Clinical trial NCT04745832
Conditions: Follicular Lymphoma (FL) Non Hodgkin Lymphoma Marginal Zone Lymphoma
Sponsor: MEI Pharma, Inc.
Start date: 2021-08-13; Completion date: 2023-03-20
Enrollment: 82 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3 study of the PI3Kδ inhibitor Zandelisib (ME-401) in combination with rituximab, in comparison to standard immunochemotherapy (Rituximab-Bendamustine or Rituximab-CHOP) in subjects with relapsed or refractory FL and MZL.

Detailed description:
This is an open label, randomized, two-arm Phase 3 study in subjects with relapsed or refractory FL and MZL to evaluate efficacy and safety of zandelisib in combination with rituximab in comparison to standard immunochemotherapy (Rituximab-Bendamustine or Rituximab-CHOP).

Subjects must have relapsed after at least one previous line of systemic immunochemotherapy. Previous treatments must have included an anti-CD20 monoclonal antibody (mAb) with chemotherapy such as Bendamustine (B), CHOP, CVP, FND, or similar regimens, or an anti-CD20 mAb with Lenalidomide (L).

Approximately 534 randomized subjects will be enrolled in this study.

Arms: arm 1: Rituximab plus Zandelisib for 6 cycles followed by Zandelisib for 20 cycles arm 2: Rituximab and Bendamustine or Rituximab with (CHOP) for 6 cycles
Interventions: intervention 1: Zandelisib intervention 2: Rituximab intervention 3: Bendamustine intervention 4: CHOP
Intervention descriptions: intervention 1: Zandelisib 60 mg capsules taken daily for two cycles followed by intermittent schedule starting at Cycle 3 intervention 2: Rituximab IV 375 mg/m2 for 6 cycles intervention 3: Bendamustine IV 90 mg/m2 on Days 1 and 2 for 6 cycles intervention 4: Cyclophosphamide, Vindcristine IV, and Prednisone daily orally

Protocol documents:
Prot_002.pdf: 
 
 
11455 El Camino Real, Suite 250, San Diego, CA 92130  USA 
Tel: +1 858 369 7100   Fax: +1 858 369 7101   www.meipharma.com 
 
PROTOCOL 
 
A PHASE 3, RANDOMIZED, OPEN-LABEL, CONTROLLED, MULTICENTER STUDY 
OF ZANDELISIB (ME-401) IN COMBINATION WITH RITUXIMAB VERSUS 
STANDARD IMMUNOCHEMOTHERAPY IN PATIENTS WITH RELAPSED 
INDOLENT NON-HODGKIN’S LYMPHOMA (INHL) –  
THE COASTAL STUDY 
 
ZANDELISIB (ME-401) 
 
NCT 04745832 
 
September 07, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
This document is confidential and is the property of MEI Pharma, Inc. No part of this document may be transmitted, 
reproduced, published, or used by other persons without written authorization from MEI Pharma, Inc. 
 
CLINICAL STUDY PROTOCOL 
Protocol Number: ME-401-004 
A Phase 3, Randomized, Open-Label, Controlled, Multicenter Study 
of Zandelisib (ME-401) in Combination with Rituximab Versus 
Standard Immunochemotherapy in Patients with Relapsed 
Indolent Non-Hodgkin’s Lymphoma (iNHL) –  
The COASTAL Study 
 
 
Sponsor: 
MEI Pharma, Inc. 
11455 El Camino Real, Suite 250 
San Diego, CA 92130 
Sponsor Contact: 
Weiming Xu, MD, Ph.D 
Senior Medical Director, Clinical Development 
MEI Pharma, Inc. 
Phone: 1-858-357-1814 
Email: wxu@meipharma.com 
Investigational Drug: 
Zandelisib (ME-401) 
IND Number: 
129,845 
EudraCT Number: 
2020-004199-16 
Amendment 2: 
 
07 September 2021 
 




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INVESTIGATOR’S SIGNATURE PAGE AND COMPLIANCE 
STATEMENT 
By signing below, the Investigator agrees to adhere to the protocol as written and agrees that any 
deviations from or changes to the protocol must be approved MEI Pharma, Inc., before seeking 
documented approval from the Institutional Review Board (IRB)/Ethics Committee (EC), except 
when necessary to eliminate any immediate hazard(s) to the study participants. 
The Investigator further agrees to conduct the study in accordance with the current International 
Council on Harmonization (ICH) Guidelines, the Guidelines for Good Clinical Practice (GCP), 
and local ethical and regulatory requirements. The Investigator agrees to ensure all staff 
members involved in the conduct of this study have the necessary training and are informed 
about their obligations to meet protocol, regulatory, and ethical commitments. 
The information contained in this protocol is proprietary and provided to me in confidence, and 
may not be disclosed to any other party, in any form, without prior authorization from 
MEI Pharma, Inc., except to the extent necessary for the conduct of the study at this study site. 
 
Principal Investigator: 
 
 
 
 
 
Signature 
 
Date 
 
 
 
 
 
Printed name 
 
 
 
 
 
 
Institution 
 
 


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PROTOCOL SYNOPSIS 
Title:  
A Phase 3, Randomized, Open-Label, Controlled, Multicenter Study of Zandelisib 
(ME-401) in Combination with Rituximab Versus Standard Immunochemotherapy 
in Patients with Relapsed Indolent Non-Hodgkin’s Lymphoma (iNHL) – The 
COASTAL Study 
Rationale:  
Indolent B-cell lymphomas (NHLs), which include follicular lymphoma (FL) and 
marginal zona lymphoma (MZL), generally have a good prognosis and median 
survival rates longer than 10 years, but are not curable with current available 
therapeutic options, especially for those with advanced stages at diagnosis. While FL 
and MZL respond initially to therapy, their natural history is characterized by 
remissions and relapses. Although most relapses can be generally treated with 
success, the quality and duration of remissions decreases over time. Finally, these 
lymphomas evolve into refractory disease or undergo transformation into an 
aggressive histologic type with poor prognosis.  
Therapeutic options for previously untreated FL and MZL include single agent anti-
CD20 immunotherapy (most commonly with rituximab (Rituxan®, MabThera®, or 
biosimilar, [R]); in this protocol, henceforth, R refers to rituximab, i.e., Rituxan, 
MabThera, or biosimilar); to anti-CD20-based immunochemotherapy (most 
commonly the combination of R with cyclophosphamide, hydroxydoxorubicin, 
vincristine and prednisone (CHOP) designated as R-CHOP or the alkylating agent 
bendamustine (B) designated as R-B. Other chemotherapy regimens are also 
acceptable in combination with an anti-CD20 antibody as well as the combination of 
R and lenalidomide (Revlimid® [L]) (R-L).  
For patients with relapsed disease, a similar immunochemotherapy approach, 
utilizing a chemotherapy regimen not previously administered, can be used. The 
combinations of R-B showed high rates of objective response of ≥90%, and median 
progression-free survival (PFS) of 23-24 months. Combination of R and 
chemotherapy for relapsed disease is associated with a PFS of about 18 months. 
Response outcome varies based on duration of prior response, disease-and 
patient-related factors. However, the disease will inevitably relapse. Therefore, 
active agents with different mechanisms of action than cytotoxic chemotherapy are 
needed for patients with relapsed disease. Furthermore, since the median age of 
patients with FL and MZL at relapse is >60 years, new treatment options must be 
well-tolerated and avoid the toxicities typically reported with chemotherapy.  
Phosphoinositide 3 kinase (PI3K) inhibitors, a novel class of drugs for B-cell 
malignancies, have proven to be active in patients with FL and MZL, but the benefit 
of therapy is often limited by class-associated toxicities potentially related to 
immune dysfunction, including effects on regulatory T-cells. These toxicities are 
often delayed and cumulative in nature, and include diarrhea and colitis, stomatitis, 
hepatitis (elevation of transaminases), infectious and non-infectious pneumonitis.  
Zandelisib (code name ME-401), is an orally bioavailable PI3Kδ inhibitor with 
optimal pharmacologic properties and high potency, with a plasma half-life (t½) of 
approximately 28 hours supporting once-daily dosing. In an ongoing Phase 1b study 
(ME-401-002), zandelisib has been evaluated in a continuous daily dosing schedule 
(CS) and an intermittent schedule (IS), with zandelisib given daily for 2 initial cycles 
followed by 1 week on, 3 weeks off therapy in every subsequent 28-day cycle. 
Preliminary data indicate that both treatment schedules were associated with a high 
and comparable response rate in subjects with indolent B-cell malignancies, while 
the IS led to a significant reduction in Grade (Gr) 3 class-related adverse events (AE) 
compared to CS. The incidence of these AEs with the IS and the CS, respectively, 
were: colitis/diarrhea (5% and 23%), rash/skin reaction (0% and 8%), stomatitis (0% 
and 3%), AST/ALT elevation (2% and 8%), pneumonia/infectious pneumonitis 
(2% and 10.0%). With IS dosing, these Gr 3 AEs were not reported beyond Cycle 3, 


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when zandelisib is administered for 1 week per cycle, whereas there is a continued 
increase in the cumulative risk of Gr 3 AEs in the CS group.  
In 36 subjects with FL in the IS group, the overall response rate (ORR) was 83% 
(76% in monotherapy group, 89% in zandelisib in combination with rituximab), and 
the median duration of response (DOR) was not reached with a median follow-up of 
13.2 months (15.4 months for monotherapy and 12.8 months in combination with 
rituximab). The ORR in 9 subjects with CLL/SLL was 89% (100% monotherapy and 
83% combination therapy with rituximab) and 100% in 4 subjects with MZL (all 
enrolled in the rituximab combination group). Therapy on IS proved to be well 
tolerated, with few subjects experiencing Gr 3 class-related AEs. Those who had 
treatment interruptions were successfully re-challenged with zandelisib therapy.  
To date, approximately 300 subjects have been treated with zandelisib as a single 
agent or in combination with other agents. Zandelisib monotherapy is being 
evaluated in a global Phase 2 study in subjects with FL who have received 2 prior 
lines of therapy. IS dosing is being evaluated in all clinical studies with zandelisib. 
Please, refer to the current Investigator’s Brochure for detailed information.  
This study aims to test the hypothesis that zandelisib in combination with rituximab 
has better clinical activity and risk/benefit profile compared to standard 2nd line 
immunochemotherapy (R-CHOP/R-B) in subjects with relapsed FL or MZL.  
Target Population: 
Subjects with relapsed or refractory FL or MZL who received ≥1 line of prior 
systemic therapy.  
Number of Subjects: 
534 randomized subjects 
Duration of Treatment: 
Standard immunochemotherapy (R-B and R-CHOP): 6 cycles (approximately 
4 to 6 months) 
Zandelisib plus rituximab: 
• R, 6 cycles (approximately 6 months) 
• Zandelisib, 26 cycles of therapy (approximately 24 months) 
Indication: 
Relapsed or refractory FL or MZL  
Investigational 
Product(s): 
Zandelisib (in combination with R) 
Control Treatment: 
Immunochemotherapy: R-B or R-CHOP for Cycles 1-6. For administration, see 
Administration section. 
Dose(s)/Route(s)/ 
Schedule(s) of 
Administration: 
Study Treatments 
Zandelisib:  
Administered in a 28-day cycle.  
Zandelisib capsule should be taken once a day on dosing days at approximately the 
same time in the morning on an empty stomach on the following schedule: 
60 mg daily for the first two cycles of therapy (56 days) followed by: 
60 mg for the first 7 days followed by 21 days off treatment in every subsequent 
28-day cycle, defined as the IS. 
Rituximab: 
R is administered by intravenous infusion according to institutional standards 
• R 375 mg/m2 body surface on Day (D)1, D8, D15, and D22 of Cycle (C)1 and 
then on D1 of C3, C4, C5, and C6 for a total of 8 doses in 6 cycles  


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Dosing of immunochemotherapy (C1-C6): 
R-B will be administered in a 28-day cycle as follows: 
• R intravenously (IV) 375 mg/m2 body surface on D1  
• B IV 90 mg/m2 body surface on D1 and D2  
R-CHOP will be administered in a 21-day cycle as follows: 
• R IV 375 mg/m2 body surface on D1  
• Cyclophosphamide IV 750 mg/m2 body surface on D1  
• Doxorubicin IV 50 mg/m2 body surface on D1  
• Vincristine IV 1.4 mg/m2 body surface (maximum dose 2 mg) on D1 
• Prednisone 100 mg daily orally (PO) from D1 to D5 
The chemotherapy regimen administered in the study must be different from the one 
used as prior line of therapy.  
• Subjects who received B with anti-CD20 antibody (R or obinutuzumab [O]) as 
a prior line of therapy will be allocated to R-CHOP if randomized to the 
R-chemotherapy treatment group 
• Subjects who received CHOP or another chemotherapy regimen, (e.g., 
cyclophosphamide, vincristine, prednisone (CVP), fludarabine, + mitoxantrone 
+ dexamethasone, [FND]), with anti-CD 20 antibody (R or O) or R-L 
previously, will be allocated to R-B if randomized to the R-chemotherapy 
group.  
Objectives:  
Primary Objective 
• To demonstrate that zandelisib in combination with R is superior to standard 
immunochemotherapy in prolonging PFS as determined by the Independent 
Response Review Committee (IRRC) in previously treated subjects with 
follicular and marginal zone lymphoma  
Secondary objectives 
• To compare zandelisib + R to standard immunochemotherapy by ORR and 
complete response rate (CRR) as determined by the IRRC 
• To compare zandelisib + R to standard immunochemotherapy by overall 
survival (OS)  
• Time to next anti-lymphoma treatment (TTNT)  
• PFS on next anti-lymphoma treatment (PFS2) 
• To evaluate Patient Reported Outcome (PRO) assessment with  
o 
FlymSI-18  
o 
PRO with EuroQol 5 Dimension 3 Level (EQ-5D-3L)  
• To evaluate the safety and tolerability of zandelisib in combination with R 
Exploratory objectives 
To evaluate 
• Efficacy:  
o 
PFS, ORR and CRR, as determined by the Investigator  
o 
ORR at week 24 by the Investigator and by the IRRC 


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o 
DOR by the Investigator and by the IRRC 
o 
Time to progression (TTP) by the Investigator and by the IRRC  
• To characterize the relationship between zandelisib exposure in plasma with 
efficacy and safety 
Study Design: 
This is an open label, randomized, two-arm Phase 3 study in subjects with relapsed 
or refractory FL and MZL to evaluate efficacy and safety of zandelisib in 
combination with rituximab in comparison to standard immunochemotherapy (R-B 
or R-CHOP). Subjects must have relapsed after at least one previous line of systemic 
immunochemotherapy. Previous treatments must have included an anti-CD20 
monoclonal antibody (mAb) with chemotherapy such as B, CHOP, CVP, FND, or 
similar regimens, or an anti-CD20 mAb with L.  
Subjects who meet the eligibility criteria will be randomly assigned in a 1:1 ratio to 
one of the treatment arms:  
• Arm 1: R plus zandelisib 
• Arm 2: R plus chemotherapy (CHOP or B) 
Subjects will be stratified based on following criteria: 
• Prior treatment regimen: anti-CD20 mAb in combination with 
non-bendamustine chemotherapy regimen or R-L vs. anti-CD20 mAb in 
combination with B  
• Number of prior therapies: 1 vs. >1 
• NHL histology: FL vs. MZL 
• Duration of treatment-free interval from the last lymphoma-directed therapy: 
≤24 months vs. >24 months  
Study treatments will be administered as detailed above. Treatment will be 
discontinued at any time in case of disease progression or unacceptable toxicity. 
Before treatment discontinuation due to any reason, including disease progression, it 
is recommended that the Investigator review the reasons with the Sponsor’s medical 
monitor or designee.  
Primary analysis will be based on assessment of efficacy by an IRRC. Subject 
management will be based on disease response assessment according to 
investigators.  
During the study, continuing review of safety data by the sponsor and an 
independent Data Monitoring Committee (DMC) will be performed. An independent 
DMC will regularly review safety and efficacy data from all subjects to assess 
benefit/risk profile of zandelisib-rituximab therapy. Details of this review will be 
outlined in a separate DMC charter document. The DMC will meet at least once 
every 3 months, with the first data review meeting occurring when approximately 
60 subjects (~30 in each arm) have completed at least 1 cycle of treatment or 
6 months after the first subject is dosed, whichever occurs first.  
The study is composed of the following periods:  
• Screening 
• Treatment 
• Follow-up (efficacy follow-up until disease progression, safety follow-up, and 
survival follow-up)  


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Duration of Study: 
The study will end when all subjects have completed follow-up for OS, or if the 
Sponsor terminates the study, whichever occurs first. Approximate duration of the 
study for a patient will be at least 5 years.  
Primary Endpoint: 
• PFS as determined by the IRRC 
Secondary Endpoints: 
• Efficacy: ORR and CRR as determined by the IRRC 
• OS  
• TTNT  
• PFS2 
• PRO – time to deterioration in the 9-item DRS-P subset of FlymSI-18  
• PRO – time to improvement in the 9-item DRS-P subset of FlymSI-18 
• PRO – functional and well-being (FWB) score and change from baseline in the 
DRS-P and FWB subscales and total score of FlymSI-18 at specified study 
visits 
• PRO – change from baseline in EQ-5D-3L total score and VAS score at 
specified study visits 
• Treatment-emergent AEs, serious AEs, and laboratory abnormalities  
Exploratory Endpoints: 
• Efficacy:  
o 
PFS, CRR, and ORR as determined by the Investigator 
o 
ORR at 24 weeks by the Investigator and by the IRRC 
o 
DOR by the Investigator and by the IRRC 
o 
TTP, by the Investigator and by the IRRC  
• Estimates of zandelisib exposure by population pharmacokinetic method and 
association with efficacy and safety variables 
Main Criteria for 
Inclusion/Exclusion: 
Criteria for inclusion: 
1. Male or female subjects ≥18 years of age, ≥19 years in Korea, or ≥20 years for 
subjects in Japan and Taiwan, at time of signing informed consent 
2. Histologically confirmed diagnosis of CD20 positive iNHL with histological 
subtype limited to: 
a. 
FL Gr 1, Gr 2, or Gr 3a 
b. MZL (splenic, nodal, or extra-nodal) 
[Histopathological report confirming diagnosis must be available during 
screening procedures] 
3. Subjects with relapsed or refractory disease who received ≥1 prior lines of 
therapy that must have included an anti-CD20 antibody in combination with 
cytotoxic chemotherapy or L, with or without subsequent maintenance therapy. 
[A line of therapy is defined as following: a minimum of 2 consecutive cycles 
of immunochemotherapy or R-L, at least 4 doses of anti-CD20 mAb (R) single 
agent therapy, a minimum of 2 consecutive cycles of therapy with an 
investigational agent. Maintenance therapy given after an induction treatment 
(e.g., R maintenance) is considered as the same line of therapy]. [Please see 
Exclusion Criteria #2 for further clarification]. Relapsed or refractory disease 
defined as: 
• 
Relapsed disease: disease progression after a response (complete response 
[CR] or partial response [PR]) lasting ≥6 months  


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• 
Refractory disease: no response to therapy (no CR or PR) or response 
lasting <6 months  
4. Subjects must have at least one bi-dimensionally measurable nodal lesion with 
the longest diameter >1.5 cm and/or an extranodal lesion >1.0 cm in the longest 
diameter (that has not been previously irradiated) according to the 
Lugano Classification  
5. Adequate hematologic parameters at screening unless abnormal values are due 
to disease per Investigator assessment: 
• 
Absolute neutrophil count (ANC) ≥1.0 × 109/L (≥1,000/mm3) 
• 
Platelet count ≥75.0 × 109/L (≥75,000/mm3) 
• 
Hemoglobin ≥9 g/dL  
6. Adequate renal and hepatic function per local laboratory reference range at 
screening as follows: 
• 
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) 
≤1.5 × upper limit of normal (ULN) 
• 
Total bilirubin ≤2.0 × ULN or ≤3 × ULN for subjects with 
Gilbert-Meulengracht syndrome  
• 
Estimated glomerular filtration rate (eGFR) >50 mL/min using the 
Cockcroft-Gault equation (Appendix 2) 
7. QT-interval corrected according to Fridericia’s formula (QTcF) ≤450 msec; 
subjects with QTc >450 msec but <480 msec may be enrolled provided the QTc 
prolongation is due to a right bundle branch block (RBBB), left bundle branch 
block (LBBB), or pacemaker and is confirmed stable by a cardiologist. 
8. Left ventricular ejection fraction (LVEF) ≥45% as measured by echocardiogram 
(ECHO) or multi-gated acquisition scan. [If LVEF <45% by ECHO, a repeat 
measurement can be conducted within the screening period.] 
9. Subjects must have completed any prior systemic anti-cancer treatment 
≥4 weeks (or ≥5 times the half-life [t½] of used therapeutics [including 
investigational therapy], whichever is longer) or radiation therapy ≥2 weeks 
before study D1, and ≥3 months before study D1 for high dose therapy with 
stem cell transplantation, radioimmunotherapy, and CAR T-cell therapy. 
10. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 
11. Life expectancy of at least 3 months 
12. All AEs and laboratory toxicities related to prior therapy must resolve to Gr ≤1 
prior to the start of the study therapy (unless otherwise specified in eligibility 
criteria) 
13. For females of childbearing potential, a negative serum human chorionic 
gonadotropin (hCG) pregnancy test within 28 days of study D1 and negative 
result (urine or serum) on study D1 
14. Subjects must agree to use appropriate contraception methods during the 
clinical study (Appendix 3) 
15. Subject is willing and able to comply with all scheduled visits, treatment plans, 
laboratory tests, and other study procedures. 
Criteria for exclusion: 
1. Histologically confirmed diagnosis of FL Gr 3b or transformed disease  
• 
For subjects with clinical signs of rapid disease progression (e.g., marked 
B-symptoms), and laboratory or radiographic indication (e.g., high lactate 
dehydrogenase level or standardized uptake value by PET), a fresh tumor 
biopsy is recommended to rule out transformed disease  
2. Subjects who received both R/O-B and R/O-CHOP (or other anthracycline-
containing regimen) as previous lines of therapy, and those who received only 
single agent anti-CD20 mAb therapy as prior line of treatment 
3. Prior therapy with PI3K inhibitors  
4. Ongoing or history of drug-induced pneumonitis 


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5. Known lymphomatous involvement of the central nervous system 
6. Seropositive for or active viral infection with hepatitis B virus: 
• 
HBsAg positive 
• 
HBsAg negative, anti-HBs positive and/or anti-HBc positive and detectable 
viral DNA by PCR 
[Note: Subjects who are HBsAg negative and viral DNA PCR negative are 
eligible. These subjects should receive prophylactic therapy for hepatitis as 
per institutional standards.] 
7. Known seropositive for, or active infection with hepatitis C virus. 
• 
Subjects with positive hepatitis C virus (HCV) antibodies are eligible with 
negative PCR test for HCV  
8. Known seropositive for, or active and uncontrolled infection with human 
immunodeficiency virus (HIV), or with acquired immunodeficiency syndrome 
(AIDS), or currently taking medications for HIV that are contraindicated for 
concomitant use in this study  
9. Known seropositive for, or active infection with human T-cell leukemia virus 
type 1  
10. Any uncontrolled clinically significant illness including, but not limited to, 
active infections requiring systemic antimicrobial therapy, hypertension, angina, 
arrhythmias or other uncontrolled cardiovascular condition, pulmonary disease, 
autoimmune dysfunction, and urinary infection or flow obstruction.  
11. Hypersensitivity or other clinically significant reaction to the study drug or its 
inactive ingredients or other therapy used in the study  
12. Major surgical procedure within 4 weeks prior to study D1 (minor surgical 
procedures, e.g., lymph node biopsy, performed within 1 day or with an 
overnight stay are allowed) 
13. Previous or concurrent cancer that is distinct in primary site or histology from 
indolent B cell NHL within 3 years before start of study treatment except for 
curatively treated cervical cancer in situ, non-melanoma skin cancer, and 
superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ], 
and T1 [tumor invades lamina propria]), and asymptomatic localized prostate 
cancer with no requirement for systemic therapy or requiring only hormonal 
therapy and with normal prostate-specific antigen values within ≥12 months 
prior to randomization 
14. History of clinically significant cardiovascular abnormalities such as congestive 
heart failure (New York Heart Association (NYHA) classification ≥ II 
[NYHA 1994]), myocardial infarction within 6 months of study entry. 
15. History of clinically significant gastrointestinal (GI) conditions, particularly: 
• 
Known GI condition that would interfere with swallowing or the oral 
absorption or tolerance of study drug 
• 
Pre-existing malabsorption syndrome or other clinical situation that would 
affect oral absorption 
16. Females who are pregnant; females who plan to breastfeed during study 
treatment through 90 days after ending treatment 
17. Substance abuse, medical, psychological or social conditions that may interfere 
with the subject’s participation in the study or evaluation of the study results. 
18. Any illness or medical conditions that are unstable or could jeopardize the 
safety of the subjects and their compliance in the study. Inability to understand 
and sign informed consent form.  
19. Received a live virus vaccination within 28 days of first dose of study drug, 
(e.g., yellow fever vaccination) 
Methodology: 
Efficacy will be assessed based on radiological tumor evaluations of neck, chest, 
abdomen and pelvis by using contrast-enhanced computed tomography (CT) scan (or 
magnetic resonance imaging (MRI) if CT scan is not tolerated) and/or PET-CT 
imaging modality. PET-CT imaging is the recommended method of assessment per 


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Lugano Classification (Cheson 2014) for 18F-fluorodeoxy glucose (FDG)-avid 
disease and will be performed at baseline, after initial 24 weeks (±1 week) on study 
(after completion of treatment in control arm and initial 6 cycles of therapy in study 
arm), and for confirmation of CR (if initially assessed by CT scan only for FDG-avid 
disease). Contrast-enhanced CT scan or MRI scan to be done at screening and all 
other timepoints. Confirmation of PD can be done using CT or PET-CT scan. The 
Investigator should discuss assessment of PD with the Sponsor’s medical monitor or 
designee. For subjects who have variable FDG-avid tumors, CT and/or MRI imaging 
can be used if PET-CT imaging is not optimal for assessment of disease status and 
response. During the treatment phase as well as during the efficacy follow-up period, 
radiological tumor assessment by CT scan will be performed every 12 weeks for the 
first 3 scans (weeks 12, 24 and 36 [±1 week]), followed by 3 scans every 16 weeks 
(weeks 52, 68 and 84 [±1 week]), a scan at week 104 (±1 week), and every 24 weeks 
(±2 weeks) thereafter. CT scans will be evaluated locally at the study site and 
assessed by central review. The response assessment will be based on the modified 
Lugano Classification (Cheson 2014). Bone marrow biopsy/aspirate will be 
mandatory at Screening if PET scan is not performed or is not evaluable. If the 
baseline biopsy is positive for lymphoma infiltration and PET scan is not utilized for 
response assessment, it will be mandatory to perform it again to confirm the first CR. 
For subjects with MZL, if gastric involvement is suspected, an endoscopy shall be 
performed at baseline. At CR, endoscopy is required if not observed radiographically 
and the endoscopy was positive at baseline.  
All subjects will be followed after treatment discontinuation for OS, TTNT, and 
PFS2, if applicable, at 3-month intervals during the follow-up period (up to 5 years 
after the last subject’s randomization), except for subjects who withdraw consent. 
Subjects or their healthcare providers will be contacted either in person, by 
telephone, or e-mail.  
Safety evaluations will be conducted at screening, and continuously during the 
treatment period, and at the safety follow-up visit. During the follow-up period, AEs 
and SAEs will be reported for up to 30 days after the last dose of study drug. After 
30 days post last dose, only SAEs deemed related to study drug will be reported.  
Sparse blood samples will be collected from all subjects randomized to the 
zandelisib + R group to measure zandelisib plasma concentrations to evaluate the 
exposure-efficacy and exposure-safety profile of zandelisib.  
Time Point/Frame of 
Measurement for 
Primary Variable(s): 
The study duration for primary completion of PFS is approximately 64 months with 
36 months enrollment period and 28 months follow-up (after last subject enrolled).  
Statistical Analyses: 
The primary objective is to demonstrate that zandelisib in combination with R is 
superior to standard immunochemotherapy in prolonging PFS as determined by the 
IRRC in previously treated subjects with FL and MZL.  
A group-sequential design including 1 interim and 1 final analysis is planned for this 
study. At each analysis, the superiority hypothesis for the primary endpoint IRRC 
assessed PFS will be tested using a 1-sided stratified log-rank test with an overall 
family-wise error rate one-sided alpha of 0.025 controlled to adjust for multiplicity, 
utilizing Lan-DeMets O'Brien-Fleming approximation spending function.  
The interim analysis is planned to take place after approximately 248 (75% of the 
330 planned) IRRC assessed PFS events have occurred. If the statistical significance 
for PFS is not achieved at the interim analysis, the primary PFS analysis will be 
performed after 330 IRRC assessed PFS events have been observed. The alpha-
spending for the interim and final analyses will be 0.0096 and 0.0221, respectively.  
If statistical significance is successfully met at the interim analysis or the primary 
analysis, the study will be declared positive based on the primary endpoint of IRRC 
assessed PFS, and the testing of selected secondary endpoints (ORR by IRRC 


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assessment, CRR by IRRC assessment, FlymSI-18 disease related symptoms 
subscale-physical ([DRSP] and OS) will proceed, by utilizing a hierarchical testing 
procedure (detailed in the Statistical Analysis Plan). 
Assuming a hazard ratio (HR) of 0.70, approximately 330 IRRC assessed PFS events 
at primary analysis are required to yield 87.5% power to detect superiority of 
zandelisib in combination with rituximab over standard immunochemotherapy.  
A planned sample size of approximately 534 is based on the following assumptions: 
• median time to PFS for the control group of 24 months  
• accrual duration of 36 months  
• annual dropout rate of 3%  
• 28 months minimal follow-up time (after the last subject is randomized)  
Efficacy analyses will be performed in the intent-to-treat (ITT) population, which is 
defined as all subjects who are randomized. All safety summaries and analyses will 
be based on the Safety Population, defined as all randomized subjects receiving at 
least 1 dose of any study drug. Safety analyses will be performed by actual treatment 
group.  
 
 
 


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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
SPONSOR’S PROTOCOL SIGNATURE PAGE ...........................................................................2 
INVESTIGATOR’S SIGNATURE PAGE AND COMPLIANCE STATEMENT ........................3 
PROTOCOL SYNOPSIS.................................................................................................................4 
ABBREVIATIONS .......................................................................................................................18 
1. 
INTRODUCTION AND RATIONALE .....................................................................23 
1.1. 
Background .................................................................................................................23 
1.1.1. 
Follicular Lymphoma .................................................................................................23 
1.1.2. 
Marginal Zone Lymphoma .........................................................................................24 
1.1.3. 
Therapeutic Options ....................................................................................................25 
1.1.4. 
Phosphoinositide 3-kinase δ (PI3Kδ) .........................................................................25 
1.1.5. 
Investigational Drug Zandelisib (Code Name ME-401) ............................................25 
1.1.6. 
Pharmacokinetic and Pharmacodynamic Profile ........................................................25 
1.1.7. 
Dose Selection and Justification .................................................................................26 
1.1.8. 
Safety, Efficacy, and Dosing Schedule .......................................................................26 
1.2. 
Study Rationale ...........................................................................................................29 
1.2.1. 
Selection of Primary Efficacy Endpoint .....................................................................30 
1.2.2. 
Study Comparators .....................................................................................................30 
2. 
STUDY OBJECTIVES ..............................................................................................31 
2.1. 
Primary Objectives .....................................................................................................31 
2.2. 
Secondary Objectives .................................................................................................31 
2.3. 
Exploratory Objectives ...............................................................................................31 
3. 
STUDY ENDPOINTS ................................................................................................32 
3.1. 
Primary Endpoint ........................................................................................................32 
3.2. 
Secondary Endpoints ..................................................................................................32 
3.3. 
Exploratory Endpoints ................................................................................................32 
4. 
STUDY DESIGN .......................................................................................................32 
4.1. 
Randomization ............................................................................................................35 
4.2. 
Blinding ......................................................................................................................35 
4.3. 
Duration of Study .......................................................................................................36 
4.4. 
End of Study ...............................................................................................................36 


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4.5. 
Dosing Schedule for Zandelisib ..................................................................................36 
4.6. 
Dosing and Schedule for Additional Study Drugs/Comparators ................................36 
4.7. 
Supportive Therapies ..................................................................................................36 
5. 
STUDY POPULATION .............................................................................................36 
5.1. 
Inclusion Criteria ........................................................................................................36 
5.2. 
Exclusion Criteria .......................................................................................................38 
5.3. 
Number of Subjects ....................................................................................................39 
6. 
TREATMENTS ..........................................................................................................40 
6.1. 
Preparation and Administration of Investigational Product(s) ...................................40 
6.1.1. 
Zandelisib ...................................................................................................................40 
6.1.2. 
Formulation .................................................................................................................40 
6.1.3. 
Storage of Zandelisib ..................................................................................................40 
6.1.4. 
Packaging and Labelling .............................................................................................40 
6.1.5. 
Dispensing of Zandelisib ............................................................................................40 
6.2. 
Dose and Administration ............................................................................................40 
6.3. 
Investigational Product Accountability and Compliance ...........................................41 
6.4. 
Concomitant Therapy .................................................................................................41 
6.4.1. 
Permitted Prophylactic Therapy .................................................................................41 
6.4.2. 
Prohibited Concomitant Medications .........................................................................41 
6.4.3. 
Advisory for Concomitant Medications .....................................................................42 
6.4.4. 
Advisory on Vaccinations ...........................................................................................42 
6.4.4.1. 
Advisory on COVID-19 Vaccination and Risk Assessment ......................................42 
6.5. 
Prohibited Therapies ...................................................................................................42 
6.6. 
Anticipated Toxicities .................................................................................................42 
6.7. 
Zandelisib Toxicity Management ...............................................................................43 
6.8. 
Adverse Events of Special Interest for Zandelisib .....................................................50 
6.9. 
Additional Study Drugs/Comparators ........................................................................50 
6.9.1. 
Sourcing of the Standard of Care Products .................................................................50 
6.9.2. 
Expected Toxicities for Additional Study Drugs/Comparators ..................................50 
6.10. 
Dose Modification of Additional Investigational Drugs ............................................51 
6.11. 
Safety Run-in for Japanese Subjects in Japan Only ...................................................51 
7. 
STUDY CONDUCT ...................................................................................................52 
7.1. 
General Instructions ....................................................................................................52 


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7.2. 
Subject Screening .......................................................................................................52 
7.3. 
Screen Failures ............................................................................................................52 
7.4. 
Deviation from Inclusion/Exclusion Criteria ..............................................................52 
7.5. 
Monitoring Subject Compliance .................................................................................52 
7.6. 
Site Closure .................................................................................................................52 
7.7. 
Follow-up for Response Assessments and Survival ...................................................53 
7.8. 
Data Monitoring Committee .......................................................................................53 
7.8.1. 
Enrollment Stopping Rules and Additional Safety Considerations ............................53 
7.8.1.1 
Stopping Rules Based on Treatment-related Mortality ..............................................53 
7.8.1.2 
Additional Safety Considerations ...............................................................................54 
7.9. 
Study Termination ......................................................................................................55 
8. 
DESCRIPTION OF STUDY PROCEDURES ...........................................................55 
8.1. 
General Procedures .....................................................................................................55 
8.1.1. 
Informed Consent .......................................................................................................55 
8.1.2. 
Screening Period .........................................................................................................55 
8.1.3. 
Randomization Assignment ........................................................................................56 
8.1.4. 
Treatment Period ........................................................................................................56 
8.1.5. 
Discontinuation of Treatment .....................................................................................56 
8.1.6. 
Early Discontinuation/Withdrawal of Subjects from Study .......................................57 
8.1.7. 
End of Treatment Visit ...............................................................................................57 
9. 
STUDY ASSESSMENTS ..........................................................................................57 
9.1. 
Assessment of Efficacy ...............................................................................................57 
9.2. 
Assessment of Adverse Events ...................................................................................58 
9.3. 
Clinical Laboratory Tests ...........................................................................................58 
9.4. 
Other Study Assessments ...........................................................................................60 
9.5. 
Pharmacokinetics ........................................................................................................60 
9.6. 
Patient Reported Outcomes ........................................................................................61 
9.6.1. 
Electronic Patient-reported Outcomes Evaluation ......................................................62 
9.7. 
Appropriateness of Measures .....................................................................................62 
9.8. 
Study Drug Administration .........................................................................................62 
10. 
ADVERSE EVENTS ..................................................................................................62 
10.1. 
Assessment of Severity ...............................................................................................63 
10.2. 
Assessment of Causality .............................................................................................63 


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10.3. 
Documenting Adverse Events ....................................................................................63 
10.4. 
Clinical Laboratory Changes ......................................................................................63 
10.5. 
Adverse Event Follow-up ...........................................................................................64 
10.6. 
Serious Adverse Events ..............................................................................................64 
10.6.1. 
Definition ....................................................................................................................64 
10.6.2. 
Definition of Terms ....................................................................................................64 
10.6.3. 
Reporting Serious Adverse Events .............................................................................65 
10.6.4. 
Overdose .....................................................................................................................66 
10.6.5. 
Pregnancies .................................................................................................................66 
11. 
STATISTICS ..............................................................................................................66 
11.1. 
Study Populations .......................................................................................................67 
11.2. 
Sample Size and Power Considerations .....................................................................67 
11.3. 
General Considerations ...............................................................................................67 
11.4. 
Statistical Methods ......................................................................................................68 
11.4.1. 
Primary Endpoint ........................................................................................................68 
11.4.2. 
Secondary Endpoints ..................................................................................................69 
11.4.3. 
Exploratory Endpoints ................................................................................................71 
11.4.4. 
Analysis of Safety .......................................................................................................72 
11.4.5. 
Study Variables ...........................................................................................................72 
11.4.6. 
Interim Analysis ..........................................................................................................73 
12. 
ETHICS AND GOVERNANCE ................................................................................73 
12.1. 
Good Clinical Practice ................................................................................................73 
12.1.1. 
Study Personnel ..........................................................................................................74 
12.2. 
Financial Disclosure ...................................................................................................74 
12.3. 
Institutional Review Board/Independent Ethics Committee ......................................74 
12.4. 
Informed Consent .......................................................................................................74 
12.5. 
Records Management .................................................................................................76 
12.6. 
Source Documentation ................................................................................................76 
12.7. 
Study Files and Record Retention ..............................................................................76 
12.8. 
Auditing and Monitoring ............................................................................................76 
12.9. 
Quality Assurance .......................................................................................................77 
12.10. 
Amendments ...............................................................................................................77 
12.11. 
Study Discontinuation ................................................................................................78 


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12.12. 
Confidentiality ............................................................................................................78 
12.13. 
Publication Policy .......................................................................................................78 
13. 
REFERENCES ...........................................................................................................79 
14. 
APPENDICES ............................................................................................................84 
APPENDIX 1. SCHEDULE OF ASSESSMENTS .....................................................................85 
APPENDIX 2. COCKCROFT-GAULT EQUATION FOR ESTIMATED 
CREATININE CLEARANCE ............................................................................91 
APPENDIX 3. GUIDELINES FOR WOMEN OF CHILDBEARING POTENTIAL 
AND FERTILE MALE SUBJECTS ..................................................................92 
APPENDIX 4. LYMPHOMA RESPONSE CRITERIA .............................................................94 
APPENDIX 5. ECOG PERFORMANCE STATUS CRITERIA................................................97 
APPENDIX 6. LIST OF CYP2C8 INHIBITORS AND INDUCERS ........................................98 
APPENDIX 7. LIST OF CYP3A INHIBITORS AND INDUCERS ..........................................99 
APPENDIX 8. LIST OF DRUGS KNOWN TO PROLONG QT/QTC INTERVAL ..............100 
APPENDIX 9. NCCN-FACT FLYMSI-18 (VERSION 2) .......................................................106 
APPENDIX 10. EQ-5D-3L HEALTH QUESTIONNAIRE .......................................................107 
APPENDIX 11. EVALUATION OF TOLERABILITY OF ZANDELISIB IN 
COMBINATION WITH RITUXIMAB IN JAPANESE SUBJECTS .............109 
 
LIST OF TABLES 
Table 1: 
Grade 3 Drug-Related Adverse Events of Special Interest (N = 96) ..........................27 
Table 2: 
Zandelisib Toxicity Management ...............................................................................44 
Table 3: 
Modified Lugano Response Criteria ...........................................................................95 
 
LIST OF FIGURES 
Figure 1: 
Number of Subjects and Time to Grade 3 Drug-Related AESI by Schedule 
(N = 96).......................................................................................................................28 
Figure 2: 
Time to First Grade ≥3 AESI (N = 57) .......................................................................28 
Figure 3: 
Study Schematic .........................................................................................................35 
 
 


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ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
AIDS 
acquired immunodeficiency syndrome 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
B 
bendamustine 
BCRP 
breast cancer resistance protein transporter 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C 
cycle 
CBC 
complete blood count 
CHOP 
combination of cyclophosphamide, hydroxydoxorubicin, vincristine and prednisone 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum plasma concentration 
CMH 
Cochran–Mantel–Haenszel 
CMV 
cytomegalovirus 
CONMED 
concomitant medication 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CRO 
Contract Research Organization 
CRR 
complete response rate 
CRF 
Case Report Form 
CT 
computer tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVP 
combination of cyclophosphamide, vincristine, prednisone 
C1D1 
Cycle 1 Day 1 
D 
day 
DLBCL 
diffuse large B-cell lymphoma 


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Abbreviation 
Definition 
DMC 
Data Monitoring Committee 
DOR 
duration of response 
DRS-E 
disease-related symptoms subscale – emotional 
DRS-P 
disease-related symptoms subscale – physical 
FWB 
functional and well-being  
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EE 
efficacy evaluable 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
ePRO 
electronic patient reported outcome 
EQ-5D-3L 
EuroQoL-5 Dimension 3 Level 
ESMO 
European Society for Medical Oncology 
FDA 
Food and Drug Administration 
FDG 
18F-fluorodeoxy glucose 
FL 
follicular lymphoma 
FlymSI-18 
Follicular Lymphoma Symptom lndex-18 
FND 
combination of fludarabine, mitoxantrone, dexamethasone 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
Gr 
grade 
HBc 
hepatitis B core protein 
HBs Ag 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
Hct 
hematocrit 
HCV 
hepatitis C virus 
HR 
hazard ratio 
HrRt 
heart rate 


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Abbreviation 
Definition 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IP 
investigational product 
IRB 
Institutional Review Board 
IRRC 
Independent Response Review Committee 
IS 
intermittent schedule 
IUD 
intrauterine device 
IV 
intravenous(ly) 
L 
lenalidomide 
LDH 
lactate dehydrogenase 
LVEF 
left ventricular ejection fraction 
mAb 
monoclonal antibody 
MCR 
metabolic complete response 
MDP 
metabolic disease progression 
MRI 
magnetic resonance imaging 
MUGA 
multi-gated acquisition scan 
MZL 
marginal zone lymphoma 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
(i)NHL 
(indolent) non-Hodgkin lymphoma 
NIP 
non-infectious pneumonitis 
NYHA 
New York Heart Association 
O 
obinutuzumab 
ORR 
overall response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PET 
positron emission tomography 


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Abbreviation 
Definition 
PFS 
progression-free survival 
PFS2 
PFS on next anti-lymphoma treatment 
P-gp 
P-glycoprotein 
PI 
prescribing information 
PI3K 
phosphoinositide 3-kinase 
PI3Kδ 
phosphoinositide 3-kinase delta isoform 
PI3Ki 
phosphoinositide 3-kinase inhibitor 
PK 
pharmacokinetic(s) 
PO 
per os, by mouth, orally 
PP 
per protocol 
PT 
prothrombin time 
PJP 
Pneumocystis jiroveci pneumonitis 
PR 
partial response 
PRO 
patient reported outcome 
QD 
once daily 
QoL 
Quality of Life 
QTc 
QT corrected (corrected QT-interval) 
QTcF 
QT-interval corrected according to Fridericia’s formula 
R 
rituximab 
R-B 
rituximab plus bendamustine 
R-CHOP 
combination of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone 
R-L 
lenalidomide plus rituximab combination therapy 
R-CVP 
combination of rituximab, cyclophosphamide, vincristine, prednisone 
R/R 
relapsed/refractory 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SIV 
site initiation visit 
SLL 
small lymphocytic leukemia 
SOC 
standard of care 
SRC 
Safety Review Committee 
TEAE 
treatment-emergent adverse event 
TENS 
toxic epidermal necrolysis syndrome  


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Abbreviation 
Definition 
TREG 
T-regulatory cell 
TSE 
treatment side effects  
TTNT 
time to next anti-lymphoma treatment 
TTP 
time to progression 
ULN 
upper limit of normal 
US(A) 
United States (of America) 
VAS 
visual analogue scale 
WBC 
white blood cell 


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1. 
INTRODUCTION AND RATIONALE 
1.1. 
Background 
Non-Hodgkin’s lymphoma (NHL) is one of the most common cancers in the world ranking as 
the 5th to 9th among cancer in most countries; almost 510,000 new cases were estimated in 2018 
(Miranda-Filho 2019, Bray 2018). It is estimated that in 2020 approximately 77,000 people will 
be diagnosed with NHL and approximately 20,000 will die from this cancer in the United States 
(US) (Cancer Facts and Figures, American Cancer Society 2020).  
NHL comprises more than 30 types; classification is based on the type of lymphocyte involved, 
B-cells or T-cell. NHL is further classified by other factors, including whether it is aggressive 
(fast-growing) or indolent (slow-growing) (Swerdlow 2016).  
1.1.1. 
Follicular Lymphoma 
Follicular lymphoma (FL) is typically an indolent form of B-cell NHL (iNHL). This lymphoma 
subtype accounts for 20 to 30 percent of all NHL cases (Provencio 2017). Of the approximately 
72,240 cases of NHL diagnosed in 2017 in the US, (National Cancer Institute 2017) 
approximately 20% were likely to be follicular lymphomas (National Cancer Institute 2017). 
About 18,000 and 25,000 new cases of FL were expected in the US and the EU, respectively, in 
2015 (Howlader 2020, Dreyling 2021). No sex preponderance is seen for follicular lymphomas, 
but the incidence increases with age, and varies across racial groups and geographic regions. In 
the US, the incidence is 2 to 3 times higher in white individuals than in those of African descent 
(Nabhan 2012).  
The overall survival (OS) rate of treated patients with FL is 77 to 86% at 5 years with a median 
survival of approximately 20 years for all patients and is better -in younger patients and those 
with better performance status, and significantly lower for patients with transformed disease 
(Provencio 2017, Mozas 2020). 
Several systemic therapeutic options are available for patients with FL, ranging from single agent 
anti-CD20 immunotherapy (most commonly with rituximab (Rituxan®, [R]; MabThera®) 
(McLaughlin 1998, Hainsworth 2005); to anti-CD20-based immunochemotherapy (most 
commonly the combination of R with cyclophosphamide, hydroxydoxorubicin, vincristine, and 
prednisone (CHOP) designated as R-CHOP (Czuczman 1999) or the alkylating agent 
bendamustine (B) designated as R-B (Rummel 2005, Robinson 2008). Other chemotherapy 
regimens are also acceptable in combination with an anti-CD20 antibody. Immunochemotherapy 
is typically preferred in younger and fit patients, and achieves an objective response rate >90%, 
with a substantial proportion of complete responses (CRs), and a progression-free survival (PFS) 
of 65.5% at 5 years of follow-up (Flinn 2019).  
Rituximab (R)-lenalidomide (L) (R-L) combination has been evaluated in randomized studies in 
patients with relapsed and/or refractory (R/R) iNHL (Leonard 2019) and for treatment of 
previously untreated patients with FL (Morschhauser 2018). It has been reported that efficacy in 
patients treated with R-L as front-line therapy are comparable with results in patients treated with 
chemoimmunotherapy, where the overall response rate (ORR) was 61% in R-L arm and 65% in 
R-chemotherapy arm, with PFS at three years of follow-up being 77% and 78% for R-L and 
R-chemotherapy, respectively (Leonard 2019).  


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This information justifies the patient population for this study as those who received prior 
therapy that included anti-CD20 antibody in combination with a chemotherapeutic regimen or L.  
For patients with relapsed disease, a similar immunochemotherapy approach, utilizing a 
chemotherapy regimen not previously administered, can be used. The combinations of R-B 
showed high rates of objective response of ≥90%, and median PFS of 23 to 24 months for R-B 
(Robinson 2008, Rummel 2005). Combination of R and chemotherapy may be employed for 
relapsed disease, but it is associated with a shorter median PFS of about 18 months (Link 2019). 
Although the current treatments for iNHL are initially effective in inducing responses in most 
patients, they are not curative and show decreasing efficacy and development of resistance to 
therapy with repeated administrations.  
However, the disease will inevitably relapse; therefore, active agents with different mechanisms 
of action than cytotoxic chemotherapy are needed for this patient population, with the goal of 
extending the duration of disease control at relapse from initial therapy. Furthermore, since the 
median age of patients with FL and marginal zone lymphoma (MZL) at relapse is >60 years, new 
treatment options must be well-tolerated and avoid the toxicities typically reported with 
chemotherapy.  
1.1.2. 
Marginal Zone Lymphoma 
MZL represents approximately 5-15% of all non-Hodgkin lymphomas (Zucca 2020) and is the 
third most common type among iNHLs (Al-Hamadani 2015); however, it remains largely 
understudied. Frontline therapy for MZL differs greatly based upon the subtype (extranodal, 
nodal, mucosal) (Swerdlow 2016), and the underlying etiology; hence, defining a standard 
treatment regimen for MZL has been difficult (Noy 2017). Treatments include anti-CD20 
antibody (rituximab) based regimens either as monotherapy or in combination with systemic 
chemotherapy. Targeted therapy with ibrutinib (a Bruton tyrosine kinase [BTK] inhibitor) is also 
now used in relapsed/refractory cases across MZL subtypes (Denlinger 2018) for patients who 
have received at least one prior anti-CD20 based therapy (Imbruvica® US prescribing 
information); ORR with ibrutinib was 48% and median PFS was 14.2 months (Noy 2017). 
Outcomes were also analyzed by MZL subtypes, the median PFS was 13.8 months for extranodal 
MZL, 19.4 months for splenic MZL, and 8.3 months for nodal MZL. The estimated 18-month 
OS rate was 81%.  
No single standard of care is available for patients who relapse after initial treatment and 
depending on disease characteristics and previously used therapies various regimens combining 
R and chemotherapy-containing regimens have classically been the treatment of choice in the 
second line of treatment, resulting in ORR of 85%–93% and complete response (CR) rate of 
54%-78% (Zucca 2017, Brown 2009, Cervetti 2010, Orciuolo 2010, Laribi 2016). 
Treatment-related toxicities with these therapies such as Grade (Gr) 3 and 4 myelosuppression 
frequently limit treatment participation in many patients (Noy 2017). Autologous and allogeneic 
hematopoietic progenitor cell transplantation has been performed in selected patients with 
relapsed/refractory MZL, achieving durable remissions and frequently cures, albeit at cost of 
significant morbidity (Shimoni 2017).  
In the current landscape of MZL, standardized treatment algorithms still lack sufficient evidence-
based guidelines required to guide optimal therapy. Combination therapies that include BTK 
inhibition as well as other agents, such as PI3Ks, are ongoing.  


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1.1.3. 
Therapeutic Options 
For patients with advanced-stage FL and MZL requiring systemic lymphoma-directed treatment, 
initial therapy typically consists of an anti-CD20 antibody given alone or in combination with 
chemotherapy. Bendamustine and CHOP are the most frequently used chemotherapy regimens, 
with CVP (cyclophosphamide, vincristine, prednisone), chlorambucil, or a pyrimidine-based 
regimen used less commonly (Zucca 2020, NCCN 2020, Denlinger 2018). Front-line therapy 
with single-agent rituximab in FL is typically reserved for patients unfit to receive 
chemotherapy-based regimens due to age and/or co-morbidities, for patients with low tumor 
burden for whom the risk/benefit assessment of chemotherapy is considered unfavorable, or for 
patients who refuse chemotherapy. Therefore, patients treated with single-agent rituximab as 
first-line therapy are a heterogeneous group with respect to baseline characteristics and treatment 
outcome. Because immunochemotherapy is more commonly used as initial therapy in FL and in 
patients with MZL whose disease had progressed after initial rituximab therapy, this Phase 3 
study will require failure of prior immunochemotherapy as a pre-requisite for eligibility.  
For patients with FL and MZL whose disease does not respond to or who relapse after treatment 
with an anti-CD20 antibody and chemotherapy, the most common treatment approach is the 
combination of R with either CHOP (R-CHOP) or B (R-B) administered for a total of 6 cycles of 
therapy, and using a chemotherapy regimen not administered in a prior line of therapy 
(Zucca 2020, NCCN 2020, Robinson 2008, Gribben 2007, Rummel 2005). These two 
immunochemotherapy regimens are the most commonly used in both front-line treatment and for 
patients with relapsed disease (NCCN 2020, Dreyling 2021). R as a single agent or in 
combination with chemotherapy has been used in 70% of patients who have received second-line 
therapy (Link 2019).  
1.1.4. 
Phosphoinositide 3-kinase δ (PI3Kδ)  
Signaling through the BCR provides a strong proliferative and survival stimulus to the cell; 
interfering with such signaling is therefore a rational approach to the treatment of B-cell 
malignancies. In leukocytes, BCR signaling is mediated partly by the activation of PI3Kδ. The 
activation of PI3Kδ ultimately leads to cell survival, proliferation, and immune regulation 
(Herman 2012).  
PI3Kδ is frequently active in B-cell malignancies and is central to multiple signaling pathways 
that drive proliferation, survival, homing, and retention of malignant B-cells in lymphoid tissue 
and bone marrow. Because PI3Kδ is the main PI3K isoform expressed in lymphoid cells, but is 
expressed at low or undetectable levels in most other tissue, inhibitors of PI3Kδ should be 
selective for the immune system and relatively non-toxic in other organs (Brown 2014).  
1.1.5. 
Investigational Drug Zandelisib (Code Name ME-401) 
1.1.6. 
Pharmacokinetic and Pharmacodynamic Profile 
Zandelisib, is an orally bioavailable PI3Kδ inhibitor with optimal pharmacologic properties, 
including high potency with half-maximal inhibitory concentration (IC50) for PI3Kδ of 0.6 nM in 
a cellular assay, plasma half-life (t½) of approximately 28 hours supporting once-daily dosing, 
and high volume of distribution indicating wide access to tissues, high specificity to the 
δ isoform at clinically relevant concentrations, and prolonged residence time on the target.  


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Maximum plasma concentration (Cmax) and area under the concentration versus time curve from 
time zero to the last timepoint (AUC(0–last)) demonstrated linear increases over the dose range of 
10 mg to 150 mg with a tmax of 5-6 h.  
1.1.7. 
Dose Selection and Justification 
Robust responses have been achieved in the ongoing Phase Ib study at various dose levels:  
60 mg, 120 mg, 180 mg.  
After continuous once daily administration of 60 mg of zandelisib, Day 28 steady-state plasma 
trough concentrations were greater than 5 ng/mL, the EC90 value for inhibition of basophil 
activation, in 18 out of 19 subjects or approximately 95% of subjects. Therefore, 60 mg once 
daily was designated as the minimum biologically effective dose of zandelisib. This concept of 
designating a minimum biologically effective dose (also referred to as an optimal biologically 
active dose) based on the extent of inhibition of the intended target enzyme/pathway, in the 
current context inhibition of PI3Kδ, has been recommended for dose selection of molecularly 
targeted agents such as zandelisib.  
In subjects enrolled at 120 mg and 180 mg dose levels, zandelisib trough concentrations were 
consistently greater than 5 ng/mL in all subjects and nearly dose proportionally higher when 
compared to trough concentrations observed values at the 60 mg dose level.  
Overall, based on pharmacokinetic (PK)-pharmacodynamic (PD) relationship identified at dose 
levels ranging from 10 mg to 150 mg and safety and efficacy in cancer patients at dose levels 
ranging from 60 mg to 180 mg once daily, the recommended phase 2 dose of zandelisib was 
established to be 60 mg administered once daily.  
1.1.8. 
Safety, Efficacy, and Dosing Schedule 
Study ME-401-002 is an ongoing study of zandelisib monotherapy and zandelisib in combination 
with rituximab or in combination with zanubrutinib in subjects with relapsed/refractory B-cell 
malignancies. The study consists of a dose escalation phase followed by a dose expansion phase 
evaluating zandelisib as a single agent, in combination with rituximab, and in combination with a 
novel BTK inhibitor zanubrutinib.  
In the dose escalation phase of the study, dose levels of 60, 120, and 180 mg, administered daily 
continuously in 28-day cycles, were evaluated with 6-12 subjects enrolled at each dose level. 
High response rates were obtained at all dose levels tested and no dose-limiting toxicities were 
observed. Based on these results, dose escalation did not proceed beyond 180 mg solely to define 
the MTD.  
There are certain adverse events (AEs) consistently associated with the use of PI3Kδ inhibitors. 
These ‘class specific’ toxicities include diarrhea/colitis, rash, stomatitis, hepatitis (elevation in 
transaminases), and pneumonitis (both infectious and non-infectious). When zandelisib was 
given initially on a daily continuous schedule (CS) these AEs, primarily involving 
diarrhea/colitis and skin rash, occurred at Gr 3 severity in approximately 1/3rd of subjects. These 
class specific toxicities were selected as AEs of special interest (AESI) that were followed in 
initial clinical studies with zandelisib.  
Emerging evidence suggests that these class specific AEs are a consequence of immune 
dysregulation, primarily involving T-regulatory cells (TREGs). In the majority of cases, these 


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class specific toxicities are delayed in nature and tend to accumulate over time. To mitigate these 
potential toxicities, a novel, rationally designed schedule was subsequently evaluated in the 
Phase 1b study (ME-401-002). This consists of 2 cycles of continuous daily dosing followed by 
subsequent cycles of 1 week of continuous daily dosing followed by 3 weeks off (intermittent 
schedule [IS]). Preliminary data indicates that the majority of subjects developed response to 
treatment after the first two cycles of daily dosing with zandelisib. Therefore, this schedule 
enables an early and constant inhibition of the target with daily dosing, followed by regular 
treatment breaks to minimize the potential effect on TREGs and development of AESI.  
Initial comparison of CS and IS shows a substantially lower number of Gr 3 drug-related AESIs 
in subjects treated on IS (Table 1). As shown in Figure 1, subjects on IS had a significantly lower 
number of related Gr 3 AESIs compared to those on CS. At the same time, the ORRs were 
similar in subjects who received CS and those who received IS. In 29 efficacy evaluable subjects 
with FL the ORR was 79% with IS dosing and in 26 evaluable subjects the ORR was 70% with 
CS dosing. For 8 evaluable subjects with CLL/SLL, the ORR was 75% with IS dosing, and in 
10 evaluable subjects with CLL/SLL the ORR was 100% with CS dosing. Also, there was no 
overall difference in ORR between subjects who received zandelisib alone or in combination 
with rituximab (Zelenetz 2019).  
Table 1: 
Grade 3 Drug-Related Adverse Events of Special Interest (N = 96) 
 
CS 
Total Group 
(N = 39) 
IS  
Total Group  
(N = 57) 
Colitis/diarrhea 
9 (23%) 
3 (5.0%) 
Rash/skin reactions 
3 (8%) 
0 
Stomatitis 
1 (3%) 
0 
AST/ALT elevation 
3 (8%) 
1 (2%) 
Pneumonia/pneumonitis 
4 (10%) 
1 (2%) 
Data cut off 16 September 2019 
Abbreviations:  CS = continuous daily dosing; IS = intermittent schedule, i.e.,1 week on and 3 weeks off therapy in 
a 4-week cycle 


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Figure 1: 
Number of Subjects and Time to Grade 3 Drug-Related AESI by Schedule 
(N = 96)  
The updated analysis (Zelenetz 2020) for the safety in 57 subjects on IS only, indicate a low 
incidence of Gr 3 AESI :  diarrhea (3.5%), colitis (3.5%), ALT/AST elevation (1.8%), rash 
(1.8%), non-infectious pneumonitis (1.8%); there were no Gr 4 or 5 AESIs reported. No Grade 3 
AESI was reported beyond Cycle 3 (Figure 2). It is important to note that all 5 subjects who had 
treatment interruption due to AESI and were re-challenged, tolerated continuing therapy well.  
Figure 2: 
Time to First Grade ≥3 AESI (N = 57)  
 


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Myelosuppression is uncommon with the following Gr 3 hematologic laboratory abnormalities 
observed:  neutropenia in 11 subjects (19.3%); thrombocytopenia in 2 subjects (3.5%), and ALT 
elevation in two subjects (3.5%). In all, 4 subjects (7%) discontinued due to AEs 
(Zelenetz 2020).  
There were no notable differences in the incidence of Gr ≥3 AESI between subjects who 
received only 1 prior systemic therapy and those who received 2 or more prior therapies.  
The incidence of Gr 3 AESIs for those receiving 60 mg of zandelisib IS regimen with 1 prior 
therapy (26 subjects) were: colitis/diarrhea 2 (7.7%), rash/skin reaction 0; ALT/AST elevation 
1 (3.8%); and pneumonia/pneumonitis 0. Of note, of the 26 subjects treated on IS after only 
1 prior systemic therapy, 16 were in combination with rituximab.  
For subjects receiving 60 mg of zandelisib IS regimen with >1 prior therapy (30 subjects), the 
incidence of Gr 3 AESIs were: colitis/diarrhea 1 (3.3%); rash/skin reaction 1 (3.3%); ALT/AST 
elevation 1 (3.3%); pneumonia1 (3.3%); and non-infectious pneumonitis 1 (3.3%).  
Continuing evaluation of zandelisib efficacy indicates strong activity in the 57 subjects dosed on 
the IS, with ORR for FL of 83% (76% in monotherapy group, 89% in combination group (R plus 
zandelisib). Median duration of response (DOR) was not reached for monotherapy and 
zandelisib in combination with rituximab. The ORR for CLL/SLL was 89% (100% monotherapy 
and 83% combination therapy), and 100% (4/4) in MZL (in combination group only).  
The efficacy and safety of zandelisib administered as a single agent using the IS is being 
evaluated in an ongoing Phase 2 study (ME-401-003, TIDAL) in subjects with relapsed or 
refractory FL whose disease failed at least two prior lines of systemic therapy (NCT03768505).  
To date, approximately 300 subjects have been dosed with zandelisib from the ongoing Phase 1b 
(ME-401-002) and Phase 2 (ME-401-003) studies. The therapy with zandelisib as single agent or 
in combination with R, given on IS dosing, has been associated with high ORR and is well 
tolerated with few discontinuations due to toxicity.  
Please refer to the current IB for full details of preclinical and clinical studies with zandelisib.  
1.2. 
Study Rationale 
For patients with relapsed FL and MZL, R in combination with chemotherapy or B (typically a 
chemotherapy regimen not used in front-line therapy) can be used. The combination of R-B 
showed satisfactory rates of objective response of ≥90%, with median PFS of 23 to 24 months 
(Robinson 2008, Rummel 2005). Combination of R and chemotherapy may be employed for 
relapsed disease, but it is associated with a shorter median PFS of about 18 months (Link 2019). 
However, repeated courses of chemotherapy is associated with cumulative toxicity, including 
myelosuppression, neuropathy, cardiac toxicity, and secondary cancers (Lunning 2012). Since 
the median age of patients with FL and MZL at relapse is ≥60 years (Robinson 2008, 
Denlinger 2018, Kahl 2010), new treatment options for relapsed disease must be well-tolerated 
and avoid the toxicities typically reported with chemotherapy, necessitating the exploration of 
new chemotherapy-free options.  
The high frequency of PI3Kδ pathway alterations in NHL led to the development of PI3Kδ 
inhibitors in this disease. Three drugs with PI3Kδ inhibitory activity, Zydelig® (idelalisib), 
Aliqopa™ (copanlisib), and Copiktra® (duvelisib) (Furman 2014, Krause 2018, Flinn 2018) have 


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been approved for clinical use in patients with multiple relapsed/refractory FL, based on single 
arm studies, in the US and other countries.  
Recently presented data about treatment patterns of patients with relapsed or refractory FL 
treated in community practice with the first-approved PI3Kδ inhibitor idelalisib indicates that 
many patients cannot tolerate long term therapy, with 46.9–91.7% discontinuing therapy due to 
toxicities, and median duration of therapy of 5.5 months (Andorsky 2019). Better tolerated 
options with strong activity are needed.  
Despite ongoing efforts in recent years to provide new therapies for patients with relapsed FL 
and MZL, the high clinical unmet need remains as patients need active and well-tolerated 
therapy to delay time to the next disease progression. As the majority of patients are >65 years 
old, finding well-tolerated therapies becomes a very important task.  
Zandelisib is a highly selective inhibitor of PI3Kδ and shows promising clinical activity alone 
and in combination with rituximab in the treatment of iNHLs. Zandelisib preliminary data 
indicate high level of activity in patients with relapsed/refractory FL and MZL, and that therapy 
can be well tolerated given on an IS. In the Phase 1b study, ORR for FL is 83% and 100% for 
MZL. With the utilization of IS, Gr 3 AESIs decreased significantly.  
This Phase 3 trial addresses the need for patients who have relapsed or progressed after receiving 
chemotherapy in combination with an anti-CD20 antibody (R) or with R and L, using a 
potentially less toxic therapeutic regimen of a PI3Kδ inhibitor in combination with rituximab 
compared to traditional immunochemotherapies (R-CHOP and R-B). Zandelisib is continuing to 
be evaluated in an ongoing Phase 1b and a Phase 2 study as a single agent or in combination with 
other therapies. It has been demonstrated that zandelisib alone or in combination with rituximab 
induces strong efficacy and is well tolerated, and that supports further evaluation in a Phase 3 
trial to introduce a chemotherapy-free option for patients with relapsed indolent NHL.  
As noted above, patients with relapsed FL and MZL have fewer choices of efficacious and 
well-tolerated treatment. After failure of initial treatment patients are treated with various 
immunochemotherapy regimens. Finding effective and well tolerated therapeutic options for 
patients who failed initial treatment remains high clinical unmet need in this patient population.  
1.2.1. 
Selection of Primary Efficacy Endpoint 
Progression-free survival (PFS) is selected as the primary efficacy endpoint. It is an established 
surrogate for OS and has been used as primary endpoint in Phase 3 registrational trials in NHL 
(Cheson 2007).  
1.2.2. 
Study Comparators 
• R in combination with B (R-B). 
• R in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone 
(R-CHOP). 
The comparator treatments used in this study namely R-B and R-CHOP are recommended 
standards of care for B-cell malignancies per the National Comprehensive Cancer Network 
(NCCN Guidelines, v1 2020) and the European Society for Medical Oncology (ESMO) 
(Dreyling 2021, Zucca 2020) guidelines for diagnosis and treatment of B-cell lymphomas, and 


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remain the first choice of therapy for patients in front line therapy. Although, other regimens and 
agents can be used for treatment of patients with relapsed or refractory disease, these two 
regimens were selected for control arm as two most commonly used options and to minimize 
potential imbalance associated with introduction of multiple options.  
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
• To demonstrate that zandelisib in combination with R is superior to standard 
immunochemotherapy in prolonging PFS as determined by the Independent Response 
Review Committee (IRRC) in previously treated subjects with follicular and marginal 
zone lymphoma 
2.2. 
Secondary Objectives 
• To compare zandelisib + R to standard immunochemotherapy by ORR and complete 
response rate (CRR) as determined by the IRRC  
• To compare zandelisib + R to standard immunochemotherapy by overall survival (OS)  
• Time to next anti-lymphoma treatment (TTNT)  
• Progression-free survival on next anti-lymphoma treatment (PFS2) 
• To Evaluate Patient Reported Outcomes (PRO) with 
o 
FlymSI-18  
o 
EuroQoL 5 Dimension 3-Level (EQ-5D-3L)  
• To evaluate the safety and tolerability of zandelisib in combination with R 
2.3. 
Exploratory Objectives 
To evaluate: 
• Efficacy:  
o 
PFS, ORR and CRR, as determined by the Investigator  
o 
ORR at week 24 by the Investigator and by the IRRC 
o 
DOR by the Investigator and by the IRRC 
o 
Time to progression (TTP), by the Investigator and by the IRRC  
• To characterize the relationship between zandelisib exposure in plasma with efficacy and 
safety  


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3. 
STUDY ENDPOINTS  
3.1. 
Primary Endpoint 
• PFS as determined by the IRRC 
3.2. 
Secondary Endpoints 
• Efficacy: ORR and CRR as determined by the IRRC 
• OS  
• TTNT  
• PFS2 
• PRO – time to deterioration in the 9-item disease-related symptoms subscale-physical 
(DRS-P) subset of FlymSI-18  
• PRO – time to improvement in the 9-item DRS-P subset of FlymSI-18 
• PRO – functional and well-being (FWB) score and change from baseline in the DRS-P 
and FWB subscales and total score of FlymSI-18 at specified study visits 
• PRO – change from baseline in EQ-5D-3L total score and VAS score at specified study 
visits 
• TEAEs, serious AEs (SAEs), and laboratory abnormalities  
3.3. 
Exploratory Endpoints 
• Efficacy:   
o 
PFS, CRR, and ORR as determined by the Investigator  
o 
ORR at 24 weeks by the Investigator and by the IRRC 
o 
DOR by the Investigator and by the IRRC 
o 
TTP by the Investigator and by the IRRC  
• Estimates of zandelisib exposure by population PK method and association with efficacy 
and safety variables  
4. 
STUDY DESIGN 
This is an open label, two-arm Phase 3 study in subjects with relapsed or refractory FL or MZL 
to evaluate efficacy and safety of zandelisib in combination with rituximab compared with 
standard immunochemotherapy (R-B [rituximab + bendamustine], or R-CHOP [combination of 
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone]). The subjects must 
have relapsed after ≥1 previous line of therapy; prior therapy must have included anti-CD20 
monoclonal antibody treatment (e.g., R, obinutuzumab [O]) in combination with a 
chemotherapeutic regimen containing an alkylating agent (B or CVP or CHOP or similar), or L.  


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Subjects will be stratified based on the following criteria: 
• Prior treatment regimen: anti-CD20 monoclonal antibody (mAb) in combination with 
non-bendamustine chemotherapy regimen or R-L vs. anti-CD20 mAb in combination 
with B 
• Number of prior lines of therapy: 1 vs. >1 
• NHL histology: FL vs. MZL  
• Duration of treatment-free interval from the last lymphoma-directed therapy:  
≤24 months vs. >24 months  
Subjects who meet the eligibility criteria will be randomly assigned in a 1:1 ratio to one of the 
treatment arms:  
• Arm 1: Rituximab plus zandelisib 
• Arm 2: Rituximab plus chemotherapy (CHOP or B) 
For Arm 2, selection of therapy regimen will depend on prior therapy, specifically, if a subject 
had received anti-CD20 mAb in combination with B as a prior therapy, then the subject will 
receive R-CHOP if randomized to control arm. If a subject received anti-CD20 mAb (e.g., R, O) 
in combination with chemotherapy regimen (e.g., CHOP or CVP, FND [fludarabine, 
+ mitoxantrone + dexamethasone], or similar regimen) or L, then the subject will receive R-B 
regimen if randomized to control arm.  
During the study, an independent Data Monitoring Committee (DMC) (Section 7.8) will 
regularly review safety and efficacy data from all subjects as outlined in a separate DMC charter 
document.  
The study is composed of the following periods:  
Screening:  
After the informed consent procedure has been completed, subjects will be screened during the 
28-day period prior to Cycle 1 (C1) Day 1 (D1) to ensure they meet the entry criteria for the 
study (for details see Section 8.1.2). 
Treatment: 
Subjects meeting eligibility criteria will be randomized 1:1 to the 2 arms of the study and will 
start treatment on Cycle 1 Day 1 (C1D1). Treatment will continue for the duration of the 
protocol prescribed period for each arm of the study. Treatment will be discontinued at any time 
in case of progression or unacceptable toxicity (see Sections 8.1.4 and 8.1.5). In case of 
intolerability to R, treatment with R may be discontinued but subjects will continue treatment 
with other therapies in that arm (zandelisib or chemotherapy).  
Disease Assessments: 
Efficacy will be assessed based on modified Lugano Criteria wherein radiological tumor 
evaluations of neck, chest, abdomen and pelvis by using intravenous (IV) (and oral, if indicated, 
per Imaging Manual) contrast-enhanced computed tomography or magnetic resonance imaging 
(CT, MRI) and positron emission tomography-computed tomography (PET-CT) imaging 
modality. PET scans will be done at baseline, after completion of 6 cycles of therapy, and to 


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confirm CR/metabolic complete response (MCR). CT scans will be done based on the schedule 
of events (Appendix 1). An independent response assessment will be performed for evaluation of 
the primary and major secondary efficacy endpoints. Disease management, toxicity, and 
laboratory assessments will be based on investigator assessments.  
Follow-up: 
For subjects who discontinue treatment due to reasons other than PD or death, efficacy follow-up 
will continue until PD, death, withdrawal of consent, or start of new anti-cancer therapy for 
lymphoma.  
All AEs will be reported for up to 30 days after the last dose of study drug (Section 10). AEs 
leading to discontinuation of study drug will be followed for a minimum of 30 days after the last 
dose of study drug or until resolution. All SAEs will be reported for 30 days after the last dose of 
study drug. After 30 days post last dose, only SAEs deemed related to study drug will need to be 
reported to the Sponsor.  
Survival Follow-up:  
After treatment discontinuation (end of treatment [EOT]), all subjects will be followed for OS 
every 3 months for 5 years after the last subject’s randomization, except for subjects who 
withdraw consent. Subjects or their healthcare providers will be contacted either in person, by 
telephone, or e-mail. During OS follow-up TTNT will be recorded.  
PFS2 Follow-up: 
All subjects will be followed for disease progression as assessed by the investigators that may 
occur during subsequent treatment following completion of protocol-specified therapy. 
Follow-up will be approximately every 3 months for collection of date of progression on 
subsequent therapy (as assessed by the investigators) and start of the next (e.g., third) anti-
lymphoma treatment if no PD is reported.  
A schematic of the study design is shown in Figure 3.  


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Figure 3: 
Study Schematic  
4.1. 
Randomization 
After meeting eligibility criteria, subjects will be randomized 1:1 using an Interactive Web (or 
Voice) Response System process to either zandelisib + rituximab or comparator arm. Subjects 
randomized to the comparator arm will be allocated to either R-B or R-CHOP according to the 
treatments they may have received previously. Treatment should begin (C1D1) within 3 days 
after randomization. Subjects will be stratified based on the following criteria: 
• Prior treatment regimen: anti-CD20 mAb in combination with non-bendamustine 
chemotherapy or R-L vs. anti-CD20 mAb in combination with B  
• Number of prior therapies: 1 vs. >1 
• NHL histology: FL vs. MZL 
• Duration of treatment-free interval from the last dose of the lymphoma-directed therapy: 
≤24 months vs. >24 months 
4.2. 
Blinding 
This is an open label study. Blinding is not appropriate based on selected therapies for control 
and investigational arms.  


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4.3. 
Duration of Study 
The study duration for primary completion of PFS is approximately 64 months with 36 months 
enrollment period and 28 months follow-up, i.e., 28 months after the last subject is randomized.  
4.4. 
End of Study 
The study will end when all subjects have been followed for survival, or lost to follow up, or 
5 years from the last subject’s randomization, whichever comes first.  
4.5. 
Dosing Schedule for Zandelisib 
Zandelisib will be administered 60 mg QD orally for the first 2 cycles of therapy (56 days). 
Starting with Cycle 3 zandelisib will be administered 60 mg QD for 7 days followed by 21 days 
off treatment (IS) through Cycle 26.  
4.6. 
Dosing and Schedule for Additional Study Drugs/Comparators 
Rituximab will be administered IV 375 mg/m2 on Days 1, 8, 15 and 22 of C1 and then on D1 of 
Cycles 3, 4, 5, and 6 for up to a total of 8 doses in 6 cycles.  
R-B will be administered every 4 weeks (q4w) as follows:  rituximab IV 375 mg/m2 body 
surface on D1 and B administered IV 90 mg/m2 body surface on D1 and D2 of each cycle for 
6 cycles. 
R-CHOP will be administered once every 3 weeks (q3w) as follows:  rituximab IV 375 mg/m2 
body surface on D1; cyclophosphamide IV 750 mg/m2 body surface on D1; doxorubicin IV 
50 mg/m2 body surface on D1; vincristine IV 1.4 mg/m2 body surface (maximum dose 2.0 mg) 
on D1, prednisone 100 mg daily orally (PO) from D1 to D5 of each cycle for 6 cycles.  
4.7. 
Supportive Therapies 
Prophylactic or support therapy (e.g., growth factors, blood products) will be managed according 
to local institutional practices.  
5. 
STUDY POPULATION 
All subjects must meet eligibility criteria at screening before randomization.  
5.1. 
Inclusion Criteria 
1. Male or female subjects ≥18 years of age, ≥19 years in Korea, or ≥20 years for subjects in 
Japan and Taiwan, at time of signing informed consent  
2. Histologically confirmed diagnosis of CD20 positive iNHL with histological subtype 
limited to: 
a. FL Gr 1, Gr 2, or Gr 3a 
b. MZL (splenic, nodal, or extra-nodal) 
[Histopathological report confirming diagnosis must be available during screening procedures.]  


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3. Subjects with relapsed disease who received ≥1 prior lines of therapy, that must have 
included an anti-CD20 antibody in combination with cytotoxic chemotherapy or L, with 
or without subsequent maintenance therapy. [A line of therapy is defined as following:  a 
minimum of 2 consecutive cycles of immunochemotherapy or R-L, or at least 4 doses of 
anti-CD20 mAb (R) single agent therapy, a minimum of 2 consecutive cycles of therapy 
with an investigational agent. Maintenance therapy given after an induction treatment 
(e.g., R maintenance) is considered as the same line of therapy] [Please see 
Exclusion Criterion #2 for further clarification]. Relapsed or refractory disease is defined 
as: 
• Relapsed disease: disease progression after a response (CR or partial response [PR]) 
lasting ≥6 months  
• Refractory disease: no response to therapy (no CR or PR) or response lasting 
<6 months  
4. Subjects must have at least one bi-dimensionally measurable nodal lesion with the 
longest diameter >1.5 cm and/or an extranodal lesion >1.0 cm (that has not been 
previously irradiated) according to the Lugano Classification  
5. Adequate hematologic parameters at screening unless abnormal values are due to disease 
per investigator assessment: 
• Absolute neutrophil count (ANC) ≥1.0 × 109/L (≥1,000/mm3) 
• Platelet count ≥75.0 × 109/L (≥75,000/mm3) 
• Hemoglobin ≥9 g/dL  
6. Adequate renal and hepatic function per local laboratory reference range at screening as 
follows: 
• AST/ALT ≤1.5 × upper limit of normal (ULN) 
• Total bilirubin ≤2.0 × ULN or ≤3 × ULN for subjects with Gilbert-Meulengracht 
syndrome  
• Estimated glomerular filtration rate (eGFR) >50 mL/min using the Cockcroft-Gault 
equation (Appendix 2) 
7. QT-interval corrected according to Fridericia’s formula (QTcF) ≤450 msec; subjects with 
QTc >450 msec but <480 msec may be enrolled provided the QTc prolongation is due to 
a right bundle branch block (RBBB), left bundle branch block (LBBB), or pacemaker and 
is confirmed stable by a cardiologist 
8. Left ventricular ejection fraction (LVEF) ≥45% as measured by echocardiogram (ECHO) 
or multi-gated acquisition scan (MUGA). [If LVEF <45% by ECHO, a repeat 
measurement can be conducted within the screening period.] 
9. Subjects must have completed any prior systemic anti-cancer treatment ≥4 weeks (or 
≥5 times the half-life [t½] of used therapeutics [including investigational therapy], 
whichever is longer) or radiation therapy ≥2 weeks before study Day 1, and ≥3 months 


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before study Day 1 for high dose therapy with stem cell transplantation, 
radioimmunotherapy, and CAR T-cell therapy 
10. Eastern Cooperative Oncology Group (ECOG) performance status 0-1  
11. Life expectancy of at least 3 months 
12. All AEs and laboratory toxicities related to prior therapy must resolve to Gr ≤1 prior to 
the start of the study therapy (unless otherwise specified in eligibility criteria)  
13. For females of childbearing potential, a negative serum human chorionic gonadotropin 
(hCG) pregnancy test within 28 days of study Day 1 and negative result (urine or serum) 
on study Day 1  
14. Subjects must agree to use appropriate contraception methods during the clinical study 
(Appendix 3) 
15. Subject is willing and able to comply with all scheduled visits, treatment plans, 
laboratory tests, and other study procedures.  
5.2. 
Exclusion Criteria 
1. Histologically confirmed diagnosis of FL Gr 3b or transformed disease  
• For subjects with clinical signs of rapid disease progression (e.g., marked 
B-symptoms), and laboratory or radiographic indication (e.g., high lactate 
dehydrogenase [LDH] level or standardized uptake value by PET), a fresh tumor 
biopsy is recommended to rule out transformed disease  
2. Subjects who received both R/O-B and R/O-CHOP (or other anthracycline-containing 
regimen) as previous lines of therapy, or those who received only single agent anti-CD20 
mAb therapy as prior line of treatment  
3. Prior therapy with PI3K inhibitors  
4. Ongoing or history of drug-induced pneumonitis  
5. Known lymphomatous involvement of the central nervous system  
6. Seropositive for or active viral infection with hepatitis B virus:  
• HBsAg positive  
• HBsAg negative, anti-HBs positive and/or anti-HBc positive and detectable viral 
DNA by PCR  
Note:  Subjects who are HBsAg negative and viral DNA PCR negative are eligible. These 
subjects should receive prophylactic therapy for hepatitis as per institutional standards.  
7. Known seropositive for, or active infection with hepatitis C virus  
• Subjects with positive hepatitis C virus (HCV) antibodies are eligible with negative 
PCR test for HCV  
8. Known seropositive for, or active and uncontrolled infection with human 
immunodeficiency virus (HIV), or with acquired immunodeficiency syndrome (AIDS), 


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or currently taking medications for HIV that are contraindicated for concomitant use in 
this study  
9. Known seropositive for, or active infection with human T-cell leukemia virus type 1 
10. Any uncontrolled clinically significant illness including, but not limited to, active 
infections requiring systemic antimicrobial therapy, hypertension, angina, arrhythmias, or 
other uncontrolled cardiovascular conditions, pulmonary disease, or autoimmune 
dysfunction, and urinary infection or flow obstruction  
11. Hypersensitivity or other clinically significant reaction to the study drug or its inactive 
ingredients or other therapy used in the study  
12. Major surgical procedure within 4 weeks prior to study Day 1 (minor surgical procedures, 
e.g., lymph node biopsy, performed within 1 day or with an overnight stay are allowed)  
13. Previous or concurrent cancer that is distinct in primary site or histology from indolent 
B-cell NHL within 3 years before start of study treatment except for curatively treated 
cervical cancer in situ, non-melanoma skin cancer, and superficial bladder tumors 
(Ta [non-invasive tumor], Tis [carcinoma in situ], and T1 [tumor invades lamina 
propria]), and asymptomatic localized prostate cancer with no requirement for systemic 
therapy or requiring only hormonal therapy and with normal prostate-specific antigen 
values within ≥12 months prior to randomization  
14. History of clinically significant cardiovascular abnormalities such as congestive heart 
failure (New York Heart Association (NYHA) classification ≥ II [NYHA 1994]), 
myocardial infarction within 6 months of study entry. 
15. History of clinically significant gastrointestinal (GI) conditions, particularly: 
• Known GI condition that would interfere with swallowing or the oral absorption or 
tolerance of study drug  
• Pre-existing malabsorption syndrome or other clinical situation that would affect oral 
absorption  
16. Females who are pregnant; females who plan to breastfeed during study treatment 
through 90 days after ending treatment  
17. Substance abuse, medical, psychological or social conditions that may interfere with the 
subject’s participation in the study or evaluation of the study results 
18. Any illness or medical conditions that are unstable or could jeopardize the safety of the 
subjects and their compliance in the study. Inability to understand and sign informed 
consent form (ICF)  
19. Received a live virus vaccination within 28 days of first dose of study drug, (e.g., yellow 
fever vaccination).  
5.3. 
Number of Subjects 
It is anticipated that approximately 534 subjects will be randomized into the study. For details of 
sample size calculation see Section 11.2.  


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6. 
TREATMENTS  
6.1. 
Preparation and Administration of Investigational Product(s) 
6.1.1. 
Zandelisib 
Zandelisib is provided as 60 mg capsules, which require no preparation prior to administration. 
Subjects should be instructed to swallow the capsules whole and to not chew or crush them.  
Zandelisib is dosed on a milligram (mg) basis with no adjustment in dosing based on subject 
weight. Zandelisib is to be taken orally once a day at approximately the same time each morning 
in accordance with the IS dosing regimen.  
6.1.2. 
Formulation  
Zandelisib drug product is supplied in Size 2 white capsules, with black printing, containing 
60 mg of active pharmaceutical ingredient which is blended with microcrystalline cellulose, 
mannitol, croscarmellose sodium, and sodium stearyl fumarate.  
6.1.3. 
Storage of Zandelisib 
Please refer to the clinical label, which provides storage conditions in accordance with the 
relevant national/regional pharmacopeial definition of room temperature.  
6.1.4. 
Packaging and Labelling 
Zandelisib is supplied as either 28-capsule or 7-capsule blister packets labelled as ME-401 
investigational product with storage instructions.  
6.1.5. 
Dispensing of Zandelisib 
Zandelisib will be dispensed according to the randomization scheme using the Interactive Web 
Response System.  
6.2. 
Dose and Administration 
Zandelisib 60 mg is taken on dosing days with a glass of liquid to aid in swallowing, on an 
empty stomach in the morning (i.e., at least 1 hour prior to food intake or 2 hours after food 
intake). If a subject routinely experiences discomfort with dosing, he or she is permitted to take 
zandelisib with a light snack. If a dose is missed, it may be taken up to 12 hours after the 
specified time. After 12 hours, the missed dose should be omitted. If possible, the subject should 
be advised to separate administration of zandelisib capsules from that of concomitant 
medications that have a known inhibitory effect on P-glycoprotein (P-gp) and breast cancer 
resistance protein transporter (BCRP).  
On days with PK sampling, subjects should be instructed not to take study drug zandelisib at 
home. Study drug administration will be done at the clinic in relation to the timing of the PK 
sample collection. For sampling days see Section 9.5.  


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6.3. 
Investigational Product Accountability and Compliance 
The Principal Investigator or their representative will account for all investigational product (IP) 
provided by the Sponsor. All IP will be stored at the site in a secure and locked location. The 
Principal Investigator shall maintain adequate records of the disposition of IP, including dates, 
quantity, and use by subjects. Upon completion of the study, all remaining IP will be accounted 
for and unused material will either be returned to the Sponsor (or designee) by a traceable 
method (UPS, FedEx, etc.) or destroyed (with documentation of drug destruction provided to the 
Sponsor), as instructed by the Sponsor.  
A compliance assessment and returned study drug accountability will be performed at each visit 
which includes study drug return (see Section 7.5 for compliance with study drug 
administration).  
6.4. 
Concomitant Therapy 
Data on concomitant medications by prescription and over-the-counter medications will be 
collected. This data will be recorded from 28 days prior to C1D1 through 30 days after last dose 
of zandelisib, treatment discontinuation, or until a subsequent anti-cancer therapy is initiated.  
Management of concomitant medications for patients taking R will be per the Rituxan USPI and 
SmPc for MabThera, and other product label applicable to comparators. 
6.4.1. 
Permitted Prophylactic Therapy 
Prophylactic therapy for hepatitis and for CMV is allowed. Prophylactic therapy for 
opportunistic infection, including Pneumocystis jiroveci pneumonitis (PJP) is allowed per 
institutional guidelines or per the investigator’s judgement. Prophylaxis for CMV should follow 
the institutional guidelines or ESMO guidelines (Dreyling 2021).  
Prophylactic therapy for hepatitis is recommended per institutional standards. 
Administration of all prophylactic and supportive treatments, and dosage must be reported on the 
concomitant medication page of the eCRF.  
6.4.2. 
Prohibited Concomitant Medications 
The following medications/therapies are prohibited while receiving study treatment: 
•
Other investigational agents
•
Systemic corticosteroids in doses >10 mg in prednisone (or equivalent dose of other
corticosteroids) are prohibited for one week prior to C1D1 and during the study
•
Drugs that are strong inhibitors and inducers of CYP3A4 (Appendix 7)
•
Inhibitors and inducers of CYP3A4, CYP2D6, or P-gp are prohibited in subjects
receiving doxorubicin. Prophylactic or supportive therapy including weak inhibitors and
inducers of CYP3A4, CYP2D6, or P-gp can be used only for AE treatment according to
local institutional practices if no other treatment is available.
During the course of study drug treatment, a short course (e.g., <2 weeks) of high-dose 
corticosteroids (>10 mg/day prednisone) is permitted for premedication to manage 


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infusion-related reactions or to manage other inflammatory reactions (e.g., asthma). 
Corticosteroids to treat the underlying FL or MZL are not allowed during the study. 
Subjects assigned to receive R-CHOP regimen are allowed to receive higher dose of prednisone 
based on treatment schedule (100 mg daily for Days 1-5 of each cycle).  
6.4.3. 
Advisory for Concomitant Medications 
The following medications/therapies should be used with caution: 
• Drugs that are strong/moderate inhibitors and inducers of CYP2C8 (Appendix 6) and 
moderate inhibitors and inducers of CYP3A4 (Appendix 7) 
• Drugs that affect the QT/QTc interval (Appendix 8)  
• Orally administered drugs known to inhibit or induce the intestinal transporters BCRP 
and P-gp. 
• Dapsone for PJP prophylaxis (prophylaxis therapy can be used per the investigator’s 
decision) 
6.4.4. 
Advisory on Vaccinations 
As per the EU Summary of Product Characteristics (SmPc) for MabThera (R), vaccination with a 
live vaccine is not recommended while on the study. As per the SmPc for bendamustine, 
vaccination with a live vaccine for yellow fever is contraindicated.  
6.4.4.1. 
Advisory on COVID-19 Vaccination and Risk Assessment 
COVID-19 vaccination, where authorized or approved, is allowed and considered a standard of 
care for patients who are currently enrolled in this study. The study will follow COVID-19 
vaccination guidance and recommendations provided by scientific and medical associations 
(European Hematology Association, American Society of Hematology, American Society of 
Clinical Oncology, and NCCN).  
The Sponsor completed a risk assessment for the use of COVID-19 vaccination while on study 
and concluded the benefit of receiving therapy for patients with R/R FL and MZL outweigh the 
potential risk of delaying treatment due to scheduled COVID-19 vaccination. Any potential risk 
for patients with NHL that is associated with COVID-19 vaccination, while on therapy for 
lymphoma, has not been fully established yet. Vaccination for patients participating in this study 
is permitted. Recommendations regarding COVID-19 vaccination for patients with NHL should 
adhere to local regulatory and institutional guidance.  
6.5. 
Prohibited Therapies 
• Obinutuzumab and ofatumumab 
• Other anti-lymphoma therapies not specified in this protocol 
6.6. 
Anticipated Toxicities 
As of the 04 January 2020 data cut-off date, the Gr ≥3 AEs noted in the Phase 1b study for the 
57 subjects administered zandelisib alone or in combination with rituximab on the IS consisted 


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of diarrhea/colitis, neutrophil count decreased (7% each), and rash, ALT increased, 
hyperglycemia, lymphocyte count decreased, blood alkaline phosphatase (ALP) increased, 
headache, and anemia (1.8% each).  
Gr 3 AESIs were:  diarrhea and colitis (3.5% each), and ALT/AST elevation, rash, non-
infectious pneumonitis (1.8% each); there were no Gr 4 or 5 AESIs reported up to date. There 
was no Gr 3 pneumonia or stomatitis reported.  
Refer to Table 2 for study drug dose interruption or treatment discontinuation in a subject if such 
toxicity occurs and is not considered related to the underlying disease or other possible 
etiologies. Subject management will be determined by the treating physician and may include 
administration of a hematopoietic growth factor for neutropenia, administration of 
corticosteroids for the treatment of colitis, pneumonitis, and other AEs considered immune 
mediated (Table 2), and other antimicrobial or anti-viral treatment for prophylactic therapy per 
institutional standards.  
Refer to the current Zandelisib IB for more details.  
6.7. 
Zandelisib Toxicity Management 
Subjects who experience toxicities should be managed according to the guidelines provided 
in Table 2. For subjects who experience a toxicity requiring treatment interruption during 
Cycle 1, 2 and 3, treatment interruption will be followed by treatment on the IS once the toxicity 
resolves. For subjects who experience toxicity during Cycles 4-26, toxicities will be managed by 
interrupting therapy or discontinuation of treatment. Once the toxicity resolves, the therapy 
should be restarted on the scheduled next cycle of therapy (example: if recovery occurs on day 
20 of a cycle, the next treatment cycle will start in 8 days). All treatment interruptions (including 
any missed doses) and discontinuations and their reasons are to be recorded in the electronic case 
report form (eCRF). Interrupted treatment is resumed after the toxicity resolves to the grade 
specified in the table. Subjects who permanently discontinue zandelisib dosing will proceed to 
the EOT visit and 30-Day Safety Follow-up visit.  
Subjects who interrupt study drug dosing for >6 continuous weeks will have zandelisib 
permanently discontinued unless restarting zandelisib is authorized by the study Medical 
Monitor.  


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Table 2: 
Zandelisib Toxicity Management 
Toxicity/Grade 
Zandelisib Management 
Treatment 
Cycles 1-3 
Cycles 4-26 
Non-hematologic Toxicities 
Diarrhea/colitis 
Gr 2 
• 
Hold zandelisib unless diarrhea is confirmed to 
be due to an infectious agent. For diarrhea of 
infectious etiology, no dose interruption is 
required. 
• 
Once diarrhea resolves to Gr ≤1 or baseline, 
resume zandelisib at 60 mg administered on the 
IS (the first 7 days of each 28-day cycle). 
If infectious cause of the 
diarrhea, including 
clostridium difficile, is ruled 
out then proceed with 
following management steps:  
• 
Hold zandelisib and start 
loperamide or similar 
anti-diarrheal agent.  
• 
If no improvement 
occurs within 48 hours, 
start prednisone 
/prednisolone 
0.5-1 mg/kg IV or oral 
budesonide 9 mg daily or 
equivalent oral systemic 
steroids based on local 
institutional practice.  
[Note: Based on data from the 
Phase 1b study, subjects with 
diarrhea that was preceded by 
rash in the prior 1-2 weeks 
often experienced more 
prolonged and severe 
diarrhea. Thus, if diarrhea is 
preceded by rash in the prior 
weeks, start prednisone/ 
prednisolone 0.5-1 mg/kg IV 
or oral budesonide 9 mg daily 
when subjects experiences 
rash.]  


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Table 2: 
Zandelisib Toxicity Management (Continued) 
Toxicity/Grade 
Zandelisib Management 
Treatment 
Cycles 1-3 
Cycles 4-26 
Non-hematologic Toxicities 
Gr 3 
• 
Hold zandelisib 
until AE resolves to 
Gr ≤1 or baseline; 
resume zandelisib 
at 60 mg 
administered on the 
IS. 
• 
For recurrence of 
Gr 3 
diarrhea/colitis, 
discontinue study 
drug permanently 
If the event is considered 
related to treatment with 
zandelisib in the opinion 
of the investigator, 
permanently discontinue 
zandelisib. 
• 
Subjects should be 
hydrated as clinically 
indicated and 
administered 
prednisone/prednisolone 
1-2 mg/kg/day IV/oral or 
equivalent IV/ oral 
systemic steroids. 
• 
If no improvement 
occurs within 2-3 days,  
• 
the corticosteroid dose 
should be increased to 
2 mg/kg/day IV or 
equivalent oral systemic 
steroids.  
• 
Once improved to Gr ≤1, 
start tapering the 
corticosteroid as 
clinically indicated. 
 
 
Gr 4 
Permanently discontinue zandelisib. 
Treat as suggested for Gr 3, 
or as per institutional standard 
of care. 
Cutaneous Reactions and Mucositis 
Gr 2 
Continue zandelisib  
• 
Monitor subjects and 
determine cause of rash.  
• 
Per Investigator’s 
discretion, 
antihistamines, topical 
steroids, and systemic 
steroids may be given. 
Gr 3 
• 
Hold zandelisib 
until AE resolves 
to Gr ≤1 or 
baseline; resume 
zandelisib at 60 mg 
administered on 
the IS.  
• 
For recurrence of 
Gr 3, permanently 
discontinue 
zandelisib. 
If the event is considered 
related to treatment with 
zandelisib in the opinion 
of the investigator, 
permanently discontinue 
zandelisib. 
• 
Monitor subjects as 
clinically indicated until 
resolution. 
• 
Oral antihistamines and 
systemic corticosteroids 
such as 
prednisone/prednisolone 
0.5-1 mg/kg/day 
(or equivalent dose of 
systemic steroids) should 
be given until rash 
resolves to Gr ≤1. 


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Table 2: 
Zandelisib Toxicity Management (Continued) 
Toxicity/Grade 
Zandelisib Management 
Treatment 
Cycles 1-3 
Cycles 4-26 
Cutaneous Reactions and Mucositis 
Other: 
Life-threatening toxicity 
(Gr 4), Stevens-Johnson 
syndrome of any grade, 
and TENS of any grade 
Permanently discontinue zandelisib. 
Treat as per Gr 3 
recommendations or per 
institutional standard of care. 
Hepatotoxicity 
Gr 2 
For ALT/AST >3–5 × ULN but <5 × ULN, 
maintain zandelisib treatment dose and schedule. 
Monitor once a week until 
resolved to Gr ≤1 or baseline 
level. 
Gr 3 
• 
For ALT/AST 
>5-20 × ULN, hold 
zandelisib.  
• 
Resume zandelisib 
at 60 mg 
administered on 
the IS.  
• 
For recurrence of 
Gr 3, permanently 
discontinue 
zandelisib. 
• 
If Hy’s law criteria 
are met (laboratory 
parameters, and no 
other reasonable 
cause for changes 
has been 
identified) then 
permanently 
discontinue 
treatment with 
zandelisib. 
• 
If the event is 
considered related to 
treatment with 
zandelisib in the 
opinion of the 
investigator, 
permanently 
discontinue 
zandelisib. 
• 
If Hy’s law criteria 
are met (laboratory 
parameters, and no 
other reasonable 
cause for changes 
has been identified) 
then permanently 
discontinue 
treatment with 
zandelisib. 
• 
Monitor once a week until 
resolved to Gr ≤1 or 
baseline level. 
• 
Treat per institutional 
standard of care, which 
may include a course of 
corticosteroids if 
clinically indicated. 
• 
Assess if Hy’s lawa 
applies. 
Gr 4 
For ALT/AST >20 × ULN, permanently 
discontinue zandelisib. 
• 
Assess if Hy’s law 
applies. 
• 
Treat per institutional 
standard of care, which 
may include a course of 
corticosteroids if 
clinically indicated. 


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Table 2: 
Zandelisib Toxicity Management (Continued) 
Toxicity/Grade 
Zandelisib Management 
Treatment 
Cycles 1-3 
Cycles 4-26 
Non-infectious pneumonitis (NIP) 
Gr 2 
• 
Hold zandelisib 
until AE resolves 
to Gr ≤1 or 
baseline. 
• 
If Gr 2 NIP recurs, 
discontinue 
treatment 
permanently. 
• 
Resume zandelisib 
at 60 mg 
administered on 
the IS. 
• 
If the event is 
considered related to 
treatment with 
zandelisib in the 
opinion of the 
investigator, 
permanently 
discontinue 
zandelisib. 
Rule out infectious etiology of 
pneumonitis based on 
institutional guidance, 
utilizing following methods:  
chest x-ray, CT scan, 
pulsometry, nasal swab, 
sputum culture and sensitivity, 
blood culture and sensitivity, 
urine culture and sensitivity.  
Treat with corticosteroids and 
per institutional standard of 
care. 
Gr ≥3 
Permanently discontinue zandelisib. 
Treat per institutional standard 
of care, including systemic 
corticosteroids. 
Lung Infection/ Pneumonia 
Gr 2 
• 
Continue treatment with zandelisib. 
Treat per institutional standard 
of care. 
Gr 3 
• 
Hold zandelisib until AE resolves to Gr ≤1 or 
baseline.  
• 
Resume zandelisib at 60 mg administered on 
the IS. 
• 
For the second occurrence of Gr 3 lung 
infection within ≥6 months from prior event, 
retreatment is allowed once patient recovers to 
Gr ≤1 or baseline. 
• 
Discontinue if same event occurs a third time. 
Treat per institutional standard 
of care. 
Gr 4 
Permanently discontinue zandelisib. 
Treat per institutional standard 
of care. 


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Table 2: 
Zandelisib Toxicity Management (Continued) 
Toxicity/Grade 
Zandelisib Management 
Treatment 
Cycles 1-3 
Cycles 4-26 
Other non-hematologic toxicities, not listed above, that are considered related to zandelisib 
Gr 2 
Continue treatment with zandelisib 
Treat per institutional standard 
of care. 
Gr 3 
• 
Hold zandelisib 
until AE resolves 
to Gr ≤1 or 
baseline.  
• 
Resume zandelisib 
at 60 mg 
administered on 
the IS. 
• 
For recurrence of 
the same Gr 3, 
discontinue 
permanently 
zandelisib. 
If the event is considered 
related to treatment with 
zandelisib in the opinion 
of the investigator, 
permanently discontinue 
zandelisib. 
Treat per institutional standard 
of care. 
Gr 4 
Permanently discontinue zandelisib. 
Treat per institutional standard 
of care. 
Cytomegalovirus 
(CMV) 
Any grade  
• 
If test is positive (PCR or antigen assessment) 
based on local laboratory assessments and 
requires treatment, then hold zandelisib until 
recovery.  
• 
Resume zandelisib on the IS after resolution of 
asymptomatic CMV reactivation if all the 
following conditions are met: 
• 
CMV reactivation is resolved per the 
Investigator assessment 
• 
CMV reactivation was not associated with end 
organ disease (e.g., pneumonia, hepatitis, 
gastroenteritis, retinitis, encephalitis) 
• 
Treat per institutional 
standard of care. 
• 
If all conditions for 
restarting study drug are 
met, then secondary CMV 
prophylaxis must be 
maintained as per 
institutional guidelines. 
QTc Prolongation 
assessed as related to 
treatment  
>60 ms increase compared to baseline/screening and >500 ms (both criteria must be 
met) will require repeated 12-lead ECG test twice and calculate mean level of QTc 
prolongation based on 3 measurements. If the changes are confirmed, then discuss 
with the Sponsor’s Medical Monitor or designee the risk/benefit assessment of 
continuing treatment with zandelisib without changes. After review with the 
Sponsor’s Medical Monitor or designee, treatment interruption maybe used until 
improvement to baseline level or QTc interval <500 ms. If treatment interruption was 
used, resume treatment with zandelisib on IS. It is very important to assess whether 
concomitant medications or medical history are more likely reasons for QTc interval 
prolongation.  


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Table 2: 
Zandelisib Toxicity Management (Continued) 
Toxicity/Grade 
Zandelisib Management 
Treatment 
Cycles 1-3 
Cycles 4-26 
Hematologic Toxicities 
Neutropenia 
Gr 3 
Zandelisib dosing may continue. 
Perform CBC weekly until 
resolves to Gr <2 (unless 
myelosuppression is due to 
follicular lymphoma). 
Gr 4 
•
Gr 4 neutropenia or
Gr ≥3 febrile
neutropenia:  hold
zandelisib until
recovery to Gr ≤2.
Resume zandelisib
at 60 mg
administered on
the IS.
•
Gr 4 neutropenia or
Gr ≥3 febrile
neutropenia:  hold
zandelisib until AE
resolves to Gr ≤2.
Resume zandelisib
at 60 mg
administered on the
IS.
•
Recurrence of Gr 4
neutropenia or
Gr ≥3 febrile
neutropenia:
discontinue
treatment
permanently.
Perform CBC weekly until 
resolves to Gr <3. 
Initiate growth factor support 
if clinically indicated. If 
subject is receiving filgrastim 
support or equivalent, CBC 
should be repeated after 
3 days. Weekly CBCs should 
continue until resolves to 
Gr <3.  
Thrombocytopenia 
Gr 3 without bleeding 
Continue therapy with zandelisib. 
•
Check platelets every
3 days until resolves
to <3.
Gr ≥3 with Gr ≥2 
bleeding 
•
Interrupt therapy until resolution to Gr ≤2
thrombocytopenia and no bleeding, resume
zandelisib at 60 mg on the IS.
•
Recurrence of thrombocytopenia Gr ≥3 with
Gr ≥2 bleeding:  discontinue treatment with
zandelisib permanently
•
Treat per institutional
standards.
Gr 4 without bleeding 
•
Treatment with zandelisib may continue or
may be interrupted based on the Investigator’s
judgement.
Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase;         
CBC = complete blood count; CMV = cytomegalovirus; CT = computed tomography; Gr = grade; IS = intermittent 
schedule; IV = intravenous; NIP = non-infectious pneumonitis; PCR = polymerase chain reaction; TENS = toxic 
epidermal necrolysis syndrome; ULN = upper limit of normal 
* 
Toxicity graded per CTCAE v5.0.
a 
Hy’s law is defined as:  cases of drug-related hepatocellular injury are defined as elevated ALT or
AST ≥3 × ULN, plus elevated total bilirubin >2 × ULN without findings of cholestasis (defined as serum 
alkaline phosphatase (ALP) activity <2 × ULN), and no other reason can be found to explain (FDA 2009). 


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6.8. 
Adverse Events of Special Interest for Zandelisib 
Certain adverse events require timely review regardless of their severity and reportability. In this 
study, the following treatment-related events are considered AESIs:  
• Diarrhea/colitis ≥Gr 3 
• Cutaneous reactions/rash ≥Gr 3 
• Mucositis ≥Gr 3 
• Transaminases elevation ≥Gr 3 
• Non-infectious pneumonitis ≥Gr 2 
• Lung infection/pneumonia ≥Gr 3 
These AESIs will be reported to the Sponsor if they led to treatment interruption or delays, 
initiation of concomitant therapy, or treatment discontinuation on zandelisib + R arm in 
expedited way.  
6.9. 
Additional Study Drugs/Comparators 
Other study drugs (R, B, cyclophosphamide, doxorubicin, vincristine, prednisone) are available 
commercially or may be provided by the Sponsor according to regional regulations and should 
be administered and managed according to the respective Prescribing Information (PI) and 
institutional standards. Rituximab biosimilar formulations are allowed for use in this study. 
Subcutaneous dosing regimen of rituximab is not allowed in this study.  
6.9.1. 
Sourcing of the Standard of Care Products  
The standard of care products listed in Section 6.9 (i.e., rituximab, bendamustine, and the 
components of CHOP) are approved in both the US and the EU to treat patients with various 
B-cell malignancies. For financial reasons, the Sponsor is sourcing the following standard of care 
products used in this study from the EU: rituximab (MabThera®, Truxima® or other biosimilar 
that is approved in both regions), bendamustine, prednisone, cyclophosphamide (Endoxan®), 
doxorubicin (Adriamycin®), and vincristine (Cellcristin®). All products sourced from the EU to 
be used in the US must also be approved for use by the US FDA.  
6.9.2. 
Expected Toxicities for Additional Study Drugs/Comparators 
Rituximab therapy is known to be associated with the following toxicities per the 
USPI for Rituxan (in the EU, MabThera Summary of Product Characteristics).  
Infusion-related reaction, severe mucocutaneous reactions, hepatitis B virus reactivation, 
progressive multifocal leukoencephalopathy, tumor lysis syndrome, infections, cardiovascular 
adverse reactions, renal toxicity, bowel obstruction and perforation, immunization, embryo-fetal 
toxicity.  
Other adverse reactions frequently observed in clinical trial in lymphoid malignancies include 
fever, chills, asthenia, headache, abdominal pain, pain, and back pain.  
For a comprehensive list of toxicities refer to the rituximab PI. Toxicities should be managed per 
best medical judgement and in accordance with institutional practices.  


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CHOP 
For comprehensive information on toxicities associated with CHOP chemotherapy refer to PI for 
doxorubicin, cyclophosphamide, vincristine, and prednisone. A summary of toxicities for each 
drug is provided below. Toxicities resulting from CHOP administration should be managed per 
best medical judgment and institutional practices.  
Doxorubicin has been associated with cardiotoxicity, myelosuppression, hepatotoxicity, and 
immunosuppression.  
Cyclophosphamide has been associated with myelosuppression (e.g., neutropenia), febrile 
neutropenia, fever, alopecia, nausea, vomiting, diarrhea, urinary tract infection, cardiotoxicity, 
pulmonary toxicity, among others.  
Vincristine has been associated with hypersensitivity, constipation, abdominal cramps, weight 
loss, nausea, vomiting, oral ulceration, diarrhea, paralytic ileus, intestinal necrosis and/or 
perforation, anorexia, polyuria, dysuria, and urinary retention, hypertension, hypotension, 
paresthesia, anemia, leukopenia, and thrombocytopenia, alopecia, and rash.  
Prednisone has been associated with fluid retention, alteration in glucose tolerance, elevation in 
blood pressure, behavioral and mood changes, increased appetite, weight gain, and increased risk 
for viral, bacterial, fungal, and protozoan infections.  
Bendamustine has been associated with myelosuppression (anemia, thrombocytopenia, 
neutropenia, lymphopenia, leukopenia), hyperbilirubinemia, pyrexia, nausea, vomiting, anorexia, 
fatigue, diarrhea, constipation, cough, headache, weight decreased, dyspnea, rash, stomatitis, 
hepatotoxicity, tumor lysis syndrome, skin reactions, anaphylaxis and infusion reactions and 
infections, cardiac disorders, and irreversible infertility. For a comprehensive list of toxicities 
refer to the bendamustine PI. Toxicities should be managed per best medical judgment and 
institutional practices.  
6.10. 
Dose Modification of Additional Investigational Drugs 
For other drugs administered in this study, any toxicity encountered should be managed 
according to the recommendations described in the US Prescribing Information or the Summary 
of Product Characteristics for the drug (R, B, cyclophosphamide, doxorubicin, vincristine, and 
prednisone) and institutional standard of care.  
Subjects will be treated for 6 cycles of R with chemotherapy. In case of intolerability to R, 
treatment with R may be discontinued but subjects will continue treatment with the other 
therapies in that arm (zandelisib or chemotherapy).  
6.11. 
Safety Run-in for Japanese Subjects in Japan Only 
Based on the request of the Japanese Pharmaceutical and Medical Device Agency (PMDA) to 
evaluate tolerability of zandelisib in combination with R, a tolerability study in Japanese subjects 
was deemed necessary. To comply with this, a safety run-in study will be conducted in Japan 
only to establish tolerability of zandelisib + R combination treatment in Japanese subjects. 
Details of the safety run-in in the Japanese population are described in Appendix 11, and the 
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7. 
STUDY CONDUCT 
7.1. 
General Instructions 
See the Schedule of Assessments (Appendix 1) for a detailed list of study procedures and 
assessments. Instructional details (where applicable) for procedures are contained in Section 8.  
7.2. 
Subject Screening 
Subjects will be screened during the 28-day period prior to C1D1 to ensure they meet the entry 
criteria for the study. The Investigator or an appropriate designee will obtain informed consent 
from each subject prior to conducting any study-specific procedures. Screening procedures may 
be completed across multiple days during the screening period and do not need to be completed 
on consecutive days. During the screening period, the Investigator should carefully review each 
subject’s medical history to ensure eligibility. All inclusion and exclusion criteria should be 
supported by corresponding documentation in the medical records, including a pathology report 
confirming the diagnosis of FL or MZL. Screening laboratory tests may be repeated once to 
confirm eligibility at the discretion of the Investigator (Appendix 1).  
7.3. 
Screen Failures 
Subjects who do not meet eligibility criteria will be deemed screen failures. Screen failure 
subjects may be rescreened one time for study participation if deemed appropriate by the 
Investigator and the Medical Monitor, and some screening procedures may need to be repeated. 
7.4. 
Deviation from Inclusion/Exclusion Criteria 
All subjects must meet the criteria for study entry. No waivers will be provided pertaining to 
inclusion and exclusion criteria.  
7.5. 
Monitoring Subject Compliance 
Subjects will receive paper diaries that they should complete to document the dates and time 
when they take their zandelisib. Subjects should be instructed to return paper diaries and used 
investigational product (IP) packages to the site at the next study visit. Site personnel should 
review the diary and inspect the returned IP packages to ensure the diary appears accurate and 
study medication was taken in accordance with the protocol. Site personnel should discuss any 
IP non-compliance with the subject and emphasize the importance of taking the study medication 
as directed. IP compliance of less than 80% or more than 120% should be documented as a 
protocol deviation.  
7.6. 
Site Closure 
The Sponsor has the right to close a site at any time. Reasons for closing a site may include, but 
are not limited to, the following: 
• Non-compliance with International Council for Harmonisation Good Clinical Practice 
(ICH-GCP) guidelines 
• Inadequate rate of subject recruitment 


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• Poor protocol adherence 
• Inaccurate or incomplete data recording 
• No study activity (i.e., all subjects have completed, and all obligations have been 
fulfilled)  
7.7. 
Follow-up for Response Assessments and Survival 
After treatment discontinuation or completion of protocol-specified therapy, all subjects who did 
not experience disease progression will be followed for response assessments as per 
protocol-defined schedule until PD, start of new anti-lymphoma therapy, or withdrawal of 
consent. Survival follow-up will continue until death, withdrawal of consent or subject is lost to 
follow-up. Survival follow-up will continue for up to 5 years after the last subject’s 
randomization. Subjects or their healthcare providers will be contacted either in person or by 
telephone.  
7.8. 
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will be established to review safety and 
efficacy data collected in the study on a regular basis with the primary purpose of protecting the 
safety of trial participants, the credibility of the trial, and the validity of trial results. The safety 
data will include, but will not be limited to, summary of Gr 5 treatment-related TEAEs, and 
AESIs, events leading to treatment discontinuation. The DMC will review the totality of the 
safety and efficacy data to assess if any changes to the study conduct or clinical study protocol 
are required. The DMC will meet at least once every 3 months, with the first data review meeting 
occurring when approximately 60 subjects (~30 in each arm) have completed at least 1 cycle of 
treatment or 6 months after the first subject is dosed, whichever occurs first. The frequency of 
meetings may change based on the DMC decision, which will be reflected in the DMC charter 
amendment. The DMC will review totality of the data during these meeting to advise the sponsor 
if any changes to study design are required. Details regarding the DMC are contained in a 
separate DMC Charter document.  
Interim analysis (see Section 11) will be performed by the DMC.  
7.8.1. 
Enrollment Stopping Rules and Additional Safety Considerations 
In addition to regular DMC safety and efficacy data review, the DMC will assess whether a 
pause of enrollment is required for comprehensive data review to evaluate if any potential 
changes to the study conduct, patient's eligibility criteria or other changes for the clinical study 
protocol are needed.  
7.8.1.1 
Stopping Rules Based on Treatment-related Mortality 
When 150 subjects (75 in each arm) have been enrolled in the clinical study and completed at 
least 1 cycle of therapy, the DMC will determine if an enrollment pause is necessary by 
assessing and comparing the risk/benefit profile of therapies in both arms based on various 
patients’ characteristics (e.g., number of prior lines of treatment). After the initial review, the 
DMC will continue to assess the data during regularly scheduled meetings every 3 months or as 
described in the DMC charter based on the DMC decision.  


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Prior to reaching an enrollment threshold of 150 patients, the DMC will evaluate the totality of 
safety data, including Gr 5 treatment-related AEs, and apply their clinical judgment to decide if a 
pause in enrollment is needed.  
After reaching an enrollment of 150 patients, the main criteria for review will be Bayesian 
model-based, recommended by the ASA Safety Workgroup (Fries 2016) and the report by 
Yao 2013, which incorporates both the observed rates for treatment-related Gr 5 TEAEs and the 
associated confidence levels around the risks. The thresholds for the observed rates are:   
• ≥5% in the zandelisib + R arm; or  
• Risk ratio for treatment-related Gr 5 TEAEs in zandelisib + R arm compared with the 
control arm ≥2.  
Historical data show that observed fatal AE rates associated with anti-CD20 
immunochemotherapy regimens (both bendamustine and CHOP) in iNHL studies range from 
0~3.3% (Fowler 2011, Robinson 2008, Rummel 2008, Sarkozy 2019, Sehn 2016, 
Van Oers 2006, EMA assessment report on idelalisib 2018). A reasonable estimate of the fatal 
AE rate to be expected in the control arm would be approximately 2.5%. Therefore, 5% of 
treatment-related Gr 5 TEAE (doubling the assumed mortality rate in the control arm) is used as 
one of the thresholds.  
7.8.1.2 
Additional Safety Considerations 
At each meeting, the DMC will review the totality of the safety data, which will include 
additional evaluation of the frequency of AESI and other AEs to assess risks associated with 
treatment. 
The DMC will review safety data in the investigational treatment arm (zandelisib plus rituximab 
combination), including a side-by-side comparison of the incidence and severity of AESIs in 
subjects who were enrolled in the study after failure of one or more than one prior line of 
therapy.  
The following AESI thresholds (% of subjects with an AESI) will be evaluated by the DMC: 
• Non-infectious pneumonitis (NIP) ≥Gr 2 in ≥7% 
• Diarrhea/colitis ≥Gr 3 in ≥15% 
• Skin toxicity ≥Gr 3 in ≥10% 
• Hepatic toxicity (AST and/or ALT elevation) ≥Gr 3 in ≥15% 
• Infection ≥Gr 3 in ≥25% 
These thresholds were selected based on the reported incidence for PI3Kδ inhibitors marketed 
for the treatment of B-cell malignancies, including ≥Gr 2 pneumonitis reported in up to 5% of 
patients, ≥Gr 3 diarrhea and colitis in up to 20%, ≥Gr 3 AST/ALT elevation in up to 18%, ≥Gr 3 
cutaneous reactions in up to 5%, and ≥Gr 3 infection in up to 31% (Aliqopa USPI, Ukoniq USPI, 
Copiktra USPI, Zydelig USPI). 
The DMC will apply their clinical judgement to overall and relative safety signals within the 
context of the disease under study. The DMC will assess the totality of the data and make its 


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recommendation as to whether the study may proceed as per protocol, if enrollment must be held 
in one or more than one patient subset, or if the study protocol requires modification. 
Details for analysis and rationale for selected methods of assessments will be described in the 
DMC charter and DMC SAP.  
7.9. 
Study Termination 
The study will end when all study treatments, study-specific assessments, and study data 
collection are completed.  
This study may be terminated or suspended at any time by the sponsor. If the study is terminated 
or suspended, the Sponsor will promptly inform the Investigators/institutions and the regulatory 
authorities. The IRB/EC should be promptly informed and provided the reason(s) for the 
termination or suspension by the Sponsor and by the Investigator/institution, as specified by the 
applicable regulatory requirement(s).  
8. 
DESCRIPTION OF STUDY PROCEDURES 
A detailed list of study procedures and schedules is presented in Appendix 1.  
8.1. 
General Procedures 
8.1.1. 
Informed Consent 
Each subject’s signature must be obtained on a written ICF that has been approved by an IRB, 
EC, or Ethical Review Board prior to any study-specific procedures being performed. The ICF 
must incorporate a Release of Medical Information that authorizes release of medical records 
to the trial Investigators, monitors, Sponsor and its designees, the Food and Drug Administration 
(FDA), or other regulatory authority. The ICF must be in a language fully comprehensible to the 
prospective subject. The consenting process must be documented in the medical chart and a 
signed copy of the ICF provided to the subject. The Investigator or an appropriate designee will 
obtain ICF from each subject prior to conducting any study-specific procedures.  
8.1.2. 
Screening Period 
Subjects will be screened during the 28-day period prior to C1D1 to ensure they meet the entry 
criteria for the study. During the screening period, the Investigator should carefully review each 
subject’s medical history to ensure eligibility. All inclusion and exclusion criteria should be 
supported by corresponding documentation in the medical records, including a pathology report 
confirming the diagnosis of FL and MZL.  
Bone marrow biopsies or aspirate performed as part of the subject’s medical care that are within 
12 weeks of C1D1 may be used for screening and eligibility determination, if necessary. 
Contrast-enhanced PET/CT or CT scans performed within 6 weeks of C1D1 may be used for 
screening and eligibility determination as long as they meet the minimum requirements per 
Lugano criteria (i.e., includes all appropriate anatomical areas of the body, a slice thickness 
≤5 mm). This avoids unnecessary repeat tests and undue burden on subjects.  


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Eligibility must be verified by the Sponsor’s medical monitor or designee (e.g., Contract 
Research Organization [CRO] Medical Monitor) prior to the initiation of dosing. Once the 
subject has been deemed eligible, the subject may be randomized and enrolled in the study. 
Dosing should be initiated within 3 days of randomization.  
8.1.3. 
Randomization Assignment 
After screening and meeting all eligibility criteria subjects will be randomized 1:1 based on 
stratification factors detailed in Section 4.1, using an Interactive Response Technology system 
into one of the two treatment arms of the study:  
• Arm 1: R + zandelisib 
• Arm 2: R-B or R-CHOP. Selection of therapy regimen will depend on prior therapy, 
specifically, if a subject had received anti-CD20 mAb in combination with B as a prior 
therapy, then the subject will receive R-CHOP if randomized to control arm. If a subject 
had received anti-CD20 mAb in combination with chemotherapy regimen (e.g., R-CHOP, 
R-CVP, FND-R, or similar regimen) or R-L, then the subject will receive R-B regimen if 
randomized to the control arm.  
8.1.4. 
Treatment Period 
Subjects meeting eligibility criteria will be randomized 1:1 to one of the two arms of the study 
and will start treatment on C1D1. It is important to assure that subjects continue to meet 
eligibility criteria prior to treatment initiation. Laboratory and general physical assessment of 
subjects to confirm eligibility should be performed prior to initial dosing on C1D1.  
Study visits during the treatment period may be conducted remotely if a subject is unable to visit 
a study site due to COVID-19. In this situation, IP may be shipped directly to a subject if this is 
deemed appropriate by the PI and is acceptable per institutional guidelines and local regulations. 
If any study visits during the treatment period are conducted via telephone or a tele-health 
platform, this will be documented in the source and any missed visit procedures will be recorded 
as protocol deviations. 
Refer to the Schedule of Assessments (Appendix 1) for details of treatment and timing of 
administration of various treatments.  
8.1.5. 
Discontinuation of Treatment 
Subjects will be discontinued from treatment for any of the following reasons: 
• Progressive disease (PD) 
• Completed treatment 
• AE/SAE 
• Start of non-protocol anti-cancer therapy  
• Death  
• Subject withdraws consent for further participation or follow-up 
• Subject lost to follow-up  


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• Pregnancy 
• Investigator decision  
All efforts should be made to continue subject’s participation in the clinical study with follow-up 
for efficacy and OS. 
• Termination of study by the Sponsor 
• Subjects who discontinue treatment for any reason except those who withdraw consent 
will be followed for safety as described in Sections 10.5 and 10.6. Subjects with PD are 
followed for survival and those who discontinue for reasons other than PD, are followed 
for response assessment until PD, then followed for survival. In case of termination of 
study, all follow-up will cease.  
• Other 
8.1.6. 
Early Discontinuation/Withdrawal of Subjects from Study 
Subjects will be discontinued permanently from the study for any of the following reasons: 
• Withdrawal of consent for further participation or follow-up  
• Subject is lost to follow-up  
• Termination of study by the Sponsor  
• Death  
8.1.7. 
End of Treatment Visit  
The EOT visit will be performed within 7 days (±3 days) from the completion of the last dose or 
treatment discontinuation. The procedures to be performed at EOT visit are noted in the schedule 
of assessments (Appendix 1).  
9. 
STUDY ASSESSMENTS 
9.1. 
Assessment of Efficacy  
Efficacy will be assessed based on radiological tumor evaluations of neck, chest, abdomen and 
pelvis by using IV (and oral, if indicated, per Imaging Manual) contrast-enhanced CT/MRI 
and/or PET-CT imaging modality. PET-CT imaging is the recommended method of assessment 
per Lugano Classification (Cheson 2014) for 18F-fluorodeoxy glucose (FDG)-avid disease and 
will be performed at baseline, after 24 weeks (±1 week) on study, and for confirmation of 
CR/MCR (if initially assessed by CT scan only for FDG-avid disease). Contrast-enhanced 
CT scan or MRI scan to be done at screening and all other timepoints. Confirmation of PD can 
be done using CT or PET-CT scans. FDG-PET scan should be performed within 1 week 
(±3 days) of CT scan if it was not done at the same time. For subjects who have variable 
FDG-avid tumors, CT and/or MRI imaging can be used if PET-CT imaging is not optimal for 
assessment of disease status and response. To rule out a potential of false positive diagnosis of 
disease progression in ambiguous cases, it is highly recommended to repeat imaging assessments 
within 4–8 weeks after initial suspicion of PD. In addition, tumor biopsy may be performed to 


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confirm disease progression in existing or new lesions, or bone marrow involvement. The 
Investigator must review disease progression assessment with the Sponsor’s medical monitor or 
designee.  
During the treatment phase as well as during the active follow-up period, radiological tumor 
assessment by imaging scans will be performed every 12 weeks from C1D1 for the first 3 scans 
(weeks 12, 24 and 36 [±1 week]), followed by 3 scans every 16 weeks (weeks 52, 68 and 84 
[±1 week]), a scan at week 104 (±1 week), and every 24 weeks (±2 weeks) thereafter.  
Imaging scans will be evaluated locally at the study site. Scans will be submitted for an 
independent central review.  
Response to treatment based on the Investigator evaluation of imaging scans will be the basis for 
subject management.  
For the primary analysis, disease response assessment will be performed by an independent 
review blinded to the Investigator’s assessment and treatment assignment.  
Bone marrow biopsy and/or aspirate will be mandatory at screening if PET scan is not performed 
or is not evaluable. If the baseline biopsy is positive for lymphoma infiltration and PET scan is 
not utilized for response assessment, it will be mandatory to perform bone marrow biopsy again 
to confirm the first CR. Bone marrow biopsy is to include surgical pathology, 
immunohistochemistry, and flow cytometry as per institutional SOC. For MZL patients, if 
gastric involvement is suspected, an endoscopy at baseline should be obtained. At CR, 
endoscopy is required if not observed radiographically and the endoscopy was positive at 
baseline.  
Response assessment will be performed based on modified Lugano Classification (Cheson 2014) 
described in Appendix 4, Table 3. 
9.2. 
Assessment of Adverse Events  
All AEs will be collected from start of treatment until 30 days after last dose of study drug or 
start of new anti-cancer treatment. For details of AE reporting see Section 10.  
Any SAE due to protocol-mandated procedures will be collected from the time of informed 
consent. Other SAEs will be collected from the start of study drug administration. All SAEs will 
be reported and followed for up to 30 days after the last dose of study drug. After 30 days post 
last dose only SAEs deemed related to study drug will be reported to the Sponsor 
(see Section 10.6.3 for details).  
9.3. 
Clinical Laboratory Tests 
Laboratory tests listed on the Schedule of Assessments (Appendix 1) will be performed and 
analyzed at the investigative site’s local laboratory and used in all safety analyses and response 
assessments (Appendix 4); PK samples discussed in Section 9.5 will be shipped to a central 
laboratory for analysis.  
The following laboratory tests are to be performed (screening, Day 1 of the first 6 cycles, Day 1 
from Cycle 7 to Cycle 10, Cycles 13, 17, 21, and 26 for Arm 1 subjects during zandelisib 
treatment period, and EOT, except as noted in the schedule of assessments (Appendix 1).  


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Hematology – Complete Blood Count 
• Hemoglobin (Hb) 
• Hematocrit (Hct) 
• Red blood cell (RBC) count 
• Mean corpuscular volume (MCV) 
• Mean corpuscular hemoglobin (MCH) 
• Mean corpuscular hemoglobin concentration (MCHC)  
• Platelet Count  
• White blood cell (WBC) count and differential 
• Absolute neutrophil count 
• Absolute lymphocyte count 
• Absolute monocyte count 
• Absolute eosinophil count 
• Absolute basophil count 
Chemistry – Metabolic Panel 
• Glucose 
• Calcium 
• Albumin 
• Total protein  
• Sodium 
• Potassium 
• Bicarbonate (total HCO3) 
• Chloride 
• Urea or blood urea nitrogen (BUN) 
• Uric Acid 
• Lactate dehydrogenase  
• Creatinine  
• Alkaline phosphatase (ALP) 
• Alanine aminotransferase (ALT) 
• Aspartate aminotransferase (AST) 
• Gamma-glutamyl transferase (GGT) 
• Total bilirubin  
• Direct bilirubin 
• Phosphorus 
Coagulation 
• Activated partial thromboplastin time (aPTT) 
• Prothrombin time (PT)/ International Normalized Ratio (INR) 
 
Urinalysis 
• Specific Gravity 
• pH 
• Protein  
• Glucose 
• Ketones  
• Blood (hemoglobin) 
• Leukocyte esterase  
• nitrite 
• Bilirubin 
• Urobilinogen 
• Microscopic examination a 
a Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase. 
Urinalysis testing will be conducted using standard commercial test strips (urine dipstick). If urinalysis cannot be 
tested by dipstick, urinalysis for leukocytes can tested by microscopic examination.  
Virus Tests at Screening and During the Study 
• Hepatitis B Core antibody (HBc)a 
• Hepatitis B Surface Antigen (HBsAg)a 
• Hepatitis B PCR monitoring monthly while on treatment with rituximab or biosimilar monoclonal antibody is 
allowed if required per institutional standards 
• HCV antibody and HCV PCR testing 
• CMV serology and PCRb 
a Hepatitis B PCR is required if hepatitis B core antibody and/or surface antigen is positive. 
b CMV (PCR and antigen) testing may be performed at any time as clinically indicated.  


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• GFR calculation (screening only)  
• Pregnancy test: hCG (screening, D1 of each cycle, and 30-day follow-up). 
Unscheduled clinical laboratory assessments may be obtained at any time during the study to 
assess potential safety concerns.  
9.4. 
Other Study Assessments 
• Complete Physical Examination (Screening and EOT)  
• Symptom-directed Physical Examination (Day 1 of the first 6 cycles, and Day 1 from 
Cycle 7 to Cycle 10, Cycles 13, 17, 21, and 26 for Arm 1 subjects during zandelisib 
treatment period)  
• ECOG performance (screening, Day 1 of the first 6 cycles, and Day 1 from Cycle 7 to 
Cycle 10, Cycles 13, 17, 21, and 26 for Arm 1 subjects during zandelisib treatment 
period, EOT, and 30-day safety follow-up visit)  
• Concomitant Medications (screening, Day 1 of the first 6 cycles, and Day 1 from Cycle 7 
to Cycle 10, Cycles 13, 17, 21, and 26 for Arm 1 subjects during zandelisib treatment 
period), EOT, and the 30-day follow-up 
• LVEF assessment by ECHO or MUGA per institutional standards for all subjects at 
baseline and as clinically indicated  
• ECG assessment: Single tracing 12-lead ECGs performed at screening, pre-dose on Day 
1 for the first 6 cycles of therapy, pre-dose Day 1 from Cycle 7 to Cycle 10, pre-dose 
Cycles 13, 17, 21, and 26 for Arm 1 subjects during zandelisib treatment period, at EOT 
visit, and as clinically indicated. On Day 1 of C1 and C3, additional ECGs will be 
performed 3-4 hours after zandelisib dose is taken.  
9.5. 
Pharmacokinetics 
PK sampling will only be performed in zandelisib arm according to the following schedule: 
• C1D1: 2 samples – 2- and 4-hours (±30 min) post-dose of zandelisib 
• C2D1: 1 sample – pre-dose (within 30-60 minutes)  
• C3D1: 2 samples – pre-dose (within 30-60 minutes) and 3 hours (±30 min) post-dose of 
zandelisib 
• C4D1: 1 sample – 3 hours (±30 min) post-dose of zandelisib  
For better modeling of exposure-efficacy and exposure-safety, an accurate estimate of the time 
from drug intake to PK sample collection is needed. Collect accurate study drug dosing history 
(i.e., time of intake) within 48-72 hours (2-3 days) prior to days when PK samples are collected. 
The subject will be asked to record information on food intake on the day preceding and on the 
day of the visit on which blood samples are obtained for plasma concentrations measurement.  
Detailed instructions on collection of plasma for determination of zandelisib PK will be provided 
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9.6. 
Patient Reported Outcomes 
The effect of treatment on the physical symptoms of lymphoma is an important issue for 
patients; therefore, the collection of this information is a routine component in many protocols.  
The main purpose of the symptom assessment in this study is to describe any differences 
between the treatment groups in (1) the time from randomization to deterioration in DRS-P of at 
least 3 points and (2) the time from randomization to improvement in DRS-P at least 3 points for 
subjects with a baseline DRS-P score 30 points or less. Physical symptoms of lymphoma will be 
assessed using the NCCN-FACT Lymphoma Symptom Index-18 (FLymSI-18), version 2 
(Appendix 9) (NCCN-FACT:  National Comprehensive Cancer Network - Functional 
Assessment of Cancer Therapy), and EQ-5D-3L (Appendix 10).  
The FLymSI-18 is an instrument that was developed to assess symptoms of lymphoma, 
symptoms of treatment of lymphoma, and health related QoL of patients with lymphoma. The 
instrument was developed in accordance with the recent FDA 2009 PRO guidance (FDA 2009) 
for the development of instruments for symptom-specific patient-reported outcomes.  
The instrument contains 18 items, each of which utilizes a Likert scale with 5 possible responses 
ranging from 0 “Not at all” to 4 “Very much”. Nine items reflect DRS-P, and the responses to 
the items are summed to calculate a DRS-P subscale score. Four items represent disease-related 
emotional symptoms (DRS-E), and the responses to those items will be used to calculate a 
DRS-E subscale score. Three items represent treatment side effects, and the responses to these 
items will be summed to calculate a treatment side-effect (TSE) subscale score. Finally, two 
items represent FWB, and responses to those items will be summed to calculate an FWB 
subscale score. The questionnaire allows for calculation of total score and four subscales:  
DRS-P, DRS-E, TSE and FWB. 
In addition, EQ-5D-3L, utility score will be evaluated. EQ-5D-3L include 6 questions, where 
5 questions measure functional and system attributes and one item. measures overall health 
assessment. This scoring system has been evaluated and endorsed as health utility standard by 
the European National Institute for Clinical Excellence and the US Agency for Healthcare 
Research and Quality (Askew 2011).  
The EQ-5D-3L is a standardized instrument developed by the EuroQoL Group for use as a 
generic, preference-based measure of health outcome. It is applicable to a wide range of health 
conditions and treatments and is available in numerous languages. The EQ-5D-3L questionnaire 
captures 2 basic types of information, a descriptive “profile,” or “health state,” and an overall 
health rating using a visual analog scale. The health states include mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression, which can be combined to produce a single 
weighted index score by applying coefficients from a validated value set. The visual analog scale 
(VAS) is a linear, thermometer like scale that respondents can use to rate their health status, with 
zero representing the worst imaginable health status and 100 the best (Scherber 2015). Estimated 
time to complete is approximately 8 minutes.  
The FLymSI-18 and EQ-5D-3L and VAS will be administered according to the schedule 
specified in the study schedule of assessments (Appendix 1).  
The FLymSI-18 and EQ-5D-3L and VAS should be completed at the start of the visit before the 
subject sees the physician and before any study-related procedure is conducted, so that any 


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interaction between the subject and physicians and knowledge of disease status does not 
influence the response to the FLymSI-18 and EQ-5D-3L questionnaires. Baseline assessment 
should occur during screening period prior to the time subject is randomized to treatment arm.  
A PRO information sheet will be provided and completed by the study personnel at each visit at 
which the FLymSI-18 and EQ-5D-3L and VAS questionnaires are to be administered, regardless 
of whether or not the FLymSI-18 and EQ-5D-3L and VAS questionnaires are completed by the 
subject. This is to document information such as questionnaire completion, date of completion, 
and reasons for non-completed questionnaires.  
9.6.1. 
Electronic Patient-reported Outcomes Evaluation 
Electronic PRO (ePRO) devices will be implemented in the study. They will be used to complete 
the FLymSI-18 and EQ-5D-3L questionnaires. A Site Manual will be provided to sites to help 
them understand how the ePRO devices work and how to use them correctly.  
9.7. 
Appropriateness of Measures 
All study assessments have been well documented and are generally regarded as reliable, 
accurate, and relevant in this disease population. This includes health outcomes measures 
considered to be appropriate for evaluating changes in quality of life, global functioning, and 
disability.  
9.8. 
Study Drug Administration 
Study drugs will be administered according to the schedule shown in Appendix 1 (Study Drug 
Administration), detailed in Section 6.2. 
10. 
ADVERSE EVENTS 
An AE is any untoward medical event that occurs in a subject following the start of study drug 
administration, whether or not the event is considered drug-related. AEs can be: 
• A pre-existing medical condition can be recorded as an AE if the condition worsens by at 
least one grade following the start of study drug administration and if the frequency, 
severity, or character of the condition worsens during the study. When recording on the 
eCRF it is important to capture applicable descriptors (e.g., more frequent arthritic pain).  
• Disease-related out-of-range laboratory values will not be considered AEs/SAEs if there 
is no change from the screening laboratory values. Any deterioration in a laboratory value 
or other clinical test that is associated with symptoms or leads to a change in study 
treatment or concomitant treatment or discontinuation from study product or deemed 
clinically significant by the Investigator will be considered an AE.  
AEs will be recorded using the terminology defined in the NCI CTCAE v5.0.  
A TEAE is defined as an AE starting or worsening in CTCAE grade after the first dose until 
30 days after the last dose of study drug, or start of new anti-cancer therapy, whichever is earlier.  
Death related to disease progression is not considered an AE. Signs and symptoms related to 
disease progression are not considered AEs. Anticipated fluctuations of pre-existing conditions, 


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including the disease under study that do not represent a clinically significant exacerbation 
or worsening, need not be considered AEs.  
Only one AE term should be recorded in the event field on the AE eCRF if a specific AE is 
attributable to a primary diagnosis. Adverse events that are secondary to other events should be 
identified by their primary cause, with the exception of severe or serious secondary events. 
For example: 
• If a subject initially had diarrhea and is subsequently diagnosed with colitis, these events 
should be consolidated to a single data point which would in this example be colitis  
• If a subject had diarrhea that resulted in mild dehydration, only diarrhea should be 
reported in the eCRF 
• If a subject who had diarrhea developed acute renal failure, both acute renal failure and 
diarrhea will be entered separately 
For AEs, a diagnosis should be recorded on the AE eCRF rather than individual signs and 
symptoms (e.g., record only colitis rather than diarrhea, abdominal pain, decreased appetite). 
However, if a constellation of signs and symptoms cannot be medically characterized as a single 
diagnosis or syndrome, each individual event should be reported on the AE eCRF. If a diagnosis 
is subsequently established, all previously reported AEs based on signs and symptoms should be 
nullified and replaced on the AE eCRF based on a single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis.  
10.1. 
Assessment of Severity 
The term “severity” is used to describe the intensity of an AE. Severity will be graded according 
to NCI CTCAE v5.0.  
10.2. 
Assessment of Causality 
The Investigator is obligated to assess the relationship between study drug and the occurrence of 
each AE. The Investigator is to use his/her best medical judgement in determining the likely 
relationship of the AE to study drug. The relationship of an AE or SAE to study drug is to be 
classified as either ‘Related’ or ‘Not Related.’ 
10.3. 
Documenting Adverse Events 
Adverse events should be documented in the source and entered on the subject’s CRF (or eCRF) 
with action taken with respect to the study drug and outcome.  
10.4. 
Clinical Laboratory Changes 
Clinical laboratory measurements are reported in the subject’s CRF (or eCRF). Laboratory 
abnormalities are to be reported as AEs only when deemed clinically significant, i.e., led to 
treatment interruption or discontinuation, associated with initiation of concomitant therapy or 
with hospitalization.  


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10.5. 
Adverse Event Follow-up 
AEs occurring on study will be followed until resolution or return to baseline. AEs leading to 
discontinuation of study drug will be followed for minimum of 30 days after the last dose of 
study drug or until resolution, whichever comes first.  
10.6. 
Serious Adverse Events 
10.6.1. 
Definition  
A SAE is any event that meets any of the following criteria: 
• Adverse event resulting in death (Gr 5 toxicity) 
• Life-threatening 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect in the offspring of a subject who received any study 
drug. 
• Other:  Important medical events that may not result in death, be life-threatening, or 
require hospitalization, may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
events are: 
o Intensive treatment in an emergency room or at home for allergic bronchospasm 
o Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
o Development of drug dependency or drug abuse 
10.6.2. 
Definition of Terms 
Life threatening:  An AE is life threatening if the subject was at immediate risk of death from the 
event as it occurred; i.e., it does not include a reaction that if it had occurred in a more serious 
form might have caused death. For example, drug induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life threatening even though drug induced 
hepatitis can be fatal.  
Hospitalization:  AEs requiring hospitalization should be considered SAEs. Hospitalization for 
elective surgery or routine clinical procedures that are not the result of AE (e.g., elective surgery 
for a pre-existing condition that has not worsened) need not be considered AEs or SAEs. If 
anything untoward is reported during the procedure, that occurrence must be reported as an AE, 
either 'serious' or 'non-serious' according to the usual criteria.  
If there is a question as to whether 'hospitalization' occurred or was necessary, the AE should be 
considered serious.  
Disability/incapacitation:  An AE is incapacitating or disabling if the experience results in a 
substantial and/or permanent disruption of the subject's ability to carry out normal life functions.  


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10.6.3. 
Reporting Serious Adverse Events 
All SAEs must be reported to the Sponsor or Sponsor’s designee (the CRO) within 24 hours of 
the Investigator becoming aware of the SAE.  
To report an SAE, please refer to the applicable study manual or eCRF for SAE reporting 
instructions. For back up paper reporting, SAEs shall be reported to MEI254808@Parexel.com. 
The 4 minimum criteria for a valid SAE report include: 
•
Study identifier
•
Subject identifier
•
Event term
•
Study drug
All SAEs will be reported to the Sponsor’s designee for up to 30 days after the last dose of study 
drug. After 30 days post last dose, only SAEs deemed related to study drug will be reported to 
the Sponsor’s designee. The Investigator must report new significant follow-up information for 
these events to the Sponsor’s designee immediately (i.e., no more than 24 hours after becoming 
aware of the information). New significant information includes the following:  
•
New signs or symptoms or a change in the diagnosis
•
Significant (requiring therapy or hospitalization) new diagnostic test results
•
Change in causality based on new information
•
Change in the event’s outcome, including recovery
•
Additional narrative information on the clinical course of the event
All SAEs must be followed until resolution or death. 
All SAEs also must be reported by each site to the appropriate IRB/EC in accordance with local 
requirements for reporting SAEs to their IRB/EC.  
Reporting requirements will be based on the Investigator's assessment of causality and 
seriousness, with allowance for upgrading by the Sponsor.  
All deaths should be recorded and reported to the Sponsor’s designee. Disease progression, 
hospitalization to assess disease progression, and death due to disease progression as determined 
by the Investigator, are not considered SAEs. All other causes of death must be reported as 
SAEs. The Investigator should make every effort to obtain and send death certificates and 
autopsy reports for all deaths to the Sponsor’s designee.  
In the event of a medical emergency (requiring immediate attention regarding operation of the 
clinical study and/or the use of study product), study site staff will apply appropriate medical 
intervention according to current standards of care and will contact the Medical Monitor 
designee (e.g., CRO representative) for further consultation and guidance. The Sponsor will be 
reporting all AEs, SAEs, and expedited safety reports (suspected unexpected serious adverse 
reactions [SUSARs]) according to local regulatory requirements.  


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10.6.4. 
Overdose 
Overdose is the accidental or intentional use of the drug in an amount higher than the dose being 
studied in a single day. Symptomatic and non-symptomatic overdose must be reported in the 
drug administration form of eCRF. Any accidental or intentional overdose with zandelisib that is 
symptomatic only if fulfilling a seriousness criterion, is to be reported to the Sponsor 
immediately (within 24 hours) using the corresponding SAE form, and following the same 
process described for SAEs. If a study drug overdose occurs, patients should be clinically 
monitored as appropriate, managing symptoms and side effects that may occur. AEs associated 
with overdose should be reported on AE eCRF; overdose should be reported on drug 
administration eCRF.  
Overdose is defined as administration of >120 mg of zandelisib in a single day because this dose 
is >2 times the planned starting dose of 60 mg QD.  
The medical monitor must be contacted if a study drug overdose occurs.  
10.6.5. 
Pregnancies 
To ensure subject safety, each pregnancy in a subject on study treatment must be reported within 
24 hours of learning of its occurrence. Pregnancy occurring up to 12 months after receiving the 
last dose of study drug must be reported.  
Study drug must be discontinued in a subject who becomes pregnant. The pregnancy must be 
followed to determine outcome, including spontaneous or voluntary termination, details of the 
birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. Subjects must be followed at least 8 weeks after giving birth to 
a child. 
Pregnancy in and of itself is not an AE; however, certain situations and/or outcomes of 
pregnancy can be (see below). Any pregnancies should be recorded on a Pregnancy Form and 
reported by the Investigator to the Sponsor or designee. Pregnancy follow-up should be recorded 
and should include an assessment of the possible relationship to the study product of any 
pregnancy outcome. Examples of pregnancy outcomes that are SAEs include reports of: 
• Congenital anomalies or developmental delay in the fetus or the child 
• Fetal death or spontaneous abortion 
• Suspected adverse reactions in the neonate that are classified as serious 
Pregnancy case information will be collected for the female partners of any males who took 
study treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.  
11. 
STATISTICS 
Full details of all statistical methods will be included in the study Statistical Analysis Plan 
(SAP).  


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11.1. 
Study Populations 
• The intent-to-treat (ITT) population is defined as all subjects who are randomized. 
• Efficacy Evaluable (EE) Population includes all subjects who receive at least one dose of 
study drug and have at least one evaluable post-baseline response assessment.  
• The safety population is defined as all subjects who were randomized and received at 
least 1 dose of any study drug. 
• The PK population is defined as all subjects who had at least two PK samples collected 
and analyzed. 
• Per Protocol (PP) Population will include all subjects who receive at least one dose of 
study drug, have at least one evaluable post-baseline response assessment, and do not 
have any major protocol deviation that affects the efficacy analysis during the study.  
11.2. 
Sample Size and Power Considerations 
It is estimated that approximately 534 subjects will be randomized into this study. 
Assuming a hazard ratio (HR) of 0.70, approximately 330 PFS events at primary analysis are 
required to yield 87.5% power to detect superiority of zandelisib in combination with rituximab 
over standard immunochemotherapy.  
An interim analysis is planned to take place after approximately 248 (75% of the 330 planned) 
IRRC assessed PFS events have occurred. If the statistical significance for PFS is not achieved at 
the interim analysis, the primary PFS analysis will be performed after IRRC assessed 330 PFS 
events have been observed.  
Assuming that the median time to PFS for the control group is 24 months, the accrual duration is 
36 months, and the annual dropout rate is 3%, a total sample size of 534 for the primary analysis 
with 28 months minimal follow-up time after last patient’s enrollment is required.  
11.3. 
General Considerations 
Study disposition, subject demographic and baseline characteristic will be analyzed using the 
ITT population.  
Efficacy analyses will be performed in the ITT population.  
Selected key efficacy analyses will be performed in the EE population and PP population. 
Safety analyses will be performed on the Safety Population. 
PK analysis will be performed for all subjects in the PK population. 
Unless otherwise noted, efficacy analyses will be performed by randomized treatment and safety 
data will be summarized by actual treatment group.  
Because the objective of the study is to test the hypothesis that zandelisib in combination with 
rituximab has better clinical activity and risk/benefit profile compared to standard 2nd line 
immunochemotherapy (R-CHOP/R-B) in subjects with relapsed FL or MZL, all tests of 
treatment effects will be conducted as 1-sided test with family-wise type I error alpha controlled 
at 0.025.  


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Primary efficacy and safety analyses will be conducted comparing the 2 treatment groups . 
Exploratory analyses may be conducted to assess any clinically meaningful differences in 
treatment effect between zandelisib plus R vs. immunochemotherapy in each subgroup defined 
by prior therapy. If differences are present, sensitivity analyses will be performed to account for 
the heterogeneity in different subgroups in order to ensure the overall consistency and robustness 
of the primary analysis.  
11.4. 
Statistical Methods 
11.4.1. 
Primary Endpoint 
Progression Free Survival (PFS) 
The primary endpoint in this study is PFS as determined by the IRRC. PFS is defined as the time 
from randomization date until the date of disease progression, or death from any cause. Subjects 
who have not progressed and are still alive at the time of analysis will be censored at the last 
disease assessment date indicating the absence of progression.  
The PFS analysis to test the superiority of zandelisib in combination with rituximab to standard 
immunochemotherapy in prolonging PFS time will use the log-rank test stratified by the 
following randomization factors: 
• Prior treatment regimen:  anti-CD20 mAb in combination with non-bendamustine 
chemotherapy regimen or R-L vs. anti-CD20 mAb with B 
• Number of prior lines of therapy:  1 vs. >1 
• NHL histology:  FL vs. MZL 
• Duration of treatment-free interval from the last lymphoma-directed therapy:  
≤24 months vs. >24 months 
The Kaplan-Meier (KM) method will be used to estimate the median PFS time with 95% CI. 
PFS rates at milestone time periods will be estimated for each treatment group.  
The Cox proportional hazard model will be used to estimate the hazard ratio and corresponding 
95% confidence interval with Wald’s test p-value after stratifying for the same randomization 
factors.  
Censoring rules for the primary endpoint, PFS, will be detailed in the SAP, following FDA 
guidance (FDA 2015, FDA 2018). In general, in the primary analysis, subjects will be censored 
at the date of last adequate assessment by the IRRC with evidence of no progression in the 
following situations: 
• No progression nor death 
• Discontinuation for any reason other than IRRC documented PD or death, including loss 
to follow-up, toxicity, withdrawal of consent, etc. 
• Start of new anti-lymphoma treatment without evidence of IRRC documented PD 
• Death or progression after two or more consecutive missed or inadequately scheduled 
tumor response assessments.  


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Supportive analyses will be conducted to evaluate the robustness of the primary analysis results, 
by considering all progressions and deaths as PFS events per the European Medicines Agency 
(EMA) guidance (EMA 2013), regardless of whether they occurred after initiating next 
anti-lymphoma treatment, after 2 or more consecutive missed scheduled assessments, or being 
reported as clinical (non-IRRC reviewed radiographic) progression.  
Subjects who discontinue study treatment for any reason other than PD, start new anti-lymphoma 
therapy, or death, will be followed for PFS, unless the subject withdraws consent (Section 7.7). 
Every effort will be made to minimize missing data for PFS assessment. The follow-up time will 
be summarized by treatment arm, and the reason for censoring will be tabulated. Supportive 
analysis will be conducted to evaluate the robustness of the primary analysis results.  
In addition, to account for violation of the assumption of proportional hazards and considering 
potential delayed treatment effect, sensitivity analysis may be conducted using weighted log-rank 
test which allocates appropriate weights to different time periods. The weight function will be 
pre-specified in the SAP.  
A group-sequential design by including 1 interim analysis and 1 primary analysis is planned for 
this study. At each analysis, the hypothesis for the primary endpoint IRRC assessed PFS will be 
tested using a 1-sided with the overall family-wise error rate alpha of 0.025 controlled to adjust 
for multiplicity, utilizing Lan-DeMets O'Brien-Fleming approximation spending function.  
The interim analysis is planned to take place after approximately 248 (75% of the 330 planned) 
IRRC assessed PFS events have occurred. If the statistical significance for PFS is not achieved at 
the interim analysis, the primary PFS analysis will be performed after 330 IRRC assessed PFS 
events have been observed. The alpha-spending for the interim and primary analyses will be 
0.0096 and 0.0221 if the two analyses are performed at exactly 248 and 330 IRRC assessed PFS 
events, respectively. The actual boundary for the final analysis will be calculated based on the 
actual number of events observed at the time of each analysis using software that implements the 
alpha-spending scheme noted above (for example SAS or similar software).  
Once statistical significance is successfully met at the interim analysis or the primary analysis, 
the study will be declared positive based on the primary endpoint of PFS, and the testing of 
selected secondary endpoints will proceed. Details of the testing strategy and control of 
family-wise error rate alpha at one-sided 0.025 will be provided in the SAP. 
The requirement for unblinding the Sponsor at the interim analysis is described in Section 11.4.6.  
11.4.2. 
Secondary Endpoints 
Secondary endpoints include ORR as determined by the IRRC, CRR as determined by the IRRC, 
TTNT, PFS2, time to deterioration and time to improvement in the 9-item DRS-P subset of 
FlymSI-18, FWB score and change from baseline in the DRS-P and FWB subscales and total 
score of FlymSI-18 at specified study visits, change from baseline in EQ-5D-3L total score and 
VAS 18 at specified study visits, and OS.  
If the statistical significance is successfully met at the interim analysis or the primary analysis, 
the testing of selected secondary endpoints (ORR, CRR, FlymSI-18 DRS-P, and OS) will 
proceed, by utilizing a hierarchical testing procedure to account for multiplicity and maintain the 
overall family-wise error rate alpha at 0.025 one-sided (detailed in the Statistical Analysis Plan).  


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Differences in ORR and CRR between treatment groups will be tested using 
Cochran-Mantel-Haenszel (CMH) method stratified by the randomization factors.  
OS, and time to deterioration and time to improvement in the 9-item DRS-P subset of FlymSI-18 
assessment will be tested between the two treatment groups using stratified log-rank test. The 
KM method will be used to estimate the median OS, and median time to deterioration and 
median time to improvement in the 9-item DRS-P subset of FlymSI-18 with 95% CI. OS rates 
will be estimated for each treatment group at Years 1, 2, 3, etc.  
Change from baseline in the DRS-P and FWB subscales and the total score of FlympSI-18, and 
EQ-5D-3L total score and VAS at specified study visits will be compared between the two 
treatment groups using ANCOVA model.  
Endpoint Definitions 
Overall response rate  
ORR is defined as the proportion of subjects who have a best overall response of CR or PR 
according to the Lugano Classification over the entire duration of the study, including the 
efficacy follow-up period.  
Complete response rate  
CRR is defined as the proportion of subjects who have a best overall response of CR during the 
study (i.e., up to time of analysis of PFS).  
Time to Next Anti-lymphoma Treatment  
TTNT is defined as the time from date of randomization to date of first documented 
administration of a new anti-lymphoma treatment (including but not limited to chemotherapy, 
radiotherapy, radioimmunotherapy or immunotherapy).  
PFS on next anti-lymphoma treatment (PFS2) 
PFS2 is defined as the time from the date of randomization to the first documented disease 
progression as reported by the investigator after the initiation of a new anti-lymphoma therapy, 
death from any cause, or start of a third anti-lymphoma therapy, whichever occurs first.  
Overall survival  
OS is defined as the time (in days) from randomization until death from any cause. For subjects 
alive at the time of analysis, they will be censored at the last documented alive date.  
Time to deterioration in the 9-item DRS-P subset of FlymSI-18  
Time to deterioration in the 9-item DRS-P subset of FlymSI-18 is defined as time from 
randomization to first decrease of DRS-P score from baseline of ≥3 points.  
Sensitivity analysis may be conducted by using difference threshold other than 3 points on this 
endpoint, considering forthcoming research findings in external emerging data. Additional 
analyses are described in the Supplemental SAP for PRO analysis.  
Time to improvement in the 9-item DRS-P subset of FlymSI-18  
Time to improvement in the 9-item DRS-P subset of FlymSI-18 is defined as time from 
randomization to first increase of DRS-P score from baseline of ≥3 points in patients with a 


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baseline DRS-P score 30 or less (i.e., patients who still have room for improvement in 
symptoms).  
Sensitivity analysis may be conducted by using different threshold on this endpoint, considering 
forthcoming research findings in external emerging data.  
FWB score and Change from baseline in the FWB subscale and Total Score of FlymSI-18 
Change from baseline in the DRS-P scale of FlymSI-18 is calculated as the FlymSI-18 DRS-P 
score at specific study visits minus the baseline score. 
Change from baseline in the FWB scale of FlymSI-18 is calculated as the FlymSI-18 FWB score 
at specific study visits minus the baseline score.  
Change from baseline in FlymSI-18 total score is calculated as the FlymSI-18 total score at 
specific study visits minus the baseline score.  
Change from baseline in EQ-5D-3L Total Score and VAS Score 
Change from baseline in EQ-5D-3L total score is calculated as the EQ-5D total score at specific 
study visits minus the baseline score. 
Change from baseline in EQ-5D-3L VAS score is calculated as the EQ-5D-3L VAS score at 
specific study visits minus the baseline VAS score.  
11.4.3. 
Exploratory Endpoints 
CRR and ORR as determined by the Investigator, and ORR during the first 24 weeks on study 
determined by both the IRRC and the investigator will be analyzed using the CMH method 
stratified by the randomization factors.  
PFS as determined by the Investigator, DOR and TTP as determined by both the IRRC and the 
Investigator, will be summarized by stratified log-rank test, KM method, and Cox proportional 
hazard model.  
Additional PRO endpoints and analyses will be specified in the Supplemental SAP for PRO 
analysis.  
The relationship of plasma zandelisib exposure to efficacy and safety will be explored by PK/PD 
modeling.  
ORR at Week 24  
ORR at Week 24 is defined as the proportion of subjects who have a response of CR or PR 
according to the Lugano Classification up to the Week 24 assessment.  
Duration of Response 
DOR is defined as the time from first observed tumor response (CR, PR) until PD, or death from 
any cause. Subjects without PD or death at the time of analysis will be censored at the date of 
their last documented tumor assessment. DOR will only be analyzed for subjects with at least 
one CR or PR.  


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Time to Progression  
TTP is defined as the time from randomization to PD. TTP does not include deaths. Analyses 
will be performed using both PD as assessed by the IRRC and the Investigator.  
Zandelisib Area Under the Curve (AUC) 
Zandelisib exposure will be estimated by determination of AUC by population PK method and 
the relationship between exposure and efficacy and exposure and safety will be assessed. The 
results of exposure-response assessments will be presented in a separate report.  
11.4.4. 
Analysis of Safety 
All safety summaries and analyses will be based on the Safety Population, defined as all 
randomized subjects receiving at least 1 dose of any study drug. Safety analyses will be 
performed by actual treatment group. Overall summary of safety will include but not limited to 
the following analyses: 
• TEAEs, including severity and possible relationship to study drug and/or study treatment 
• AESIs 
• Treatment-emergent SAEs 
• Discontinuations from study treatment due to AEs 
• Treatment-emergent changes in laboratory values 
Time to AESIs will be calculated from randomization date to first occurrence of AESI, utilizing 
KM methodology.  
Due to likely imbalance of treatment duration between 2 treatment arms, exposure-adjusted 
analysis may be performed for safety endpoints. The exposure-adjusted event rate is defined as 
the total number of specified events over the total exposure duration.  
Clinical laboratory values will be graded according to NCI CTCAE Version 5.0 for applicable 
tests. Shift from baseline to worst severity grade observed during the treatment will be displayed 
by treatment group.  
Vital signs abnormality will be presented by treatment group. Normal ranges of vital signs will 
be defined in the SAP.  
11.4.5. 
Study Variables 
All study variables, e.g., demographic and baseline characteristics, previous therapy, 
concomitant medications, etc., will be summarized for the ITT population by treatment arm.  
Summary statistics for continuous variables will include the mean, standard deviation, median, 
and range (minimum/maximum). Categorical variables will be presented as frequency counts and 
percentages. Time-to-event variables will be summarized using KM methods (median, 95% CI, 
number of events, number censored, KM figures). Data listings will be created to support data 
review.  


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11.4.6. 
Interim Analysis 
The interim analysis is planned to take place after approximately 248 (75% of the 330 planned) 
IRRC assessed PFS events have occurred. The objective of this interim analysis is to examine the 
efficacy to allow an early declaration of success. If the statistical significance for PFS is not 
achieved at the interim analysis, the primary PFS analysis will be performed after IRRC assessed 
330 PFS events have been observed. The alpha-spending for the interim and primary analyses 
will be 0.0096 and 0.0221, respectively. The interim PFS analysis will be performed by the 
DMC.  
If statistical significance is successfully met at the interim analysis or the final analysis, the study 
will be declared positive based on the primary endpoint of PFS, and the testing of selected 
secondary endpoints will proceed, by utilizing a hierarchical testing procedure to account for 
multiplicity and maintain the overall family-wise error rate alpha at 0.025 at one-sided (detailed 
in the Statistical Analysis Plan).  
Based on our estimated recruitment rate and PFS event rates, the planned interim analysis is 
projected to occur after all subjects have been enrolled and a projected median time on study of 
approximately 30 months (range: 12-48). Also, it is anticipated that all subjects randomized to 
the control arm would have completed their treatment regimen at the planned interim analysis.  
12. 
ETHICS AND GOVERNANCE 
12.1. 
Good Clinical Practice 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation 
of this study, are designed to ensure that the Sponsor and the Investigator abide by Good Clinical 
Practice (GCP) guidelines and the guiding principles detailed in the Declaration of Helsinki. The 
study will also be carried out in keeping with applicable local law(s) and regulation(s). 
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations. When necessary, an extension, amendment or renewal of the IEC/IRB approval 
must be obtained and also forwarded to the sponsor. The responsible unit (e.g., IEC/IRB, head of 
the study center/medical institution) must supply to the sponsor, upon request, a list of the 
IEC/IRB members involved in the vote and a statement to confirm that the IEC/IRB is organized 
and operates according to GCP and applicable laws and regulations.  
Strict adherence to all specifications laid down in this protocol is required for all aspects of study 
conduct; the Investigator may not modify or alter the procedures described in this protocol.  
All the changes to the study protocol will be done through protocol amendment. The Investigator 
or the sponsor may implement a deviation from, or a change of, the protocol to eliminate an 
immediate hazard(s) to the trial subjects without prior IEC/IRB/sponsor approval/favorable 
opinion. As soon as possible, the implemented deviation or change, the reasons for it and if 
appropriate the proposed protocol amendment should be submitted to the IEC/IRB/head of 
medical institution/sponsor. Any deviations from the protocol must be explained and 
documented by the Investigator.  
Details on discontinuation of the entire study or parts thereof can be found in Section 7.9.  


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12.1.1. 
Study Personnel 
The list of all study personnel will be updated as needed; an abbreviated version with personnel 
relevant for the centers will be available in each center’s investigator site file. 
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the Principal 
Investigator at the site, or an appropriately qualified, trained and delegated individual of the 
investigational site. 
The Principal Investigator of each center must sign the protocol signature page and must receive 
all required external approvals (e.g., health authority, ethics committee, sponsor) before subject 
recruitment may start at the respective center. Likewise, all amendments to the protocol must be 
signed by the Principal Investigator and must have received all required external approvals 
before coming into effect at the respective center.  
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the Sponsor’s study file.  
12.2. 
Financial Disclosure  
Investigators must maintain compliance with the current country-specific guidelines and 
regulations concerning financial disclosure.  
12.3. 
Institutional Review Board/Independent Ethics Committee 
Approval of this study will be obtained from an IRB/EC prior to enrolling subjects and will be 
reviewed and approved on an annual basis by the IRBs/ECs representing the participating 
institutions. Such IRBs/ECs must be appropriately constituted and meet all requirements as 
described in Title 21, Part 56 of the Code of Federal Regulations, and any applicable country 
and/or regional requirements. The review must include the protocol, subject recruitment 
materials, the IB, the ICF, and any other study-specific material that will be provided to subjects 
(including study product compliance diaries). A copy of the letter or notice of approval from the 
IRB/EC must be received by the Sponsor or designee prior to shipment of drug supplies to the 
Investigator. The IRB/EC membership list or Federal Wide Assurance number must be 
submitted to the Sponsor or designee with the written IRB approval, and lists must be updated, if 
applicable. 
12.4. 
Informed Consent 
All relevant information on the study will be summarized in an integrated information sheet for 
trial subjects and the ICF provided by the sponsor or the study center. A sample information 
sheet for subjects and ICF is provided as a document separate to this protocol.  
Based on this information sheet, the Investigator or designee will explain all relevant aspects of 
the study to each subject/legal representative or proxy consenter (if the subject is under legal 
protection), prior to his/her entry into the study (i.e., before any examinations and procedures 
associated with the selection for the study are performed or any study-specific data is recorded 
on study-specific forms).  
The Investigator will also mention that written approval of the IRB/IEC has been obtained. 


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Each subject/legal representative or proxy consenter will be informed about the following 
aspects of premature withdrawal: 
• Each subject has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision.  
• The subject’s consent covers end-of-study examinations as specified in the visit 
description described in Section 8.1.7 to be conducted after withdrawal of consent.  
• The subject’s data that have been collected until the time of withdrawal will be retained 
and statistically analyzed in accordance with the statistical analysis plan.  
• Subject-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g., image reading); these data would also be retained and 
statistically analyzed in accordance with the statistical analysis plan. The subject has the 
right to object to the generation and processing of this post-withdrawal data. For this, the 
subject’s oral objection may be documented in the subject’s source data. Each 
subject/legal representative or proxy consenter will have ample time and opportunity to 
ask questions.  
Only if the subject/legal representative or proxy consenter voluntarily agrees to sign the 
informed consent form and has done so, may he/she enter the study. Additionally, the 
Investigator will personally sign and date the form. The subject/legal representative or proxy 
consenter will receive a copy of the signed and dated form.  
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the subject’s note/file of the medical institution.  
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject’s clinical record must clearly show that informed consent 
was obtained prior to these procedures. Certain results from diagnostic testing performed as part 
of the standard of practice prior to the informed consent date and time may be used to fulfill 
screening criteria. This includes results from tumor scans (CT/MRI and/or PET-CT), bone 
marrow sample, HIV testing which may also be used provided that they fall into the 
protocol-specified time window. Tumor scans must also meet the quality standards of the 
Imaging Manual.  
If the subject is not capable of providing a signature, a verbal statement of consent can also be 
given in the presence of an impartial witness (independent of the Sponsor and the Investigator). 
This is to be documented by a signature from the informing physician as well as by a signature 
from the witness.  
For adults under legal protection, consent shall be given by the legal guardian(s). The consent of 
an adult under legal protection shall also be requested where such a person is able to express 
his/her own will. His/her refusal or the withdrawal of his/her consent may not be disregarded. 
The ICF and any other written information provided to subjects, legal representatives, or proxy 
consenters will be revised whenever important new information becomes available that may be 
relevant to the subject’s consent, or there is an amendment to the protocol that necessitates a 
change to the content of the subject information and/or the written informed consent form. The 
Investigator will inform the subject/legal representative or proxy consenter of changes in a 


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timely manner and will ask the subject to confirm his/her participation in the study by signing the 
revised informed consent form. Any revised written informed consent form and written 
information must receive the IEC/IRB’s approval / favorable opinion in advance of use.  
12.5. 
Records Management 
Study data will be stored and transmitted using electronic case report forms (eCRFs), using a 
system determined by the Sponsor. The Sponsor or designee will provide secure access and 
eCRF completion guidelines, as well as study-specific training, as needed, to each site. The 
eCRFs should be completed as soon as possible after each study visit or contact.  
12.6. 
Source Documentation 
Data recorded in the eCRFs must be supported by information captured in source documents, 
which must be available at all times for inspection by authorized representatives of the Sponsor, 
the FDA, or other regulatory agencies.  
12.7. 
Study Files and Record Retention 
The Investigator will retain the records of the study for two (2) years following the last date that 
a marketing application for zandelisib is approved in any ICH region, or if marketing approval is 
not obtained, for two (2) years after the Investigational New Drug (IND) application for 
zandelisib has been closed in the US or until there are no pending contemplated marketing 
applications in an ICH region. These documents should be retained for a longer period, however, 
if required by the applicable regulatory requirements or by an agreement with the Sponsor. The 
Sponsor will notify Investigators when study records retention is no longer required. 
The site will retain copies of all versions of the protocol, IB, correspondence with the IRB/EC 
(including submission and approval letters, approved ICFs), curricula vitae and medical licenses 
of the Investigator and sub-Investigator(s), Form FDA 1572 or similar forms, correspondence, 
laboratory documentation (including accreditation documents, reference ranges, and manuals), 
Delegation of Authority Log (documenting procedures delegated by the Investigator to be 
performed by study staff), IP study product records (including receipt, storage, dispensing, and 
return records), source documents (including clinic charts, medical records, laboratory results, 
radiographic reports), training records, screening/enrollment logs, monitoring visit logs, and 
study procedure manuals. 
Should the Investigator leave the institution or otherwise withdraw from the investigation or 
should there be any changes in the archival arrangements for the study records, the Sponsor will 
be notified. The Sponsor will be notified of the identity of any individual assuming responsibility 
for maintaining the study records and the location of their storage. If no other individual at the 
investigational site is willing to assume this responsibility, the Sponsor will assume 
responsibility for maintaining the study records.  
12.8. 
Auditing and Monitoring 
A Sponsor-designated study monitor will conduct a site initiation visit (SIV) prior to the first 
subject signing the ICF. The SIV may be conducted in person or as a ‘virtual’ visit. The study 
monitor will conduct routine monitoring visits at periodic intervals during the course of the 


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study, including a visit shortly after enrollment of the first subject, as per the study-specific 
monitoring plan. Monitoring visits may be conducted in person or remotely.  
The primary purposes of the site visits are to: 
1. Ensure the safety and welfare of study subjects 
2. Ensure the accuracy and completeness of eCRF entries, as verified against the source 
documentation 
3. Verify that the conduct of the study adheres to the written protocol approved by the 
IRB/EC, as well as regulatory requirements 
4. Verify that regulatory and other study-specific documentation is maintained and current 
5. Perform study drug product accountability (reconcile study product receipt, storage, 
dispensing, and return records) 
Site audits and vendor audits may be performed by the Sponsor at any time during the study and 
at the time of site or vendor closure to ensure adherence to the protocol and GCP quality 
standards. 
12.9. 
Quality Assurance 
Quality assurance is maintained using risk-based approaches and is documented in written 
procedures that ensure trials are conducted and data are generated, documented (recorded), and 
reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s). 
Written agreements are established with vendors, investigators, and CROs, to ensure proper 
execution of trials and allow direct access to all trial-related sites, source data/documents, and 
reports to ensure oversight of monitoring, periodic auditing, and inspections by applicable 
regulatory authorities. Quality checks are applied to each stage of data handling to ensure that all 
data are reliable and have been processed correctly.  
12.10. 
Amendments 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by the Sponsor. A protocol change intended to eliminate an apparent immediate 
hazard to subjects may be implemented immediately, provided the IRB/IEC is notified within 
5 days.  
Any permanent change to the protocol must be handled as a protocol amendment. The written 
amendment must be submitted to the IRB/IEC and the Investigator must await approval before 
implementing the changes. The Sponsor will submit protocol amendments to the appropriate 
regulatory authorities for approval.  
If in the judgment of the IRB/IEC, the Investigator, and/or the Sponsor, the amendment to the 
protocol substantially changes the study design and/or increases the potential risk to the subject 
and/or has an impact on the subject's involvement as a study participant, the currently approved 
written ICF will require similar modification. In such cases, informed consent will be renewed 
for subjects enrolled in the study before continued participation.  


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12.11. 
Study Discontinuation  
Both the Sponsor, and the Principal Investigator reserve the right to terminate the study at the 
Investigator’s site at any time. Should this be necessary, the Sponsor, or a specified designee will 
inform the appropriate regulatory authorities of the termination of the study and the reasons for 
its termination, and the Principal Investigator will inform the IRB/IEC of the same. In 
terminating the study, the Sponsor and the Principal Investigator will assure that adequate 
consideration is given to the protection of the subjects’ interests.  
12.12. 
Confidentiality 
The Principal Investigator and designees, employees, and agents involved with this study will 
comply with relevant local, state, federal and regional laws, as applicable, relating to the 
confidentiality, privacy, and security of subjects’ health information.  
Subject names will not be supplied to the Sponsor. Only the subject number will be recorded in 
the CRF, and if the subject’s name appears on any other document (e.g., pathologist report), it 
must be obliterated before a copy of the document is supplied to the Sponsor. Study findings 
stored on a computer will be stored in accordance with local data protection laws. As part of the 
informed consent process, the subjects will be informed in writing that representatives of the 
Sponsor, IEC/IRB, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws.  
If the results of the study are published, the subject’s identity will remain confidential.  
12.13. 
Publication Policy 
The Sponsor will make the information regarding the study protocol and results publicly 
available on the internet at www.clinicaltrials.gov and the relevant European competent 
authorities in the European Clinical Trials register (https://www.clinicaltrialsregister.eu/).  
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the Sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators. 
Regarding public disclosure of study results, the Sponsor will fulfill its obligations according to 
all applicable laws and regulations. The Sponsor is interested in the publication of the results of 
every study it performs.  
The Sponsor recognizes the right of the Investigator to publish the results upon completion of the 
study. However, the Investigator, whilst free to utilize study data derived from his/her center for 
scientific purposes, must obtain written consent of the Sponsor on the intended publication 
manuscript before its submission. To this end, the Investigator must send a draft of the 
publication manuscript to the Sponsor within a time period specified in the contract. The Sponsor 
will review the manuscript promptly and will discuss its content with the Investigator to reach a 
mutually agreeable final manuscript.  


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survival with rituximab plus chlorambucil versus either chlorambucil or rituximab monotherapy. 
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Zucca E, Arcaini L, Buske C, et al. Marginal zone lymphomas: ESMO Clinical Practice 
Guidelines for diagnosis, treatment and follow-up. Annals Oncol 2020;31(1):17-29. 
Zydelig® [Prescribing Information], Foster City, CA. Gilead Sciences, Inc; 2018. 


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14. 
APPENDICES 
 


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APPENDIX 1. SCHEDULE OF ASSESSMENTS 
Assessment/Procedure 
Screening b 
Cycle 1 
Cycle 2 to Cycle 6 
Cycle 7 - 10, 
Cycles 13, 17, 
21 and 26 
End of 
Treatment 
(EOT) c 
30-Day Safety 
Follow-up d 
Post-Treatment 
Long-Term 
Follow-up e 
Cycle Day(s) a 
-28 to -1 
1 
2 
8, 15, 22 
1 
2 
1 
 
 
  
Screening and Enrollment 
Eligibility/ICF 
X 
 
 
 
  
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test f 
X 
X 
 
 
X 
 
Xf 
 
X 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
Vital signs/Weight g 
X 
X 
X g 
X 
X 
Xg 
X 
X 
X 
 
Hepatitis B and C testing h 
X 
X 
 
 
X 
 
 
X 
 
 
GFR calculation 
X 
 
 
 
 
 
 
 
 
 
Complete Physical Examination i 
X 
 
 
 
 
 
 
X 
 
 
Symptom Directed Physical 
Examination j 
 
X 
 
 
X 
 
X 
 
 
 
ECOG performance status 
X 
X 
 
 
X 
 
X 
X 
X 
 
Adverse events k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication l 
X 
X 
 
 
X 
 
X 
X 
X 
 
Compliance Diary m 
 
X 
 
 
X 
 
X 
X 
 
 
12-lead ECG n  
X 
X 
 
 
X 
 
X n 
X 
 
 
LVEF by ECHO or MUGA o  
X 
 
 
 
 
 
 
 
 
 
CBC with differential p 
X 
X 
 
 
X 
 
X p 
X 
X 
 
Serum chemistry q 
X 
X 
 
 
X 
 
X q 
X 
X 
 
Coagulation r 
X 
X 
 
 
 
 
 
X 
 
 
CMV testing s 
X 
X 
 
 
X s 
 
X s 
 
 
 
Urinalysis t 
X 
X 
 
 
X 
 
X t 
X 
 
 
Dispense study drug u 
 
X 
 
 
X 
 
X 
 
  
 


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APPENDIX 1. SCHEDULE OF ASSESSMENTS (CONTINUED) 
Assessment/Procedure 
Screening b 
Cycle 1 
Cycle 2 to Cycle 6 
Cycle 7 - 10, 
Cycles 13, 17, 
21 and 26 
End of 
Treatment 
(EOT) c 
30-Day Safety 
Follow-up d 
Post-Treatment 
Long-Term Follow-
up e 
Cycle Day(s) a 
-28 to -1 
1 
2 
8, 15, 22 
1 
2 
1 
 
 
 
PRO Questionnaires (FLymSI-
18) and EQ-5D-3L and VAS v 
X 
X v 
 
 
X v 
 
X v 
X v 
X v 
 
PK Sampling w 
 
X w 
 
 
X w 
 
 
 
 
 
Survival follow-up x 
 
 
 
 
 
 
 
 
 
X 
 
Efficacy Assessments 
Response Assessment y  
Screening 
Week 12 
(±1 week) 
Week 24 
(±1 week) 
Week 36 
(±1 week) 
Week 52 
(±1 week) 
Week 68 
(±1 week) 
Week 84 
(±1 week) 
Week 104 
(±1 week) 
Every 24 weeks 
thereafter 
(±2 weeks) 
CT/PET/MRI y,z 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bone marrow biopsy/aspirate aa 
X 
 
 
 
 
 
 
 
 
Endoscopy with biopsy bb 
X 
 


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APPENDIX 1. SCHEDULE OF ASSESSMENTS (CONTINUED) 
Study Drug Administration 
Zandelisib+ R (q4w)  
28-day cycle cc 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 to 26 
Rituximab IV 375 mg/m2 
(maximum 6 cycles)  
D1, D8, D15, D22 
 
D1 
D1 
D1 
C6 D1 only 
Zandelisib 60 mg QD 
orally 
Every day 
D1 to D7 
then 21 days off 
D1 to D7 
then 21 days off 
D1 to D7 
then 21 days off 
D1 to D7 
then 21 days off 
 
R-B (q4w)  
28-day cycle dd 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Rituximab IV 375 mg/m2  
D1 
D1 
D1 
D1 
D1 
D1 
Bendamustine IV 
90 mg/m2 
D1 
D2 
D1 
D2 
D1 
D2 
D1 
D2 
D1 
D2 
D1 
D2 
 
R-CHOP (q3w) 
21-day cycle ee 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Rituximab IV 375 mg/m2  
D1 
D1 
D1 
D1 
D1 
D1 
Cyclophosphamide IV 
750 mg/m2 
D1 
D1 
D1 
D1 
D1 
D1 
Doxorubicin IV 50 mg/m2 
D1 
D1 
D1 
D1 
D1 
D1 
Vincristine IV 1.4 mg/m2 
D1 
D1 
D1 
D1 
D1 
D1 
Prednisone 100 mg daily 
orally  
D1 to D5 
D1 to D5 
D1 to D5 
D1 to D5 
D1 to D5 
D1 to D5 
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANC = absolute neutrophil count; aPTT = activated partial thromboplastin time; 
AST = aspartate aminotransferase; BP = blood pressure; BUN = blood urea nitrogen; C = cycle; CBC = complete blood count; CMV = cytomegalovirus; 
HCO3 = Bicarbonate dioxide; CT = computed tomography; D = day; ECG = electrocardiogram; ECHO = echocardiography; ECOG = Eastern Cooperative 
Oncology Group; EOT = end of treatment; FDG = 18F-fluorodeoxy glucose; GFR = glomerular filtration rate; GGT = gamma-glutamyl transferase; 
Hct = hematocrit; Hb = hemoglobin; hCG = human chorionic gonadotropin; HIV = human immunodeficiency virus; HrRt = heart rate; ICF = informed consent 
form; INR = international normalized ratio; IV = intravenous; LDH = lactate dehydrogenase; LVEF = left ventricular ejection fraction; MCH = mean corpuscular 
hemoglobin; MCR = metabolic complete response; MDP = metabolic disease progression; MUGA = multigated acquisition scan; PCR = polymerase chain 


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reaction; PK = pharmacokinetic; PRO = patient reported outcome; PT = prothrombin time; RBC = red blood cell; SOC = standard of care; TTNT = time to next 
anti-lymphoma treatment; WBC = white blood cell 
a. 
Study Assessment Day(s) –Visits will occur based on assigned treatment schedule. For assessment timing, a window relative to Cycle 1 Day 1 is allowed 
starting on Cycle 2. If a cycle is missed, it will be skipped to the next cycle. For Cycles 2 through 26, the allowable window is ±7 days. For post treatment 
long term follow-up, the allowable window is ±1 month for each clinic visit and its associated assessments. 
b. Screening – Screening assessments are to be performed within 28 days prior to randomization. After confirmation of eligibility, subjects should be treated 
within 3 days of randomization. It is important to assure that subjects continue to meet eligibility criteria prior to treatment initiation. Laboratory and general 
physical assessment of subjects to confirm eligibility should be performed prior to initial dosing on C1D1. Laboratory assessments need not be repeated on 
C1D1 if performed within 3 days prior. Physical examination need not be repeated on C1D1 if performed within 7 days prior. Some tests performed prior to 
obtaining ICF (e.g., CT scan, bone marrow biopsy/aspirate) may not need to be repeated for the study as long as they were performed within the allowed 
screening window.  
c. 
EOT visit – Performed within 7 days (±3 days) from the last dose or treatment discontinuation.  
d. 30-Day safety follow-up visit – Visit will be completed 30 (±3) days post last dose of study drug (or prior to starting a new anti-cancer treatment if urgent 
treatment is required) or from study drug discontinuation.  
e. 
Post-treatment long-term follow-up procedures - During the treatment phase as well as during the active follow-up period, subjects will be followed for 
response assessments every 12 weeks for the first 3 scans (weeks 12, 24, and 36 [±1 week]), followed by 3 scans every 16 weeks (weeks 52, 68, and 
84 [±1 week]), a scan at week 104 (±1 week), and every 24 weeks (±2 weeks) thereafter. Survival follow up will be every 3 months for 5 years after the last 
patient’s randomization.  
f. 
Pregnancy test – The screening serum pregnancy test for human chorionic gonadotropin (hCG) in females of childbearing potential must be completed 
within 7 days prior to C1D1. A urine or serum pregnancy test must also be performed on C1D1. For women of childbearing potential, serum or urine 
pregnancy test will be conducted on D1 of every dosing cycle (when a subject has a visit) and 30 days after discontinuation of dosing.  
g. Day 2 vital signs and weight to be recorded for R-B arm only 
h. Hepatitis B and C testing – Hepatitis B core antibody, Hepatitis B surface antigen and hepatitis C antibody are required. Hepatitis B PCR is required if 
hepatitis B core antibody and/or surface antigen is positive. Hepatitis B PCR monitoring monthly while on treatment with rituximab or biosimilar 
monoclonal antibody is allowed if required per institutional standards. Post-treatment monitoring is per institutional standards. Hepatitis C PCR is required if 
hepatitis C antibody is positive. Prophylactic therapy for hepatitis is recommended per institutional standards. 
i. 
Complete physical exam – Only at screening and EOT. If physical exam is performed >7 days prior to C1D1 it must be repeated on C1D1.  
j. 
Brief symptom-directed physical exam – Performed on Day 1 of Cycles 1 to 6 only as clinically indicated, based on interim history. For zandelisib arm, 
Day 1 of Cycles 1 to 6, and then every 2 to 3 months (when a subject has a visit). 
k. Adverse events – AEs will be collected continuously from start of dosing until the 30-Day safety follow-up visit or start of new anti-cancer treatment, 
whichever occurs first (AEs that may be related to screening procedures will be collected from baseline). SAEs will be followed until resolution. All SAEs 
must be reported and followed for 30 days after the last dose of study drug. After 30 days, only SAEs deemed related to study drug will be reported to the 
Sponsor. AEs leading to discontinuation of study drug will be followed for minimum of 30 days after the last dose of study drug or until resolution, 
whichever comes first. AEs will be assessed at all site visits.  
l. 
Concomitant medications – Recorded from Screening until the 30-Day Safety Follow-up visit, or start of new anti-cancer treatment, whichever occurs first.  
m. Issue and review compliance diary for zandelisib – Compliance diary to record daily study drug administration will be issued on Day 1 of each cycle 


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(when a subject has a visit). Returned diaries are to be assessed for study product compliance. New compliance diary is to be issued with each dispensing of 
zandelisib.  
n. ECG – Single tracing 12-lead ECGs performed at screening, pre-dose on Day 1 for the first 6 cycles, pre-dose on Day 1 from Cycle 7 to Cycle 10, pre-dose 
Cycles 13, 17, 21 and 26 for Arm 1 subjects during zandelisib treatment period, at EOT visit, and as clinically indicated. On Day 1 of C1 and C3, additional 
ECGs will be performed 3-4 hours after zandelisib dose is taken.  
o. LVEF – to be measured using ECHO or MUGA at screening and at any time if clinically indicated. The Investigator must discuss decisions leading to 
treatment changes, interruptions due to LVEF abnormalities with the Sponsor’s medical monitor or designee.  
p. CBC with differential – WBC, ANC, RBC, HGB, HcT, lymphocytes, eosinophils, monocytes, basophils, platelets, MCV, MCH, and MCHC. Screening 
labs must be repeated if performed >7 days prior to C1D1. If screening labs are drawn within 3 days of C1D1, they do not need to be repeated on C1D1 . 
During C7 to C26, to be done on D1 of C7-C10, C13 C17, C21, C26, and EOT.  
q. Serum chemistry – Glucose, BUN or urea, uric acid, creatinine, sodium, potassium, chloride, calcium, bicarbonate, ALP, AST, ALT, GGT, LDH, total 
bilirubin, direct bilirubin, total protein, phosphorous, and albumin. Screening labs must be repeated if performed >7 days prior to C1D1. Need not be 
performed on C1D1 if screening labs were done within 3 days of C1D1. During C7 to C26, to be done on D1 of C7-C10, C13 C17, C21, C26, and EOT.  
r. 
Coagulation – aPTT, PT, INR, to be performed at screening, EOT, and as clinically indicated per the institutional standard of care. Screening labs must be 
repeated if performed >7 days prior to C1D1. Need not be performed on C1D1 if screening labs were done within 3 days of C1D1.  
s. 
CMV testing – At screening, C1D1, C3D1, C6D1, and D1 of Cycles 9, 13, 17, 21, 26 for Arm 1 subjects during zandelisib treatment period until subject 
discontinues treatment, and as clinically indicated. CMV testing at screening must include CMV serology (IgG, IgM) and CMV DNA PCR testing. Subject 
must have a negative result for CMV DNA PCR, which is below the limit of quantitation at screening to be eligible for the study. Prophylactic therapy for 
CMV is allowed.  
t. 
Urinalysis – Dipstick or urine test (pH, specific gravity, glucose, ketones, blood, leukocyte esterase, bilirubin, urobilinogen, protein, and microscopic 
examination). Screening labs must be repeated if performed >7 days prior to C1D1. Need not be performed on C1D1 if screening labs were done within 
3 days of C1D1. During C7 to C26, to be done on D1 of C7-C10, C13 C17, C21, C26, and EOT.  
u. Dispense study drug – Study drug is to be taken orally once a day on an empty stomach at least 1 hour prior to food at the same time each morning. On 
days of PK sampling, subjects are instructed to not take study drug at home; on these days study drug will be administered at the clinic in relation to the 
timing of the PK sample collection.  
v. Patient Reported Outcome (PRO) (FlymSI 18 and EQ-5D-3L and VAS) - Baseline assessment should occur during screening period prior to the time 
subject is assigned to treatment arm. Subjects in both arms will complete the questionnaires on D1 of every cycle of therapy during first 6 cycles of therapy. 
After first 6 months of therapy, subjects will complete the FLymSI-18 and EQ-5D-3L and VAS questionnaires at the same visits as follow-up tumor 
assessments: week 36, 52, 68, 84, 104 and then every 24 weeks until response assessment is performed. PRO assessments also will be done at the EOT, and 
at the 30-day safety follow-up visit for subjects in each treatment arm. (for more detail see Section 9.6). 
w. PK sampling – PK samples are to be collected only in the zandelisib arm: 
• 
C1D1: 2 samples – 2- and 4-hours (±30 min) post-dose of zandelisib 
• 
C2D1: 1 sample – pre-dose (within 30-60 minutes) 
• 
C3D1: 2 samples – pre-dose (within 30-60 minutes) and 3 hours (±30 min) post-dose of zandelisib 
• 
C4D1: 1 sample – 3 hours (±30 min) post-dose of zandelisib  
Note:  On days of PK sampling when a pre-dose sample is drawn, subjects are instructed to not take study drug until after pre-dose PK sample is drawn. 


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x. After treatment discontinuation, all subjects will be followed for OS every 3 months for 5 years after the last subject’s randomization, except for subjects 
who withdraw consent. Subjects or their healthcare providers will be contacted either in person, by telephone, or e-mail. During OS follow-up, TTNT will be 
recorded.  
y. Response assessment (CT and PET scans) – Response assessment will be performed every 12 weeks (from C1D1) for the first 3 scans (weeks 12, 24 and 
36 [±1 week]), followed by 3 scans every 16 weeks (weeks 52, 68 and 84 [±1 week]), a scan at week 104 (±1 week), and every 24 weeks (±2 weeks) 
thereafter.  
z. 
PET/CT/MRI – PET/CT at baseline, week 12, week 24 (after completion of treatment in control arm and initial 6 cycles of therapy in study arm), and for 
confirmation of CR/MCR (if initially assessed by CT scan only for FDG-avid disease). FDG-PET scan should be performed within 1 week (±3 days) of CT 
scan if it was not done at the same time. Contrast-enhanced CT scan to be done at screening and all other timepoints. PET and/or CT scan can be used to 
confirm PD. Scans will be evaluated locally at the study site for response assessment. Scans will be submitted for an independent central review. If a subject 
is intolerant to contrast agent then MRI can be used consistently throughout the study for that subject. 
aa. Bone marrow biopsy – Bone marrow biopsy/aspirate will be mandatory at screening and to confirm CR if PET scan is not performed or is not evaluable 
and the patient had bone marrow involvement at screening.  
bb. For subjects with MZL having gastric involvement an endoscopy at baseline should be obtained. At CR, endoscopy is required if not observed 
radiographically and the endoscopy was positive at baseline.  
cc. Zandelisib + R: 
• 
Zandelisib 60 mg QD orally for the first 2 cycles of therapy (56 days), then 60 mg for 7 days followed by 21 days off treatment in every 28-day cycle.  
• 
Rituximab IV 375 mg/m2 on D1, D8, D15 and D22 of C1 and then on D1 of C3, C4, C5, and C6 for up to a total of 8 doses in 6 cycles. Rituximab 
infusion should start approximately one hour after zandelisib on clinic days, and on PK collection days infusion can be prior to the post dose PK 
collection for zandelisib.  
dd. R-B will be administered every 4 weeks (q4w) as follows: rituximab IV 375 mg/m2 body surface on Day 1 (D1) and B administered IV 90 mg/m2 body 
surface on D1 and D2 of each cycle for 6 cycles  
ee. R-CHOP will be administered once every 3 weeks (q3w) as follows: rituximab IV 375 mg/m2 body surface on D1; cyclophosphamide IV 750 mg/m2 body 
surface on D1; doxorubicin IV 50 mg/m2 body surface on D1; Vincristine IV 1.4 mg/m2 body surface (maximum dose 2.0 mg) on D1, prednisone 100 mg 
daily orally (PO) from D1 to D5 of each cycle for 6 cycles  


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APPENDIX 2. COCKCROFT-GAULT EQUATION FOR ESTIMATED 
CREATININE CLEARANCE 
Estimate the subject’s creatinine clearance using the serum creatinine value provided by the local 
laboratory, actual body weight, and the appropriate Cockcroft-Gault formula (if necessary, 
convert serum creatinine values from µmol/L to mg/dL by dividing by 88.4; for example, 
100 µmol/L divided by 88.4 equals 1.131 mg/dL): 
Estimated Creatinine Clearance (CCr) by the Cockcroft-Gault Equation: 
𝐶𝐶𝐶𝐶𝐶𝐶= (140 −𝑎𝑎𝑎𝑎𝑎𝑎 𝑖𝑖𝑖𝑖 𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦) × (𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 𝑖𝑖𝑖𝑖 𝑘𝑘𝑘𝑘)
72 × (𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑖𝑖𝑖𝑖 𝑚𝑚𝑚𝑚/𝑑𝑑𝑑𝑑)
 × (0.85 𝑖𝑖𝑖𝑖 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓) 
Abbreviation:  CCr = creatinine clearance (in mL/minute) 


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APPENDIX 3. GUIDELINES FOR WOMEN OF CHILDBEARING 
POTENTIAL AND FERTILE MALE SUBJECTS 
For females of childbearing potential, defined as all premenopausal women capable of becoming 
pregnant, must agree to use a medically effective contraceptive method (has a failure rate of <1% 
per year) starting with the first dose of study drug through 12 months after the last dose of study 
drug.  
Postmenopausal women are defined as no menstrual periods for at least 12 consecutive months 
OR FSH greater than 40 IU/L on at least two occasions.  
Fertile male subjects, defined as all males physiologically capable of conceiving offspring who 
are sexually active with a female partner of child-bearing potential, must agree to use a medically 
effective contraceptive method and to refrain from donating sperm for at least 6 months after the 
last dose of study drugs, CHOP, zandelisib or bendamustine, and 12 months after the last dose of 
rituximab, whichever is longest.  
Men/women should also seek advice about sperm/oocyte preservation before treatment if 
desired, because of possible irreversible infertility due to study drugs. 
Acceptable Contraception Methods:  
Highly effective contraception is defined as: 
 
True 
Abstinence 
When this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception. 
Sterilization 
When a woman of childbearing potential has had surgical bilateral oophorectomy 
(with or without hysterectomy) or tubal ligation at least six weeks prior to study 
entry. In case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow-up hormone level assessment. 
Male Partner 
Sterilization 
When the appropriate post-vasectomy documentation of the absence of sperm in 
the ejaculate. 
 


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Use of a combination 
of any two of the 
following (one from a + 
one from b): 
a. Placement of an intrauterine device (IUD) or intrauterine system or 
established use of oral, injected, or implanted hormonal methods of 
contraception 
b. Barrier methods of contraception: Male Condom or Occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/vaginal suppository. 
Unacceptable Contraception Methods:  
Unacceptable contraception methods include:  
c. IUD progesterone T  
d. Female condom  
e. Natural family planning (rhythm method) or breastfeeding  
f. Fertility awareness  
g. Withdrawal  
h. Cervical shield 
 
Pregnancy in a subject on study treatment must be reported within 24 hours of learning of its 
occurrence. Pregnancy occurring up to 12 months after receiving the last dose of study drug must 
be reported to the sponsor.  


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APPENDIX 4. LYMPHOMA RESPONSE CRITERIA 
SELECTION OF TARGET LESIONS 
Up to six of the largest dominant nodes or tumor masses selected according to all of the 
following: 
1. Clearly measurable in two diameters (longest diameter and shortest diameter) at baseline 
a. All nodal lesions must measure >1.5 cm in longest diameter regardless of short axis 
measurement  
b. All measurable extranodal lesions should have a longest tumor diameter >1.0 cm 
2. All other lesions (including nodal, extranodal, and assessable disease) should be followed 
as non-target lesions  
3. If possible, the lesions should be from disparate regions of the body 
4. Should include mediastinal and retroperitoneal areas of disease whenever these sites are 
involved  
SELECTION OF NON-TARGET LESIONS 
Non-target lesions will be qualitatively assessed at each subsequent timepoint. All of the sites of 
disease present at baseline and not classified as target lesions will be classified as non-target 
lesions, including any measurable lesions that were not chosen as target lesions. 
Examples of non-target lesions include: 
1. All bone lesions, irrespective of the modality used to assess them 
2. Lymphangitis of the skin or lung 
3. Cystic lesions 
4. Irradiated lesions 
5. Measurable lesions beyond the maximum number of six 
6. Groups of lesions that are small and numerous 
7. Pleural/pericardial effusions and/or ascites 
a. Effusions, ascites, or other fluid collections will be followed as non-target lesions 
b. At each assessment point, radiologists will check for the presence or absence of 
effusions/ascites. If there is a significant volume increase in the absence of a benign 
etiology, progression can be assessed 
c. Significant new effusions, ascites, or other fluid collections, which are 
radiographically suggestive of malignancy should be recorded as new lesions and 
should be assessed 
Response should be determined on the basis of radiographic and clinical evidence of disease. For 
subjects who achieve a CR by CT criteria, an FDG-PET will be performed. FDG-PET scan 
should be performed within 1 week (±3 days) of CT scan if they were not done at the 
same time. Assessment by FDG-PET should follow the criteria described by Cheson 2014 
which is summarized in Table 3. 


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Overall response should be determined based upon the Modified Lugano response criteria 
(Table 3). 
SPLEEN INVOLVEMENT 
Splenomegaly defined as enlargement of spleen measured by vertical (cranial or caudal) length 
of >13 cm. Measurable lesions in spleen defined as extra-nodal lesions can be selected and 
followed as target, non-target or new lesions.  
LIVER INVOLVEMENT 
CT measurements used for qualitative assessment of liver involvement, and FDG-PET used for 
assessment of response (e.g., new uptake indicative of disease progression). Measurable lesions 
in liver defined as extra-nodal lesions can be selected and followed as target, non-target or new 
lesions.  
Table 3: 
Modified Lugano Response Criteria 
Morphologic 
Response 
Metabolic 
Response 
Bone Marrow 
Biopsy/Aspirate 
Prior Combined 
Response 
Lugano Combined Response 
NE/No CT 
CMR 
 
 
CRa 
PMR 
 
 
SD unless the previous CT 
scan indicated CR or PR, then 
combined response is PRb 
NMR 
 
 
SD 
PMD 
 
 
PD 
NE/No PET 
 
 
NE 
PD 
CMR 
 
 
PD 
PMR 
 
 
PD 
NMR 
 
 
PD 
PMD 
 
 
PD 
NE/No PET 
 
 
PD 
SD 
CMR 
 
 
CR 
PMR 
 
 
SDb 
NMR 
 
 
SD 
PMD 
 
 
PD 
NE/No PETc 
 
 
SD 
PR 
CMR 
 
 
CR 
PMR 
 
 
PR 
NMR 
 
 
PRb 
PMD 
 
 
PD 
NE/No PETc 
 
 
PR 


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Table 3: 
Modified Lugano Response Criteria (Continued) 
Morphologic 
Response 
Metabolic 
Response 
Bone Marrow 
Biopsy/Aspirate 
Prior Combined 
Response 
Lugano Combined Response 
CR 
CMR 
 
 
CR 
PMR 
 
 
PR 
NMR 
 
 
PR 
PMD 
 
 
PD 
NE/No PET 
 
No prior PET 
response 
PR 
NE/No PET 
 
No prior response 
and prior PET was 
negative 
CR 
NE/No PET 
 
SD 
PR 
NE/No PET 
 
PR 
PR 
NE/No PET 
 
CR 
CR 
NE/No PET 
 
PD and prior 
evaluable PET was 
not PMD 
PR 
NE/No PETc 
 
PD and prior PET 
was PMD 
NE 
NE/No PET 
CRd 
 
CR 
Abbreivations:  BMB = bone marrow biopsy; CMR = complete metabolic response; CR = complete response; 
CT = computed tomography; NE = not evaluated; NMR = no metabolic response; PD = progressive disease; 
PET = positron emission tomography; PMD = progressive metabolic disease; PMR = partial metabolic response; 
PR = partial response; SD = stable disease 
a 
If the lesion(s) on CT were non-FDG avid at baseline, the assessment will be based on a prior morphological 
response.  
b 
Lugano combined response criteria for this response combination has been modified per FDA request. 
c 
When a timepoint does not have an evaluable PET scan, the morphologic response is not PD, and the most 
recent evaluable PET scan indicated a metabolic response of PMD, then the combined response will be NE. An 
improved combined response without evidence that the findings in the prior PET scan have resolved isn’t 
justified. However, there is not PET-based evidence that the subject has continuing PMD, so the response is 
designated as NE. 
d 
When a PET scan is not acquired or not evaluable, a bone marrow biopsy (BMB)/aspirate is required to confirm 
a CR by CT. If no BMB is taken (and no PET can be acquired for this time point), the best possible overall 
response is a PR unless the prior overall response meets either criteria: prior overall response was CR or there 
was no prior overall response and the baseline/prior PET was negative.  


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APPENDIX 5. ECOG PERFORMANCE STATUS CRITERIA 
Score 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature (e.g., light housework, office work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more 
than 50% of waking hours. 
3 
Capable of only limited self- care, confined to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead 
References: Oken 1982. 
 


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APPENDIX 6. LIST OF CYP2C8 INHIBITORS AND INDUCERS 
Following is a table of known inducers and inhibitors of CYP2C8. 
Inhibitors of CYP2C8 can be classified by their potency, such as: 
• Strong inhibitor being one that causes at least a 5-fold increase in the plasma AUC 
values, or more than 80% decrease in clearance. 
• Moderate inhibitor being one that causes at least a 2-fold increase in the plasma AUC 
values, or 50–80% decrease in clearance.  
• Weak inhibitor being one that causes at least a 1.25-fold but less than 2-fold increase in 
the plasma AUC values, or 20–50% decrease in clearance.  
Inhibitors 
Inducers 
Strong inhibitor 
gemfibrozil 
 
Moderate inhibitor 
trimethoprim 
glitazones 
montelukast 
quercetin 
Unspecified potency 
rifampin 
Note:  Medicines on this list must be reviewed by Principal Investigators on an ongoing basis to 
assure updates.  
Please note the following: This is not an exhaustive list. For an updated list, see the following 
links: 
• https://www.fda.gov/drugs/development-resources/drug-interactions-labeling  
• http://medicine.iupui.edu/clinpharm/ddis/main-table/  


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APPENDIX 7. LIST OF CYP3A INHIBITORS AND INDUCERS 
Strong CYP3A Inhibitors 
Antibiotics: clarithromycin, telithromycin, troleandomycin 
Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole 
Antivirals: boceprevir, telaprevir 
Other: cobicistat, conivaptan, elvitegravir, mibefradil, nefazodone 
Protease inhibitors: indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir 
Moderate CYP3A Inhibitors 
CYP3A4, CYP3A5, CYP3A7 
Antibiotics: ciprofloxacin, erythromycin 
Antifungals: fluconazole, clotrimazole 
Protease inhibitors: amprenavir, atazanavir, darunavir/ritonavir, fosamprenavir 
Calcium channel blockers: diltiazem, verapamil 
Tyrosine kinase inhibitors (anticancer): imatinib, crizotinib 
Food products: grapefruit juice (citrus paradisi juice) 
Herbal medications: Schisandra sphenanthera 
Others:  amiodarone, aprepitant, casopitant, cimetidine, cyclosporine, dronedarone, tofisopam 
Strong inducers 
Moderate inducers 
Weak inducers 
CYP3A 
apalutamide, 
carbamazepine(e), 
enzalutamide(g), mitotane, 
phenytoin(b), rifampin(a), St. 
John’s wort(h) 
bosentan, efavirenz(f), etravirine, 
phenobarbital, primidone 
armodafinil, modafinil(i), 
rufinamide 
Abbreviations:  CYP = cytochrome P450 
Note: The list of drugs in this table is not exhaustive. Please refer to the prescribing information of concomitant 
medication to check for CYP3A inhibition or induction risks or contact the medical monitor of the protocol. 
Source: Food and Drug Administration Drug Development and Drug Interactions: Table of Substrates, Drug 
Development and Drug Interactions and Inducers. Flockhart DA. Drug Interactions: Cytochrome P450 Drug 
Interaction Table. Indiana University School of Medicine. 
Note: Strong, moderate, and weak inducers are drugs that decreases the AUC of sensitive index substrates of a given 
metabolic pathway by ≥80%, ≥50% to <80%, and ≥20% to <50%, respectively.  
This table provides examples of clinical index inducers and not intended to be an exhaustive list.  
http://medicine.iupui.edu/flockhart/table.htm 
Drug Development and Drug Interactions | Table of Substrates, Inhibitors and Inducers | FDA 


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APPENDIX 8. LIST OF DRUGS KNOWN TO PROLONG QT/QTC 
INTERVAL 
The table below includes a list of drugs known to prolong QT/QTc interval from  
https://www.cpsbc.ca/files/pdf/Methadone-Drugs-QT-Interval-Prolongation.pdf  
Note: Medicines on this list must be reviewed by Principal Investigators on an ongoing basis to 
assure updates.  
Generic Name 
Brand Names (Partial List) 
Alfuzosin 
Uroxatral® 
Amantadine 
Symmetrel®, Symadine® 
Amiodarone 
Cordarone®, Pacerone®, Nexterone® 
Amisulpride (Only on Non US Market) 
Solian®, Supitac®, Soltus®, Amitrex®, Amazeo® 
Amitriptyline 
Elavil® (Discontinued 6/13), Tryptomer®, Tryptizol®, 
Laroxyl®, Saroten®, Sarotex® Lentizol®, Endep® 
Anagrelide 
Agrylin®, Xagrid® 
Apomorphine 
Apokyn®, Ixense®, Spontane®, Uprima® 
Aripiprazole 
Abilify®, Aripiprex® 
Arsenic trioxide 
Trisenox® 
Artenimol+piperaquine 
Eurartesim® 
Asenapine 
Saphris®, Sycrest® 
Astemizole (Removed from Market) 
Hismanal® 
Atazanavir 
Reyataz® 
Atomoxetine 
Strattera® 
Azithromycin 
Zithromax®, Zmax® 
Bedaquiline 
Sirturo® 
Bepridil (Removed from Market) 
Vascor® 
Bortezomib 
Velcade®, Bortecad® 
Bosutinib 
Bosulif® 
Ceritinib 
Zykadia® 
Chloral hydrate 
Aquachloral®, Novo-Chlorhydrate®, Somnos®, Noctec®, 
Somnote® 
Chloroquine 
Aralen® 
Chlorpromazine 
Thorazine®, Largactil®, Megaphen® 
Cilostazol 
Pletal® 
Ciprofloxacin 
Cipro®, Cipro-XR®, Neofloxin® 
Cisapride (Removed from Market) 
Propulsid® 
Citalopram 
Celexa®, Cipramil® 


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APPENDIX 8. 
LIST OF DRUGS KNOWN TO PROLONG QT/QTC 
INTERVAL (CONTINUED) 
Generic Name 
Brand Names (Partial List) 
Clarithromycin 
Biaxin®, Prevpac® 
Clomipramine 
Anafranil® 
Clozapine 
Clozaril®, Fazaclo®, Versacloz® 
Cocaine 
Cocaine 
Crizotinib 
Xalkori® 
Cyamemazine (cyamepromazine) (Only on 
Non-US Market) 
Tercian® 
Dabrafenib 
Tafinlar® 
Dasatinib 
Sprycel® 
Degarelix 
Firmagon® 
Delamanid (Only on Non-US Market) 
Deltyba® 
Desipramine 
Pertofrane®, Norpramine® 
Dexmedetomidine 
Precedex®, Dexdor®, Dexdomitor® 
Diphenhydramine 
Benadryl®, Nytol®, Unisom®, Sominex®, Dimedrol®, 
Daedalon® 
Disopyramide 
Norpace® 
Dofetilide 
Tikosyn® 
Dolasetron 
Anzemet® 
Domperidone (Only on Non-US Market) 
Motilium®, Motillium®, Motinorm Costi®, Nomit® 
Donepezil 
Aricept® 
Doxepin 
Sinequan®, Silenor®, Aponal®, Adapine®, Doxal®, Deptran®, 
Sinquan® 
Dronedarone 
Multaq® 
Droperidol 
Inapsine®, Droleptan®, Dridol®, Xomolix® 
Eribulin mesylate 
Halaven® 
Erythromycin 
E.E.S.®, Robimycin®, EMycin®, Erymax®, Ery-Tab®, Eryc 
Ranbaxy®, Erypar®, Eryped®, Erythrocin Stearate Filmtab®, 
Erythrocot®, E-Base®, Erythroped®, Ilosone®, MY-E®, 
Pediamycin®, Zineryt®, Abboticin®, Abboticin-ES®, Erycin®, 
PCE Dispertab®, Stiemycine®, Acnasol®, Tiloryth® 
Escitalopram 
Cipralex®, Lexapro®, Nexito®, Anxiset-E® (India), Exodus® 
(Brazil), Esto® (Israel), Seroplex®, Elicea®, Lexamil®, Lexam®, 
Entact® (Greece), Losita® (Bangladesh), Reposil® (Chile), 
Animaxen® (Colombia), Esitalo® (Australia), Lexamil® (South 
Africa) 
Famotidine 
Pepcid®, Fluxid®, Quamatel® 


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APPENDIX 8. 
LIST OF DRUGS KNOWN TO PROLONG QT/QTC 
INTERVAL (CONTINUED) 
Generic Name 
Brand Names (Partial List) 
Felbamate 
Felbatol® 
Fingolimod 
Gilenya® 
Flecainide 
Tambocor®, Almarytm®, Apocard®, Ecrinal®, Flécaine® 
Fluconazole 
Diflucan®, Trican® 
Fluoxetine 
Prozac®, Sarafem®, Fontex® 
Foscarnet 
Foscavir® 
Furosemide (frusemide) 
Lasix®, Fusid®, Frumex® 
Galantamine 
Reminyl®, Nivalin®, Razadyne-ER®, 
Gatifloxacin (Removed from Market) 
Tequin® 
Gemifloxacin 
Factive® 
Granisetron 
Kytril®, Sancuso®, Granisol® 
Grepafloxacin 
Raxar® 
Halofantrine 
Halfan® 
Haloperidol 
Haldol® (US & UK), Aloperidin®, Bioperidolo®, Brotopon®, 
Dozic®, Duraperidol® (Germany), Einalon S®, Eukystol®, 
Halosten®, Keselan®, Linton®, Peluces®, Serenace®, Serenase®, 
Sigaperidol® 
Hydrochlorothiazide 
Apo-Hydro®, Aquazide H®, BP Zide®, Dichlotride®, 
Hydrodiuril®, HydroSaluric®, Hydrochlorot®, Microzide®, 
Esidrex®, Oretic® 
Hydrocodone - ER 
Hysingla™ ER, Zohydro ER 
Hydroxychloroquine 
Plaquenil®, Quineprox® 
Hydroxyzine 
Atarax®, Vistaril®, Aterax®, Alamon®, Durrax®, Equipose®, 
Masmoran®, Orgatrax®, Paxistil® Quiess®, Tran-Q®, 
Tranquizine® 
Ibutilide 
Corvert® 
Iloperidone 
Fanapt®, Fanapta®, Zomaril® 
Imipramine (melipramine) 
Tofranil® 
Indapamide 
Lozol®, Natrilix®, Insig® 
Isradipine 
Dynacirc® 
Itraconazole 
Sporanox®, Onmel® 
Ivabradine 
Procoralan®, Coralan®, Corlentor®, Coraxan®, Ivabid®, Bradia® 
Ketoconazole 
Nizoral®, Sebizole®, Ketomed®, Keton® 
Lapatinib 
Tykerb®, Tyverb® 
Lenvatinib 
Lenvima® 


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APPENDIX 8. 
LIST OF DRUGS KNOWN TO PROLONG QT/QTC 
INTERVAL (CONTINUED) 
Generic Name 
Brand Names (Partial List) 
Leuprolide 
Lupron®, Eligard®, Viadur®, Carcinil®, Enanton®, Leuplin®, 
Lucrin®, Procren®, Prostap® and others 
Levofloxacin 
Levaquin®, Tavanic® 
Levomepromazine (Only on Non-US Market) 
Nosinan®, Nozinan®, Levoprome® 
Levomethadyl (Removed from Market) 
Orlaam® 
Lithium 
Eskalith®, Lithobid® 
Mesoridazine (Removed from Market) 
Serentil® 
Methadone 
Dolophine®, Symoron®, Amidone®, Methadose®, Physeptone®, 
Heptadon® 
Metoclopramide 
Reglan®, Afipran®, Maxolon®, Cerucal®, Clopamon®, Clopra®, 
Maxeran®, Maxolon®, Metozolv®, Plasil®, Pramin®, 
Primperan®, Perinorm® 
Metronidazole 
Flagyl® and many others 
Mifepristone 
Korlym®, Mifeprex® 
Mirabegron 
Myrbetriq® 
Mirtazapine 
Remeron 
Moexipril/HCTZ 
Uniretic®, Univasc® 
Moxifloxacin 
Avelox®, Avalox®, Avelon® 
Nelfinavir 
Viracept® 
Nicardipine 
Cardene® 
Nilotinib 
Tasigna® 
Norfloxacin 
Noroxin®, Ambigram® 
Nortriptyline 
Pamelor®, Sensoval®, Aventyl®, Norpress®, Allegron®, 
Noritren®, Nortrilen® 
Ofloxacin 
Floxin® 
Olanzapine 
Zyprexa®, Zydis®, Relprevv® 
Ondansetron 
Zofran®, Anset®, Ondemet®, Zuplenz®, Emetron®, Ondavell®, 
Emeset®, Ondisolv®, Setronax® 
Osimertinib 
Tagrisso® 
Oxaliplatin 
Eloxatin® 
Oxytocin 
Pitocin®, Syntocinon® 
Paliperidone 
Invega®, Xepilon® 
Panobinostat 
Farydak® 
Pantoprazole 
Protonix® and others 
Papaverine HCl 
none 


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APPENDIX 8. 
LIST OF DRUGS KNOWN TO PROLONG QT/QTC 
INTERVAL (CONTINUED) 
Generic Name 
Brand Names (Partial List) 
Paroxetine 
Paxil®, Aropax®, Pexeva®, Seroxat®, Sereupin® 
Pasireotide 
Signifor® 
Pazopanib 
Votrient® 
Pentamidine 
Pentam® 
Perflutren lipid microspheres 
Definity® 
Pimozide 
Orap® 
Pipamperone (Only on Non-US Market) 
Dipiperon (E.U), Propitan (Japan) 
Posaconazole 
Noxafil®, Posamol® 
Probucol (Removed from Market) 
Lorelco® 
Procainamide 
Pronestyl®, Procan® 
Promethazine 
Phenergan® 
Propofol 
Diprivan®, Propoven® 
Quetiapine 
Seroquel® 
Quinidine 
Quinaglute®, Duraquin®, Quinact®, Quinidex®, Cin-Quin®, 
Quinora® 
Quinine sulfate 
Qualaquin® 
Ranolazine 
Ranexa®, Ranozex® 
Rilpivirine 
Edurant®, Complera®, Eviplera® 
Risperidone 
Risperdal® 
Ritonavir 
Norvir® 
Roxithromycin (Only on Non-US Market) 
Rulide®, Xthrocin®, Roxl-150®, Roxo®, Surlid®, Rulide®, 
Biaxsig®, Roxar®, Roximycinv®, Roxomycin®, Rulid®, 
Tirabicin®, Coroxin® 
Saquinavir 
Invirase®(combo) 
Sertindole (Only on Non-US Market) 
Serdolect®, Serlect® 
Sertraline 
Zoloft®, Lustral®, Daxid®, Altruline®, Besitran®, Deprax®, 
Elrval®, Emergen®, Gladem®, Implicane®, Sedoran®, Sealdin®, 
SerivoLowfin®, Stimuloton®, Tresleen®, Sertralin Bluefish® 
Sevoflurane 
Ulane®, Sojourn® 
Solifenacin 
VESIcare® 
Sorafenib 
Nexavar® 
Sotalol 
Betapace®, Sotalex®, Sotacor® 
Sparfloxacin (Removed from Market) 
Zagam® 
Sulpiride (Only on Non-US Market) 
Dogmatil®, Dolmatil®, Eglonyl®, Espiride®, Modal®, Sulpor® 


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APPENDIX 8. 
LIST OF DRUGS KNOWN TO PROLONG QT/QTC 
INTERVAL (CONTINUED) 
Generic Name 
Brand Names (Partial List) 
Sunitinib 
Sutent® 
Tacrolimus 
Prograf®, Prograf®, Advagraf®, Protopic® 
Tamoxifen 
Nolvadex®(discontinued 6/13), Istubal®, Valodex® 
Telaprevir 
Incivo® 
Telavancin 
Vibativ® 
Telithromycin 
Ketek® 
Terfenadine (Removed from Market) 
Seldane® 
Tetrabenazine 
Nitoman®, Xenazine® 
Thioridazine 
Mellaril®, Novoridazine®, Thioril® 
Tizanidine 
Zanaflex®, Sirdalud® 
Tolterodine 
Detrol®, Detrusitol® 
Toremifene 
Fareston® 
Torsemide 
Demadex®, Diuver®, Examide® 
Trazodone 
Desyrel® (discontinued 6/13), Oleptro®, Beneficat®, Deprax®, 
Desirel®, Molipaxin®, Thombran®, Trazorel®, Trialodine®, 
Trittico®, Mesyrel® 
Trimipramine 
Surmontil®, Rhotrimine®, Stangyl® 
Tropisetron (Only on Non-US Market) 
Navoban®, Setrovel® 
Vandetanib 
Caprelsa® 
Vardenafil 
Levitra® 
Vemurafenib 
Zelboraf® 
Venlafaxine 
Effexor®, Efexor® 
Voriconazole 
VFend® 
Vorinostat 
Zolinza® 
Ziprasidone 
Geodon®, Zeldox® 
 


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APPENDIX 9. NCCN-FACT FLYMSI-18 (VERSION 2)  
Please circle or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
 
 
Not 
at 
all 
A 
little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
 
GP1  
I have a lack of energy...................................  
0  
1  
2  
3  
4  
 
GP4  
I have pain .....................................................  
0  
1  
2  
3  
4  
D 
C2  
I am losing weight .........................................  
0  
1  
2  
3  
4  
R 
Leu1  
I am bothered by lumps or swelling in certain parts 
of my body (e.g., neck, armpits, or groin)  
0  
1  
2  
3  
4  
S 
BMT6  
I get tired easily .............................................  
0  
1  
2  
3  
4  
P 
BP1  
I have bone pain ............................................  
0  
1  
2  
3  
4  
 
HI8  
I have trouble concentrating ..........................  
0  
1  
2  
3  
4  
 
GF5  
I am sleeping well ..........................................  
0  
1  
2  
3  
4  
 
C6  
I have a good appetite ....................................  
0  
1  
2  
3  
4  
D 
GE6  
I worry that my condition will get worse ......  
0  
1  
2  
3  
4  
R 
BRM9  
I have emotional ups and downs ...................  
0  
1  
2  
3  
4  
S 
E 
Leu4  
Because of my illness, I have difficulty planning 
for the future ...................................  
0  
1  
2  
3  
4  
 
Leu5  
I feel uncertain about my future health..........  
0  
1  
2  
3  
4  
T 
GP2  
I have nausea .................................................  
0  
1  
2  
3  
4  
S 
N3  
I worry about getting infections ....................  
0  
1  
2  
3  
4  
E 
GP5  
I am bothered by side effects of treatment ....  
0  
1  
2  
3  
4  
FW 
GF3  
I am able to enjoy life ....................................  
0  
1  
2  
3  
4  
B 
GF7  
I am content with the quality of my life right now 
........................................................  
0  
1  
2  
3  
4  
Abbreviations:  DRS-P = Disease-Related Symptoms Subscale – Physical; DRS-E = Disease-Related Symptoms 
Subscale – Emotional; TSE = Treatment Side Effects Subscale; FWB = Function and Well-Being Subscale English 
(Universal) 03 March 2010 Copyright 2001  
 
 
 


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APPENDIX 10. EQ-5D-3L HEALTH QUESTIONNAIRE  
 
 


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APPENDIX 10. 
EQ-5D-3L HEALTH QUESTIONNAIRE (CONTINUED) 
 
 
 


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APPENDIX 11. EVALUATION OF TOLERABILITY OF ZANDELISIB IN 
COMBINATION WITH RITUXIMAB IN JAPANESE 
SUBJECTS 
Evaluation Part 1:  
Tolerability of zandelisib in combination with R in Japanese subjects will be evaluated in the 
first 3 Japanese subjects who are randomized to the zandelisib in combination with R arm. The 
Safety Review Committee (SRC), which is composed of the Sponsor/in-country caretaker, 
person designated by the Medical Monitor (person in charge from CRO), and the Principal 
Investigators/Investigators, will discuss and evaluate the tolerability of zandelisib in combination 
with R based on the adverse events reported in Cycle 1. Tolerability will be evaluated according 
to the criteria and procedures specified in the SRC Charter. Subject enrollment in Japan will be 
suspended when the start of administration is confirmed for the first 3 Japanese subjects in the 
zandelisib in combination with R arm. If zandelisib in combination with R is tolerated in these 
3 Japanese subjects, enrollment of Japanese subjects in this study will resume. Subjects who 
signed the ICF at the time the first 3 Japanese subjects received zandelisib in combination with R 
can then be enrolled in the study following confirmation of eligibility. Henceforth, if a subject is 
randomized to the zandelisib in combination with R arm, tolerability of zandelisib in 
combination with R will be evaluated in the subject.  
Evaluation Part 2:  
If it is deemed necessary to evaluate tolerability in additional subjects, according to the 
procedures described in Evaluation Part 1, subject enrollment in Japan will be suspended again 
following confirmation that 3 additional subjects were randomized to the zandelisib in 
combination with R arm. Tolerability of zandelisib in combination with R in Evaluation Part 2 
will be evaluated in a total of 6 subjects consisting of 3 subjects in Evaluation Part 1 and 
3 additional subjects in Evaluation Part 2.  
The SRC, will discuss and evaluate the tolerability of zandelisib in combination with R based on 
adverse events reported in Cycle 1. Tolerability will be evaluated according to the criteria and 
procedures specified in the SRC Charter. If zandelisib in combination with R is tolerated, 
enrollment of Japanese subjects in this study will resume. Subjects who signed the ICF at the 
time the first 3 Japanese subjects in the zandelisib in combination with R arm of this Part can 
then be enrolled in the study. Henceforth, if a subject is randomized to the zandelisib in 
combination with R arm, tolerability of zandelisib in combination with R will be evaluated in the 
subject. 
Details for the safety evaluations are described in the SRC Charter.  
 


Signature Page for VV-CLIN-000217 v4.0
Signature Page for VV-CLIN-000217 v4.0
Approval
Richard Ghalie
Clinical
22-Sep-2021 18:51:36 GMT+0000
Approval
Staci Ellis
Regulatory
22-Sep-2021 20:27:32 GMT+0000

SAP_003.pdf: 
 
 
 
 
Statistical Analysis Plan 
 
A PHASE 3, RANDOMIZED, OPEN-LABEL, CONTROLLED, MULTICENTER STUDY 
OF ZANDELISIB (ME-401) IN COMBINATION WITH RITUXIMAB VERSUS 
STANDARD IMMUNOCHEMOTHERAPY IN PATIENTS WITH RELAPSED 
INDOLENT NON-HODGKIN’S LYMPHOMA (INHL) – 
THE COASTAL STUDY 
ZANDELISIB (ME-401) 
NCT 04745832 
 
 
August 26, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11455 El Camino Real, Suite 250, San Diego, CA 92130 USA 
Tel: +1 858 369 7100 Fax: +1 858 369 7101 www.meipharma.com 


Statistical Analysis Plan 
Protocol: ME-401-004 
MEI Pharma, Inc. 
1 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
A Phase 3, Randomized, Open-Label, Controlled, Multicenter Study of 
Zandelisib (ME-401) in Combination With Rituximab Versus Standard 
Immunochemotherapy in Patients With Relapsed Indolent Non-Hodgkin’s 
Lymphoma (iNHL) 
 
 
 
Protocol Number: 
ME-401-004 
Protocol Version: 
Original: 21 July 2020 
Sponsor: 
MEI Pharma, Inc. 
11455 El Camino Real, Suite 250 
San Diego, CA 92130 
Sponsor Representative: 
Joanne Li, PhD 
Ex. Director, Biometrics 
MEI Pharma, Inc. 
Document Date: 
August 26, 2020 
Document Version: 
1.0 


Statistical Analysis Plan 
Protocol: ME-401-004 
MEI Pharma, Inc. 
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CONFIDENTIAL 
 
 
 
SIGNATURE PAGE 
 
 
Sponsor: 
MEI Pharma, Inc. 
Protocol Title: 
A Phase 3, Randomized, Open-Label, Controlled, 
Multicenter Study of Zandelisib (ME-401) in 
Combination With Rituximab Versus Standard 
Immunochemotherapy in Patients With Relapsed or 
Refractory Indolent Non-Hodgkin’s Lymphoma 
(iNHL) 
Protocol Number: 
ME-401-004 
Document Date: 
Version: 
August 26, 2020 
1.0 
Joanne Li 
Sr. Director, Biometrics 
MEI Pharma Inc. 
Signature: 
 
Date: 
 
Igor Gorbatchevsky 
VP, Clinical Development 
MEI Pharma Inc. 
Signature: 
 
Date: 
 


Statistical Analysis Plan 
Protocol: ME-401-004 
MEI Pharma, Inc. 
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TABLE OF CONTENTS 
LIST OF TABLES ...................................................................................................................................... 4 
LIST OF FIGURES..................................................................................................................................... 5 
Abbreviations .............................................................................................................................................. 6 
1. 
Introduction ......................................................................................................................................... 8 
2. 
Objective ............................................................................................................................................. 8 
3. 
Study Design ....................................................................................................................................... 9 
3.1. 
Synopsis of Study Design ............................................................................................................ 9 
3.2. 
Study Schema .............................................................................................................................. 9 
4. 
Analysis Population and Subgroups .................................................................................................. 11 
4.1. 
Analysis Population ................................................................................................................... 11 
4.2. 
Subgroups .................................................................................................................................. 11 
5. 
Endpoints and Definitions ................................................................................................................. 13 
5.1. 
Primary ...................................................................................................................................... 13 
5.2. 
Secondary .................................................................................................................................. 13 
5.3. 
Exploratory ................................................................................................................................ 13 
5.4. 
Definitions ................................................................................................................................. 13 
6. 
Statistical Method .............................................................................................................................. 16 
6.1. 
Sample Size and Power ............................................................................................................. 16 
6.2. 
General Method ......................................................................................................................... 16 
6.3. 
Data Handling ............................................................................................................................ 17 
6.3.1. 
Handling of missing data ................................................................................................... 17 
6.4. 
Subject Disposition .................................................................................................................... 17 
6.5. 
Important protocol Deviations ................................................................................................... 17 
6.6. 
Demographic and baseline characteristics .................................................................................. 18 
6.7. 
Efficacy Analyses ...................................................................................................................... 18 
6.7.1. 
Analysis of primary efficacy endpoints .............................................................................. 18 
6.7.2. 
Analysis of secondary efficacy endpoints .......................................................................... 20 
6.7.3. 
Analysis of exploratory efficacy endpoints ........................................................................ 25 
6.8. 
Safety Analyses ......................................................................................................................... 26 
6.8.1. 
Adverse Events .................................................................................................................. 26 
6.8.2. 
Laboratory Data ................................................................................................................. 27 
6.8.3. 
Vital Signs ......................................................................................................................... 27 
6.8.4. 
Concomitant Medications .................................................................................................. 27 
6.8.5. 
Exposures .......................................................................................................................... 27 
6.9. 
Interim Analysis ........................................................................................................................ 28 
7. 
Changes to Planned Analyses ............................................................................................................ 29 
8. 
References ......................................................................................................................................... 30 


Statistical Analysis Plan 
Protocol: ME-401-004 
MEI Pharma, Inc. 
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LIST OF TABLES 
 
Table 1. Censoring Rules for the Primary Analysis of Progression-free Survival ...................................... 19 
Table 2. Censoring Rules for the Sensitivity Analysis of PFS ................................................................... 20 
Table 3. Censoring Rules for DOR ............................................................................................................ 25 
Table 4. Censoring Rules for TTNT .......................................................................................................... 26 


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MEI Pharma, Inc. 
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LIST OF FIGURES 
Figure 1. Study Schematic ......................................................................................................................... 10 
Figure 2. Illustrative of FWER spending within interim analysis and primary analysis, and between 
primary analysis .......................................................................................................................... 22 
Figure 3. Graphical testing scheme for FWER control withing secondary endpoint family ....................... 22 


Statistical Analysis Plan 
Protocol: ME-401-004 
MEI Pharma, Inc. 
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ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
B 
bendamustine 
C 
cycle 
CHOP 
combination of cyclophosphamide, hydroxydoxorubicin, vincristine and prednisone 
CMH 
Cochran–Mantel–Haenszel 
CR 
Complete Response 
CRR 
Complete Response Rate 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVP 
Combination of Cyclophosphamide, Vincristine, Prednisone 
D 
Day 
DMC 
Data Monitoring Committee 
DOR 
Duration of Response 
DRS-P 
Disease-Related Symptoms Subscale – Physical 
EE 
Efficacy Evaluable 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
HR 
Hazard Ratio 
(i)NHL 
(indolent) Non-Hodgkin Lymphoma 
IPD 
Important Protocol Deviation 
IRRC 
Independent Response Review Committee 
ITT 
Intent to Treat 
KM 
Kaplan-Meier 
L 
lenalidomide 
mAb 
monoclonal antibody 
O 
obinutuzumab 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PK 
pharmacokinetic(s) 
PP 
Per Protocol 
PR 
Partial Response 
PRO 
Patient Reported Outcome 
QoL 
Quality of Life 
R-B 
rituximab plus bendamustine 
R-CHOP 
combination of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone 
R-CVP 
combination of rituximab, cyclophosphamide, vincristine, prednisone 
R-L 
lenalidomide plus rituximab combination therapy 
SAE 
Serious Adverse Event 


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Protocol: ME-401-004 
MEI Pharma, Inc. 
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Abbreviation 
Definition 
SAP 
Statistical Analysis Plan 
TEAE 
Treatment-Emergent Adverse Event 
TTNT 
Time to Next Anti-Lymphoma Treatment 
TTP 
Time to Progression 
WHODRUG 
World Health Organization Drug 


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MEI Pharma, Inc. 
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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to provide details of the statistical analyses 
that have been outlined within the protocol for Study ME-401-004 dated 21 July 2020. The 
scope of this plan includes the safety, efficacy, and key Patient-Reported analysis (PRO). PKPD 
analysis plan will be provided in a separate PKPD analysis plan. Detailed PRO analysis will be 
provided in a separate supplement SAP. 
 
2. Objective 
Primary Objective: 
 
• To demonstrate that zandelisib in combination with Rituxumab [R] is superior to standard 
immunochemotherapy in prolonging PFS as determined by the Independent Response 
Review Committee (IRRC) in previously treated subjects with follicular and marginal zone 
lymphoma 
 
Secondary objectives 
 
• To compare zandelisib + R to standard immunochemotherapy by the following efficacy 
measures 
 
o Complete response rate (CRR), Objective Response Rate (ORR), duration of response 
(DOR) as determined by the IRRC 
 
o Overall survival (OS) 
 
• To evaluate the safety and tolerability of zandelisib in combination with R 
• To evaluate Patient Reported Outcome (PRO) assessment with FlymSI-18 
Exploratory objectives 
 
• To evaluate: 
o PFS, CRR, ORR, and DOR as determined by the Investigator 
 
o ORR at week 24 by the Investigator and by the IRRC 
 
o Time to progression (TTP) by the Investigator and by the IRRC 
 
o Time to next anti-lymphoma treatment (TTNT) 
 
• To correlate zandelisib exposure in plasma with efficacy and safety 


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MEI Pharma, Inc. 
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3. Study Design 
3.1. Synopsis of Study Design 
 
This is an open label, two-arm Phase 3 study in subjects with relapsed or refractory FL or MZL 
to evaluate efficacy and safety of zandelisib in combination with rituximab compared with 
standard immunochemotherapy (R-B [rituximab + bendamustine], or R-CHOP [combination of 
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone]). The subjects must 
have relapsed after ≥1 previous line of therapy; prior therapy must have included anti-CD20 
monoclonal antibody treatment (e.g., R, obinutuzumab [O]) in combination with a 
chemotherapeutic regimen containing an alkylating agent (B or CVP or CHOP or similar), or 
lenalidomide [L]. Subjects will be stratified based on the following criteria: 
 
• Prior treatment regimen: anti-CD20 monoclonal antibody (mAb) in combination with 
non-bendamustine chemotherapy regimen or R-L vs. anti-CD20 mAb in combination 
with B 
• NHL histology: FL vs. MZL 
• Duration of treatment-free interval from the last lymphoma-directed therapy: ≤24 months 
vs. >24 months 
 
Patients who meet the eligibility criteria will be randomly assigned in a 1:1 ratio to one of the 
treatment arms: 
 
• Arm 1: Rituximab plus zandelisib 
• Arm 2: Rituximab plus chemotherapy (CHOP or B) 
During the study, an independent Data Monitoring Committee (DMC) will regularly review 
safety and efficacy data from all subjects as outlined in a separate DMC charter document. 
 
3.2. Study Schema 
 
The study is composed of the following periods (Figure 1): 
 
• Screening: Subjects will be screened during the 28-day period prior to Day 1 (D1) Cycle 1 
(C1) to ensure they meet the entry criteria for the study. 
• Treatment: After meeting eligibility criteria, subjects will be randomized 1:1 the 2 arms. 
Subjects randomized to the comparator arm will be allocated to either R-B or R-CHOP 
according to the treatments they may have received previously. 
o Arm 1 (Rituximab plus zandelisib): Rituximab will be administered for up to a total of 8 
doses in 6 cycles. Zandelisib will be administered 60 mg qd for the first 2 cycles of therapy 
(56 days), then 60 mg for 7 days followed by 21 days off treatment in every 28-day cycle, 
for up to 26 cycles 
o Arm 2: R-B or R-CHOP: R-B will be administered every 4 weeks (q4w) for 6 cycles. R- 
CHOP will be administered once every 3 weeks (q3w) for 6 cycles. 
• Safety Follow-up: 30 days from the last dose of study drug 


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MEI Pharma, Inc. 
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• Efficacy Follow-up: Subjects who discontinue study treatment for any other reason than 
progressive disease (PD) or death will be followed for PFS till PD, death, withdrawal of 
consent, or start of new anti-cancer therapy for lymphoma. 
• Survival follow up: After treatment discontinuation, all subjects will be followed for OS, and 
TTNT, if applicable, every 3 months for 5 years after the last subject started study treatment, 
except for subjects who withdraw consent. 
 
The study duration for primary completion of PFS is approximately 64 months with 36 months 
enrollment period and 28 months follow-up. 
 
Figure 1. Study Schematic 
 
 


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MEI Pharma, Inc. 
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4. Analysis Population and Subgroups 
4.1. Analysis Population 
 
The following analysis populations will be evaluated and used for presentation and analyses of 
the data. 
 
• The intent-to-treat (ITT) population: all subjects who are randomized. 
• Efficacy Evaluable (EE) Population: all subjects who receive at least one dose of study 
drug and have at least one response assessment post baseline 
 
• The safety population: all subjects who were randomized and received at least 1 dose of 
any study drug. 
 
• The PK population is defined as all subjects who had at least two PK samples collected 
and analyzed. 
 
• Per Protocol (PP) Population: all subjects who receive at least one dose of study drug, 
have at least one response assessment after Day 1, and do not have any major protocol 
deviation during the study. 
 
4.2. Subgroups 
 
Exploratory analyses to examine the consistency of the treatment effect for the primary endpoint 
and selected secondary endpoints will be performed within the subgroups defined by each 
stratification factor: 
 
• Prior treatment regimen: anti-CD20 mAb in combination with any chemotherapy 
regimen other than bendamustine/Other vs. anti-CD20 mAb with bendamustine 
• NHL histology: FL vs. MZL 
• Duration of treatment-free interval from the last lymphoma-directed therapy: ≤24 months 
vs. >24 months 
 
For these stratification factors, data collected by CRF will be used in subgroup analyses, if there 
are discrepancies between the CRF and stratification factors used in IWRS. 
 
Additional subgroup analyses for the efficacy endpoints will include, but not limited to the 
following factors: 
 
• Age (≥65, <65) 
• Sex (M, F) 
• Race (White, Asian, other) 
• Geographical region 
• # of prior anti-lymphoma therapies (1, >1) 
• Relapse or refractory to last therapy/regimen prior to study enrollment 
• Longest diameter of the longest node (>=60 mm, <60 mm) at baseline 


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MEI Pharma, Inc. 
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• Longest diameter of the longest node (>=50 mm, <50 mm) at baseline 
• Baseline ECOG status (0, 1) 
• Ann Arbor disease stage (1-2 vs 3-4) 
• Duration of treatment-free interval from the last lymphoma-directed therapy: ≤6 months, 
6-24 months vs. >24 months 
 
Safety endpoints including but not limited to SAEs and Grade 3 and above TEAEs will be 
descriptively summarized within subgroups defined by each stratification factor, and in addition 
defined by the following variables: 
 
• Age (≥65, <65) 
• Sex (M, F) 
• Race (White, Asian, other) 
• Geographical region 
• # of prior anti-lymphoma therapies (1, >1) 
 
In addition to support regional regulatory submissions, key efficacy and safety analyses will be 
performed including all patients in the corresponding regions or countries. 


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MEI Pharma, Inc. 
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5. Endpoints and Definitions 
5.1. Primary 
• Progression Free Survival (PFS) as determined by the IRRC. 
5.2. Secondary 
• Efficacy: CRR, ORR, and DOR as determined by the IRRC 
• OS 
• TEAEs, Serious AEs (SAEs), and laboratory abnormalities 
• PRO– time to deterioration in the 9-item disease-related symptoms subscale-physical 
(DRS-P) subset of FlymSI-18 of ≥5 points 
 
5.3. Exploratory 
• Efficacy: 
o PFS, CRR, ORR, and DOR as determined by the Investigator 
o ORR at 24 weeks by the Investigator and by the IRRC 
o TTP by the Investigator and by the IRRC 
o TTNT 
• Estimates of zandelisib exposure by population PK method and association with efficacy 
and safety variables 
 
5.4. Definitions 
The definitions for the efficacy endpoints are based on Lugano criteria (Error! Reference 
source not found., 2007) and FDA guidance (Error! Reference source not found.Error! 
Reference source not found.Error! Reference source not found.Error! Reference source not 
found.Error! Reference source not found., 2015) and (Error! Reference source not found., 
2018). 
 
PFS 
 
PFS time is measured from randomization date until the date of disease progression or death 
from any cause. Patients who have not progressed and are still alive at the time of analysis will 
be censored at the last disease assessment date indicating the absence of progression. Detailed 
censoring rules are provided in Section 6.7.1. 


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MEI Pharma, Inc. 
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ORR 
 
ORR is defined as the proportion of subjects achieving the best response rating of CR or PR 
based on the Lugano Classification over the entire duration of the study, including the efficacy 
follow-up period. 
 
ORR at Week 24 
 
ORR is defined as the proportion of subjects achieving the best response rating of CR or PR 
based on the Lugano Classification at the Week 24 assessment. 
 
CRR 
 
CRR is defined as the proportion of subjects achieving the best response rating of CR based on the 
Lugano Classification over the entire duration of the study, including the efficacy follow-up 
period. 
 
CRR at Week 24 
 
CRR is defined as the proportion of subjects achieving the best response rating of CR based on the 
Lugano Classification at the Week 24 assessment. 
 
Duration of response (DOR) 
 
DOR is defined as the time from first observed tumor response (CR or PR) until PD. Patients 
who achieved an objective response (PR or CR) and who did not have a PD at the time of 
analysis will be censored at the date of their last documented tumor assessment demonstrating an 
objective response. DOR will only be analyzed for patients with at least one CR or PR. 
 
OS 
 
Overall survival is defined as the time from randomization until death from any cause. Patients 
alive are censored at the last documented alive date. OS is measured in the intent-to-treat 
population. 
 
Time to Progression (TTP) 
 
TTP is defined as the time from randomization to PD. Patients without PD at the time of analysis 
will be censored at the date of their last documented tumor assessment demonstrating no 
evidence of PD. 
 
Time to next anti-lymphoma treatment (TTNT) 
 
Time to next anti-lymphoma treatment (TTNT) is defined as the time from date of randomization 
to date of first documented administration of a new anti-lymphoma treatment (including, but not 
limited to chemotherapy, radiotherapy, radioimmunotherapy or immunotherapy). Patients 
continuing in response or who are lost to follow-up will be censored on their last visit date. 


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MEI Pharma, Inc. 
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Patients who died (due to any cause) before having received a new anti-lymphoma treatment will 
be censored at the date of death. 
 
Time to deterioration in the 9-item DRS-P subset of FlymSI-18 
 
Time to deterioration in the 9-item DRS-P subset of FlymSI-18 is defined as time from 
randomization to first increase of DRS-P score from baseline ≥5 points. 
 
TEAE 
 
A TEAE is defined as an AE starting or worsening per CTCAE grade after the first dose until 30 
days after the last dose of study drug, or start of new anti-cancer therapy, whichever is earlier. 


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MEI Pharma, Inc. 
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6. Statistical Method 
6.1. Sample Size and Power 
The sample size estimation is determined based on the primary endpoint PFS. 
 
It is estimated that approximately 534 subjects will be randomized into this study. 
 
Assuming a hazard ratio (HR) of 0.70, 330 PFS events at primary analysis are required to yield 
87.5% power to detect superiority of zandelisib in combination with rituximab over standard 
immunochemotherapy. 
 
An interim analysis is planned to take place after approximately 248 (75% of the 330 planned) 
PFS events have occurred. If the statistical significance for PFS is not achieved at the interim 
analysis, the primary PFS analysis will be performed after 330 PFS events have been observed. 
 
Assuming a median time to PFS for the control group of 24 months, an accrual duration of 36 
months, and an annual drop-out rate is 3%, a total sample size of approximately 534 is required 
with 28 months minimal follow-up time from the last patient enrolled to conduct the planned 
primary analysis. 
 
OS is a secondary endpoint. The testing procedure for OS and all other secondary endpoints is 
specified in Section 6.7.2. There will be no additional interim looks driven specifically by total 
OS events, as OS will be analyzed at the same time when the interim and primary analysis for 
PFS take place. 
 
6.2. General Method 
Study disposition, patient demographic and baseline characteristic will be analyzed using the ITT 
population. 
 
Efficacy analyses will be performed in the ITT population. 
 
Primary efficacy endpoint and selected secondary efficacy analyses will be performed in the EE 
population and PP population. 
 
Safety analyses will be performed on the Safety Population. 
 
PK analysis will be performed for all subjects in the PK population. 
 
Unless otherwise noted, all analyses will be performed by assigned treatment arm. 
 
Because the objective of the study which is to test the hypothesis that zandelisib in combination 
with rituximab has better clinical activity and risk/benefit profile compared to standard 2nd line 
immunochemotherapy (R-CHOP/R-B) in patients with relapsed FL or MZL, all tests of 
treatment effects will be conducted at a 1-sided alpha level of 0.025, unless otherwise stated. 


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Protocol: ME-401-004 
MEI Pharma, Inc. 
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Primary efficacy and safety analyses will be conducted comparing the 2 treatment groups 
(pooled control versus pooled experimental); however, exploratory analyses will be conducted to 
assess any clinically meaningful differences in treatment effect between zandelisib plus 
rituximab vs. immunochemotherapy in each subgroup defined by prior therapy. If differences 
are present, sensitivity analyses will be performed to account for the heterogeneity in different 
subgroups in order to ensure the overall consistency and robustness of the primary analysis. 
 
Continuous variables will be summarized by the non-missing sample size (n), mean, standard 
deviation, median, first and third quartiles, minimum, and maximum. Categorical variables will 
be summarized by the n and percentage in each category. Time to event endpoints will be 
summarized with hazard ratios, Kaplan-Meier (KM) curves, KM proportions at select time 
points, KM quartiles (when estimable), the number of subjects with events, the number of 
subjects censored, and the pattern of censoring. Point estimates for efficacy endpoints will be 
accompanied by 2-sided 95% confidence intervals including estimates of KM quartiles 
(Brookmeyer and Crowley, 1982), KM proportions (Kalbfleisch and Prentice, 1980), and 
binomial proportions (Clopper CJ and Pearson, 1934). 
 
Hypotheses and/or Estimations 
 
The null hypothesis is that there is no difference between treatment groups with respect to PFS 
versus the alternative hypothesis that rituximab plus zandelisib is superior to rituximab plus 
chemotherapy. The null hypothesis will be rejected if the p-value from a one-sided stratified log- 
rank test is less than the value specified by the alpha spending function specified in Section 6.7.1 
at the given analysis (interim or primary). 
 
6.3. Data Handling 
6.3.1. Handling of missing data 
 
Rules for handling missing data related to endpoints are described in the endpoint definitions 
(Section 5) or in the description of analyses. If dates are partially provided, provide the worst 
case scenario. If a date is missing, provide the last day of month. If a month is missing, provide 
the last month of year. If a year is missing, then the date will not be imputed. 
 
6.4. Subject Disposition 
The number and percent of subjects who were screened, randomized, received protocol-specified 
therapy along with the reasons for discontinuing protocol-specified therapy and discontinuing 
study will be summarized by treatment group. The number and percent of subjects randomized 
will be tabulated by study site. Key study dates for the first subject randomized, last subject 
randomized, and data cut-off date for analysis will be presented. 
 
6.5. Important protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before the first 
subject’s visit and updated during the IPD reviews throughout the study prior to database lock. 


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These definitions of IPD categories, sub-category codes and descriptions will be used during the 
course of the study. 
 
6.6. Demographic and baseline characteristics 
Demographic (ie, age, age group [<65, ≥65], sex, race, and geographical region) and baseline 
disease characteristics (including but not limited to the randomization factors) will be 
summarized by treatment group and overall using descriptive statistics for the ITT population. 
 
6.7. Efficacy Analyses 
6.7.1. Analysis of primary efficacy endpoints 
 
The primary endpoint in this study is PFS. PFS time is measured from randomization date until 
the date of disease progression, or death from any cause. Subjects who discontinue study 
treatment for any other reason than progressive disease (PD) will be followed for PFS. Detailed 
censoring rules are specified in Table 1 (FDA guidance [FDA, 2015] and [FDA, 2018]). 
 
The PFS analysis to test the superiority of zandelisib in combination with rituximab to standard 
immunochemotherapy in prolonging PFS time will use the log-rank test stratified by the 
following randomization factors: 
 
The Kaplan-Meier (KM) method will be used to estimate the median time to PFS with 95% CI. 
Landmark PFS rates at Years 1,2 and 3 will be estimated for each treatment group and compared 
by chi-squared test based on the LOGLOG transformation of the corresponding rates. 
 
The Cox proportional hazard model will be used to estimate the hazard ratio and corresponding 
95% confidence interval with Wald’s test p-value after stratifying for the same randomization 
factors. Additional covariates will be considered in the Cox model in exploratory analyses, eg., 
demographical variables and baseline disease characteristics. 
 
In addition, accounting for violation of proportional hazard ratio assumption and considering 
potential delayed treatment effect, stratified Fleming(0,1) test (Fleming and Harrington, 1981) 
which gives more weight to later events will be utilized as a sensitivity analysis: 
 
proc lifetest data=datasetname ; 
time time_variable*censor_variable(list of censored values); 
strata strat_variable_1 strat_variable_2 strat_variable_3 
/group=tx_variable test=Fleming(0,1) 
run; 


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Table 1. Censoring Rules for the Primary Analysis of Progression-free Survival 
 
Situation 
Date of Event or Censoring 
Outcome 
Progression documented 
Date of earliest assessment which revealed 
progression determined by the IRRC 
Event 
Death before first PD 
assessment 
Date of death 
Event 
Death between adequate 
assessment visits 
Date of death 
Event 
Incomplete or no baseline 
tumor assessments 
Randomization 
Censored 
No progression, nor death 
Date of last adequate assessment with evidence of 
no progression by the IRRC 
Censored 
Treatment discontinuation for 
any reason other than 
documented PD or death 
Date of last adequate assessment with evidence of 
no progression by the IRRC 
Censored 
New anti-lymphoma treatment 
started without evidence of PD 
by IRRC 
Date of last adequate assessment with evidence of 
no progression by the IRRC before the start of 
new anti-lymphoma treatment 
Censored 
Death or progression after two 
or more consecutive missed 
scheduled visits 
Date of last adequate assessment with evidence of 
no progression by the IRRC 
Censored 
 
Every effort will be made to minimize missing data for PFS assessment. The follow-up time and 
the reason for censoring will be summarized for the 2 treatment arms and the impact on PFS 
outcome will be assessed. 
 
Sensitivity analysis will be conducted to evaluate the robustness of the primary analysis results, 
by considering all progressions and deaths as events per European Medicines Agency (EMA) 
guidance (EMA, 2013), regardless of whether they occurred after initiating next anti-lymphoma 
treatment, after 2 or more consecutive missed scheduled assessments, or being reported as 
clinical (non-IRRC reviewed radiographic) progression. 
 
Below are the censoring rules for sensitivity analysis of PFS: 


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Table 2. Censoring Rules for the Sensitivity Analysis of PFS 
 
Situation 
Date of Event or Censoring 
Outcome 
Progression documented 
Date of earliest assessment which revealed 
progression determined by the IRRC 
Event 
Death before first PD 
assessment 
Date of death 
Event 
Death between adequate 
assessment visits 
Date of death 
Event 
Incomplete or no baseline 
tumor assessments 
Randomization 
Censored 
No progression, nor death 
Date of last adequate assessment with evidence of 
no progression by the IRRC 
Censored 
Treatment discontinuation for 
any reason other than 
documented PD or death 
Date of last adequate assessment with evidence of 
no progression by the IRRC 
Censored 
New anti-lymphoma treatment 
started * 
Date of earliest assessment which revealed 
progression determined by the IRRC or death 
Event 
Death or progression after two 
or more consecutive missed 
scheduled visits * 
Date of earliest assessment which revealed 
progression determined by the IRRC or death 
Event 
Investigator claim of clinical 
progression leading to 
treatment discontinuation * 
Date of clinical progression 
Event 
* Outcome definitions are different from primary analysis of PFS 
 
6.7.2. Analysis of secondary efficacy endpoints 
 
If the statistical significance is successfully met at the interim analysis or the primary analysis, 
the testing of secondary endpoints will proceed, by utilizing a graphical testing procedure. 
 
A graphical multiple testing approach ([Bretz, 2009] and [Alosh, 2014]) will be implemented to 
control the overall Family-wise Error Rate (FWER) pre-specified at interim analysis and primary 
analysis respectively (Figure 2), for all primary and secondary efficacy endpoints (Figure 3). 
This graphical approach is a closed testing procedure; hence, it strongly controls the family-wise 
error rate across all endpoints. Each hypothesis is represented as a node in a graph. Directed 


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arrows between the nodes with associated weights represent how alpha is passed from its initial 
allocation to other nodes, i.e., proportion of the alpha which will be propagated to the 
corresponding endpoint(s). The weights being spent from each node (i.e., going out from each 
node) will sum up to 1. The testing scheme are fully pre-specified by the graph (including nodes, 
arrows, and weights) along with the initial alpha allocation. Figure 3 describes the graphical 
scheme, and pre-specified alpha at interim and primary analysis will be allocated to the primary 
endpoint PFS by IRRC initially. 
 
The testing scheme will be finalized before the database lock for interim analysis. 


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Figure 2. Illustrative of FWER spending within interim analysis and primary analysis, and 
between primary analysis 
 
Family-Wise Error Rate (FWER) = 0.025 one-sided * 
 
Interim Analysis 
𝛼𝛼 = 0.0096 one-sided 
Primary Analysis 
𝛼𝛼 = 0.0221 one-sided 
 
 
*Alpha-spending based on Lan-DeMets O'Brien-Fleming approximation spending function 
 
 
 
Figure 3. Graphical testing scheme for FWER control withing secondary endpoint family 
 
PFS by IRRC 
𝛼𝛼=Pre-specified 𝛼𝛼1 or 𝛼𝛼2 at Interim or Primary Analysis 
 
𝟏𝟏 
 
DOR by IRRC 
 
𝟏𝟏 
 
ORR by IRRC 
 
0.5 
0.5 
 
1 
CRR by IRRC 
 
PRO 
 
𝟏𝟏 
 
OS 
 
*PRO = time to deterioration in the 9-item disease-related symptoms subscale-physical (DRS-P) 
subset of FlymSI-18 of ≥5 points 
Primary Endpoint: 
PFS by IRRC 
𝜶𝜶1 = 𝟎𝟎. 𝟎𝟎𝟎𝟎𝟎𝟎𝟎𝟎 
Secondary Endpoint 
Family 
Primary Endpoint: 
PFS by IRRC 
𝜶𝜶𝟐𝟐 = 0.0221 
Secondary Endpoint 
Family 


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ORR and CRR 
 
Differences in ORR and CRR between treatment groups will be tested using Cochran–Mantel– 
Haenszel (CMH) method stratified by the randomization factors. In addition, the percentage of 
subjects in each treatment group with an OR (or CR) will be summarized with an exact binomial 
95% confidence interval. Subjects missing post-baseline disease assessments will be considered 
not to have achieved OR (or CR). The primary analysis will be performed on the ITT Set. 
Sensitivity analyses may be performed on the EE set and Per Protocol Set. 
 
DOR and OS 
 
DOR and OS will be tested between the two treatment groups using stratified log-rank test. The 
Kaplan-Meier (KM) method will be used to estimate the median OS (or DOR) with 95% CI. 
Landmark overall survival rates at specific time points (Years 2,3,4,5) will be estimated from 
KM curves. 
 
DOR will only include the progressions as determined by the IRRC as events. Subjects without 
progressions documented by the IRRC will be censored. Table 3 provides detailed censoring 
rules for DOR. 
 
OS will be censored at the last date that the subject was known to be alive for subjects who were 
alive at the time of analysis and for subjects who were lost to follow-up. Last date known alive is 
defined as the last valid date of subject assessment prior to or on the data cutoff date in the clinical 
database. For subjects who have withdrawn consent during the study, the last date known alive will 
be the date of consent withdrawal from the study. For all other subjects, the last date known alive 
will be derived by searching through all valid assessment dates in all study datasets to identify the 
last valid subject assessment date available for each subject. If the last valid subject assessment date 
available is on or prior to the data cutoff date, it is used as the last date known alive. If the last valid 
subject assessment date available is after the data cutoff date, the data cut-off date is used as the last 
date known alive. 
 
Patient-Reported Outcome (PRO) Analyses 
 
Time to deterioration in the 9-item DRS-P subset of FlymSI-18 will be summarized by stratified 
log-rank test and KM method. 
Time to deterioration in the 9-item DRS-P subset of FlymSI-18 is defined as time (in months) 
from randomization to the occurrence of one of the following, whichever occurs earliest: 
• First increase of DRS-P score from baseline ≥3 points 
• Disease progression as determined by the IRRC 
• Death from any cause 
For patients without any event of above but had at least one assessment of DRS-P, they will be 
censored at last assessment of DRS-P. For patients without any event of above and no 
assessment of DRS-P, they will be censored at randomization date. 
 
Sensitivity analysis for time to deterioration in the 9-item DRS-P subset of FlymSI-18 may be 
defined by using different threshold (e.g, >=3, 4, 6, or 7 points). 


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Summary statistics will be provided for the 9-item DRS-P subset of FlymSI-18 by visits for both 
treatment arms. 
 
Additional PRO analyses may be specified in a supplemental SAP. 


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Table 3. Censoring Rules for DOR 
 
Situation 
Date of Event or Censoring 
Outcome 
Progression determined by the IRRC 
Date of earliest assessment 
which revealed progression 
determined by the IRRC 
Event 
No progression including 
• No progression determined by the 
IRRC 
• Death with no progression documented 
by the IRRC 
• Treatment discontinuation due to 
progression which was not determined 
by the IRRC 
Date of last adequate assessment 
with evidence of no progression 
by the IRRC 
Censored 
Treatment discontinuation for toxicity or other 
reason 
Date of last adequate assessment 
with evidence of no progression 
by the IRRC 
Censored 
New anti-lymphoma treatment started 
Date of last adequate assessment 
with evidence of no progression 
by the IRRC before the start of 
new anti-lymphoma treatment 
Censored 
Progression after two or more consecutive 
missed scheduled visits 
Date of last adequate assessment 
with evidence of no progression 
by the IRRC 
Censored 
 
 
6.7.3. Analysis of exploratory efficacy endpoints 
 
Exploratory endpoints including TTP, TTNT will be summarized by stratified log-rank test, KM 
method, and Cox proportional hazard model. 
 
The censoring rules for TTP are the same as the ones for DOR (Table 3). 
The censoring rules for TTNT are provided in Table 4. 


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MEI Pharma, Inc. 
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Table 4. Censoring Rules for TTNT 
 
Situation 
Date of Event or Censoring 
Outcome 
Administration of any new anti-lymphoma 
treatment (e.g., chemotherapy, radiotherapy, 
radio-immunotherapy, immunotherapy) 
Date of first administration of the 
treatment 
Event 
Death without any new anti- lymphoma treatment 
Date of death 
Censored 
No Death or new administration of any new anti- 
lymphoma treatment 
Last day know alive 
Censored 
 
6.8. Safety Analyses 
 
All safety summaries and analyses will be based on the Safety Population, defined as all enrolled 
patients receiving at least 1 dose of any study drug. Safety analyses will be performed by 
randomized group. 
 
6.8.1. Adverse Events 
 
Overall summary of subject incidence of AEs will include: 
 
• TEAEs, including severity and possible relationship to study drug and/or study treatment 
• AESI s 
• SAEs 
• TEAEs leading to study treatment discontinuation 
• Deaths during treatment period (from first dose date to 30 days after last dose date of any 
study drug) 
 
• Treatment-emergent changes in laboratory values 
• Treatment-emergent changes in vital signs. 
Time to AESIs will be calculated from the first day of study treatment to first occurrence of 
AESI, utilizing KM method. 
 
Due to likely imbalance of treatment duration between 2 treatment arms, exposure duration 
adjusted analysis will be performed for AESIs and SAEs. The exposure duration adjusted rate is 
defined as the total number of specified events over the total person years, where the person year 
for each individual subject is calculated as the days from first dose till last dose date plus 30 days 
divided by 365.25. The confidence interval will be constructed using exact method with F 
distribution (Ulm, 1990). 


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Safety endpoints including but not limited to SAEs and Grade 3 and above AESIs will be 
descriptively summarized within subgroups defined in Section 4.2. 
 
Listings will be provided for subjects who had SAEs, AEs leading to treatment discontinuation, 
and died during treatment period. 
 
6.8.2. Laboratory Data 
 
Shift tables between the worst post-baseline and baseline grades for select laboratory parameters. 
Plots or other summaries overtime will be presented for select laboratory parameters including 
but not limited to white blood cell, absolute lymphocyte count, absolute neutrophil count, 
platelets, hemoglobin, alanine transaminase, aspartate transaminase, and creatinine by treatment 
group. 
 
6.8.3. Vital Signs 
 
The number and percentage of subjects with abnormal changes in systolic blood pressure, 
diastolic blood pressure and heart beat rate will summarized by treatment group for subjects in 
the Safety Population. 
 
6.8.4. Concomitant Medications 
 
The number and proportion of subjects receiving concomitant medications from study day 1 
through end of treatment will be summarized by preferred term as coded by the World Health 
Organization Drug (WHODRUG) dictionary by treatment group in the Safety Population. 
 
In addition, the number and proportion of subjects receiving other anti-cancer therapies during 
efficacy and survival follow-up will be summarized by WHODRUG preferred term for each 
treatment group in the Safety Set. 
 
6.8.5. Exposures 
 
Descriptive statistics will be produced to describe the exposure to study drugs by treatment group 
for subjects in the Safety Population. For both treatment groups, the number of cycles of 
protocol-specified therapy administered will be summarized. In addition, the duration of 
therapy, the cumulative dose, and treatment compliance (proportion of actual dose /intended 
dose) will be summarized for both arms. The number and percent of subjects with dose 
modifications (eg, dose changes, dose interruptions) and reason for modification will be 
summarized for both treatment groups. 


Statistical Analysis Plan 
Protocol: ME-401-004 
MEI Pharma, Inc. 
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6.9. Interim Analysis 
A group-sequential design by including 1 interim analysis and 1 primary analysis is planned for 
this study. At each analysis, the hypothesis for the primary endpoint PFS will be tested using a 
1-sided with the family-wise error rate alpha of 0.025 controlled to adjust for multiplicity, 
utilizing Lan-DeMets O'Brien-Fleming approximation spending function. 
 
The interim analysis is planned to take place after approximately 248 (75% of the 330 planned) 
PFS events have occurred. The objective of this interim analysis is to examine the efficacy to 
allow an early declaration of success. Based on our estimated recruitment velocity and PFS 
event rates, the planned interim analysis will occur after all subjects have been enrolled and a 
projected median time on study of approximately 30 months (range: 12-48). Also, it is 
anticipated that all subjects randomized to the control arm would have completed their treatment 
regimen at the planned interim analysis. 
 
If the statistical significance for PFS is not achieved at the interim analysis, the primary PFS 
analysis will be performed after 330 PFS events have been observed. The alpha-spending for the 
interim and primary analyses will be 0.0096 and 0.0221 if the two analyses are performed at 
exactly 248 and 330, respectively. The actual boundary for the final analysis will be calculated 
based on the actual number of events observed at the time of each analysis using software that 
implements the alpha-spending scheme noted above (for example SAS or similar software). 
 
The interim PFS analysis will be performed by the DMC. 
 
Once statistical significance is successfully met at the interim analysis or the primary analysis, 
the study will be declared positive based on the primary endpoint of PFS, and the testing of 
secondary endpoints will proceed. 


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MEI Pharma, Inc. 
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7. Changes to Planned Analyses 
No changes in the planned analysis have been made at this time. 


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8. References 
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Statistics in Medicine, 33:693-713. 
 
Bretz F, Maurer W, Brannath W, Posch M (2009) A graphical approach to sequentially rejective 
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Brookmeyer R, & Crowley J (1982). A Confidence Interval for the Median Survival 
Time. Biometrics, 38(1): 29-41. 
 
Cheson BD, Pfistner B, Juweid ME (2007). Revised response criteria for malignant lymphoma. 
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Clopper C, Pearson E (1934). The Use of Confidence or Fiducial Limits Illustrated in the Case of 
the Binomial. Biometrika, 26(4): 404-413. 
 
EMA (2013) Appendix 1 to the guideline on the evaluation of anticancer medicinal products in 
man (CHMP/EWP/205/95 Rev.4): methodological considerations for using progression-free 
survival (PFS) or disease-free survival (DFS) in confirmatory trials. 
EMA/CHMP/27994/2008/Rev.1. 
 
FDA 2015 Guidance for Industry: Clinical Trial Endpoints for the Approval of Non-Small Cell 
Lung Cancer Drugs and Biologics 
 
FDA 2018 Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics 
 
Fleming TR and Harrington DP (1981). “A Class of Hypothesis Tests for One and Two Samples 
of Censored Survival Data”. Communications in Statistics—Theory and Methods, 10: 763–794. 
 
Kalbfleisch JD, Prentice RL (1980). The statistical analysis of failure time data. John Wiley & 
Sons. 
 
Ulm K (1990). A simple method to calculate the confidence interval of a standardized mortality 
ratio. American Journal of Epidemiology, 131(2):373-375.