1, Th2 and Th17+ CD4+ T-cells, monocyte subsets, macrophage subsets, and MDSC 
subsets. Assessment may include functional markers, i.e., PD-1, Tim-3, CTLA-4, PD-L1, HLA-
DR, Ki67, CD47, SIRP and/or CD40.
5.3.4
Histo-cytometry/Multiplex Staining Technologies
Tissues samples will be provided to the laboratory of Dr. Ronald Germain (NIAID/NIH) for 
recently developed multiplex staining technologies in 2D and 3D.  Dr. Germain's laboratory 
(NIAID/NIH) will return confocal images and quantitative analyses of these images in figure 
format for interpretation and analysis. Dr. Germain's group (NIAID/NIH) will not have direct 
access to the key that links sample identifiers with personally-identifiable information.
5.3.5
DNA/RNA Sequencing 
Genomic DNA and total RNA will be extracted from tumor samples using a Qiagen All-prep kit. 
For individual target genes that are recurrently mutated in indolent NHL, classical Sanger 
sequencing will be performed on PCR amplicons, using primers surrounding the known sites of 
mutation. To broadly assess mutations, next generation sequencing (e.g., on an Illumina HiSeq 
2000 platform) will be employed, using a paired end sequencing strategy of libraries constructed 
from tumor DNA. DNA will either be sequenced in its entirety from a whole genome library or 
will be first enriched for exonic sequences using the Agilent Sure Select system, aiming for 30X 
or 100X average coverage per base, respectively. The sequence fragments will be mapped back to 
the genome using the BWA algorithm. Of sequences overlapping a particular base pair in the 
genome, the percent mutant calls greater that 20% with a minimum of 25X coverage will be 


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considered as an arbitrary threshold for single nucleotide variants (SNVs). SNVs that are not 
present in the matched normal sample will be considered candidate somatic mutations. 
A related technology, RNA-Seq, utilizes RNA from the tumor specimen to create a cDNA library 
for high-throughput sequencing. RNA-seq will be performed using Illumina kits followed by high-
throughput sequencing on an Illumina HighSeq 2000 machine. The cutoffs for coverage and 
percent mutant calls mentioned above will also be used to identify putative SNVs. RNA 
sequencing will also be used to read out digital gene expression across the genome as described.
Recent advances in genomic technologies enable GEP at the single cell level, a distinct advantage 
over conventional GEP which cannot always distinguish tumor vs non-tumor gene expression(95, 
96).  Single-cell approaches allow identification of the evolution of rare populations of resistant 
tumor cells, as well as identification of TME cells critical for the survival of the tumor. The Center 
for Cancer Research (CCR) has recently opened a single cell analysis core facility with expert staff 
headed by Dr. Michael Kelly within the CCR Genomics Core.  This facility has the ability to take 
purified viably frozen cells banked from patient biopsies and prepare them, using well-validated 
10X Genomics technology, for single-cell RNA sequencing.  This core is directly integrated with 
the NCI Sequencing core facility to provide high-quality, deep-sequencing of the single cell RNA-
SEQ samples, as well as ‘first-pass’ data processing and analysis.  Data will then be transferred to 
lymphoma researchers and bio-informaticians in the Staudt lab for further analysis of gene 
expression patterns and cellular population dynamics.
5.3.6
Metabolic Tumor Imaging
Under the direction of Dr. Ahlman, special research analyses/readings of standard 18F-FDG PETs 
collected per standard of care will be performed to evaluate metabolic tumor volume and total 
lesion glycolysis.  
5.3.7
DNA Copy Number Analysis 
Array comparative genomic hybridization (e.g., on Agilent 240K or Affy SNP 6.0 microarrays) 
will be used to assess DNA copy number alterations as described, in tumor DNA to yield 
somatically acquired regions of copy number gain and loss.
5.3.8
Pharmacokinetics (PK) and Anti-drug Antibodies (ADA) Analysis
Validated assays will be used to measure magrolimab serum concentration and presence of anti-
magrolimab antibodies. Coded (linked) samples (Section 5.4.2) will be sent to a contracted 
laboratory at the request of Gilead Sciences, Inc. for analysis of magrolimab pharmacokinetics and 
presence of anti-magrolimab antibodies:  PPD Laboratories. 
PPD will run validated assays to measure magrolimab serum concentration and presence of anti-
magrolimab antibodies. See Appendix F for additional details.
The laboratory contact information is as follows:
5.3.8.1
Shipping Information
PPD Laboratories
Attn: Specimen Mgmt Dept, LiMajor Pittman
2246 Dabney Road
Richmond, VA 23230


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5.3.8.2
Contact
LiMajor Pittman
Phone: 1-804-977-8459
            Email: LiMajor.Pittman@ppdi.com
5.3.9
Other Analyses
Other analyses include the following:

Cell analysis and histological (e.g., H&E), immunohistochemical review and analysis per 
standard and established research techniques (e.g., PD-1/PD-L1 expression [Dako], FISH 
for 9p24 amplicon, and other IHC analyses in blood and tissue).

Cytokine analysis (e.g., IL-6, IL-10, interferon beta, TNF-alpha)

cfDNA/ctDNA for liquid genotyping as a non-invasive dynamic monitoring of disease as 
well as monitoring for individual molecular aberrations that herald progression or disease 
transformation; specifically, amplification and sequencing of the VDJ segment of the 
immunoglobulin receptor is planned
5.3.10 Future Use
Any blood, tissue, or other (e.g., CSF) products or portions leftover from other analyses will be 
stored for future research.   
5.4
SAMPLE STORAGE, TRACKING AND DISPOSITION
5.4.1
General
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.  Samples 
will not be sent outside NIH without appropriate approvals and/or agreements, if required.
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that are 
remaining at the completion of the protocol will be stored in the conditions described below.  The 
study will remain open so long as sample or data analysis continues.  Samples from consenting 
patients will be stored until they are no longer of scientific value or if a subject withdraws consent 
for their continued use, at which time they will be destroyed. The PI will record any loss or 
unanticipated destruction of samples as a deviation. Reporting will be per the requirements of 
Section 7.2. 
If the patient withdraws consent his/her data will be excluded from future distributions, but data 
that have already been distributed for approved research use will not be able to be retrieved.
5.4.2
Clinical Pharmacology Program (Figg Lab)
5.4.2.1
Sample Data Collection
All samples sent to the Blood Processing Core (BPC) of the Clinical Pharmacology Program under 
the direction of Dr. Figg will be barcoded, with data entered and stored in the Labmatrix utilized 
by the BPC. This is a secure program, with access to Labmatrix limited to defined Figg lab 
personnel, who are issued individual user accounts. Installation of Labmatrix is limited to 
computers specified by Dr. Figg. These computers all have a password restricted login screen. All 
Figg lab personnel with access to patient information annually complete the NIH online Protection 
of Human Subjects course. 


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Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without Labmatrix access. The data recorded for each sample includes the patient 
ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, as well 
as box and freezer location. Patient demographics associated with the clinical center patient 
number are provided in the system. For each sample, there are notes associated with the processing 
method (delay in sample processing, storage conditions on the ward, etc.).
5.4.2.2
Sample Storage 
Barcoded samples are stored in barcoded boxes in a locked freezers at appropriate temperatures 
(e.g., -20ºC to -80ºC) according to stability requirements.  These freezers are located onsite in the 
BPC and offsite at NCI Frederick Central Repository Services in Frederick, MD. Visitors to the 
laboratory are required to be accompanied by laboratory staff at all times. 
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused samples 
must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to ensure that 
the samples requested are being used in a manner consistent with IRB approval.
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
Labmatrix. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables.
5.4.3
Hematopathology Section of Laboratory of Pathology (Tissue samples)
Archival and/or freshly collected and processed tumor tissue may be stored in the 
Hematopathology Section of Laboratory of Pathology until ready for planned and/or future 
research assays if the patient has agreed to allowing specimens to be used in future research studies.  
IRB approval will be obtained before using any samples to conduct studies that are not described 
within this protocol.  Samples will be stored under conditions appropriate to the type of sample 
and processing (e.g., ambient or frozen).  
Tissue that is given to the technician will be assigned an accession number (HP#) in the HP Case 
Log book; sample tracking also takes place with a FileMaker Pro data base called HP Patient 
Information and Specimen Inventory.   A Patient background sheet may be filled out and filed with 
any accompanying paperwork, with final reports and any supplemental reports that follow added 
as completed. 
5.4.4
Staudt Lab
5.4.4.1
Sample Data Collection
Patient samples, collected for research under this IRB approved protocol, may be archived in the 
Staudt laboratory.  All data associated with archived clinical research samples is entered into the 
web-based NCI Labmatrix database, a centralized system with access controlled via centralized 
login.  Access to this database for samples collected from this study is limited to Dr. Staudt and 
his research staff, each requiring individual login and password.  All staff in the laboratory receive 
annually updated NIH/CITI or other training, as appropriate, and maintain standards of computer 
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The data recorded for each sample may include the patient ID, trial name/protocol number, date 
drawn/collected, treatment cycle/time point, sample source (e.g., peripheral blood, marrow, tissue, 
etc.) as well as box and freezer location.  All received samples will be given a unique bar code 
number, which will be added to the sample NCI Labmatrix database.  Only this bar code will be 
recorded on the sample vial and the vials will not be traceable back to patients without authorized 
access to the NCI Labmatrix database.
5.4.4.2
Sample Storage 
Samples are stored in freezers at -80°C (e.g., sera, plasma, tissue samples) or under liquid nitrogen 
(e.g., cells), according to established stability requirements.  These freezers are located onsite 
under the direction of Dr. Staudt.  Access to samples from this protocol for research purposes will 
be as outlined in this protocol or by permission of the Principal Investigator only.  
5.4.5
Nuclear Medicine/Tumor Imaging (Ahlman)
As Dr. Ahlman is also a clinical nuclear medicine clinician reading the images also for standard 
of care, he will have access to identifiers of the subjects; however, his assessments specifically for 
the research metabolic tumor imaging analyses will not be recorded in the medical record, but only 
in the research records similar to other research-specific data and results.  
5.4.6
CAT-I Laboratory (Germain Lab)
The CAT-I laboratory (CAT-I) will obtain coded samples from Dr. Roschewski and his staff.   
Upon sample acquisition, members of the CAT-I laboratory will enter these samples into 
CEREBRO, an advanced sample labeling system that tracks each sample through every step of the 
workflow.  To meet requirements for availability of primary data and for quality assurance checks, 
CAT-I will maintain a detailed inventory of the type (slide, tissue, frozen OCT block) and location 
of each sample in the laboratory.  More specifically, frozen OCT blocks and accompanying slides 
will be physically stored in the CAT- I laboratory.  Tissues provided will be fixed, frozen, and 
stored in the CAT-I’s -80°C freezer. The CAT-I laboratory will be locked when CAT-I lab 
members are not present.  Unprocessed samples will be held by the CAT-I or returned upon their 
request.  Finally, the CAT-I will comply with requirements for annual Biospecimen Reporting at 
the NIH.
5.5
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.5.1
Description of the scope of genetic/genomic analysis
The research correlates for this study are expected to include DNA/RNA sequencing of tumors, 
including circulating tumor DNA.  In addition, whole exome sequencing may include evaluation 
for known lymphoma mutations.  For any genetic studies performed, the results will be deposited 
in a database such as dbGaP per NIH requirements.  Although there is controlled access to such a 
database, such a submission carries theoretical risks of revealing the identity of the subject.  This 
is discussed in the consent.
5.5.2
Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized
Confidentiality for genetic samples will be maintained as described (Section 5.4).  In addition, a 
Certificate of Confidentiality has been obtained for this study.


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5.5.3
Management of Results
Subjects will be contacted if a clinically actionable gene variant is discovered.  Clinically 
actionable findings for this study are defined as disorders appearing in the American College of 
Medical Genetics and Genomics recommendations for the return of incidental findings that is 
current at the time of primary analysis. (A list of current guidelines is maintained on the CCR 
intranet: https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists).
5.5.4
Genetic Counseling
Subjects will be contacted with a request to provide a sample to be sent to a CLIA certified 
laboratory.  If the research findings are verified in the CLIA certified lab, the subject will be offered 
the opportunity to come to NIH to have genetic education and counseling to explain this result; at 
the time of any such event(s), these activities will be funded by the NCI/CCR in consideration of 
the specific circumstances.  If the subject does not want to come to NIH, a referral to a local genetic 
healthcare provider will be provided (at their expense).
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis.
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
6.1.1
Summary
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11 compliant data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and timeliness.  
The principal investigator, associate investigators/research nurses and/or a contracted data 
manager will assist with the data management efforts. Primary and final analyzed data will have 
identifiers so that research data can be attributed to an individual human subject participant.
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event.  
Document AEs from the first study intervention, Day 1 through 30 days after the last dose of study 
agent was administered. Beyond the 30 day period after the last drug was administered, only 
adverse events which are serious and related to the study intervention need to be recorded. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in Section 7.2.1. 
6.1.2
Data Collection/Recording Exceptions
6.1.2.1
Abnormal Laboratory Values
An abnormal laboratory value will be recorded as an AE only if the laboratory abnormality is 
characterized by any of the following:

Results in discontinuation from the study

Is associated with clinical signs or symptoms 


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
Requires treatment or any other therapeutic intervention

Is associated with death or another serious adverse event, including hospitalization. 

Is judged by the Investigator to be of significant clinical impact

If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome.
6.1.2.2
Hospitalizations
Hospitalizations or prolonged hospitalization for the following will not be recorded unless one of 
the other criteria for seriousness are met (Section 8.1.2):

Closer monitoring and/or prophylaxis of TLS during any cycle

Closer monitoring and/or prophylaxis of IRR during any cycle
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows:
_X_ Coded, linked data in an NIH-funded or approved public repository.  
_X_ Coded, linked data in another public repository
_X_ Coded, linked data in BTRIS (automatic for activities in the Clinical Center)
_X_ Identified or coded, linked data with approved outside collaborators under appropriate 
agreements.
How and where will the data be shared? 
Data will be shared through:
_X_ An NIH-funded or approved public repository.  Insert name or names: ClinicalTrials.gov, 
dbGaP.
_X_ BTRIS (automatic for activities in the Clinical Center)
_X_ Approved outside collaborators under appropriate individual agreements.  
_X_ Publication and/or public presentations.
When will the data be shared?
_X_ Before publication.
_X_ At the time of publication or shortly thereafter.
6.2.2
Genomic Data Sharing Plan
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy.
6.3
RESPONSE CRITERIA 
In general, response rate will be assessed according to the Lugano response criteria for FL, MCL 
and MZL; and the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria 
for CLL. Notable exceptions are mentioned below. 


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
iwCLL criteria may also be used for MCL when the disease involves peripheral blood, 
bone marrow or spleen without significant lymphadenopathy. 

Separate response criteria for splenic marginal zone lymphoma as proposed by Matutes et 
al.(121)

For patients with MALT lymphoma of the ocular adnexa, an MRI based response criteria 
will be used in conjunction with ophthalmologic evaluation.(122) 

Group d’Etudedes Lymphomes de l’Adult (GELA) grading system to define the histologic 
response of gastric MALT lymphoma will be utilized for gastric marginal zone lymphoma 
of MALT type.(123) 
6.3.1
Response Criteria – FL, MCL and MZL
The Lugano Classification of Response will be used to assess response in subjects with FL, MZL 
and MCL, with the exception of CLL.  
Lugano classification of response criteria with PET (Cheson et al., 2014)(124):
Response and Site
PET-CT Based Response
CT-Based Response
Complete
Complete metabolic response
Complete radiologic response
All of the following:
Score 1, 2, or 3* with or without a 
residual mass on 5PS†
Target nodes/nodal masses must regress to ≤1.5 
cm in LDi
No extralymphatic sites of disease
Lymph nodes and 
extralymphatic sites
NOTE:  It is recognized that in Waldeyer’s ring or extranodal sites with high physiologic uptake or 
with activation within spleen or marrow (e.g., with chemotherapy or myeloid colony-stimulating 
factors), uptake may be greater than normal mediastinum and/or liver. In this circumstance, complete 
metabolic response may be inferred if uptake at sites of initial involvement is no greater than 
surrounding normal tissue even if the tissue has high physiologic uptake.
Nonmeasured lesions
Not applicable
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in 
marrow
Normal by morphology; if indeterminate, IHC 
negative
Partial
Partial metabolic response
Partial remission
All of the following:
Lymph nodes and 
extralymphatic sites
Score 4 or 5† with reduced uptake 
compared with baseline and residual 
mass(es) of any size
At interim, these findings suggest 
responding disease.
At end of treatment, these findings indicate 
residual disease.
≥50% decrease in SPD of up to 6 target 
measurable nodes and extranodal sites
When a lesion is too small to measure on CT, assign 5 
mm x 5 mm as the default valve; when no longer visible, 0 
x 0 mm. For a node >5 mm x 5 mm, but smaller than 
normal, use actual measurement for calculation.
Nonmeasured lesions
Not applicable
Absent/normal, regressed, but no increase
Organ enlargement
Not applicable
Spleen must have regressed by >50% in length 
beyond normal
New lesions
None
None


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Response and Site
PET-CT Based Response
CT-Based Response
Bone marrow
Residual uptake higher than uptake in 
normal marrow but reduced compared 
with baseline (diffuse uptake 
compatible with reactive changes from 
chemotherapy allowed). If there are 
persistent focal changes in the marrow 
in the context of a nodal response, 
consideration should be given to 
further evaluation with MRI or biopsy 
or an interval scan.
Not applicable
No response or 
stable disease
No metabolic response
Stable disease
Target nodes/nodal 
masses, extranodal 
lesions
Score 4 or 5 with no significant 
change in FDG uptake from baseline 
at interim or end of treatment
<50% decrease from baseline in SPD of up to 6 
dominant, measurable nodes and extranodal sites; 
no criteria for progressive disease are met
Nonmeasured lesions
Not applicable
No increase consistent with progression
Organ enlargement
Not applicable
No increase consistent with progression
New lesions
None
None
Bone marrow
No change form baseline
Not applicable
Progressive disease
Progressive metabolic disease
Progressive disease
Requires at least 1 of the following:
Individual target
nodes/nodal masses
Score 4 or 5 with an increase in
intensity of uptake from baseline;
and/or
An individual node/lesion must be abnormal with: 
LDi >1.5 cm, and 
Increase by ≥ 50% from PPD nadir, and 
An increase in LDi or SDi from nadir:
o
0.5 cm for lesions ≤2 cm
o
1.0 cm for lesions >2 cm
Extranodal lesions
New FDG-avid foci consistent with 
lymphoma at interim or end of 
treatment assessment
In the setting of splenomegaly, the splenic length 
must increase by >50% of the extent of its prior 
increase beyond baseline (e.g., a 15-cm spleen 
must increase to >16 cm). If no prior 
splenomegaly, must increase by at least 2 cm 
from baseline.
New or recurrent splenomegaly
Nonmeasured lesions
None
New or clear progression of preexisting 
nonmeasured lesions
New lesions
New FDG-avid foci consistent with 
lymphoma rather than another etiology 
(e.g., infection, inflammation). If 
uncertain regarding etiology of new 
lesions, biopsy or interval scan may be 
considered.
Regrowth of previously resolved lesions
A new node >1.5 cm in any axis
A new extranodal site >1.0 cm in any axis; if 
<1.0 cm in any axis, its presence must be 
unequivocal and must be attributable to 
lymphoma
Assessable disease of any size unequivocally 
attributable to lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement


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Response and Site
PET-CT Based Response
CT-Based Response
Abbreviations: 5PS, 5-point scale; CT computed tomography; FDG, fluorodeoxyglucose; IHC, immunohistochemistry; 
LDi, longest transverse diameter of a lesion; MRI, magnetic resonance imaging; PET, positron emission tomography; 
PPD, cross product of the LDi and perpendicular diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the 
product of the perpendicular diameters for multiple lesions.
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim 
scan. However, in trails involving PET where de-escalation is investigated, it may be preferable to consider a score of 3 as 
inadequate response (to avoid under treatment). Measured dominant lesions: Up to 6 of the largest dominant nodes, nodal 
masses, and extranodal lesions selected to be clearly measurable in 2 diameters. Nodes should preferably be from 
disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal 
lesions include those in solid organs (e.g., liver spleen, kidneys, and lungs), GI involvement, cutaneous lesions, or those 
noted on palpation. Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly assessable 
disease should be considered not measured. These sites include any nodes, nodal masses, and extranodal sites not selected 
as dominant or measurable or that do not meet the requirements for measurability but are still considered abnormal, as 
well as truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively with 
measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other 
lesions that cannot be confirmed and followed by imaging. In Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, 
bone marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response but should be no 
higher than surrounding normal physiologic uptake (e.g., with marrow activation as a result of chemotherapy of myeloid 
growth factors). 
†PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake 
moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to be related 
to lymphoma.
6.3.2
Response Criteria – CLL 
The response rate in CLL patients will be calculated based on iwCLL response criteria (Hallek et 
al 2018)(90):
Complete remission (CR)
Requires all of the following criteria: 

Absolute lymphocyte count <4000/microL (4 × 109/L). 

No lymph nodes >1.5 cm in diameter. 

No hepatomegaly or splenomegaly. 

No constitutional symptoms attributable to CLL.* 

Bone marrow recovery as demonstrated by ANC >1500/microL (1.5 × 109/L), platelet count 
>100,000/microL (100 × 109/L), and hemoglobin concentration >11 g/dL (110 g/L) in the absence of 
transfusion or growth factor support. 

Bone marrow at least normocellular for age, without evidence for typical CLL lymphocytes by 
morphologic criteria and immunohistochemistry and without nodular lymphoid aggregates.¶
CR with incomplete bone marrow recovery (CRi)
Fulfills all requirements for CR except has persistent neutropenia, anemia, or thrombocytopenia thought to be 
unrelated to the disease and likely related to drug toxicity. These patients must have a normal bone marrow 
aspirate and biopsy with no evidence of clonal infiltrates.
Partial remission (PR)
At least two of these criteria must be documented: 

A decrease in the peripheral absolute lymphocyte count by at least 50% from the level prior to therapy. 


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
A reduction in previously enlarged nodes by at least 50% with no increase in the size of any single 
lymph node and no new enlarged lymph nodes. An increase of <25% in a lymph node <1.5 cm is not 
considered significant. 

A decrease in the size of the liver and/or spleen by at least 50%. 
One of the following hematologic parameters must be met in addition to two of the above criteria in order to 
qualify for a PR: 

Platelet count ≥100,000/microL (100 × 109/L) or at least 50% improvement over baseline (if this value 
was abnormally low at baseline). 

Hemoglobin concentration ≥11 g/dL (110 g/L) or 50% improvement over baseline (if this value was 
abnormally low at baseline) without red blood cell transfusions or erythropoietin support. 
If only one parameter was abnormal before therapy, only one needs to improve to achieve PR.
Nodular PR 
Persistent bone marrow nodules on bone marrow biopsy in patients achieving a CR or PR. Lymphoid aggregates 
should be evaluated with immunohistochemistry to determine whether they are comprised of CLL cells, 
lymphocytes other than CLL cells, or T cells. If nodules are not composed of CLL cells, a CR can be documented 
provided all other criteria are met.
Progressive disease (PD)Δ
At least one of these criteria must be documented: 

The appearance of a newly enlarged lymph node (>1.5 cm), splenomegaly, hepatomegaly, or other organ 
infiltration. 

An increase of 50% or more in size of a previously involved site (e.g., lymph nodes, spleen, or liver) 
measuring ≥1.5 cm. 

An increase of 50% or more in the total circulating lymphocyte count with absolute lymphocyte count of 
5000/microL (5 × 109/L) or greater.◊

Richter's transformation documented by lymph node or other tissue biopsy. 

Development of neutropenia, anemia, or thrombocytopenia attributable to CLL.§
Stable disease 
Patients who do not meet the criteria for a complete remission, partial remission, or progressive disease, have 
stable disease. Stable disease is therapeutically equivalent to a nonresponse (i.e., refractory disease).
For patients treated with a therapy for a defined treatment duration, response assessment should be performed at 
least two months after the completion of therapy. For those receiving continued therapies or treatment strategies 
that include a maintenance phase, response assessment should be performed at least two months after achieving 
"maximum response" defined as a treatment phase where no additional improvement is seen during at least two 
months of therapy.
CLL: chronic lymphocytic leukemia; SLL: small lymphocytic lymphoma; ANC: absolute neutrophil count.
* These include ≥10% unintentional weight loss within the previous six months, fatigue that interferes with work 
or usual activities, fevers greater than 100.5°F (>38°C) for ≥2 weeks, or night sweats for >1 month.
¶ Assessment of residual CLL cells in the bone marrow for this purpose is not based on flow cytometry. 
Assessment for measurable residual disease (MRD, also called 'minimal residual disease') is reserved for clinical 
trials. Although bone marrow biopsy is required to confirm a CR, it is not always recommended in general 
practice as it may not impact management. If the above clinical and hematologic parameters are compatible with 
a CR and the clinician chooses not to perform a bone marrow biopsy, the documented response can be "partial 
remission."
Δ Transient increases in lymph node size may occur during treatment with novel inhibitors and should not be 
considered PD.
◊ For patients treated with therapies that may cause lymphocytosis (e.g., kinase inhibitors), an increase in blood 
lymphocyte count, by itself, does not uniformly indicate an increased tumor burden, but may reflect redistribution 
of leukemia cells from lymphoid tissues. In such cases, increased lymphocytosis alone is not a sign of treatment 
failure or progressive disease.


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§ Cytopenias cannot be used to determine disease progression during active therapy since they may be due to 
administered cytotoxic agents. Cytopenias that occur at least three months after the completion of therapy and are 
accompanied by an infiltrate of clonal CLL cells on bone marrow biopsy can be used to define disease 
progression. Specific values that define progression include a decrease in hemoglobin level by more than 2 g/dL 
(20 g/L) or to less than 10 g/dL (100 g/L) or a decrease in platelet count by more than 50% or to less than 
100,000/microL (100 × 109/L).
6.3.3
Response Criteria – Splenic Marginal Zone Lymphoma(121) 
Partial response: 50% or greater decrease in spleen size. A reduction in previously enlarged nodes 
(if present) by at least 50% with no increase in the size of any single lymph node and no new 
enlarged lymph nodes. An increase of <25% in a lymph node <1.5 cm is not considered significant.  
In addition to the above two criteria, one of the following hematologic parameters must be met in 
order to qualify for a PR: 
•
Platelet count ≥100,000/microL (100 × 109/L) or at least 50% improvement over baseline 
(if this value was abnormally low at baseline). 
•
Hemoglobin concentration ≥12 g/dL (110 g/L) or 50% improvement over baseline (if this 
value was abnormally low at baseline) without red blood cell transfusions or erythropoietin 
support.
Complete response: Resolution of organomegaly, normalization of the blood counts (Hb>12 g/dL; 
platelets >100,000/uL and absolute neutrophil count > 1500 /uL and no evidence of circulating 
clonal B cells). No evidence or minor BM infiltration detected by immunohistochemistry. 
No response: Patients who do not meet the criteria for a complete remission, partial remission, or 
progressive disease, have stable disease. Stable disease is therapeutically equivalent to a 
nonresponse (i.e., refractory disease). 
Progressive disease: At least one of these criteria must be documented: 

The appearance of a newly enlarged lymph node (>1.5 cm), splenomegaly, hepatomegaly, 
or other organ infiltration. 

An increase of 50% or more in size of a previously involved site (e.g., lymph nodes, spleen, 
or liver) measuring ≥1.5 cm. 

Development of neutropenia, anemia, or thrombocytopenia attributable to SMZL. 
6.3.4
Response Criteria – MALT lymphoma of the ocular adnexa(122)
Partial Response: 50% or greater reduction in the maximum diameter of the lesion from its 
original tumor size on imaging (CT/MRI) or ophthalmologic evaluation. 
Complete Response: Complete resolution of the lesion on imaging (CT/MRI) or ophthalmologic 
evaluation.


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6.3.5
Response Criteria - Gastric MZL of MALT type
Response (score)
Description
Histological Characteristics
CR
Complete histological remission
Normal or empty LP and/or fibrosis with absent or 
scattered plasma cells and small lymphoid cells in the 
LP, no LEL
pMRD
Probable minimal residual 
disease
Empty LP and/or fibrosis with aggregates of lymphoid 
cells or lymphoid nodules in the LP/MM and/or SM, 
no LEL
rRD
Responding residual disease
Focal empty LP and/or fibrosis with dense, diffuse or 
nodular lymphoid infiltrate, extending around glands in 
the LP, focal LEL or absent
NC
No change
Dense, diffuse or nodular lymphoid infiltrate, LEL 
usually present
LEL, lymphoepithelial lesions; LP, lamina propria; MM, muscularis mucosa; SM, submucosa.
6.3.6
Definitions
6.3.6.1
Best Overall Response
The best overall response rate (ORR) is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  
6.3.6.2
Duration of Response
The duration of response (DOR) is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started), death, or, in the absence of PD, date of last assessment.
6.3.6.3
Progression-Free Survival
Progression-free survival (PFS) is defined as the duration of time from the date of study enrollment 
until time of disease relapse, disease progression, or death, whichever occurs first.
6.3.6.4
Event-Free Survival
Event-free survival (EFS) is defined as the duration of time from the date of study enrollment until 
time of disease relapse, disease progression, alternative anti-lymphoma therapy including 
radiation, or death, whichever occurs first.
6.3.6.5
Overall Survival
Overall survival (OS) is defined as the time from study enrollment until death from any cause. 
6.3.6.6
Complete Response Rate 
The proportion of patients who achieve a PET-negative complete response (CR) in accordance 
with the 2014 Lugano classification of the International Working Group Criteria for Non-
Hodgkin’s Lymphoma(125) or International Workshop Group on CLL (iwCLL) criteria.
6.3.6.7
Complete Molecular Remission Rate
The proportion of patients who achieve both a complete response and are negative on molecular 
assays for MRD after therapy.


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6.3.6.8
Objective Tumor Response Rate 
The proportion of patients who achieve at least a partial response (PR) to therapy. 
6.4
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study. The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. 
All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy 
of 
the 
CTCAE 
version 
5.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
7
NIH REPORTING REQUIREMENTS / DATA SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING/IRB REPORTING
7.2.1
 Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. Note: Only IND Safety 
Reports that meet the definition of an unanticipated problem will need to be reported per these 
policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
7.3
NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary.
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet on a regular basis (approximately weekly) when patients are 
being actively treated on the trial to discuss each patient. The clinical research team will prepare a 


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monthly report on the occurrence of any grade 3 or 4 hemolytic anemia events. This report will be 
provided to Sponsor (OSRO) who will share the information with Gilead and Genentech. In the 
event of a grade 3 or 4 hemolytic anemia event(s), the clinical research team will confer with the 
Sponsor, Gilead, and Genentech to discuss the full safety profile including SAEs and DLTs. 
Minutes and formal decisions will be documented. Gilead and Genentech will be informed when 
decision is made to dose de-escalate due to observed DLTs. Decisions about trial continuation will 
be made based on the efficacy data from prior patients at appropriate time points per the statistical 
plan. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting described in Section 
7.2.1 will be submitted within the appropriate timelines. 
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy.  The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
7.4.2
Safety Monitoring Committee (SMC)
This protocol will be periodically reviewed by an intramural Safety Monitoring Committee. 
comprising physicians, biostatisticians and a lay member selected based on experience, area of 
expertise, reputation for objectivity, absence of conflicts of interest and knowledge of or 
experience with clinical trial research. Initial review will occur as soon as possible after the annual 
NIH Intramural IRB continuing review date. Subsequently, each protocol will be reviewed as close 
to annually as the quarterly meeting schedule permits or more frequently as may be required by 
the SMC based on the risks presented in the study. For initial and subsequent reviews, protocols 
will not be reviewed if there is no accrual within the review period. The SMC will operate under 
the rules of an approved charter that will be written and reviewed at the organization meeting of 
the SMC.  Each review will focus on unexpected protocol-specific safety issues that are identified 
during the conduct of the clinical trial.
Written outcome letters will be generated in response to the monitoring activities and submitted to 
the Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI.
8
SPONSOR PROTOCOL/SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH E6 (R2))
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:


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
Death,

A life-threatening adverse event (see Section 8.1.3)

Inpatient hospitalization or prolongation of existing hospitalization 
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject convenience) is not considered a serious adverse 
event. 
o
Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria.

Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions

A congenital anomaly/birth defect

Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32)
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.
8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.  

Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.

Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.1.6
Adverse Events of Special Interest (AESI)
There are no AESI with respect to the NCI CCR Sponsor representative for this protocol. 
AESI for the pharmaceutical collaborator, Genentech, include the following: 

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law:


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
Treatment-emergent ALT or AST > 3 x ULN in combination with total bilirubin > 2 x 
ULN

Treatment-emergent ALT or AST > 3 x ULN in combination with clinical jaundice

Data related to a suspected transmission of an infectious agent by the study drug 
(STIAMP), as defined below:

Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent.  A transmission of an infectious agent may be suspected from clinical symptoms or 
laboratory findings that indicate an infection in a patient exposed to a medicinal product.  
This term applies only when a contamination of the study drug is suspected.
8.1.6.1
Venetoclax-specific AESI

Tumor Lysis Syndrome (irrespective of seriousness)
8.1.6.1.1 Obinutuzumab-specific AESI

All Tumor Lysis Syndrome (irrespective of seriousness, causality or severity)

Second Malignancies
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity and 
relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution.
SAEs will be:

Assessed for severity and relationship to study product and alternate etiology (if not related 
to study product) by a licensed study physician listed on the Form FDA 1572 as the site 
principal investigator or sub-investigator.

Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.

Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor with the exception of any listed in section 8.4. 
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the expedited 
reporting requirements are found in Section 8.4.
All SAE reporting must include the elements described in 8.2.


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SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form 
and instructions can be found here: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions. 
Following the assessment of the SAE by OSRO, other supporting documentation of the event may 
be requested by the OSRO Safety and should be provided as soon as possible.
8.4
WAIVER OF EXPEDITED REPORTING TO CCR
As death/hospitalization due to disease progression are part of the study objectives (DOR, PFS)  
and captured as an endpoints in this study, they will not be reported in expedited manner to the 
sponsor. However, if there is evidence suggesting a causal relationship between the study drug and 
the event, report the event in an expedited manner according to Section 8.3.
8.5
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS
Reporting to Gilead Sciences, Inc., and Genentech, Inc., will be per the respective collaborative 
agreements.
8.6
REPORTING PREGNANCY 
All required pregnancy reports/follow-up to OSRO will be submitted to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  Forms and instructions 
can be found here: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
8.6.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy become known.
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (Section 8.1.2) should be reported as SAEs. 
The outcome of all pregnancies should be followed up and documented.
8.6.2
Paternal exposure
Male patients should refrain from fathering a child or donating sperm from the first dose until 90 
days after the last dose of magrolimab, 30 days after the last dose of venetoclax, 6 months after 
the last dose of obinutuzumab or whichever is later.  
Pregnancy of the patient’s partner is not considered to be an AE. The outcome of all pregnancies 
occurring from the date of the first dose until 90 days after the last dose of magrolimab, 30 days 
after the last dose of venetoclax, and 6 months after the last dose of obinutuzumab or whichever 
is later should, if possible, be followed up and documented. Pregnant partners may be offered the 
opportunity to participate in an institutional pregnancy registry protocol (e.g., the NIH IRP 
pregnancy registry study) to provide data about the outcome of the pregnancy for safety 
reporting purposes.
8.7
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 


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adverse reaction that is both serious and unexpected.  CCR will report an AE as a suspected adverse 
reaction only if there is evidence to suggest a causal relationship between the study product and 
the adverse event.  CCR will notify FDA and all participating investigators (i.e., all investigators 
to whom the sponsor is providing drug under its INDs or under any investigator’s IND) in an IND 
safety report of potential serious risks from clinical trials or any other source, as soon as possible, 
in accordance to 21 CFR Part 312.32. 
All serious events will be reported to the FDA at least annually in a summary format.
8.8
SPONSOR PROTOCOL DEVIATION REPORTING
A Protocol Deviation is defined as any noncompliance with the clinical trial Protocol, Manual of 
Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial.
It is the responsibility of the study Staff to document any protocol deviation identified by the Staff 
or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online application. 
The entries into the PDTS online application should be timely, complete, and maintained per CCR 
PDTS user requirements.
 In addition, any deviation to the protocol should be documented in the participant’s source records 
and reported to the reviewing IRB per their guidelines. OSRO required protocol deviation 
reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 Compliance 
with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol deviations.
9
CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure:

that the rights of the participants are protected; 

that the study is implemented per the approved protocol, Good Clinical Practice and 
standard operating procedures; and 

the quality and integrity of study data and data collection methods are maintained.  
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory 
Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. 
Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) Good 
Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable regulatory 
requirements.
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 
subject protections and integrity of the study data. OSRO will determine the intensity and 
frequency of monitoring based on several factors, including study type, phase, risk, complexity, 
expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will 
conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change 
to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger 
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OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle 
of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit 
(SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) 
(IMVs), and a study Close-Out Visit (COV).
Some monitoring activities may be performed remotely, while others will occur at the study site(s). 
Monitoring visit reports will describe visit activities, observations, and associated action items or 
follow-up required for resolution of any issues, discrepancies, or deviations. Monitoring reports 
will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, coordinating 
center (if applicable), and the Sponsor regulatory file.
The site Monitor will inform the study team of any deviations observed during monitoring visits. 
If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR Protocol 
Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as applicable per 
institutional and IRB guidance.
10 STATISTICAL CONSIDERATIONS  
10.1
STATISTICAL HYPOTHESIS
10.1.1 Primary Endpoint

To determine the safety and tolerability of the triplet combination of venetoclax, 
magrolimab and obinutuzumab in relapsed and refractory indolent B-cell malignancies 
10.1.2 Secondary Endpoints

Overall response rate (ORR = CR+PR) after triplet combination therapy with magrolimab, 
obinutuzumab, and venetoclax 

Complete molecular remission rate (CMR) by flow cytometry or similar assays as they 
become available in patients after triplet combination therapy with magrolimab, 
obinutuzumab, and venetoclax (in CLL patients only)

Duration of response (DOR)

Event-free survival (EFS)

Progression-free survival (PFS) 

Overall survival (OS)
10.2
SAMPLE SIZE DETERMINATION AND STATISTICAL PLAN
The primary endpoint of this trial is to determine the safety and tolerability of the combination of 
magrolimab and obinutuzumab with venetoclax. We will be assessing this endpoint by using a 
venetoclax dose-finding scheme. During dose-finding, patients will receive magrolimab and 
obinutuzumab at fixed doses, and venetoclax will be administered at DL1. If required, dose de-
escalation of venetoclax will be explored. Patients will be enrolled in two cohorts for this 
evaluation: follicular lymphoma (FL) in Cohort 1, marginal zone lymphoma (MZL), chronic 
lymphocytic leukemia (MCL), and mantle cell lymphoma (CLL) in the Cohort 2. Unless dose de-
escalation is required, 6 total patients will be enrolled from Cohort 1 into Arm 1, and 6 total patients 
will be enrolled from Cohorts 2 into Arm 2. Both Cohorts 1 and 2 will include a single dose de-
escalation DL(-1) if needed. A maximum of 6 treated patients will be needed to complete the dose 
de-escalation scheme (if required) for Cohort 1, Arm 1, and a maximum of 6 treated patients will 


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be needed to complete the dose de-escalation scheme (if required) for Cohort 2, Arm 2 (total 24 
patients).  
At the MTD of venetoclax, dose expansion cohorts will enroll patients to assess the secondary 
clinical response outcomes in a preliminary fashion. The dose expansion cohorts (Cohorts 3, 4, 5 
and 6), based on the results of dose-escalation in Cohorts 1 and 2, will open to accrue up to 18 
additional FL patients, 6 additional MZL patients, 12 additional MCL patients and 6 additional 
CLL patients.  These numbers were chosen based on the expected number of patients which could 
be accrued in two years after completion of the dose-finding phase. A total of 42 treated patients 
will be required to complete the dose expansion phase of the study.  
Based on these estimates, up to 24 patients may be required for venetoclax dose-finding. These, in 
addition to 42 total treated patients required to complete the dose expansion phase brings the total 
number of patients required to complete the study to 66. To allow for a small number of inevaluable 
patients and screen failures, the accrual ceiling will be set at 76 patients. It is expected that 3 to 4 
years may be required to complete accrual, including dose-finding and expansion cohorts. Patients 
enrolled in dose-finding cohorts who are treated at the same dose-level as the expansion cohorts 
may be analyzed together with the dose-expansion cohorts at the end of the study (Cohort 1 with 
Cohort 3, and Cohort 2 with Cohorts 4, 5 and 6, respectively). 
As mentioned earlier in Section 1.2.6.2.1.2, recent reports indicate that MZL patients may be at a 
higher risk of infection-related AEs with fatal outcome when obinutuzumab was used in 
combination with chemotherapy. As an early stopping rule, if ≥2 subjects have infection-related 
SAEs or any subject experiences a fatal infection-related AEs from the first 6 subjects on study, 
we will hold further enrollment, and a comprehensive safety analysis will be performed.
In addition, an early stopping rule will be implemented for all histologies, if a substantial number 
of patients have to discontinue therapy due to unacceptable toxicity. If at any point after the first 
20 patients are enrolled, 25% or more patients have been unable to complete therapy due to 
unacceptable toxicity or if at any point 2 or more deaths or grade 4 hemolytic anemia events occur 
that are probably or definitely related to study therapy, then study enrollment for all histologies 
will be suspended for a formal assessment of the overall safety profile of the study design. This 
early stopping rule is applicable throughout the duration of the study.
10.3
POPULATIONS FOR ANALYSES
10.3.1 Evaluable for Toxicity
All patients who have received at least one dose of any of the study drugs will be evaluable for 
toxicity. 
10.3.2 Evaluable for Objective Response
Only those patients who have measurable disease present at baseline, have received at least one 
cycle of treatment (magrolimab+obinutuzumab) therapy, and have had their disease re-evaluated 
will be considered evaluable for response. (NOTE: Patients who exhibit objective disease 
progression after receiving at least one cycle of magrolimab+obinutuzumab will also be considered 
evaluable.)
10.3.3 Evaluable Non-Target Disease Response
Patients who have lesions present at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one cycle of therapy, and have had their disease re-


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evaluated will be considered evaluable for non-target disease response assessment.  The response 
assessment is based on the presence, absence, or unequivocal progression of the lesions.
10.4
STATISTICAL ANALYSES
10.4.1 General Approach
Toxicity profile of the combination therapy will be reported, and important toxicities described. 
Response rates will be reported as percentage, and time-to-event outcomes will be reported using 
Kaplan-Meier curves.
10.4.2 Analysis of the Primary Endpoints
The type, number and frequency of DLTs to triplet combination therapy will be reported and 
described. 
10.4.3 Analysis of the Secondary Endpoints
The type, number and frequency of DLTs to doublet combination therapy (during the ‘window’) 
will be reported and described. The ORR, and CR rate will be determined and reported from 
individual cohorts and histological diagnosis. CMR rate by flow cytometry or similar assays as 
they become available will be determined and reported separately for the CLL cohort. Responses 
will also be reported along with 95% confidence intervals, with waterfall plots, when appropriate. 
The duration of response (DOR; beginning at the date clinical response is first identified), 
progression free survival (PFS), event-free survival (EFS), and overall survival (OS) will be 
estimated using Kaplan-Meier curves, along with 95% confidence intervals at the median when 
appropriate. 
10.4.4 Safety Analyses
The type, grade and frequency of toxicities will be reported. DLTs, MTD of venetoclax in 
combination with magrolimab and obinutuzumab; and SAEs will be reported as well.  
10.4.5 Baseline Descriptive Statistics
Baseline characteristic of all cohorts will be explained including demographics, prior therapies and 
functional status.
10.4.6 Planned Interim Analyses
No interim analyses are planned 
10.4.7 Sub-Group Analyses
None planned.
10.4.8 Tabulation of Individual Participant Data
None planned.
10.4.9 Exploratory Analyses
The following are the exploratory analyses planned:

Overall response rate (ORR) after doublet-combination therapy with magrolimab and 
obinutuzumab


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
Complete molecular remission rate (CMR) by ctDNA assay or similar assays as they 
become available after doublet-combination therapy with magrolimab and obinutuzumab

Complete molecular remission rate (CMR) by ctDNA assay or similar assays as they 
become available after triplet-combination therapy with magrolimab, obinutuzumab and 
venetoclax

Lead time for ctDNA assay in detecting molecular relapse prior to clinical progression

Identify potential biomarkers and molecular correlates that are associated with response 
and/or resistance to the study treatment

Test immunogenicity of magrolimab and asses the effect of anti-drug antibodies (ADA) 
on the pharmacokinetics, pharmacodynamic markers, efficacy, and safety of magrolimab.
The ORR and CMR rates will be determined and reported from individual cohorts and histological 
diagnosis. Responses will also be reported with waterfall plots, when appropriate. The exploratory 
objectives such as seeking to identify potential biomarkers and molecular correlates that are 
associated with response and/or resistance to the study treatment, will be assessed using descriptive 
statistics as well as non-parametric methods such as exact Wilcoxon rank sum tests. The analyses 
will be done without formal adjustment for multiple comparisons, but in the context of the number 
of tests performed.
Magrolimab PK data will be summarized using summary statistics (mean, median, range, standard 
deviation, etc.) at each time point. The overall rate of ADA occurrence and type of ADA (e.g., 
transient vs persistent) will be summarized for all patients. PK in ADA positive and negative 
patients will be tabulated at each timepoint. If relevant, the impact of ADA occurrence on efficacy 
and safety will be assessed through summary statistics.
11 COLLABORATIVE AGREEMENTS
11.1
CLINICAL TRIAL AGREEMENT (CTA)
11.1.1 Gilead Sciences, Inc.
There is a CTA with Gilead Sciences, Inc. (#01181-20).
11.1.2 Genentech
There is a CTA with Genentech, Inc. (#01182-20).
12 HUMAN SUBJECTS PROTECTIONS 
12.1
RATIONALE FOR PATIENT SELECTION
This trial is designed as a novel-novel targeted therapy with magrolimab as backbone for patients 
with indolent lymphomas. Median age for all 4 histologies included in this study are over 60 years 
of age and male predominance is noted in MZL and CLL. Pregnant or nursing mothers are 
excluded because of the potential teratogenic effects of therapy.  Given the small number of 
patients on our study, we expect a gender-even to a slightly male predominant patient population 
for our study. 


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12.2
PARTICIPATION OF CHILDREN
Since safety data is not available for magrolimab in children, patients <18 years of age will be 
excluded from the study. Also, most of the histologies of indolent lymphomas we are testing are 
rare in children. 
12.3
RISK/BENEFIT ASSESSMENT
12.3.1 Known Potential Risks
The most common (>10%) adverse reactions with magrolimab are anemia (43%), nausea (41%), 
fatigue (30%), constipation (39%), diarrhea (39%), infusion-related reactions (33%), headache 
(32%), dyspnea (30%), pyrexia (39%), cough (27%),  thrombocytopenia (25%), decreased appetite 
(25%), febrile neutropenia (25%), chills (23%), vomiting (23%), dizziness (20%), and 
hypokalemia (21%), and bilirubin increase (15%), and pneumonia (10%). Other common AEs 
with magrolimab include hemolysis (≥1% and <10%, SAR 1.2% serious), sepsis (≥1% and <10%, 
0.4% serious), and hypotension (≥10%, 0.2% serious). Common AEs with venetoclax-
obinutuzumab combination were neutropenia, thrombocytopenia, diarrhea, infections, fatigue and 
nausea. Severe neutropenia may occur with magrolimab use. Grade 3 (absolute neutrophil count 
[ANC] 500 to <1000 cells/uL) and Grade 4 (ANC <500 cells/uL) have been reported. Additionally, 
fatal events of febrile neutropenia have been reported in patients treated with magrolimab. Close 
hematological monitoring will be performed for all patients during treatment (at least once a month 
while on therapy). In cases of neutropenia, consider antimicrobial prophylaxis and administration 
of granulocyte colony-stimulating factor (G-CSF) if clinically appropriate. If febrile neutropenia 
occurs, administer antibiotics and antimycotics. Dose modifications/delays will be per Section 
3.3.2. 
Serious infections (Grades 3 or 4) have been reported in patients treated with magrolimab, 
including fatal events of pneumonia and sepsis. Patients will be regularly monitored for signs and 
symptoms of infection during monthly clinic visits while on therapy. For patients with prolonged 
neutropenia or patients at risk, infection prophylaxis using appropriate antibiotics will be 
considered in accordance with current guidelines. Dose modifications/delays will be per Section 
3.3.2.
TLS has been observed with venetoclax, but rigorous precautions, slow ramp-up of dose and early 
detection and treatment has improved the safety profile. Individually, both magrolimab (in FL) 
and venetoclax (in CLL, FL, MZL and MCL) have shown promising activity.
As noted in Section 3.2, premedication will be given to reduce the risk of AEs occurring.  Subjects 
will be monitored closely, and manufacturer recommendations for delaying and discontinuing 
study medications and initiating supportive therapy will be followed.
12.3.1.1 Biopsy Risk
The risks associated with biopsies are pain and bleeding at the biopsy site. In order to minimize 
pain, conscious sedation or local anesthesia will be used. Rarely, there is a risk of infection at the 
sampling site. CT guidance may be used for biopsies.
12.3.1.2 Conscious Sedation 
The common side effects of conscious sedation include drowsiness, delayed reflexes, hypotension, 
headache, and nausea. These are generally mild and last no more than a few hours.


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12.3.1.3 Bone Marrow Biopsy
Bone marrow biopsy is minimally invasive and is typically a very safe procedure. Usually, the 
hipbone is numbed with anesthesia. Using a needle, the solid and liquid portion of bone marrow 
is taken out. This procedure causes some pain. Very rarely, infection or bleeding may occur at the 
needle site.
12.3.1.4  Radiation Risk
The study will involve radiation from the following sources:

Up to 7 CT scan of chest abdomen pelvis (1 during screening)

Up to 4 [18F]-FDG-PET/CT

Up to 2 CT-guided biopsies as referenced above 
Subjects in this study may be exposed to approximately 14.1 rem. This amount is more than would 
be expected from everyday background radiation. Being exposed to excess radiation can increase 
the risk of cancer. The risk of getting cancer from the radiation exposure in this study is 1.4 out of 
100 (1.4%) and of getting a fatal cancer is 0.7 out of 100 (0.7%). 
12.3.1.5 Scans
The radiation risks of the FDG and CT scans are discussed above.  In addition to radiation risks, 
CT scans that employ contrast may cause allergic reactions, injection site reactions abdominal 
discomfort and fainting.  MRIs carry no radiation risks, but are contraindicated in participants with 
metal in their bodies. In patients that receive gadolinium contrast with MRIs, allergic reactions, 
injection site reactions and kidney damage may occur. 
12.3.1.6 Risk related to blood sampling
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. 
Up to 6.4 tablespoons of blood may be collected at any day and up to 26.9 tablespoons may be 
collected within 8 weeks.
12.3.1.7 Non-Physical Risks of Genetic Research
Risk of receiving unwanted information, anxiety and stress at the information, and breach of 
confidentiality.
12.3.2 Known Potential Benefits
Although the potential for SAEs exists but owing to differing mechanism of action and non-
overlapping toxicities, the incidence of them is expected to be much lower than chemotherapy.
12.3.3 Assessment of Potential Risks and Benefits
We are aiming to develop a combination of novel agents that individually appear to be safe.   
Patients may obtain direct benefit from treatment with this combination with a high response rate 
and deep remissions.
12.4
CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant for review prior to consenting.  A designated study investigator will carefully explain 
the procedures and tests involved in this study, and the associated risks, discomforts and benefits. 
In order to minimize potential coercion, as much time as is needed to review the document will be 
given, including an opportunity to discuss it with friends, family members and/or other advisors, 


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and to ask questions of any designated study investigator. A signed informed consent document 
will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with  
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant.  Whether in person or remote, the privacy of the subject will be 
maintained. Consenting investigators (and participant when in person) will be located in a private 
area (e.g., clinic consult room). When consent is conducted remotely, the participant will be 
informed of the private nature of the discussion and will be encouraged to relocate to a more private 
setting if needed.
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document. When required, witness signature will be 
obtained similarly as described for the investigator and participant.
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent at 
the NIH Clinical Center, this study will use the following to obtain the required signatures:

Adobe platform (which is not 21 CFR Part 11 compliant); or,  

iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the same 
screen may be used when in the same location but is not required.  
Both the investigator and the subject will sign the document using a finger, stylus or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) found at:
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
13 REGULATORY AND OPERATIONAL CONSIDERATIONS 
13.1
STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigator, funding agency, the Investigational New Drug (IND) sponsor and regulatory 
authorities.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) 
will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and 
will provide the reason(s) for the termination or suspension.  Study participants will be contacted, 
as applicable, and be informed of changes to study visit schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Insufficient compliance to protocol requirements


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
Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB, and as applicable Food and Drug Administration (FDA).
13.2
QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan 
will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted, and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Council on Harmonisation 
Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory 
Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities.
13.3
CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial.  The study leadership in conjunction with the National Cancer Institute/Center for 
Cancer Research has established policies and procedures for all study group members to disclose 
all conflicts of interest and will establish a mechanism for the management of all reported dualities 
of interest.
13.4
CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) collaborators, as applicable. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 


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(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records.
The study participant’s contact information will be securely stored at the/each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB and Institutional policies, or sponsor 
requirements.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be stored at the NCI CCR. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems used by the 
clinical site(s) will be secured and password protected. At the end of the study, all study databases 
will be archived at the NIH Clinical Center.
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued 
by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants.
14 PHARMACEUTICAL INFORMATION  
The clinical investigations outlined will be conducted under an NCI CCR-held IND; IND 
#148205).  
14.1
MAGROLIMAB 
Magrolimab is a recombinant IgG4 humanized IgG4 monoclonal antibody of the IgG4 kappa 
isotype containing a Ser-Pro (S-P) substitution in the hinge region (position 228) of the heavy 
chain to reduce Fab arm exchange. It comprises a disulfide-linked glycosylated tetramer, 
consisting of two identical 444 amino acid heavy gamma chains and two identical 219 amino acid 
kappa light chains. Magrolimab targets the human CD47 antigen.
Molecular Formula: C6462H9960N1718O2027S48
14.1.1 Source/ Acquisition and Accountability
Drug (investigational supplies) will be provided by Gilead Sciences, Inc. for use by subjects in this 
clinical trial.  
14.1.2 Toxicity
See Section 1.2.4.4 and Section 12.3.1 for a summary of AEs and SAEs.
14.1.3 Formulation and preparation
Magrolimab drug product is formulated in 0.01% (w/v) Polysorbate 20, 5% (w/v) Sorbitol, and 10 
mM Sodium acetate, pH 5.0, and Sterile Water for Injection. The drug product is a sterile, clear to 
slightly opalescent, colorless, preservative-free liquid supplied at a protein concentration of 20 


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mg/mL in 10 mL (200 mg) single-use vials. Magrolimab drug product is provided in a liquid 
dosage form intended for intravenous (IV) infusion. 
The desired amount of magrolimab should be withdrawn from the vial(s) and diluted in a polyvinyl 
chloride (PVC) infusion bag containing 0.9% Sodium Chloride Injection United States 
Pharmacopeia (USP) to a final concentration of approximately 0.03 to 6.0 mg/mL. The clinical 
dose will be prepared (diluted in saline) as an IV infusion through a standard infusion set. The 
initial priming dose will be administered as a continuous IV infusion in 250 mL over 180 minutes 
to reduce the risk of acute hemagglutination.  All other infusions for doses greater than 1 mg/kg 
will be administered in 500 mL over 120 minutes. The bag should be gently inverted to mix the 
solution. Before administration, the parenteral drug products should be inspected visually. If 
particulate matter or discoloration is noted, drug should not be administered, and the sponsor 
should be notified. The prepared drug solution can be stored at refrigerated temperature between 
2°C to 8°C (36°F to 46°F) for up to 16 hours and / or stored at room temperature for up to 8 hours 
from the preparation start time.
Precautions

Recommended safety measures for preparation and handling of magrolimab include 
laboratory coats and gloves.

Magrolimab cannot be mixed with any other drug in the infusion bag or the administration 
set.

Magrolimab should NOT be administered as a bolus injection.
14.1.4 Stability and storage
Magrolimab drug product is shipped refrigerated and must be stored at 2-8°C (36-46°F) until use, 
with access limited to pharmacy personnel, the Principal Investigator, or a duly designated person. 
A temperature log must be kept to document the refrigerator temperature. If the temperature is not 
maintained, the sponsor should be contacted. 
Magrolimab should be protected from light. Sufficient protection from light is provided by the 
secondary container. No specific light protection is needed during preparation of the dosing 
solution and infusion. DO NOT SHAKE. Magrolimab is not formulated with a preservative. 
Therefore, once the sterile vials are entered, all dose preparations should be performed aseptically. 
14.1.5 Administration procedures
Refer to Section 3.2.1 for administration details. 
14.1.6 Incompatibilities
Magrolimab cannot be mixed with any other drug in the infusion bag or the administration set.
14.2
VENETOCLAX (VENCLEXTA®)
Venetoclax is a selective inhibitor of BCL-2 protein. It is a light yellow to dark yellow solid with 
the empirical formula C45H50ClN7O7S and a molecular weight of 868.44. Venetoclax has very low 
aqueous solubility. Venetoclax has the following chemical structure: 


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Venetoclax is a small molecule administered orally and is primarily metabolized by 
cytochrome P450 3A4 (CYP3A4/5).  Details of interactions and dose adjustments are mentioned 
in Section 3.3.  Please refer to the package insert for full drug interactions and toxicities. 
14.2.1 Source/Acquisition and Accountability
Venetoclax is a commercially available agent manufactured by Abbvie, but will be provided by 
Genentech to the NCI (investigational supplies) for dispensing to the study participants as per an 
arranged research agreement.
14.2.2 Toxicity
See Section 1.2.5.1 for a summary of AEs and SAEs. 
14.2.3 Formulation and preparation
Venetoclax comes in 10 mg, 50 mg and 100 mg tablets.  Excipients include:  copovidone, colloidal 
silicon dioxide, polysorbate 80, sodium stearyl fumarate, calcium phosphate dibasic.  In addition, 
the 10 mg and 100 mg tablet coating contains iron oxide yellow, polyvinyl alcohol, titanium 
dioxide, polyethylene glycol, and talc; the 50 mg tablet coating contains iron oxide yellow, iron 
oxide red, iron oxide black, polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.  

Venetoclax 10 mg film-coated tablets are round, biconvex shaped, pale yellow debossed 
with “V” on one side and “10” on the other side. 

Venetoclax 50 mg film-coated tablets are oblong, biconvex shaped, beige debossed with 
“V” on one side and “50” on the other side. 

Venetoclax 100 mg film-coated tablets are oblong, biconvex shaped, pale yellow debossed 
with “V” on one side and “100” on the other side. 
14.2.4 Stability and storage
Venetoclax tablets will be packaged in high-density polyethylene plastic bottles to accommodate 
the study design.  Each bottle will be labeled per local regulatory requirements.  A desiccant 
canister may be included in the bottle. If supplied with a desiccant, the desiccant canister should 
be returned to the bottle directly after each tablet removal. Store at or below 86°F (30°C). 


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14.2.5 Administration procedures
See Section 3.2.3 for details regarding venetoclax administration. 
14.2.6 Incompatibilities
See Appendix C for details regarding medications that have possible interactions with venetoclax. 
14.3
OBINUTUZUMAB
14.3.1 Source/Acquisition and Accountability
Obinutuzumab is commercially available agent,but will be provided by Genentech to the NCI 
(investigational supplies) for dispensing to the study participants as per a research agreement.
14.3.2 Toxicity
See Section 1.2.6.2 for a summary of AEs and SAEs. Additionally, coagulation abnormalities 
including disseminated intravascular coagulation (DIC) have been reported in patients receiving 
obinutuzumab for treatment of FL and CLL. In the majority of cases, the events have involved 
subclinical (asymptomatic) changes in platelets and laboratory coagulation parameters following 
the first infusion, with spontaneous resolution usually occurring by Day 8. In some cases, the 
events were associated with IRRs and/or TLS. No specific baseline risk factors for DIC have been 
identified. 
14.3.3 Formulation and Preparation
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 highly purified water (HPW). HPW meets the specified limits of HPW according to 
Pharm. Eur. and for water for injections (WFI) according to USP. 
14.3.4 Stability and Storage 
The recommended storage conditions for obinutuzumab drug product are between 2°C and 8°C, 
protected from light. For further instructions, as well as information on in-use stability, see the 
packaging label.
14.3.5 Administration procedures
See Section 3.2.2for details about obinutuzumab administration. 
14.3.6 Incompatibilities
No formal drug interaction studies have been performed with obinutuzumab. Please refer to the 
package insert and PDR for full drug interactions and toxicities. 


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16 APPENDICES
APPENDIX A:  PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Grade
Descriptions
0
Normal activity.  Fully active, able to carry on all pre-disease performance without 
restriction.
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).
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.
3
In bed >50% of the time.  Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours.
4
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined 
to bed or chair.
5
Dead.


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APPENDIX B:  GUIDELINES FOR PREGNANCY AND NURSING 
Contraception
Magrolimab, venetoclax and/or obinutuzumab may have adverse effects on a fetus in utero.  
Furthermore, it is not known if magrolimab, venetoclax and/or obinutuzumab have transient 
adverse effects on the composition of sperm.   
Magrolimab is contraindicated in pregnancy. In an enhanced embryo-fetal prenatal and postnatal 
development study in a pregnant cynomolgus monkey, there was an increased incidence of 
stillbirths at the high dose, and morbidity and mortality in the offspring at the high dose (secondary 
to severe anemia). In the clinical development program, pregnant or active breastfeeding women 
were excluded from participation the clinical studies.
For this trial, male patients will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical condition).  
Female patients will be considered of non-reproductive potential if they are either: 
1. postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement therapy. In the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.); OR 
2. have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; OR 
3. have a congenital or acquired condition that prevents childbearing.
Female and male patients of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 90 days after the last dose 
of magrolimab, 18 months after the last dose of obinutuzumab, and 30 days after the last dose of 
venetoclax, whichever is later, by complying with one of the following:  
1. practice abstinence† from heterosexual activity; OR 
2. use (or have their partner use) contraception methods that result in a failure rate of <1% 
per year during heterosexual activity.  
With a female partner of childbearing potential who is not pregnant, men who are not surgically 
sterile must use a condom plus an additional contraceptive method that together result in a failure 
rate of <1% per year. 
With a pregnant female partner, men must use a condom.
Acceptable methods of contraception are‡:
Single method 
Use of one of the following is acceptable:

intrauterine device (IUD)

vasectomy of a female subject’s male partner 


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114

contraceptive rod implanted into the skin
Combination method 
Requires use of two of the following:

diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide)

cervical cap with spermicide (nulliparous women only)  

contraceptive sponge (nulliparous women only) 

male condom or female condom (cannot be used together)

hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only 
pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive 
injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently 
employed as the subject’s preferred and usual lifestyle and if considered acceptable by local regulatory agencies 
and ERCs/IRBs.  Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) 
and withdrawal are not acceptable methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as an 
acceptable method of contraception for patients participating at sites in this country/region.
Patients should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study patients of childbearing potential must adhere to the contraception requirement (described 
above) from the day of study medication initiation, throughout the study period, and up to the time 
frames after the last dose of trial therapy as noted above.  If there is any question that a subject of 
childbearing potential will not reliably comply with the requirements for contraception, that 
subject should not be entered into the study.
Use in Pregnancy
If a subject inadvertently becomes pregnant while on study treatment, the subject will immediately 
be removed from the study treatment.  The site will contact the subject at least monthly and 
document the subject’s status until the pregnancy has been completed or terminated. The outcome 
of the pregnancy will be reported to Gilead Sciences, Inc. and Genentech without delay, especially 
if the outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).  
If a male subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to Gilead Sciences, Inc. and Genentech and followed as 
described above. 
Use in Nursing Women
It is unknown whether magrolimab is excreted in human milk.  Since many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions in the nursing infant, 
patients who are breast-feeding are not eligible for enrollment.


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APPENDIX C:  INHIBITORS AND INDUCERS OF CYP3A AND P-GP
A 
comprehensive 
list 
of 
inhibitors 
can 
be 
found 
at 
the 
following 
website: 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx. The general categorization into strong, 
moderate, and weak inhibitors according to the website and venetoclax FDA label is displayed 
below. 
Inhibitors of CYP3A
Inducers of CYP3A
Inhibitors of P-gp
Strong inhibitors: 
INDINAVIR 
NELFINAVIR 
RITONAVIR 
CLARITHROMYCIN
ITRACONAZOLE 
KETOCONAZOLE 
NEFAZODONE 
SAQUINAVIR 
TELITHROMYCIN 
CONIVAPTAN
POSACONAZOLE 
VORICONAZOLE
Moderate inhibitors: 
aprepitant 
erythromycin 
diltiazem 
fluconazole 
grapefruit juice 
seville orange juice 
verapamil
 
Weak inhibitors: 
cimetidine 
All other inhibitors: 
amiodarone 
azithromycin 
chloramphenicol 
boceprevir 
ciprofloxacin 
delaviridine 
diethyl-dithiocarbamate 
fluvoxamine 
gestodene 
imatinib 
mibefradil 
mifepristone 
norfloxacin 
norfluoxetine 
star fruit 
telaprevir 
troleandomycin 
voriconazole
carbamazepine 
efavirenz 
nevirapine 
barbiturates 
glucocorticoids 
modafinil 
oxcarbarzepine 
phenobarbital 
phenytoin 
pioglitazone 
rifabutin 
rifampin 
St. John’s Wort 
troglitazone 
amiodarone 
azithromycin
dronedarone
captopril
carvedilol
cyclosporine
felodipine
quercitin
quinidine
ranolazine
ticagrelor
Source: http://medicine.iupui.edu/clinpharm/ddis/table.aspx and 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208573s000lbl.pdf


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APPENDIX D:  STUDY DRUG DIARY (OPTIONAL)
Patient Name:  
Cycle:  
Instructions:

Use this diary to record all doses of oral study medication taken.  

You should bring this study drug diary and each of your study medications (including 
leftover pills and empty bottles) with you to each clinic visit. 

Contact us if you have any side effects or before starting any new medications or over-the-
counter drugs.

If you have questions at any time, please contact your doctor or nurse.
Study Drugs:
The study medications should be taken as follows; the doses will be assigned to you by your doctor:  
Venetoclax
Venetoclax tablets to be taken by mouth, with a glass of water and food 
Magrolimab
Magrolimab is given by IV, in the clinic
Obinutuzumab
Obinutuzumab is given by IV, in the clinic
Additional Information:

The venetoclax should be taken at about the same time each day 

If you do not remember to take all or any of the medications on any day, please tell us.  Do 
not make-up the dose or take extra the following day to make-up for the missed dose.

If you vomit after taking a dose, you should not take another dose that day.  However, if 
vomiting occurs within 15 minutes after taking venetoclax and all expelled tablets are still 
intact, another dose may be given.
EXAMPLES – Study Drug Diary (Cycle 2-12):
These are examples of how you might take the study drugs:

Day 1:  Come to clinic.  Take the venetoclax when advised by the study staff. 

Days 2 through 14:  Take the venetoclax. 

Day 15:  Come to clinic. Take the venetoclax when advised by the study staff. 

Days 16-28: Take the venetoclax. 
STAFF USE ONLY
Date returned/reviewed:  
Staff member:  
Notes/Comments:


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117
Please record the dose/number of pills of each study drug taken in the table below:
Study Drugs
Cycle 
Day
Date
Venetoclax
Obinutuzumab
Magrolimab
Comments
1
In Clinic, IV
In Clinic, IV
2
3
4
5
6
7
8
9
10
11
12
13
14
15
In Clinic, IV
16
17
18
19
20
21
22
23
24
25
26
27
28


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APPENDIX E:  CAIRO-BISHOP DEFINITION FOR TLS
The Cairo-Bishop definition proposed in 2004 (Table 21), provided specific laboratory criteria for 
the diagnosis of TLS both at presentation and within seven days of treatment. It also incorporated 
a grading system to help delineate the degree of severity of TLS (Table 22). 
Table 21: Cairo-Bishop laboratory TLS definition 
Parameter
Value
Change from baseline
Uric acid
≥476 micromol/L (8 mg/dL)
25% increase
Potassium
≥6.0 mmol/L (or 6 mEq/L)
25% increase
Phosphorus
≥1.45 mmol/L (4.5 mg/dL) for adults
25% increase
Calcium
≤1.75 mmol/L (7 mg/dL)
25% increase
Laboratory TLS is defined as any two or more abnormal serum values, as mentioned in the above 
table (Table 21), present within three days before or seven days after instituting therapy in the 
setting of adequate hydration (with or without alkalization) and use of a hypouricemic agent.
Clinical TLS is defined as laboratory TLS plus one or more of the following that was not directly 
or probably attributable to a therapeutic agent: increased serum creatinine concentration (≥1.5 
times the upper limit of normal [ULN]), cardiac arrhythmia/sudden death, or a seizure.
Table 22: Cairo-Bishop clinical TLS definition and grading
Grade
Complication
0
1
2
3
4
5
Creatinine
≤ 1.5 x ULN
1.5 x ULN
>1.5-3.0 x ULN
> 3.0-6.0 x ULN
> 6.0 x ULN
Death
Cardiac 
arrhythmia
None
Intervention 
not 
indicated
Nonurgent medical 
intervention 
indicated
Symptomatic 
and incompletely 
controlled 
medically or 
controlled with 
device (e.g., 
defibrillator)
Life-threatening 
(e.g., arrhythmia 
associated with 
HF, hypotension, 
syncope, shock)
Death
Seizure
None
-
One brief, 
generalized 
seizure; seizure(s) 
well controlled by 
anticonvulsants or 
infrequent focal 
motor seizures not 
interfering with 
ADL
Seizure in which 
consciousness is 
altered; poorly 
controlled 
seizure disorder; 
with 
breakthrough 
generalized 
seizures despite 
medical 
intervention
Seizure of any 
kind which are 
prolonged, 
repetitive or 
difficult to 
control (e.g., 
status 
epilepticus, 
intractable 
epilepsy)
Death


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APPENDIX F:  MAGROLIMAB PK AND ADA SAMPLE COLLECTION, PROCESSING, AND SHIPPING 
INSTRUCTION 


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Abbreviated Title:  VENOM in R/R B-Cell NHL 
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122
APPENDIX G:  STUDY CALENDAR
Window 
Portion†
Triplet
Combination 
Therapy∆
Response-
Based 
Therapy
Disease Evaluations
Active Monitoring/ 
Surveillance Follow-Up
Procedure
Screening
Baseline
C -2
D1
C -1 
D1
C1-C6
D1
C7-C12
D1
Window C-1/ 
Pre-C1, 
Cycles 6 & 12
Cycles 
3 & 9
End of 
Treatment 
or PD
Safety
(Day 30)
Follow-Up
(Prior to PD)
Survival
(Post-PD)
Scheduling Window (Days):
-28 to 
-11
-282
-14* or -7^
-3
-3
-3
Last 7 days of the cycle
Treatment 
discon./PD3
+7
Every 3 or 6 
months4
Every 3 
months5
Confirmation of Diagnosis
X
Physical Exam6
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
CBC with Differential7
X
X
X*
X
X
X
X
X
X
Chemistry Panels8 
X
X
X*
X
X
X
X
X
X
LDH
X
X
X*
X
X
X
X
X
X
Total protein
X
X*
X
X
X
X
X
X
PT/INR and aPTT
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X*
X
X
X
X
X
X
Pregnancy Test (urine/serum; 
WOCBP)
X
X
X^
X
X
X
X
X
Hepatitis and HIV Testing
X
Haptoglobin
X
Quantitative serum 
immunoglobulin (IG) levels
X
X
X
X
X
X
X
X
Beta-2 microglobulin
X
X
X
X
X
X
X
X
Direct Anti-Globulin (DAT)
X
X
X
X
X
X
X
X
X
RBC Phenotyping, Type and 
Screen
X
Lymphocyte Phenotype 
(T, B, NK cell subsets)
X
X
X
X
X
X
X
X
Peripheral Blood Flow 
Cytometry9
X
X
(C-2 D8, 
15)
X
X


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123
Window 
Portion†
Triplet
Combination 
Therapy∆
Response-
Based 
Therapy
Disease Evaluations
Active Monitoring/ 
Surveillance Follow-Up
Procedure
Screening
Baseline
C -2
D1
C -1 
D1
C1-C6
D1
C7-C12
D1
Window C-1/ 
Pre-C1, 
Cycles 6 & 12
Cycles 
3 & 9
End of 
Treatment 
or PD
Safety
(Day 30)
Follow-Up
(Prior to PD)
Survival
(Post-PD)
Scheduling Window (Days):
-28 to 
-11
-282
-14* or -7^
-3
-3
-3
Last 7 days of the cycle
Treatment 
discon./PD3
+7
Every 3 or 6 
months4
Every 3 
months5
Bone Marrow Aspiration (with 
flow cytometry)/ Biopsy10
X
X
X
CT Scans or MRI11
X
X
X
X
X
X
18F-FDG-PET/CT Scan12
X
X
X
X
Symptoms/Adverse Events, 
Concomitant Medication 
Reviews
X
X
X
X
X
X
X
X
Research Tissues 
(archival/fresh biopsy, bone 
marrow biopsy/aspiration)13
See Research Sample Calendar in Section 5.1
Research Saliva/Buccal 
(baseline), Blood Samples14
See Research Sample Calendar in Section 5.1
Survival Status
X
†Window Portion:  Applies only to patients enrolled in the dose expansion cohorts.
∆Additional monitoring for TLS during C1 of triplet combination therapy is described in Section 4.1.2.
NOTE:  Perform any other assessments and/or tests as clinically indicated at the discretion of the investigator.  
1 Screening and Baseline evaluations should be performed within 28 days prior to enrollment and dosing, respectively, with the following exceptions:  
Confirmation of diagnosis (no time limit); HIV antibody, Hepatitis B surface antigen and Hepatitis C antibody (within 3 months); Bone marrow 
assessments (within 12 months).  See Section 2.2.  NOTE:  Any screening tests performed within the time frame for baseline do not need to be repeated.
2 Within 28 days prior to dosing in Window on Cycle -1 Day 1, unless otherwise noted to be within 14 days (*) or 7 days (^).


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124
3 To be done at treatment discontinuation (+/- 2 weeks) or may coincide with the safety follow-up visit.  If treatment is discontinued for a reason other 
than disease progression, assessments should be repeated at the time of progression.  If subject to initiate new anti-cancer therapy assessments should 
occur before the first dose of the new therapy.  
4 Follow-up prior to disease progression to occur about every 3 months (+/- 2 weeks) for first 2 years after therapy, every 6 months for years 3-5 (+/- 4 
weeks), and then annually (+/- 6 weeks) at the discretion of investigator.  
5 After disease progression or initiation of new anti-cancer therapy, contact for survival about every 3-6 months (+/- 4 weeks).
6 Physical exams to include history, vitals, weight, and height (screening only).
7 Complete Blood Count with Differential will be performed prior to each dose and 3-6 hours after the first and second doses of magrolimab - Cycle 1, 
Days 2 and 8 for dose-finding arms (Arms 1 and 2), and Cycle -2, Days 2 and 8 for dose-escalation arms (Arms 3 and 4). 
8 Chemistry panels include: Acute care, Hepatic, and Mineral and 24-hour urine creatinine clearance (if needed to measure CrCl).
9 Peripheral blood flow cytometry for diagnostic and staging purposes; repeat in follow-up to assess disease status and response.  See also Section 5 for 
flow cytometry to be collected also for research purposes.
10 Bone marrow aspiration (± flow cytometry)/biopsy within 12 months prior to starting treatment, unless repeat at screening/baseline felt to be clinically 
indicated (see Section 2.2); repeat in follow-up to confirm response or progression only if bone marrow involvement is present at baseline.  
11 CT scans (preferred) of chest, abdomen and pelvis to be performed at each disease evaluation; may be adjusted to assess additional known sites of 
disease, as needed.  Scans are to be done after completion of window with magrolimab and obinutuzumab (i.e., after 2 cycles of treatment; up to 7 days 
prior to Cycle 1, Day 1 pre-dose); after Cycle 3, Cycle 6, and Cycle 9 (if applicable), up to 7 days prior to next cycle; after Cycle 12 (if applicable), 21-28 
days after completion of the treatment
12 PET scans to be performed at baseline, after completion of the window with magrolimab and obinutuzumab, after Cycles 6 and 12 (if applicable), and 
at the end of treatment; repeat additionally if clinically indicated
13 If adequate archival tissue at baseline, fresh tumor biopsy is optional.  Optional “on-treatment” and bone marrow sampling will be performed, as 
indicated in Section 5.
14 Samples for correlative research blood and saliva (preferred)/buccal swab samples to be collected as indicated in Section 5.

ICF_001.pdf: 
IRB NUMBER: 20C0162
IRB APPROVAL DATE: 5/30/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 05/16/2023
Page 1 of 14
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR: Mark Roschewski, M.D.
STUDY TITLE: A Phase 1 Study of Venetoclax added to Magrolimab and Obinutuzumab for 
Relapsed and Refractory Indolent B-cell Malignancies
STUDY SITE: NIH Clinical Center
Cohort: Screening consent, Affected patient
 
Consent Version: 05/16/2023
 
WHO DO YOU CONTACT ABOUT THIS STUDY? 
           Principal Investigator:    Mark Roschewski, M.D.  
Phone:  240-760-6183
Email:  mark.roschewski@nih.gov
KEY INFORMATION ABOUT THIS RESEARCH 
This consent form describes a research study and is designed to help you decide if you would 
like to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
This section provides the information we believe is most helpful and important to you in making 
your decision about participating in this study. Additional information that may help you decide 
can be found in other sections of the document. Taking part in research at the NIH is your choice.
You are being asked to take part in this study because you have an indolent B-cell lymphoma 
and your disease has returned or progressed after other treatment. 
This consent is for “screening.” This part of the study will allow us to find out if you are able to 
take part in the treatment part of the study.
The main purpose of this study is to find out if it is safe to give the combination of three drugs 
– magrolimab, obinutuzumab, venetoclax – to patients with B-cell lymphomas. Specifically, we 
will look at patients with follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle 
cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL).  
Although obinutuzumab (GAZYVA®) and venetoclax (VENCLEXTATM) have been approved 
and used either alone or in combination to treat types of lymphoma, magrolimab has not. The 
use of magrolimab in this research study is experimental, which means that the FDA has 
not approved its use for cancer treatment or treatment of any other disease. In addition, 
the combination of magrolimab, obinutuzumab, venetoclax in this study is experimental, 
which means that while the FDA has approved obinutuzumab and venetoclax for cancer 
treatment, they have not approved the combination of obinutuzumab and venetoclax with 
magrolimab. 


IRB NUMBER: 20C0162
IRB APPROVAL DATE: 5/30/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 05/16/2023
Page 2 of 14
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
We want to study the side effects of these drugs when given together. We also want to see if the 
combination of these drugs is an effective treatment for your disease, and hope to learn about 
how they work together to treat B-cell lymphomas.  
If you decide to be screened for this study, here are some things that will happen:

We will review your health history, prior tests and biopsy samples that you have had 
taken before, or take a new biopsy if needed, and will perform tests to find out whether 
you are able to take part (screening) in the study. Some of tests to be done include a 
physical examination, blood and urine tests, bone marrow testing, and imaging (such as 
CT, MRI, and PET/CT scans). 

Some possible side effects from the screening tests for include bruising, bleeding, and 
pain where samples are taken (such as blood and biopsy), and discomfort with the 
procedures.  

We do not know which side effects you will experience.
There may be no direct benefit to you from taking part in the study. This screening part will help 
us decide if you are able to take part in the next step of this research study. You will also have 
the benefit of seeing our NIH doctors to discuss your treatment. If you would like, we can share 
the results of these screening tests and notes with your personal physician.
The screening portion of this study will take between a few days and a week. If you move on to 
the treatment portion of the study, you may be in the study for several years depending on how 
you tolerate the treatment. You can stop taking part in the trial at any time. 
The remaining document will now describe the research study in more detail.  This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information in this document. Some people have personal, religious, or ethical beliefs 
that may limit the kinds of medical or research treatments they would want to receive (such as 
blood transfusions). Take the time you need to ask any questions and discuss this study with NIH 
staff, and with your family, friends, and personal health care providers.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
This part of the study is to determine if you are suited for this study.
B-cell lymphoma is a cancer of certain white blood cells (called lymphocytes) that are found in 
lymph nodes and the cancer affects the lymphatic system. The lymphatic system helps to fight 
infections and disease. The purpose of this research study is to see if the combination of 
magrolimab, obinutuzumab, and venetoclax is safe and effective at treating different types of B-
cell lymphoma. We are asking you to join this research study because you have either follicular 


IRB NUMBER: 20C0162
IRB APPROVAL DATE: 5/30/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 05/16/2023
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL) or chronic 
lymphocytic leukemia (CLL) and your disease has returned or progressed. 
Additional information is provided about each of the drugs being combined for the purposes of 
this study: 

Venetoclax (VENCLEXTATM) is a drug that targets a specific protein in the body called 
BCL-2.  When normal cells are damaged or old, your body tells them to self-destruct. This 
natural process is called apoptosis. In some lymphomas, BCL-2 may build up and prevent 
cancer cells from self-destructing naturally. By targeting BCL-2 with venetoclax, the 
process of apoptosis may be restored, allowing your body to destroy cancer cells.  

Obinutuzumab (GAZYVA®) is a type of drug called a “monoclonal antibody”. It is 
believed that obinutuzumab works by targeting a specific protein in the body called CD20.  
CD20 is found on the surface of B-cells in the body, often in high amounts in some types 
of lymphoma. By using obinutuzumab to target CD20 and attach to it, it may work by 
causing the cell to die or by signaling your immune system to destroy the cancer cells.  

Magrolimab is also a “monoclonal antibody”. It is believed that magrolimab works by 
targeting a specific protein in the body called CD47. CD47 is a protein on the surface of 
cancer cell that sends a “do not eat me” signal to the body’s immune system. Blocking this 
protein with an anti-CD47 antibody such as magrolimab may allow the body’s immune 
system to recognize and kill these cancer cells. 
Although obinutuzumab (GAZYVA®) and venetoclax (VENCLEXTATM) have been approved and 
used either alone or in combination to treat types of lymphoma, magrolimab has not. The use of 
magrolimab in this research study is experimental, which means that the FDA has not 
approved its use for cancer treatment or treatment of any other disease. In addition, the 
combination of magrolimab, obinutuzumab, venetoclax in this study is experimental, which 
means that while the FDA has approved obinutuzumab and venetoclax for cancer treatment, they 
have not approved the combination of obinutuzumab and venetoclax with magrolimab. However, 
the FDA has given us permission to use these drugs together in this study. 
We want to study the side effects of these drugs when given together. We also want to see if the 
combination of these drugs is effective treatment for your disease and hope to learn about how 
these drug work together to treat B-cell lymphomas.  
You may not be eligible for our study for several reasons, such as the presence of certain other 
diseases, infections, or problems with your organ function. If it is found that you are not suited to 
take part in the treatment, you will be removed from the study.
WHAT WILL HAPPEN DURING THE STUDY?
All of these tests or procedures are part of your regular care and may be done even if you are not 
being considered to join the study. If you have had some of these tests or procedures recently, they 
may or may not have to be repeated. The following tests and procedures are needed to determine 
whether you are eligible for this trial: 

Medical history: A complete review of your medical history, including obtaining 
information about your diagnosis and previous treatments, and reviewing information 


IRB NUMBER: 20C0162
IRB APPROVAL DATE: 5/30/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 05/16/2023
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MEDICAL RECORD
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about your other conditions.  If you have medical records from another clinic or hospital, 
you will be asked to get copies of these records, or your study doctor may be able to request 
them on your behalf.

Physical examination: This will include taking your vital signs (such as temperature, blood 
pressure, heart rate, breathing rate), seeing how you function in your daily activities, any 
current symptoms of your condition and a review of all medications that you take

Blood tests:  Blood will be drawn from either an arm vein or a central venous access 
device, if you have one.  This will be used for measurements including: 
o
Blood counts, liver and kidney function, serum chemistries and other routine tests 
such as how well your blood clots
o
Tests routinely done in patients with your type of cancer to confirm the status of 
your disease
o
Hepatitis A, B, and C infection testing
o
HIV: As part of this study, we will test you for infection with the human 
immunodeficiency virus (HIV), the virus that causes AIDS.  If you are infected 
with HIV you will not be able to participate in this study.  We will tell you what 
the results mean, how to find care, how to avoid infecting others, how we report 
HIV infection, and the importance of informing your partners at possible risk 
because of your HIV infection

Pregnancy test:  For women who could have children, a pregnancy test will be done (urine 
or blood sample). You will not be able to participate if you are pregnant.

Urine tests:  Urine will be collected for routine testing (urinalysis), including to check for 
possible infection.

Pathology review:  A sample of tissue from any previous biopsy will be tested at NCI to 
confirm your diagnosis, stage, and status of your disease. If no sample is available a fresh 
biopsy will be required.

Bone marrow aspiration and/or biopsy:  A bone marrow aspiration and/or biopsy will be 
done prior to starting treatment if not done within the last 12 months since completing the 
last treatment received to confirm the stage and status of your disease. These are done by 
numbing your hipbone using a small needle containing local anesthesia, and then a needle 
will be put into the hipbone, and a small amount of bone marrow will be taken out through 
the needle

Imaging:  The following scans may be done, as directed by your doctor and based upon 
your disease:  Imaging to show all sites of your disease with imaging scans, such as a CT 
scan of your chest, abdomen and pelvis, brain MRI and other scans if needed
HOW LONG WILL THE STUDY TAKE?
If you agree to take part, your involvement is expected to last for up to a few weeks on the screening 
portion. After the evaluations are complete, we will determine if you are eligible to participate in 
the treatment portion of the study. 


IRB NUMBER: 20C0162
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HOW MANY PEOPLE WILL PARTICIPATE IN THIS STUDY?
We plan to have approximately 76 people participate in this study at the NIH. 
WHAT ARE THE RISKS AND DISCOMFORTS OF BEING IN THE STUDY?
The primary risks or discomforts of taking part in screening are those that may be caused by the 
tests and procedures. The following describes the most common risks of these tests and procedures. 
Your doctor or nurse will also discuss with you in detail any risks or discomforts of the procedures 
or test(s) you will be scheduled to undergo.
The risks of taking part may include the following:  

Blood draws:
o
Likely: discomfort, swelling, bruising, and/or bleeding at the site of the needle 
insertion. 
o
Less likely: dizziness or feeling faint. 
o
Rare: infection (symptoms may include fever, shaking, chills, fatigue, confusion, joint 
aches, or rapid pulse). 

Biopsy (if needed): 
o
Likely: discomfort or pain, redness, swelling, and/or bruising at the site of the needle 
insertion.
o
Less likely: Bleeding from the site of the needle insertion
o
Rare: significant infection or bleeding from this procedure, allergic reaction to the 
anesthetic, or formation of a scar at the site of needle entry. 
If you will have sedation with the procedure, these risks will be discussed with you prior to the 
procedure.  You will be asked to sign a separate consent form prior to any biopsy procedure.

Imaging:  The following may be done as directed by your doctor based on your disease:  
o
CT Scan (computerized tomography):  There is a slight risk of developing an allergic 
reaction to the iodine contrast material.  The reaction can be mild (itching, rash) or severe 
(difficulty breathing or sudden shock).  Death resulting from an allergic reaction in this 
setting is rare.  Most reactions can be controlled using drugs.  Be sure to tell your doctor if 
you have allergies of any kind (such as hay fever, iodine allergy, eczema, hives, or food 
allergies).
The contrast material used during CT scanning can cause water loss or damage to the 
kidneys that may lead to kidney failure.  This is a concern if you have poor kidney function, 
dehydration, or diabetes, especially if you take Metformin® (Glucophage) to control 
diabetes.
You may also experience discomfort related to lying still in an enclosed space for a 
prolonged period of time.
o
MRI Risks:  MRI uses a strong magnetic field and radio waves to take pictures of the body.  
We may obtain pictures of your brain or other parts of your body for this study.  The MRI 
scanner is a metal cylinder surrounded by a strong magnetic field.  During the MRI, you 


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will lie on a table that can slide in and out of the cylinder.  We will place soft padding or a 
coil around your head. You will be in the scanner about 45 minutes. You may be asked to 
lie still for up to 15 minutes at a time. While in the scanner you will hear loud knocking 
noises, and you will be fitted with earplugs or earmuffs to muffle the sound. You will be 
able to communicate with the MRI staff at all times during your scan, and you may ask to 
be moved out of the machine at anytime.
It is very important for the experiment that you do not move your head or body inside the 
scanner. We will use padding around your head to help keep it in place. 
We may place a bar in your mouth to help keep your head still. 
People are at risk for injury from the MRI magnet if they have some kinds of metal in their 
body. It may be unsafe for you to have an MRI scan if you have pacemakers or other 
implanted electrical devices, brain stimulators, some types of dental implants, aneurysm 
clips (metal clips on the wall of a large artery), metal prostheses (including metal pins and 
rods, heart valves, and cochlear implants), permanent eyeliner, tattoos, an implanted 
delivery pump, or shrapnel fragments. Welders and metal workers may have small metal 
fragments in the eye. You will be screened for these conditions before having any MRI 
scan. If you have a question about metal in your body, you should inform the staff. You 
will be asked to complete an MRI screening form before each MRI scan you have. 
In addition, all magnetic objects (like watches, coins, jewelry, and credit cards) must be 
removed before entering the MRI scan room.
People with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner.  The noise from the 
scanner is loud enough to damage hearing, especially in people who already have hearing 
loss. Everyone having a research MRI scan will be fitted with hearing protection. If the 
hearing protection comes loose during the scan, you should let us know right away.
There are no known long-term risks of MRI scans.
Risks for gadolinium enhanced MRI scans:
Procedure:  During part of the MRI you may receive gadolinium, a contrast agent, through 
an intravenous (IV) catheter. It will be done for medical purposes.
It is not known if MRI with contrast is completely safe for a developing fetus. Therefore, 
all women of childbearing potential will have a pregnancy test performed no more than 24 
hours before each MRI scan with contrast. The scan will not be done if the pregnancy test 
is positive.
Risks: The risks of an IV catheter include bleeding, infection, or inflammation of the skin 
and vein with pain and swelling.  
Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it 
and usually go away quickly.  Mild symptoms may include coldness in the arm during the 
injection, a metallic taste, headache, and nausea.  In an extremely small number, fewer than 
one in 300,000 people, more severe symptoms have been reported including shortness of 
breath, wheezing, hives, and lowering of blood pressure. You should not receive 


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gadolinium if you previously had an allergic reaction to it.  You will be asked about such 
allergic reactions before gadolinium is given.   
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis” which has resulted in a very small number of deaths.  A 
blood test of your kidney function may be done within the month before an MRI scan with 
gadolinium contrast. You will not receive gadolinium for a research MRI scan if your 
kidney function is not normal or if you received gadolinium within the previous month. 
Most of the gadolinium contrast leaves the body in the urine.  However, the FDA has issued 
a safety alert that indicates small amounts of gadolinium may remain in the body for 
months to years.  The effects of the retained gadolinium are not clear. At this time, retained 
gadolinium has not been linked to health risks in people whose kidneys work well.
Some types of gadolinium contrast drugs are less likely to remain in the body than 
others.  In this study, we will use the gadolinium contrast drugs that are less likely to remain 
in the body. 
Please tell your research team if you have had any MRI scans in the past 12 months. 
We will also give you additional information called a “Medication Guide.”  Upon request, 
we will give you individual information about retained gadolinium we see on your studies. 
What are the risks related to pregnancy? 
You may not participate in this study if you are pregnant. If you are able to become pregnant, we 
will perform a pregnancy test before exposing you to radiation. You must tell us if you may have 
become pregnant within the previous 14 days because the pregnancy test is unreliable during that 
time.
What are the risks of radiation from being in the study? 
During your participation in screening for this research study, you will be exposed to radiation 
from a CT scan of the chest, abdomen and pelvis. The amount of radiation exposure you will 
receive from these procedures is equal to approximately 1.1 rem. A rem is a unit of absorbed 
radiation.
Every day, people are exposed to low levels of radiation that comes from the sun and the 
environment around them. The average person in the United States receives radiation exposure of 
0.3 rem per year from these sources.  This type of radiation is called “background radiation.” No 
one knows for sure whether exposure to these low amounts of radiation is harmful to your body.
The CT scan that you get in this study will expose you to the roughly the same amount of radiation 
as 3.7 years’ worth of background radiation. Most of the time, this amount of extra radiation is not 
harmful to you. However, scientists believe that being exposed to too much radiation can cause 
harmful side effects. This could include getting a new cancer.  We estimate that this could happen 
in about 1 out of every 1000 people who get a very large amount of extra radiation.
WHAT ARE THE BENEFITS OF BEING IN THE STUDY?
You might not benefit from being in this study. 


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However, you may gain clinical information about your disease or your organ function that will 
be helpful to your overall medical care.  This testing may show that you are eligible for the 
treatment trial for B-cell lymphoma. 
WHAT OTHER OPTIONS ARE THERE FOR YOU?
Before you decide whether or not to be in this study, we will discuss other options that are available 
to you. Instead of being in this study, you could may choose not to be tested for eligibility or to 
have any other studies done.
DISCUSSION OF FINDINGS
New information about the study
If we find out any new information that may affect your choice to participate in this study, we 
will get in touch with you to explain what we have learned. This may be information we have 
learned while doing this study here at the NIH or information we have learned from other 
scientists doing similar research in other places.
Return of research results
All of the clinical test results will be shared with you. We will discuss any findings that are 
abnormal with you.  We can also share the findings of these screening evaluations with any medical 
provider that you wish to have this information. 
EARLY WITHDRAWAL FROM THE STUDY 
You will be removed from the study if:

You are found to be ineligible for the study
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you.
STORAGE, SHARING AND FUTURE RESEARCH USING YOUR SPECIMENS AND 
DATA
Will your specimens or data be saved for use in other research studies?
As part of this study, we are obtaining specimens and data from you. We will remove all the 
identifiers, such as your name, date of birth, address, or medical record number and label your 
specimens and data with a code so that you cannot easily be identified. However, the code will 
be linked through a key to information that can identify you. We plan to store and use these 
specimens and data for studies other than the ones described in this consent form that are going 
on right now, as well as studies that may be conducted in the future. These studies may provide 
additional information that will be helpful in understanding cancer, or other diseases or 
conditions. This could include studies to develop other research tests, treatments, drugs, or 
devices, that may lead to the development of a commercial product by the NIH and/or its research 
or commercial partners. There are no plans to provide financial compensation to you if this 


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happens. Also, it is unlikely that we will learn anything from these studies that may directly 
benefit you.
I give permission for my coded specimens and data to be stored and used for future research as 
described above.
_____ Yes
_____ No
Initials
Initials
Will your specimens or data be shared for use in other research studies?
We may share your coded specimens and data with other researchers.  If we do, while we will 
maintain the code key, we will not share it, so the other researchers will not be able to identify 
you.  They may be doing research in areas that are similar to this study or in other unrelated 
areas. These researchers may be at NIH, other research centers and institutions, or commercial 
entities.
I give permission for my coded specimens and data to be shared with other researchers and used 
by these researchers for future research as described above.
_____ Yes 
_____ No
Initials
Initials
If you change your mind and do not want us to store and use your specimens and data for future 
research, you should contact the research team member identified at the top of this document. 
We will do our best to comply with your request but cannot guarantee that we will always be 
able to destroy your specimens and data. For example, if some research with your specimens and 
data has already been completed, the information from that research may still be used. Also, for 
example, if the specimens and data have been shared already with other researchers, it might not 
be possible to withdraw them. 
In addition to the planned use and sharing described above, we might remove all identifiers and 
codes from your specimens and data and use or share them with other researchers for future 
research at the NIH or other places.  When we or the other researchers access your anonymized 
data, there will be no way to link the specimens or data back to you.  We will not contact you to 
ask your permission or otherwise inform you before we do this.  We might do this even if you 
answered "no" to the above questions.  If we do this, we would not be able to remove your 
specimens or data to prevent their use in future research studies, even if you asked, because we 
will not be able to tell which are your specimens or data.
NIH policies require that your clinical and other study data be placed in an internal NIH database 
that is accessible to other NIH researchers for future research. Usually, these researchers will not 
have access to any of your identifiers, such as your name, date of birth, address, or medical 
record number; and your data will be labeled with only a code. We cannot offer you a choice of 


IRB NUMBER: 20C0162
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whether your data to be placed in this database or not.  If you do not wish to have your data 
placed in this database, you should not enroll in this study.  
How long will your specimens and data be stored by the NIH?
Your specimens and data may be stored by the NIH. When this study is closed, we will keep the 
samples for future research indefinitely.
Risks of storage and sharing of specimens and data
When we store your specimens and data, we take precautions to protect your information from 
others that should not have access to it. When we share your specimens and data, we will do 
everything we can to protect your identity, for example, when appropriate, we remove information 
that can identify you. Even with the safeguards we put in place, we cannot guarantee that your 
identity will never become known or someone may gain unauthorized access to your information. 
New methods may be created in the future that could make it possible to re-identify your specimens 
and data.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
On this study, the NCI will reimburse the cost for some of your expenses.  Some of these costs 
may be paid directly by the NIH and some may be reimbursed after you have paid. The amount 
and form of these payments are determined by the NCI Travel and Lodging Reimbursement Policy. 
You will be given a summary of the policy which provides more information.
If your travel to the NIH Clinical Center (e.g., flight, hotel) is arranged and paid for by the NIH, 
the agency making the reservations and their representatives will have access to your identifiable 
information.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 

If some tests and procedures are performed outside the NIH Clinical Center, you may have 
to pay for these costs if they are not covered by your insurance company.

Medicines that are not part of the study treatment will not be provided or paid for by the 
NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be provided 
by the NIH Clinical Center.


IRB NUMBER: 20C0162
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CONFLICT OF INTEREST (COI) 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a COI Guide.  You may ask your research team for a copy 
of the COI Guide or for more information.  Members of the research team who do not work for 
NIH are expected to follow these guidelines or the guidelines of their home institution, but they 
do not need to report their personal finances to the NIH.
The following pharmaceutical collaborators are providing the following drugs for this 
study to NIH without charge:

Gilead Sciences, Inc. is providing magrolimab 

AbbVie, Inc., manufactures venetoclax 

Genentech, Inc., is providing venetoclax and obinutuzumab
No NIH investigator involved in this study receives payments or other benefits from any 
company whose drug, product or device is being tested. However, there are some research 
partners not associated with the NIH working on this study who may receive payments or 
benefits, limited by the rules of their workplace. 
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Some of your health information, and/or information about your specimen, from this study will 
be kept in a central database for research. Your name or contact information will not be put in 
the database. Your test results will be identified by a unique code and the list that links the code 
to your name will be kept separate from your sample and health information. Your information 
may be given out if required by law. For example, certain states require doctors to report to health 
boards if they find a disease like tuberculosis. However, the researchers will do their best to 
make sure that any information that is released will not identify you.
Will your medical information be kept private?
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

The study Sponsor, Center for Cancer Research, or their agent(s)

Qualified representatives from Gilead Sciences, Inc., the pharmaceutical company who 
provides magrolimab.


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
Qualified representatives from AbbVie, Inc., the pharmaceutical company who produces 
venetoclax.

Qualified representatives from Genentech, Inc., the pharmaceutical company who provides 
venetoclax and obinutuzumab.
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons.
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.  However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections.  
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical information 
that we collect under the authority of the Public Health Service Act.  In some cases, the Privacy 
Act protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy 
Act allows release of information from your record without your permission, for example, if it is 


IRB NUMBER: 20C0162
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requested by Congress. Information may also be released for certain research purposes with due 
consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting,  to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Mark 
Roschewski, M.D., Building 10, Room 4N115, Telephone:  240-760-6183. You may also call the 
NIH Clinical Center Patient Representative at 301-496-2626, or the NIH Office of IRB Operations 
at 301-402-3713, if you have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.


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Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness should sign below if either: 
1. A short form consent process has been used to enroll a non-English speaking subject or
2. An oral presentation of the full consent has been used to enroll a blind or illiterate subject
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not also 
serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.