Rituximab and High-Dose Methylprednisolone Debulking Prior to Venetoclax for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Phase: PHASE1
Conditions: Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Sponsor: University of California, San Diego

Rituximab and High-Dose Methylprednisolone 
Debulking Prior to Venetoclax for Patients with 
Relapsed or Refractory Chronic Lymphocytic Leukemia 
or Small Lymphocytic Lymphoma
NCT04981912
Document Date: 12/17/2024 

HDMP-R Debulking + Venetoclax for CLL 
 
Version: 5 (Dec-2024) 
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Version Date: 
12/17/2024 
Rituximab and High-Dose Methylprednisolone Debulking Prior to Venetoclax for Patients with 
Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma 
PRINCIPAL INVESTIGATOR 
Michael Choi, MD 
Hematology/Oncology 
3855 Health Sciences Drive, #0820 
La Jolla, CA 92093-0820 
Phone: (858) 534-1765 
Fax: (858) 534-5620 
E-mail:  mychoi@ucsd.edu
Protocol Number: 
182029 
Investigational Product: 
Venetoclax 
IND Number:  
143570 
IND Holder:  
 Michael Choi, MD 

 
 
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LIST OF INVESTIGATORS 
 
PRINCIPAL INVESTIGATOR 
Michael Choi, MD 
Hematology/Oncology 
3855 Health Sciences Drive, #0820 
La Jolla, CA 92093-0820 
Phone: (858) 534-1765 
Fax: (858) 534-5620 
mychoi@ucsd.edu   
 
 
CO-INVESTIGATOR  
Thomas Kipps, MD/PhD 
Hematology/Oncology 
3855 Health Sciences Drive, #0820 
La Jolla, CA 92093-0820 
Phone: 858-534-5400 
Fax: 
858-534-5620 
tkipps@ucsd.edu 
 
 
BIOSTATISTICIANS 
Karen Messer and Minya Pu 
Family Medicine and Public Health 
3855 Health Sciences Drive 
La Jolla, CA 92093-0901 
Phone: 858-822-4334 
Fax: 858-822-2399 
kmesser@ucsd.edu 
mpu@ucsd.edu 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

 
 
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Rituximab and High-Dose Methylprednisolone Debulking Prior to Venetoclax for Patients with 
Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name: _____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 
 
 
 

 
 
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LIST OF INVESTIGATORS ............................................................................................................................ 2 
1.0 
SCHEMA ............................................................................................................................................... 18 
2.0 
BACKGROUND ................................................................................................................................. 18 
2.1 
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) ................................................................................................ 18 
2.2 
VENETOCLAX .............................................................................................................................................. 19 
2.3 
HIGH DOSE METHYLPREDNISOLONE ......................................................................................................... 23 
2.4 
STUDY RATIONALE ..................................................................................................................................... 24 
3.0 
OBJECTIVES ..................................................................................................................................... 24 
4.0 
STUDY DESIGN ................................................................................................................................. 25 
4.1 
DESCRIPTION ............................................................................................................................................. 25 
4.2 
ENDPOINT ASSESSMENT: .......................................................................................................................... 26 
4.3 
RATIONALE FOR STUDY DESIGN ................................................................................................................. 26 
5.0 
STUDY POPULATION ....................................................................................................................... 26 
5.1 
INCLUSION CRITERIA .................................................................................................................................. 27 
5.2 
EXCLUSION CRITERIA ................................................................................................................................ 28 
5.3 
PRIOR AND CONCOMITANT THERAPY ........................................................................................................ 29 
6.0 
TREATMENT PLAN / STUDY PROCEDURES ................................................................................ 31 
6.1 
SCREENING PROCEDURES ........................................................................................................................ 34 
6.2 
CYCLE 0: HDMP + RITUXIMAB .................................................................................................................. 36 
6.3 
CYCLE 1: VENETOCLAX RAMP-UP ............................................................................................................. 37 
6.4 
CYCLES 2 TO 6: VENETOCLAX + RITUXIMAB ............................................................................................. 40 
6.5 
CYCLES 7-24: VENETOCLAX...................................................................................................................... 40 
6.6 
END OF STUDY ASSESSMENT .................................................................................................................... 41 
6.7 
LONG-TERM FOLLOW-UP ............................................................................................................................ 41 
6.8 
SUBJECT WITHDRAWAL OR TREATMENT DISCONTINUATION: ................................................................... 41 
7.0 
STUDY MEDICATIONS ..................................................................................................................... 41 
7.1 
METHYLPREDNISOLONE SODIUM SUCCINATE ........................................................................................... 42 
7.2 
RITUXIMAB (RITUXAN) ............................................................................................................................. 44 
7.3 
VENETOCLAX .............................................................................................................................................. 48 
8.0 
EVALUATION OF RESPONSE ......................................................................................................... 53 
8.1 
ASSESSMENT OF TUMOR BURDEN ............................................................................................................ 54 
8.2 
INTERNATIONAL WORKING GROUP CLL (IWCLL) CLINICAL RESPONSE ASSESSMENT ........................... 54 
8.3 
MINIMAL RESIDUAL DISEASE ASSESSMENT .............................................................................................. 56 
8.4 
CORRELATIVE STUDIES ............................................................................................................................. 56 
8.5 
SPECIMEN BANKING ................................................................................................................................... 57 
9.0 
STATISTICAL CONSIDERATIONS .................................................................................................. 57 
9.1 
GENERAL CONSIDERATIONS ............................................................................................................................... 57 
9.2 
SAMPLE SIZE JUSTIFICATION ............................................................................................................................... 58 
9.3 
ANALYSIS POPULATIONS ................................................................................................................................... 59 

 
 
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9.4 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ................................................................................................. 59 
9.5 
DEFINITION OF BASELINE MEASUREMENTS ........................................................................................................... 59 
9.6 
STUDY DRUG EXPOSURE, CONCOMITANT MEDICATIONS, AND NONPROTOCOL CANCER THERAPY ................................... 59 
9.7 
GENERAL CONSIDERATIONS OF STATISTICAL ANALYSES ............................................................................................ 59 
9.8 
ANALYSIS OF SAFETY ........................................................................................................................................ 60 
9.9 
HANDLING OF DROPOUTS AND MISSING DATA ..................................................................................................... 61 
10.0 
ADVERSE EVENT REPORTING ...................................................................................................... 61 
11.0 
STUDY MANAGEMENT .................................................................................................................... 64 
11.1 
SUBJECT DATA PROTECTION .............................................................................................................................. 64 
11.2 
DATA AND SAFETY MONITORING........................................................................................................................ 64 
11.3 
RECORD RETENTION ........................................................................................................................................ 65 
11.4 
OBLIGATIONS OF INVESTIGATORS ....................................................................................................................... 65 
12.0 
REFERENCES ................................................................................................................................... 65 
13.0 
APPENDICES ..................................................................................................................................... 66 
 
 
 

 
 
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Table 1. Synopsis (including required elements for IIS protocols with Venetoclax): 
 
Section  
1.0 
 General Information 
 
Study 
Flowchart 
See Main Protocol Table of Events 
 
Overall Study Schema: 
 
 
 
 
1.1 
Study Title: 
 
Rituximab and High-Dose Methylprednisolone Debulking Prior to 
Venetoclax for Patients with Relapsed or Refractory Chronic 
Lymphocytic Leukemia or Small Lymphocytic Lymphoma  
 
(Version Date 09/18/2019, Version 4) 
 
1.2 
Institution 
Name: 
 
UC San Diego, Moores Cancer Center 
 
1.3 
Investigator 
Contact 
Information: 
 
 
Michael Choi, MD 
Hematology/Oncology 
3855 Health Sciences Drive, #0820 
La Jolla, CA 92093-0820 
Phone: (858) 534-1765 
Fax: (858) 534-5620 
E-mail:  mychoi@ucsd.edu  
 
 
 

 
 
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2.0 
Background Information 
2.1 
Rationale 
& 
Background 
Information 
 
The combination of venetoclax and rituximab is an effective and 
FDA-approved regimen to treat patients with CLL or SLL who have 
previously received treatment. In a randomized phase 3 clinical 
trial, the 2-year PFS was 84.9% (bendamustine-rituximab 
comparator arm 2-year PFS was 36.3%); the ORR was 93.3% with 
a CR rate of 26.8% (Seymour et al, 2018).  
 
In part due to highly potent apoptosis induction, there is a known 
risk of tumor lysis syndrome (TLS) with venetoclax. This risk is 
mitigated by careful prophylactic and monitoring measures during 
the initiation of venetoclax, including inpatient hospitalization and 
serial lab monitoring for patients who have a high tumor burden. 
With such measures, the rate of grade 3 or 4 TLS was 3.1% in the 
venetoclax-rituxmab trial (Seymour et al, 2018). However, further 
TLS risk mitigation will improve outcomes with this treatment. 
 
This risk of TLS is associated with the amount of tumor burden. 
Patients with Low Tumor Burden (absolute lymphocyte count less 
than 25k/uL; all lymph nodes less than 5 cm in diameter) are 
considered to have low TLS risk, and can be monitored without 
hospitalization (Venetoclax prescribing information). Therefore, 
decreasing the CLL tumor burden prior to initiation of venetoclax 
can also be a risk mitigation strategy.  
 
The combination of High-Dose Methylprednisolone (HDMP) and 
rituximab has been evaluated as a treatment for patients with CLL 
(Castro et al, 2008 and Castro et al, 2009). For patients with 
fludarabine-refractory CLL, the ORR was 96%, the CR rate was 
36%, and all patients would have met the above criteria for Low 
Tumor Burden at the completion of therapy. Imaging was not done 
after just 1 cycle, so the precise degree of debulking at that time 
point is not known; however, the ALC values reduced in majority of 
patients within the 1st cycle.  
 
Therefore, HDMP + Rituximab is a potential debulking strategy 
prior to initiation of venetoclax based on the following rationale: 
- high rate of improvement of lymphadenopathy and lymphocytosis 
in previous publications. 
- lack of added myelotoxicity; and manageable overall toxicity 
profile compared to rituximab + venetoclax alone. 
- administration in an outpatient setting. 
3.0 
Core Protocol 
3.1 
Study 
Objectives 
and Purpose 
Purpose: to determine the feasibility of treating patients with 
HDMP + rituximab as a means of debulking prior to initiating 
venetoclax. 
 
Objectives: 
Primary:  

 
 
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1. To determine the percentage of patients who have a reduction 
of lymphadenopathy (from greater than to less than 5 cm in largest 
diameter) and/or absolute lymphocyte count (from greater than to 
less than 25k/uL) following 1 or 2 cycles of HDMP + rituximab.   
 
Secondary: 
1. To determine the rate of laboratory or clinical TLS with this 
strategy. 
2. To determine the safety (CTCAE4) of this approach. 
3. To determine the overall efficacy (iwCLL) of this overall strategy. 
4. To determine the percentage of patients who have undetectable 
minimal residual disease in the bone marrow. 
 
Endpoints: 
Primary:  
1. Percentage of patients that have a decrease in tumor burden 
from levels of disease that meet “Medium/High-tumor burden” 
criteria to meet “Low tumor burden” criteria for disease burden 
following 1 or 2 cycles of HDMP + Rituximab. 
 
Secondary: 
1. Percentage of patients that have a decrease in tumor burden 
from levels of disease that meet “Medium/High-tumor burden” c 
criteria to meet “Low tumor burden” criteria for disease burden 
following 1 cycle of HDMP + Rituximab. 
2. Percentage of patients that have a decrease in tumor burden 
from levels of disease that meet “Medium/High-tumor burden” 
criteria to meet “Low tumor burden” criteria for disease burden 
following 2 cycles of HDMP + Rituximab. 
3. Rate of laboratory TLS (from start of treatment until completion 
of venetoclax ramp-up) 
4. Rate of clinical TLS (from start of treatment until completion of 
venetoclax ramp-up) 
5. Adverse events by CTCAE4 definitions 
6. Overall Response rate, Partial Response rate, and Complete 
response rate per iwCLL criteria after 9 months of venetoclax and 
at completion of treatment. 
7. Undetectable minimal residual disease (MRD) rate based on 
bone marrow biopsy after 9 months of venetoclax, and at 
completion of treatment. 
4.0 
Study Design 
Single center, open-label, pilot/feasibility study to determine the 
feasibility of HDMP/R as a debulking approach prior to venetoclax. 
 
Patients with CLL/SLL who require therapy, and have disease 
burden meeting criteria for Medium or High Risk Tumor Burden 
(based on: lymph nodes >/= 5 cm in diameter and/or absolute 
lymphocyte count >/= 25k/uL) are enrolled. 
 

 
 
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- Patients will receive HDMP + Rituximab for 1 cycle, followed by 
reassessment of Tumor Burden,  
- Patients will initiate venetoclax dose ramp-up, with ramp-up 
schedule according to venetoclax package insert. 
 
Upon completion of ramp-up (venetoclax to 400 mg), all patients 
will continue Venetoclax 400 mg (or highest tolerated dose) for up 
to 2 years. Patients will also continue rituximab 500 mg/m2 q 28 
days through Cycle 6. 
 
Endpoint Assessment: 
1. Assessment of the disease burden after a maximum of 2 cycles 
of HDMP + Rituximab is the primary endpoint. 
2. Assessment of the disease burden after 1 cycle of HDMP + 
Rituximab. 
3. Clinical and laboratory TLS events between start of treatment 
and the completion of venetoclax dose-ramp up (Cycle 2, Day 1) 
4. Presence or absence of detectable MRD in the marrow will be 
assessed after approximately 9 months of venetoclax and 
completion of treatment.  
5. Radiology assessment after approximately 9 months of 
venetoclax and completion of study (unless prior imaging studies 
are without measurable disease)  
 
5.1 
Inclusion 
Criteria 
Patients must meet the following criteria for study entry: 
1. Subjects must be age 18 or older. 
2. Both men and women of all races and ethnic groups are eligible 
for this trial. 
3. Ability to understand and willingness to sign a written informed 
consent. 
4. Diagnosis: CLL or SLL, as documented in the medical record 
5. Disease Status/ Prior Therapy:  
- Must have had treatment for CLL/SLL with at least 1 line of prior 
therapy. (There is not requirement nor restriction for specific type 
of previous therapy, with the following exceptions: prior treatment 
with venetoclax within 6 months, prior progressive disease on 
venetoclax, or prior grade 3 or 4 toxicity (not including TLS) that 
directly 
lead 
to 
discontinuation 
of 
venetoclax; 
Prior 
HDMP/Rituximab is allowed unless there was no response (Stable 
Disease or Progressive Disease) or was within 3 months.) 
- Indication for CLL or SLL therapy based on international working 
group (iwCLL) guidelines, which include: constitutional symptoms, 
bulky or symptomatic lymphadenopathy, bulky or symptomatic 
splenomegaly, rapid doubling of the ALC (approximately 6 months 
or less), or Rai stage 3 or 4 disease. 
- Disease burden meets criteria for Medium or High Tumor Burden, 
based on Absolute lymphocyte count >/= 25k/uL or any lymph node 
5 cm or greater in diameter. The ALC criteria must be met during 
the screening period. The imaging criteria may be based on 
radiologic study within 30 days of Cycle 0, Day 1. 

 
 
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6. Has recovered from the toxic effects of prior therapy to their 
clinical baseline. 
7. Women of child-bearing potential (not postmenopausal for at 
least one year or not surgically incapable of bearing children) must 
agree to not become pregnant for the duration of the study. Both 
men and women must agree to use a barrier method of 
contraception for the duration of the study and until 5 half-lives after 
the final dose of venetoclax (approximately 1 week), and at least 5 
half-lives of final dose of Rituximab. 
8. ECOG performance status of 0-2 
9. Adequate hematologic function: Platelet count >/= 30k/uL, 
hemoglobin > 7 g/dL, AND ANC > 500/uL. (Values may be lower if 
due to marrow infiltration by CLL). 
10. Adequate renal function: creatinine clearance based on 24 hr 
collection >/= 40 ml/min; OR Calculated Creatinine clearance 
(CrCl) ≥ 40 mL/min (based upon the Cockcroft-Gault Equation 
[CrCl = (140-age) * actual wt (in kg) * (0.85 if female) / (72 * Cr)]. 
11. Adequate hepatic function:  
- Aspartate transaminase (AST) and alanine transaminase (ALT) < 
3.0X ULN 
- Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s 
syndrome or of non-hepatic origin) 
 
5.2 
Exclusion 
Criteria 
Patients who meet any of the following criteria will be excluded from 
study entry: 
 
1. Subject is known to be positive for HIV.  (HIV testing is not 
required.) 
 
2. Evidence of other clinically significant uncontrolled condition(s) 
including, but not limited to: 
- Uncontrolled and/or active systemic infection (viral, bacterial or 
fungal) 
- Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring 
treatment.  Note: subjects with serologic evidence of prior 
vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-
, anti-HBs antibody positive and anti-hepatitis B core (HBc) 
antibody negative) or positive anti-HBc antibody from intravenous 
immunoglobulins (IVIG) may participate.  
 
3. Treatment with any of the following within 7 days prior to the first 
dose of venetoclax: 
- Steroid therapy for anti-neoplastic intent 
- moderate or strong cytochrome P450 3A (CYP3A) inhibitors (see 
Appendix C for examples) 
- moderate or strong CYP3A inducers (see Appendix C for 
examples) 
 
4. 
Prior CLL therapy: 
- Biologic agent (monoclonal antibody) within 30 days for anti-
neoplastic intent. 

 
 
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- Chemotherapy (purine analog or alkylating agent) or target small 
molecule agent within 14 days or 5 half-lives (whichever is shorter), 
or has not recovered to less than CTC grade 2 clinically significant 
adverse effect(s)/toxicity(s) of previous therapy. 
 
5. History of severe allergic or anaphylactic reactions to 
monoclonal antibody therapy  
6. Known hypersensitivity to any of the study drugs  
7. History of other malignancy that could affect compliance with the 
protocol or interpretation of results (example: patients with a history 
of curatively treated basal or squamous cell carcinoma of the skin 
or in situ carcinoma of the cervix are generally eligible. Patients 
with a malignancy that has been treated, but not with curative 
intent, will also be excluded, unless the malignancy has been in 
remission without treatment for 2 years prior to enrollment.) 
8. Known active bacterial, viral, fungal, mycobacterial, or other 
infection (excluding fungal infections of nail beds); or any major 
episode of infection requiring treatment with IV antibiotics or 
hospitalization (related to the completion of the course of 
antibiotics) within 4 weeks before the start of Cycle 0 
9. Major surgery (within 4 weeks prior to the start of Cycle 0), other 
than for diagnosis 
10. Women who are pregnant or lactating 
11. Uncontrolled diabetes mellitus (related to high dose steroid risk) 
12. Myocardial infarction within 6 months of starting study drug or 
other clinically significant heart disease (NYHA class 3 heart 
failure, uncontrolled hypertension) 
 
(Avoid grapefruit products, Seville oranges, and starfruit during 
treatment with VENCLEXTA, as they contain inhibitors of CYP3A. See 
Protocol Section 5.3 for other Excluded and Cautionary Prior and 
Concomitant Medications.) 
 
 
6.0 
Study 
Procedures 
See Main Protocol for details. 
 
Procedures, in brief: 
Screening Procedures:  
- Physical examination, CBC diff, CMP, Hepatitis B serologies 
(Standard of Care (SOC) prior to anti-CD20 therapy) and CT scan 
or MRI thorax, abdomen, pelvis. 
- Initiate allopurinol 3 days prior treatment initiation 
 
Cycle 0 (28 days in duration): HDMP + Rituximab 
- Methylprednisolone 1000 mg/m2 days 1-3 
- Rituximab 100 mg day 1; 375 mg/m2 days 2-4 
- Repeat CBC diff, CT scan or MRI thorax, abdomen, pelvis 
between Day 15 to Day 28 of Cycle 0. (SOC prior to venetoclax) 
 
Cycle 1 (35 days in duration): Venetoclax Ramp-Up 

 
 
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- Continue allopurinol, acyclovir, and septra (or equivalent drugs, 
unless contraindication). Must stop fluconazole 7 days prior to first 
venetoclax dose. 
- Week 1: Venetoclax 20 mg daily 
- Week 2: Venetoclax 50 mg daily 
- Week 3: Venetoclax 100 mg daily 
- Week 4: Venetoclax 200 mg daily 
- Week 5: Venetoclax 400 mg daily 
- TLS Monitoring per venetoclax package insert. 
 
Cycles 2-6 (28 days in duration each): Venetoclax + Rituximab 
- Continue Venetoclax 400 mg PO daily (or highest tolerated dose) 
- Rituximab 500 mg/m2 on day 1 of each cycle. 
 
Cycle 7-26: Single agent Venetoclax 
- Continue Venetoclax 400 mg PO daily (or highest tolerated dose) 
 
End of Study: 
- Marrow biopsy and aspirate to assess for detectable CLL (MRD) 
 
Long-term f/up: No specific visits required. With patient consent, 
date of progression or next CLL therapy will be recorded. 
 
Concomitant Medications: 
- It is prohibited to take other intended CLL therapies concurrently, 
including purine analog, alkylating drugs, other anti-CD20 
monoclonal antibody, ibrutinib, Idelalisib, etc. Corticosteroids are 
permitted (in cycle 0 as CLL therapy; in cycles 2-6 as anti-CD20 
infusion reaction prophylaxis; and at other times for treatment of 
conditions other than CLL).  
- Required wash out for the above is 5 half-lives or 1 month, 
whichever is shorter. 
- GCSF, EPO, and blood transfusion are not restricted, and can be 
used as clinically indicated or as per clinician judgement. 
- TLS prophylaxis is recommended from 3 days prior to Cycle 0 
Day 1 until Cycle 2 Day 1: Allopurinol 300 mg daily (dose modified 
if needed; alternative uric acid lowering medication can be 
substituted). 
- Anti-Infection Prophylaxis is recommended from 3 days prior to 
Cycle 0 day 1:  
- Fluconazole 100 mg daily (or alternative per clinician discretion) 
until Cycle 1 Day 21;  
- Acyclovir 400 mg BID (or alternative per clinician discretion) until 
Cycle 3 Day 1 (or may continue longer) 
- Septra DS BID 2 days/week (or alternative per clinician discretion) 
until Cycle 3 Day 1 (or may continue longer)  
 
It is prohibited to receive live viral vaccines or other investigational 
agents. 
 
Subject Withdrawal or Treatment Discontinuation: 

 
 
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Patients who meet or develop the following criteria should be 
discontinued from the study 
- Active HBV infection or hepatitis. Patients who are carriers of 
hepatitis B at the time of discontinuation from study treatment will 
continue to be followed for clinical and laboratory signs of active 
HBV infection and for signs of hepatitis. 
- Severe or life-threatening anaphylaxis or hypersensitivity reaction 
to rituximab. Patients that discontinue rituximab for that reason can 
continue to receive HDMP and venetoclax if clinically indicated.  
- Patients who meet the following criteria should discontinue 
HDMP: Grade 4 psychosis; Active HBV infection or hepatitis as 
above. HDMP doses can be delayed for acute infection or as 
clinically indicated. 
- Inability of patient to comply with study requirements 
- Determination by the investigator that it is no longer safe for the 
patient to continue therapy 
 
For patients who withdraw from all study therapy: No specific visits 
required. With patient consent, date of progression or next CLL 
therapy will be recorded. 
 
Specific Drug 
Supply 
Requirements 
1. Methylprednisolone 1000 mg/m2 IV days 1-3 of Cycle 0 will be 
obtained as a standard of care treatment for patients with CLL. 
 
2. Rituximab 100 mg IV day 1 of cycle 0; 375 mg/m2 days 2-4 of 
Cycle 0; and 500 mg/m2 day 1 of cycles 2-6 will be obtained as a 
standard of care treatment for patients with CLL. Substitution of 
rituximab with other equivalent preparations is allowed, including 
the following: biosimilars of rituximab (including Ruxience or other 
FDA-approved rituximab product).  
 
3. Venetoclax starter-kit (20 mg PO daily x 1 week, 50 mg PO daily 
x 1 week, 100 mg PO daily x 1 week, 200 mg PO daily x 1 week) 
and Venetoclax 400 mg PO daily for 24 months will be supplied by 
Abbvie and stored, dispensed, and/or destroyed by the UCSD 
Investigational Drug Services (IDS) Pharmacy, pursuant to 
ICH/GCP Guidelines. 
9.7 
Statistical 
Analysis and 
Sample 
Size 
Justification 
This is a pilot/feasibility clinical trial, with the primary feasibility 
endpoint being debulking of tumor burden to meet criteria for Low 
Tumor Burden upon the completion of cycle 0.  
 
Sample Size Justification: 17 patients are enrolled to evaluate the 
primary endpoint. A success rate of 60% of patients adequately 
debulking (defined as having Low Tumor Burden at the end of cycle 
0) will be considered compelling, establishing the feasibility of this 
approach, and support further studies. A success rate of 30% 
would be not compelling for further studies. With 17 patients, the 
study is adequately powered to evaluate this. A Simon’s two-stage 
minimax design is utilized, with stopping for futility if an insufficient 
number of patients are debulked by HDMP/Rituximab: 
 

 
 
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The null hypothesis that the true debulking rate is 30% will be 
tested against a one-side alternative. In the first stage, 10 patients 
will be accrued. If there are 2 or fewer responses (patients 
achieving Low Tumor Burden) in these 10 patients, the study will 
be stopped. Otherwise, 7 additional patients will be accrual for a 
total of 17. The null hypothesis will be rejected if 9 or more 
responses are observed in 17 patients. This design yields a type I 
error rate of 0.04 and power of 80% when the true response rate is 
60%. 
Under this design, if the null hypothesis is true, the probability of 
stopping the trial early will be 38.3%. The sample size calculation 
was done using PASS version 14.0.3 (released September 22, 
2015). 
10.0 
Safety 
Reporting 
SAE definition: 
An AE should be classified as an SAE if the following criteria are 
met: 
• 
It results in death (i.e., the AE actually causes or leads to death) 
• 
It is life threatening (i.e., the AE, in the view of the investigator, 
places the patient at immediate risk of death. It does not include 
an AE that, had it occurred in a more severe form, might have 
caused death). 
• 
It requires or prolongs inpatient hospitalization 
• 
It results in persistent or significant disability/incapacity (i.e., the 
AE results in substantial disruption of the patient’s ability to 
conduct normal life functions) 
• 
It results in a congenital anomaly/birth defect in a 
neonate/infant born to a mother exposed to the IMP 
• 
It is considered a significant medical event by the investigator 
based on medical judgment (e.g., may jeopardize the patient or 
may require medical/surgical intervention to prevent one of the 
outcomes listed above) 
 
SAE Reporting: 
Events meeting the following criteria need to be submitted to the 
FDA as expedited IND Safety Reports according to the following 
guidance and timelines: 
 
7 Calendar Day Telephone or Fax Report 
The Investigator is required to notify the FDA of any fatal or life-
threatening AE that is unexpected and assessed by the investigator 
to be possibly related to the use of HDMP, Rituximab, and 
venetoclax. An unexpected AE is one that is not already described 
in the venetoclax investigator brochure or the methylprednisolone 
and rituximab prescribing information.  Such reports are to be 
telephoned or faxed to the FDA within 7 calendar days of first 
learning of the event. 
 
15 Calendar Day Written Report 
The Investigator is also required to notify the FDA and all 
participating investigators, in a written IND Safety Report, of any 

 
 
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serious, unexpected AE that is considered reasonably or possibly 
related to the use of HDMP, rituximab, or venetoclax.  An 
unexpected AE is one that is not already described in the 
venetoclax investigator brochure or the methylprednisolone and 
rituximab prescribing information. 
 
Written IND Safety reports should include an Analysis of Similar 
Events in accordance with regulation 21 CFR § 312.32.  All safety 
reports previously filed by the investigator with the IND concerning 
similar events should be analyzed and the significance of the new 
report in light of the previous, similar reports commented on. 
 
Written IND safety reports with analysis of similar events are to be 
submitted to the FDA, Abbvie, and all participating investigators 
within 15 calendar days of first learning of the event. MedWatch 
3500 form or alternative formats will be used (e.g., summary letter).  
 
Contact Information for IND Safety Reports 
FDA fax number for IND safety reports: 
Fax: 1 (800) FDA 0178 
 
In addition to compliance with all FDA reporting requirements 
pursuant to 21 CFR 312, the Principal Investigator shall: 
a) Report to Abbvie all serious adverse events experienced by 
a study subject receiving an AbbVie product within 24 hours 
of learning of the event regardless of the relationship of the 
event to the AbbVie product.  Principal Investigator shall 
make available to AbbVie promptly such records as may be 
necessary and pertinent to investigate any such event, if 
specifically requested by AbbVie; and in addition, report all 
non-serious adverse events of tumor lysis syndrome for 
studies involving ABT-199. 
b) Copy AbbVie on the submission to the FDA of events 
meeting the definition of IND safety reports at the time of 
submission to the Agency; and, 
c) Notify AbbVie upon any subjects receiving an AbbVie 
Product whose pregnancy has resulted in a negative 
outcome or untoward event during the course of pregnancy 
or upon delivery. 
 
AbbVie’s contact for reporting serious adverse drug experiences, 
pregnancy experiences, non-serious adverse events of tumor lysis 
syndrome, and communication of FDA submissions of IND safety 
reports shall be PPDINDPharmacovigilance@abbvie.com 
 
Product Complaints:  In addition to compliance with all FDA 
requirements pursuant to 21 CFR 211 and 21 CFR 820, Principal 
Investigator will report to AbbVie within 24 hours any suspected 
quality defect in an AbbVie Product or its AbbVie-provided 
packaging, labeling, or medical device component (collectively, 
“Product Complaint”).  Principal Investigator will report Product 

 
 
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Complaints that involve an AbbVie Product, whether AbbVie has 
supplied the AbbVie Product used in the Study or not.  AbbVie’s 
contact 
for 
reporting 
Product 
Complaints 
shall 
be 
RD_PQC_QS@abbvie.com 
 
 
12.0 
References 
Main References: 
 
1. 
Castro JE, James DF, Sandoval-Sus JD, Jain S, Bole J, 
Rassenti L, et al. Rituximab in combination with high-dose 
methylprednisolone for the treatment of chronic lymphocytic 
leukemia. Leukemia. 2009;23(10):1779-89. 
2. 
Castro JE, Sandoval-Sus JD, Bole J, Rassenti L, Kipps TJ. 
Rituximab in combination with high-dose methylprednisolone for 
the 
treatment 
of 
fludarabine 
refractory 
high-risk 
chronic 
lymphocytic leukemia. Leukemia. 2008;22(11):2048-53. 
3. 
Seymour JF. Effective mitigation of tumor lysis syndrome 
with gradual venetoclax dose ramp, prophylaxis, and monitoring in 
patients with chronic lymphocytic leukemia. Ann Hematol. 
2016;95(8):1361-2. 
4. 
Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D'Rozario J, 
Assouline S, et al. Venetoclax-Rituximab in Relapsed or Refractory 
Chronic 
Lymphocytic 
Leukemia. 
N 
Engl 
J 
Med. 
2018;378(12):1107-20. 
5. 
Seymour JF, Ma S, Brander DM, Choi MY, Barrientos J, 
Davids MS, et al. Venetoclax plus rituximab in relapsed or 
refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet 
Oncol. 2017;18(2):230-40. 
6. 
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, 
Dighiero G, Dohner H, et al. Guidelines for the diagnosis and 
treatment of chronic lymphocytic leukemia: a report from the 
International Workshop on Chronic Lymphocytic Leukemia 
updating the National Cancer Institute-Working Group 1996 
guidelines. Blood. 2008;111(12):5446-56. 
 
 
Study 
Timelines 
Provide the estimated study timelines below: 
 
Milestone 
Est. 
Date 
(Month/Year) 
Duration* 
Enrollment = 1 year; 
F/up and Treatment = 
2 years.  
Total study duration  = 
3 years 
First Subject First Visit 
(FSFV) 
Sept/2019 
Last Subject Last Visit 
(LSLV) 
Sept/2023 
Final 
Report 
(e.g., 
manuscript/ publication) 
Initial Reporting based 
on primary endpoint: 

 
 
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Dec 
2023. 
Final 
Publication Dec 2023. 
*Duration is defined as FSFV to LSLV in months. 
 
 
 

 
 
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1.0 
Schema 
 
  
 
 
2.0 
Background 
2.1 
Chronic Lymphocytic Leukemia (CLL) 
 
Chronic Lymphocytic Leukemia (CLL) is a malignancy of B-cells and is the most common form of 
leukemia in the western world, with an incidence of 3-5 per 100,000 (1). Although treatment 
options for CLL have expanded considerably in the recent years, it remains incurable. In the front-
line setting, chemoimmunotherapy, in particular, the combination of rituximab with purine analogs 
and/or alkylator therapy, is one standard treatment for young and/or fit individuals with CLL who 
require treatment (2-4). Ibrutinib, a small molecule therapy that inhibits the tyrosine kinase Btk, is 
also an approved standard initial treatment for patients with CLL, with a high overall response 
rate of 89% (29% complete response) and 5-year progression-free survival of greater than 90% 
of patients who continue on ibrutinib (5-7).  
 
There is not a standard of care therapy in the relapsed or refractory setting. Many patients cannot 
tolerate chemoimmunotherapy in that setting due to age, comorbidities, or compromised bone 
marrow function 4, 5. Ibrutinib is an approved standard of care, though some comorbid conditions 
such as bleeding, requirement for anticoagulation, or heart disease may increase the risk of 
adverse events.  
 

 
 
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The combination of venetoclax and rituximab approved by the US FDA in 2018 as a standard 
treatment for patients with CLL who have received 1 prior therapy, regardless of cytogenetics or 
the specific prior therapy. Background regarding venetoclax follows. 
2.2 
Venetoclax 
2.2.1 Venetoclax Overview 
Venetoclax (VENCLEXTA™) is a potent, orally administered inhibitor of B-cell lymphoma 2 (BCL-
2) co-developed by AbbVie Inc and Genentech Inc for the treatment of B-cell malignancies.  
Venetoclax has been approved in the US for the treatment of patients with CLL with 17p deletion, 
as detected by an FDA approved test, who have received at least one prior therapy.  
 
The Bcl-2 family proteins are important regulators of the intrinsic apoptosis pathway. The Bcl-2 
oncogene was first identified in follicular lymphoma (FL) where the t(14;18) chromosomal 
translocation results in significant over-expression of the protein in B-cells. The Bcl-2 family of 
genes encodes a family of closely related proteins that possess either pro-apoptotic or anti-
apoptotic activity and share up to four Bcl-2 Homology (BH) domains. Bcl-2 overexpression is a 
major contributor to the pathogenesis of some types of lymphoid malignancies. Bcl-2 is also 
overexpressed in acute and chronic leukemias. Chronic lymphocytic leukemia (CLL) is a genetic 
disease where the microRNAs miR15a and miR16-1 that negatively regulate the transcription of 
Bcl-2 are deleted or down-regulated, resulting in uncontrolled expression of Bcl-2. 
 
Venetoclax (also known as ABT-199) is a novel, orally available, small molecule Bcl-2 family 
protein inhibitor that binds with high affinity (Ki <0.010 nM) to Bcl-2 and with lower affinity to other 
Bcl-2 family proteins Bcl-XL and Bcl-w (>4,000-fold and >2,000- to >20,000-fold lower affinity than 
to Bcl-2, respectively). Selective inhibition by venetoclax disrupts Bcl-2 signaling and rapidly 
induces multiple hallmarks of apoptotic cell death in Bcl-2- dependent human tumor cell lines 
(venetoclax IB). 
2.2.2 Summary of Nonclinical Data  
In vitro, venetoclax demonstrated broad cell killing activity against patient-derived CLL and acute 
myeloid leukemia (AML) cells, and a variety of lymphoma and leukemia cell lines including B-cell 
follicular lymphomas (FLs), mantle cell lymphomas (MCLs), diffuse large B-cell lymphomas 
(DLBCLs), AMLs, and multiple myeloma cell lines. Venetoclax was especially potent against cell 
lines expressing high levels of Bcl-2. A detailed discussion of the non-clinical toxicology, 
metabolism, and pharmacology can be found in the venetoclax IB. 
 
2.2.3 Summary of Venetoclax Clinical Data 
 
2.2.3.1 Clinical Pharmacokinetics 
Following multiple oral administrations under fed conditions, maximum plasma concentration of 
venetoclax was reached 5-8 hours after dose. Venetoclax steady state AUC increased 
proportionally over the dose range of 150-800 mg.  
 

 
 
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Food can increase venetoclax exposure (3.4-fold with a low-fat meal and 5.1- to 5.3-fold with a 
high-fat meal). Venetoclax should be administered with a meal. The population estimate for the 
terminal elimination half-life of venetoclax was approximately 26 hours. In vitro studies 
demonstrated that venetoclax is predominantly metabolized by CYP3A4/5. Less than 0.1% of 
venetoclax is excreted renally. 
 
Venetoclax exposures in subjects with mild or moderate renal impairment are similar to those 
with normal renal function. The pharmacokinetics of venetoclax has not been studied in subjects 
with severe renal impairment (CrCl <30 mL/min) or subjects on dialysis.  
 
Venetoclax exposures are similar in subjects with mild and moderate hepatic impairment and 
normal hepatic function based on the NCI Organ Dysfunction Working Group criteria. Mild hepatic 
impairment was defined as normal total bilirubin and aspartate transaminase (AST) > upper limit 
of normal (ULN) or total bilirubin >1.0 to 1.5 times ULN, moderate hepatic impairment as total 
bilirubin >1.5 to 3.0 times ULN, and severe hepatic impairment as total bilirubin >3.0 times ULN. 
The pharmacokinetics of venetoclax has not been studied in subjects with severe hepatic 
impairment. 
 
For the most comprehensive information regarding pharmacokinetics (PK) and product 
metabolism, please refer to the current version of the venetoclax IB. 
 
2.2.3.2 Summary of Clinical Safety 
Doses administered in venetoclax clinical studies have ranged from 20 mg to 1200 mg. As of 28 
November 2015 and version 7 of the Investigator’s Brochure, on the basis of data available in the 
AbbVie and Genentech/Roche clinical databases, a total of 1662 subjects have been exposed to 
at least 1 dose of venetoclax in the oncology and immunology development programs. A total of 
1493 oncology subjects have data available in AbbVie and Genentech/Roche studies as of 28 
November 2015. Of these 1493, there are 935 subjects with CLL/ SLL, 346 subjects with NHL, 
110 subjects with MM, 102 with AML.  An additional 66 subjects are healthy volunteers. A total of 
560 oncology subjects received the drug as monotherapy, 933 have received the drug in 
combination with other therapies, and 1 subject received venetoclax as a single dose in a drug-
drug interaction study and did not re-enroll into a subsequent monotherapy study. Additionally, 98 
subjects have been exposed to at least 1 dose of venetoclax in the AbbVie immunology study, 
Study M13-093, as of 28 November 2015. Of the 935 subjects with CLL/SLL that have been 
treated in the venetoclax oncology clinical program: 336 patients have received venetoclax 
monotherapy and 599 have received venetoclax in combination with other agents including 
rituximab, obinutuzumab, and bendamustine. 
 
The most common adverse events (incidence >20%) reported for all subjects in CLL/SLL 
monotherapy studies were diarrhea (40.2%), neutropenia (38.7%), nausea (37.8%), fatigue 
(27.4%), upper respiratory tract infection (26.5%), and anemia (25.3%). The most common Grade 
3 and above adverse events were neutropenia (36.0%), anemia (14.6%), and thrombocytopenia 
(13.1%). The most common serious adverse events were pneumonia (5.7%), febrile neutropenia 
and malignant neoplasm progression (5.7% each). The safety profile in combination studies is 
consistent with that observed in monotherapy studies and with known toxicity profile of 
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In combination with rituximab, serious adverse reactions were reported in 46% of patients, with 
the most frequent (≥5%) being pneumonia (9%). The most common adverse reactions (≥20%) of 
any grade were neutropenia (65%), diarrhea (40%), upper respiratory tract infection (39%), 
fatigue (22%), cough (22%), and nausea (21%). 
 
Tumor lysis syndrome (TLS) is an important risk, particularly in subjects with CLL. Tumor lysis 
syndrome, including fatal events and renal failure requiring dialysis, have occurred in previously 
treated CLL patients with high tumor burden when treated with venetoclax. As a result of on-target 
effects, the potential for TLS with venetoclax was identified early in the program when the initial 
3 subjects with relapsed/refractory CLL/SLL received starting doses of 100 mg or 200 mg and 
experienced TLS, which was reported as an adverse event for each. The starting dose was 
reduced to 20 mg and prophylaxis and monitoring instituted, with 3 week ramp-up.  
 
Subsequently, 2 fatal events in the setting of TLS and another event of clinical TLS in subjects 
with CLL/SLL occurred in December 2012. After comprehensive review of all safety data available 
from studies with venetoclax, a revised dosing regimen with a ramp-up period of 5 weeks (starting 
from 20 mg) and enhanced TLS prophylaxis and monitoring measures were implemented in all 
CLL studies. A subsequent analysis of data from subjects with CLL/SLL following the 
implementation of prophylaxis measures, who completed monotherapy, indicated a marked 
reduction in severity and frequency of TLS when compared to the previous analysis. None of the 
subjects experienced any serious (including fatal) or non-serious event of clinical TLS (CTLS) or 
had study treatment discontinued because of TLS. Overall, the clinical data strongly support that 
the risk of TLS with venetoclax in CLL/SLL subjects is highest when initiating venetoclax dosing, 
especially with a higher initial dose of venetoclax, as well as being greater in subjects with a large 
tumor burden.  
 
The earlier clinical trials identified risk factors for tumor lysis syndrome. The risk of TLS is a 
continuum based on multiple factors, including tumor burden and comorbidities. Reduced renal 
function (CrCl <80 mL/min) further increases the risk. In addition, measurements of tumor burden, 
including maximum lymph node diameter and absolute lymphocyte count define TLS risk.  
 
Subjects have been classified in 3 risk categories based on risk for developing medically 
concerning TLS with venetoclax administration. The tumor burden assessed by the nodal disease 
and absolute lymphocyte count has been used to defined each category as below: 
 
Tumor Burden 
Category 
Criteria 
Low 
All measurable lymph nodes with the largest diameter < 5 
cm by radiologic assessment AND ALC < 25k/uL 
Medium 
Any measurable lymph node with the largest diameter >/= 5 
cm but < 10 cm by radiographic assessment  
OR ALC >/= 25k/uL 
High 
Any measurable lymph node with the largest diameter >/= 
10 cm by radiologic assessment OR 

 
 
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ALC >/= 25k/uL AND any measurable lymph node with the 
largest diameter >/= 5 cm 
 
Patients should be assessed for risk and should receive appropriate prophylaxis for TLS, including 
hydration and anti-hyperuricemics. 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 and 
at each dose increase. Venetoclax prescribing information include standard of care 
recommendations for monitoring of blood chemistries, and use of more intensive measures 
(intravenous hydration, frequent monitoring, and hospitalization) as overall risk of TLS increases 
(see Appendix D and E: Prophylaxis and Management of TLS).  
 
Grade 3 or 4 neutropenia occurred in 41% (98/240) of patients treated with venetoclax in the 
pivotal previously treated CLL 17p deletion study. Monitor complete blood counts throughout the 
treatment period. Interrupt dosing or reduce dose for severe neutropenia. Consider supportive 
measures including antimicrobials for signs of infection and use of growth factors (eg, G-CSF). In 
addition, 49 patients with CLL were treated with venetoclax + rituximab in a phase 1 M13-365 
clinical trial. The rate of neutropenia (grade 3 and above) was 53.1%. 
 
Do not administer live attenuated vaccines prior to, during, or after treatment with venetoclax 
until B-cell recovery occurs. The safety and efficacy of immunization with live attenuated vaccines 
during or following venetoclax therapy have not been studied. Advise patients that vaccinations 
may be less effective. 
2.2.3.3 Summary of Clinical Efficacy of Venetoclax with Rituximab  
The combination of venetoclax and rituximab was evaluated in a randomized, open-label, phase 
3 trial. 389 patients were randomized to receive venetoclax for up to 2 years (from day 1 of cycle 
1) plus rituximab for the first 6 months (venetoclax-rituximab group) or bendamustine plus 
rituximab for 6 months (bendamustine-rituximab group). The trial design did not include crossover. 
The primary end point was investigator-assessed progression-free survival.  
 
The treatment regimen utilized the same dose escalation/ ramp-up strategy as utilized in early 
monotherapy trials. Rituximab was added on week 6, after completion of the ramp-up. Patients 
received rituximab 375 mg/m2 for the 1st dose, then 500 mg/m2 for 5 additional monthly doses.  
 
After a median follow-up period of 23.8 months, the rate of investigator-assessed progression-
free survival was significantly higher in the venetoclax-rituximab group (32 events of progression 
or death in 194 patients) than in the bendamustine-rituximab group (114 events in 195 patients); 
the 2-year rates of progression-free survival were 84.9% and 36.3%, respectively (hazard ratio 
for progression or death, 0.17; 95% confidence interval [CI], 0.11 to 0.25; P<0.001 by the stratified 
log-rank test). The benefit was maintained across all clinical and biologic subgroups, including 
the subgroup of patients with chromosome 17p deletion; the 2-year rate of progression-free 
survival among patients with chromosome 17p deletion was 81.5% in the venetoclax-rituximab 
group versus 27.8% in the bendamustine-rituximab group (hazard ratio, 0.13; 95% CI, 0.05 to 
0.29), and the 2-year rate among those without chromosome 17p deletion was 85.9% versus 

 
 
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41.0% (hazard ratio, 0.19; 95% CI, 0.12 to 0.32). The benefit of venetoclax plus rituximab over 
bendamustine plus rituximab was confirmed by an independent review committee assessment of 
progression-free survival and other secondary efficacy end points.  
 
The rate of grade 3 or 4 neutropenia was higher in the venetoclax-rituximab group than in the 
bendamustine-rituximab group, but the rates of grade 3 or 4 febrile neutropenia and infections or 
infestations were lower with venetoclax than with bendamustine. The rate of grade 3 or 4 tumor 
lysis syndrome in the venetoclax-rituximab group was 3.1% (6 of 194 patients). (8)  
2.3 
High Dose Methylprednisolone 
Corticosteroids have long been used in regimens to treat B-cell malignancies.  High dose 
methylprednisolone (HDMP) has been studied as a single agent in treatment of advanced CLL. 
A small study was conducted using high dose methylprednisolone at a dose of 1 gm/m2 daily for 
five days repeated every four weeks in subjects with chemotherapy refractory CLL (Thornton et 
al., 1999). In this study no complete responses were noted, however, 6 of 11 (55%) subjects had 
partial responses following, on average four cycles of treatment.  In addition to improving the 
subjects’ sense of well-being and reducing lymphadenopathy, treatment with HDMP was 
associated with marked improvement in hematological parameters including rise in hemoglobin 
and platelet counts indicating improved bone marrow function.  
 
In vitro and in vivo data suggest that there is a synergistic effect of methylprednisolone and 
Rituximab (9). This is demonstrated by the fact that CLL cells lose the survival protection 
conferred by stromal cells and undergo apoptosis when incubated in the presence of 
methylprednisolone and Rituximab. Our preliminary data from a study in subjects refractory to 
fludarabine has shown that the combination of HDMP-Rituximab can be safely administered with 
no major Grade III or IV side effects. All treated subjects showed response to this treatment 
regimen when evaluated at two months after completion of treatment (4 subjects with complete 
response and 3 subjects with partial response). A long-term follow up analysis of those subjects 
has shown that the median time to progression is 18 months, which is unexpectedly high in this 
group of fludarabine refractory CLL subjects.  
 
In addition, the combination of HDMP-Rituximab in previously untreated subjects has been 
evaluated. (9) A total of 28 subjects with a median age of 65 years were enrolled in this study. 
Subjects received HDMP at 1 g/m2 each day for 3 days during each of the three 4-week cycles 
together with rituximab and prophylactic antimicrobial therapy. The treatment was well-tolerated 
and the main toxicities were Grade ≤ II and included, hyperglycemia, insomnia, fluid retention. 
We also observed 2 transient episodes of grade III-IV toxicity secondary to infection, resulting in 
pneumonia or sinusitis that resolved completely after antibiotic treatment. The overall response 
rate was 96% (N=27). Nine subjects (32%) achieved a complete remission (CR), two of which 
were without detectable minimal residual disease (MRD). Six subjects with MRD received 
consolidation with alemtuzumab; five of these subjects achieved an MRD-negative CR. With over 
3 years of follow-up median progression-free survival was 30.3 months with only 39% of subjects 
requiring additional therapy, and an overall survival that was 96%.  Most subjects showed 
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recovery of cytopenias. Pharmacodynamic studies showed that leukemia cells from subjects 
responding to this combination regimen were induced to express pro-apoptotic molecules, such 
as Bid, Apaf-1, Smac-Diablo, and to down regulate expression of anti-apoptotic molecules, such 
as XIAP and Mcl-1.  
 
2.4 
Study Rationale 
 
The combination of venetoclax and rituximab is an effective and FDA-approved regimen to treat 
patients with CLL or SLL who have previously received treatment, though brings risk of tumor 
lysis syndrome (TLS) upon initiation of venetoclax. This risk is currently mitigated by careful 
prophylactic and monitoring measures during the initiation of venetoclax, including inpatient 
hospitalization and serial lab monitoring for patients who have a high tumor burden. Further 
mitigating the TLS risk will improve this treatment. 
This risk of TLS is associated with the amount of tumor burden, and patients with Low Tumor 
Burden (absolute lymphocyte count less than 25k/uL; all lymph nodes less than 5 cm in diameter) 
are considered to have low TLS risk, and can be monitored without hospitalization (Venetoclax 
prescribing information). Therefore, decreasing the CLL tumor burden prior to initiation of 
venetoclax can also be a risk mitigation strategy.  
The combination of High-Dose Methylprednisolone (HDMP) and rituximab has been evaluated as 
a treatment for patients with CLL. For patients with fludarabine-refractory CLL, the ORR was 96%, 
the CR rate was 36%, and all patients would have met the above criteria for Low Tumor Burden 
at the completion of therapy. The ALC values reduced in majority of patients within the 1st cycle. 
Therefore, HDMP + Rituximab is an ideal potential debulking strategy prior to initiation of 
venetoclax based on the following rationale: 
- 
high rate of improvement of lymphadenopathy and lymphocytosis in previous 
publications. 
- 
lack of added myelotoxicity; manageable overall toxicity profile compared to rituximab 
+ venetoclax alone. 
- 
administered in an outpatient setting. 
 
3.0 
Objectives 
 
Purpose: to determine the feasibility of treating patients with HDMP + rituximab as a means of 
debulking prior to initiating venetoclax. 
 
Objectives: 
Primary:  
1. To determine the percentage of patients who have a reduction of lymphadenopathy (from 
greater than to less than 5 cm in largest diameter) and/or absolute lymphocyte count (from greater 
than to less than 25k/uL) following 1 or 2 cycles of HDMP + rituximab (only 1 cycle permitted if 
subject enrolled after protocol v5 approval).   

 
 
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Secondary: 
1. To determine the rate of laboratory or clinic TLS with this strategy. 
2. To determine the safety (CTCAE4) of this approach. 
3. To determine the overall efficacy (iwCLL) of this overall strategy.  
4. To determine the percentage of patients who have undetectable minimal residual disease in 
the bone marrow. 
Endpoints: 
Primary:  
1. Percentage of patients that have a decrease in tumor burden from levels of disease that meet 
“Medium/High-tumor burden” criteria to “Low tumor burden” criteria for disease burden following 
a maximum of 2 cycles of HDMP + Rituximab (following a maximum of 1 cycle if subject 
enrolled after protocol v5 approval). 
Secondary: 
1. Percentage of patients that have a decrease in tumor burden from levels of disease that meet 
“Medium/High-tumor burden” to meet “Low tumor burden” criteria for disease burden following 1 
cycle of HDMP + Rituximab. 
2. Percentage of patients that have a decrease in tumor burden from levels of disease that meet 
“Medium/High-tumor burden” to meet “Low tumor burden” criteria for disease burden following 2 
cycles of HDMP + Rituximab. 
3. Rate of laboratory TLS (from start of treatment until completion of venetoclax ramp-up) 
4. Rate of clinical TLS (from start of treatment until completion of venetoclax ramp-up) 
5. Adverse events by CTCAE4 definitions 
6. Overall Response rate, Partial Response rate, and Complete response rate per iwCLL criteria 
after 9 months of venetoclax and at completion of treatment. 
7. Undetectable minimal residual disease (MRD) rate based on bone marrow biopsy after 9 
months of venetoclax, and at completion of treatment. 
4.0 
Study Design 
4.1 
Description 
This is a single center, open-label, pilot/feasibility study designed to evaluate the feasibility of 
HDMP/Rituximab as an approach to decrease TLS risk for patients who receive venetoclax for 
treatment of CLL/SLL. 
Patients with CLL/SLL who require therapy, and have disease burden meeting criteria for Medium 
or High Tumor Burden (based on: lymph nodes >/= 5 cm in diameter and/or absolute lymphocyte 
count >/= 25k/uL) are enrolled. 

 
 
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- 
Patients will receive HDMP + Rituximab for 1 cycle, followed by reassessment of Tumor 
burden.  
- 
Patients will then initiate venetoclax dose ramp-up, with ramp-up schedule according to 
venetoclax package insert. 
- 
If Tumor Burden classification is still Medium/High after 1 cycle of HDMP + rituximab, 
patients are also given the option to repeat a 2nd cycle of HDMP + Rituximab prior to the 
venetoclax dose ramp-up.  
Upon completion of ramp-up (venetoclax to 400 mg), all patients will continue Venetoclax 400 mg 
(or highest tolerated dose) for up to 2 years. Patients will also continue rituximab 500 mg/m2 q 28 
days through Cycle 6. 
4.2 
Endpoint Assessment: 
1. Assessment of the disease burden after a maximum of 2 cycles of HDMP + Rituximab is the 
primary endpoint for HDMP/R as an approach to decrease risk of TLS.  
2. Assessment of the disease burden after 1 cycle of HDMP + Rituximab. 
3. Assessment of the disease burden after 2 cycles of HDMP + Rituximab (for the subset of 
patients that do not meet criteria for low tumor burden after 1 cycle). 
4. Clinical and laboratory TLS events between start of treatment and the completion of venetoclax 
dose-ramp up (Cycle 2, Day 1) 
5. Presence or absence of detectable MRD in the marrow will be assessed after approximately 9 
months of venetoclax and completion of treatment.  
6. Radiology assessment after approximately 9 months of venetoclax and at the completion of 
therapy, and as clinically indicated (unless prior imaging studies are without measurable 
disease)  
4.3 
Rationale for study design 
 
Rationale for Primary Feasibility Endpoint: 
Classification of Tumor Burden into Low-, Medium-, and High- is a validated system that aids in 
TLS risk stratification based on prior venetoclax clinical trials, and is in accordance with standard 
clinical practice and the venetoclax prescribing information. This then serves as an appropriate 
endpoint to evaluate the feasibility of using HDMP/R as a means to lower the risk of TLS. Using 
actual TLS rate would require a much larger study as the absolute rate is relatively low. There is 
also clinical value in decreasing the Tumor Burden to “low” prior to venetoclax administration, as 
less intensive monitoring is required (ie, no inpatient hospitalization).  
 
5.0 
Study Population 
 

 
 
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Subjects will undergo screening procedures within 28 days prior to initial study drug 
administration. Adult male and female subjects who meet the inclusion criteria and who do not 
meet any of the exclusion criteria will be eligible for enrollment into the study. 
 
5.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. Subjects must be age 18 or older. 
2. Both men and women of all races and ethnic groups are eligible for this trial. 
3. Ability to understand and willingness to sign a written informed consent. 
4. Diagnosis: CLL or SLL, as documented in the medical record 
5. Disease Status/ Prior Therapy:  
- 
Must have had treatment for CLL/SLL with at least 1 line of prior therapy. (There is not 
requirement nor restriction for specific type of previous therapy, with the following 
exceptions: prior treatment with venetoclax within 6 months, prior progressive disease 
on venetoclax, or prior grade 3 or 4 toxicity (not including TLS) that directly lead to 
discontinuation of venetoclax; Prior HDMP/Rituximab is allowed unless there was no 
response (Stable Disease or Progressive Disease) or was within 3 months. 
- 
Indication for CLL or SLL therapy based on international working group (iwCLL) 
guidelines, which include: constitutional symptoms, bulky or symptomatic 
lymphadenopathy, bulky or symptomatic splenomegaly, rapid doubling of the ALC 
(approximately 6 months or less), or Rai stage 3 or 4 disease. 
- 
Disease burden meets criteria for Medium or High Risk for TLS, based on Absolute 
lymphocyte count >/= 25k/uL or any lymph node 5 cm or greater in diameter. The ALC 
criteria must be met during the screening period. The imaging criteria may be based on 
radiologic study within 30 days of Cycle 0, Day 1, if scans were done prior to consent or 
initiation of the screening period.  
6. Has recovered from the toxic effects of prior therapy to their clinical baseline. 
7. Women of child-bearing potential (not postmenopausal for at least one year or not 
surgically incapable of bearing children) must agree to not become pregnant for the 
duration of the study. Both men and women must agree to use a barrier method of 
contraception for the duration of the study and until 5 half-lives after the final dose of 
venetoclax (approximately 1 week), and at least 5 half-lives after the final dose of 
Rituximab. 
8. ECOG performance status of 0-2 
9. Adequate hematologic function: Platelet count >/= 30k/uL, hemoglobin > 7 g/dL, AND ANC 
> 500/uL. (Values may be lower if due to marrow infiltration by CLL). 
10. Adequate renal function: Creatinine clearance based on 24 hr collection >/= 40 ml/min; 
OR Calculated Creatinine clearance (CrCl) ≥ 40 mL/min (based upon the Cockcroft-Gault 
Equation [CrCl = (140-age) * actual wt (in kg) * (0.85 if female) / (72 * Cr)]. 
11. Adequate hepatic function per local laboratory reference range as follows: 
a. Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0X ULN 
b. Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-
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5.2 
Exclusion Criteria 
 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Subject is known to be positive for HIV.  (HIV testing is not required.) 
 
2. Evidence of other clinically significant uncontrolled condition(s) including, but not limited 
to: 
a. Uncontrolled and/or active systemic infection (viral, bacterial or fungal) 
b. Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment.  Note: 
subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B 
surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B 
core (HBc) antibody negative) or positive anti-HBc antibody from intravenous 
immunoglobulins (IVIG) may participate.  
 
3. Treatment with any of the following within 7 days prior to the first dose of venetoclax: 
a. Steroid therapy for anti-neoplastic intent 
b. moderate or strong cytochrome P450 3A (CYP3A) inhibitors (see Appendix C for 
examples) 
c. moderate or strong CYP3A inducers (see Appendix C for examples) 
 
 
4. Prior CLL therapy: 
a. Biologic agent (monoclonal antibody) within 30 days for anti-neoplastic intent. 
b. Chemotherapy (purine analog or alkylating agent) or target small molecule agent 
within 14 days or 5 half-lives (whichever is shorter), or has not recovered to less 
than CTC grade 2 clinically significant adverse effect(s)/toxicity(s) of previous 
therapy. 
 
5. History of severe allergic or anaphylactic reactions to monoclonal antibody therapy  
6. Known hypersensitivity to any of the study drugs  
7. History of other malignancy that could affect compliance with the protocol or interpretation 
of results (example: patients with a history of curatively treated basal or squamous cell 
carcinoma of the skin or in situ carcinoma of the cervix are generally eligible. Patients with 
a malignancy that has been treated, but not with curative intent, will also be excluded, 
unless the malignancy has been in remission without treatment for 2 years prior to 
enrollment.) 
8. Known active bacterial, viral, fungal, mycobacterial, or other infection (excluding fungal 
infections of nail beds); or any major episode of infection requiring treatment with IV 
antibiotics or hospitalization (related to the completion of the course of antibiotics) within 
4 weeks before the start of Cycle 0 
9. Major surgery (within 4 weeks prior to the start of Cycle 0), other than for diagnosis 
10. Women who are pregnant or lactating 
11. Uncontrolled diabetes mellitus (related to high dose steroid risk) 

 
 
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12. Myocardial infarction within 6 months of starting study drug or other clinically significant 
heart disease (NYHA class 3 heart failure, uncontrolled hypertension) 
5.3 
Prior and Concomitant Therapy 
If a subject reports taking any over-the-counter or prescription medications, vitamins and/or herbal 
supplements or if administration of any medication becomes necessary beginning with the 
Screening visit through the end of the study, the name of the medication, dosage information 
including dose, route and frequency, date(s) of administration including start and end dates, and 
reason for use must be recorded on the appropriate case report form.  
Subjects should receive full supportive care during study participation, including hematopoietic 
growth factors, transfusion of blood products, fluid and electrolyte replacement, and antibiotics 
when appropriate. Subjects who use oral contraceptives, hormone replacement therapy, or other 
maintenance therapy should continue their use. 
Steroid therapy for anti-neoplastic intent is prescribed in Cycle 0. Aside from this, however, 
steroids for anti-neoplastic intent will not be allowed during or within 7 days of study treatment. 
Inhalational steroids for the treatment of asthma or COPD, topical steroids, replacement 
corticosteroid therapy for an inherited or acquired deficiency, or brief corticosteroids for rituximab 
infusion-reaction management or prevention are allowed. 
In addition, limited corticosteroid treatment (i.e. for approximately 21 days with rapid taper) is 
allowed while on study for significant active autoimmune cytopenias, eg. Autoimmune hemolytic 
anemia (AIHA) or immune thrombocytopenia (ITP). IVIG (intravenous immune globulin) is also 
allowable. Eltrombopag is another treatment option for ITP.  
Guidelines regarding excluded and cautionary medications are summarized in the following table. 
 
 
 
 
 
Table 2: Excluded and Cautionary Medications (See Appendix C for Examples of the 
Medications) 

 
 
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Excluded 
Anticancer therapies including chemotherapy, radiotherapy, or other investigational therapy, including targeted small 
molecule agents: Excluded 5 half-lives prior to first dose and throughout venetoclax administration (except the HDMP/R 
prescribed on study) 
 
Biologic agents (e.g., monoclonal antibodies) for anti-neoplastic intent: 
Excluded 30 days prior to first dose and throughout venetoclax administration (except the HDMP/R prescribed on study) 
Excluded during ramp-up phase and Cautionary during maintenance/target dose:  
Strong and Moderate CYP3A inhibitors  
Exclude during ramp-up phase and consider alternative medications. If subject requires use of these medications at the cohort 
designated dose, use with caution and reduce the venetoclax dose by 50% for moderate inhibitors and at least 75% for strong 
inhibitors during co-administration.  After discontinuation of CYP3A inhibitor, wait for 2 to 3 days before venetoclax dose is 
increased back to the initial maintenance/target dose. 
Strong and Moderate CYP3A inducers 
Exclude during ramp-up phase and consider alternative medications. If subject requires use of these medications at the cohort 
designated dose, use with caution and contact PI for guidance. 
Cautionary (See Appendix C for examples) 
Warfarin  
P-gp substrates 
BCRP substrates 
OATP1B1/1B3 substrates 
P-gp inhibitors 
BCRP inhibitors 
 
Furthermore, administration or consumption of any of the following starting 3 days prior to the first 
dose of venetoclax is restricted: 
a. grapefruit or grapefruit products 
b. Seville oranges (including marmalade containing Seville oranges) 
c. star fruit 
 
Recommended concomitant therapies: 
In addition to the cautionary/excluded medications, there are also recommended concomitant 
prophylactic therapies: 
- Allopurinol (or alternative uric acid reducing drug, dosing per clinician judgement) is 
recommended starting 3 days prior to first treatment, until the completion of the venetoclax ramp-
up (Cycle 1, Day 30) 

 
 
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- Acyclovir (or alternative anti-VZV / HSV drug, dosing per clinician judgement) is recommended 
for prophylaxis for patients in Arm 1, starting C0D1 to C2D28.  
- Septra (or alternative anti-pneumocystis agent, dosing per clinician judgement) is recommended 
for prophylaxis for patients in Arm 1, starting C0D1 to C2D28. 
- Fluconazole (or alternative anti-fungal agent, dosing per clinician judgement) is recommended 
for prophylaxis for patients in Arm 1, starting C0D1 to C0D21 (stopping 7 days prior to venetoclax). 
6.0 
Treatment Plan / Study Procedures 
 
Table 3. Schedule of Events 
 
 
 
 
 
(only 1 cycle permitted if subject enrolled after protocol v5 approval). 

 
 
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6.1 
Screening Procedures 
 
Unless otherwise stated, the baseline measurement for any given variable will be defined as the 
last value obtained prior to the first dose of study drug. 
 
Informed Consent 
 
Signed informed consent will be obtained from the subject or the subject’s legally acceptable 
representative before any study-specific procedures are undertaken or before any prohibited 
medications are withheld from the subject in order to participate in this study. Informed consent 
is also required for pharmacodynamic sample collections. 
 
Medical and Oncologic History 
 
The following will be collected during the Screening Visit: 
- 
Complete medical history, including documentation of any clinically significant medical 
conditions. 
- 
Detailed oncologic history, including: 
o Date of CLL diagnosis 
o Cytogenetics (if known from prior testing)  
o IgVH mutation status (if known from prior testing) 
o Somatic mutations in CLL cells (if known from prior testing) 

 
 
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o Treatments administered (including approximate dates, response to treatment if 
known, and reason for treatment discontinuation). 
- 
Detailed and concomitant medication usage including dates of usage and dosing 
information for all medications and supplements taken.  
- 
Prior to the first treatment visit (C0D1), any changes observed from the Screening 
assessments (prior to dosing) will be recorded in the subject’s medical history. 
 
Physical examination 
Physical examination performed should include evaluate of presence and degree of enlarged 
lymph nodes in two dimensions in cervical, supraclavicular, axillary, and inguinal regions; 
hepatomegaly; and splenomegaly. Additional physical exam of other organ systems are per 
clinical standard of care. 
If during physical examination, signs or symptoms suggestive of Richter’s Syndrome are observed 
further assessment (i.e, node biopsy or PET scan) should be considered if clinically indicated to 
assess for or confirm Richters. 
Vitals signs 
Body temperature, weight, blood pressure, and pulse will be measured. 
ECOG performance status 
Subject’s performance status will be assessed based on the ECOG system. See Appendix A for 
description/definition. 
Clinical Laboratory Tests: 
Local laboratories will be utilized to process and provide results for the clinical laboratory tests. 
Investigator should review, initial, and date the laboratory results. The following labs are collected 
during the screening period: 
 - CBC with differential (automated or manual) 
 - Comprehensive Metabolic Panel  
 - Hepatitis B and C serologies. This a standard of care assessment prior to administration of any 
anti-CD20 therapy and not done for the sole purpose of research). HBsAg, anti-HBs, total anti-
HBc, IgM anti-HBc, HCV ab or RNA. If during screening a subject present with a positive Hepatitis 
B core antibody, Hepatitis B Viral DNA PCR test should be performed to rule out an active 
infection. If there are known results of hepatitis serologies within 6 months without at risk 
exposure, they do not need to be repeated. 
- If female of child-bearing potential: serum pregnancy test within 14 days of initiation of therapy 
on trial. 
Computed Tomography (CT) Scans (or Magnetic Resonance Imaging [MRI]) 

 
 
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A CT scan must be performed within 30 days prior to study drug administration for all subjects. A 
CT scans should include chest, abdomen, and pelvis sequences. Contrast is preferred though 
can be omitted if contraindication. A contrast-enhanced MRI of chest, abdomen, and pelvis may 
be used for subjects in whom a CT is medically contraindicated (example: contrast allergy). 
Whichever method is used at Screening is preferred to be used consistently through the duration 
of the study for that subject. 
Justification: The CT or MRI scans at baseline is a standard of care assessment prior to initiation 
of venetoclax in order assess tumor burden and risk for TLS, as this will guide optimal 
management to mitigate the risk of TLS. This test is necessary to determine if some patients may 
safely start venetoclax with outpatient monitoring, infusion center monitoring, or inpatient 
monitoring. Although this is also part of the primary endpoint assessment, it is also a needed and 
standard test for patient safety and in accordance with the prescribing information when 
venetoclax is prescribed even outside of clinical trials.  
Initiation and prescription of prophylactic medication 
After confirmation of eligibility, patients are prescribed allopurinol 300 mg PO daily (or dose 
adjusted per clinical indication such as renal failure, or alternate medication per clinician 
judgement), and instructed to start 3 days prior to treatment initiation. 
6.2 
Cycle 0: HDMP + Rituximab  
Cycle 0 is 28 days in duration.  
On Day 1, the following are done:  
• 
Medical history, physical exam, and vital signs 
 
• 
Laboratory examinations: CBC w/ differential, comprehensive metabolic panel, 
phosphorous, uric acid, and LDH. (Potassium, Phosphorous, Calcium, uric acid, and 
creatinine are necessary and clinically indicated to assess for possible tumor lysis 
syndrome, and not simply as markers of disease burden). 
• 
Collection of correlative pharmacodynamic sample, prior to treatment (4, approximately 8-
10 mL anticoagulated tubes – ACD or heparin) 
• 
Methylprednisolone 1000 mg/m2 IV 
• 
Rituximab 100 mg IV 
On Day 2 and 3, the following are done: 
• 
Vital signs 
• 
Laboratory examinations: CBC w/ differential, comprehensive metabolic panel, 
phosphorous, uric acid, and LDH. (Potassium, Phosphorous, Calcium, uric acid, and 

 
 
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creatinine are necessary and clinically indicated to assess for possible tumor lysis 
syndrome, and not simply as markers of disease burden). 
• 
Methylprednisolone 1000 mg/m2 IV 
• 
Rituximab 375 mg/m2 IV  
On Day 4, the following are done: 
• 
Vital signs 
• 
Laboratory 
examinations: 
CBC 
w/differential, 
comprehensive 
metabolic 
panel, 
phosphorous, uric acid, LDH  
• 
Rituximab 375 mg/m2 IV  
Between Day 15 and Day 28 of Cycle 0, disease burden is reassessed to determine risk of TLS 
prior to Venetoclax initiation, including: 
• 
Laboratory examinations: CBC w/ differential, comprehensive metabolic panel, 
phosphorous, uric acid, LDH 
• 
CT or MRI of thorax, abdomen, and pelvis. IF medically necessary to reassess TLS risk. 
Areas that did not have enlarged lymph nodes 1.5 cm or greater in long-axis diameter may 
be skipped for this radiographic reassessment. (Justification: This is again a necessary 
procedure to determine Tumor Burden and to optimally manage and mitigate TLS risk for 
patients prior to starting Venetoclax). 
6.3 
Cycle 1: Venetoclax Ramp-up 
Cycle 1 is 35 days in duration and consists of venetoclax dose-ramp up, following standard dosing 
and TLS risk mitigation strategies as per Venetoclax prescribing information. 
On Day 1 of Cycle 1, the following are completed: 
• 
History and physical examination including vital signs. 
• 
Current medications will be recorded in the subject's medical record. 
• 
Laboratory examinations: CBC w/differential, comprehensive metabolic panel, 
phosphorous, uric acid, LDH Collection of correlative research sample 
• 
Dispense and take initial dose of Venetoclax 20 mg PO.  
• 
Tumor lysis syndrome monitoring as per Appendix D and E, which includes additional 
chemistry monitoring, potential IV fluid administration, and potential inpatient 
hospitalization if clinically indicated and in accordance with venetoclax standard of care. 
 

 
 
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On Day 2 of Cycle 1, the following are completed: 
• 
Laboratory examinations: hematology (CBC w/differential), comprehensive metabolic 
panel, phosphorous, uric acid, LDH. 
• 
Dispensing Venetoclax 20 mg 6 day supply 
• 
2nd dose of venetoclax 20 mg PO after labs are resulted and reviewed by treating physician 
or investigator.  
• 
Patients continue venetoclax 20 mg PO daily C1D2 – C1D7. 
 
On Day 8 of Cycle 1, the following are completed: 
• 
Current medications will be recorded in the subject's medical record. 
• 
Laboratory examinations: CBC w/differential, comprehensive metabolic panel, 
phosphorous, uric acid, LDH  
• 
Dispense and take initial dose of Venetoclax 50 mg PO dose level.  
• 
Tumor lysis syndrome monitoring as per Appendix D and E, which includes additional 
chemistry monitoring, potential IV fluid administration, and potential inpatient 
hospitalization if clinically indicated and in accordance with venetoclax standard of care. 
 
On Day 9 of Cycle 1, the following are completed: 
• 
Laboratory examinations: CBC w/differential, comprehensive metabolic panel, 
phosphorous, uric acid, LDH  
• 
Dispensing Venetoclax 50 mg 6 day supply 
• 
2nd dose of venetoclax 50 mg PO after labs are resulted and reviewed by treating physician 
or investigator. 
• 
Patients continue venetoclax 50 mg PO daily C1D9 – C1D14. 
 
On Day 15 of Cycle 1, the following are completed: 
• 
Current medications will be recorded in the subject's medical record. 
• 
Laboratory examinations: CBC w/differential, comprehensive metabolic panel, 
phosphorous, uric acid, LDH  
• 
Dispense and take initial dose of Venetoclax 100 mg PO dose level. (7 day supply). 
• 
Tumor lysis syndrome monitoring as per Appendix D and E, which includes additional 
chemistry monitoring, potential IV fluid administration, and potential inpatient 
hospitalization if clinically indicated and in accordance with venetoclax standard of care. 
 
(Only required if High Tumor Burden prior to venetoclax initiation): On Day 16 of Cycle 1, the 
following are completed: 

 
 
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• 
Laboratory examinations: CBC w/differential, comprehensive metabolic panel, 
phosphorous, uric acid, LDH  
• 
2nd dose of venetoclax 100 mg PO after labs are resulted and reviewed by treating 
physician or investigator. 
• 
Patients continue venetoclax 100 mg PO daily C1D16 – C1D21. 
 
On Day 22 of Cycle 1, the following are completed: 
• 
Current medications will be recorded in the subject's medical record. 
• 
Laboratory examinations: CBC w/differential, comprehensive metabolic panel, 
phosphorous, uric acid, LDH  
• 
Dispensing and initial dose of Venetoclax 200 mg PO dose level. (7 day supply). 
• 
Tumor lysis syndrome monitoring as per Appendix D and E, which includes additional 
chemistry monitoring, potential IV fluid administration, and potential inpatient 
hospitalization if clinically indicated and in accordance with venetoclax standard of care. 
 
(Only required is High Tumor Burden prior to venetoclax initiation): On Day 23 of Cycle 1, the 
following are completed: 
• 
Laboratory examinations: CBC w/differential, comprehensive metabolic panel, 
phosphorous, uric acid, LDH  
• 
2nd dose of venetoclax 200 mg PO after labs are resulted and reviewed by treating 
physician or investigator. 
• 
Patients continue venetoclax 200 mg PO daily C1D23 – C1D28. 
 
On Day 29 of Cycle 1, the following are completed: 
• 
Current medications will be recorded in the subject's medical record. 
• 
Laboratory examinations: CBC w/differential, comprehensive metabolic panel, 
phosphorous, uric acid, LDH  
• 
Dispensing and initial dose of Venetoclax 400 mg PO dose level (7 day supply). 
• 
Tumor lysis syndrome monitoring as per Appendix D and E, which includes additional 
chemistry monitoring, potential IV fluid administration, and potential inpatient 
hospitalization if clinically indicated and in accordance with venetoclax standard of care. 
 
(Only required is High Tumor Burden prior to venetoclax initiation): On Day 30 of Cycle 1, the 
following are completed: 
• 
Laboratory examinations: CBC w/differential, comprehensive metabolic panel, 

 
 
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phosphorous, uric acid, LDH  
• 
2nd dose of venetoclax 400 mg PO after labs are resulted and reviewed by treating 
physician or investigator. 
• 
Patients continue venetoclax 400 mg PO daily C1D31 onward. 
 
6.4 
Cycles 2 to 6: Venetoclax + Rituximab 
All subsequent cycles are 28 days each in duration. 
On Day 1 of Cycle 2-6, the following are completed: 
• 
History and physical examination including vital signs. 
• 
Current medications will be recorded in the subject's medical record. 
• 
Laboratory examinations: CBC w/differential, comprehensive metabolic panel, 
phosphorous, uric acid 
• 
Dispensing of Venetoclax 400 mg PO dose (or highest tolerated dose), 30 day supply. 
• 
Rituximab 500 mg/m2 IV 
 
6.5 
Cycles 7-24: Venetoclax  
Cycles 7-24 are 28 days each in duration 
Patients are scheduled to be seen in clinic every 3 months 
On Day 1 of Cycles 7, 10, 13, 16, 19, and 22, the following are completed: 
• 
History and physical examination including vital signs. 
• 
Current medications will be recorded in the subject's medical record. 
• 
Laboratory examinations: CBC w/differential, comprehensive metabolic panel, 
phosphorous, uric acid 
• 
Dispensing of Venetoclax 400 mg PO dose (or highest tolerated dose), 90 day supply. 
 
In addition, on Day 1 of Cycle 10  
• 
CT or MRI of thorax, abdomen, and pelvis. Areas that did not have enlarged lymph nodes 
(greater than 1.5 cm in long-axis diameter on the prior scan) or spleen may be skipped for 
this radiographic reassessment.  
• 
Marrow biopsy and aspirate if clinical examination is consistent with a complete remission 
(ie, absolute lymphocyte count less than 4k/uL) and if clinically indicated to determine 
subsequent therapy (eg: stopping therapy if undetectable minimal residual disease). 
 

 
 
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6.6 
End of Study Assessment 
Within 2 weeks before or after Cycle 24, Day 28, the following are completed: 
• 
History and physical examination including vital signs. 
• 
Current medications will be recorded in the subject's medical record. 
• 
Laboratory examinations: CBC w/differential, comprehensive metabolic panel. 
• 
Collection of correlative sample. 
• 
CT or MRI of thorax, abdomen, and pelvis. 
• 
Marrow biopsy and aspirate if clinical examination is consistent with a complete remission 
(ie, absolute lymphocyte count less than 4k/uL) and if clinically indicated to determine 
subsequent therapy (e.g.: stopping therapy if undetectable minimal residual disease). 
6.7 
Long-term follow-up 
No long-term follow-up visits are scheduled or required per study. 
With patient consent, date of progression or next CLL therapy will be recorded based on chart 
review if data are available, or phone call no more than every 6 months. 
6.8 
Subject Withdrawal or Treatment Discontinuation: 
Patients who meet or develop the following criteria should be discontinued from the study 
- Active HBV infection or hepatitis. Patients who are carriers of hepatitis B at the time of 
discontinuation from study treatment will continue to be followed for clinical and laboratory signs 
of active HBV infection and for signs of hepatitis. 
- Severe or life-threatening anaphylaxis or hypersensitivity reaction to rituximab. Patients that 
discontinue rituximab for that reason can continue to receive HDMP and venetoclax if clinically 
indicated.  
- Patients who meet the following criteria should discontinue HDMP: Grade 4 psychosis; Active 
HBV infection or hepatitis as above. HDMP doses can be delayed for acute infection or as 
clinically indicated. 
- Inability of patient to comply with study requirements 
- Determination by the investigator that it is no longer safe for the patient to continue therapy 
With the exception of following HBV, patients who withdraw from all study therapy do not have 
required follow-up visits and can enter long-term follow-up (6.7). With patient consent, date of 
progression or next CLL therapy will be recorded. 
 
7.0 
Study Medications 
 

 
 
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7.1 
Methylprednisolone Sodium Succinate 
7.1.1 
Formulation Storage and Preparation 
Each vial of methylprednisolone contains 1g of a white powder material. Inactive ingredients 
include: Benzyl Alcohol, Sodium Hydroxide, Sodium Phosphate, Dibasic Sodium Phosphate and 
Monobasic Sodium Phosphate. The product is reconstituted in 0.9% saline solution that should 
be protected from light. Once the product is reconstituted it may be stored at controlled room 
temperature (68 to 77 degrees F) for use within 48hours.  
Methylprednisolone will be prescribed as a standard treatment. Supply: Commercial Supply 
7.1.2 
Dosage and Administration 
Only methylprednisolone sodium succinate should be used for intravenous administration.   
HDMP will be administered at 1gr/m2 on Days 1-3 of cycles 0 (with optional repeat for subset of 
patients who do not greater than low-risk for TLS after 1 cycle).  HDMP will be given over 90 
minutes and subsequent to the completed infusion, the infusion of Rituximab will be initiated. It 
will be diluted on 0.9% normal saline and administered directly into a vein over 90 minutes. 
7.1.3 
Adverse Reactions 
Adverse Reactions Significant (Frequency not defined). 
Cardiovascular: Arrhythmias, bradycardia, cardiac arrest, cardiomegaly, circulatory collapse, 
congestive heart failure, edema, fat embolism, hypertension, hypertrophic cardiomyopathy in 
premature infants, myocardial rupture (post MI), syncope, tachycardia, thromboembolism, 
vasculitis 
Central nervous system: Delirium, depression, emotional instability, euphoria, hallucinations, 
headache, intracranial pressure increased, insomnia, malaise, mood swings, nervousness, 
neuritis, personality changes, psychic disorders, pseudotumor cerebri (usually following 
discontinuation), seizure, vertigo 
Dermatologic: Acne, allergic dermatitis, alopecia, dry scaly skin, ecchymoses, edema, erythema, 
hirsutism, hyper-/hypopigmentation, hypertrichosis, impaired wound healing, petechiae, rash, 
skin atrophy, sterile abscess, skin test reaction impaired, striae, urticarial 
Endocrine & metabolic: Adrenal suppression, amenorrhea, carbohydrate intolerance increased, 
Cushing's syndrome, diabetes mellitus, fluid retention, glucose intolerance, growth suppression 
(children), hyperglycemia, hyperlipidemia, hypokalemia, hypokalemic alkalosis, menstrual 
irregularities, negative nitrogen balance, pituitary-adrenal axis suppression, protein catabolism, 
sodium and water retention. 
Gastrointestinal: Abdominal distention, appetite increased, bowel/bladder dysfunction (after 
intrathecal administration), gastrointestinal hemorrhage, gastrointestinal perforation, nausea, 

 
 
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pancreatitis, peptic ulcer, perforation of the small and large intestine, ulcerative esophagitis, 
vomiting, weight gain. 
Hematologic: Leukocytosis (transient). 
Hepatic: Hepatomegaly, transaminases increased. 
Local: Thrombophlebitis. 
Neuromuscular & skeletal: Arthralgia, arthropathy, aseptic necrosis (femoral and humoral heads), 
fractures, muscle mass loss, muscle weakness, myopathy (particularly in conjunction with 
neuromuscular disease or neuromuscular-blocking agents), neuropathy, osteoporosis, 
parasthesia, tendon rupture, vertebral compression fractures, weakness. 
Ocular: Cataracts, exophthalmoses, glaucoma, intraocular pressure increased. 
Renal: Glycosuria. 
Respiratory: Pulmonary edema. 
Miscellaneous: Abnormal fat disposition, anaphylactoid reaction, anaphylaxis, angioedema, 
avascular necrosis, diaphoresis, hiccups, hypersensitivity reactions, infections, secondary 
malignancy, venous thrombosis.  
7.1.4 
Management of HDMP Induced Hyperglycemia 
Subjects that received HDMP frequently present with hyperglycemia. This will be managed 
following institutional policies including consultation with Endocrinology or Diabetes clinic. A 
summary of management recommendations is the following: 
Subjects will have blood glucose (BG) measured on Days 1-3 of each Cycle during the days of 
HDMP administration. BG will be measured using a finger stick glucometer after the infusion of 
HDMP is completed. If a subject has a BG over 201mg/dl, glycemic control will be achieved by 
giving regular insulin subcutaneously according to the sliding scale below: 
BG - 201-250, 4U regular insulin SQ 
BG - 251-300, 6U regular insulin SQ  
BG - 301-350, 8U regular insulin SQ 
BG - 351-400, 10U regular insulin SQ 
Those subjects with BG >400 will be managed accordingly to institutional policies and at discretion 
of the treating physician. Management options will include hypoglycemic agents and insulin. 
Subjects with BG > 400 will have a fasting BG drawn on Day 3 of Cycle 0 when HDMP is 

 
 
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administered. If this fasting BG is > 200, the subject may be evaluated by an endocrinologist for 
recommendations regarding their blood sugar management. The same criteria will be applied to 
any subject with a fasting BG > 200 prior to HDMP administration; this practice will cover those 
subjects at risk for developing steroid induced diabetes.  Long lasting insulin will not be used, nor 
will the subject be monitored with finger sticks BG during the rest of the treatment cycle unless 
recommended by Endocrinology-Diabetes clinic. 
7.1.5 Dose Adjustment 
There are no recommended or planned methylprednisolone dose adjustments. Dosing can be 
held or stopped for toxicity, as above. 
7.2 
Rituximab (RITUXAN) – Background information for Rituxan follow in sections 7.2.1 
to 7.2.4. However, substitution of rituximab with other equivalent preparations is 
allowed, including the following: biosimilars of rituximab (including Ruxience or other 
FDA-approved rituximab product).  
 
7.2.1 Formulation, Storage, and Preparation 
RITUXAN vials [100 mg/10 mL single-use vials (NDC 50242-051-21) and 500 mg/50 mL single-
use vials (NDC 50242-053-06)] are stable at 2-8C (36F-46F). RITUXAN vials should be protected 
from direct sunlight. Do not freeze or shake.  
Rituxan is prescribed as a standard treatment, Supply: Commercial Supply 
7.2.2 Dosage and Administration 
Rituximab dosage: Cycle 0 (with HDMP): 100 mg day 1, 375 mg/m2 days 2-4. Cycles 2-6 (with 
Venetoclax): 500 mg/m2 day 1. 
 
Rituximab is administered as per local clinical standard practices. Specific recommendations are 
below: 
 
Preparation for Administration: Use appropriate aseptic technique. Withdraw the necessary 
amount of rituximab and dilute to a final concentration of 1 to 4 mg/mL into an infusion bag 
containing either 0.9% Sodium Chloride USP or 5% Dextrose in Water USP. Gently invert the bag 
to mix the solution. Discard any unused portion left in the vial. Parenteral drug products should 
be inspected visually for particulate matter and discoloration prior to administration.  Rituximab 
solutions for infusion are stable at 2° to 8°C (36° to 46°F) for 24 hours and at room temperature 
for an additional 12 hours. No incompatibilities between rituximab and polyvinylchloride or 
polyethylene bags have been observed. 
 
Administration: DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. 
Hypersensitivity reactions may occur.  Pre-medication, consisting of acetaminophen and 
diphenhydramine, may be administered before each infusion of rituximab.  Pre-medication may 
attenuate infusion-related events. Since transient hypotension may occur during rituximab 

 
 
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infusion, consideration should be given to withholding anti-hypertensive medications 12 hours 
prior to rituximab infusion.  
 
Rituximab will be administered as a split dose for the initial rituximab infusion. Routine 
premedications include diphenhydramine 25-50 mg orally or IV (or other antihistamine), and 
acetaminophen orally all administered approximately 30 – 60 minutes before the initiation of 
rituximab infusion. Antiemetics are not routinely administered with rituximab. 
 
Administration of rituximab will be performed in a setting with access to emergency equipment 
and personnel who are trained to monitor for and respond to medical emergencies. Patients will 
be monitored during each infusion of study treatment for any adverse effects. Rituximab infusion 
should be interrupted for severe reactions, and resumed when symptoms have completely 
resolved. Decrease infusion rate or interrupt infusion if infusion-related events occur. Employ a 
slower infusion rate (i.e., at least 50% reduction in rate) when therapy is resumed following 
complete resolution of symptoms. 
 
7.2.3 Adverse Reactions and Precautions 
Infusion Reactions  
RITUXAN can cause severe, including fatal, infusion reactions. Severe reactions typically 
occurred during the first infusion with time to onset of 30-120 minutes. RITUXAN-induced infusion 
reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, 
pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular 
fibrillation, cardiogenic shock, anaphylactoid events, or death.  
 
Premedicate patients with an antihistamine and acetaminophen prior to dosing. For RA and PV 
patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes 
prior to each infusion. Institute medical management (e.g. glucocorticoids, epinephrine, 
bronchodilators, or oxygen) for infusion reactions as needed. Depending on the severity of the 
infusion reaction and the required interventions, temporarily or permanently discontinue 
RITUXAN. Resume infusion at a minimum 50% reduction in rate after symptoms have resolved. 
Closely monitor the following patients: those with pre-existing cardiac or pulmonary conditions, 
those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of 
circulating malignant cells (≥25,000/mm3)  
 
Severe Mucocutaneous Reactions  
Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with RITUXAN. 
These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid 
dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these 
reactions has been variable and includes reports with onset on the first day of RITUXAN exposure. 
Discontinue RITUXAN in patients who experience a severe mucocutaneous reaction. The safety 
of re- administration of RITUXAN to patients with severe mucocutaneous reactions has not been 
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Hepatitis B Virus (HBV) Reactivation  
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure 
and death, can occur in patients treated with drugs classified as CD20-directed cytolytic 
antibodies, including RITUXAN. Cases have been reported in patients who are hepatitis B surface 
antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core 
antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have 
resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive and hepatitis B surface 
antibody [anti-HBs] positive).  
HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid 
increase in serum HBV DNA levels or detection of HBsAg in a person who was previously HBsAg 
negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., 
increase in transaminase levels. In severe cases increase in bilirubin levels, liver failure, and 
death can occur.  
Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment 
with RITUXAN. For patients who show evidence of prior hepatitis B infection (HBsAg positive 
[regardless of antibody status] or HBsAg negative but anti-HBc positive), consult with physicians 
with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral 
therapy before and/or during RITUXAN treatment.  
Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of 
hepatitis or HBV reactivation during and for several months following RITUXAN therapy. HBV 
reactivation has been reported up to 24 months following completion of RITUXAN therapy.  
In patients who develop reactivation of HBV while on RITUXAN, immediately discontinue 
RITUXAN and any concomitant chemotherapy, and institute appropriate treatment. Insufficient 
data exist regarding the safety of resuming RITUXAN treatment in patients who develop HBV 
reactivation. Resumption of RITUXAN treatment in patients whose HBV reactivation resolves 
should be discussed with physicians with expertise in managing HBV.  
Progressive Multifocal Leukoencephalopathy (PML)  
JC virus infection resulting in PML and death can occur in RITUXAN-treated patients with 
hematologic malignancies or with autoimmune diseases. The majority of patients with 
hematologic malignancies diagnosed with PML received RITUXAN in combination with 
chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune 
diseases had prior or concurrent immunosuppressive therapy. Most cases of PML were 
diagnosed within 12 months of their last infusion of RITUXAN.  
Consider the diagnosis of PML in any patient presenting with new-onset neurologic 
manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, 
brain MRI, and lumbar puncture.  
Discontinue RITUXAN and consider discontinuation or reduction of any concomitant 
chemotherapy or immunosuppressive therapy in patients who develop PML.  
Tumor Lysis Syndrome (TLS)  

 
 
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Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from 
tumor lysis, sometimes fatal, can occur within 12-24 hours after the first infusion of RITUXAN in 
patients with NHL. A high number of circulating malignant cells (>25,000/mm3) or high tumor 
burden, confers a greater risk of TLS.  
Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high 
risk for TLS. Correct electrolyte abnormalities, monitor renal function and fluid balance, and 
administer supportive care, including dialysis as indicated.  
Infections  
Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during 
and following the completion of RITUXAN-based therapy. Infections have been reported in some 
patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11 
months after rituximab exposure). New or reactivated viral infections included cytomegalovirus, 
herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and 
C. Discontinue RITUXAN for serious infections and institute appropriate anti-infective therapy. 
RITUXAN is not recommended for use in patients with severe, active infections.  
Cardiovascular Adverse Reactions  
Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic 
shock may occur in patients receiving RITUXAN. Discontinue infusions for serious or life-
threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of 
RITUXAN for patients who develop clinically significant arrhythmias, or who have a history of 
arrhythmia or angina. 
Renal Toxicity  
Severe, including fatal, renal toxicity can occur after RITUXAN administration in patients with 
NHL. Renal toxicity has occurred in patients who experience tumor lysis syndrome and in patients 
with NHL administered concomitant cisplatin therapy during clinical trials. The combination of 
cisplatin and RITUXAN is not an approved treatment regimen. Monitor closely for signs of renal 
failure and discontinue RITUXAN in patients with a rising serum creatinine or oliguria.  
Bowel Obstruction and Perforation  
Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in 
patients receiving RITUXAN in combination with chemotherapy. In postmarketing reports, the 
mean time to documented gastrointestinal perforation was 6 (range 1-77) days in patients with 
NHL. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur.  
Immunization  
The safety of immunization with live viral vaccines following RITUXAN therapy has not been 
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For RA patients, physicians should follow current immunization guidelines and administer non-
live vaccines at least 4 weeks prior to a course of RITUXAN.  
The effect of RITUXAN on immune responses was assessed in a randomized, controlled study in 
patients with RA treated with RITUXAN and methotrexate (MTX) compared to patients treated 
with MTX alone.  
A response to pneumococcal vaccination (a T-cell independent antigen) as measured by an 
increase in antibody titers to at least 6 of 12 serotypes was lower in patients treated with RITUXAN 
plus MTX as compared to patients treated with MTX alone (19% vs. 61%). A lower proportion of 
patients in the RITUXAN plus MTX group developed detectable levels of anti-keyhole limpet 
hemocyanin antibodies (a novel protein antigen) after vaccination compared to patients on MTX 
alone (47% vs. 93%).  
A positive response to tetanus toxoid vaccine (a T-cell dependent antigen with existing immunity) 
was similar in patients treated with RITUXAN plus MTX compared to patients on MTX alone (39% 
vs. 42%). The proportion of patients maintaining a positive Candida skin test (to evaluate delayed 
type hypersensitivity) was also similar (77% of patients on RITUXAN plus MTX vs. 70% of patients 
on MTX alone).  
Most patients in the RITUXAN-treated group had B-cell counts below the lower limit of normal at 
the time of immunization. The clinical implications of these findings are not known.  
Embryo-Fetal Toxicity  
Based on human data, RITUXAN can cause fetal harm due to B-cell lymphocytopenia in infants 
exposed to rituximab in-utero. Advise pregnant women of the risk to a fetus. Females of 
childbearing potential should use effective contraception while receiving RITUXAN and for 12 
months following the last dose of RITUXAN.  
7.2.4 Dose Adjustment 
There are no recommendations for or planned Rituximab dose adjustments. Doses can be held 
or skipped for toxicity, as summarized above. 
7.3 
Venetoclax 
 
7.3.1 Formulation, Storage 
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 must be stored at 15 to 25 degrees C (59-77 degrees F). Venetoclax is supplied from 
Research Supply, provided by Abbvie. 
7.3.2 Dosage and Administration 
Administration Guidelines from package insert: 

 
 
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Advise patients to take VENCLEXTA exactly as prescribed and not to change their dose or to 
stop taking VENCLEXTA unless they are told to do so by their doctor. Advise patients to take 
VENCLEXTA orally once daily, at approximately the same time each day, according to their 
doctor’s instructions and that the tablets should be swallowed whole with a meal and water without 
being chewed, crushed, or broken.  
Advise patients to keep VENCLEXTA in the original packaging during the first 4 weeks of 
treatment, and not to transfer the tablets to a different container.  
Advise patients that if a dose of VENCLEXTA is missed by less than 8 hours, to take the missed 
dose right away and take the next dose as usual. If a dose of VENCLEXTA is missed by more 
than 8 hours, advise patients to wait and take the next dose at the usual time.  
Advise patients not to take any additional dose that day if they vomit after taking VENCLEXTA, 
and to take the next dose at the usual time the following day.  
7.3.3 Adverse Reactions and Precautions 
The safety of single agent VENCLEXTA at the 400 mg recommended daily dose following a dose 
ramp-up schedule is based on pooled data of 240 patients with previously treated CLL from two 
phase 2 trials and one phase 1 trial. In the pooled dataset, the median age was 66 years (range: 
29 to 85 years), 95% were white, and 69% were male. The median number of prior therapies was 
3 (range: 1 to 12). The median duration of treatment with VENCLEXTA at the time of data analysis 
was approximately 10.3 months (range: 0 to 34.1 months). Approximately 46% of patients 
received VENCLEXTA for more than 48 weeks.  
The most common adverse reactions (≥20%) of any grade were neutropenia, diarrhea, nausea, 
anemia, upper respiratory tract infection, thrombocytopenia, and fatigue.  
Serious adverse reactions were reported in 43.8% of patients. The most frequent serious adverse 
reactions (≥2%) were pneumonia, febrile neutropenia, pyrexia, autoimmune hemolytic anemia 
(AIHA), anemia, and TLS.  
In combination with rituximab, serious adverse reactions were reported in 46% of patients, with 
the most frequent (≥5%) being pneumonia (9%). The most common adverse reactions (≥20%) of 
any grade were neutropenia (65%), diarrhea (40%), upper respiratory tract infection (39%), 
fatigue (22%), cough (22%), and nausea (21%). 
Discontinuations due to adverse reactions occurred in 8.3% of patients. The most frequent 
adverse reactions leading to drug discontinuation were thrombocytopenia and AIHA.  
Dosage adjustments due to adverse reactions occurred in 9.6% of patients. The most frequent 
adverse reactions leading to dose adjustments were neutropenia, febrile neutropenia, and 
thrombocytopenia.  
Specific warnings and precautions: 
Tumor Lysis Syndrome  

 
 
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Tumor lysis syndrome, including fatal events and renal failure requiring dialysis, has occurred in 
previously treated CLL patients with high tumor burden when treated with VENCLEXTA. 
VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for TLS in the initial 5- 
week ramp-up phase. 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 VENCLEXTA and at 
each dose increase.  
The risk of TLS is a continuum based on multiple factors, including tumor burden and 
comorbidities. Reduced renal function (CrCl <80 mL/min) further increases the risk. Patients 
should be assessed for risk and should receive appropriate prophylaxis for TLS, including 
hydration and anti-hyperuricemics. Monitor blood chemistries and manage abnormalities 
promptly. Interrupt dosing if needed. Employ more intensive measures (intravenous hydration, 
frequent monitoring, hospitalization) as overall risk increases.  
Concomitant use of VENCLEXTA with strong or moderate CYP3A inhibitors and P-gp inhibitors 
increases venetoclax exposure, may increase the risk of TLS at initiation and during ramp-up 
phase and may require VENCLEXTA dose adjustment. Strong CYP3A inhibitors are 
contraindicated during dose ramp-up. (see appendix C) 
For patients who take a strong or moderate CYP3A Inhibitor or P-gp inhibitor during steady daily 
dosage (after ramp-up phase), consider alternate medications or adjust VENCLEXTA dosage (as 
shown in the following table) and closely monitor for signs of VENCLEXTA toxicities. 
 
Neutropenia  
Grade 3 or 4 neutropenia occurred in 41% (98/240) of patients treated with VENCLEXTA. Monitor 
complete blood counts throughout the treatment period. Interrupt dosing or reduce dose for 

 
 
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severe neutropenia. Consider supportive measures including antimicrobials for signs of infection 
and use of growth factors (e.g., G-CSF).  
Immunization  
Do not administer live attenuated vaccines prior to, during, or after treatment with VENCLEXTA 
until B-cell recovery occurs. The safety and efficacy of immunization with live attenuated vaccines 
during or following VENCLEXTA therapy have not been studied. Advise patients that vaccinations 
may be less effective.  
Embryo-Fetal Toxicity  
Based on its mechanism of action and findings in animals, VENCLEXTA may cause embryo- fetal 
harm when administered to a pregnant woman. In an embryo-fetal study conducted in mice, 
administration of venetoclax to pregnant animals at exposures equivalent to that observed in 
patients at the recommended dose of 400 mg daily resulted in post-implantation loss and 
decreased fetal weight. There are no adequate and well-controlled studies in pregnant woman 
using VENCLEXTA. Advise females of reproductive potential to avoid pregnancy during 
treatment. If VENCLEXTA is used during pregnancy or if the patient becomes pregnant while 
taking VENCLEXTA, the patient should be apprised of the potential hazard to the fetus. 
7.3.4 Dose Adjustment and Management of Toxicity 
There is no specific antidote for venetoclax. For subjects who experience overdose, closely 
monitor and provide appropriate supportive treatment; during ramp-up phase interrupt venetoclax 
and monitor carefully for signs and symptoms of TLS along with other toxicities. Based on 
venetoclax large volume of distribution and extensive protein binding, dialysis is unlikely to result 
in significant removal of venetoclax. 
Dosing interruption and/or dose reduction may be required. See Table 3 for dose modifications 
for hematologic and other toxicities related to venetoclax. For subjects who have had a dosing 
interruption greater than 1 week during the first 5 weeks of ramp-up phase or greater than 2 weeks 
when at the daily dose of 400 mg, reassess for risk of TLS to determine if reinitiation with a 
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Management of Neutropenia 
Based on clinical observations with the 1st generation Bcl-2 inhibitor, navitoclax and in vitro 
colony-forming assays to assess Bcl-2-selective inhibitor effects on granulocyte precursors, it is 
possible that subjects treated with venetoclax might experience neutropenia.  Subjects with a 
history of neutropenia, who have received multiple prior therapies and/or have significant bone 
marrow involvement, may be at particular high risk.  If determined to be clinically indicated by the 
treating physician in compliance with ASCO guidelines, G-CSF may be administered during 
dosing of venetoclax.  The use of G-CSF support is strongly recommended for subjects with 
Grade 4 neutropenia (ANC < 500/μL).  If the subject presents with febrile neutropenia or Grade 4 
neutropenia for more than one week despite the use of optimal G-CSF support, venetoclax dosing 
should be interrupted until ANC recovery to > 500/μL.  Venetoclax may then be re-initiated at a 
Table 4. Venetoclax Recommended Dose Modification for Toxicities: 

 
 
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lower dose as defined in the following table.  Subjects not responding to G-CSF despite 
venetoclax interruption should undergo further evaluation to determine the etiology of the 
neutropenia. 
 
Table 5. Dose Modification for Toxicity during Venetoclax Treatment. 
Venetoclax Dose 
Reduced Dose 
400 mg 
300 mg 
300 mg 
200 mg 
200 mg  
100 mg 
100 mg 
50 mg 
50 mg 
Re-challenge at 20 mga 
a. Subjects who do not tolerate 20 mg will discontinue venetoclax, but may remain on study to 
assess for progression. 
 
Management of Lymphopenia 
There is a potential for clinically significant lymphopenia in this study.  If clinically indicated, anti-
infective prophylaxis should be implemented at the investigator's discretion, including appropriate 
prophylaxis for viral, fungal, bacterial or Pneumocystis infections.  Potential for drug-drug 
interactions should be considered.  Most anti-fungals are excluded and other commonly used 
agents may be cautionary or prohibited due to drug- drug interactions.   
Management of Hematologic Toxicities Other Than Neutropenia or Lymphopenia  
Venetoclax treatment should be withheld for any Grade 4 hematologic toxicity. Once the toxicity 
has resolved to Grade 1 or baseline level (recovery), venetoclax may be re-started at the same 
dose. If the toxicity recurs, the dose reduction guidelines in Table 4 should be followed when 
resuming study treatment following resolution. Additional dose reductions may occur at the 
discretion of the physician.  
Management of Non-Hematologic Toxicity  
Venetoclax treatment should be withheld for any clinically relevant Grade ≥3 non-hematologic 
toxicity. Once the toxicity has resolved to Grade 1 or baseline level (recovery), venetoclax may 
be re-started at the same dose. If the toxicity recurs, the dose reduction guidelines in Table 4 
should be followed when resuming study treatment following resolution. Additional dose 
reductions may occur at the discretion of the physician. 
Management of Decrease in Spermatogenesis 
Based on findings in a preclinical study, there is a potential for decreased spermatogenesis.  Male 
subjects should consider sperm banking before treatment with venetoclax if they are considering 
preservation of fertility. 
8.0 
Evaluation of Response 
 

 
 
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8.1 
Assessment of Tumor Burden 
Earlier clinical trials with venetoclax identified risk factors for tumor lysis syndrome, in particular 
measurements of tumor burden, including maximum lymph node diameter and absolute 
lymphocyte count. Subjects have been classified in 3 risk categories based on risk for developing 
medically concerning TLS with venetoclax administration. The tumor burden assessed by the 
nodal disease and absolute lymphocyte count has been used to define each category as below: 
 
Tumor Burden Category 
Criteria 
Low 
All measurable lymph nodes with the largest 
diameter < 5 cm by radiologic assessment 
AND ALC < 25k/uL 
Medium 
Any measurable lymph node with the largest 
diameter >/= 5 cm but < 10 cm by radiographic 
assessment OR ALC >/= 25k/uL 
High 
Any measurable lymph node with the largest 
diameter >/= 10 cm by radiologic assessment 
OR 
ALC >/= 25k/uL AND any measurable lymph 
node with the largest diameter >/= 5 cm 
 
8.2 
International Working Group CLL (iwCLL) Clinical Response Assessment 
Criteria for response will utilize the 2008 IWCLL Guidelines for response, which includes clinical, 
hematological, and bone marrow feature: 
Complete response: Requires all of the following for a period of at least two months from 
completion of therapy:  
• 
Absence of significant lymphadenopathy (e.g. >1.5cm in diameter) on physical exam; 
• 
No hepatomegaly or splenomegaly on physical exam; 
• 
Absence of constitutional symptoms; 
• 
Blood counts within the following values: lymphocytes < 4,000/uL, polymorphonuclear 
leukocytes >1500/μL, platelets >100,000/μL, hemoglobin >11.0 g/dL (untransfused); absences 
of clonal lymphocytes; 
• 
Bone marrow aspirate and biopsy must be normocellular for age with <30% of nucleated 
cells being lymphocytes. Lymphoid nodules must be absent. If the marrow is hypocellular, a 
repeat determination should be performed in one month. 
• 
The marrow should be analyzed by flow cytometry and/or immunohistochemistry to 
demonstrate that the marrow is free of clonal B- CLL cells. 
• 
A CT scan or MRI documenting absence of significant lymphadenopathy should be 
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• 
Patients who fulfill the criteria for CR after induction with the exception of a persistent 
cytopenia that is believed to be treatment related will be considered CR with incomplete bone 
marrow recovery (CRi). Additionally, patients who fulfill the criteria of CR with exception of 
having bone marrow lymphoid nodules will be considered a nodular PR. 
Partial response: Requires at least 2 of the following criteria from group A, and at least one of 
the criteria from group B, and for a period of at least 2 months: 
Group A: 
• 
≥50% decrease in peripheral absolute lymphocyte count from pretreatment value, or less 
than 4,000/uL 
• 
≥50% reduction in lymphadenopathy by examination or scan, or less than 1.5cm in size. 
• 
≥50% reduction in splenomegaly (cm below costal margin) by examination or scan 
• 
≥50% reduction hepatomegaly (total liver span) by examination or scan 
• 
50% reduction in marrow infiltrate or B-lymphoid nodules 
Group B: 
• 
Polymorphonuclear leukocytes ≥1,500/μL or 50% improvement from pre-treatment 
value; 
• 
Platelets >100,000/μL or 50% improvement from pre-treatment value; 
• 
Hemoglobin >11.0 g/dl (un-transfused) or 50% improvement from pre-treatment value. 
Progressive Disease: Characterized by any one of the following events:  
• 
≥50% increase in the products of at least two lymph nodes on two consecutive 
determinations two weeks apart (at least one lymph node must be ≥2 cm); appearance of new 
palpable lymph nodes. 
• 
≥50% increase in the size of the liver and/or spleen as determined by measurement 
below the respective costal margin; appearance of palpable hepatomegaly or splenomegaly, 
which was not previously present. 
• 
An increase in the number of blood lymphocytes by 50% or more with at least 5000 B 
lymphocytes per microliter. 
• 
Transformation to a more aggressive histology (i.e., Richter’s syndrome or 
prolymphocytic leukemia with ≥56% prolymphocytes). 
• 
During therapy, patients not fulfilling the above criteria for progressive disease but 
demonstrating a decrease in hemoglobin >2 gm/dL, decrease >50% in platelet or granulocyte 

 
 
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count will not be rated as progressive disease because these may occur as both a consequence 
of therapy. A bone marrow biopsy in such settings is strongly encouraged.  
• 
After treatment, The progression of any cytopenia (unrelated to autoimmune cytopenia), 
as documented by a decrease of Hb levels by more than 20 g/L (2 g/dL) or to less than 100 g/L 
(10 g/dL), or by a decrease of platelet counts by more than 50% or to less than 100 × 109/L 
(100 000/μL), which occurs at least 3 months after treatment, defines disease progression, if the 
marrow biopsy demonstrates an infiltrate of clonal CLL cells. 
Stable Disease: Patients who do not fulfill the criteria for complete or partial response as defined 
above but do not exhibit progressive disease will be considered as having stable disease. 
8.3 
Minimal Residual Disease Assessment  
 
Primary clinical efficacy analysis will be assessment of marrow for detectable CLL after 24 cycles 
(or sooner if treatment is discontinued early) by flow cytometry and immunohistochemistry per 
standard practice by local hematopathologist. A threshold of 0.01% will define undetectable 
versus detectable minimal residual disease (MRD).  
8.4 
Correlative Studies 
 
Limited correlative studies will be performed in the Kipps laboratory to correlate with clinical 
responses. Samples will be taken at baseline/screening and during treatment and after treatment. 
However, not all assays will be performed for all time points for all patients, based on sample 
availability and leukemic cell number. Specimens will be banked in the CLL research consortium 
tissue repository (see below). 
 
Isolation of leukemic cells by Ficoll-hypaque separation and assessment, which may include: 
• 
 ZAP-70 and Immunoglobulin heavy chain variable region (IgVH) mutation in CLL cells 
• 
Genomic assessment including Next generation sequencing or gene expression analysis 
 
Sampling Schedule: 
Blood sample for correlative studies will be collected at the following time points: 
• 
Day 1, cycle 0, pre-dose  
• 
Day 1, cycles 1, pre-dose  
• 
End of treatment visit 
 
Sample Collection and Handling Instructions 
Blood samples (approximately 40 ml on screening, 10 ml on other time points) will be collected in 
anti-coagulated (CPT) tubes for pharmacokinetic evaluation. The exact time that the sample is 
drawn along with the exact time that treatments are administered should be recorded.  
 
Sample Processing 
Samples will be processed in the translational lab of Dr. Thomas Kipps, with separation of plasma 
(for blood and apheresis products), followed by isolation of mononuclear cells by Ficoll differential 
centrifugation, respectively.  
 
Sample Labeling 

 
 
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Each tube must be labeled with the patient’s study number and the date and time the sample was 
drawn.  Data should be recorded on the Correlative Study Form, which must accompany the 
sample(s). 
 
8.5 
Specimen Banking 
Patient samples collected for this study will be retained at the UCSD School of Medicine (Kipps 
Laboratory). Specimens will be stored indefinitely or until they are used up. If future use is denied 
or withdrawn by the patient, best efforts will be made to stop any additional studies and to destroy 
the specimens. Samples will be labeled with the subject’s de-identified study number and 
collection date. The link between study number and medical record number will be viewed over a 
password secured encrypted server-client.   
 
The following information obtained from the subject's medical record may be provided to research 
collaborators when specimens are made available:   
• 
Diagnosis  
• 
Collection time in relation to study treatment 
• 
Clinical outcome – if available 
• 
Demographic data 
 
9.0 
Statistical Considerations 
9.1 
General Considerations 
This is a pilot/feasibility clinical trial, with the primary feasibility endpoint being debulking of tumor 
burden to meet criteria for low Tumor Burden upon the completion of cycle 0 
 
.The primary efficacy endpoint is the percentage of patients that have a decrease in tumor 
burden from levels of disease that meet “Medium/High-tumor burden” criteria to “Low tumor 
burden” criteria for disease burden following a maximum of 2 cycles of HDMP + Rituximab 
(called cycle 0 in the protocol schedule of events). 
Tumor burden will be assessed prior to initiation of therapy, and after each cycle of HDMP + 
Rituximab (maximum 2 cycles). See section 8.1 for the definition of these categories of tumor 
burden. 
The secondary endpoints are as follows: 
• 
Percentage of patients that have a decrease in tumor burden from levels of disease that 
meet “Medium/High-tumor burden” to meet “Low tumor burden” criteria for disease 
burden following 1 cycle of HDMP + Rituximab. 
• 
Percentage of patients that have a decrease in tumor burden from levels of disease that 
meet “Medium/High-tumor burden” to meet “Low tumor burden” criteria for disease 
burden following 2 cycles of HDMP + Rituximab. 
• 
Rate of laboratory TLS (from start of treatment until completion of venetoclax ramp-up). 
See Appendix B for definition and grading of TLS.  
• 
Rate of clinical TLS (from start of treatment until completion of venetoclax ramp-up) 

 
 
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• 
Adverse events by CTCAE4 definitions and iwCLL definition for hematologic AEs (see 
section 10.0 for iwCLL definition of hematologic AE). 
• 
Overall Response rate (ORR), Partial Response (PR) rate, and Complete response (CR) 
rate per iwCLL criteria after 9 months of venetoclax and at completion of treatment. See 
section 8.2 for iwCLL criteria for definitions of each level of response. ORR includes all 
patients who have either a PR or CR. 
• 
Undetectable minimal residual disease (MRD) rate based on bone marrow biopsy after 9 
months of venetoclax, and at completion of treatment. Undetectable MRD is defined as 
less than 0.01% CLL cells. 
 
9.2 
Sample size justification 
Seventeen patients are enrolled to evaluate the primary endpoint. A success rate of 60% of 
patients adequately debulking (defined as having low Tumor Burden at the end of cycle 0) will be 
considered compelling, establishing the feasibility of this approach, and support further studies. 
A success rate of 30% would be not compelling for further studies. With 17 patients, the study is 
adequately powered to evaluate this. A Simon’s two-stage minimax design is utilized, with 
stopping for futility if an insufficient number of patients are debulked by HDMP/Rituximab. This 
design will have 80% power to reject the null hypothesis at 4% significance level and conclude 
that the true debulking rate at cycle 0 is above 30%, if the observed rate is ≥60%. Note that if 
patients are still meeting med/high tumor burden, they may repeat cycle 0 once more. 
The null hypothesis that the true debulking rate is 30% at Cycle 0 will be tested against 
a one-side alternative. In the first stage, 10 patients will be accrued. The study 
enrollment will be put on hold for interim analysis until the response results for Stage 1 
patients are known. If there are 2 or fewer responses (patients achieving low Tumor 
Burden) in these 10 patients, the study will be stopped. Otherwise, 7 additional patients 
will be accrual for a total of 20. The null hypothesis will be rejected if 9 or more 
responses are observed in 17 patients.   
 
Early stopping probability: Under this design, if the null hypothesis is true, 
the probability of stopping the trial early will be 38.3%. The sample size 
calculation was done using PASS version 14.0.3 (released September 22, 
2015). Sample size calculation did not incorporate the safety endpoint. 
Statistics for safety outcomes will be presented descriptively.   
 
Accrual and study duration 
 
We expect to accrue 1-2 patients every month. All patients will be accrued 
within 12-24 months. Patients will be followed for 24 months. The total 
duration of this study will be about 36 months. 
 

 
 
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9.3 
Analysis Populations 
The Treated population will include all treated subjects who receive at least 1 dose of 
methylprednisone or rituximab.  
9.4 
Demographics and Baseline Characteristics 
Subject baseline characteristics will be listed and summarized for the Treated population, 
including subject age, gender, prior therapy, IgVH mutational status, and molecular profiling 
including cytogenetics and mutation testing (if available).  
9.5 
Definition of Baseline Measurements 
Baseline measurements will be the last measurement for the corresponding variable prior to the 
first study drug dose. 
9.6 
Study Drug Exposure, Concomitant Medications, and Nonprotocol Cancer therapy 
Descriptive information will be provided regarding drug exposure: the number of cycles of 
HDMP + Rituximab, the number of months of venetoclax treatment, the number of prescribed 
dose modifications and interruptions; and the reasons for dose modifications and interruptions. 
Concomitant medications will be listed and summarized as appropriate. 
Subsequent non-protocol cancer therapy will be listed and summarized as appropriate, if 
available. 
9.7 
General considerations of statistical analyses 
 
The statistical analysis of the data obtained for this study will be documented 
using summary tables and subject data listings. Continuous variables will be 
summarized using descriptive statistics, specifically the number of 
observations, mean, median, standard deviation, and minimum and maximum 
values. Categorical variables will be summarized by frequencies and 
percentages. For proportions, a 95% confidence interval will be calculated 
using the exact method. For survival outcomes, median survival times 
together with their 95% confidence intervals will be estimated with the Kaplan-
Meier method, and report number of events.  
 
All statistical tests will be two-sided at the 5% significance levels, unless otherwise noted. 
 
9.7.1 
Primary Efficacy Analyses 
If applicable, “Intention-to-treat” analyses will be performed for the primary 
efficacy endpoint. To be specific, if the endpoint for a subject cannot be 

 
 
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assessed (for example, a subject drops out early prior to the tumor burden 
assessments due to any reason), it will be considered to be an event that does 
not favor the study therapy (e.g., disease progression for the primary 
outcome).  
 
Primary efficacy analysis includes interim efficacy analysis and final efficacy analysis for 
the primary endpoint.  
  
The interim efficacy analysis will be conducted at the end of Stage 1. The study 
enrollment will be put on hold for interim analysis until debulking response results for 
Stage 1 patients are known. 
 
The final efficacy analysis will calculate the UMVUE estimate, p-value and 95% CI for 
the primary endpoint. 10-11 The calculation will be performed using R clinfun package 
(www.r-project.org).  
 
9.7.2 
Secondary Analyses 
 
Analysis for the secondary analyses will use the data combined from both the stages. Linear 
models, logistic models or Cox models will be used to adjust for covariates including the stage 
variable and whether a patient has a debulking response after the first cycle.  
9.8 
Analysis of Safety 
The safety outcomes of this study include the frequency of adverse events (AE) and severe 
adverse events (as defined in section 10.0). Descriptive statistics will be presented, including 
the number and percentage of subjects with any AE.  
Summaries will be prepared for all treatment emergent AEs, including: 
- 
Study-drug-related AEs 
- 
AEs that are Grade 3, 4, or 5 in severity 
- 
AEs leading to dose modification 
- 
AEs leading to study drug discontinuation 
- 
SAEs 
Safety analyses will be performed for all patients having received at least one dose 
of study treatment. The proportion of subjects experiencing adverse events, serious 
adverse events, and treatment delays will be summarized. Tolerability will be 
assessed based on dosage delays and discontinuation due to adverse events.   
 
All AEs will be listed, documenting the course, outcome, severity, and relationship to the study 
treatment. Incidence rates of AEs and the proportion of subjects prematurely withdrawn from the 
study due to AEs will be shown. 

 
 
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9.9 
Handling of Dropouts and Missing Data 
No data imputation will be performed. 
 
10.0 
Adverse Event Reporting 
 
The investigator will monitor each subject for clinical and laboratory evidence of adverse events 
on a routine basis throughout the study. The investigator will assess and record any adverse 
event in detail, including the date of onset, event diagnosis (if know) or sign/symptom, severity, 
time course (end date, ongoing, intermittent), relationship of the adverse event to study drug, and 
any action(s) taken.  
An adverse event (AE) is defined as 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. A treatment-emergent adverse event is defined as any 
AE reported by a subject with onset or worsening from the time that the first dose of HDMP + 
Rituximab is administered until 30 days have elapsed following the discontinuation of study drug 
administration. 
The severity of non-hematologic adverse events will be rated according to National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE Version 4.0).  
The severity of hematologic adverse events will be rated according to 2008 iwCLL grade scale. 
As is the case with virtually all of the hematological malignancies, an evaluation of the 
hematological toxicity in patients with CLL must consider the high frequency of marrow 
involvement and consequent medullar compromise at the initiation of therapy. A substantial 
proportion of patients will have hematological parameters within the range of Grade 2 – 4 
hematological toxicity before therapy is given; therefore, a modified schema will be used to 
monitor hematological toxicity in patients with CLL. The modified hematological toxicity schema 
(taken directly from Hallek et al, 2008 IWCLL criteria) is displayed: 

 
 
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If the reported AE increases in severity, the initial adverse events should be given final outcome 
date and a new adverse event must be reported to reflect the change in severity.  
SAE definition: 
An AE should be classified as an SAE if the following criteria are met: 
• 
It results in death (i.e., the AE actually causes or leads to death) 
• 
It is life threatening (i.e., the AE, in the view of the investigator, places the patient at immediate 
risk of death. It does not include an AE that, had it occurred in a more severe form, might have 
caused death). 

 
 
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• 
It requires or prolongs inpatient hospitalization 
• 
It results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the patient’s ability to conduct normal life functions) 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
the IMP 
• 
It is considered a significant medical event by the investigator based on medical judgment 
(e.g., may jeopardize the patient or may require medical/surgical intervention to prevent one 
of the outcomes listed above) 
SAE Reporting: 
Events meeting the following criteria need to be submitted to the FDA as expedited IND Safety 
Reports according to the following guidance and timelines: 
7 Calendar Day Telephone or Fax Report 
The Investigator is required to notify the FDA of any fatal or life-threatening AE that is unexpected 
and assessed by the investigator to be possibly related to the use of HDMP, Rituximab, and 
venetoclax. An unexpected AE is one that is not already described in the venetoclax investigator 
brochure or the methylprednisolone and rituximab prescribing information.  Such reports are to 
be telephoned or faxed to the FDA within 7 calendar days of first learning of the event. 
15 Calendar Day Written Report 
The Investigator is also required to notify the FDA and all participating investigators, in a written 
IND Safety Report, of any serious, unexpected AE that is considered reasonably or possibly 
related to the use of HDMP, rituximab, or venetoclax.  An unexpected AE is one that is not already 
described in the venetoclax investigator brochure or the methylprednisolone and rituximab 
prescribing information. 
Written IND Safety reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32.  All safety reports previously filed by the investigator with the IND 
concerning similar events should be analyzed and the significance of the new report in light of the 
previous, similar reports commented on. 
Written IND safety reports with analysis of similar events are to be submitted to the FDA, Abbvie, 
and all participating investigators within 15 calendar days of first learning of the event. MedWatch 
3500 form or alternative formats will be used (e.g., summary letter).  
Contact Information for IND Safety Reports 
FDA fax number for IND safety reports: 
Fax: 1 (800) FDA 0178 
 

 
 
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In addition to compliance with all FDA reporting requirements pursuant to 21 CFR 312, the 
Principal Investigator shall: 
d) Report to Abbvie all serious adverse events experienced by a study subject receiving an 
AbbVie product within 24 hours of learning of the event regardless of the relationship of 
the event to the AbbVie product.  Principal Investigator shall make available to AbbVie 
promptly such records as may be necessary and pertinent to investigate any such event, 
if specifically requested by AbbVie; and in addition, report all non-serious adverse events 
of tumor lysis syndrome for studies involving ABT-199. 
e) Copy AbbVie on the submission to the FDA of events meeting the definition of IND safety 
reports at the time of submission to the Agency; and, 
f) Notify AbbVie upon any subjects receiving an AbbVie Product whose pregnancy has 
resulted in a negative outcome or untoward event during the course of pregnancy or upon 
delivery. 
AbbVie’s contact for reporting serious adverse drug experiences, pregnancy experiences, non-
serious adverse events of tumor lysis syndrome, and communication of FDA submissions of IND 
safety reports shall be PPDINDPharmacovigilance@abbvie.com 
Product Complaints:  In addition to compliance with all FDA requirements pursuant to 21 CFR 
211 and 21 CFR 820, Principal Investigator will report to AbbVie within 24 hours any suspected 
quality defect in an AbbVie Product or its AbbVie-provided packaging, labeling, or medical device 
component (collectively, “Product Complaint”).  Principal Investigator will report Product 
Complaints that involve an AbbVie Product, whether AbbVie has supplied the AbbVie Product 
used in the Study or not.  AbbVie’s contact for reporting Product Complaints shall be 
RD_PQC_QS@abbvie.com 
 
11.0 
Study Management 
11.1 Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), subjects who have 
provided written informed consent must also sign a subject authorization to release medical information 
to the study Sponsor and allow a regulatory authority, or Institutional Review Board access to subject’s 
medical information relevant to the study. 
11.2 Data and Safety Monitoring 
In addition to adverse event monitoring and clinical oversight by the Study Chair, site principal investigator 
and co-investigators, quality assurance of the study will be performed by the clinical trials office internal 
monitor. Monitoring frequency will be after 7 patients (part 1 of the trial) and then annually. 
 
This study will also use the UCSD Moores Cancer Center Data Safety and Monitoring Board (DSMB) to 

 
 
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provide oversight in the event that this treatment approach leads to unforeseen toxicities. Data from this 
study will be reported every year, and will include: 
1) 
the protocol title, IRB protocol number, and the activation date of the study.  
2) 
the number of patients enrolled to date  
3) 
the date of first and most recent patient enrollment 
4) 
a summary of all adverse events regardless of grade and attribution   
5) 
a response evaluation for evaluable patients when available 
6) 
a summary of any recent literature that may affect the ethics of the study.  
11.3 Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol 
and amendments, IRB correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all reports 
and records necessary for the evaluation and reconstruction of the clinical research study. 
Study documents should be kept on file until three years after the completion and final study report of 
this investigational study. 
11.4 Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance with 
Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Principal Investigator 
is responsible for personally overseeing the treatment of all study patients. The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study staff members, adhere to 
the study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
12.0 
References 
1. 
Kipps TJ, Stevenson FK, Wu CJ, Croce CM, Packham G, Wierda WG, et al. Chronic 
lymphocytic leukaemia. Nat Rev Dis Primers. 2017;3:17008. 
2. 
Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, et al. First-line 
chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, 
and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an 
international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 
2016;17(7):928-42. 
3. 
Fischer K, Cramer P, Busch R, Bottcher S, Bahlo J, Schubert J, et al. Bendamustine in 
combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: 
a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin 
Oncol. 2012;30(26):3209-16. 

 
 
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4. 
Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, et al. Addition of 
rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: 
a randomised, open-label, phase 3 trial. Lancet. 2010;376(9747):1164-74. 
5. 
Jain P, Thompson PA, Keating M, Estrov Z, Ferrajoli A, Jain N, et al. Long-term 
outcomes for patients with chronic lymphocytic leukemia who discontinue ibrutinib. Cancer. 
2017;123(12):2268-73. 
6. 
O'Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K, et al. Single-Agent 
Ibrutinib in Treatment-Naive and Relapsed/Refractory Chronic Lymphocytic Leukemia: A 5-Year 
Experience. Blood. 2018. 
7. 
O'Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, Blum KA, et al. Ibrutinib as 
initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic 
lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15(1):48-58. 
8. 
Seymour JF, Ma S, Brander DM, Choi MY, Barrientos J, Davids MS, et al. Venetoclax 
plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. 
Lancet Oncol. 2017;18(2):230-40. 
9. 
Castro JE, Sandoval-Sus JD, Bole J, Rassenti L, Kipps TJ. Rituximab in combination 
with high-dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic 
lymphocytic leukemia. Leukemia. 2008;22(11):2048-53. 
10. Jung SH, Kim KM. On the estimation of the binomial probability in multistage clinical trials. 
Statistics in Med. 2004; 23: 881-96. 
 
11. Koyama T, Chen H.   Proper inference from Simon’s two-stage designs. Statistics in Med. 
2008; 27: 3145-54. 
 
13.0 
Appendices 
 
Appendix A: ECOG Performance Status 
Developed by the Eastern Cooperative Oncology Group, Robert L. Comis, MD, Group Chair.* 
GRADE ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol. 1982;5:649-655. 

 
 
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Appendix B: Tumor Lysis Syndrome Definitions 
Cairo-Bishop Clinical Tumor Lysis Syndrome Definition and Grading 
Complication 
Grade 
0 
1 
2 
3 
4 
5 
Creatinine*,†  
≤ 1.5 × 
ULN 
1.5 
× 
ULN 
1.5 – 3.0 × ULN 
> 3.0 – 6.0 × 
ULN 
> 
6.0 
× 
ULN 
Death 
Cardiac 
Arrhythmia* 
None 
Intervent
ion 
not 
indicated 
Non-urgent 
medical 
intervention 
indicated 
Symptomatic 
and 
incompletely 
controlled 
medically 
or 
controlled with 
device 
(e.g., 
defibrillator) 
Life-
threatening 
(e.g., 
arrhythmia 
associated 
with 
CHF, 
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 
ULN = upper limit of normal; CHF = congestive heart failure; ADL = activities of daily living 
* 
Not directly or probably attributable to therapeutic agent. 
† 
If no institutional ULN is specified, age/sex ULN creatinine may be defined as follows:  Cairo-Bishop Clinical Tumor Lysis 
Syndrome Definition and Grading. 
Note: 
Laboratory tumor lysis syndrome and at least one clinical complication. 
 
Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome 
This definition comprises ≥ 2 of the following metabolic abnormalities occurring within 7 days from 
first dose at initial dosing or at dose escalation. 
Element 
Value 
Change from Baseline 
Uric Acid 
≥ 476 μmol/L or 8 mg/dL 
25% increase 
Potassium 
≥ 6.0 mmol/L or 6 mEq/L 
25% increase 
Inorganic Phosphorus 
≥ 1.45 mmol/L 
25% increase 
Calcium 
≤ 1.75 mmol/L 
25% decrease 
 

 
 
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Howard Definition of Laboratory Tumor Lysis Syndrome 
This definition comprises ≥ 2 of the following metabolic abnormalities. 
Element 
Value 
Uric Acid 
≥ 476 μmol/L or 8 mg/dL 
Potassium 
≥ 6.0 mmol/L or 6 mEq/L 
Inorganic Phosphorus 
≥ 1.45 mmol/L 
Calcium 
≤ 1.75 mmol/L 
 
 
 
 
 

 
 
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Appendix C.  Sample List of Excluded and Cautionary Medications 
Excluded during ramp-up phase and Cautionary at the Cohort Designated Dose:  
Strong CYP3A inducers - avasimibe, carbamazepine, enzalutamine, mitotane, phenytoin, rifampin, St. John's wort 
Moderate CYP3A inducers - bosentan, efavirenz, etravirine, modafinil, nafcillin 
Strong CYP3A inhibitors - boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, elvitegravir/ritonavir, 
idelalisib,* indinavir, itraconazole, ketoconazole,  mibefradil, lopinavir/ritonavir, nefazodone, nelfinavir, ritonavir, 
paritaprevir/ritonavir combinations, posaconazole, saquinavir, telaprevir, telithromycin, tipranavir/ritonavir, voriconazole 
Moderate CYP3A inhibitors - amprenavir, aprepitant, atazanavir, cimetidine, ciprofloxacin, clotrimazole, crizotinib*, 
cyclosporine*, 
darunavir/ritonavir, 
diltiazem1, 
erythromycin, 
fluconazole, 
fosamprenavir, 
imatinib*, 
isavuconazole,  tofisopam,  verapamil 
Cautionary 
Warfarin** 
P-gp substrates 
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus*, fexofenadine, lapatinib*, loperamide, 
maraviroc, nilotinib*, ranolazine, saxagliptin, sirolimus*, sitagliptin, talinolol, tolvaptan, topotecan* 
BCRP substrates 
Methotrexate*, mitoxantrone*,  irrinotecan*, lapatinib*, rosuvastatin, sulfasalazine, topotecan* 
OATP1B1/1B3 substrates 
Atrasentan, atorvastatin, ezetimibe, fluvastatin, glyburide, rosuvastatin, simvastatin acid, pitavastatin, pravastatin, 
repaglinide, telmisartan,  valsartan, olmesartan 
P-gp inhibitors 
Amiodarone, captopril, carvedilol, dronedarone, felodipine, quercetin, quinidine, ronalzine, ticagrelor 
BCRP inhibitors 
Geftinib* 
Note that this is not an exhaustive list. For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm080499.htm  
In addition to the medications listed in this table, subjects receiving venetoclax should not 
consume grapefruit, grapefruit products, Seville oranges (including marmalade containing 
Seville oranges) or Star fruits. 
* These are anticancer agents and not allowed on trial. 
** Closely monitor the international normalized ratio (INR). 
1 Moderate CYP3A inhibitor per venetoclax FDA USPI. 

 
 
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Appendix D:  Risk Assessment and Prophylaxis for Tumor Lysis Syndrome: 
Recommendations for Venclexta Prescribing Information 
Venclexta can cause rapid reduction in tumor and thus poses a risk of TLS in the 5-week ramp-
up phase. 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 Venclexta and at each dose increase. 
The risk of TLS is a continuum based on multiple factors, including tumor burden and 
comorbidities. Perform tumor burden assessments, including radiographic evaluation (e.g. CT 
scan), assess blood chemistry (potassium, uric acid, phosphorous, calcium, and creatinine) in all 
patients and correct pre-existing abnormalities prior to initiation of treatment with venetoclax. 
Reduced renal function (creatinine clearance < 80 ml/min) further increases the risk. The risk may 
decrease as tumor burden decreases.  
The following table describes the recommends TLS prophylaxis and monitoring during venetoclax 
treatment based on tumor burden determination from clinical trial data. 

 
 
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Tumor Burden Categories and TLS Monitoring and Risk Mitigation Recommendations 
Tumor 
Burden 
Category 
Tumor Burden at 
start 
of 
venetoclax 
Prophylaxis 
 
Blood 
chemistry 
monitoring c,d 
 
 
Hydration a 
Anti-
hyperuricemics 
Setting and Freqeuncy of 
Assessments 
Low 
All measurable LN 
with 
the 
largest 
diameter < 5 cm by 
radiologic 
assessment 
AND 
ALC < 25 × 109/L 
Oral (1.5 – 2L) 
Allopurinol b 
Outpatient 
- Pre-dose, 6 to 8 hours, 24 
hr at first dose of 20 mg and 
50 mg 
- Pre-dose at subsequent 
ramp-up doses 
Medium 
Any measurable LN 
with 
the 
largest 
diameter ≥ 5 cm but < 
10 cm by radiologic 
assessment OR ALC 
≥ 25 × 109/L 
Oral (1.5 – 2L) 
and consider 
additional 
intravenous 
Allopurinol 
Outpatient 
- Pre-dose, 6 to 8 hours, 24 
hr at first dose of 20 mg and 
50 mg 
- Pre-dose at subsequent 
ramp-up doses 
- Consider hospitalization 
for patients with CrCl < 80 
ml/min at first dose of 20 mg 
and 50 mg; see below for 
monitoring in hospital 
High 
Any measurable LN  
with 
the 
largest 
diameter ≥ 10 cm by 
radiologic 
assessment  
OR 
ALC ≥ 25 × 109/L 
AND any measurable 
LN with the largest 
diameter ≥ 5 cm  
Oral (1.5 – 2L) 
and intravenous 
(150 – 200 ml/hr 
as tolerated) 
Allopurinol; 
consider 
rasburicase if 
baseline uric 
acid is elevated 
In hospital at first dose of 20 
mg and 50 mg 
- Pre-dose, 4, 8, 12 and 24 
hours 
 
Outpatient at subsequent 
ramp-up doses 
- pre-dose, 6 to 8 hours, 24 
hours. 
ALC = absolute lymphocyte count; LN = lymph node 
aAdminister intravenous hydration for any patient who cannot tolerate oral hydration. 
bStart allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of VENCLEXTA. cEvaluate 
blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); review in real time. 
dFor patients at risk of TLS, monitor blood chemistries at 6 to 8 hours and at 24 hours at each 
subsequent ramp-up dose.  
 

 
 
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Any subject, who at any dose level develops clinically significant electrolyte abnormalities, must 
have their subsequent venetoclax dose held until the electrolyte abnormalities resolve.  Electrolyte 
changes should undergo aggressive management and further monitoring as per Appendix E 
(Recommendations for Initial Management of Electrolyte Abnormalities and Prevention of Tumor 
Lysis Syndrome [TLS]).  The subject may resume dosing based on a risk assessment (including 
tumor burden status), as determined by the investigator.  All subjects must receive the intended 
dose for at least 7 days before increasing to the next higher dose. 
 
 
 

 
 
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Appendix E: Recommendations for Initial Management of Electrolyte Abnormalities and 
Prevention of Tumor Lysis Syndrome (TLS) 
 
Section 1:  First Dose of Venetoclax on study or Dose Escalation 
• 
Within the first 24 hours after either the first dose on study or dose escalation, if any 
laboratory criteria below are met, the patient should be hospitalized for monitoring and 
the investigator notified.  No additional venetoclax doses should be administered until 
resolution.  A rapidly rising serum potassium is a medical emergency. 
• 
IV fluids (e.g., D5 1/2 normal saline) should be initiated at a rate of at least 1 mL/kg/hr 
rounded to the nearest 10 mL (target 150 to 200 mL/hr; not < 50 mL/hr).  Modification 
of fluid rate should also be considered for individuals with specific medical needs. 
• 
Monitor for symptoms or signs of TLS (e.g., fever, chills, tachycardia, nausea, 
vomiting, diarrhea, diaphoresis, hypotension, muscle aches, weakness, paresthesias, 
mental status changes, confusion and seizures).  If any clinical features are observed, 
recheck potassium, phosphorus, uric acid, calcium and creatinine within 1 hour STAT. 
• 
Vital signs should be taken at time of all blood draws or any intervention. 
• 
The management recommendations below focus on the minimum initial responses 
required.  If a diagnosis of TLS is established, ongoing intensive monitoring and multi-
disciplinary management will be per institutional protocols. 
 
In addition to the recommendations in the table below, for subjects receiving the first dose of 
venetoclax: 
• 
For potassium increase ≥ 0.5 mmol/L from baseline, or any value > 5.0 mmol/L, 
recheck potassium, phosphorus, uric acid, calcium and creatinine within 1 hour STAT 
and follow first guideline. 
• 
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 within 1 
hour STAT. 
 
 
Abnormality 
Management Recommendations 
Hyperkalemia (Including Rapidly Rising Potassium) 
Potassium 
≥ 
0.5 
mmol/L 
increase 
from 
prior 
value 
(even if 
potassium 
within 
normal limits [WNL]) 
• 
Recheck potassium, phosphorus, uric acid, calcium 
and creatinine in 1 hour STAT.  If further ≥ 0.2 mmol/L 
increase in potassium, but still < upper limit of normal 
(ULN), manage as per potassium ≥ ULN.  Otherwise 
recheck in 1 hour.  
• 
Resume per protocol testing if change in potassium 
is < 0.2 mmol/L, and potassium < ULN, and no other 
evidence of tumor lysis. 

 
 
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Abnormality 
Management Recommendations 
• 
At the discretion of the investigator, may recheck prior 
to hospitalization.  If stable or decreased, and still 
WNL, hospitalization is at the discretion of the 
investigator.  Potassium, phosphorus, uric acid, 
calcium and creatinine must be rechecked within 24 
hours.  
Potassium > upper limit of 
normal 
• 
Perform STAT ECG and commence telemetry. 
• 
Nephrology 
(or 
other 
acute 
dialysis 
service) 
notification with consideration of initiating dialysis. 
• 
Administer Kayexalate 60 g (or Resonium A 60 g). 
• 
Administer furosemide 20 mg IV × 1. 
• 
Administer calcium gluconate 100 to 200 mg/kg IV 
slowly if there is ECG/telemetry evidence of 
life-threatening arrhythmias. 
• 
Recheck potassium, phosphorus, uric acid, calcium 
and creatinine in 1 hour STAT. 
o 
If potassium < ULN 1 hour later, repeat 
potassium, phosphorus, uric acid, calcium and 
creatinine 1, 2 and 4 hrs., if no other evidence of 
tumor lysis. 
Hyperkalemia (Including Rapidly Rising Potassium) (continued) 
Potassium 
≥ 
6.0 
mmol/L 
(6.0 mEq/L) 
and/or 
symptomatic 
(e.g., 
muscle 
cramps, 
weakness, 
paresthesias, nausea, vomiting, 
diarrhea) 
• 
Perform STAT ECG and commence telemetry. 
• 
Nephrology 
(or 
other 
acute 
dialysis 
service) 
assessment with consideration of initiating dialysis. 
• 
Administer Kayexalate 60 g (or Resonium A 60 g). 
• 
Administer furosemide 20 mg IV × 1. 
• 
Administer insulin 0.1 U/kg IV + D25 2 mL/kg IV. 
• 
Administer sodium bicarbonate 1 to 2 mEq IV push. 
o 
If sodium bicarbonate is used, rasburicase 
should not be used as this may exacerbate 
calcium phosphate precipitation. 
• 
Administer calcium gluconate 100 to 200 mg/kg IV 
slowly if there is ECG/telemetry evidence of 
life-threatening arrhythmias.  Do not administer in 
same IV line as sodium bicarbonate. 
• 
Recheck potassium, phosphorus, uric acid, calcium 
and creatinine every hour STAT. 
Hyperuricemia 
Uric 
acid 
≥ 
8.0 
mg/dL 
(476 µmol/L) 
• 
Consider 
rasburicase 
(dose 
based 
on 
local 
guidelines and/or institutional standards). 
o 
If rasburicase is used, sodium bicarbonate 
should not be used as this may exacerbate 
calcium phosphate precipitation. 
• 
Recheck potassium, phosphorus, uric acid, calcium 
and creatinine in 1 hr STAT. 
Uric 
acid 
≥ 
10 
mg/dL 
(595 µmol/L) 
 
• 
Administer rasburicase (dose based on local 
guidelines and/or institutional standards). 
o 
When rasburicase is used, sodium bicarbonate 

 
 
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Abnormality 
Management Recommendations 
OR 
 
Uric 
acid 
≥ 
8.0 
mg/dL 
(476 µmol/L) with 25% increase 
and 
creatinine 
increase 
≥ 0.3 mg/dL (≥ 0.027 mmol/L) 
from pre-dose level 
should not be used as this may exacerbate 
calcium phosphate precipitation. 
• 
Notify nephrology (or other acute dialysis service). 
• 
Recheck potassium, phosphorus, uric acid, calcium 
and creatinine in 1 hour STAT. 
o 
If uric acid < 8.0 mg/dL 1 hour later, repeat 
potassium, phosphorus, uric acid, calcium and 
creatinine 2 and 4 hrs., later, if no other evidence 
of tumor lysis. 
Hypocalcemia 
Calcium 
≤ 
7.0 
mg/dL 
(1.75 mmol/L) 
 
AND 
 
Patient 
symptomatic 
(e.g., muscle 
cramps, 
hypotension, tetany, cardiac 
arrhythmias) 
• 
Administer calcium gluconate 50 to 100 mg/kg IV 
slowly with ECG monitoring. 
• 
Telemetry. 
• 
Recheck potassium, phosphorus, uric acid, calcium 
and creatinine in 1 hr STAT. 
o 
If calcium normalized 1 hour later, repeat 
potassium, phosphorus, uric acid, calcium and 
creatinine 2 and 4 hrs., later, if no other evidence 
of tumor lysis. 
• 
Calculate corrected calcium and check ionized 
calcium if albumin low. 
Hyperphosphatemia 
Phosphorus 
≥ 
5.0 
mg/dL 
(1.615 
mmol/L) 
with 
≥ 0.5 mg/dL 
(0.16 mmol/L) 
increase 
• 
Administer a phosphate binder (e.g., aluminum 
hydroxide, calcium carbonate, sevelamer hydroxide, 
or lanthanum carbonate). 
• 
Nephrology 
(or 
other 
acute 
dialysis 
service) 
notification 
(dialysis 
required 
for 
phosphorus 
≥ 10 mg/dL). 
• 
Recheck potassium, phosphorus, uric acid, calcium 
and creatinine in 1 hr STAT. 
o 
If phosphorus < 5.0 mg/dL 1 hour later, repeat 
potassium, phosphorus, uric acid, calcium and 
creatinine 2 and 4 hrs., later, if no other evidence 
of tumor lysis. 
Creatinine 
Increase ≥ 25% from baseline 
• 
Start or increase rate of IV fluids. 
• 
Recheck potassium, phosphorus, uric acid, calcium 
and creatinine in 1 to 2 hours STAT. 
 

 
 
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Section 2:  Ongoing Dosing of Venetoclax 
Management of electrolyte changes from last value at intervals > 24 hours after either the first 
dose or dose escalation (e.g., 48 or 72 hours) are as below. 
Note:  If the patient is hospitalized, no additional venetoclax doses should be administered until 
resolution. 
• 
For potassium, admit patient for any increase ≥ 1.0 mmol/L (1.0 mEq/L), or any level 
> upper limit of normal. 
• 
Refer to the management guidelines for electrolyte changes observed within the 
first 24 hours after either the first dose or dose escalation (see prior table). 
• 
If a smaller potassium increase is observed that does not meet the criteria for 
admission above, recheck potassium, phosphorus, uric acid, calcium and creatinine 
in 24 hours and confirm no evidence of tumor lysis prior to further venetoclax dosing. 
• 
For uric acid, calcium, phosphorus and creatinine, refer to the management guidelines 
for electrolyte changes observed within the first 24 hours after either the first dose or 
dose escalation (see prior table). 
 
 
 

 
 
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Appendix F: Venetoclax Patient Calendar for ramp-up