Conditions: Recurrent B-Cell Non-Hodgkin Lymphoma Recurrent Grade 1 Follicular Lymphoma Recurrent Grade 2 Follicular Lymphoma Recurrent Grade 3a Follicular Lymphoma Recurrent Mantle Cell Lymphoma Recurrent Marginal Zone Lymphoma Recurrent Small Lymphocytic Lymphoma Refractory B-Cell Non-Hodgkin Lymphoma Refractory Grade 1 Follicular Lymphoma Refractory Grade 2 Follicular Lymphoma Refractory Grade 3a Follicular Lymphoma Refractory Mantle Cell Lymphoma Refractory Marginal Zone Lymphoma Refractory Small Lymphocytic Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
This phase II trial studies the effect of polatuzumab vedotin, venetoclax, and rituximab and hyaluronidase human in treating patients with mantle cell lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Polatuzumab vedotin is a monoclonal antibody, polatuzumab, linked to a toxic agent called vedotin. Polatuzumab attaches to CD79B positive cancer cells in a targeted way and delivers vedotin to kill them. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cell growth. Rituximab hyaluronidase is a combination of rituximab and hyaluronidase. Rituximab binds to a molecule called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Hyaluronidase allows rituximab to be given by injection under the skin. Giving rituximab and hyaluronidase by injection under the skin is faster than giving rituximab alone by infusion into the blood. Giving polatuzumab vedotin, venetoclax, and rituximab and hyaluronidase human may work better than standard therapy in treating patients with mantle cell lymphoma.

Detailed description:
PRIMARY OBJECTIVE:

I. To evaluate the end of induction (EOI) complete response rate (CR) for treatment with the regimen of rituximab and hyaluronidase human + polatuzumab vedotin + venetoclax (RSc + Pola + Ven) in relapsed/refractory mantle cell lymphoma (MCL).

SECONDARY OBJECTIVES:

I. To evaluate the EOI overall response rate (ORR) for the combination of RSc + Pola + Ven in relapsed/refractory MCL.

II. To evaluate the best response (CR, partial response \[PR\]) in patients who continue on to maintenance therapy and evaluate the improvement in the depth of response.

III. To evaluate the progression free survival (PFS) and overall survival (OS) for the combination of RSc + Pola + Ven) in relapsed/ refractory MCL.

IV. To compare the ORR, CR, PFS, and OS in ibrutinib refractory compared to ibrutinib naive patients.

V. To evaluate regimen-related toxicity for patients treated with RSc + Pola + Ven.

CORRELATIVE RESEARCH OBJECTIVES:

I. To evaluate changes in minimal residual disease (MRD) status in both responding and non-responding patients at EOI and end of maintenance and compared to baseline as well as correlate MRD status with PFS and OS.

II. To evaluate changes in systemic immune profiles and T cell activation induced by treatment with RSc + Pola + Ven.

III. To evaluate the prognostic importance of high risk cytogenetic alterations, and other risk stratification scores in patients with relapsed/refractory MCL receiving RSc + Pola + Ven.

IV. To evaluate features of the tumor microenvironment in patients with relapsed/refractory MCL receiving RSc +Pola+Ven.

V. To evaluate molecular features associated with response in PDX models from patients with relapsed/refractory MCL receiving RSc +Pola+Ven.

OUTLINE:

INDUCTION: Patients receive rituximab intravenously (IV) on day 1 of cycle 1 and rituximab and hyaluronidase human subcutaneously (SC) over 5 minutes on day 1 of cycles 2-6. Patients also receive polatuzumab vedotin IV over 30-90 minutes on day 1 and venetoclax orally (PO) daily on days 1-21. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive venetoclax PO daily on days 1-21 and rituximab and hyaluronidase human SC over 5 minutes every 60 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 90 days for up to 5 years.

Arms:
arm 1: INDUCTION: Patients receive rituximab IV on day 1 of cycle 1 and rituximab and hyaluronidase human SC over 5 minutes on day 1 of cycles 2-6. Patients also receive polatuzumab vedotin IV over 30-90 minutes on day 1 and venetoclax PO daily on days 1-21. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive venetoclax PO daily on days 1-21 and rituximab and hyaluronidase human SC over 5 minutes every 60 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Polatuzumab Vedotin intervention 2: Rituximab intervention 3: Rituximab and Hyaluronidase Human intervention 4: Venetoclax
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given SC intervention 4: Given PO

Protocol document:
Prot_SAP_000.pdf: 
ACCRU LY-1806
1
 
Protocol Version Date: 03FEB2022 
 
 
 
 
Academic and Community Cancer Research United (ACCRU) 
 
A Phase 2 Trial of the Combination of Polatuzumab Vedotin, Venetoclax and Rituximab and 
Hyaluronidase Human for Relapsed and Refractory Mantle Cell Lymphoma 
 
For any communications regarding this protocol, please contact the person indicated on the Protocol 
Resource page. This is a stand-alone document found on the ACCRU web site 
. 
 
Study Chair: 
 
ACCRU: 
 
  
  
 
FDA IND: 
Sponsor/Investigator: 
 
 
 
 
 
 
 
 
 
 
 
Statistician: 
  
 
 
 
 
 
 


Drug Availability 
Drug Company Supplied: rituximab, venetoclax, polatuzumab vedotin, rituximab and hyaluronidase 
human 
 
 Study contributor(s) not responsible for patient care. 
 
 
  
 
 
 
 
 
 
 
 
Document History 
 
 
(effective date) 
Initial Version  
 
 
09/28/2020 
Preactivation   
 
 
02/03/2021 
 
 
 
Amendment 1  
 
 
02/03/2022 
 
 
 
 
 


ACCRU LY-1806
2
 
Protocol Version Date: 03FEB2022 
 
 
 
 
Index 
 
Schema 
1.0 
Background 
2.0 
Goals 
3.0 
Patient Eligibility 
4.0 
Test Schedule 
5.0 
Grouping Factors 
6.0 
Registration/Randomization Procedures 
7.0 
Protocol Treatment 
8.0 
Dosage Modification Based on Adverse Events 
9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring 
11.0 
Treatment Evaluation 
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient 
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
 
Appendix I- Sample List of Excluded and Cautionary Medications for Patients treated with of 
polatuzumab vedotin, venetoclax, and rituximab and hyaluronidase human 
 
Appendix II- Recommendations for Initial Management of Electrolyte Imbalances and Prevention of 
Tumor Lysis Syndrome 
 
Appendix III- Prophylaxis and Management of Tumor Lysis Syndrome for Patients Being Treated with 
venetoclax 
 
Appendix IV- Guidelines for Defining Tumor Lysis Syndrome 
 
 Appendix V- Subject Medication Diary


4 
 
Protocol Version Date: 03FEB2022 
 
 
 
 
Registration 
Schema 
 
For the safety portion only: Prior to discussing protocol entry with the patient, call the ACCRU 
Registration Office (
 or email 
for dose level and to ensure that 
a place on the protocol is open to the patient. 
 
First 6-12 patients with Relapsed/Refractory B cell NHL treated in safety portion as described in section 
7.0. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients who end treatment 
without progression7 or alternative 
therapy 
Patients who end treatment due to 
progression7 or alternative therapy 
1,6Induction: rituximab2 + 
rituximab and hyaluronidase human3 + 
polatuzumab vedotin5 + venetoclax4 
 
Safety Portion: B cell NHL 
 
Expansion Portion: Relapsed or 
Progressed MCL 
8Maintenance: 
venetoclax 
+rituximab and hyaluronidase human 
Clinical follow up every 90 days 
until progression, receipt of 
subsequent anti-cancer treatment, 
or max. of 2 years 
 
Survival follow up every 180 
days for a max of 5 years from 
registration 


5 
 
Protocol Version Date: 03FEB2022 
 
 
 
 
If a patient is deemed ineligible or a cancel, please refer to Section 13 for follow-up information. 
1 Induction cycle length = 21 days 
2 rituximab given day 1 of cycle 1 only 
3 rituximab and hyaluronidase human on day 1 of cycle 2+ 
4 venetoclax daily 
5 polatuzumab vedotin on day 1 
6 Total of 6 cycles for induction (See Section 7.2) 
7 Progressive disease is based on either PET-CT based or CT based response criteria 
8 Maintenance for 1 year (see section 7.3); Cycle length = 30 days 
 
Generic name: venetoclax  
Brand name(s): Venclexta  
Availability: McKesson
Generic name: polatuzumab vedotin  
Brand name(s): Polivy 
Availability: McKesson
Generic name: rituximab and hyaluronidase human 
Brand name(s): Rituxan Hycela  
Availability: McKesson
Generic name: rituximab  
Brand name(s): Rituxan  
Availability: McKesson


6 
 
Protocol Version Date: 03FEB2022 
 
 
 
 
1.0 
Background 
 
1.1 
Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma that is 
considered incurable with conventional therapy. While fit younger MCL patients who 
receive aggressive induction therapy followed by autologous stem cell transplant (ASCT) 
may have a prolonged overall survival (OS) with responses up to and beyond 5-8 years, 
there are no curative regimens for older patients who cannot undergo treatments of this 
intensity. For relapsed patients, ibrutinib, lenalidomide, and bortezomib are all FDA- 
approved options however these do not represent curative approaches. While ibrutinib 
has a high overall response rate (ORR) of 67% in heavily pre-treated patients, the 2-year 
progression-free survival (PFS) is only 31%, and patients who progress on ibrutinib have 
a dismal prognosis, with an overall survival of 3 months. Acalabrutinib has recently 
received accelerated approval for relapsed MCL based on Phase 1 data which 
demonstrated an ORR of 80% and a 12-month PFS of 67% in ibrutinib naïve patients, the 
longer-term durability and the outcome for patients who progress on this agent are still 
unknown. Moreover, this drug is not approved for ibrutinib treated patients, and 
strategies in MCL that do not rely on BTK targeting remain an unmet medical need. 
Novel approaches to improve outcomes for patients with relapsed/refractory MCL are an 
urgent unmet medical need. 
 
Therapies derived from a biologic understanding of MCL pathogenesis should lead the 
development of the next generation of therapeutic platforms for MCL. The hallmarks of 
MCL are the chromosomal translocation t(11;14) (q13;q32), resulting in overexpression 
of the cell cycle protein cyclin D1 and cell cycle dysregulation, and constitutive B cell 
receptor (BCR) complex signaling. Crosslinking of BCR by antigen triggers the 
phosphorylation of CD79 and initiates activation of multiple tyrosine kinases including 
Bruton’s tyrosine kinase (BTK) which plays a critical role in amplifying the B cell 
activation signal and activating downstream pathways. Aberrant TLR and chemokine 
signaling further enhances BCR signaling. Recent studies have shown that high levels of 
constitutive BCR signaling in MCL correlated with high surface expression of CD79,and 
was associated with resistance to BTK inhibition and decreased survival. High expression 
of CD79 also leads through ERK kinase and other downstream mediators to up-
regulation of the anti-apoptotic protein BCL-2 and its family members, a primary driver 
of MCL pathogenesis. 
 
1.2 
Polatuzumab vedotin 
 
1.21 
Background on Polatuzumab Vedotin 
 
CD79b is a cell-surface antigen whose expression is restricted to all mature B 
cells except plasma cells. It is expressed in a majority of B cell−derived 
malignancies, including nearly all NHL and CLL samples tested (Dornan et al. 
2009). Antibodies bound to CD79b are rapidly internalized, which makes CD79b 
ideally suited for targeted delivery of cytotoxic agents (Polson et al. 2007; Polson 
et al. 2009). Polatuzumab vedotin (DCDS4501A) is an antibody−drug conjugate 
(ADC) that contains a humanized IgG1 anti−human CD79b monoclonal antibody 
(MCDS4409A) and a potent anti-mitotic agent, mono-methyl auristatin E 
(MMAE), linked through a protease-labile linker, maleimidocaproyl-valine- 
citrulline-p-aminobenzyloxycarbonyl. MMAE has a mode of action that is 


7 
 
Protocol Version Date: 03FEB2022 
 
 
 
 
similar to that of vincristine, which is a component of standard chemotherapy 
(e.g., R-CHOP used for treatment of lymphoma). Following binding at the cell- 
surface epitope and internalization of the ADC by the targeted cell, MMAE is 
released following cleavage of the linker by lysosomal enzymes. MMAE then 
binds to tubulin and disrupts the microtubule network, resulting in inhibition of 
cell division and cell growth (Doronina et al. 2003). This therapeutic approach 
takes advantage of the specific targeting capability of the antibody, the cytotoxic 
activity of MMAE, and the increased potency of MMAE compared with 
vincristine. It is hypothesized that polatuzumab vedotin in combination with 
other novel agents will provide enhanced efficacy and safety to patients with 
NHL. 
 
1.22 
Preclinical Studies with Polatuzumab Vedotin 
 
Comprehensive pharmacologic, pharmacokinetic (PK), pharmacodynamic, and 
toxicology studies were conducted to support the entry of polatuzumab vedotin 
into clinical trials. Because polatuzumab vedotin specifically recognizes CD79b 
on B cells of humans but not on those of the cynomolgus monkey, rat, or 
mouse⎯a surrogate ADC (DCDS5017A) that binds to cynomolgus monkey 
CD79b was generated to assess the antigen-dependent activities in cynomolgus 
monkeys. The structure, binding epitope, and binding affinity of the surrogate 
ADC are similar to that of polatuzumab vedotin. Polatuzumab vedotin has 
demonstrated efficacy in nonclinical mouse xenograft models of human CD79b- 
positive NHL. Additionally, polatuzumab vedotin when combined with rituximab 
plus chemotherapy (R-CHP or bendamustine) demonstrated better anti-tumor 
activity compared with polatuzumab vedotin as single agent or compared with a 
current standard-of-care regimen (R-CHOP or rituximab plus bendamustine 
[BR]) in xenograft models of NHL. The pharmacokinetics and safety of 
polatuzumab vedotin and the surrogate ADC were characterized in repeat-dose 
toxicity studies in rats and cynomolgus monkeys. Polatuzumab vedotin and the 
surrogate ADC were well tolerated in both species at the tested doses. The 
predominant antigen-independent findings associated with polatuzumab vedotin 
or surrogate ADC exposure were reversible bone marrow toxicity and associated 
peripheral blood cell effects in both monkeys and rats. The PK profiles of 
polatuzumab vedotin and the surrogate ADC suggested that the pharmacokinetics 
of the ADC were driven mainly by the antibody component (similar serum 
concentration−time profile between ADC and total monoclonal antibody). Refer 
to the polatuzumab vedotin Investigator’s Brochure for complete details of the 
biochemical composition and nonclinical studies. 
 
1.23 
Clinical Studies with Polatuzumab Vedotin 
 
Clinical data on polatuzumab vedotin in patients with NHL or CLL are available 
from one completed Phase I/Ib study (DCS4968g) and the ongoing Phase Ib/II 
studies (GO27834, GO29044, GO29834, BO29561, and GO29365) in patients 
with B-cell lymphoma. DCS4968g evaluated polatuzumab vedotin as a single 
agent and in combination with rituximab in patients with R/R B-cell lymphoma. 
GO27834 is evaluating polatuzumab vedotin in combination with either 
obinutuzumab or rituximab in patients with R/R FL or DLBCL. GO29044 is 


8 
 
Protocol Version Date: 03FEB2022 
 
 
 
 
evaluating polatuzumab vedotin in combination with R-CHP or G-CHP in 
patients with newly diagnosed or R/R B-cell lymphoma. GO29365 is evaluating 
polatuzumab vedotin in combination with bendamustine plus rituximab or 
obinutuzumab in patients with R/R FL or DLBCL. GO29834 is evaluating 
polatuzumab vedotin in combination with lenalidomide and either obinutuzumab 
or rituximab in patients with R/R FL or DLBCL. BO29561 is evaluating 
polatuzumab vedotin in combination with atezolizumab and either obinutuzumab 
or rituximab in patients with R/R FL or DLBCL. Available safety results and 
efficacy results from these studies are summarized in Section 1.231 and Section 
1.232 respectively. For more detailed clinical information on polatuzumab 
vedotin, including clinical pharmacology data, refer to the polatuzumab vedotin 
Investigator’s Brochure. 
 
1.231 Clinical Safety of Polatuzumab Vedotin 
 
Clinical safety data are available from 327 patients with NHL or CLL 
who received polatuzumab vedotin as a single agent (DCS4968g), in 
combination with rituximab (DCS4968g and GO27834), in combination 
with obinutuzumab (GO27834), in combination with obinutuzumab or 
rituximab plus CHP (GO29044), and in combination with obinutuzumab 
or rituximab plus bendamustine (GO29365). In Study DCS4968g, Grade 
≥ 3 adverse events were reported in 74% of patients with R/R B-cell 
lymphoma who received single−agent polatuzumab vedotin; the most 
common (reported in ≥ 5% of patients) Grade ≥ 3 adverse events were 
neutropenia (38% of patients), anemia and peripheral sensory neuropathy 
(9% each), and leukopenia (6%). In the dose-escalation phase of Study 
DCS4968g, dose-limiting toxicities (DLTs) of Grade 4 neutropenia 
occurred in 1 of 10 DLT-evaluable patients treated with 2.4 mg/kg 
polatuzumab vedotin and 1 of 9 DLT-evaluable patients treated with 2.4 
mg/kg polatuzumab vedotin in combination with rituximab. polatuzumab 
vedotin at a dose of 2.4 mg/kg given every 3 weeks was chosen as the 
recommended Phase II dose (RP2D) when administered as a single agent 
and in combination with rituximab. The overall safety profile of 
polatuzumab vedotin (1.8 mg/kg and 2.4 mg/kg doses) in combination 
with rituximab was comparable to that of single agent polatuzumab 
vedotin. In Study GO27834, the most frequent (≥ 5%) Grade ≥ 3 adverse 
events were neutropenia (19 of 79 patients [24%]), diarrhea (5 of 79 
patients [6%]), and febrile neutropenia (4 of 79 patients [5%]). No fatal 
adverse events were reported for the combination. 
 
Serious adverse events were reported for 37% of all patients treated with 
polatuzumab vedotin alone or in combination with rituximab in Studies 
DCS4968g and GO27834 combined. The most frequently reported (≥ 
2%) serious adverse events were febrile neutropenia (5%), pyrexia (4%), 
and diarrhea (2%). In Studies DCS4968g and GO27834 combined, 
33%−41% of patients discontinued polatuzumab vedotin because of an 
adverse event. The most frequently reported adverse events leading to 
discontinuation were peripheral sensory neuropathy, peripheral 
neuropathy, and peripheral motor neuropathy. In Study GO29044, Grade 


9 
 
Protocol Version Date: 03FEB2022 
 
 
 
 
≥ 3 adverse events were reported in 19 of 40 patients (48%) with B-cell 
lymphoma who received polatuzumab vedotin (1.8 mg/kg) in 
combination with obinutuzumab or rituximab plus CHP. The most 
frequent events (≥ 10% of patients) were fatigue (33%), diarrhea (33%), 
and nausea (30%). Serious adverse events were reported for 33% of 
patients in this treatment group. In Study GO29365, Grade ≥ 3 adverse 
events were reported in 11 of 21 patients (52%) with B-cell lymphoma 
who received polatuzumab vedotin in combination with rituximab plus 
bendamustine and in 17 of 28 patients (61%) who received polatuzumab 
vedotin in combination with obinutuzumab plus bendamustine. The most 
frequent events (≥ 10% of patients) were nausea (43%), diarrhea (41%), 
and fatigue (35%). Serious adverse events were reported for 33% of 
patients receiving polatuzumab vedotin in combination with rituximab 
plus bendamustine and 39% of patients receiving polatuzumab vedotin in 
combination with obinutuzumab plus bendamustine. A total of 44 deaths 
have been reported: 11 deaths in patients treated with single agent 
polatuzumab vedotin and 33 in patients treated with polatuzumab vedotin 
combined with rituximab or obinutuzumab. The majority of deaths were 
judged as related to disease progression. 
 
1.232 Clinical Efficacy of Polatuzumab Vedotin 
 
Polatuzumab vedotin demonstrated clinical activity as a single agent. In 
Study DCS4968g, at the 2.4-mg/kg dose, objective responses (CR or PR) 
were observed in 7 of 16 patients (44%) with R/R indolent B−cell 
lymphoma (FL, marginal zone lymphoma [MZL], or small lymphocytic 
lymphoma [SLL]) and 14 of 27 patients (52%) with R/R DLBCL. At a 
dose of 1.8 mg/kg, a PR was observed in 2 of 4 patients with DLBCL 
and in 2 of 2 patients with MCL, and no objective responses were 
observed in the 5 patients with CLL. The median duration of response 
was 6.2 months (95% CI: 3.3, 19.3 months) for the 2.4 mg/kg dose and 
6.6 months (95% CI: 2.3, 11.4 months) for the 1.8 mg/kg dose. At the 
2.4-mg/kg dose, median PFS was 7.9 months (95% CI: 3.0, 11.6 months) 
for patients with indolent B-cell lymphoma and 5.0 months (95% CI: 2.3, 
6.8 months) for patients with DLBCL. Median PFS was 4.6 months 
(95% CI: 1.4, 13.9 months) for patients with DLBCL treated at the 1.8- 
mg/kg dose. 
 
Polatuzumab vedotin also demonstrated clinical activity when 
administered in combination with rituximab. In Study DCS4968g, at a 
dose of 2.4 mg/kg, objective responses were observed in 7 of 9 patients 
with indolent B-cell lymphoma, DLBCL, or MCL (78%); 2 of the 7 
patients had CRs. Median duration of response among these patients was 
12.3 months (95% CI: 4.3, not estimable [NE]). Median PFS was 12.5 
months (95% CI: 6.9, 17.4 months). Preliminary data for patients in 
Study GO27834 who received polatuzumab vedotin (2.4 mg/kg) in 
combination with rituximab, objective responses were observed in 14 of 
20 patients with R/R FL (70%; 9 patients with CRs) and 21 of 39 patients 
with R/R DLBCL (54%; 8 patients with CRs). For patients who received 


10
 
Protocol Version Date: 03FEB2022 
 
 
 
 
polatuzumab vedotin (1.8 mg/kg) in combination with rituximab, 
objective responses were observed in 15 of 20 patients with FL (75%; 6 
patients with CRs). Median duration of response was 12.9 months (95% 
CI: 6.7, NE) and 13.2 months (95% CI: 7.2, 21.2) for patients who 
received polatuzumab vedotin 1.8 mg/kg (FL) or 2.4 mg/kg (FL or 
DLBCL), respectively. At the 2.4 mg/kg dose, median PFS was 15.1 
months (95% CI: 11.8, NE) among the 20 patients with FL and 5.6 
months (95% CI: 4.2, 12.7) among the 39 patients with DLBCL. Among 
the 20 patients with R/R FL treated with 1.8 mg/kg polatuzumab vedotin 
in combination with rituximab, median PFS was 18.1 months (95% CI: 
9.9, NE). For patients in Study GO27834 who received polatuzumab 
vedotin (1.8 mg/kg) in combination with obinutuzumab, overall 
responses were observed in 8 of 12 patients with R/R FL (67%; 1 patient 
with CR) and 3 of 15 patients with R/R DLBCL (20%; 0 patients with 
CR). Preliminary data from Study GO29044 in patients treated with 
polatuzumab vedotin (1.0−1.8 mg/kg) in combination with R-CHP 
showed overall responses in 29 of 31 patients (94%; 24 patients with 
CRs). When polatuzumab vedotin (1.4 or 1.8 mg/kg) was combined with 
G-CHP, overall responses were seen in 10 of 12 patients (83%; 10 
patients with CRs). Preliminary data from GO29365 in FL patients 
treated with polatuzumab vedotin (1.8 mg/kg) in combination with 
bendamustine showed overall responses in 7 of 7 patients (100%; 2 
patients with CRs) when combined with rituximab and in 3 of 4 patients 
(75%; 1 patient with CR) when combined with obinutuzumab. Patients 
with DLBCL treated with polatuzumab vedotin (1.8 mg/kg) in 
combination with bendamustine showed overall responses in 3 of 7 
patients (43%; 2 patients with CRs) when combined with rituximab and 
in 6 of 8 patients (75%; 2 patients with CR) when combined with 
obinutuzumab. 
 
While development is currently focused on FL and DLBCL early studies 
demonstrated promising activity in MCL. In a phase I/Ib study of single 
agent polatuzumab vedotin 6 of 7 patients with relapsed/refractory MCL 
achieved a response (Lancet Oncol 2015; 16: 704–15). 
 
1.3 
Venetoclax 
 
1.31 
Background on Venetoclax 
 
Venetoclax (synonymous with ABT-199 and GDC-0199) is a highly selective, 
orally available small−molecule Bcl-2 family protein inhibitor that binds with 
high affinity (dissociation constant [Ki] < 0.10 nM) to Bcl-2 and with lower 
affinity to other Bcl-2 family proteins Bcl-XL and Bcl-w (> 480- and > 2000-fold 
lower affinity than to Bcl-2, respectively). Overexpression of anti−apoptotic Bcl- 
2 family proteins is associated with resistance to chemotherapy, and antagonism 
of the action of these proteins might overcome resistance and enhance response 
to therapy. Anti−apoptotic Bcl-2 family members are associated with tumor 
initiation, disease progression, and drug resistance, making them compelling 
targets for anti-tumor therapy. 


11
 
Protocol Version Date: 03FEB2022 
 
 
 
 
 
 
1.32 
Preclinical Studies with Venetoclax 
 
In vitro, venetoclax demonstrated broad cell-killing activity against a panel of 
lymphoma and leukemia cells, including B-cell FL, mantle cell lymphoma 
(MCL), DLBCL, and acute myeloid leukemia. Venetoclax was especially potent 
against cell lines that expressed high levels of Bcl-2. Leukemia and lymphoma 
cell lines that bear the t(14;18) translocation were significantly more sensitive to 
venetoclax than wild−type cell lines. Venetoclax inhibited subcutaneous (SC) 
murine xenograft growth of human tumor cell lines derived from acute 
lymphoblastic leukemia and NHL. The PK profile of venetoclax was evaluated in 
multiple animal species. In mice, rats, monkeys, and dogs, low plasma clearance 
and low volumes of distribution characterized the venetoclax PK profile. Half- 
lives ranged from 2.2 hours in monkeys to 12 hours in dogs. Food had a marked 
effect on the oral bioavailability in dogs. Venetoclax demonstrated high protein 
binding to human, rat, dog, and monkey plasma proteins (> 99.9%). In rats, 
venetoclax was widely distributed into liver, kidneys, spleen, heart, lungs, small 
intestine, and white fat, but was poorly distributed in testes, brain, muscle, and 
bone. Liver metabolism was the major route of elimination with biliary excretion 
of the parent drug playing the secondary role in rats. Venetoclax showed 
moderate metabolic stability in in vitro hepatic systems across species tested, 
except for low to moderate stability in dog hepatocytes. In vitro, venetoclax is 
metabolized by cytochrome (CYP) 3A4 and is a moderate inhibitor of CYP2C8 
and a potent inhibitor of CYP2C9. It is not a potent inhibitor of CYP3A4, 
CYP1A2, CYP2B6, CYP2C19, or CYP2D6 (IC50 > 30 μM) and does not induce 
CYP3A4 or CYP1A2 at concentrations up to 10 μM. Venetoclax has the 
potential to inhibit P-glycoprotein (P-gp). A more detailed discussion of the 
nonclinical activity of venetoclax, including pharmacokinetic, toxicology, and 
metabolism, is provided in the current venetoclax Investigator’s Brochure. 
 
1.33 
Clinical Studies with Venetoclax 
 
As of 28 November 2014, a total of 639 patients had been dosed with venetoclax 
in AbbVie and Genentech/Roche oncology studies. Doses administered in 
venetoclax clinical studies ranged from 20 to 1200 mg. A total of 345 patients 
with CLL/SLL and 155 patients with NHL have been treated with venetoclax as 
single agent or in combination. Two studies, GP28331 and GO27878, include the 
combination of obinutuzumab and venetoclax in CLL and NHL, respectively. In 
addition, Study BO25323, a randomized Phase III study evaluating the efficacy 
of obinutuzumab plus venetoclax compared with obinutuzumab plus 
chlorambucil in patients with previously untreated CLL, has recently been 
initiated. For more detailed clinical information on venetoclax, including results 
in the CLL cohorts of the clinical studies and clinical pharmacology data, refer to 
the venetoclax Investigator’s Brochure. 
 
1.331 Clinical Pharmacokinetics and Pharmacodynamics 
 
Preliminary PK data with venetoclax are available from ongoing Studies 


12
 
Protocol Version Date: 03FEB2022 
 
 
 
 
M12-175, M12-630, and M13-365 in patients with hematologic 
malignancies. The venetoclax formulation currently used in clinical 
studies is a tablet formulation with strengths of 10, 50, and 100 mg. The 
tablet formulation was orally administered after a low-fat meal. Food 
increased the bioavailability of venetoclax by 3- to 4-fold. Preliminary 
PK results indicated that the absorption of venetoclax after the oral 
dosing was relatively slow. Venetoclax plasma concentrations peaked at 
approximately 6 hours after dosing. The mean terminal-phase 
elimination half-life of venetoclax was approximately 17 hours, and the 
mean oral clearance was approximately 13 L/hr after a single dose. There 
was no apparent difference in the pharmacokinetics of venetoclax in 
patients with CLL/SLL or NHL. The combined data from patients with 
CLL/SLL and NHL suggested that venetoclax exposure was 
approximately dose proportional across the 150- to 900-mg dose levels. 
In the limited number of patients to date, co-administration of BR did not 
show apparent effect on venetoclax pharmacokinetics. 
 
1.332 Safety and Activity Data for Venetoclax 
 
Study M12-175, the first in-human venetoclax monotherapy dose- 
escalation study, is ongoing in patients with R/R CLL/SLL and NHL. 
Two DLTs have been reported in patients with NHL who were treated 
with venetoclax in Study M12-175. Both DLTs occurred at the 600-mg 
dose in Cohort 5 (which enrolled a total of 10 patients and had a 300-mg 
lead-in dose and 600-mg designated cohort dose). One patient 
experienced a DLT of serious Grade 3 febrile neutropenia, and the other 
patient experienced a DLT of non-serious Grade 4 neutropenia. Dosing 
was interrupted and patients were treated with medication; the events 
resolved, and the patients restarted therapy at a reduced venetoclax dose 
of 300 mg. No DLTs were reported in Cohorts 6−8, with the maximum 
dose studied of 1200 mg. The most common adverse events in the NHL 
cohort of Study M12-175 were nausea, anemia, diarrhea, and fatigue, all 
occurring in ≥ 20% of patients. Grade ≥ 3 hematologic toxicity was less 
common in patients with NHL than in patients with CLL. In Study M12- 
175, 13% of patients with NHL experienced Grade ≥ 3 neutropenia and 
10% experienced Grade ≥ 3 thrombocytopenia. As of 4 December 2014, 
a total of 105 patients with R/R NHL had been enrolled (70 in the dose- 
escalation cohorts and 35 in the safety expansion cohort) and evaluated 
for objective response following the International Working Group 
criteria (patients with Waldenstrom's macroglobulinemia [WM] were 
evaluated using the International Workshop-WM criteria). In the dose- 
escalation cohorts, the objective response rate (ORR) was 57%, the CR 
rate was 11%, and median time in the study was approximately 6 
months. In the safety expansion cohort, the ORR was 17%, the CR rate 
was 3%, and median time in the study was approximately 3 months. This 
group had limited follow-up at the time of the clinical cutoff. 
 
Study M12-630 is a study of venetoclax in combination with BR in 
patients with R/R NHL. Patients receive this regimen for 6 cycles. In 


13
 
Protocol Version Date: 03FEB2022 
 
 
 
 
Study M12-630, preliminary efficacy data are available for 27 patients 
(17 male patients [63%]) with R/R NHL as of 7 October 2014. 
Hematologic toxicity in Study M12-630 (venetoclax in combination with 
BR in patients with NHL) was not significantly greater than that 
expected with BR alone. The ORR was 64% (18 of 27 evaluable 
patients): 4 patients (14%) with CR and 14 patients (50%) with PR. An 
additional 3 patients (11%) had stable disease. Efficacy data are not yet 
available for the other NHL studies listed. Data on venetoclax and human 
pregnancy or venetoclax and drug abuse and drug dependency are not 
available. Additional details on the clinical activity and safety of 
venetoclax are provided in the venetoclax Investigator’s Brochure. 
 
1.4 
Rationale for Study Combination 
 
This study will evaluate the activity of a novel triplet combination of rituximab and 
hyaluronidase human, polatuzumab vedotin, and venetoclax for relapsed MCL. 
 
B-cell lymphoma, including MCL, express the CD20 antigen, and anti-CD20 therapy 
(rituximab) has been demonstrated to provide enhanced anti-tumor activity in 
combination with other agents, leading to increased response rates, PFS, and OS1. 
 
Polatuzumab vedotin is an ADC designed for the targeted delivery of MMAE, a potent 
microtubule inhibitor to lymphoma cells that express CD79b. MMAE has a mechanism 
of action that is similar to that of vincristine. Venetoclax is a specific inhibitor of the Bcl- 
2 anti−apoptotic protein expressed in many NHL cells. Bcl-2 is overexpressed in most FL 
and many DLBCLs as a consequence of the t(14;18) chromosomal translocation or gene 
amplification and is associated with a poor prognosis in multiple tumor types (Cory and 
Adams 2002; Cory et al. 2003; Reed 2008; Iqbal et al. 2011). Bcl-2 has been shown to 
contribute to resistance of malignant cells to chemotherapies with varied mechanisms of 
action, consistent with its role as an inhibitor of the final common steps of apoptosis and 
is likely to play a role in resistance to the pro-apoptotic activities of immunotherapy and 
chemotherapy. In solid and hematologic tumor models, anti-mitotic drugs (taxanes and 
auristatin) were shown to modulate Bcl-2 pro-survival proteins to induce cell death in 
vitro (Haldar et al 1996; Poruchynsky et al. 1998; Wertz et al. 2011). MMAE in 
polatuzumab vedotin may be able to down regulate Mcl-1, a known resistant factor for 
venetoclax. Therefore, the addition of venetoclax, a Bcl-2 inhibitor, to a polatuzumab 
vedotin-containing regimen may have the potential to significantly enhance the anti- 
lymphoma activity and to result in improved clinical outcomes. Nonclinical data that 
support the triplet combination of CD 20 antibody, polatuzumab vedotin, and venetoclax 
include WSU-DLCL2 model in CB17 severely compromised immunodeficient (SCID) 
mice that demonstrated significantly improved anti-tumor activity of the triplet 
combination over the activity of any treatment regimen alone or doublet combination 
(obinutuzumab plus venetoclax or obinutuzumab plus polatuzumab vedotin; see Figure 
1). 
 
Progress has been made in the treatment of MCL, however cure is still not attainable for 
most patients, and options to prolong remission and survival for relapsed patients remain 
limited. There is a need for the continued development of safe and effective therapies for 
patients with relapsed disease after front line therapy, and particularly for patients who 
relapse or progress on ibrutinib who have a dismal prognosis. 


14
 
Protocol Version Date: 03FEB2022 
 
 
 
 
Figure 1 
 
There is a strong scientific rationale for combining these agents. Recent studies have 
shown that high levels of constitutive BCR signaling in MCL correlated with high 
surface expression of CD79,and was associated with resistance to BTK inhibition and 
decreased survival. High expression of CD79 also leads through ERK kinase and other 
downstream mediators to up-regulation of the anti-apoptotic protein BCL-2 and its family 
members, a primary driver of MCL pathogenesis. The contribution of impaired immune 
activation to ibrutinib resistance is unknown. We hypothesize that by targeting CD79 
expressing B cells in conjunction with enhancing apoptosis through Bcl-2 inhibition we 
will abrogate the effects of constitutive BCR signaling, and that this regimen will be 
highly active in relapsed MCL. Preclinical data supporting the triplet combination of 
obinutuzumab, polatuzumab vedotin, and venetoclax has been demonstrated in a WSU- 
DLCL2 model in CB17 severely compromised immunodeficient (SCID) mice showing 
significantly improved anti-tumor activity of the triplet combination over the activity of 
any treatment regimen alone or doublet combination (Figure 1) Existing data from 
protocol GO29833 demonstrate that these agents can be safely combined in other B cell 
NHL without significant overlapping toxicity. For patients with relapsed MCL who 
progress after BTK inhibition, treatment options and survival are profoundly limited, and 
the use of these agents in earlier line therapy may potentially have an adverse effect on 
OS. Treatments with manageable toxicity and a high CR rate remain an unmet medical 
need for patients with relapsed MCL, as well as for unfit and elderly patients who cannot 
tolerate aggressive induction regimens. While venetoclax has high ORR in relapsed 
MCL, the CR rate remains suboptimal at around 21%. This novel triplet regimen has the 
potential to both increase ORR and deepen CR extending chemotherapy free remission, 
and decreasing toxicity by sparing patients cytotoxic chemotherapy, and improving upon 
individual agents used as part of current standard of care. If this trial confirms high 
activity and tolerability, this regimen may have a place as first line therapy of older and 
unfit patients, potentially replacing components of standard systemic chemotherapy and 
enhancing both efficacy and tolerability, or as a standard of care second line salvage 
regimen for BTK naïve or resistant patients. 
 
1.5 
Correlative Research 
 
1.51 
Studies have shown that achieving MRD negativity in the peripheral blood and in 
the bone marrow prior to consolidation correlates with improved outcome in 
MCL regardless of the treatment approach and molecular remission is regarded 
as an independent predictor of clinical outcome (23-26). Thus, molecular 


15
 
Protocol Version Date: 03FEB2022 
 
 
 
 
monitoring can be used to guide treatment decisions to intensify treatment 
interventions in some patients and avoiding unnecessary treatments in others. In 
addition to its potential use in response-adaptive treatment strategies, MRD status 
in clinical remission after treatment has been shown to be predictive of 
subsequent PFS (23, 27, 28). MRD assessment by real-time quantitative PCR 
(RQ-PCR) has been the most standardized technique (29), but more recently, a 
novel commercial assay that uses multiplex PCR and next-generation sequencing 
(NGS) of immunoglobulin and T-cell receptor rearrangements to detect and 
quantify gene sequences in DNA from peripheral blood or bone marrow samples 
has been available. The ClonoSEQ® assay, formerly ClonoSight™, measures the 
level of MRD and is able to detect 1 in 1 million cells (30). Based on data that 
showed that the MRD assessment with ClonoSEQ® in B-ALL and multiple 
myeloma patients correlated with EFS and PFS, respectively (31), FDA granted 
marketing authorization of ClonoSEQ in September 2018 (32) for myeloma and 
leukemia, and its use for MCL is currently under investigation. We will evaluate 
MRD in responding patients at EOI to learn the role of maintenance therapy, may 
contribute to deepening remission and extending progression free survival. Other 
NSG based MRD tests may also be evaluated in addition to ClonoSEQ using 
residual material. 
1.52 
The contribution of immune dysregulation to lymphomagensis is significant, but 
the impact of response to therapy on restoration of normal immune function in 
MCL has not been studied. Moreover, immune dysfunction and restoration can 
manifest in multiple ways, including changes in cell subset frequency, altered 
expression of costimulatory proteins, or impaired cytokine production22. Using 
high parameter, single cell technologies, we will correlate immune profiles with 
clinical features and EOI response. The restoration of immune function may 
suggest improved anti-tumor immune surveillance, and potentially be correlated 
with deeper or prolonged response. Our findings may uncover mechanisms that 
could be targeted with immunotherapy, or combination approaches in future 
trials. 
We have previously identified immunological differences amongst patients with 
different therapeutic outcomes. Using our Checkpoint Ligand panel, which 
identifies subsets of myeloid cells, DC, and measures the expression of many 
ligands of checkpoint molecules, we evaluated pre- and post-treatment samples 
from melanoma patients, clustering the data for all patients and overlaying a 
density gradient to indicate the frequency of cells defined by each cluster. This 
method allowed comparison across patient groups. We selected clusters that 
differed between the two patient groups and found that they comprised GAL9+ 
and OX40L+ GAL9+ cells, compared the frequency of cells expressing these 
markers for each patient group, and observed a statistically significant difference 
between responders and non-responders. These preliminary data demonstrate our 
ability to acquire, visualize, statistically analyze, and interpret complex data. We 
are also able to identify functional traits that differ across patient groups, using a 
novel new single cell technology for measurement of cytokine secretion, which 
enumerates 39-cytokines simultaneously from 20,000 cells per chip (IsoLight by 
IsoPlexus, Bramford, CT) (Rossi J, Paczkowski P, Shen YW, et al. Preinfusion 
polyfunctional anti-CD19 chimeric antigen receptor T cells are associated with 
clinical outcomes in NHL. Blood 2018;132:804-14. 


16
 
Protocol Version Date: 03FEB2022 
 
 
 
 
 
We applied this technology to melanoma patients on an immunotherapy trial and 
found that non-responders had more Granzyme B+ cells and molecules than 
responders. Notably, these cells did not secrete the delivery molecule perforin, 
demonstrating our ability to deeply characterize cells. Although our most 
developed data is in melanoma, these assays have been performed in lymphoma. 
In Hodgkins lymphoma (HL), our cytokine secretion analysis demonstrated that 
patients who fail therapy have higher levels of IL9 (p=0.0028) and IL22 
(p=0.021) at diagnosis compared to those who respond to treatment. We have 
also identified a suite of cytokines that increase over the course of disease 
treatment (including IL4, IL5, IL10; p=0.001) only in patients who fail therapy 
(ASH abstract 128366). 
 
1.53 
Mantle cell lymphoma international prognostic index (IPI) prognostic score is a 
continuous variable derived from 4 factors including age, ECOG PS, LDH and 
WBC count, and classifies MCL patients into 3 risk groups (low-risk, 
intermediate-risk, and high-risk) with differential survival (33). Other markers at 
diagnosis that have been shown to be prognostic in MCL are Ki-67 proliferation 
index (34, 35) and complex cytogenetics (36). Complex karyotype is defined as 3 
or more detectable chromosomal abnormalities. Ki-67 staining performed on the 
tissue biopsy at diagnosis will be used to calculate the proliferation index, 
defined as the percentage of Ki-67 positive lymphoma cells, and to categorize 
patients into < 10%, 10-30% and > 30% subgroups. The MIPI score, proliferation 
index and complex cytogenetics status at MCL diagnosis will be correlated with 
the MRD rate prior to the 4th cycle of the proposed regimen. The interim MRD 
positivity alone and also in combination with the at-diagnosis prognostic factors 
will be tested for association with the treatment response at EOI according to the 
Lugano 2014 response criteria based on PET-CT scans. 
2.0 
Goals 
 
2.1 
Primary Endpoint 
 
2.11 
To evaluate the end of induction (EOI) complete response rate (CR) for treatment 
with the regimen of rituximab and hyaluronidase human + polatuzumab vedotin 
+ venetoclax (RSc+Pola+Ven) in relapsed/ refractory MCL. 
 
2.2 
Secondary Endpoints 
 
2.21 
To evaluate the EOI overall response rate (ORR) for the combination of 
RSc+Pola+Ven in relapsed/ refractory MCL. 
 
2.22 
To evaluate the best response (CR, PR) in patients who continue on to 
maintenance therapy and evaluate the improvement in the depth of response. 
 
2.23 
To evaluate the progression free survival (PFS) and overall survival (OS) for the 
combination of RSc+Pola+Ven in relapsed/ refractory MCL. 
 
2.24 
To compare the ORR, CR, PFS, and OS in ibrutinib refractory compared to 
ibrutinib naïve patients. 
 


17
 
Protocol Version Date: 03FEB2022 
 
 
 
 
2.25 
To evaluate regimen-related toxicity for patients treated with RSc+Pola+Ven. 
 
2.3 
Correlative Research 
 
2.31 
To evaluate changes in minimal residual disease (MRD) status in both 
responding and non-responding patients at EOI and end of maintenance and 
compared to baseline as well as correlate MRD status with PFS and OS. 
 
2.32 
To evaluate changes in systemic immune profiles and T cell activation induced 
by treatment with RSc+Pola+Ven. 
 
2.33 
To evaluate the prognostic importance of high-risk cytogenetic alterations, and 
other risk stratification scores in patients with relapsed/refractory MCL receiving 
RSc+Pola+Ven. 
 
2.34 
To evaluate features of the tumor microenvironment in patients with 
relapsed/refractory MCL receiving RSc+Pola+Ven. 
 
2.35 
To evaluate molecular features associated with response in PDX models from 
patients with relapsed/refractory MCL receiving RSc+Pola+Ven. 
 
3.0 
Patient Eligibility 
 
For patients in the safety run in, prior to discussing protocol entry with the patient, call the 
ACCRU Registration Office (
) or email at 
to ensure 
that a place on the protocol is open to the patient. 
 
NOTE: Waivers to eligibility criteria are not allowed per ACCRU policy 
 
3.1 
Registration – Inclusion Criteria 
 
3.11 
Age ≥ 18 years. 
 
3.12 
Pathologically confirmed relapsed or primary refractory mantle cell lymphoma 
with concurrent or prior tissue sample IHC positive for cycle in D1 or that is 
positive for FISH or cytogenetics for t(11;14). 
 
NOTE: Safety Portion only: MCL or indolent B cell NHL (FL (grades I-IIIa) 
MZL), or SLL stratified as low risk for TLS, relapsed or progressed after at least 
two lines of therapy, or one line of a BTK inhibitor containing therapy, or 
Autologous Stem Cell Transplant (AutoSCT). No limit to prior lines of therapy. 
 
NOTE: Expansion Portion only: MCL relapsed or progressed after at least two 
lines of therapy, or one line of a BTK inhibitor containing therapy, or Autologous 
Stem Cell Transplant (AutoSCT). No limit to number of prior therapies. May 
have received prior BTK inhibitor therapy. 
 
3.13 
Measurable disease as defined with at least one lesion measuring > 1 x 1.5cm by 
PET/CT using Lugano criteria.  
 
3.14 
ECOG Performance Status of 0, 1, or 2. (Form is available on the ACCRU web 


18
 
Protocol Version Date: 03FEB2022 
 
 
 
 
site under Study Resources -> Forms) 
 
3.15 
The following laboratory values obtained  14 days prior to registration. 
 
Absolute neutrophil count (ANC) ≥1000/mm3 
 
Platelet count 75,000/mm3 
 
Hemoglobin ≥9.0 g/dL 
 
International normalized ratio ≤ 1.5 x ULN for patients not receiving 
therapeutic anticoagulation 
 
Partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN 
 
Adequate liver function, as indicated by: AST and ALT  2.5  ULN 
 
Total bilirubin  1.5  ULN (or  3  ULN for patients with documented 
Gilbert syndrome) 
 
Adequate renal function as indicated by: calculated Cr clearance ≥45 ml/min 
using the modified Cockcroft-Gault formula (eCCr; with the use of ideal 
body mass [IBM] instead of mass): 
 
 
eCCr 
(140  Age)  IBM (kg)  [0.85 if female] 
72 x serum creatinine (mg/dL) 
 
Or, if serum creatinine is in mol/L: 
 
eCCr 
(140  Age)  IBM (kg)  [1.23 if male, 1.04 if female]
serum creatinine (mol/L)
 
 
3.16 
Negative serum pregnancy test done ≤7 days prior to registration, for women of 
childbearing potential only. 
NOTE: A female of childbearing potential is a sexually mature female who:  
1) has not undergone a hysterectomy or bilateral oophorectomy; or  
2) has not been naturally postmenopausal for at least 12 consecutive 
months (i.e. has had menses at any time in the preceding 12 consecutive 
months). 
 
3.17 
Able to provide informed written consent, and ability to comply with study 
related procedures. 
 
3.18 
Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
 
3.19a 
Willing to provide tissue samples for mandatory correlative research (see Section 
17.0). 
 
3.19b For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a contraceptive method with a failure rate of 
1% per year during the treatment period and for at least 30 days after the last 
dose of venetoclax or 18 months after the last dose of rituximab and 
hyaluronidase human, whichever is longer. 
For men: agreement to remain abstinent (refrain from heterosexual intercourse) 


19
 
Protocol Version Date: 03FEB2022 
 
 
 
 
or use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below: 
With female partners of childbearing potential, men must remain 
abstinent or use a condom plus an additional contraceptive method that 
together result in a failure rate of  1% per year during the treatment 
period and for at least 6 months after the last dose. Men must refrain 
from donating sperm during this same period. 
With pregnant female partners, men must remain abstinent or use a 
condom during the treatment period and for at least 6 months after the 
last dose to avoid exposing the embryo. 
3.2 
Registration – Exclusion Criteria 
3.21 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown 
 
Pregnant women 
 
Nursing women 
 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception 
 
3.22 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 
 
3.23 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
 
3.24 
Receiving any other investigational or chemotherapeutic agent which would be 
considered as a treatment for the primary neoplasm. 
 
3.25 
Known CD20-negative status at relapse or progression. 
 
3.26 
Prior allogeneic SCT. 
 
3.27 
Completion of autologous SCT ≤ 100 days prior to registration. 
 
3.28 
Treatment with radioimmunoconjugate ≤ 12 weeks prior to registration. 
 
3.29a 
Monoclonal antibody or Antibody-drug Conjugate (ADC) therapy within 5 half-
lives or 4 weeks prior to registration, whichever is longer. 
 
3.29b Radiotherapy, chemotherapy, hormonal therapy, or targeted small-molecule 
therapy within 2 weeks prior to registration (with the exception of ibrutinib to 
prevent tumor flare, patients taking ibrutinib who are progressing must 
discontinue ibrutinib 2 half-lives or 2 days prior to initiating protocol therapy) 
 


20
 
Protocol Version Date: 03FEB2022 
 
 
 
 
3.29c  Clinically significant toxicity (other than alopecia) from prior therapy that has 
not resolved to Grade ≤ 2 (per NCI CTCAE v5.0) prior to registration. 
 
3.29d   Current Grade > 1 peripheral neuropathy. 
 
3.29e   Any history of CNS lymphoma or leptomeningeal infiltration 
 
3.29f 
Treatment with systemic corticosteroids > 20 mg/day prednisone or equivalent 
Patients who are receiving corticosteroids ≤ 20 mg/day, prednisone or equivalent, 
for non-lymphoma treatment reasons must be documented to be on a stable dose 
for ≥ 4 weeks prior to registration. If corticosteroid treatment is urgently required 
for lymphoma symptom control prior to the start of study treatment, up to 100 
mg/day of prednisone or equivalent can be given for a maximum of 5 days, but 
all tumor assessments must be completed prior to start of corticosteroid 
treatment. 
 
3.29g History of severe allergic or anaphylactic reaction or known sensitivity to 
humanized or murine monoclonal antibodies, rituximab, polatuzumab vedotin, or 
venetoclax.  
 
3.29h  Active bacterial, viral, fungal, or other infection. 
 
3.29i 
Requirement for warfarin treatment (because of potential DDIs that may increase 
the exposure of warfarin). 
 
3.29j 
Treatment with the following agents ≤7 days prior to registration – Strong and 
moderate CYP3A inhibitors such as fluconazole, ketoconazole, and 
clarithromycin (see Appendix I for examples) – Strong and moderate CYP3A 
inducers such as rifampin and carbamazepine (see Appendix I for examples). If 
subject is taking proton pump inhibitors, subject is willing to avoid co-
administration and stagger venetoclax dosing. 
 
3.29k Consumption of grapefruit, grapefruit products, Seville oranges (including 
marmalade that contains Seville oranges), or star fruit ≤ 3 days prior to 
registration. 
 
3.29l 
Clinically significant history of liver disease, including viral or other hepatitis, 
current alcohol abuse, or cirrhosis. 
 
3.29m  Active hepatitis B or hepatitis C infection.  
NOTE: Patients who have been successfully treated and cleared their virus as 
evidenced by a negative Hep B or Hep C PCR are eligible. 
 
3.29n  Known history of HIV positive status or known infection with human T-cell 
leukemia virus 1. For patients with unknown HIV status, HIV testing will be 
performed at screening. 
 
3.29o  History of PML (Progressive Multifocal Leukoencephalopathy).  
 
3.29p  Vaccination with a live virus vaccine ≤ 28 days prior to registration. 
 


21
 
Protocol Version Date: 03FEB2022 
 
 
 
 
3.29q History of other malignancy that could affect compliance with the protocol or 
interpretation of results, with the exception of the following: Curatively treated 
carcinoma in situ of the cervix, good-prognosis ductal carcinoma in situ of the 
breast, basal- or squamous-cell skin cancer, Stage I melanoma, or low-grade, 
early-stage localized prostate cancer 
 
3.29r  Any previously treated malignancy that has been in remission without treatment 
for ≤ 3 years prior to registration. 
 
3.29s 
Evidence of any significant, uncontrolled concomitant disease that could affect 
compliance with the protocol or interpretation of results, including significant 
cardiovascular disease (such as New York Heart Association Class III or IV 
cardiac disease, myocardial infarction within the previous 6 months, unstable 
arrhythmia, or unstable angina) or significant pulmonary disease (such as 
obstructive pulmonary disease or history of bronchospasm). 
 
 
3.29t  Major surgical procedure other than for diagnosis ≤ 28 days prior to Day 1 of Cycle 
1, or anticipation of a major surgical procedure during the course of the study. 
 
3.29u Inability or unwillingness to swallow pills. 
 
3.29v History of malabsorption syndrome or other condition that would interfere with 
enteral absorption. 
 
3.29w  History of inflammatory bowel disease (e.g., Crohn’s disease or ulcerative 
colitis) or active bowel inflammation (e.g., diverticulitis).


ACCRU LY-1806
22
Protocol Version Date: 03FEB2022 
 
 
 
 
4.0 
Test Schedule 
 
 
 
 
 
Tests and Procedures 
Days Prior to 
Registration 
Induction (21-day cycles) 
EOI 1 
Maintenance
(12 months)
EOM 2 
 
Post- Treatment 
clinical follow-
up period  
(q3m for 2 years
+/- 14 days) 
 30 
days 
14 
days 
Cycle 1 
(±1 d) 
Cycle 2 
(±2 d) 
Cycles 3-6 
(±2 d) 
After last 
induction 
dose 
Monthly 
(30days) 
(±1 week) 
D1
35 days after last 
dose 
(±14 days) 
D1
D8 D15
D1 
D1 
Complete Medical history 
X 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
X 
 
X
X
X
X 
X 
X 
X 
X 
X 
Physical exam, weight and vital 
signs (blood pressure, pulse, O2)4
X 
 
X 
X
X
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
12-lead EKG8 
X 
 
 
 
 
 
 
 
 
 
 
MUGA/echocardiogram8 
X 
 
 
 
 
 
 
 
 
 
 
Hematology (CBC and diff) 
 
X 
X16 X 
X 
weekly18 
X 
X 
X 
X 
 
Chemistry Labs 7 
 
X 
X 16
X 
X 
X 
X 
X 
X 
X 
 
Coagulation (INR, aPTT [or 
PTT], and PT) 
 
X 
 
 
 
 
 
 
 
 
 
Serum Pregnancy test 3 
 
X3 
X3 
 
 
X3 
X3 
X 
X3 
X3 
 
HIV 14, HBV 13, HCV 6 
X 
 
 
 
 
 
 
 
 
 
 
Quantitative IgA, IgG, IgM 
 
X 
 
 
 
 
X 
 
X 
X 
Optional Whole blood for MRD17
 
 
X 
 
 
 
 
X 
 
X 
 
Optional Immunology Research 
Blood 12 R
 
 
X12
 
 
 
X12 
X12 
X12 
 
X12 


ACCRU LY-1806
23
 
Protocol Version Date: 03FEB2022 
 
 
 
 
 
 
 
 
 
Tests and Procedures 
Days Prior to 
Registration 
Induction (21-day cycles) 
EOI 1 
Maintenance
(12 months)
EOM 2 
 
Post- Treatment 
clinical follow-
up period  
(q3m for 2 years 
+/- 14 days) 
 30 
days 
14 
days 
Cycle 1 
(±1 d) 
Cycle 2 
(±2 d) 
Cycles 3-6 
(±2 d) 
After last 
induction 
dose 
Monthly 
(30days) 
(±1 week) 
D1
35 days after last 
dose 
(±14 days) 
D1
D8 D15
D1 
D1 
Review Patient Medication 
Diary15
 
 
 
X 
X 
X 
X 
X 
X 
 
 
Optional tissue specimen R 
 
 
 
 
X11
 
 
X11 
Mandatory tissue specimen 19 R 
X 
 
 
 
 
 
 
 
Concomitant medications 
X 
 
To be recorded continually until end of treatment 
 
Adverse Event Assessment5 
X 
 
To be assessed continually 
PET-CT scan 
X 
 
 
 
 
 
 
X 
X9 
X 
X9 
Bone marrow biopsy and aspirate
X 10 
 
 
 
 
 
 
X10 
 
 
 
1 End of induction (EOI) is between 28-42 days after the last induction dose of rituximab and hyaluronidase human and polatuzumab vedotin. 
2 End of maintenance (EOM) visit may take place at 35 days +/- 14 days from the last dose of venetoclax treatment. 
3 For women of childbearing potential only. Must be done 7 days prior to registration, D1 of each induction cycle, Day 1 of each maintenance cycle, 
and end of maintenance. Test done ≤7 days prior to cycle1 day 1 can serve as cycle 1 day 1 test. 
4 For first infusion only, vital signs to be collected prior to dosing, every 15 minutes (+/- 5 minutes) during dosing and 30 minutes (+/- 10 minutes) 
after treatment completion until vital signs normalize or return to baseline. For vital signs that are normal/return to baseline at the 30 minutes (+/-
10 minutes) assessment, no additional vitals are required. For subsequent infusions, vital signs should be collected prior to dosing and every 30 
minutes (+/- 10 minutes) during dosing. After treatment completion: Patients who have never had a documented infusion reaction, post-dosing 
vital signs may be obtained at 30 minutes post infusion for the second infusion, and thereafter at 15 minutes after treatment completion. 
Additionally, O2 should be monitored as a vital sign during each visit. In cycle 1 if the investigator feels that the patient is at significant risk of 
tumor lysis patients should be monitored for tumor lysis per institutional standard. 
5 Adverse events will be assessed at the end of each induction cycle, EOI, EOM, and end of each maintenance cycle, and during clinical follow up  
6 At screening, testing should be performed for HIV antibody, hepatitis C antibody, and HBs antigen. These tests could be repeated later during the 
course of the study if clinically indicated. 
7 Chemistry laboratory analysis includes albumin, amylase, lipase, urea or BUN, creatinine, ALT, AST, LDH, serum alkaline phosphatase, direct 
and total bilirubin, glucose, total protein, sodium, potassium, chloride, HCO3 (CO2; venous blood), calcium, phosphorous. These labs must be 
done and reviewed before infusion. If labs for baseline are done within one week of starting therapy, they do not need to be repeated unless they 
are abnormal and need to be repeated per SOC. Serum chemistry will be obtained prior to administering venetoclax (predose) and 8 and 24 hours 
after dosing for the first dose only. Laboratory samples should be sent and analyzed immediately. This will be done for each ramp up dose. 


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8 Patients with known cardiac dysfunction are required to have EKGs and assessments of left ventricular ejection fraction at screening and as 
clinically indicated afterwards. 
9 PET/CT in maintenance and post treatment every 6 months or per standard of care. 
10 Baseline bone marrow biopsy and aspirate can be collected within 90 days of registration if negative. However, if bone marrow is positive after 
most recent therapy (even if greater than 90 days prior to registration), bone marrow biopsy and aspirate does not need to be repeated, but must 
be recorded as positive on the pre-treatment staging. Repeat Bone Marrow biopsy only in patients who are bone marrow positive at baseline and 
a CR at EOI to confirm EOI CR. Repeat Bone Marrow biopsy not needed in maintenance. 
11 Tissue specimen optional at the end of cycle 1 and optional at the time of progression. See Section 17.0 for additional details. 
12 Draw at baseline (drawn after registration but prior to cycle 1 treatment), day 1 of cycle 3, day 1 of cycle 7, day 1 of final maintenance cycle, 
and one year after completion of maintenance if patient is a CR. See Section 14.0 for further details. 
13 Screen all patients for hepatitis B (HBV) infection before initiating treatment with Rituxan. For patients who show evidence of prior hepatitis 
infection, consult an expert in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy before and/or during 
Rituxan treatment (see Section 9.5). 
14 If HIV testing is done ≤ 180 days prior to registration it does not need to be repeated. 
15 Patients will be required to keep a medication diary for venetoclax using the diary in Appendix V. Sites will be required to upload medication 
diary to RAVE at the end of each cycle. 
16 Hematology and chemistry will be obtained prior to administering venetoclax (predose) and 8 and 24 hours after the first dose only. Laboratory 
samples should be sent and analyzed immediately.  
17 MRD Testing to be completed at Mayo Clinic Rochester for patients who consent to optional collection.  
18 Subjects must return to the consenting ACCRU institution for CBC evaluation, or have outside laboratory CBC every 7 days during the first 6 
weeks of therapy 
19 Tissue is to be submitted no more than 30 days after registration. See Section 17.0 for more details.   
R Research funded 
 
4.1 
Survival Follow-up 
 
 
Survival Follow-up Phase 1 
Every 90 days 
until subsequent 
treatment or PD2
At subsequent 
treatment or 
PD2 
After subsequent 
treatment or PD2 
q. 180 days 
 
 
Death 
 
 
New Primary 
Survival Follow 
Up 
X 
X 
X 
X 
At each occurrence 
1 If a patient is still alive 5 years after registration and they have completed protocol therapy, no further follow-up is required. 
2 Progressive disease is based on either PET-CT based or CT based response criteria 
 
 
  NOTE: A +/-14 day window is allowed for all survival follow-up visits. 


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5.0 
Grouping Factors: 
 
5.1 
Cohort: Safety portion vs. expansion portion 
 
 
5.2 
Venetoclax Dosing Safety Lead-In: Dose 0 vs Dose -1  
 
5.3 
Previous ibrutinib exposure: ibrutinib naïve vs. ibrutinib pre-treated 
 
NOTE: To ensure equal distribution of both ibrutinib naïve and pretreated patients at the 
dose level determined during the safety run-in, a minimum of 25 patients must be ibrutinib 
naïve. Therefore, accrual of ibrutinib pretreated patients will stop after 26 Ibrutinib 
pretreated patients are accrued 
 
6.0 
Registration Procedures 
 
6.1 
Site Procedures 
 
6.11 
Study staff will need to complete the required training prior to gaining access to 
the registration application. This is located on the ACCRU web page at 
 Refer to Study Resources → Applications. Near the bottom of 
the page there will be a link to the “Research Registration Application Training.” 
After training is complete, study staff must complete the “Attestation of 
Training” and send to the ACCRU Registration Office at 
     
 
6.12 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients. Approvals should be uploaded using 
the online ACCRU Regulatory Management System (ARMS). 
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) with ACCRU. Approvals 
should be uploaded using the online ACCRU Regulatory Management System 
(ARMS). If the necessary documentation is not submitted in advance of 
attempting patient registration, the randomization will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved.  
 
Submission of annual IRB approvals is required until the study has been closed 
through your IRB. 
 
6.2 
Safety Portion 
 
Prior to discussing protocol entry with the patient, call the ACCRU Registration 
Office 
to ensure that a place on 
the protocol is open to the patient. 
 
6.21 
To register a patient, fax 
a 
completed eligibility checklist to the Academic and Community Cancer Research 
United (ACCRU) Registration Office between 8 a.m. and 4:30 p.m. central time 
Monday through Friday. 
 
6.3 
Expansion Portion 
 


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6.31 
To register a patient, access the ACCRU web page at 
go to the 
Study Resources → Application section and click on “Registration” and enter the 
registration application. The registration application is available 24 hours a day, 7 
days a week. Back up and/or system support contact information is available on 
the Web site. If unable to access the Web site, call the Academic and Community 
Cancer Research United (ACCRU) Registration Office at 
 
between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday through 
Friday). 
 
Instructions for the registration application are available on the above web page 
under the Study Resources → Application section. Please refer to the “Research 
Registration Application Training” or Quick Reference Guide for instructions.  
 
Prior to initiation of protocol study intervention, this process must be completed 
in its entirety and a ACCRU subject ID number must be available as noted in the 
instructions. It is the responsibility of the individual and institution registering the 
patient to confirm the process has been successfully completed prior to release of 
the study agent. Patient registration via the registration application can be 
confirmed in any of the following ways: 
 
Contact the ACCRU Registration Office 
 If the patient was 
fully registered, the ACCRU Registration Office staff can access the 
information from the centralized database and confirm the registration. 
 
Refer to the Research Registration Application training on the ACCRU 
website under Study Resources → Applications.  
 
6.4 
Safety and Expansion Portions 
 
6.41 
Correlative Research 
 
A mandatory correlative research component is part of this study, the patient will 
be automatically registered onto this component (see Sections 3.19a, and 17.1). 
 
An optional correlative research component is part of this study, there will be an 
option to select if the patient is to be registered onto this component (see Sections 
14.1 and 17.1). 
 
Patient has/has not given permission to give his/her blood sample for 
research testing.  
 
Patient has/has not given permission to give his/her tissue sample for 
research testing.  
 
6.42 
Prior to accepting the registration, registration application will verify the 
following: 
 
IRB approval at the registering institution 
 
Patient eligibility 
 
Existence of a signed consent form 
 
Existence of a signed authorization for use and disclosure of protected health 
information 
 
6.43 
At the time of registration, the following will be recorded: 
 
Patient has/has not given permission to store and use his/her blood sample(s) 


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for future research to learn about, prevent, or treat cancer. 
 
Patient has/has not given permission to store and use his/her blood sample(s) 
for future research to learn, prevent, or treat other health problems (for 
example: diabetes, Alzheimer’s disease, or heart disease). 
 
Patient has/has not given permission to store and use his/her tissue sample(s) 
for future research to learn about, prevent, or treat cancer. 
 
Patient has/has not given permission to store and use his/her tissue sample(s) 
for future research to learn, prevent, or treat other health problems (for 
example: diabetes, Alzheimer’s disease, or heart disease). 
 
Patient has/has not given permission for ACCRU to give his/her sample(s) to 
outside researchers. 

6.44 
Treatment cannot begin prior to registration and must begin  21 days after 
registration. 
 
6.45 
Pretreatment tests/procedures (see Section 4.0) must be completed within 
guidelines specified on the test schedule.  
 
6.46 
All required baseline symptoms (see Section 10.52) must be documented and 
graded. 
 
6.47 
Treatment on this protocol must commence at an ACCRU institution under the 
supervision of a medical oncologist or hematologist. 
 
6.48  Blood draw kit is available on site. 
 
7.0 
Protocol Treatment 
 
Safety Portion: An initial 6 patients will receive rituximab via IV on day 1 of cycle 1. On day 1 
of cycles 2-6 patients will receive rituximab and hyaluronidase human subcutaneously. On day 1 
of cycles 1-6 patients will receive polatuzumab vedotin via IV. Patients will also receive 
venetoclax daily during all cycles. See Table 7.2 for details. 
Expansion Portion: After confirming the optimal and safe tolerable dose of venetoclax, patients 
will continue with the same schedule of rituximab and hyaluronidase human. The safety portion 
will determine the frequency of venetoclax dosage. 
7.1 
Treatment Schedule - Use actual weight or estimated dry weight if fluid retention 
Pretreatment medication 
Agent
Dose
Route
Day
Dexamethasone1
10-20 mg 
IV or PO 
Within 1 hour of R/ScHyc/Pola 
Acetaminophen1
650mg
PO
Within 1 hour of R/ScHyc/Pola
Benadryl1and 
25-50 mg 
IV2 
30 minutes prior to R/ScHyc/Pola 
Ranitidine or 
50 mg 
Cimetidine or
300 mg
Famotidine
20 mg
Allopurinol 
100mg 
PO 
Three times daily from day 1 of 
cycle 1 to day 1 of cycle 3.


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Acyclovir
400mg
PO
Twice daily
Bactrim DS 
1 tablet three times 
a week
oral 
Continuously during treatment. 
Monday/Wednesday/Friday
1. If taken within 8 hours of Rituximab and polatuzumab, each premedication will only 
need to be taken once per cycle  
2. Benadryl can be taken PO or IV 
 
7.2 
Induction (Cycles 1-6): 
 
Patients will receive rituximab 375mg/m2 IV on day 1 of cycle 1, and rituximab and 
hyaluronidase human SQ day 1 of cycles 2-6 
 
Patients will receive polatuzumab vedotin 1.8 mg/kg IV on Day 1 of each 21-day 
cycle for a total of 6 cycles. 
 
Patients will receive venetoclax PO 20 mg beginning on day 1 of cycle 1. On day 7 of 
cycle 1 they will begin ramp-up increasing over 5 weeks to 400 mg po daily days 1-21 
cycles 1-6. If not tolerated venetoclax will be dose reduced. 
 
Missed/skipped/vomited doses will not be made up (i.e. the patient should not double 
their dose if the previous dose was missed). 
 
For first infusion only, vital signs to be collected prior to dosing, every 15 minutes 
(+/- 5 minutes) during dosing and 30 minutes (+/- 10 minutes) after treatment 
completion until vital signs normalize or return to baseline. For vital signs that are 
normal/return to baseline at the 30 minutes (+/-10 minutes) assessment, no additional 
vitals are required. For subsequent infusions, vital signs should be collected prior to 
dosing and every 30 minutes (+/- 10 minutes) during dosing. After treatment 
completion: Patients who have never had a documented infusion reaction, post-
dosing vital signs may be obtained at 30 minutes post infusion for the second 
infusion, and thereafter at 15 minutes after treatment completion. Additionally, O2 
should be monitored as a vital sign during each visit. In cycle 1, if the investigator 
feels that the patient is at significant risk of tumor lysis, patients should be monitored 
for tumor lysis per institutional standard. 
 
When study treatments are given on the same day, they will be administered 
sequentially in the following order: 
Order of Administration (See section 15 for individual drug instructions)  
1) Venetoclax# (No time constraints) 
2) Rituximab/rituximab and hyaluronidase human (if no reaction 30 minutes after 
completion, patient can receive polatuzumab vedotin) 
3) Polatuzumab vedotin 
# First dose of venetoclax will be given at the treatment center. All other doses may 
be taken at home 
Table 7.2a Induction (21 Day Cycles) 
 
Agent 
Dose 
Route 
Day2 
Rituximab
375mg/m2
IV
Day 1 Cycle 1
Rituximab and 
hyaluronidase human1
1,400 mg/23,400 Units 
SQ over  
5minutes
Day 1 Cycles 2-6 
Polatuzumab vedotin
1.8 mg/kg
IV
Day 1 Cycles 1-6
Venetoclax 
20 mg week 1 increasing over 5 weeks up to 
400 mg po daily days 1-21 cycles 1-6 3 See 
table 7.2b below 
PO 
Daily for Days 1-21
Cycles 1-6 
1. Rituximab IV is given in cycle 1, rituximab and hyaluronidase human is started on Cycle 2; All 
patients must receive and tolerate one full dose of rituximab by IV before starting with rituximab 


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and hyaluronidase human. 
2. 
 A +/- 3 day window is allowed for day 1 of treatment during induction. 
3. If 400 mg days 1-21 is not tolerated in the safety portion, venetoclax will dose reduced as 
outlined in Section 7.61. 
 
Table 7.2b Dosing Schedule for venetoclax Ramp-Up 
 
Venetoclax Daily Dose
Week 1 (Cycle 1 week 1)
20 mg
Week 2 (Cycle 1 week 2)
50 mg
Week 3 (Cycle 1 week 3)
100 mg
Week 4 (Cycle 2 week 1)
200 mg
Week 5 and beyond (Cycle 2 week 2 and beyond)
400 mg
 
After completion of induction treatment, patients will continue to receive daily 
venetoclax treatment (during Month 1) until response is assessed at EOI. Patients who 
have a CR, or PR at EOI will then receive venetoclax and rituximab and hyaluronidase 
human in maintenance as outlined in Table 7.3. Polatuzumab will not be given in 
maintenance. All therapy will be discontinued if response assessments at EOI indicate 
that a patient is not eligible for post- induction treatment (referred to as maintenance). 
Maintenance treatment will continue for 12 months or until disease progression. 
7.3 
Maintenance (Cycles 7-18): 
Table 7.3 (30 Day Cycles) 
 
Agent 
Dose 
Route 
Day2 
venetoclax 
maintenance
400mg daily 
for up to 1 year
PO 
*Daily for Days 1-21 
Rituximab and 
hyaluronidase human
1,400 
mg/23,400 
Units 
SQ over 5 
minutes 
First dose 6 weeks after end of 
rituximab and hyaluronidase human 
and polatuzumab vedotin induction 
treatment (+/- 2 weeks) 
 
Remaining treatments thereafter 
will be every 60 days for 1 year.1
1. Since cycle length is 30 days, rituximab and hyaluronidase human maintenance is 
given once every other cycle. A total of 6 rituximab and hyaluronidase human 
treatments during the maintenance phase. 
2. A +/- 7 day window is allowed for day 1 of treatment during maintenance.  
NOTE: No polatuzumab vedotin will be administered. 
3.   All subjects who get a dose reduction of Venetoclax during induction, will be   
maintained on the same corresponding dose in maintenance.   
* If 400 mg days 1-21 is not tolerated in the safety run-in, venetoclax will be given 
400 mg days 1-10. 
 
 
4.   For Venetoclax dose reductions in Maintenance refer to Table 8.21. 
 
7.4 
For this protocol, the patient must return to the consenting ACCRU institution for CBC 
evaluation, or have outside laboratory CBC every 7 days during the first 6 weeks of 
therapy, every 30 days during maintenance, and every 3 months during clinical follow-up 
(Active Monitoring Phase). 
 


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7.5 
Study treatment by a local medical doctor (LMD) is not allowed. 
 
7.6 
Safety Portion: Rules for Dose De-escalation 
 
Dose de-escalation will be considered if the initial safety portion dose level (venetoclax 
400 mg days 1-21) per Table 7.2a proves excessively toxic, with 2 or more subjects 
having excessive significant toxicity as defined in Section 7.7.  Dose de-escalation will 
proceed per section 7.6.1. 
7.61 
The first cohort of three patients will be treated at the starting dose level of 
Venetoclax (400 mg days 1-21) and observed for at least 63 days (3 cycles) from 
the start of treatment to assess toxicity. If significant toxicity as defined in 
Section 7.7 is observed in 0 or 1 of these 3 patients, 3 new patients will be 
accrued and treated at same dose level of Venetoclax (400 mg days 1-21) and 
observed for 3 cycles. After enrolling 6 patients on Venetoclax dose level of 400 
mg days 1-21, if ≤1 patient experience significant toxicity, then this dose will be 
considered safe and the rest of the patients in expansion cohort will be treated at 
this dose level of Venetoclax. However, if 2 or more out of the first 3 or 6 
patients experience significant toxicity, then the dose of venetoclax may be de-
escalated to 300mg days 1-21. In this case, another safety analysis using similar 
3+3 design approach will be conducted at the reduced dose level of venetoclax. 
 
7.7 
Definitions of significant toxicity 
 
7.71 
Toxicity will be measured per NCI-CTCAE version 5. For this protocol, 
significant toxicity will be defined as an adverse event occurring during the first 
3 cycles of treatment that is possibly, probably, or definitely related as follows: 
NOTE: All significant non-hematologic toxicities must be resolved to a 
minimum of grade 1 for ongoing treatment at any cycle of treatment. 
 
7.711 Non-Hematological significant toxicities. Any Grade 3 or Grade 4 non-
hematological toxicity that is possibly, probably or definitely attributable 
to the regimen of RSC+Pola+Ven is considered a significant toxicity, 
including the following: 
 Non-hematologic toxicity that causes a delay of >14 days in 
initiating cycle 2. 
 Any type of grade 3-4 hypersensitivity reaction (i.e.: allergic 
reaction, anaphylaxis, serum sickness, skin disorders, etc.), 
regardless of attribution, that necessitate discontinuation of study 
drug. 
 Any type of grade 3-4 immune related adverse event or immune 
system disorder including skin reactions. 
 Grade 3 or greater colitis and bowel perforation 
 Grade 3 ALT/AST elevation 
 Grade 3 or greater TLS 
 
NOTE: The following events are exclusions and are NOT considered a 
significant toxicity for this protocol, regardless of attribution or specific 
type: 
 Grade 3 nausea, vomiting, diarrhea, or oral mucositis with < 3 days 


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duration. 
 Grade 3 fever. 
 Grade 3 peripheral sensory neuropathy that is decreased by at least 
one grade within 7 days. 
 Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or 
hypomagnesemia responsive (i.e.: decreased by at least one grade) 
to oral supplementation within 7 days. 
 Grade 3 hypertriglyceridemia that returns to < Grade 2 prior to the 
beginning of cycle 2. 
 Grade 3 hyperglycemia that returns to < Grade 2 (with or without 
the use of insulin or oral diabetic agents) prior to the beginning of 
cycle 2. 
 
7.713 Hematological significant toxicity.  The following hematological 
toxicity possibly, probably or definitely attributable to the regimen of 
RSC+Pola+Ven is considered a significant toxicity: 
 Grade 4 neutropenia for > 7 days without growth factor support 
 Grade 4 febrile neutropenia 
 NOTE: Grade 4 non-febrile neutropenia will not be a significant 
toxicity but should warrant growth factor support on subsequent 
doses. 
 Platelet count < 25,000/uL on 2 separate days, or requiring a 
platelet transfusion on 2 separate days within a 7-day period 
 Myelosuppression that causes a delay of > 14 days in initiating 
cycle 2 
 Grade 3 thrombocytopenia with grade > 2 bleeding 
 
NOTE: Growth factors are allowed per treating investigator’s discretion 
in patients at high risk for febrile neutropenia after cycle 2, or in a patient 
who has demonstrated neutropenia on previous doses. Patients who are 
otherwise eligible per protocol with demonstrated bone marrow 
infiltration, may be treated with prophylactic growth factor support. 
 
7.8 
Patients will be required to keep a medication diary for venetoclax using the diary in 
Appendix V. Sites will be required to upload medication diary to RAVE at the end of 
each cycle. 
 
 
8.0 
Dosage Modification Based on Adverse Events 
 
Dose modification guidelines are provided specifically for venetoclax, polatuzumab vedotin, 
rituximab, and rituximab/hyaluronidase human in the tables below. In addition, Venetoclax dose 
reductions will be discussed in Section 8.21. 
 
If the patient requires a dose reduction, no dose re-escalation (e.g. no return to the baseline dose) 
is permitted. 
 
Additional dose reductions may be employed at investigator discretion as clinically appropriate to 
ensure patient safety, and exact modification, timing, and reasons should be recorded. 
 
8.1 
Assessment of Safety 


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The safety plan for patients in this study is based on clinical experience with rituximab, 
rituximab and hyaluronidase human, polatuzumab vedotin, and venetoclax. The anticipated 
important safety risks of rituximab, rituximab and hyaluronidase human, polatuzumab 
vedotin, and venetoclax are outlined below. Please refer to the rituximab, rituximab and 
hyaluronidase human, polatuzumab vedotin, and venetoclax Investigator's Brochures for a 
complete summary of safety information. 
 
8.2 
Venetoclax Dose Reduction and Re-Escalation Steps 
 
The dose of venetoclax may be reduced. If administration of chemotherapy is delayed, the 
administration of Pola and R/SC should be delayed for the same timeframe; for example, 
if polatuzumab and rituximab and hyaluronidase are delayed, administration of venetoclax 
should also be delayed so that they are given together beginning on Day 1 of the same 
cycle. 
 
For non-hematologic toxicities, dosing of Pola and R/SC  may be resumed upon resolution 
to Grade 1 or baseline status. Resumption of dosing without complete resolution of toxicity 
may only be considered after careful weighing of the benefits and risks with the patient. A 
dose delay of 21 days is permitted for immunochemotherapy to allow recovery of 
hematologic toxicities to Grade 2 or non-hematologic toxicities to Grade 1 or baseline 
status for the first episode. Actions for recurrent hematologic adverse events are described 
in Table 8.31. If treatment is delayed for more than 3 weeks, the patient should be 
withdrawn from study treatment except in exceptional circumstances which may be 
discussed with the study chair. (NOTE: Lymphopenia is not considered a cytopenic 
toxicity, as it is an expected outcome of therapy). Patients who discontinue all study 
treatment for adverse events should proceed to clinical follow up and remain in the study. 
 
The dose of venetoclax may be reduced according to the following dose reduction steps 
based on the starting dose.  
 
Table 8.21: Venetoclax Dose Reduction Steps during Induction and Maintenance (Duration of 
Venetoclax in Maintenance is 1 year). 
 
Venetoclax Dose Reduction 
Starting Dose 
(Dose 0) 
Step 1 
(Dose -1) 
Step 2 
(Dose -2) 
400 mg 
(days 1-21)
300mg 
(days 1-21)
200mg 
(days 1-21)
300mg 
(days 1-21) 
200mg 
(days 1-21) 
100mg 
(days 1-21) 
200mg 
(days 1-21)
100mg 
(days 1-21)
50mg 
(days 1-21)
100mg 
(days 1-21) 
50mg 
(days 1-21) 
20mg 
(days 1-21) 
50mg 
(days 1-21)
20mg 
(days 1-21)
 
 
 


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8.3 
Toxicities during Induction Treatment 
 
Table 8.31: Guidelines for Management of Hematologic Toxicities That Occur During Induction 
Treatment. 
Event
Action to Be Taken
Grade 3 or 
4 
Hematogic 
Toxicity 1 
For patients who have had one or no prior venetoclax or polatuzumab vedotin 
dose reduction: 
 
Withhold study treatment.1 
 
Administer RBCs or platelets as required. 
 
If patient has not already initiated G-CSF, initiate prophylactic G-CSF for 
current and subsequent cycles. 
 
Resume venetoclax and polatuzumab vedotin at same dose after 
interruption for 1st occurrence, once the toxicity has resolved to Grade 1 
or baseline level 
 
Resume venetoclax and polatuzumab vedotin at one level dose reduction 
after interruption for 2nd occurrence, once the toxicity has resolved to 
Grade 1 or baseline level. Refer to table 8.21 for dose reduction steps. 
 
For patients who develop platelet count of 20,000/L while receiving 
LMWH, reduce the dose of LMWH. For patients who develop platelet 
count of 20,000/L while receiving platelet inhibitors, consider temporarily 
withholding platelet inhibitors. 
No more than 2 dose level reductions in venetoclax and 
polatuzumab vedotin are allowed during induction. 
 
Consider discontinuation of study drug for patients who require 
withholding study drug for more than 21 days. 
For patients who have had two prior venetoclax dose reductions: 
 
Permanently discontinue study treatment. 
 
For grade 4 thrombocytopenia ≥ 7 days or grade 3 thrombocytopenia with 
≥ grade 2 bleeding resume venetoclax and polatuzumab at one dose level 
dose reduction after the toxicity has resolved to Grade 1 or baseline level
 
(G-CSF) granulocyte colony-stimulating factor; (LMWH) low molecular weight heparin. 
1 Treatment delays apply to all toxicities; dose modifications apply only to toxicities that are 
considered to be related to any of the study treatment components. Toxicities that occur during 
the cycle and subside prior to the next cycle should not trigger the suggested dose 
modifications. 


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Table 8.32: Guidelines for Management of Non-Hematologic Toxicities That Occur During Induction 
Event
Action to Be Taken
General guidance for 
treatment delays and 
discontinuation 
 If study treatment is withheld for 21 days because of a toxicity that is attributable to study treatment, permanently 
discontinue study treatment. 
 When a treatment cycle is delayed because of toxicity resulting from any component of the regimen, all study treatment 
should be held and resumed together to remain synchronized.
TLS 
 Withhold study treatment. a 
 Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including 
dialysis as indicated. 
 If symptoms have resolved completely, resume rituximab and hyaluronidase human and polatuzumab at full dose and 
resume venetoclax at current dose. 
 During venetoclax ramp-up, if venetoclax was withheld for 7 days or less, resume venetoclax at same dose level or at one 
lower dose level, as determined by the investigator (based on risk assessment, including tumor burden status). Refer to 
Table 8.21 for dose reduction steps. 
 During venetoclax ramp-up, if venetoclax was withheld for more than 7 days, the dose must be resumed at one lower dose 
level, with the exception of the first dose (20 mg). Refer to Table 8.21 for dose reduction steps. 
 If resolved within 24 to 48 hours of last dose, resume venetoclax at the same dose. 
 For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose. Refer to Table 8.21 
for dose reduction steps. 
 For any events of clinical TLS, resume at a reduced dose following resolution. Refer to Table 8.21 for dose reduction 
steps.
New-onset neurologic 
manifestations 
suggestive of PML 
 Withhold study treatment. a 
 Consult with a neurologist if PML is suspected. 
 If PML is ruled out, resume rituximab and hyaluronidase human, polatuzumab vedotin and venetoclax at current dose. 
 If PML is confirmed, permanently discontinue study treatment.
AST, ALT, or bilirubin 
increase: Grade 3 (or 
10x ULN for patients 
with liver involvement)
 Withhold study treatment. a 
 If improvement to Grade 1, resume rituximab and polatuzumab vedotin at full dose and resume venetoclax at next lower 
dose for current and subsequent cycles per guidelines in Table 8.21. No more than 2 dose level reductions from original 
dose of venetoclax are allowed during induction. Patients who have had two prior dose reductions should be permanently 
discontinued. Refer to Table 8.21 for dose reduction steps. 
 Permanently discontinue study treatment for life-threatening livertoxicity.
Infections and 
Infestations; AE: 
Hepatitis viral
 Discontinue therapy and treat hepatitis 
  
 


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Table 8.32: Guidelines for Management of Non-Hematologic Toxicities That Occur During Induction (cont.) 
Event 
Grade 
Action to Be Taken 
Peripheral Neuropathy Grade 4 
 Permanently discontinue polatuzumab vedotin and all other study treatment. 
Grade 2 
or 3 
1. Delay study treatment. a 
2. If improvement to Grade 1 within 21 days, resume study treatment for current and subsequent cycles as 
follows: 
a. Resume rituximab or rituximab and hyaluronidase human at full dose 
b. Resume venetoclax at current dose a 
c. For patients who started at 1.8 mg/kg, resume polatuzumab vedotin at the permanently reduced 
dose of 1.4 mg/kg; 
Other 
non-hematologic 
toxicities (i.e., not 
described above), 
excluding alopecia, 
nausea, and vomiting 
Grade 3 
or 4 
For patients who have had no prior dose reductions: 
 Withhold study treatment. a 
 If improvement to Grade 1 or baseline, resume rituximab and polatuzumab vedotin at full dose and resume 
venetoclax at next lower dose a for current and subsequent cycles per guidelines. 
For patients who have had one prior dose reduction: 
Grade 4 events 
 Permanently discontinue study treatment. Grade 3 events 
 Withhold study treatment. a 
 If improvement to Grade 1 or baseline, rituximab and polatuzumab vedotin at full dose and resume venetoclax
at next lower dose a for current and subsequent cycles per guidelines. No more than two dose level reductions
from the original dose of venetoclax are allowed during induction. 
For patients who have had two prior dose reductions: 
 Permanently discontinue study treatment.
Grade 2 
 Withhold study treatment. a 
 If improvement to Grade 1 or baseline, resume rituximab and polatuzumab vedotin, and venetoclax at full 
dose.
IRR-infusion-related reaction; PML-progressive multifocal leukoencephalopathy; TLS-tumor lysis syndrome; ULN-upper limit normal. 
a Treatment delays apply to all events; dose modifications apply only to events that are considered to be related to any of the study treatment components. 
Toxicities that occur during the cycle and subside prior to the next cycle should not trigger the suggested dose modifications. 


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8.4 
Toxicities during Maintenance Treatment provides guidelines for management of 
toxicities that occur during maintenance treatment. 
Table 8.43: Guidelines for Management of Toxicities That Occur during Maintenance Treatment 
Event 
Action to Be Taken 
Hematologic toxicity: 
Grade 3 or 4 
Withhold rituximab and hyaluronidase human and venetoclax 
 Administer G-CSF for neutropenia per institutional guidelines. 
 Administer RBCs or platelets as required. 
 If improvement to Grade 2, resume rituximab and hyaluronidase 
human at full dose and resume venetoclax next lower dose (Refer 
to table 8.21 for dose reduction steps.)  
Patients who are not eligible for further venetoclax dose 
reductions should be permanently discontinued. 
 If study treatment is withheld for 21 days, permanently 
discontinue study treatment.
Non-hematologic toxicity: 
Grade 2 
Withhold rituximab and hyaluronidase human and venetoclax  
If improvement to Grade ≤ 1 or baseline, resume rituximab and 
hyaluronidase human at full dose and resume venetoclax at next 
lower dose (Refer to table 8.21 for dose reduction steps). 
o 
a for subsequent cycles per guidelines 
o Patients who are not eligible for further venetoclax dose 
reductions should be permanently discontinued.  
 If study treatment is withheld for 21 days, permanently 
discontinue study treatment.
Infections and Infestations: 
Hepatitis Viral 
 Discontinue therapy and treat hepatitis 
G-CSF granulocyte colony-stimulating factor. 
 
Table 8.44: Prophylaxis and Assessments for Tumor Lysis Syndrome 
 
High Risk 
Regular Risk 
Definition 
 Bulky disease defined as: Any lymph node 
≥ 10 cm on the screening CT scan 
 Circulating lymphoma cells 
 Other characteristics deemed by the 
investigator to confer high risk of TLS 
 All other patients not meeting 
definition of high risk 
Hospitalization Required for intensive monitoring during 
initial dose of venetoclax (See Hospitalization 
section below) 
Not required, but may be 
hospitalized per discussion with 
the investigator and Medical 
Monitor 
Assessments 
On the day of the initial visit with administration of venetoclax (Cycle 1, Day 1): 
Serial vital signs will be recorded 
 
Patients who demonstrate electrolyte changes suggestive of TLS should 
undergo aggressive management and further monitoring as per standard 
of care and outlined in Appendix II. 
 
Patients still at risk of TLS before the subsequent dose should receive 
adequate prophylaxis and monitoring.
LDH=lactate dehydrogenase; TLS=tumor lysis syndrome Obinutuzumab, rituximab, polatuzumab vedotin, and 
venetoclax-F. Hoffman-La Roche Ltd Protocol GO29833, Version 4 


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8.5 
Management of Adverse Reactions for polatuzumab 
 
Table 8.51 Management of Peripheral Neuropathy, Infusion-Related Reaction, and Myelosuppression 
Event 
Dose Modification 
Grade 2–3 Peripheral 
Neuropathy 
 Hold polatuzumab dosing until improvement to Grade 1 or lower. 
 If recovered to Grade 1 or lower on or before Day 14, restart 
polatuzumab with the next cycle at a permanently reduced dose of 1.4 
mg/kg. 
 If a prior dose reduction to 1.4 mg/kg has occurred, discontinue 
polatuzumab. 
 If not recovered to Grade 1 or lower on or before Day 14, discontinue 
polatuzumab.
Grade 4 Peripheral 
Neuropathy 
 Discontinue polatuzumab. 
Grade 1–3 Infusion- 
Related Reaction 
 Interrupt polatuzumab infusion and give supportive treatment. 
 For the first instance of Grade 3 wheezing, bronchospasm, or generalized 
urticaria, permanently discontinue polatuzumab. 
 For recurrent Grade 2 wheezing or urticaria, or for recurrence of any 
Grade 3 symptoms, permanently discontinue polatuzumab. 
 Otherwise, upon complete resolution of symptoms, infusion may be 
resumed at 50% of the rate achieved prior to interruption. In the absence 
of infusion related symptoms, the rate of infusion may be escalated in 
increments of 50 mg/hour every 30 minutes. 
 For the next cycle, infuse polatuzumab over 90 minutes. If no infusion- 
related reaction occurs, subsequent infusions may be administered over 
30 minutes. Administer premedication for all cycles.
Grade 4 Infusion- 
Related Reaction 
 Stop polatuzumab infusion immediately. Give supportive treatment. 
 Permanently discontinue polatuzumab.
Grade 3–4 
Neutropeniaa,b 
 Hold all treatment until ANC recovers to greater than 1000/microliter. 
 If ANC recovers to greater than 1000/microliter on or before Day 7, 
resume all treatment without any additional dose reductions. Consider 
granulocyte colony-stimulating factor prophylaxis for subsequent cycles, 
if not previously given.
Grade 3–4 
Thrombocytopenia a,b 
 Hold all treatment until platelets recover to greater than 
75,000/microliter. 
 If platelets recover to greater than 75,000/microliter on or before Day 7, 
resume all treatment without any additional dose reductions.
Infections and 
Infestations: Hepatitis 
Viral 
 Discontinue therapy and treat hepatitis  
a Severity on Day 1 of any cycle. 
b If primary cause is due to lymphoma, dose delay or reduction may not be needed. 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Antiemetic’s may be used at the discretion of the attending physician. 
 
9.2 
Blood products and growth factors should be utilized as clinically warranted and 


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following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the American Society of Clinical Oncology (ASCO), 
Recommendations for the Use of WBC Growth Factors: American Society of Clinical 
Oncology Clinical Practice Guideline Update. J Clin Oncol 2015;33:3199-3212. 
 
9.3 
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records. 
 
9.4 
Diarrhea: This could be managed conservatively with loperamide. The recommended 
dose of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea 
free (maximum 16 mg/day). 
 
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed: 
hydration, octreotide, and antidiarrheals. 
 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed. 
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be hospitalized for intravenous hydration and correction of electrolyte imbalances. 
 
9.5 
Carriers of hepatitis B virus (HBV) should be closely monitored for clinical and 
laboratory signs of active HBV infection and for signs of hepatitis during and for up to 
several months following Rituxan therapy. In patients who develop viral hepatitis, 
Rituxan and any concomitant chemotherapy should be discontinued and appropriate 
treatment, including antiviral therapy, initiated. There are insufficient data regarding the 
safety of resuming Rituxan therapy in patients who develop hepatitis subsequent to HBV 
reactivation. 
 
9.6 
Prohibited Medications or Therapies 
 
 
9.61 
CYP3A Inhibitors/Inducers 
 
Treatment with strong and moderate inhibitors or inducers of CYP3A is not 
allowed during this trial. See Appendix I for more information. In addition, 
grapefruit or grapefruit products, Seville organs or products from Seville organs, 
and Star fruit should be avoided for the duration of the trial due to their effect on 
CYP3A4.  
 
9.62 
Proton pump inhibitors 
 
If subject is taking proton pump inhibitors, subject should be advised to avoid co-
administration and stagger venetoclax dosing. 
 
9.63 
Treatment with warfarin is prohibited due to potential DDIs that may increase the 
exposure of warfarin.   
 
 


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9.64 
Vaccination with a live virus vaccine is prohibited during this trial.  
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
The site principal investigator is responsible for reporting any/all adverse events to the sponsor as 
described within the protocol. Refer to the adverse event and serious adverse event sections of the 
protocol for detailed information. 
 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following: 
 
Any suspected adverse reaction that is both serious and unexpected. 
 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity. 
 
Any findings from epidemiological studies, pooled analysis of multiple studies, or clinical 
studies, whether or not conducted under an IND and whether or not conducted by the 
sponsor, that suggest a significant risk in humans exposed to the drug. 
 
Any clinically important increase in the rate of a serious suspected adverse reaction over the 
rate stated in the protocol or Investigator’s Brochure (IB). 
 
 
Definitions 
 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. 
 
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event. 
 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team 
becoming aware of the event. 
 
Routine Reporting 
Events reported to sponsor via case report forms 
 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited 
reporting, but that for a specific protocol are being reported via expedited means 
in order to facilitate the review of safety data (may be requested by the FDA or 
the sponsor). 
 
10.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site: 
 
 


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a. Adverse event monitoring and reporting is a routine part of every clinical trial. 
b. Identify the grade and severity of the event using the CTCAE version 5.0. 
c. Determine whether the event is expected or unexpected (see Section 10.2). 
d. Determine if the adverse event is related to the study intervention (agent, 
treatment or procedure) (see Section 10.3). 
e. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4). 
f. Determine if other reporting is required (see Section 10.5). 
g. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.53 
and 18.0). 
 
 
Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA Lowest 
Level Term (LLT). 
 
NOTE: A severe AE, as defined by the above grading scale, is NOT the same as serious 
AE which is defined in the table in Section 10.4. 
 
10.2 
Expected vs. Unexpected Events 
 
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan). 
 
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or procedure, 
the following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s).  
Probable - The adverse event is likely related to the agent(s).  
Possible - The adverse event may be related to the agent(s).  
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a medical 
treatment suggest there is evidence to indicate a causal relationship between the 
drug/device and the adverse event. 
 


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10.31 EXPECTED Serious Adverse Events: Protocol Specific Exceptions to Expedited 
Reporting 
For this protocol only, the following Adverse Events/Grades are expected to occur within 
this population and do not require Expedited Reporting. These events must still be 
reported via Routine Reporting (see Section 10.53).* 
 
 
System Organ Class 
(SOC) 
 
Adverse event/ Symptoms 
 
CTCAE Grade at which the event will 
not be expeditedly reported. 
General disorders and 
administrations site 
conditions
Fatigue
<Grade 3
Malaise 
≤Grade 3 
Blood and lymphatic 
system disorders 
Febrile Neutropenia 
≤Grade 3
Neutrophil count decreased 
≤Grade 3 
Thrombocytopenia
≤Grade 3
Investigations
Blood bilirubin increased
≤Grade 3
Metabolism and nutrition 
disorders
Tumor lysis syndrome 
≤Grade 3 
 
These exceptions only apply if the adverse event does not result in hospitalization. If the 
adverse event results in hospitalization, then the standard expedited adverse events 
reporting requirements must be followed. 
 
The following hospitalizations are not considered to be SAEs because there is no 
“adverse event” (i.e., there is no untoward medical occurrence) associated with the 
hospitalization: 
• 
Hospitalizations for respite care 
• 
Hospitalization planned before informed consent (where the condition requiring 
the hospitalization has not changed post study drug administration) 
• 
Hospitalization for administration of study drug or insertion of access for 
administration of study drug 
• 
Hospitalization for routine maintenance of a device (e.g., battery replacement) 
that was in place before study entry 
 
*Report any clinically important increase in the rate of a serious suspected adverse reaction 
(at your study) site over that which is listed in the protocol or investigator brochure as an 
expedited event. 
*Report an expected event that is greater in severity or specificity than expected as an 
expedited event. 
*An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with a 
higher degree of severity or specificity, expedited reporting is required. 
A list of known/expected AEs is reported in the investigator brochure, package insert or 
the literature, including AEs resulting from a drug overdose 
 


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10.311 Death 
 
Any death occurring within 30 days of the last dose, regardless of 
attribution to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
 
Any death occurring greater than 30 days with an attribution of 
possible, probable, or definite to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
Reportable categories of Death 
 
Death attributable to a CTCAE term. 
 
Death Neonatal: A disorder characterized by cessation of life 
during the first 28 days of life. 
 
Death NOS: A cessation of life that cannot be attributed to a 
CTCAE term associated with Grade 5. 
 
Sudden death NOS: A sudden (defined as instant or within one 
hour of the onset of symptoms) or an unobserved cessation of 
life that cannot be attributed to a CTCAE term associated with 
Grade 5. 
 
Death due to progressive disease that cannot be attributed to a 
CTCAE term associated with Grade 5 should be reported as 
Grade 5 “Disease progression” under the system organ class 
(SOC) of General Disorders and Administration Site Conditions. 
Evidence that the death was a manifestation of underlying 
disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease 
process) should be submitted. 
 
10.312 Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy). A secondary malignancy is not 
considered a metastasis of the initial neoplasm. 
 
All secondary malignancies that occur following treatment with an agent 
under an IND/IDE to be reported. Three options are available to describe 
the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
10.313 Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy). 
Second malignancies require ONLY routine reporting. 
 
10.314 Pregnancy 
Prior to obtaining private information about a pregnant woman and her 


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infant, the investigator must obtain consent from the pregnant woman 
and the newborn infant’s parent or legal guardian before any data 
collection can occur. A consent form will need to be submitted to the 
IRB for these subjects if a pregnancy occurs. If informed consent is not 
obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion the mother is the patient. 
In cases where the child/fetus experiences a serious adverse event other 
than fetal death, the child/fetus is the patient. 
 
NOTE: When submitting 
 
the potential risk of 
exposure of the fetus to the investigational agent(s) or chemotherapy 
agent(s) should be documented in the “Description of Event” section. 
Include any available medical documentation. 
 
 
10.4 
Expedited Adverse Event Reporting Requirements for IND/IDE Agents 
 
10.41 Phase 1 and Early Phase 2 Studies: Expedited Reporting via the MedWatch 
form for Adverse Events That Occur Within 30 Days1 of the Last Dose of the 
Investigational Agent 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death 
2) A life-threatening adverse event 
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
5) 
A congenital anomaly/birth defect. 
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A 
and ICH E6).
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within the 
timeframes detailed in the table below.
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization ≥24 hrs
7 Calendar Days 
 
24-Hour; 3 Calendar Days 
Not resulting in 
Hospitalization ≥24 hrs
Not required 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, followed by 
a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days of learning 
of the AE.


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1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have an 
attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
 All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
 Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the
nearest whole day, after the agent/intervention was last administered. Footnote “1” above applies after this reporting period. 
Effective Date: May 5, 2011
 
Special Instructions: 
Follow site-specific reporting guidelines. 
1) Submit SAE’s using the MedWatch form 3500A. 
or found on the ACCRU web site) along with the ACCRU Safety 
Reporting Cover Page (found on the ACCRU web site under Study Resources → 
Forms) to the ACCRU SAE Coordinator via email at 
 
 
2) The ACCRU SAE Coordinator will forward to Genentech at 
   
 
3) The ACCRU SAE Coordinator will forward to ACCRU IND Coordinator 
 as appropriate. The ACCRU IND 
Coordinator will assist the sponsor-investigator in notifying the FDA if required. 
4) ACCRU must be notified via email at 
if the 
following occurs: 
 
Data related to a suspected transmission of an infectious agent by the study 
drug (STIAMP), as defined below. 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product. This term applies only 
when a contamination of the study drug is suspected. 
 
This event will require expedited reporting and will be treated like a serious 
adverse event with regard to reporting timeframes. 
 
Genentech Adverse Events of Special Interest (AESI): AEs of Special Interest 
are defined by Genentech as a potential safety problem identified as a result of 
ongoing safety monitoring of their products. As such, surveillance for the AESIs 
below MUST be undertaken at each treatment evaluation. The following events 
are events of special interest and will require expedited reporting AT ANY 
GRADE and will be treated like a serious adverse event with regard to reporting 
timeframes.  
 
Events of clinical interest for this trial include:  
Potential drug-induced liver injury (DILI) as defined by Hy’s Law 
a. Investigations 
i. Alanine aminotransferase increase 
ii. Aspartate aminotransferase increase  


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b. Metabolism and nutritional disorders 
i. Tumor Lysis Syndrome 
c. Secondary Malignancies 
i. Treatment related secondary malignancy  
 
Adverse Event 
Form(s) 
Needed 
Site 
timeline to 
report to  
ACCRU
ACCRU timeline to 
report to sponsor 
Non-Serious 
Adverse Event 
(Sections 10.52- 
10.53)
Adverse Events 
form (see CRF 
packet) 
At each 
evaluation 
Quarterly 
Adverse Events of 
Special Interest 
(Section 
10.41 special 
instructions) 
Adverse Events 
of Special 
Interest Form**
At each 
occurrence
Within 1 business day of 
receipt 
Adverse 
Events 
form (if criteria in 
10.5 is met)
Quarterly 
Pregnancy 
(Section 10.314) 
MedWatch 
Form** 
At each 
occurrence
Within 1 business day of 
receipt 
 Serious Adverse 
Events (Section 
10.41)* 
MedWatch 
Form** 
At each 
occurrence
Within 1 business day of 
receipt 
Adverse Events 
form (see CRF 
packet) 
Quarterly 
*If an adverse event meets the criteria for both an AE of Special Interest and a Serious Adverse 
Event, please report only as a Serious Adverse Event. 
** MedWatch form can be found on the ACCRU website. 
10.42 Reporting of re-occurring SAEs 
ALL SERIOUS adverse events that meet the criteria outlined in Table 10.41 
MUST be immediately reported to the sponsor within the timeframes detailed in 
the corresponding table. This reporting includes but is not limited to SAEs that 
re-occur again after resolution. 
10.5 
Other Required Reporting 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 


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involved in the research); and 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
If the event meets the criteria for an UPIRTSO, submit to your IRB as required 
by your institutional policies. 
 
10.52 Baseline and Adverse Events Evaluations 
 
The following pre-treatment symptoms/conditions are to be graded at baseline 
and at each evaluation using CTCAE v5.0 grading. 
 
System Organ Class 
(SOC) 
Adverse 
Event/Symptoms 
Baseline 
Each 
evaluation 
Nervous system disorders 
Peripheral Sensory 
Neuropathy
X 
X 
Blood and 
lymphatic system disorders
Anemia 
X 
X 
Investigations 
Neutrophil count 
decreased
X 
X 
10.53 Case Report Forms - Academic and Community Cancer Research United 
(ACCRU) 
Submit the following AEs not specified in Section 10.5. Submit via appropriate 
Academic and Community Cancer Research United (ACCRU) Case Report 
Forms (i.e., paper or electronic, as applicable) the following AEs experienced by 
a patient and not specified in Section 10.5: 
 
10.531 Grade 2 AEs deemed possibly, probably, or definitely related to 
the study treatment or procedure. 
 
10.532 Grade 3 and 4 AEs regardless of attribution to the study treatment 
or procedure 
 
10.533 Grade 5 AEs (Deaths) 
-Any death within 30 days of the patient’s last study treatment or 
procedure regardless of attribution to the study treatment or 
procedure requires expedited reporting within 24-hours . 
-Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, with a 
CTCAE type and attribution assigned. 
 
10.54 Late occurring adverse events are any adverse events that occur during Clinical 


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Follow-Up and Survival Follow-Up reporting periods. These are reported in 
compliance with Section 4.0 and Section 18.0. 
 
10.55 Reconciliation: ACCRU agrees to conduct reconciliation for the product. 
Genentech and ACCRU will agree to the reconciliation periodicity and format 
but agree at maximum to exchange quarterly line listings of cases received by the 
other party. If discrepancies are identified, the Sponsor and Genentech will 
cooperate in resolving the discrepancies. The responsible individuals for each 
party shall handle the matter on a case-by-case basis until satisfactory resolution. 
10.56 Quarterly Report: ACCRU will provide Genentech with accrual and a toxicity 
report on a quarterly basis. 
10.57 IND Annual Reports: All IND annual reports submitted to the FDA by the 
Sponsor-Investigator should be copied to Genentech. 
 
11.0 
Treatment Evaluation 
 
Lugano Classification Response Criteria 
 
11.1 
Response Considerations 
 
Schedule of Evaluations: PET/CT scans are required at baseline for all patients. For the 
purposes of this study, patients should be reevaluated for disease progression at the end 
of induction therapy and every 6 months during maintenance or per standard of care. 
Definitions for clinical response for patients with lymphoma are from the recently revised 
Cheson’s et al criteria published in 2014, derived from the original criteria published in 
2007. (Cheson et al, 2014) (Cheson et al, 2007). Lymph node measurements should be 
taken from the CT portion of the PET/CT, or other dedicated CT scans where applicable. 
Measurement of lymphadenopathy for purposes of assessing for PR will be determined 
by adding the sum of the products of the maximal perpendicular diameters of measured 
lesions (SPD). The PPD of a single node is sufficient to evaluate for PD (see Table 11.2). 
Measurable extranodal disease should be assessed in a manner similar to that for nodal 
disease. For these recommendations, the spleen is considered nodal disease. Disease that 
is only assessable (eg, pleural effusions, bone lesions) will be recorded as present or 
absent only, unless, while an abnormality is still noted by imaging studies or physical 
examination, it is found to be histologically and pathologically negative. 
 
Response is based on PET/CT based on the revised 2014 Lugano Classification. (Cheson 
et al, 2014). 
 
Progressive disease is based on either PET-CT based or CT based response criteria. PET 
confirmation of progressive disease is per physician discretion. 
 
11.2 
Lugano Classification Response criteria (Cheson et al, 2014) 
 
 
PET-CT Based Response 
CT-Based Response 
Complete 
Response 
Complete metabolic response (CR) 
Complete radiologic response (CR) 
(all of the following) 


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Lymph nodes 
and 
extralymphatic 
sites 
Score 1, 2, or 3* with or without a residual 
mass on 5PS† 
It is recognized that in Waldeyer’s ring or 
extranodal sites with high physiologic 
uptake or with activation within spleen or 
marrow (eg, with chemotherapy or myeloid 
colony-stimulating factors), uptake may be 
greater than normal mediastinum and/or 
liver. In this circumstance, complete 
metabolic response may be inferred if 
uptake at sites of initial involvement is no 
greater 
than surrounding normal tissue even if the 
tissue has high physiologic uptake
Target nodes/nodal masses must regress 
to ≤ 1.5 cm in LDi 
No extralymphatic sites of disease 
Nonmeasured 
lesion
Not applicable 
Absent 
Organ 
enlargement
Not applicable 
Regress to normal 
New lesions
None
None
Bone marrow 
No evidence of FDG-avid disease in 
marrow
Normal by morphology; if 
indeterminate, IHC negative
Partial 
Response 
Partial metabolic response (PR) 
Partial remission (PR) (all of the following)
Lymph nodes 
and 
extralymphatic 
sites 
Score 4 or 5† with reduced uptake 
compared with baseline and residual 
mass(es) of any size 
At interim, these findings suggest 
responding disease 
At end of treatment, these findings indicate 
residual disease 
≥ 50% decrease in SPD of up to 6 target 
measurable nodes and extranodal sites 
When a lesion is too small to measure on CT, 
assign 5 mm X 5 mm as the default value 
When no longer visible, 0 X 0 mm For a node 
> 5 mm X 5 mm, but smaller than normal, use 
actual measurement for calculation 
Nonmeasured 
lesions
Not applicable 
Absent/normal, regressed, but no increase 
Organ 
enlargement
Not applicable 
Spleen must have regressed by > 50% in 
length beyond normal
New lesions
None
None
Bone marrow 
Residual uptake higher than uptake in 
normal marrow but reduced compared with 
baseline (diffuse uptake compatible with 
reactive changes from chemotherapy 
allowed). If there are persistent focal 
changes in the marrow in the context of a 
nodal response, consideration should be 
given to further evaluation with MRI or 
biopsy or an interval scan
Not Applicable 


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No Response 
or Stable 
Disease 
No metabolic response (SD) 
Stable disease (SD) 
Target 
nodes/nodal 
masses, 
extranodal 
lesions
Score 4 or 5 with no significant change in 
FDG uptake from baseline at interim or 
end of treatment 
< 50% decrease from baseline in SPD of up to 
6 dominant, measurable nodes and extranodal 
sites; no criteria for progressive disease are 
met 
Nonmeasured 
lesions
Not applicable 
No increase consistent with progression 
Organ 
enlargement
Not applicable 
No increase consistent with progression 
New lesions
None
None
Bone marrow
No change from baseline
Not Applicable
Progressive 
disease 
Progressive metabolic disease (PD) 
Progressive disease (PD) 
requires at least 1 of the following 
Individual 
target 
nodes/nodal 
masses
Score 4 or 5 with an increase in intensity of 
uptake from baseline and/or 
 
New FDG-avid foci consistent with 
lymphoma at interim or end-of-treatment 
assessment 
PPD progression: 
An individual node/lesion must be abnormal 
with: 
LDi > 1.5 cm and 
Increase by ≥ 50% from PPD nadir and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions ≤2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, the splenic 
length must increase by > 50% of the extent of 
its prior increase beyond baseline (eg, a 15- 
cm spleen must increase to 
> 16 cm). If no prior splenomegaly, must 
increase by at least 2 cm from baseline 
New or recurrent splenomegaly
Extranodal 
lesions 
Nonmeasured 
lesions
None 
New or clear progression of preexisting 
nonmeasured lesions
New lesions 
New FDG-avid foci consistent with 
lymphoma rather than another etiology (eg, 
infection, inflammation). If uncertain 
regarding etiology of new lesions, biopsy 
or interval scan may be considered 
Regrowth of previously resolved lesions 
A new node > 1.5 cm in any axis A new 
extranodal site > 1.0 cm in 
any axis; if < 1.0 cm in any axis, its presence 
must be unequivocal and must be attributable 
to lymphoma Assessable disease of any size 
unequivocally attributable to 
lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance imaging; 
PET, positron emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, 
shortest axis perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for multiple 
lesions. 
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time 


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of an interim scan. However, in trials involving PET where de-escalation is investigated, it may be 
preferable to consider a score of 3 as inadequate response (to avoid under treatment). Measured dominant 
lesions: Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly 
measurable in two diameters. Nodes should preferably be from disparate regions of the body and should 
include, where applicable, mediastinal and retroperitoneal areas. Non- nodal lesions include those in solid 
organs (eg, liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. 
Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly assessable disease 
should be considered not measured. These sites include any nodes, nodal masses, and extranodal sites not 
selected as dominant or measurable or 
that do not meet the requirements for measurability but are still considered abnormal, as well as truly 
assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively 
with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal 
masses, and other lesions that cannot be confirmed and followed by imaging. In Waldeyer’s ring or in 
extranodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with 
complete metabolic response but should be no higher than surrounding normal physiologic uptake (eg, with 
marrow activation as a result of chemotherapy or myeloid growth factors). 
†PET Deauville 5PS: 1, no uptake above background; 2, uptake≤mediastinum; 3, uptake > mediastinum but 
≤ liver; 4, uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas 
of uptake unlikely to be related to lymphoma.
 
 
12.0 
Descriptive Factors 
 
12.1 
International Prognostic Index (IPI) [Shipp et al, 1993]: low risk (0 or 1 risk factors) vs. 
low intermediate (2 risk factors) vs. high intermediate (3 risk factors) vs. high (4 or 5 risk 
factors) 
 
Risk Factors 
0 points 
1 point 
Age 
≤ 60 yrs. 
> 60 yrs. 
Serum LDH 
≤ 1 x normal 
> 1 x normal 
ECOG PS 
0 or 1 
≥2 
Stage 
I or II 
III or IV 
Extranodal involvement 
≤1 site 
>1 site 
 
 
Total number of risk factors = sum of the number of points for each prognostic factor. 
 
12.2 
Mantle Cell Lymphoma International Prognostic Index (Formula-based MIPI): Scores 
determine risk group: Low risk (<5.7) vs. Intermediate risk (≥5.7-<6.2) vs. High risk (≥ 
6.2). 
 
The MIPI score is calculated by this formula: [0.03535 × age (years)] + 0.6978 (if ECOG 
> 1)+ [1.367 × log10(LDH/ULN)]+ [0.9393 × log10(WBC count per µL)]. 
 
Note: The MIPI score will be calculated in Rave once the components are entered. 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
 
13.1 
Patients who achieve a CR or PR at EOI will receive post induction maintenance treatment 
with rituximab and hyaluronidase human + venetoclax for up to one year (see Section 7.0). 
 
13.2 
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follow-up, every 90 days (3 months) +/- 14 days for 2 years. 
 
13.3 
Patients who complete 2 years of clinical follow-up will continue to survival follow up 
for a maximum of 5 years from registration. 
 
13.4 
Patients who go off treatment for adverse events will proceed to clinical follow up. 
 
 
13.5 
Patients who receive alternative therapy or develop progression by CT-based criteria or 
by PET-CT based criteria at any time while receiving therapy or while in clinical follow-
up will go to survival follow up. 
 
13.6 
Patients who go off protocol treatment for reasons other than progression or alternative 
therapy will go to clinical follow-up. 
 
13.7 
Additional reasons for study treatment discontinuation. 
 
13.71 Patients will go to survival follow-up if pregnancy occurs. 
 
13.72 If a patient develops any medical condition that the investigator determines may 
jeopardize the patient’s safety if they continue to receive study treatment they 
will be removed from treatment and continue to clinical follow up. 
 
13.8 
Reasons for patient discontinuation from study. No further follow up of any kind will be 
required. 
 
13.81 Patient withdrawal of consent for all follow-up 
 
13.82 Study termination or site closure 
 
13.83 Patient non-compliance, defined as failure to comply with protocol requirements 
as determined by the investigator 
 
13.9a 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. 
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable). 
 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted. Survival follow-up will be required per Section 
18.0 of the protocol. 
 
If the patient never received treatment, on-study material and the off-treatment 
form must be submitted. No further data submission is necessary. 
 
13.9b A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable. All data up until the point of confirmation of a major violation must be 
submitted. The patient will go directly to the survival follow-up phase of the study. The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered. Survival follow-up 
will be required per Section 18.0 of the protocol. 
 


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13.9c 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the Off Treatment Form must be 
submitted. No further data submission is necessary. 
 
14.0 
Body Fluid Biospecimens 
 
14.1 
Summary Table of Research Blood/Blood Products to Be Collected for This Protocol 
Correlative 
Study  
Mandatory or
Optional 
Blood or 
Body Fluid 
being 
Collected
Type of 
Collection 
Tube (color 
of tube top)
Volume to 
collect per 
tube (# of 
tubes to be  
collected) 
Baseline 
(Drawn after 
registration 
but prior to 
cycle 1 
treatment) 
Day 1
Cycle 
3 
End of 
Induction 
Day 1 
Cycle 7 
End of 
Maintenance 
Day 1 Cycle
18 
One year post 
final 
maintenance 
treatment for 
patients who 
remain in 
CR1
Temperature/ 
Conditions 
MRD  
Optional 
Blood 
EDTA 
(purple)
10ml (1)
X 
 
X 
X 
 
Ambient 
Banking 
Optional 
Blood 
EDTA 
(purple)
10ml (4)
X 
X 
X 
X 
X 
Ambient 
Banking 
Optional 
Blood 
Streck CF 
DNA 
10ml (2) 
X 
X 
X 
X 
X 
Ambient 
1 +/-8 weeks 
After all samples have been processed according to kit instructions, ship all specimens according to 
shipping instructions (see Section 14.2 for detailed shipping instructions.) 
 
14.2 
Blood/Blood Products Handling 
 
14.21 Kits are provided for this study. 
 
The kit contains supplies and instructions for collecting, processing, and shipping 
specimens. 
 
Participating institutions may obtain kits by e-mailing the Mayo Hematology 
Research Tissue Bank at 
 E-mail requests 
should include the site address, contact information and number of kits being 
requested. 
 
Kits will be sent via FedEx® Ground at no additional cost to the participating 
institutions. Allow 3 to 4 business days to receive the kits. 
 
 
14.22 Label specimen tubes with the protocol number, the patient’s initials (last, first, 
middle), study patient ID number (if available) and date of blood collection. 
 
14.23 Collect all peripheral blood according to specific kit instructions (see table 
above). 
 
14.24 Shipping 
 
Specimens must be shipped the same day they are drawn. 
 
Ship the EDTA and Streck whole blood tubes in the provided Styrofoam kits; no 
cold pack is required but may be used. The Fed Ex air bill is pre-addressed. 
 
Ship specimens via Priority Overnight service on Monday – Thursday 


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(Friday only if you coordinate with lab contact) directly to: 
 
  
  
  
 
 
 
 
Please send email message to 
The 
message should include the study name, sample type, Fed Ex air bill tracking 
number, contact name and telephone number. Phone calls if necessary, to 
 
Shipping costs will be covered by the study if these kits and Fed Ex air bills are 
used for shipping specimens. Each kit contains the required tubes. 
 
 
14.3 
Handling and storage of specimens  
 
14.31 Blood samples: Plasma (from Streck cfDNA BCT® and EDTA tubes) and buffy 
coat (containing peripheral blood mononuclear cells from EDTA tubes) will be 
harvested and stored. In addition, aliquots of peripheral blood mononuclear cells 
will be cryopreserved. 10 mL EDTA tube will be forwarded to BAP for MRD 
testing.  
 
14.4 
Study Methodology and Storage Information  
 
14.41 All research blood samples (plasma, cells) will be stored for future correlative 
research.  
 
14.42 Return of Genetic Testing Research Results 
Future correlative research may involve DNA and/or RNA extracted from 
banked blood or blood cell specimens. Results of the research involving these 
DNA and/or RNA are not currently anticipated to have clinical relevance to the 
patient or their family members, and the genetic results will not be disclosed to 
the patients or their physicians. 
 
If, at any time, genetic results are obtained that may have clinical relevance, IRB 
review and approval will be sough regarding the most appropriate manner of 
disclosure and whether or not validation in a CLIA-certified setting will be 
required. Sharing of research data with individual patients should only occur 
when data have been validated by multiple studies and testing has been done in 
CLIA-approved laboratories. 
 
15.0 
Drug Information 
 
IND number 152666 
 
Investigator brochure will be made available on the ACCRU website. 
 
15.1 
Venetoclax (ABT-199, GDC-0199, Venclexta®) 
 


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15.11 Background: Venetoclax is a small-molecule B-cell lymphoma-2 (Bcl-2) family 
inhibitor in the biarylacylsulfonamide chemical class. Venetoclax binds with high 
affinity to antiapoptotic protein Bcl-2 and with lower affinity to other 
antiapoptotic Bcl-2 family proteins, like Bcl-XL and Bcl-w. 
 
15.12 Formulation: Venetoclax is available as 10, 50, and 100 mg tablets. The 
excipients are: copovidone, colloidal silicon dioxide, Polysorbate 80, sodium 
stearyl fumarate and calcium phosphate dibasic. Venetoclax 10 mg and 100 mg 
coating contains iron oxide yellow, polyvinyl alcohol, polyethylene glycol, talc, 
and titanium oxide. Venetoclax 50 mg coating contains iron oxide yellow, iron 
oxide red, iron oxide black, polyvinyl alcohol, titanium dioxide, polyethylene 
glycol and talc.  
 
High Dose venetoclax tablets are available as 160 and 200 mg tablets.  The 
excipients are: copovidone, colloidal silicon dioxide, polysorbate 80, and sodium 
stearyl fumarate.  The coating contains iron oxide yellow, polyvinyl alcohol, 
titanium dioxide, polyethylene glycol, and talc. 
 
15.13 Preparation and storage: The clinical supply for all formulations can be stored 
at not more than 25°C (77°F). Actual labeled storage conditions may be more 
conservative based on country specific regulations. 
 
15.14 Administration: Venetoclax tablets should be taken orally once daily with a 
meal and water. Do not chew, crush, or break tablets. If the patient misses a dose 
of venetoclax within 8 hours of the time it is usually taken, the patient should 
take the missed dose as soon as possible and resume the normal daily dosing 
schedule. If a patient misses a dose by more than 8 hours, the patient should not 
take the missed dose and should resume the usual dosing schedule the next day. 
If the patient vomits following dosing, no additional dose should be taken that 
day. 
 
15.15 Pharmacokinetic information: 
Absorption: The maximum plasma concentration of venetoclax was attained 5 to 
8 hours after dosing. In subjects with CLL, venetoclax showed minimal 
accumulation, and steady-state AUC increased proportionally over the dose range 
of 150 to 800 mg. 
Food increased the bioavailability of venetoclax by approximately 3- to 5-fold. 
Distribution: Venetoclax is highly bound to plasma proteins with unbound 
fraction (fu) < 0.01. Blood-to-plasma concentration ratios show venetoclax do 
not partition preferentially into the cellular compartment. 
Metabolism: Biotransformation of venetoclax in humans primarily involves 
enzymatic oxidation on the dimethyl cyclohexenyl moiety to form metabolites. 
One of the metabolites, M5, undergoes CYP- mediated cyclization at the α-
carbon of piperazine to generate M27. In human, M27 was identified as a major 
metabolite with an inhibitory activity against BCL-2 that is at least 58-fold lower 
than venetoclax in vitro. 
Half-life elimination: 17-41 hours following a single dose of venetoclax 
Excretion: Venetoclax is primarily eliminated as metabolites in feces (99.9 ± 
5.0%) with negligible renal elimination (< 0.1%).  Based on the population 
pharmacokinetic analysis, age, sex, race, weight, mild or moderate hepatic 
impairment and mild, moderate, or severe renal impairment do not have a 


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clinically meaningful effect on venetoclax clearance. 
 
Special patient populations: Venetoclax should not be administered to pregnant 
women. It is not known whether venetoclax is excreted in human milk, so 
venetoclax should not be administered to nursing mothers. 
 
 
Hepatic Impairment: Mean venetoclax AUC exposures in subjects with severe 
hepatic impairment were approximately 2.3- to 2.7-fold higher as compared with 
subjects with normal hepatic function. On the basis of these results, a dose 
adjustment in patients with severe hepatic impairment is recommended. 
 
15.16 Potential Drug Interactions: Venetoclax is predominately metabolized by 
CYP3A4 in vitro, thus CYP3A4 inhibitors or inducers are expected to cause 
changes in venetoclax exposures. Venetoclax should not be used with strong 
CYP3A inhibitors (e.g., ketoconazole, ritonavir, clarithromycin, itraconazole, 
voriconazole) at initiation and during ramp-up phase. Concomitant use of 
venetoclax with moderate CYP3A inhibitors (e.g., erythromycin, ciprofloxacin, 
diltiazem, fluconazole, verapamil), or strong CYP3A inducers (e.g., 
carbamazepine, phenytoin, rifampin, St. John's wort), or moderate CYP3A 
inducers (e.g., bosentan, efavirenz, etavirine) should be avoided. For patients 
who have completed the ramp-up phase and are on a steady daily dose of 
venetoclax, concomitant use of strong and moderate CYP3A inhibitors may be 
allowed with venetoclax dose reductions. If a strong CYP3A inhibitor must be 
used after the ramp-up phase, reduce the venetoclax dose by at least 75%. If a 
moderate CYP3A inhibitor must be used, reduce the venetoclax dose by at least 
50%. 
 
Advise patients to avoid consuming grapefruit products, Seville oranges, or 
starfruit during treatment with venetoclax. 
 
Venetoclax should be administered using caution with weak inhibitors or 
inducers of CYP3A, substrates or inhibitors of P-gp, BCRP, or OATP1B1/B3. If 
a P-gp inhibitor must be used, reduce the venetoclax dose by at least 50%. If a 
narrow therapeutic index P-gp substrate must be used, it should be taken at least 
6 hours before venetoclax. Avoid co-administration with proton pump inhibitors, 
and stagger venetoclax dosing with H2-receptor antagonists and antacids as 
described in the USPI. 
 
If venetoclax is co-administered with warfarin, the international normalized ratio 
(INR) should be monitored closely. 
 
Live-virus vaccines should not be given within 28 days prior to the initiation of 
study treatment, at any time during study treatment, or in the 30 days following 
last dose of study treatment. 
 
15.17 Known potential toxicities: 
 
Very common (≥ 10%): edema, skin rash, hyperglycemia, hyperkalemia, 
hypoalbuminemia, hypocalcemia, hyponatremia, hypophosphatemia, 
abdominal pain, constipation, diarrhea, nausea, stomatitis, vomiting, 
anemia, leukopenia, lymphocytopenia, neutropenia, thrombocytopenia, 
increased serum aspartate aminotransferase, dizziness, fatigue, headache, 


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arthralgia, musculoskeletal pain, cough, dyspnea, lower respiratory 
infection, pneumonia, upper respiratory infection, fever  
Common (≥ 1% to < 10%): febrile neutropenia, tumor lysis syndrome, 
sepsis 
Frequency not defined: hemolytic anemia 
 
Tumor lysis syndrome (TLS) is an important identified risk for venetoclax 
in oncology studies, especially in CLL and MCL. The risk is during the 
first 5 weeks of ramp-up period. A low starting dose followed by gradual 
dose ramp-up allows for the tumor size to be gradually reduced and has 
been effective in reducing the risk of TLS. 
 
Serious infection is an important identified risk for venetoclax. Serious 
infections, including sepsis and fatal events, have been reported in the 
oncology clinical studies; these events are confounded by the underlying 
disease, comorbidities, and prior or concomitant immunosuppressive 
medications in the majority of cases. Serious infections occur with and 
without neutropenia, and to date, no clear relationship has been noted 
between the onset of neutropenia events and serious infectious events in 
the context of venetoclax. Prophylactic antibiotic treatment is 
recommended/required (depending on the combination) in all protocols as 
a preventative measure. 
 
15.18 Drug procurement: Investigational venetoclax will be provided free of charge 
to study participants. 
 
Genentech will supply investigational supply to McKesson . Each participating 
ACCRU treating location will order the drug from McKesson. Submit the Drug 
Order Request Form (found on the ACCRU web site) to:  
 
McKesson  
 
  
Each participating ACCRU treating location will be responsible for 
monitoring the supply of venetoclax and will use the Drug Order Request 
Form to order additional supplies as needed. 
 
Outdated or remaining drug is to be destroyed on-site as per procedures 
in place at each institution. 
 
15.19 Nursing Guidelines: 
 
15.191  Agent should be taken with a meal and water. Patients should be 
instructed not to crush, chew, or break tablet. Patients who miss their 
dose by more than 8 hours should not make up dose. 
15.192  Assess patients medication both prescription and over the counter. 
Venetoclax should not be taken with strong CYP3A inhibitors. 
 
15.193  Patients should be advised not to consume grapefruit, Seville oranges, or 
starfruit or their juices while taking venetoclax. 


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15.194  Patients who are also taking Coumadin while on venetoclax should be 
advised to have their INR checked more frequently. 
 
15.195  Venetoclax can cause tumor lysis syndrome. Patients should be 
monitored closely during the ramp up phase, including monitoring 
electrolytes, and renal function. 
 
15.196  Cytopenias are very common. Instruct patient to report any unusual 
bruising or bleeding and/or signs or symptoms of infection to the study 
team. 
 
15.197  Gastrointestinal side effects are common and include nausea, vomiting, 
diarrhea, and constipation. Treat symptomatically and monitor for 
effectiveness of intervention. 
 
15.198  Rarely patients can experience URI symptoms, cough and pneumonia. 
Instruct patients to report any cough, shortness of breath and/or chest 
pain to study team. 
 
15.199 Patients who have severe hepatic impairment should have a dose 
adjustment 
 
15.199a Live virus vaccines should not be given within 28 days prior to initiation 
of treatment, during treatment, or for 30 days afterwards. See Section 9.6 
Prohibited Medications or Therapies.  
 
15.199b Monitor LFT’s. 
 
15.199c Due to high risk of infection/sepsis, prophylactic antibiotic treatment is 
recommended and in some situations required, given combinatorial 
regimens. 
 
15.19a  Temperature excursions that occur at the site should be reported by the site using 
the Genentech Temperature Excursion Form found on the ACCRU web site for 
this study and emailed to: 
 
 
Any shipment deviations (those not occurring at the site) should be 
reported to McKesson via email to: 
 
 
15.2 
Polatuzumab Vedotin (RO5541077, Polivy™): 
 
Investigator brochure will be made available on the ACCRU website. 
 
15.21 Background: Polatuzumab vedotin is an antibody-drug conjugate that contains a 
humanized immunoglobulin-G1 (IgG1) anti-human CD79b monoclonal antibody 
and a potent anti-mitotic agent, monomethyl auristatin E (MMAE), linked 
through a protease-labile linker. CD79b is a surface antigen that is expressed on 
mature B cells, with the exception of plasma cells. CD79b is expressed in a 


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majority of the B-cell-derived malignancies, including B-cell lymphomas and 
chronic lymphocytic leukemia (CLL). MMAE exerts its cytotoxicity by binding 
to microtubules and inhibiting microtubule polymerization, inhibiting cell 
division, and inducing apoptosis. 
 
15.22 Formulation: Polatuzumab vedotin is available as: freeze-dried lyophilisate 
containing 140 mg of polatuzumab vedotin as a white to grayish-white 
lyophilized powder in a single-dose vial for reconstitution and further dilution. 
Reconstitution with sterile water for injection (SWFI) results in a colorless, liquid 
solution composed of 20 mg/mL polatuzumab vedotin in polysorbate-20 (8.4 
mg), sodium hydroxide (3.80 mg), succinic acid (8.27 mg), sucrose (288 mg). 
 
15.23 Preparation and storage: 
Store refrigerated at 2°C to 8°C (36°F to 46°F) in original carton to protect from 
light. Do not use beyond the expiration date shown on the carton. Do not freeze. 
Do not shake. 
 
Polatuzumab vedotin is a cytotoxic drug. Follow applicable special handling and 
disposal procedures. 
1. Reconstitute immediately before dilution. 
2. More than one vial may be needed for a full dose. Calculate the dose, the 
total volume of reconstituted polatuzumab vedotin solution required, and 
the number of polatuzumab vedotin vials needed. 
3. Reconstitute each 140 mg polatuzumab vedotin vial by using a sterile 
syringe to slowly inject 7.2 mL of Sterile Water for Injection, USP with 
the stream directed toward the inside wall of the vial to obtain a 
concentration of 20 mg/mL of polatuzumab vedotin. 
4. Swirl the vial gently until completely dissolved. Do not shake. 
5. Inspect the reconstituted solution for discoloration and particulate matter. 
The reconstituted solution should appear colorless to slightly brown, 
clear to slightly opalescent, and free of visible particulates. Do not use if 
the reconstituted solution is discolored, is cloudy, or contains visible 
particulates. Do not freeze or expose to direct sunlight. 
6. If needed, store unused reconstituted polatuzumab vedotin solution 
refrigerated at 2°C to 8°C (36°F to 46°F) for up to 48 hours or at room 
temperature (9°C to 25°C, 47°F to 77°F) up to a maximum of 8 hours 
prior to dilution. Discard vial when cumulative storage time prior to 
dilution exceeds 48 hours. 
7. Dilute polatuzumab vedotin to a final concentration of 0.72–2.7 mg/mL 
in an intravenous infusion bag with a minimum volume of 50 mL 
containing 0.9% Sodium Chloride Injection, USP, 0.45% Sodium 
Chloride Injection, USP, or 5% Dextrose Injection, USP. 
8. Determine the volume of 20 mg/mL reconstituted solution needed based 
on the required dose. 
9. Withdraw the required volume of reconstituted solution from the 
polatuzumab vedotin vial using a sterile syringe and dilute into the 
intravenous infusion bag. Discard any unused portion left in the vial. 
10. Gently mix the intravenous bag by slowly inverting the bag. Do not 
shake. 
11. Inspect the intravenous bag for particulates and discard if present. 


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12. If not used immediately, store the diluted polatuzumab vedotin solution 
as specified in the table. Discard if storage time exceeds these limits. Do 
not freeze or expose to direct sunlight. 
Diluent Used to Prepare 
Solution for Infusion 
Diluted polatuzumab vedotin Solution 
Storage Conditions* 
0.9% Sodium Chloride 
Injection, USP 
Up to 24 hours at 2°C to 8°C (36°F to 46°F) or 
up to 4 hours at room temperature (9 to 25°C, 
47 to 77°F) 
0.45% Sodium Chloride 
Injection, USP 
Up to 18 hours at 2°C to 8°C (36°F to 46°F) or 
up to 4 hours at room temperature (9 to 25°C, 
47 to 77°F) 
5% Dextrose Injection, USP 
Up to 36 hours at 2°C to 8°C (36°F to 46°F) or 
up to 6 hours at room temperature (9 to 25°C, 
47 to 77°F) 
 
15.24 Administration: 
Polatuzumab vedotin must be administered using a dedicated infusion line 
equipped with a sterile, non-pyrogenic, low-protein binding in-line or add-on 
filter (0.2- or 0.22-micron pore size) and catheter. Do not mix polatuzumab 
vedotin with or administer as an infusion with other drugs. 
 
Administer the initial dose of polatuzumab vedotin over 90 minutes. Monitor 
patients for infusion-related reactions during the infusion and for a minimum of 
90 minutes following completion of the initial dose. If the previous infusion was 
well tolerated, the subsequent dose of polatuzumab vedotin may be administered 
as a 30-minute infusion and patients should be monitored during the infusion and 
for at least 30 minutes after completion of the infusion. 
 
If a planned dose of polatuzumab vedotin is missed, administer as soon as 
possible. Adjust the schedule of administration to maintain a 21-day interval 
between doses. 
 
15.25 Pharmacokinetic information: 
Absorption: Mild accumulation for both acMMAE (antibody- conjugated 
MMAE) and total antibody is observed for the q3w dosing regimen of 
polatuzumab vedotin with the steady state reached approximately after 3 cycles 
of dosing. 
Distribution: The acMMAE central volume of distribution estimated based on 
population PK analysis is 3.15 L. For human, MMAE plasma protein binding is 
71% to 77% and the blood to plasma ratio is 0.79 to 0.98, in vitro. 
Metabolism: In vitro studies indicate that MMAE is predominantly metabolized 
by CYP3A4/5. 
Half-life elimination: The acMMAE terminal half-life is approximately 12 days 
(95% CI: 8.1 to 19.5 days) at Cycle 6 with predicted clearance of 
0.9 L/day. The unconjugated MMAE terminal half-life is approximately 4 days 
after the first polatuzumab vedotin dose. 
Distribution and Excretion: Following IV administration of radiolabeled 
polatuzumab vedotin (tritium radiolabel on MMAE) to rats, the percentage of 


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injected radioactivity recovered in rats over 14 days was approximately 103% in 
feces and approximately 5% in urine. 
 
Avoid the administration of polatuzumab vedotin in patients with moderate or 
severe hepatic impairment (bilirubin greater than 1.5 × ULN). Patients with 
moderate or severe hepatic impairment are likely to have increased exposure to 
MMAE, which may increase the risk of adverse reactions. Polatuzumab vedotin 
has not been studied in patients with moderate or severe hepatic impairment. 
No adjustment in the starting dose is required when administering polatuzumab 
vedotin to patients with mild hepatic impairment (bilirubin greater than ULN to 
less than or equal to 1.5 × ULN or AST greater than ULN). 
 
Patients with mild or moderate renal impairment have similar conjugate 
(acMMAE) and unconjugated MMAE exposures as the patients with normal 
renal function. PK in patients with severe renal impairment has not been studied. 
 
15.26 Potential Drug Interactions: 
In vitro studies indicate that MMAE is predominantly metabolized by 
CYP3A4/5. MMAE is a weak time-dependent inhibitor of CYP3A4/5 but does 
not competitively inhibit CYP3A4/5 at clinically relevant concentrations. MMAE 
does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. 
MMAE is not an inducer of CYP enzymes. Concomitant use of polatuzumab 
vedotin with ketoconazole (strong CYP3A inhibitor) is predicted to increase 
unconjugated MMAE AUC by 45%. Concomitant use of polatuzumab vedotin 
with rifampin (strong CYP3A inducer) is predicted to decrease unconjugated 
MMAE AUC by 63%. Unconjugated MMAE is not predicted to alter the AUC of 
concomitant drugs that are CYP3A substrates (e.g., midazolam). In vitro data 
indicate that MMAE is a P-gp substrate. In vitro, MMAE is not a substrate of 
OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MRP2, or BCRP. MMAE does not 
inhibit P-gp, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, 
BSEP, MRP2, or BCRP at clinically relevant concentrations. 
 
Patients who are receiving strong CYP3A4 inhibitors and p-gp inhibitors 
concomitantly with vc-MMAE ADCs should be closely monitored for adverse 
events.  
 
Polatuzumab vedotin is being studied in combination with other drugs including 
rituximab, obinutuzumab, bendamustine, cyclophosphamide, doxorubicin and 
prednisone/prednisolone, venetoclax, lenalidomide, and atezolizumab, and it is 
not fully known whether or how the addition of polatuzumab vedotin might 
affect the safety and efficacy of other drugs, or vice versa. 
 
15.27 Known potential toxicities: 
Serious Adverse Drug Reactions: pneumonia, sepsis, neutropenic sepsis, septic 
shock, upper respiratory tract infection, rhinovirus infection, neutropenia, febrile 
neutropenia, leukopenia, peripheral motor neuropathy, peripheral sensory 
neuropathy, diarrhea, abdominal pain, vomiting, pyrexia, asthenia  
 
 
Potential Risks: anemia, thrombocytopenia, infections, progressive multifocal 
leukoencephalopathy, infusion related reactions, immunogenicity (anti-drug 


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antibodies), hepatic toxicity (hyperbilirubinemia, transaminase [AST or ALT] 
elevation), reproductive toxicity, fatigue, hyperglycemia, renal toxicity 
(increased serum creatinine), gastrointestinal toxicity (nausea, constipation, 
anorexia), pulmonary toxicity (interstitial lung diseases), joint 
pain/arthralgia/skeletal pain, alopecia, cardiac arrhythmias, ocular toxicity, 
dysgeusia, tumor lysis syndrome, genotoxicity/carcinogenicity (myelodysplastic 
syndrome) 
 
 
There is also a risk of embryo-fetal toxicity.  Advise females of reproductive 
potential of the potential risk to a fetus and to use effective contraception during 
treatment and for 9 months after the last dose and for 6 months after the last dose 
of polatuzumab vedotin for male patients with female partners of reproductive 
potential. 
 
15.28 Drug procurement: Investigational supply is provided free of charge to study 
participants. 
 
F. Hoffmann-La Roche will supply investigational supply to McKesson. Each 
participating ACCRU treating location will order the drug from McKesson. 
Submit the Drug Order Request Form (found on the ACCRU web site) to: 
 
McKesson  
 
 
 
Each participating ACCRU treating location will be responsible for monitoring 
the supply of polatuzumab and will use the Drug Order Request Form to order 
additional supplies as needed. 
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place 
at each institution. 
 
15.29a Nursing Guidelines: 
 
15.291 Cytopenias are common, including febrile neutropenia. Monitor CBC 
w/diff and instruct patient to report fever or sign/symptoms and/or 
unusual bruising or bleeding of infection to the study team. Sepsis has 
been reported.  
 
15.292 Patients may experience infusion related reactions. Monitor and treat per 
protocol. 
 
15.293 Monitor LFT’s 
 
15.294 Monitor renal function 
 
15.295 Gastrointestinal side effects that have been seen are diarrhea, nausea, 
vomiting and constipation. Treat symptomatically and monitor for 
effectiveness. 
 
15.296 Instruct patients to report any dyspnea, cough or chest pain as interstitial 


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lung toxicity has been seen. 
 
15.297 Patients may experience joint pain/arthralgia/skeletal pain. Treat 
symptomatically and monitor for effectiveness. 
 
15.298 Patients may experience Tumor lysis syndrome. Monitor labs 
appropriately. 
 
15.299 Instruct females of child bearing potential of the risks to a fetus and that 
they should use effective contraception throughout treatment and for 9 
months after their last dose. For male patients they should use effective 
contraception throughout treatment and for 6 months after drug 
discontinuation. 
 
15.29b Temperature excursions that occur at the site should be reported by the site using 
the Genentech Temperature Excursion Form found on the ACCRU web site for 
this study and emailed to:
 
 
Any shipment deviations (those not occurring at the site) should be reported to 
McKesson via email to: 
 
 
15.3 
Rituximab and Hyaluronidase Human (Rituxan Hycela®): 
 
Investigator brochure will be made available on the ACCRU website. 
 
15.31 Background: Rituximab is a monoclonal antibody directed against the CD20 
antigen on B-lymphocytes. CD20 regulates cell cycle initiation; and, possibly, 
functions as a calcium channel. Rituximab binds to the antigen on the cell 
surface, activating complement-dependent cytotoxicity; and to human Fc 
receptors, mediating cell killing through an antibody-dependent cellular toxicity. 
 
Hyaluronidase increases the absorption rate or rituximab-containing products by 
increasing permeability of subcutaneous tissue through temporary 
depolymerization of hyaluronan; at the recommended doses, hyaluronidase acts 
locally, and the effects are reversible. Permeability of the subcutaneous tissue is 
restored in 24 to 48 hours. 
 
15.32 Formulation: Rituximab and hyaluronidase human is supplied as a ready-to- use 
liquid formulation with rituximab at a concentration of 120 mg/mL. It is 
available as individually packaged single dose: 1400mg/23400 units per 11.7 mL. 
The drug product is a sterile, colorless to yellowish, clear to opalescent liquid 
that contains 2,000 U/mL recombinant human hyaluronidase (rHuPH20, 
manufactured in a Chinese hamster ovary [CHO] cell line) acting as a permeation 
enhancer, histidine/histidine-HCl (buffer), α,α-trehalose (tonicity adjuster), 
methionine (stabilizer), and polysorbate 80 (surfactant) in water for injection at 
pH 5.5. 
 
15.33 Preparation and storage: Store vials at refrigeration temperature, 2°C to 8°C 
(36°F to 46°F) in the original carton to protect from light. Do not freeze. Protect 
vials from direct sunlight. Once transferred from the vial to the syringe, the 


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solution of rituximab and hyaluronidase human is physically and chemically 
stable for 48 hours at 2°C − 8°C and subsequently for 8 hours at 30°C in diffuse 
daylight. Rituximab and hyaluronidase human is ready to use. To avoid needle 
clogging, attach the hypodermic injection needle to the syringe immediately prior 
to administration. Rituximab and hyaluronidase human is compatible with 
polypropylene and polycarbonate syringe material and stainless-steel transfer and 
injection needles. Visually inspect the product for particulate matter and 
discoloration prior to administration. Rituximab and hyaluronidase human should 
be a clear to opalescent and colorless to yellow liquid. Do not use if particulates 
or discoloration is present. 
 
15.34 Administration: 
NOTE: All patients must receive at least one full dose of rituximab by 
intravenous infusion before starting treatment with rituximab and 
hyaluronidase human. 
 
Inject rituximab and hyaluronidase human into the subcutaneous tissue of the 
abdomen over approximately 5 to 7 minutes and never inject into areas where the 
skin is red, bruised, tender or hard, or areas where there are moles or scars. No 
data are available on performing the injection at other sites of the body. 
 
Inject 11.7 mL of rituximab and hyaluronidase human 1400 mg/23400 units 
subcutaneously into the abdomen over approximately 5 minutes. 
 
15.35 Pharmacokinetic information: 
Duration: CLL patients remained B-cell depleted until month 9, where signs of 
repletion were seen. In follicular lymphoma patients, B-cell repletion begins after 
6 months. 
Absorption: Model based simulations showed that a fixed dose of 1400 mg 
rituximab SC would achieve Ctrough values non-inferior to those observed with 
rituximab IV 375 mg/m2 administered q2m or q3m in maintenance and q3w in 
induction. 
Distribution: Vdss subcutaneous 8.52L (CLL); 8.09L (FL) Bioavailability 
(compared to IV rituximab): 63.4% (CLL); 64.6% (FL) 
Half-life elimination: 32 days (CLL); 34.1 days (FL) 
 
 
15.36 Potential Drug Interactions: 
Increased Effect/Toxicity: Monoclonal antibodies may increase the risk for 
allergic reactions to rituximab due to the presence of HAC antibody. 
Antihypertensive medications may exacerbate hypotension. 
Decreased Effect: Currently recommended not to administer live vaccines 
during rituximab treatment. Inactivated vaccines should be complete at least 2 to 
4 weeks prior to starting therapy. Rituximab may diminish the effects of 
sipuleucel-T. 
 
Immunosuppressants: Rituximab may enhance the adverse/toxic effects of 
immunosuppressants, including:certolizumab pegol, pimecrolimus, tacrolimus, 
fingolimod, leflunomide, natalizumab, roflumilast,and to a lesser extent of 
denosumab,ophthalmic chloramphenicol, trastuzumab. 
 
Myelosuppressants: Rituximab may enhance the adverse/toxic effects of 


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myelosuppressants, including: abatacept, belimumab, clozapine, deferiprone, 
dipyrone, promazine, and tofacitinib. 
 
15.37 Known potential toxicities: 
Consult the Investigator’s Brochure and package insert for the most current and 
complete information. Refer to the package insert pertaining to the following 
boxed warnings: Progressive multifocal leukoencephalopathy (PML); Hepatitis B 
virus reactivation; and severe and sometimes fatal mucocutaneous reactions. 
 
Common known potential toxicities, > 10%: 
Central nervous system: Fatigue, chills, paresthesia, headache, peripheral 
neuropathy, paresthesia 
Dermatologic: Alopecia, dermatological reaction, erythema, skin rash (including 
severe mucocutaneous reactions) 
Gastrointestinal: Nausea, constipation, vomiting, diarrhea, abdominal pain 
Hematologic & oncologic: Neutropenia, anemia, leukopenia, febrile neutropenia, 
thrombocytopenia 
Immunologic:  Antibody development, anti-rituximab antibodies 
Infection:  Serious infection 
Local:  Erythema at injection site 
Neuromuscular & skeletal: arthralgia, asthenia 
Respiratory: Cough, upper respiratory tract injection, dyspnea, pneumonia 
Miscellaneous: Fever 
 
Less common known potential toxicities, 1% - 10%: 
Cardiovascular: Peripheral edema, chest pain, hypertension, hypotension 
Central nervous system: insomnia, dizziness 
Dermatologic: Pruritis 
Endocrine & metabolic: Weight loss 
Gastrointestinal: Decreased appetite, dyspepsia, stomatitis, upper 
abdominal pain 
Genitourinary:  Urinary tract infection 
Hematologic & oncologic: Lymphocytopenia 
Infection:  Influenza 
Local:  Infusion site reaction 
Neuromuscular & skeletal: Limb pain, ostealgia, back pain, muscle spasm, 
myalgia 
Ophthalmic:  Conjunctivitis 
Respiratory: Nasopharyngitis, oropharyngeal pain, bronchitis, sinusitis, 
flu-like symptoms, respiratory tract infection 
 
Frequency not defined: 
Fulminant hepatitis, hepatic failure, hypersensitivity reaction, JC virus 
infection, reactivation of HBV, infusion-related reaction, tumor lysis 
syndrome, gastrointestinal perforation 
 
Rare known potential toxicities, <1% (Postmarketing and/or case reports): 
Bone marrow depression, bronchiolitis obliterans, 
hypogammaglobulinemia (prolonged), interstitial pulmonary disease, 
intestinal obstruction, intestinal perforation, Kaposi sarcoma, Lupus-like 
syndrome, optic neuritis, pancytopenia, pleurisy, polyarthritis, progressive 


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multifocal leukoencephalopathy, serum sickness, uveitis, vasculitis 
(systemic, with rash), viral infection 
 
Maternal IgG enters breast milk and rituximab has been reported to be 
excreted at low concentrations in human breast milk. Given that the 
clinical significance of this finding for infants is unknown, rituximab 
should not be administered to nursing mothers. 
 
15.38 Drug procurement: Investigational supply is provided free of charge to study 
participants by F. Hoffmann-La Roche. 
 
 
F. Hoffmann-La Roche will supply investigational supply to McKesson . Each 
participating ACCRU treating location will order the drug from McKesson. 
Submit the Drug Order Request Form (found on the ACCRU web site) to: 
 
McKesson  
 
 
 
Each participating ACCRU treating location will be responsible for monitoring 
the supply of rituximab and hyaluronidase human and will use the Drug Order 
Request Form to order additional supplies as needed. 
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place 
at each institution. 
 
15.381  Temperature excursions that occur at the site should be reported by the 
site using the Genentech Temperature Excursion Form found on the 
ACCRU web site for this study and emailed to:  
 
 
 
Any shipment deviations (those not occurring at the site) should be 
reported to McKesson via email to: 
 
 
15.39 Nursing Guidelines: 
 
All patients must receive at least one full dose of rituximab by intravenous 
infusion before starting treatment with rituximab and hyaluronidase 
human. 
 
15.391  Patients should not receive live vaccines during rituximab treatment. 
Inactivated vaccines should be administered 2-4 weeks prior to starting 
therapy.  
 
15.392  Patients may experience reactivation of Hepatitis B (HBV). Patients who 
are at risk of hepatitis B virus should be screened prior to initiation of 
therapy. 
 
15.393  Inject rituximab and hyaluronidase human into the subcutaneous tissue of 


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the abdomen over approximately 5 to 7 minutes and never inject into areas 
where the skin is red, bruised, tender or hard, or areas where there are 
moles or scars. 
 
 
15.394  Assess patient’s concurrent medications as those that are on 
immunosuppression and/or myelosuppresive agents can see increased 
effects from those drugs while receiving rituximab. 
 
15.395  Cytopenias are common and can be long term. Monitor CBC. Instruct 
patient to report signs and symptoms of infection, excessive bruising 
and/or bleeding to the health care team 
 
15.396  GI disturbances (Nausea, abdominal pain and less commonly diarrhea, 
vomiting, dyspepsia) headache, and weakness are common side effects. 
Treat as necessary. Monitor for effectiveness 
 
 
15.397  Monitor for injection site reactions and treat as needed. 
 
15.398  Reports of PML (progressive multifocal leukoencephalopathy) has been 
seen. Instruct patient to report any changes in cognition, level of 
consciousness, headache, lethargy, or progressive weakness to the study 
team immediately. 
 
15.4 
Rituximab (Rituxan®, C2B8) 
 
Refer to package insert for complete, up-to-date information. 
 
15.41 Background: rituximab is a monoclonal antibody directed against the 
CD20 antigen on B-lymphocytes. CD20 regulates cell cycle initiation; 
and, possibly, functions as a calcium channel. rituximab binds to the 
antigen on the cell surface, activating complement-dependent 
cytotoxicity; and to human Fc receptors, mediating cell killing through 
an antibody-dependent cellular toxicity. 
 
15.42 Formulation: Commercially available for injection, solution 
[preservative free]: 10 mg/mL (10 mL, 50 mL) [contains Polysorbate 80]. 
 
15.43 Preparation, storage, and stability: Refer to package insert for 
complete preparation and dispensing instructions. Store vials at 
refrigeration temperature do not freeze or shake. Protect vials from direct 
sunlight. Withdraw the necessary amount of rituximab and dilute to a 
final concentration of 1-4 mg/mL with 0.9% NaCL or D5W. Gently 
invert the bag to mix the solution; do not shake. Solutions for infusion 
are stable at 2ºC to 8ºC for 24 hours and at room temperature for an 
additional 24 hours. 
 
15.44 Administration: Do not administer I.V. push or bolus. Refer to 
treatment section for specific infusion instructions. Suggested 
administration guidelines are: 
Initial infusion: Start rate of 50 mg/hour; if there is no reaction, increase 


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the rate by 50 mg/hr every 30 minutes, to a maximum of 400 mg/hour. 
Subsequent infusions: If patient did not tolerate initial infusion follow 
initial infusion guidelines. If patient tolerated initial infusion, start at 100 
mg/hour; if there is no reaction; increase the rate by 100 mg/hour every 
30 minutes, to a maximum of 400 mg/hour. 
Note: If a reaction occurs, slow or stop the infusion. If the reaction 
abates, restart infusion at 50% of the previous rate. 
 
Accelerated infusion rate (90 minutes): Accelerated infusion rate is not 
an option for cycle 1. It is an option in cycle 2 and beyond for patients 
who have had a mild reaction and cannot yet be transitioned to rituximab 
and hyaluronidase human. For patients with previously untreated 
follicular NHL and diffuse large B-cell NHL who are receiving a 
corticosteroid as part of their combination chemotherapy regimen, have a 
circulating lymphocyte count <5000/mm3, or have no significant 
cardiovascular disease. After tolerance has been established (no grade 3 
or 4 infusion-related event) at the recommended infusion rate in cycle 1, 
a rapid infusion rate may be used beginning with cycle 2. The daily 
corticosteroid, acetaminophen, and diphenhydramine are administered 
prior to treatment, then the rituximab dose is administered over 90 
minutes, with 20% of the dose administered over the first 30 minutes and 
the remaining 80% is given over 60 minutes. If the 90-minute infusion in 
cycle 2 is tolerated, the same rate may be used for the remainder of the 
treatment regimen (through cycles 6 or 8). 
 
15.45 Pharmacokinetic information: 
Duration: Detectable in serum 3-6 months after completion of 
treatment; B-cell recovery begins ~6 months following completion of 
treatment; median B-cell levels return to normal by 12 months following 
completion of treatment 
Distribution: RA: 3.1 L; GPA/MPA: 4.5 L 
Absorption: Immediate and results in a rapid and sustained depletion of 
circulating and tissue-based B cells 
Half-life elimination: Proportional to dose; wide ranges reflect variable 
tumor burden and changes in CD20 positive B-cell populations with 
repeated doses: 
Following first dose: Mean half-life: 3.2 days Following fourth dose: 
Mean half-life: 8.6 days CLL: Median terminal half-life: 32 days 
NHL: Median terminal half-life: 22 days RA: Mean terminal half-life: 18 
days GPA/MPA: 23 days 
 
Excretion: Uncertain; may undergo phagocytosis and catabolism in the 
reticuloendothelial system 
 
15.46 Potential Drug Interactions: 
Increased Effect/Toxicity: Monoclonal antibodies may increase the risk 
for allergic reactions to rituximab due to the presence of HAC antibody. 
Antihypertensive medications may exacerbate hypotension. 
Decreased Effect: Currently recommended not to administer live 
vaccines during rituximab treatment. Inactivated vaccines should be 
complete at least 2 to 4 weeks prior to starting therapy. rituximab may 


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diminish the effects of sipuleucel-T. 
 
Immunosuppressants: rituximab may enhance the adverse/toxic effects 
of immunosuppressants, including:certolizumab pegol, pimecrolimus, 
tacrolimus, fingolimod, leflunomide, natalizumab, roflumilast,and to a 
lesser extent of denosumab,ophthalmic chloramphenicol, trastuzumab. 
 
Myelosuppressants: rituximab may enhance the adverse/toxic effects of 
myelosuppressants, including: abatacept, belimumab, clozapine, 
deferiprone, dipyrone, promazine, and tofacitinib. 
 
15.47 Known potential adverse events: Consult the package insert for the 
most current and complete information. Refer to the package insert 
pertaining to the following boxed warnings: Severe infusion reactions; 
Progressive multifocal leukoencephalopathy (PML); Tumor lysis 
syndrome leading to acute renal failure; and severe and sometimes fatal 
mucocutaneous reactions (lichenoid dermatitis, paraneoplastic 
pemphigus, Stevens-Johnson syndrome, toxic epidermal necrolysis and 
vesiculobullous dermatitis). 
Common known potential toxicities, > 10%: Cardiovascular: 
Peripheral edema, hypertension 
Central nervous system: Fatigue, chills, neuropathy, headache, insomnia, 
pain 
Dermatologic: Skin rash, pruritus, night sweats Endocrine & metabolic: 
Weight gain Gastrointestinal: Nausea, diarrhea, abdominal pain 
Hematologic: Lymphocytopenia, anemia, leukopenia, neutropenia, 
thrombocytopenia, cytopenia, febrile neutropenia 
Hepatic: ALT increased Hypersensitivity: Angioedema Immunologic: 
Antibody development Infection: Infection, bacterial infection 
Neuromuscular & skeletal: Weakness, muscle spasm, arthralgia 
Respiratory: Cough, rhinitis, epistaxis 
Miscellaneous: Infusion related reaction, fever 
 
Less common known potential toxicities, 1% - 10%: Cardiovascular: 
Hypotension, flushing 
Central nervous system: Dizziness, anxiety, migraine, paresthesia 
Dermatologic: Urticaria 
Endocrine & metabolic: Hyperglycemia, increased lactate dehydrogenase 
Gastrointestinal: Vomiting, dyspepsia Infection: Viral infection, fungal 
infection 
Neuromuscular & skeletal: Back pain, myalgia, 
Respiratory: Dyspnea, throat irritation, bronchospasm, upper respiratory 
tract infection, sinusitis 
 
Rare known potential toxicities, <1% (Postmarketing and/or case 
reports): 
Acute mucocutaneous toxicity, acute renal failure (associated with tumor 
lysis syndrome), acute respiratory distress, anaphylactoid 
reaction/anaphylaxis, angina pectoris, aplastic anemia, arthritis 
(polyarticular), bone marrow depression, bronchiolitis obliterans, cardiac 


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arrhythmia, cardiac failure, cardiogenic shock, encephalitis, fulminant 
hepatitis, gastrointestinal perforation, hemolytic anemia, hepatic failure, 
hepatitis, hypogammaglobulinemia (prolonged), hypoxia, increased 
serum immunoglobulins (hyperviscosity syndrome in Waldenstrom’s 
macroglobulinemia), interstitial pneumonitis, intestinal obstruction, 
Kaposi’s sarcoma (progression), laryngeal edema, lichenoid dermatitis, 
lupus-like syndrome, mucositis, myelitis, MI, nephrotoxicity, optic 
neuritis, pancytopenia, paraneoplastic pemphigus, pleurisy, pneumonia, 
pneumonitis, polymyositis, progressive multifocal leukoencephalopathy, 
pure red cell aplasia, reactivated pure red cell aplasia, reactivated 
tuberculosis, reactivation of HBV, reversible posterior 
leukoencephalopathy syndrome, serum sickness, Stevens-Johnson 
syndrome, supraventricular arrhythmia, toxic epidermal necrolysis, 
uveitis, vasculitis with rash, ventricular fibrillation, ventricular 
tachycardia, vesiculobullous dermatitis, viral reactivation (includes JC 
virus [PML], cytomegalovirus, herpes simplex virus, parvovirus B19, 
varicella zoster virus, West Nile virus, and hepatitis C), wheezing 
 
15.48 Drug procurement: Investigational supply is provided free of charge to 
study participants by F. Hoffmann-La Roche. 
 
F. Hoffmann-La Roche will supply investigational supply to McKesson. 
Each participating ACCRU treating location will order the drug from 
McKesson. Submit the Drug Order Request Form (found on the ACCRU 
web site) to: 
 
McKesson  
 
 
 
Each participating ACCRU treating location will be responsible for 
monitoring the supply of rituximab and will use the Drug Order Request 
Form to order additional supplies as needed. 
 
Outdated or remaining drug is to be destroyed on-site as per procedures 
in place at each institution. 
 
15.49a  Temperature excursions that occur at the site should be reported by the 
site using the Genentech Temperature Excursion Form found on the 
ACCRU website for this study and emailed to: 
 
 
Any shipment deviations (those not occurring at the site) should be 
reported to McKesson via email to: 
 
 
15.49b  Nursing Guidelines 
 
 
Do not administer as an IV push or bolus since it increases the risk of a 
hypersensitivity reaction. 


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Hypotension, bronchospasms, and angioedema have occurred in 
association with Rituxan infusion. Because of this it is recommended that 
patients be pre-medicated with acetaminophen and diphenhydramine 
before infusion. Stop infusion for severe reaction. Infusion may be 
restarted at 50% rate after resolution of symptoms. It is recommended 
that diphenhydramine, acetaminophen, epinephrine, bronchodilators, IV 
saline, and corticosteroids are available for immediate use in the event of 
a hypersensitivity reaction during administration. 
 
 
Patients should be cautioned to withhold their anti-hypertensive 
medication for 12 hours prior to drug administration. 
 
 
Patients with preexisting cardiac conditions including arrhythmias and 
angina have had recurrences of these events during Rituxan therapy and 
should be monitored throughout the infusion and immediate post-
infusion period. 
 
 
It has been found that patients with bulky disease (lesion >10 cm in 
diameter) have an increased incidence of adverse events. Monitor for 
signs and symptoms of tumor lysis syndrome, and acute renal failure. 
 
 
An infusion-related symptom complex consisting of fever and 
chills/rigors occurs in the majority of patients during the first infusion. 
These reactions generally occur within 30 minutes to 2 hours of 
beginning the first infusion and resolve with slowing or stopping the 
infusion and giving supportive care. The incidence of adverse reactions 
decreased from 80% to 40% with subsequent infusions. 
 
 
Cytopenias are common and can be long term. Monitor CBC. Instruct 
patient to report signs and symptoms of infection, excessive bruising 
and/or bleeding to the health care team. 
 
 
GI disturbances (Nausea, abdominal pain and less commonly diarrhea, 
vomiting, dyspepsia) headache, and weakness are common side effects. 
Treat as necessary. Monitor for effectiveness. 
 
 
Adequate birth control measures should be used during therapy and for 
12 months following therapy. Women should not breastfeed while drug 
is detectable in serum.  
 
15.49c  Endocrine and metabolic disturbances can be seen (hyper/hypoglycemia, 
hypocalcemia, hypocholesterolemia, hyperphosphatemia, hyperuricemia. 
Monitor labs and for signs or symptoms of these conditions. Treat 
accordingly. 
 
16.0 
Statistical Considerations and Methodology 
 
16.1 
Overview: 
 
This is a single arm Phase II study of combination of polatuzumab vedotin, venetoclax 


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and rituximab and hyaluronidase human in patients with relapsed or refractory mantle 
cell lymphoma (MCL). The relapsed/refractory MCL patient population will include both 
ibrutinib-naive and ibrutinib-pretreated patients. An early safety analysis will be 
conducted in patients with B cell NHL who have relapsed or progressed after at least one 
line of therapy prior to continuing accrual in this phase II study. 
 
16.11 Primary Endpoint: The primary endpoint of this trial is the complete response 
rate at the end of induction by PET-CT scans according to Lugano 2014. A 
complete response will be considered synonymous with “success”, unless 
specified otherwise. All patients meeting the eligibility criteria, who have signed 
a consent form and have begun treatment, will be evaluable for response, unless 
they are determined to be a major violation. 
 
16.2 
Statistical Design 
 
16.21 Decision Rule: The largest success proportion where the proposed treatment 
regimen would be considered ineffective in this population is 15%, and the 
smallest success proportion that would warrant subsequent studies with the 
proposed regimen in this patient population is 35%. The following one-stage 
design with an interim analysis is based on a two-stage Simon optimum design2 
and requires 46 evaluable patients to test the null hypothesis that the true success 
proportion in this patient population is at most 15%. 
 
16.211 Interim Analysis: Enter 16 evaluable patients into the study. If 3 or fewer 
successes are observed in the first 16 evaluable patients, we will consider 
this regimen ineffective in this patient population and terminate the 
study. Otherwise, if the number of successes is at least 4, we will 
continue accrual. 
 
16.212 Final Decision Rule: Enter an additional 30 evaluable patients into the 
study. If 10 or fewer successes are observed in the first 46 evaluable 
patients, we will consider this regimen ineffective in this patient 
population and terminate the study. Otherwise, if the number of success 
is at least 11, this will be considered evidence of promising activity and 
the treatment may be recommended for further testing in subsequent 
studies in this population. 
 
16.213 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision-making process. Analysis involving over accrued 
patients is discussed in section 16.313.  
 
NOTE: We will not suspend accrual at the interim analysis to allow the 
first 16 patients to become evaluable, unless undue toxicity is observed. 
Given the limited overall sample size and the inclusion of an AE 
stopping rule, we feel it is ethical to not halt accrual for the interim 
analysis. However, if accrual is extremely rapid, we may temporarily 
suspend accrual in order to obtain safety data on these patients before re- 
opening accrual to further patients. 
 


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16.214 Dose de-escalation in safety analysis: A safety analysis will be 
performed in the first 6 evaluable patients per Section 16.4. In the case of 
unacceptable toxicity, the dose will be de-escalated. If this occurs, the 
first 6 patients will be evaluated separately and will not be included in 
any decision-making criteria. 
 
16.22 Sample Size: The one stage design with an interim analysis to be utilized is fully 
described above. A minimum of 16 and a maximum of 46 evaluable patients with 
MCL will be accrued onto this phase II study unless undue toxicity is 
encountered. Patients with MCL treated at the final dose level in the early safety 
analysis will be included in phase II. If dose de-escalation is required during the 
safety analysis, an additional 6 evaluable patients will be accrued per section 
16.4. We anticipate accruing an additional 5 (10%) patients to account for 
ineligibility, cancellation, major treatment violation, or other reasons for a total 
of up to 57 patients. If none of the six patients with B cell NHL enrolled in safety 
portion are MCL, the total sample size will be 63 patients. 
 
16.23 Accrual Rate and Study Duration: The anticipated accrual rate is 2-3 evaluable 
MCL patients per month. At this rate, it will likely take about 2 years to enroll 
the patients. The maximum total study duration is expected to be approximately 5 
years, or until the last patient accrued has been observed for at least 3 years. The 
earliest date anticipated for presentation of results is at approximately 2.5 years 
for the primary endpoint, or when the last patient accrued has been observed for 
at least 6 months. 
 
16.24 Power and Significance Level: Assuming that the number of successes is 
binomially distributed, the significance level is .05, i.e. there is a 5% chance of 
finding the drug to be effective when it truly is not. The probability of declaring 
that this regimen warrants further study (i.e. statistical power) and the probability 
of stopping at the interim analysis under various success proportions can be 
tabulated as a function of the true success proportion as shown in the following 
table. 
 
If the true success proportion is… 
0.15 
0.20 
0.25 
0.30 
0.35 
Then the probability of declaring that the 
regimen warrants further studies is…
0.049 0.212 0.467 0.700 0.851 
And the probability of stopping at the interim 
analysis is…
0.790 0.598 0.405 0.246 0.134 
 
16.25 Other Considerations: AEs, quality/duration of response, and patterns of 
treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study. 
 
16.3 
Analysis Plan 
 
The analysis for this trial will commence at planned time points (see 16.2) and at the time 
the patients have become evaluable for the primary endpoint. The Statistician and Study 
Chair will make the decision, in accord with CCS Standard Operating Procedures, 
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data maturity. It is anticipated that the earliest date in which the results will be made 
available via manuscript, abstract, or presentation format is when last patient has been 
followed for at least 6 months. 
 
16.31 Primary Outcome Analysis 
 
16.311 Definition: The primary endpoint of this trial is the complete response 
rate at the end of induction as determined by investigator on the basis of 
PET-CT scans according to Lugano 2014. A complete response is 
defined as an objective status of CR at the end of induction. All patients 
meeting the eligibility criteria who have signed a consent form and have 
begun treatment will be evaluable for response, unless they are 
determined to be a major violation. Only MCL patients treated at the 
final dose level will be included when evaluating the decision rules in 
Sections 16.211 and 16.212. Patients without MCL and patients treated 
at other dose levels will be summarized separately. 
 
16.312 Estimation: The proportion of success will be estimated by the number of 
success divided by the total number of evaluable patients. 95% 
confidence intervals for the true success proportion will be calculated 
according to the approach of Duffy and Santner3. 
 
16.313 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision-making process; however, they will be included in final 
point estimates and confidence intervals. 
 
16.32 Secondary Outcome Analysis 
 
16.321 The overall response rate (ORR) at the end of induction will be estimated 
by the total number of patients who achieve a CR or PR by PET-CT 
scans according to Lugano 2014 divided by the total number of evaluable 
patients. All evaluable patients will be used for this analysis. Exact 
binomial 95% confidence intervals for the true overall response rate will 
be calculated. The ORR between ibrutinib-naive and ibrutinib-pretreated 
patients will be compared using Fisher’s exact test. 
 
16.322 The Best Response Rate to maintenance therapy will be evaluated. CR, 
PR and SD rates for patients who continue to maintenance will be 
estimated by number of patients who continue on maintenance therapy 
and achieve CR, PR or SD, respectively, at the end of maintenance 
divided by the total number of evaluable patients who continue to 
maintenance. Conversion rate from PR to CR will be evaluated by the 
number of patients achieving CR at EOM divided by the total number of 
patients who continue to maintenance in PR. Conversion rate from SD to 
PR or SD to CR will be evaluated by the number of patients achieving 
PR or CR, respectively at EOM divided by the total number of patients 
who continue to maintenance in SD. 
 
 
16.323 Progression free survival (PFS) is defined as the time from registration to 
the earliest date of documentation of disease progression by CT or 


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PET/CT or death due to any cause. The distribution of progression-free 
survival will be estimated using the method of Kaplan-Meier4. The PFS 
between ibrutinib-naive and ibrutinib-pretreated patients will be 
compared using log-rank test. 
 
16.324 Overall survival (OS) is defined as the time from registration to death due 
to any cause. The distribution of OS will be estimated using method of 
Kaplan-Meier. The OS between ibrutinib-naive and ibrutinib-pretreated 
patients will be compared using log-rank test. 
 
16.325 AEs: All eligible patients that have initiated treatment will be considered 
evaluable for assessing AE rate(s). The maximum grade for each type of 
AE from each patient will be used for analysis, and frequency tables will 
be reviewed to determine patterns. Additionally, the relationship of the 
AE(s) to the study treatment will be taken into consideration. 
 
16.326 Correlative Analysis: Due to the small overall sample size, the results of 
these analyses will be considered exploratory and hypothesis- generating 
in nature. 
 
16.327 MRD Analysis: MRD will be assessed on whole blood using the Roche 
panel at pre-treatment, end of induction, and end of maintenance. 
MRD status for both responders and non-responders at each time point 
will be reported descriptively and explored for correlation with clinical 
factors and patient outcomes such as PFS and OS. Changes in MRD 
status from baseline to end of induction and end of maintenance will also 
be summarized. 
 
16.328 T cell and cytokine subsets: Systemic immune profiles and T cell 
activation will be investigated using multi-parameter flow cytometry, 
and cytokine analysis in the peripheral blood of patients at the following 
timepoints: a) pre-treatment, b) early in treatment (cycle 3), 
c) end of induction (cycle 7), d) end of maintenance year 1 (cycle 18), 
f) end of maintenance year 2. The results from T cell and Cytokine subsets 
analysis will be reported descriptively by median, min, max, and 
interquartile range. 
 
16.329 High risk cytogenetic alterations and other risk stratification scores will 
be summarized using frequency and percentages. 
 
16.4 
Early Safety Analysis 
 
 
The first cohort of three patients will be treated at the starting dose level of Venetoclax 
(400 mg days 1-21) and observed for at least 63 days (3 cycles) from the start of 
treatment to assess toxicity. If significant toxicity as defined in section 7.7 is observed in 
0 or 1 of these 3 patients, 3 new patients will be accrued and treated at same dose level of 
Venetoclax (400 mg days 1- 21) and observed for 3 cycles. After enrolling 6 patients on 
Venetoclax dose level of 400 mg days 1-21, if ≤1 patient experience significant toxicity, 
then this dose will be considered safe and rest of the patients in expansion cohort will be 
treated at this dose level of Venetoclax. 


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However, if 2 or more out of the first 3 or 6 patients experience significant toxicity, then 
the dose of venetoclax may be de-escalated to 300 mg days 1-21 (Dose Level -1, Table 
8.21). In this case, another safety analysis using similar 3+3 design approach will be 
conducted at the reduced dose level of venetoclax. 
Safety will be assessed through summaries of adverse events and changes from baseline 
laboratory results. All adverse events occurring on or after first study treatment will be 
summarized by NCI CTCAE v5.0 grade. Deaths reported during the treatment period and 
during post-treatment follow-up will be listed and summarized. 
 
16.5 
Data & Safety Monitoring 
 
16.51 The principal investigator(s) and the study statistician will review the study at 
least twice a year to identify accrual, AE, and any endpoint problems that might 
be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety Monitoring 
Board (DSMB) is responsible for reviewing accrual and safety data for this trial 
at least twice a year, based on reports provided by the MCCC Statistical Office. 
 
16.52 Adverse Event Stopping Rules: The stopping rules specified below are based on 
the knowledge available at study development. We note that the AE Stopping 
Rule may be adjusted in the event of either (1) the study re-opening to accrual or 
(2) at any time during the conduct of the trial and in consideration of newly 
acquired information regarding the AE profile of the treatment(s) under 
investigation. The study team may choose to suspend accrual because of 
unexpected AE profiles that have not crossed the specified rule below. 
 
16.521 Safety Cohort: By the nature of the “cohorts of three” safety portion, stopping 
rules are in place for dose level of Venetoclax. Specifically, if 2 or more 
significant toxicities are observed during cycle 3 at the given dose level, accrual 
to that dose level will be stopped, and patients will be accrued to the next lower 
dose level until a maximum of 6 patients are treated at the lower level. Note that 
significant toxicities that affects dose de-escalation is only that which is observed 
in the first three cycles of treatment. However, all cycles will be reviewed, and 
the study team will determine whether the dose level needs to be adjusted for 
future patients if patients experience a Grade 4 or higher non- hematologic 
adverse event over all cycles at any given dose level unless it is considered 
definitely unrelated to treatment. 
 
16.522  Expansion Cohort: Accrual will be temporarily suspended to this study as 
documented below in both the safety run in and the full study population if at any 
time, we observe events considered at least possibly related to study treatment 
(i.e. an AE with attribute specified as “possible,” “probable,” or “definite”) that 
satisfy one of the following: 
 
 
If 4 or more patients in the first 12 treated patients experience a grade 4 
non-hematologic AE at least possibly related to treatment 
 
If after the first 12 patients have been treated, 30% of all patients 
experience a grade 4 non-hematologic AE at least possibly related to 
treatment. 
 
If 4 or more patients in the first 12 patients require discontinuation of 
therapy due to grade 3-4 hematologic AE of at least possibly related to 


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treatment 
 
If after the first 12 patients are treated 30% of all patients require 
discontinuation of therapy due to grade 3-4 hematologic AE 
 
If 2 patients experienced a grade 5 AE, at least possibly related to 
treatment. 
 
We note that we will review grade 4 and 5 AEs deemed “unrelated” or “unlikely 
to be related”, to verify their attribution and to monitor the emergence of a 
previously unrecognized treatment-related AE. 
 
Note: If safety analysis fails in first 6 patients, those patients will not be used to 
evaluate the stopping rule. in expansion cohort. 
 
16.6 
Results Reporting on ClinicalTrials.gov 
 
At study activation, this study will have been registered within the “ClincialTrails.gov” 
website. The Primary and Secondary Endpoints along with other required information for 
this study will be reported on 
 For purposes of timing of the 
Results Reporting, the initial estimated completion date for the Primary Endpoint of this 
study is 2.5 years after the study opens to accrual. The definition of “Primary Endpoint 
Completion Date” (PECD) for this study is at the time all patients registered have 
achieved a confirmed complete response during induction or have completed induction 
treatment without achieving a confirmed complete response. 
 
16.7 
Subset Analysis for Minorities 
 
16.71 Study availability: This study will be available to all eligible patients, regardless 
of gender, race or ethnic origin. 
 
16.72 Statistical analysis by subset: There is no information currently available 
regarding differential effects of this regimen in subsets defined by race, gender, 
or ethnicity, and there is no reason to expect such differences to exist. Therefore, 
although the planned analysis will, as always, look for differences in treatment 
effect based on racial and gender groupings, the sample size is not increased in 
order to provide additional power for subset analyses. 
 
16.73 Regional population: The geographical region served by MCCC has a population 
which includes approximately 5% minorities. Based on prior MCCC studies 
involving similar disease sites, we expect about 5-7% of patients will be 
classified as minorities by race and about 25% of patients will be women. 
 
Accrual Estimates by Gender/Ethnicity/Race  
Ethnic Category 
Sex/Gender
Females
Males
Unknown
Total
Hispanic or Latino
1
3
0
4
Not Hispanic or Latino
15
44
0
59
Ethnic Category: Total of all Patients * 
16
47
0
63
Racial Category 
American Indian or Alaskan Native
0
0
0
0
Asian
0
0
0
0


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Black or African American
1
4
0
5
Native Hawaiian or other Pacific Islander
0
0
0
0
White
15
43
0
58
Racial Category: Total of all Patients* 
16
47
0
63
 
Ethnic Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish origin” 
can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino Racial Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, Southeast 
Asia, or the Indian subcontinent including, for example, Cambodia, China, India, Japan, 
Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam. (Note: 
Individuals from the Philippine Islands have been recorded as Pacific Islanders in 
previous data collection strategies.) 
Black or African American – a person having origins in any of the black racial groups 
of Africa. Terms such as “Haitian” or “Negro” can be used in addition to “Black or 
African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
 
17.0 
Pathology Considerations/Tissue Biospecimens 
 
17.1 
Tissue Biospecimen Submission 
 
NOTE: Patients must have consented to submission of the optional tissue(s) listed in the 
following table. 
 
17.11 Summary Table of Tissue Biospecimens for This Protocol 
 
Type of tissue biospecimen to submit 
Mandatory or 
optional 
When to submit 
Formalin-fixed paraffin- embedded (FFPE) tissue 
blocks with corresponding H&E (OR 
unstained slides with corresponding 
H&E)
Mandatory 
Within 30 days of registration 
Viably cryopreserved core needle biopsy
Optional
Within 30 days of registration
Formalin-fixed paraffin- embedded (FFPE) tissue 
blocks with corresponding H&E (OR 
unstained slides with corresponding H&E)
Optional 
End of cycle 1 
Viably cryopreserved core needle biopsy
Optional
End of cycle 1
Formalin-fixed paraffin- embedded (FFPE) tissue 
blocks with corresponding H&E (OR 
unstained slides with 
corresponding H&E)
Optional 
Progression 


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Viably cryopreserved core needle biopsy
 
Optional
 
Progression
 
 
NOTE: Viably cryopreserved core needle biopsy is preferred when possible. However, FFPE and/or 
viably cryopreserved core needle biopsies will be accepted.  
17.2 
All Diagnostic Slides from initial and relapse confirmatory biopsy original and/or 
recurrent tissue  
 
17.2.1 Paraffin Embedded Tissue Blocks/Slides 
 
17.2.1.1 Submit one formalin fixed paraffin embedded (FFPE) tumor tissue block 
with largest amount of invasive tumor (at least 1 cm of tumor for cases 
of surgical resection) (from original and recurrent) surgery. Please 
submit biopsy material from each surgery if available. Submission of 
materials from at least one biopsy is required. 
 
17.2.1.2 The FFPE tissue block is preferred; however, if an institution is unable 
to provide a tissue block, cut 15 five-micron sections and mount on 
charged glass slides.  Label the slides with ACCRU patient ID 
number, accession number, and order of sections. The unstained 
slides will be processed as described in 17. Ideally, each slide must have 
a minimum of 75% tumor tissue on the slide to be deemed adequate for 
study. Do not bake or place covers slips on the slides. 
 
17.2.1.3 The following materials below are mandatory (unless indicated 
otherwise) and required for shipment: 
 
Paraffin embedded tissue blocks OR 15 unstained slides 
 
Research Tissue Specimen Submission Form 
 
Surgical Pathology Report 
 
Note: Please include the ACCRU patient ID number on all materials 
listed above. Please do not place sticky labels on slides. 
 
17.2.1.4 The block/slides must be appropriately packed to prevent damage (e.g., 
slides should be placed in appropriate slide container) and placed in an 
individual plastic bag. Label the bag with the protocol number, ACCRU 
patient ID number, and patient initials. 
 
17.2.1.5 Tissue specimens must be shipped ≤ 30 days after registration. 
 
17.2.1.6Verify that the appropriate sections of the Tissue Specimen Submission 
Form are completed and filled in correctly. Enter information from the 
Tissue Specimen Submission Form into the remote data entry system on 
the same day the specimen is submitted (see Forms Packet). 
 
17.2.1.7 Ship all block/slide tissue specimens and accompanying materials to the 
ACCRU Research Base (no frozen tissue): 
 
ACCRU Operations Office 


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17.2.1.8 Assessment of tissue quality will occur at the time the translational 
studies are performed. 
 
17.2.1.9 After the pathologist assesses the tissue quality, the block and 
appropriate paperwork will be returned to the ACCRU Operations 
Office. 
 
17.2.1.10 When an appropriate request is submitted, the ACCRU Operations 
Office will forward the block/slides to the ACCRU Research Base PRC 
Shared Resource, Stabile 13-10B, Mayo Clinic Rochester (Attn: PRC 
Supervisor) for processing as outlined in Section 17. 
 
17.3 
Frozen Tumor tissue 
 
 
17.31 Submit one core from optional biopsies for viable cryopreservation. 
 
17.32 Viably cryopreserved one core in fetal bovine serum with 10% dimethyl 
sulfoxide (DMSO) in a screw cap cryovial. Store in vapor phase of liquid 
nitrogen. 
 
17.33 Ship all frozen tissue specimens and accompanying materials to the Mayo 
Clinic BAP Freezer:  
 
 
 
 
 
 
 
 
 
 
 
17.4 
Study Methodology and Storage Information 
 
17.41 Submitted tissue samples will be analyzed as follows: Tissue will be stored for 
future analysis. 
 
17.42 At the completion of the study, any unused/remaining material will be stored in 
the ACCRU Central Operations Office (Attn.: Pathology Coordinator) for future 
research according to the patient consent permission. Potential future research 
may include immunohistochemistry (IHC) analyses to analyze predictive 
biomarkers, changes in expression pattern with therapy, and correlation with 
response and/or adverse events. When a protocol is developed, it will be 
presented for IRB review and approval. 
 
17.43 Banking of tumor tissue, according to the patient consent permission is for future 
research. As protocols are developed, they will be presented for ACCRU and 
IRB review and approval. 
 
17.44 The institutional pathologist will be notified by the Pathology Coordinator if the 
block may be depleted. 


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17.45 Blocks requested to accommodate individual patient management will be 
returned promptly upon request. 
 
17.46 Return of Genetic Testing Research Results: No genetic specimens will be 
collected from tissue biospecimens for this study. If future genetic testing is 
being requested for stored tissue, patient reconsent is required. 
 
 
18.0 
Records and Data Collection Procedures 
 
18.1 
Submission Timetable 
 
Data submission instructions for this study can be found in the Data Submission 
Schedule. 
 
18.2 
Survival Follow-up 
 
See Section 4. 
 
18.3 
CRF completion 
 
This study will use Medidata Rave® for remote data capture (rdc) of all study data. Data 
collection for this study will be done exclusively through the Medidata Rave® clinical 
data management system. Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in Regulatory Support 
System (RSS). To access Rave via iMedidata, the site user must have an active account 
and the appropriate Rave role (Rave CRA, Read-Only, Site Investigator) on the 
organization roster at the enrolling site. 
 
18.4 
Site responsibilities 
 
Each site will be responsible for ensuring that all materials contain the patient’s initials, 
ACCRU registration number, and ACCRU protocol number. All PHI must be redacted 
from any documentation. 
 
18.5 
Supporting documentation 
 
Upload a copy of documentation of response or progression in RAVE on the Supporting 
Documentation Form. 
 
Baseline: The following documents are required for diagnosis and eligibility verification: 
Imaging report, Pathology report, and Lab report. These documents should be submitted 
within 14 days of registration. 
 
At patient progression or restaging for evidence of response: Imaging report, Pathology 
report, Operative report, Lab report, Clinic note, etc. 
 
18.6 
Labeling of materials 
 
Each site will be responsible for ensuring that all materials contain the patient’s initials, 
ACCRU registration number, and ACCRU protocol number. Patient’s name must be 


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removed. 
 
18.7 
Overdue lists 
 
 
A list of overdue forms and outstanding queries will be available in Rave through the 
Rave Task Summary. In addition to this, the Overdue Materials report is available on the 
ACCRU website. Only site staff rostered with the Rave CRA role will have access to 
these reports. 
 
All data must be entered by Remote Date Entry (RDE) and completed by qualified and 
authorized personnel. Access the RAVE RDE system through the iMedidata portal at 
 All data on the CRF must reflect the corresponding source 
document. Please refer to the ACCRU website for instructions 
 
 
19.0 
Budget 
 
Each site should review the test schedule (Section 4.0), taking into account local and regional 
coverage policies, to determine which items are standard of care and which are research at their 
site. Refer to the payment synopsis for funding provided per accrual for covering study costs, as 
well as any additional invoiceables that may be allowed. 
20.0 
References 
 
1. Coiffier et al. 2002, 2007, 2010; Feugier et al. 2005; Hiddemann et al. 2005; Habermann et al. 
2006; Herold et al. 2007; Marcus et al. 2008; Pfreundschuh et al. 2008; Salles et al. 2008). 
Rituximab has been accepted as a standard component in initial therapy. Hycela a 
subcutaneous form of Rituximab has been demonstrated to have equivalent efficacy 
2  Simon R. (1989) Optimal two-stage designs for phase II clinical trials. Controlled Clinical 
Trials, 10(1):1-10. 
3. Duffy D, Santner T. (1987) Confidence intervals for a binomial parameter based on 
multistage tests. Biometrics. 43:81-93. 
4. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 
53:457-81, 1958 
5. Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). 
Eur J Cancer 45(2): 228-247, 2009. 
6. Maddocks K. Update on mantle cell lymphoma. Blood 2018;132:1647-56. 
7. Young RM, Staudt LM. Targeting pathological B cell receptor signalling in lymphoid 
malignancies. Nat Rev Drug Discov 2013;12:229-43. 
8. Merolle MI, Ahmed M, Nomie K, Wang ML. The B cell receptor signaling pathway in 
mantle cell lymphoma. Oncotarget 2018;9:25332-41. 
9. Kraus M, Alimzhanov MB, Rajewsky N, Rajewsky K. Survival of resting mature B 
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By Autologous Stem Cell Transplant. Blood. 2015;126(23):5095. 


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 Appendix I: Sample List of Excluded and Cautionary Medications for Patients 
treated with of polatuzumab vedotin, venetoclax, and rituximab and hyaluronidase 
human 
 
Type 
Medication 
Excluded during the venetoclax ramp-up period and cautionary after patients are on 400 mg/day of 
venetoclax 
Strong CYP3A inducers 
Avasimibe, carbamazepine (Tegretol ), phenobarbital, phenytoin 
(Dilantin ), rifampin (Rifadin ), and St. John's wort 
Moderate CYP3A inducers 
Bosentan, efavirenz, etravirine, modafinil, and nafcillin 
Strong CYP3A inhibitors a 
Boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, 
ketoconazole, mibefradil, lopinavir/ritonavir, nefazodone, 
nelfinavir, ritonavir, posaconazole, saquinavir, telaprevir, 
telithromycin, and voriconazole 
Moderate CYP3A inhibitors a 
Amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinibb, 
darunavir/ritonavir, diltiazem, erythromycin, fluconazole, 
fosamprenavir, imatinib b, and verapamil 
Cautionary throughout the study 
 
Warfarin 
 
 
Weak CYP3A inducers 
Amprenavir, aprepitant, armodafinil, clobazamechinacea, 
pioglitazone, prednisone, rufinamide, and vemurafenib b 
Weak CYP3A inhibitors 
Alprazolam, amiodarone, amlodipine, atorvastatin, bicalutamideb, 
cilostazol, cimetidine, cyclosporine b, fluoxetine, fluvoxamine, 
ginkgo, goldenseal, isoniazid, 
nilotinibb, oral contraceptives, pazopanibb, ranitidine, ranolazine, 
tipranavir/ritonavir, ticagrelor, and zileuton 
P-gp substrates 
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, 
everolimusb, fexofenadine, lapatinibb, loperamide, maraviroc, 
nilotinibb, ranolazine, saxagliptin, sirolimusb, sitagliptin, talinolol, 
tolvaptan, and topotecan b 
BCRP substrates 
Methotrexateb, mitoxantroneb, irrinotecanb, lapatinibb, rosuvastatin, 
sulfasalazine, and topotecanb 
OATP1B1/1B3 substrates 
Atrasentan, atorvastatin, ezetimibe, fluvastatin, glyburide, 
rosuvastatin, simvastatin acid, pitavastatin, pravastatin, repaglinide, 
telmisartan, valsartan, and olmesartan 
P-gp inhibitors 
Amiodarone, azithromycin, captopril, carvedilol, dronedarone, 
felodipine, quercetin, ronalzine, and ticagrelor 


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Appendix II: Recommendations for Initial Management of Electrolyte Imbalances and 
Prevention of Tumor Lysis Syndrome 
FIRST DOSE OF VENETOCLAX OR DOSE ESCALATION 
• Within the first 24 hours after either the first dose 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 level is a medical emergency. 
• Nephrology (or acute dialysis service) must be consulted/contacted on admission (per institutional 
standards to ensure emergency dialysis is available). 
• Intravenous (IV) fluids (e.g., D5 1/2 normal saline) should be initiated at a rate of at least 1 
mL/kg/h rounded to the nearest 10 mL (target 150−200 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 tumor lysis syndrome (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 multidisciplinary management 
will be as per institutional protocols. 
 
 In addition to the recommendations for patients with chronic lymphocytic leukemia/ small 
lymphocytic lymphoma receiving 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. 


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Appendix III: Prophylaxis and Management of Tumor Lysis Syndrome for Patients Being 
Treated with venetoclax 
TLS is a risk for patients with CLL who are treated with high cell-killing agents like venetoclax. . Clinical 
data from patients with CLL treated to date with venetoclax suggest that patients with baseline lymph 
nodes ≥ 5 cm diameter are at a greater risk for TLS than those with baseline lymph nodes < 5 cm. In 
addition, the data showed that CrCl of ≤ 80 mL/min at screening was a secondary risk factor for TLS. A 
detailed description of risk factors for developing TLS following treatment with venetoclax is available in 
the venetoclax Investigator’s Brochure. 
 
Based on the data review performed by the Sponsors, the following three risk categories for developing 
TLS after treatment with venetoclax were defined (see Table 8). These risk groups were developed using 
assessments of nodal disease burden obtained from imaging tests performed at screening in several other 
studies of venetoclax in CLL. Therefore, assigning a patient’s TLS risk MUST be made based on an 
imaging test performed at screening. Assessments of TLS risk categorization and monitoring/prophylaxis 
guidance is being continuously assessed throughout the venetoclax program, and future updates to these 
guidelines are possible. 
 
Table 8 Risk Categories for Developing Tumor Lysis Syndrome 
 
TLS Risk Category 
Definition 
Low 
 
 
Medium 
 
 
High 
All measurable lymph nodes with the largest diameter < 5 cm 
and < 25 × 109/L ALC. Lymph node size will be determined by radiologic 
assessment. 
Any measurable lymph node with the largest diameter ≥ 5 cm but < 10 cm OR ≥ 
25 × 109/L ALC. Lymph node size will be determined by radiologic assessment. 
Any measurable lymph node with the largest diameter ≥ 10 cm or the presence of 
both ≥ 25 × 109/L ALC AND any measurable lymph node with the largest diameter 
≥5 cm but <10 cm. Lymph node size will be 
determined by radiologic assessment. 
ALC= absolute lymphocyte count; CT = computed tomography; MRI= magnetic resonance 
imaging; TLS= tumor lysis syndrome. 
TLS Risk Assessment MUST be made based on measurements of nodal disease burden based 
on radiologic assessments (CT scan or MRI) performed during the screening period. 
 
All patients enrolling in the study will be assessed at screening and categorized in a risk category as 
described above. Investigators may reassess patient’s TLS risk after they start treatment and may assign 
them to a lower risk group. For example, patients classified as TLS high-risk at screening because of an 
ALC of ≥ 25 × 109 AND a measurable lymph node with the largest diameter ≥ 5 cm but < 10 cm by 
radiologic assessment may have a re-evaluation of their TLS risk category based on their most recent 
ALC after initiating study treatment. If the patient’s ALC decreases to < 25 × 109/L, the patient may be 
categorized as TLS medium-risk and may follow the management guidelines for the TLS medium-risk 
category at subsequent visits and during the venetoclax ramp-up period. Re-assessment of the patient’s 
TLS risk category can occur continuously during Cycle 1 and the venetoclax dose ramp-up period. If a 
patient is re-assigned to a lower risk group, the investigator may follow the prophylaxis guidance for the 
lower risk group to which they are assigned. 
 


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However, patients who are classified as high-risk because they have a lymph node with largest diameter ≥ 
10 cm MAY NOT have their TLS risk re-assessed and should follow the prophylaxis plan for high-risk 
patients throughout the venetoclax ramp-up period. 
 
Patients who develop signs or symptoms of TLS regardless of the risk group to which they were assigned 
may have additional monitoring at subsequent visits at the investigator’s discretion. 
 
This section describes the management of patients throughout dosing given their risk factors for 
developing TLS identified upon study entry. 


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Table 9 
Summary of Tumor Lysis Syndrome Prophylaxis for venetoclax and Monitoring Measures 
 
 
 
 
 
TLS Risk 
Category 
 
 
 
Day 1 of 
Dose Level
 
 
 
 
 
Prophylaxis Medication 
Hospitalization 
 
 
 
 
Hydration a 
 
 
 
 
Laboratory Assessments b, e 
 
 
 
 
 
 
 
 
 
 
 
 
TLS 
low-risk 
 
 
 
 
 
 
 
 
 
 
 
20, 50, 
100, 200, 
400 mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
No 
 
Hematology and chemistry samples will be taken 
 
 
predose and 8 and 24 hours after dosing. 
 
 
Predose is defined as up to 4 hours before venetoclax 
administration, and results must be reviewed prior to
 
 
dosing; if it is not possible to review results from a 
sample taken up to 4 hours predose, then it is
acceptable to take a predose hematology and chemistry
sample within 24 hours prior to dosing. The results of
these samples must be reviewed prior to dosing. If
Oral uric acid reducer (such as 
Oral hydration of 
laboratory values from this sample have demonstrated 
allopurinol 300 mg/day) beginning at 
least 72 hours prior to dose and 
continued until the end of the 
ramp-up period with venetoclax is 
completed (C3D1). 
1.5-2 L/day beginning at 
least 48 hours prior to dose 
and continuing for at least 
24 hours after dose. 
no clinically significant abnormalities, the hematology 
and chemistry samples drawn on the day of venetoclax 
administration prior to dosing are not required to be 
reviewed prior to dose administration. However, these 
predose (0 4 
hours prior to dosing) laboratory samples
should still be drawn, and these will serve as baseline
for later laboratory values when assessing for laboratory
evidence of TLS at the 8 and 24 hours after dosing
 
 
timepoints. 
 
 
The 8-hour chemistry results must be reviewed before 
 
 
the patient leaves the outpatient clinic that day. 
 
 
The investigator or subinvestigator must review the 
24-hour laboratory results prior to dosing on the next
 
 
day. 


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Table 9  
Summary of Tumor Lysis Syndrome Prophylaxis for venetoclax and Monitoring Measures (cont.) 
 
 
 
 
 
 
TLS Risk 
Category 
 
 
 
 
Day 1 of 
Dose 
Level 
 
 
 
 
 
 
Prophylaxis Medication 
Hospitalization 
 
 
 
 
 
Hydration a 
 
 
 
 
 
Laboratory Assessments b, e 
 
 
 
 
 
 
 
 
 
 
 
TLS 
medium- risk
 
 
 
 
 
20 and 
50 mg 
 
 
 
Oral uric acid reducer (such as 
allopurinol 300 mg/day) beginning at 
least 72 hours prior to dose and 
continued until the end of the ramp up 
period with venetoclax is completed 
(C3D1). 
 
 
 
 
 
 
 
 
 
 
 
No c,d 
Oral hydration of 
Hematology and chemistry samples will be taken 
1.5-2 L/day beginning at 
predose and 8, and 24 hours after dosing timepoints. 
least 48 hours prior to dose 
and continuing for at least 
24 hours after dose. In 
addition to oral hydration, 
IV hydration (1.5-2 L) will 
be given in 
the outpatient setting during 
the clinic stay. 
Predose is defined as up to 4 hours before venetoclax 
administration, and results must be reviewed prior to dosing; if 
it is not possible to review results from a sample taken up to 4 
hours predose, then it is acceptable to take a predose 
hematology and chemistry sample within 24 hours prior to 
dosing. The results of these samples must be reviewed prior to 
dosing. If laboratory values from this sample have 
demonstrated no clinically significant abnormalities, the 
hematology and chemistry samples drawn on the day of 
venetoclax administration prior to dosing are not required to be 
reviewed prior to dose administration. However, these 
 
 
 
 
 
 
Oral hydration of 
1.5-2 L/day beginning at 
predose (0-4 hours prior to dosing) laboratory samples should 
still be drawn, and these will serve as baseline for later 
laboratory values when assessing for laboratory 
100, 200, 
Continue oral uric-acid reducer as 
least 48 hours prior to 
evidence of TLS at the 8 and 24 hours after dosing
400 mg 
above. 
dose and continuing for 
timepoints.
 
 
at least 24 hours after dose. 
The 8-hour chemistry results must be reviewed before the 
patient leaves the outpatient clinic that day. 
 
 
 
The investigator or subinvestigator must review the 
 
 
 
24-hour laboratory results prior to dosing on the next 
 
 
 
day. 


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Table 9 
Summary of Tumor Lysis Syndrome Prophylaxis for venetoclax and Monitoring Measures (cont.) 
 
 
 
 
 
 
TLS Risk 
Category 
 
 
 
 
Day 1 of 
Dose 
Level 
 
 
 
 
 
 
Prophylaxis Medication 
Hospitalization 
 
 
 
 
 
Hydration a 
 
 
 
 
 
Laboratory Assessments b, e 
 
 
 
 
 
 
 
 
 
 
 
TLS 
high-risk 
 
 
 
 
 
 
 
 
 
 
 
20 and 
50 mg 
 
 
 
 
 
 
 
 
 
 
 
Yes d 
 
Hematology and chemistry samples will be taken 
Oral uric acid reducer (such as allopurinol 
 
predose and 8, 12, and 24 hours after dosing. 
300 mg/day) beginning at least 72 hours 
 
Predose is defined as up to 4 hours before 
prior to dose and continued until the first 
 
venetoclax administration, and results must be 
week of combination therapy with 
 
reviewed prior to dosing; if it is not possible to 
venetoclax is completed. 
 
review results from a sample taken up to 4 hours 
Rasburicase must be administered per 
Oral hydration of 
predose, then it is acceptable to take a predose 
regional standards/institutional guidelines 
1.5-2 L/day beginning at 
hematology and chemistry sample within 24 hours 
as prophylaxis prior to the first dose of 
least 48 hours prior to dose 
prior to dosing. The results of these samples must 
venetoclax for high-risk patients with high 
and continuing for at least 
be reviewed prior to dosing. If laboratory values 
uric acid levels at pre-dose (above the local 
laboratory ULN or the Howard et al. [2011] 
threshold of 8 mg/dL 
24 hours after dose. Upon 
hospital admission, IV 
hydration should be 
from this sample have demonstrated no clinically 
significant abnormalities, the hematology and chemistry 
samples drawn on the day of venetoclax 
(475.8 mol/L). For patients with a 
started with a target of 
administration prior to dosing are not required to 
contraindication to rasburicase 
(i.e., glucose 6 phosphate dehydrogenase 
approximately 2-3 L per day 
or as clinically 
be reviewed prior to dose administration. 
However, these predose (0-4 hours prior to 
deficiency), the TLS risk-mitigation plan 
appropriate. 
dosing) laboratory samples should still be drawn, 
must be reviewed with the Medical 
 
and these will serve as baseline for later laboratory 
Monitor. Uric acid levels following 
 
values when assessing for laboratory evidence of 
treatment with rasburicase must be 
 
TLS. 
analyzed using specific guidelines 
 
The investigator or subinvestigator must review the 24- 
hour laboratory results prior to dosing on the 
 
 
next day. 


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Table 9 Summary of Tumor Lysis Syndrome Prophylaxis for venetoclax and Monitoring Measures (cont.) 
 
TLS Risk 
Category 
Day 1 of 
Dose Level
Prophylaxis Medication 
 
Hospitalization 
Hydration a 
Laboratory Assessments b, e 
 
 
 
 
 
 
 
 
 
 
 
TLS 
high-risk 
 
 
 
 
 
 
 
 
 
 
 
100, 200, 
400 mg 
 
 
 
 
 
 
 
 
 
 
 
 
Continue oral uric acid reducer as above 
 
 
 
 
 
 
 
 
 
 
No c,d 
 
 
 
 
 
 
 
Oral hydration of 
1.5-2 L/day beginning at least 
48 hours prior to dose and 
continuing for at least 24 hours 
after dose. 
In addition to oral hydration, IV 
hydration (1.5-2L) will be 
given in the outpatient setting 
during the clinic stay. 
Patients who are not hospitalized at these timepoints will 
have hematology and chemistry samples taken predose 
and 8 and 24 hours after dosing. 
Predose is defined as up to 4 hours before venetoclax 
administration, and results must be reviewed prior to 
dosing; if it is not possible to review results from a 
sample taken up to 4 hours predose, then it is acceptable 
to take a predose hematology and chemistry sample 
within 24 hours prior to dosing. The results of these 
samples must be reviewed prior to dosing. If laboratory 
values from this sample have demonstrated no clinically 
significant abnormalities, the hematology and chemistry 
samples drawn on the day of venetoclax administration 
prior to dosing are not required to be reviewed prior to 
dose administration. However, 
these predose (0-4 hours prior to dosing) 
laboratory samples should still be drawn, and these will 
serve as baseline for later laboratory values when 
assessing for laboratory evidence of TLS. The 
investigator or subinvestigator must review the 24- hour 
laboratory results prior to dosing on the next day. 
Patients who are hospitalized at these timepoints will 
have chemistry and hematology samples obtained 
predose, 8, 12, and 24 hours postdose. These results must 
be reviewed promptly by the investigator or 
subinvestigator. The 24 hour postdose laboratory results 
must be reviewed by the investigator or subinvestigator 
before the patient leaves the hospital or receives any 
additional study drug.


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Table 9 Summary of Tumor Lysis Syndrome Prophylaxis for venetoclax and Monitoring Measures (cont.) 
 
C = cycle; CrCl = creatinine clearance; D = day; IV = intravenous; TLS = tumor lysis syndrome; ULN = upper limit of normal. 
a For patients unable to maintain oral hydration at 1.5-2 L/day starting at least 48 hours prior to the start of treatment, IV hydration in the outpatient setting on the day of dosing 
during the clinic stay is recommended (unless being hospitalized) in order to assure that this full amount of hydration is achieved. For patients for whom volume overload is 
considered a significant risk, hospitalization should be considered. 
b For laboratory samples drawn on days of study treatment, “predose” laboratory samples should be drawn within 0-4 hours before the dose. Other laboratory samples 
occurring on the same day should be obtained within a ± 15-minute window of any exact scheduled time. Any laboratory tests occurring at time intervals greater than or 
equal to 24 hours after dose should be obtained within a ± 2-hour window of the scheduled time. If it is not possible to review a sample taken up to 4 hours predose, then it 
is acceptable to take a predose hematology and chemistry sample within 24 hours prior to dosing. The results of these samples must be reviewed prior to dosing. If 
laboratory values from this sample have demonstrated no clinically significant abnormalities, the hematology and chemistry samples drawn on the day of venetoclax 
administration prior to dosing are not required to be reviewed prior to dose administration. However, these predose (0-4 hours prior to dosing) laboratory samples should 
still be drawn, and these will serve a baseline for later laboratory values when assessing for laboratory evidence of TLS. 
c Patients with CrCl < 80 mL/min and/or who have a higher tumor burden (defined per the discretion of the investigator) may be handled as TLS high-risk patients. 
Currently, limited clinical experience has been gained with venetoclax in patients with CrCl 30-50mL/min. Therefore, these patients should receive additional 
consideration by the investigator with regard to their management, including the decision on whether to administer IV hydration and to hospitalize the patient to facilitate 
monitoring and expedite response to electrolyte changes at initial dosing as well as at each first dose during the ramp-up period. 
d Nephrology (or acute dialysis service) consultation should be considered on admission (per institutional standards or based on investigator discretion) for hospitalized 
patients to ensure emergency dialysis is available and the appropriate staff is aware and prepared to handle any necessary intervention for TLS. Telemetry should also be 
considered. 
e Any patient who, at any dose, develops clinically significant electrolyte abnormalities must have subsequent venetoclax dose withheld until the electrolyte abnormalities 
resolve. 
Patients who develop electrolyte abnormalities should undergo aggressive management and further monitoring per Appendix 4. Any time during the ramp-up period, if 
venetoclax was withheld for 7 days or less, the patient may resume venetoclax at the same dose level or at one lower dose-level as determined by the investigator based on 
a risk assessment (including tumor burden status). The dose must be resumed at one lower dose-level if dose was withheld more than 7 days, with the exception of initial  


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Initial Doses: venetoclax 20 and 50 mg 
All patients, irrespective of their TLS risk category at the first dose of venetoclax, must receive 
the following TLS prophylaxis measures prior to the initiation of the first doses of venetoclax: 
• 
 
 
• 
Oral hydration consisting of fluid intake of approximately 1.5−2 L/day starting at least 48 
hours prior to the start of treatment and continued for at least 24 hours after the first dose 
• 
Serum chemistry and hematology laboratory samples must be drawn prior to administering 
venetoclax (predose). If clinically significant laboratory abnormalities are observed in this 
baseline laboratory assessment, the first dose of venetoclax must be delayed until resolution 
and management per the protocol and recommendations for Initial Management of 
Electrolyte Imbalances and Prevention of TLS must be initiated. If needed, patient should 
receive additional prophylactic treatment prior to the initiation of dosing. 
Predose is defined as up to 4 hours before venetoclax administration, and results must 
be reviewed prior to dosing; if it is not possible to review results from a sample taken 
up to 4 hours predose, then it is acceptable to take a predose hematology and 
chemistry sample within 24 hours prior to dosing. The results of these samples must 
be reviewed prior to dosing. If laboratory values from this sample have demonstrated 
no clinically significant abnormalities, the hematology and chemistry samples drawn 
on the day of venetoclax administration prior to dosing are not required to be reviewed 
prior to dose administration. However, these predose (0−4 hours prior to dosing) 
laboratory samples should still be drawn, and these will serve as baseline for later 
laboratory values when assessing for laboratory evidence of TLS. 
 
Additional TLS prophylaxis and monitoring procedures are tailored to the individual TLS risk 
category as follows. 
 
TLS Low Risk 
• 
Low-risk patients will receive their initial doses of 20 and 50 mg venetoclax as outpatients. 
• 
For patients unable to maintain oral hydration at 1.5−2 L/day starting at least 
48 hours prior to the start of treatment, IV hydration in the outpatient setting on the day of 
dosing during the clinic stay is recommended in order to assure that this full amount of 
hydration is achieved. For patients for whom volume overload is considered a significant 
risk, hospitalization should be considered. 
• 
Serum chemistry, hematology, and vital signs will be obtained prior to administering 
venetoclax (predose) and 8 and 24 hours after dosing. Laboratory samples should be sent 
and analyzed immediately. 
 
Predose is defined as up to 4 hours before venetoclax administration, and results must be 
reviewed prior to dosing; if it is not possible to review results from a sample taken up to 4 
hours predose, then it is acceptable to take a predose hematology and chemistry sample 
within 24 hours prior to dosing. The results of these samples must be reviewed prior to 
dosing. If laboratory values from this sample have demonstrated no clinically significant 
abnormalities, the hematology and chemistry samples drawn on the day of venetoclax 
administration prior to dosing are not required to be reviewed prior to dose 
administration. However, these predose (0−4 hours prior to dosing) laboratory samples 
should still be drawn, and these will serve as baseline for later laboratory values when 
Administration of an oral uric acid reducer (such as allopurinol 300 mg/day) beginning 
at least 72 hours prior to dose and continued to the end of the venetoclax ramp-up period 
(Cycle 3, Day 1). 


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assessing for laboratory evidence of TLS. 
The 8-hour chemistry results must be reviewed before the patient leaves the outpatient 
clinic that day. 
Furthermore, the investigator or subinvestigator must review the 24-hour laboratory 
results prior to dosing on the next day. 
Additional laboratory assessments may be performed per investigator discretion. 
 
TLS Medium Risk 
• 
Medium-risk patients who have CrCl ≥ 80 mL/min will receive their initial doses of 20 and 
50 mg venetoclax as outpatients. Patients with CrCl < 80 mL/min and/or who have higher 
tumor burden (defined per the discretion of the investigator) may be handled as High-Risk 
patients (see the High Risk section for details of hydration, laboratory, etc.). 
• 
In addition to oral hydration stated above, IV hydration (1.5−2 L) will be given in the 
outpatient setting during the clinic stay. For patients for whom volume overload is 
considered a significant risk, hospitalization should be considered. 
• 
Serum chemistry, hematology, and vital signs will be obtained prior to administering 
venetoclax (predose) and 8 and 24 hours after dosing timepoints. Laboratory samples should 
be sent and analyzed immediately. 
Predose is defined as up to 4 hours before venetoclax administration, and results must 
be reviewed prior to dosing; if it is not possible to review results from a sample taken 
up to 4 hours predose, then it is acceptable to take a predose hematology and chemistry 
sample within 24 hours prior to dosing. The results of these samples must be reviewed 
prior to dosing. If laboratory values from this sample have demonstrated no clinically 
significant abnormalities, the hematology and chemistry samples drawn on the day of 
venetoclax administration prior to dosing are not required to be reviewed prior to dose 
administration. However, these predose (0−4 hours prior to dosing) laboratory samples 
should still be drawn, and these will serve as baseline for later laboratory values when 
assessing for laboratory evidence of TLS. 
The 8-hour chemistry results must be reviewed before the patient leaves the outpatient 
clinic that day. 
Furthermore, the investigator or subinvestigator must review the 24-hour laboratory 
results prior to dosing on the next day. 
 
Additional laboratory assessments may be performed per investigator discretion. 
 
TLS High Risk 
• 
High-risk patients will be hospitalized to receive their initial doses of 20 and 50mg 
venetoclax. Hospitalization will begin the evening prior to each initial dose of venetoclax 
and continue for 24 hours after each dose. 
• 
Upon admission, serum chemistry and hematology laboratory samples should be drawn, 
and IV hydration should be started with a target of 2−3 L per day or as clinically 
appropriate. 
• 
Rasburicase must be administered per regional standards/institutional guidelines as 
prophylaxis prior to the first dose of venetoclax for high-risk patients with high uric acid 
levels at pre-dose (above the local laboratory ULN or Howard et al. [2011] threshold of 8 
mg/dL [475.8 µmol/L]). For patients with a contraindication to rasburicase (i.e., glucose-6- 


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phosphate dehydrogenase deficiency), the TLS 
risk-mitigation plan must be reviewed with the Medical Monitor. Uric acid levels following 
treatment with rasburicase must be analyzed using specific guidelines described in the 
following: 
Please note that at room temperature, rasburicase causes enzymatic degradation of 
the uric acid in blood, plasma, and serum samples, which could potentially result in 
spuriously low plasma uric acid assay readings. The following special sample 
handling procedure must be followed to avoid ex vivo uric acid degradation: 
Uric acid must be analyzed in plasma. 
Blood must be collected into prechilled tubes containing heparin 
anticoagulant. Immediately immerse plasma samples for uric acid 
measurement in an ice water bath. 
Plasma samples must be prepared by centrifugation in a precooled 
centrifuge (4°C). 
The plasma must be maintained in an ice water bath and analyzed for uric 
acid within 4 hours of collection. 
• 
Nephrology (or acute dialysis service) consultation should be considered on admission (per 
institutional standards or based on investigator discretion) for hospitalized patients to ensure 
emergency dialysis is available and the appropriate staff is aware and prepared to handle 
any necessary intervention for TLS. Telemetry should also be considered. 
• 
Serum chemistry, hematology, and vital signs will be obtained prior to administering 
venetoclax (predose) and at 8, 12, and 24 hours after dosing. These samples are to be sent 
immediately to the laboratory, and the results must be reviewed promptly by the 
investigator or subinvestigator. 
Predose is defined as up to 4 hours before venetoclax administration, and results must 
be reviewed prior to dosing; if it is not possible to review results from a sample taken 
up to 4 hours predose, then it is acceptable to take a predose hematology and chemistry 
sample within 24 hours prior to dosing. The results of these samples must be reviewed 
prior to dosing. If laboratory values from this sample have demonstrated no clinically 
significant abnormalities, the hematology and chemistry samples drawn on the day of 
venetoclax administration prior to dosing are not required to be reviewed prior to dose 
administration. However, these predose (0−4 hours prior to dosing) laboratory samples 
should still be drawn, and these will serve as baseline for later laboratory values when 
assessing for laboratory evidence of TLS. 
The 24-hour post-dose laboratory results must be reviewed by the investigator or 
subinvestigator before the patient leaves the hospital or receives any additional study 
drug. 
Additional laboratory assessments may be performed per investigator discretion. 
 
Subsequent Dose Increases during the venetoclax Ramp-Up Period 100, 200, and 400 mg venetoclax 
All patients, irrespective of their risk category, must receive the following TLS prophylaxis 
measures prior to subsequent dose increases of venetoclax: 
• 
Continued administration of an oral uric acid reducer as indicated above. 
• 
Oral hydration consisting of fluid intake of approximately 1.5−2 L/day starting at least 48 
hours prior to dosing. IV hydration is encouraged at subsequent dose increases for patients 


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unable to maintain such oral hydration. IV hydration in the outpatient setting on the day of 
dosing during the clinic stay is recommended in order to assure this full amount of 
hydration is achieved. For patients for whom volume overload is considered a significant 
risk, hospitalization should be considered. 
• 
Serum chemistry and hematology laboratory samples must be drawn prior to administering 
venetoclax (predose). If clinically significant laboratory abnormalities are observed in this 
laboratory assessment, dose of venetoclax must be delayed until resolution, and 
management per the protocol, Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome, must be initiated. If needed, patient 
should receive additional prophylactic treatment prior to the initiation of dosing. 
Predose is defined as up to 4 hours before venetoclax administration, and results must 
be reviewed prior to dosing; if it is not possible to review results from a sample taken 
up to 4 hours predose, then it is acceptable to take a predose hematology and chemistry 
sample within 24 hours prior to dosing. The results of these samples must be reviewed 
prior to dosing. If laboratory values from this sample have demonstrated no clinically 
significant abnormalities, the hematology and chemistry samples drawn on the day of 
venetoclax administration prior to dosing are not required to be reviewed prior to dose 
administration. However, these predose (0 to 4 hours prior to dosing) laboratory 
samples should still be drawn, and these will serve as baseline for later laboratory 
values when assessing for laboratory evidence of TLS. 
 
Additional TLS prophylaxis and monitoring procedures are tailored to the individual 
TLS risk category as  follows. 
 
TLS Low Risk 
• 
Low-risk patients will receive the subsequent dose increases (100, 200, and 400 mg 
venetoclax) as outpatients. 
• 
Serum chemistry, hematology, and vital signs will be obtained prior to administering 
venetoclax (predose) and at 8 and 24 hours after dosing. Laboratory samples should be sent 
and analyzed immediately. 
Predose is defined as up to 4 hours before venetoclax administration, and results must 
be reviewed prior to dosing; if it is not possible to review results from a sample taken 
up to 4 hours predose, then it is acceptable to take a predose hematology and chemistry 
sample within 24 hours prior to dosing. The results of these samples must be reviewed 
prior to dosing. If laboratory values from this sample have demonstrated no clinically 
significant abnormalities, the hematology and chemistry samples drawn on the day of 
venetoclax administration prior to dosing are not required to be reviewed prior to dose 
administration. However, these predose (0 to 4 hours prior to dosing) laboratory 
samples should still be drawn, and these will serve as baseline for later laboratory 
values when assessing for laboratory evidence of TLS. 
The 8-hour chemistry results must be reviewed before the patient leaves the outpatient 
clinic that day. 
Furthermore, the investigator or subinvestigator must review the 24-hour laboratory 
results prior to dosing on the next day. 
Additional laboratory assessments may be performed per investigator discretion. 
 
TLS Medium Risk 


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• 
Medium-risk patients who have CrCl ≥ 80 mL/min will receive their subsequent dose 
increases as outpatient. Patients with CrCl < 80 mL/min and/or who have high tumor 
burden (defined per the discretion of the investigator) may be hospitalized. 
• 
For patients who receive this subsequent dose increases as outpatient, serum chemistry, 
hematology, and vital signs will be obtained prior to administering venetoclax (predose) 
and at 8 and 24 hours after dosing. Laboratory samples should be sent and analyzed 
immediately. 
Predose is defined as up to 4 hours before venetoclax administration, and results must 
be reviewed prior to dosing; if it is not possible to review results from a sample taken 
up to 4 hours predose, then it is acceptable to take a predose hematology and chemistry 
sample within 24 hours prior to dosing. The results of these samples must be reviewed 
prior to dosing. If laboratory values from this sample have demonstrated no clinically 
significant abnormalities, the hematology and chemistry samples drawn on the day of 
venetoclax administration prior to dosing are not required to be reviewed prior to dose 
administration. However, these predose (0 to 4 hours prior to dosing) laboratory 
samples should still be drawn, and these will serve as baseline for later laboratory 
values when assessing for laboratory evidence of TLS. 
The 8-hour chemistry results must be reviewed before the patient leaves the outpatient 
clinic that day. 
Furthermore, the investigator or subinvestigator must review the 24-hour laboratory 
results prior to dosing on the next day. 
Additional laboratory assessments may be performed per investigator discretion. 
• 
For patients hospitalized during subsequent dose increases, serum chemistry, hematology, 
and vital signs will be obtained prior to dosing (predose, defined as up to 4 hours before 
venetoclax dose) and 8, 12, and 24 hours after dosing. These samples are to be sent 
immediately to the laboratory, and the results must be reviewed promptly by the 
investigator or subinvestigator. The 24-hour after dosing laboratory results must be 
reviewed by the investigator or subinvestigator before the patient leaves the hospital or 
receives any additional study drug. 
• 
IV hydration should be started with a target of approximately 2−3 L per day oras clinically 
appropriate for patients who are hospitalized. 
 
TLS High Risk 
• 
High-risk patients with CrCl of ≥ 80 mL/min will receive the subsequent dose increases as 
outpatients. Patients with CrCl < 80 mL/min and/or high tumor burden (defined per the 
discretion of the investigator) may be hospitalized. Hospitalization will begin the evening 
prior to the dose of venetoclax and continue for 24 hours after the dose. 
• 
IV hydration (1.5−2 L) will be given in the outpatient setting during the clinic stay. For 
patients who are hospitalized, IV hydration should be started with a target of approximately 
2−3 L per day or as clinically appropriate. 
• 
For patients who are not hospitalized, serum chemistry, hematology, and vital signs will be 
obtained prior to administering venetoclax and at 8 and 24 hours after dosing timepoints. 
Laboratory samples should be sent and analyzed immediately. 
Predose is defined as up to 4 hours before venetoclax administration, and results must 
be reviewed prior to dosing; if it is not possible to review results from a sample taken 
up to 4 hours predose, then it is acceptable to take a predose hematology and chemistry 


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sample within 24 hours prior to dosing. The results of these samples must be reviewed 
prior to dosing. If laboratory values from this sample have demonstrated no clinically 
significant abnormalities, the hematology and chemistry samples drawn on the day of 
venetoclax administration prior to dosing are not required to be reviewed prior to dose 
administration. However, these predose (0 to 4 hours prior to dosing) laboratory 
samples should still be drawn, and these will serve as baseline for later laboratory 
values when assessing for laboratory evidence of TLS. 
The 8-hour chemistry results must be reviewed before the patient leaves the outpatient 
clinic that day. 
 
 
Furthermore, the investigator or subinvestigator must review the 24-hour laboratory 
results prior to dosing on the next day. 
• 
For patients who are hospitalized during subsequent dose increases, serum chemistry, 
hematology, and vital signs will be obtained prior to dosing (predose, defined as up to 4 hours 
before venetoclax dose) and 8, 12, and 24 hours after dosing. These samples are to be sent 
immediately to the laboratory, and the results must be reviewed promptly by the investigator or 
subinvestigator. The 24-hour after dosing laboratory results must be reviewed by the 
investigator or subinvestigator before the patient leaves the hospital or receives any additional 
study drug. 
Additional laboratory assessments may be performed per investigator discretion. 
 
Any patient who, at any dose, develops clinically significant electrolyte abnormalities must have his 
or her subsequent venetoclax dose withheld until the electrolyte abnormalities resolve. Patients who 
develop electrolyte abnormalities should undergo aggressive management and further monitoring 
per Appendix II, Recommendations for Initial Management of Electrolyte Imbalances and 
Prevention of Tumor Lysis Syndrome. Any time during the ramp-up period, if venetoclax was 
withheld for 7 days or less, the patient may resume venetoclax at the same dose level or at one 
lower dose level as determined by the investigator based on a risk assessment (including tumor 
burden status). The dose must be resumed at one lower dose-level if interruption lasted more than 7 
days, with the exception of the initial dose level of 20 mg (400 mg → 200 mg, 200 mg → 100 mg, 
100 mg → 50 mg, 50 mg → 20 mg). All patients must receive the intended dose for at least 7 days 
before increasing to the next ramp-up dose. 
 
For patients who are at high risk of TLS: 
• 
Hospitalized patients should receive TLS prophylaxis as described above for initial venetoclax 
dosing. Nephrology (or acute dialysis service) must be consulted/contacted on admission (per 
institutional standards) to ensure emergency dialysis is available and the appropriate staff are 
aware and prepared to handle any necessary intervention for TLS. Telemetry should also be 
considered. 


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Appendix IV: Guidelines for Defining Tumor Lysis Syndrome 
 
Howard et al. (2011) defined laboratory tumor lysis syndrome as the presence of two or more electrolyte 
changes above or below the thresholds described above occurring during the same 24-hour period within 
3 days before the start of therapy or 7 days after the start of therapy. For the purposes of this study, this 
window applies to the initiation of any study therapy and each dose escalation of venetoclax. Furthermore, 
this assessment assumes that a patient has or will receive adequate hydration (±alkalinization) and a 
hypouricemic agent(s). 
 
Howard Definition of Laboratory Tumor Lysis Syndrome 
Laboratory Assessment
Range
Uric acid
>476 µmol/L (>8.0 mg/dL)
Potassium
>6.0 mmol/L (>6.0 mEq/L)
Phosphorous
>1.5 mmol/L (>4.5 mg/dL)
Corrected calcium
<1.75 mmol/L (<7.0 mg/dL) or ionized calcium <1.12 (0.3 mmol/L) a
 
Note: Howard et al. (2011) defined laboratory tumor lysis syndrome as the presence of two or more 
electrolyte changes above or below the thresholds described above occurring during the same 24-hour 
period within 3 days before the start of therapy or 7 days afterward. For the purposes of this study, this 
window applies to the initiation of any study therapy and each dose escalation of venetoclax. 
Furthermore, this assessment assumes that a patient has or will receive adequate hydration (± 
alkalinization) and a hypouricemic agent(s). 
a The corrected calcium level in mg/dL is the measured calcium in mg/dL +(0.8 x[4-albumin in g/dL]). 


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Appendix V: ACCRU-LY-1806 SUBJECT MEDICATION DIARY 
 
Name:
Subject ID Number:
Cycle:
You will take:
ORAL MEDICATION DIARY 
Subject Instructions 
 Please bring your Medication Diary and any empty or unused medication container(s) 
with you to every appointment 
 Please use an ink pen when completing the Medication Diary as these will be retained in 
our research record. 
 Please contact your physician and study coordinator any time you go into the hospital. 
Your physician can advise if you should continue or stop taking your medication. 
 To correct a mistake, please make a single line through that entry and write your initials 
and the date next to the mistake. 
 Please indicate on the calendar on the next page that you took your study medication by 
recording the date and dose taken on the line under the date. 
 If you miss a dose, place a “0” under the date, but remember to take your prescribed 
dose at the next regularly scheduled time. 
 If you accidentally take more than you are instructed to, contact your doctor or the 
emergency room immediately. 
 If you miss a dose of venetoclax within 8 hours of the time it is usually taken, you 
should take the missed dose as soon as possible and resume the normal daily dosing 
schedule. If you miss a dose by more than 8 hours, you should not take the missed dose 
and should resume the usual dosing schedule the next day.


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ACCRU-LY-1806 SUBJECT MEDICATION DIARY 
 
Study 
Drug/Dose 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Date 
 
 
 
 
 
 
 
 
Venetoclax 
(mg)
 
 
 
 
 
 
 
 
 
Study 
Drug/Dose 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Date 
 
 
 
 
 
 
 
 
Venetoclax 
(mg)
 
 
 
 
 
 
 
 
 
Study 
Drug/Dose 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Date 
 
 
 
 
 
 
 
 
Venetoclax 
(mg)
 
 
 
 
 
 
 
 
Days 22-30 Included As Needed for Subjects with Venetoclax Treatment Delays 
 
Study 
Drug/Dose 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Date 
 
 
 
 
 
 
 
 
Venetoclax 
(mg)
 
 
 
 
 
 
 
 
 
Study 
Drug/Dose 
Day 29 
Day 30 
Date 
 
 
 
Venetoclax 
(mg)
 
 
 
 
 
Date:  
Subject’s Signature  
 
 


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Area Below Only To Be Completed only by Coordinator 
 
Week 
1 
2 
3 
4 
Discrepancy (Yes or 
No)
Date of Pill Count
 
 
 
 
 
Number of Pills 
Returned
 
 
 
 
 
Study Coordinator 
Initials