Conditions: Non Hodgkin Lymphoma
Keywords: Non-Hodgkin lymphoma, Tenalisib RP6530
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

Brief summary:
To assess the anti-tumor activity and safety of Tenalisib in patients with relapsed/refractory indolent Non-Hodgkin's Lymphoma (iNHL),

Detailed description:

Arms:
arm 1: Participants receive Tenalisib 800 mg BID in 28-Days Cycle for 8 Cycles

Interventions: intervention 1: Tenalisib,
Intervention descriptions: intervention 1: BID, Orally

Protocol document:
SAP_002.pdf: 
  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1802   
 
Rhizen Pharmaceuticals SA Confidential 
FINAL 1.0 Dated 07AUG2020 
 
                                                                                                                                                                               Page 1 of 20 
 
 
 
 
 
 
 
 
 
PROTOCOL NO. RP6530-1802 
 
 
An Open label, Phase II study to evaluate the efficacy and safety of Tenalisib 
(RP6530), a novel PI3K δ/γ dual inhibitor in adult patients with 
relapsed/refractory indolent Non-Hodgkin’s Lymphoma (iNHL) 
 
 
Statistical Analysis Plan 
 
 
 
Author and Designation: 
Arti Kanujia 
Senior Statistician II 
Covance Scientific Services & Solutions Pvt. Ltd. 
Version and Date 
Final 1.0, 07AUG2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1802   
 
Rhizen Pharmaceuticals SA Confidential 
FINAL 1.0 Dated 07AUG2020 
 
                                                                                                                                                                               Page 2 of 20 
 
 
 
Revision History: 
 
 
VERSION  
CHANGE DESCRIPTION 
AUTHOR 
DATE 
1.0 
Not Applicable 
Arti Kanujia 
07AUG2020 
 
 
 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1802   
 
Rhizen Pharmaceuticals SA Confidential 
FINAL 1.0 Dated 07AUG2020 
 
                                                                                                                                                                               Page 3 of 20 
 
Signature Page  
 
 
Signature above indicates approval of this plan, for the analysis and reporting of this study. Approval of the SAP 
and approval of any subsequent amendments is the responsibility of the Head of Statistics function or equivalent.   
The approver serves as a single point of accountability for approval and must ensure that all relevant functions are 
in agreement with the final SAP. 
 
TITLE  
NAME 
SIGNATURE 
DATE 
Authoring Statistician 
Arti Kanujia 
 
 
Reviewing Statistician 
Shirsendu Sarkar 
 
 
Manager Statistics  
(or equivalent) 
Sponsor Representative 
Dr Prajak Barde 
 
 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1802   
 
Rhizen Pharmaceuticals SA Confidential 
FINAL 1.0 Dated 07AUG2020 
 
                                                                                                                                                                               Page 4 of 20 
 
Table of Contents 
 
1. 
Amendments from Previous Version(s) ......................................................................................... 7 
2. 
Introduction ...................................................................................................................................... 7 
2.1 
Rationale ......................................................................................................................................................................................... 7 
3. 
Study Objectives .............................................................................................................................. 7 
3.1 
Primary Objective ........................................................................................................................................................................ 7 
3.2 
Secondary Objective.................................................................................................................................................................... 7 
4. 
Study Endpoints ............................................................................................................................... 7 
4.1 
Efficacy Endpoints ....................................................................................................................................................................... 7 
4.2 
Safety Endpoints ........................................................................................................................................................................... 8 
5. 
Study Design ..................................................................................................................................... 8 
5.1 
The Expected Duration of Subject Participation and Follow-up ................................................................................ 9 
6. 
Sample Size Considerations ............................................................................................................ 9 
7. 
Analysis Populations ........................................................................................................................ 9 
7.1 
Modified Intent-to-Treat Population (mITT) .................................................................................................................... 9 
7.2 
Per-Protocol (PP) Population ................................................................................................................................................... 9 
7.3 
Safety Population ....................................................................................................................................................................... 10 
7.4 
Full Analysis Set (FAS) ............................................................................................................................................................ 10 
8. 
Randomization and Blinding ........................................................................................................ 10 
9. 
Method of Analysis ........................................................................................................................ 10 
9.1 
Statistical Hypotheses ............................................................................................................................................................... 10 
9.2 
Interim Analysis ......................................................................................................................................................................... 10 
9.3 
Handling of Missing Data ........................................................................................................................................................ 11 
9.3.1 
Missing Dates for Adverse Events and Concomitant Medications ........................................................................... 11 
9.3.2 
Missing Dates for Efficacy Endpoints................................................................................................................................. 12 
9.3.3 
Missing dates for Primary Diagnosis/Prior therapy ...................................................................................................... 12 
10. Statistical Analysis ......................................................................................................................... 12 
10.1 Patient Disposition ..................................................................................................................................................................... 13 
10.2 Demographic and Baseline Characteristics ...................................................................................................................... 13 
10.3 Medical and Surgical History ................................................................................................................................................ 13 
10.4 Prior and Concomitant Medications ................................................................................................................................... 13 
10.5 Efficacy Analysis ........................................................................................................................................................................ 14 
10.5.1 
Objective Response Rate (ORR) ..................................................................................................................................... 14 
10.5.2 
Complete Response (CR) Rate ......................................................................................................................................... 14 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1802   
 
Rhizen Pharmaceuticals SA Confidential 
FINAL 1.0 Dated 07AUG2020 
 
                                                                                                                                                                               Page 5 of 20 
 
10.5.3 
Progression Free Survival (PFS) ..................................................................................................................................... 15 
10.5.4 
Duration of Response (DoR) ............................................................................................................................................. 15 
10.5.5 
Best Overall Response ......................................................................................................................................................... 15 
10.6 Safety Analysis ............................................................................................................................................................................ 15 
10.6.1 
Treatment Exposure and Compliance........................................................................................................................... 16 
10.6.2 
Adverse Events ...................................................................................................................................................................... 16 
10.6.3 
Clinical Laboratory Tests .................................................................................................................................................. 17 
10.6.4 
Physical Examinations ........................................................................................................................................................ 18 
10.6.5 
Vital Signs ............................................................................................................................................................................... 18 
10.6.6 
Electrocardiogram ............................................................................................................................................................... 19 
10.6.7 
ECOG ....................................................................................................................................................................................... 19 
11. Protocol Deviations ........................................................................................................................ 19 
12. Listings ............................................................................................................................................ 19 
13. References ....................................................................................................................................... 20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1802   
 
Rhizen Pharmaceuticals SA Confidential 
FINAL 1.0 Dated 07AUG2020 
 
                                                                                                                                                                               Page 6 of 20 
 
List of Abbreviations 
 
Abbreviation 
Term 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical  
BID 
Twice Daily 
CI 
Confidence Interval 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DoR 
Duration of Response 
DRC 
Data Review Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
FAS 
Full Analysis Set 
FL 
Follicular lymphoma 
IgM 
Immunoglobulin M 
    iNHL 
   Indolent non-Hodgkin’s Lymphoma 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
LPL 
Lymphoplasmacytic lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MRI 
Magnetic Resonance Imaging 
MZL 
Marginal Zone Lymphoma 
NCI 
National Cancer Institute 
ND 
Not Done 
NE 
Not Evaluable 
NHL 
Non-Hodgkin’s Lymphoma 
ORR 
Objective Response Rate 
PET 
Positron Emission Tomography 
PFS 
Progression-Free Survival 
PP 
Per-Protocol 
PR 
Partial Response 
PT 
Preferred Term 
Q1 
First Quartile 
Q3 
Third Quartile 
QTcF 
QT interval with Fridericia's correction 
SAE 
Serious Adverse Events 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SD 
Stable Disease 
SOC 
System Organ Class 
SLL 
Small Lymphocytic Lymphoma 
TEAE 
Treatment-Emergent Adverse Event 
TID 
Thrice Daily 
WHO 
World Health Organization 
WM 
Waldenstrom Macroglobulinemia 
 
 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1802   
 
Rhizen Pharmaceuticals SA Confidential 
FINAL 1.0 Dated 07AUG2020 
 
                                                                                                                                                                               Page 7 of 20 
 
1. 
Amendments from Previous Version(s) 
Not Applicable. 
 
2. 
Introduction 
Note: In this document, any text taken directly from the protocol (Number RP6530-1802, 
Amendment 1 to Version 1.0, Dated 15 March 2018; Amendment Version dated 04 December 
2018) is italicized. 
 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study RP6530-1802. This document may modify the plans outlined in the final 
protocol. 
   
2.1 
Rationale 
Approximately one third of NHLs are indolent. These indolent NHLs (iNHLs) are slow- growing 
tumors with a prolonged natural history, and most patients present with advanced disease. 
iNHLs are highly treatable but rarely cured.  
 
The safety and tolerability of Tenalisib has been established up to doses of 1200 mg BID and 800 
mg TID. In recent study, Tenalisib 800 mg BID (Fasting) is established as a MTD dose in 
patients with T-cell lymphoma. Therefore, Tenalisib (800 mg BID) is considered for this study. It 
is expected that proposed monotherapy has the potential to improve response rates in the 
proposed patient population. 
 
3. 
Study Objectives  
3.1 
Primary Objective 
• To assess the anti-tumor activity of Tenalisib, as determined by the Objective Response 
Rate (ORR), Duration of Response (DoR) and Progression Free Survival (PFS). 
3.2 
Secondary Objective 
• To characterize safety and tolerability of Tenalisib in patients with iNHL. 
4. 
Study Endpoints 
4.1 
Efficacy Endpoints 
• ORR is defined as sum of CR and PR rates and will be assessed according to the Lugano 
Classification for initial evaluation, staging, and response assessment of Non-Hodgkin 
lymphoma. (Cheson-2014) 
 
• CR rate will be assessed according to the Lugano Classification for initial evaluation, 
staging, and response assessment of non-Hodgkin lymphoma. 
 
• DoR is measured from the initial response to disease progression or death. 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1802   
 
Rhizen Pharmaceuticals SA Confidential 
FINAL 1.0 Dated 07AUG2020 
 
                                                                                                                                                                               Page 8 of 20 
 
 
• PFS is defined as the time of the first dose of Tenalisib to disease progression or death. 
4.2 
Safety Endpoints 
• Adverse Event (AE), Grade 3/ 4 AEs, Serious and fatal Adverse Event (SAE), graded using 
NCI CTCAE Version 5.0. 
 
5. 
Study Design 
The study is designed as a Phase II, open label, two parts study in relapsed/refractory iNHL 
patients. The mandatory Part 1 of the study will assess the efficacy and safety of Tenalisib in 
20 patients with iNHL. After all patients enrolled in Part 1 have had the opportunity to provide 
at least three tumor outcome assessments, the Data Review Committee (DRC) will evaluate 
the efficacy (anti-tumor activity) and safety results for each of the subtypes (e.g. FL, MZL or 
WM). If the committee believes there are potential clinically meaningful responses for certain 
subtype, the committee will recommend initiation of Part 2 to evaluate efficacy and safety for 
that subtype. If not, the study will be terminated without initiating Part 2. The sample size for 
Part 2 will be derived based on the outcome from Part 1. Data from Part 1 will not be included 
in the analysis of Part 2 of the study. 
 
The study treatment Tenalisib (800 mg BID) will be administered orally in 28-days of cycle 
over a period of 8 months in absence of definitive disease progression or unacceptable toxicity. 
Treatment will be continued in patients experiencing clinical benefit until the occurrence of 
definitive disease progression, unacceptable toxicity, or withdrawal from the study due to 
investigator decision or other reasons; maximum for up to 24 months. 
 
The efficacy response will be evaluated on Weeks 8 (C3D1± 7 days), Weeks 16 (C5D1± 7 
days) and then every 12 weeks thereafter, and/ or at the EOT or as clinically indicated (if 
clinical progression is suspected or for confirmation of complete response/disease 
progression).  
 
Group 
N 
Patient population 
Tenalisib 
Part 1 
20 
Refractory/ relapsed iNHL. 
800 mg BID in 28-Days 
Cycle for 8 Cycles1 
Part 2 
The sample 
size will be 
derived based 
on the outcome 
from Part 1 
Refractory/ relapsed iNHL 
patients of one of the specific 
subtype (e.g. FL, MZL, WM) 
800 mg BID in 28-Days 
Cycle for 8 Cycles1 
1Post cycle 8, treatment will be continued in patients experiencing clinical benefit up to 24 months 
unless progression of disease or toxicity warranting discontinuation of therapy. The decision to 
continue the treatment will be determined by the PI after consultation with Sponsor on case to case 
basis. 
 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1802   
 
Rhizen Pharmaceuticals SA Confidential 
FINAL 1.0 Dated 07AUG2020 
 
                                                                                                                                                                               Page 9 of 20 
 
5.1 The Expected Duration of Subject Participation and Follow-up 
The expected duration of subject participation in the study will be 8 months. Treatment will be 
continued in patients experiencing clinical benefit up to 2 years unless progression of disease 
or toxicity warranting discontinuation of therapy. The decision to continue the treatment will 
be taken by PI after consultation with sponsor on case to case basis. 
Notes:  
• After reviewing the emerging efficacy data, the study has been closed due to absence of 
clinically meaningful response to single agent Tenalisib in Part 1 of the study. Therefore, 
Part 2 will not be performed. 
• The analysis proposed in this SAP is considering the available data at the time of 
completion of the study. 
• The data on DLT was erroneously captured on the CRF and which is not applicable for 
this study.  Hence, the DLT information will not be displayed in any of the reports.  
 
6. 
Sample Size Considerations 
The sample size for Part 1 is not based on statistical considerations. After all patients enrolled 
in Part 1 had the opportunity to provide at least three tumor outcome assessments, the DRC 
will evaluate the efficacy and safety results for each of the subtypes. If the committee believes 
there are potential clinically meaningful benefits for certain subtype, the committee will 
recommend initiation of Part 2 to evaluate efficacy and safety for that subtype. The sample size 
for Part 2 will be derived based on ORR data from Part 1. 
Part 1: 20 patients with relapsed/refractory iNHL will be enrolled. 
 
Part 2 will not be initiated as the study is closed due to absence of clinically meaningful 
response to single agent Tenalisib  
 
7. 
Analysis Populations 
The following 4 analysis populations are planned for Part 1 of the study.  
 
7.1 
Modified Intent-to-Treat Population (mITT) 
The mITT is the primary efficacy analysis population and will include data from all patients who 
received at least 1 dose of study medication and provide at least 1 post-baseline efficacy 
assessment. 
 
7.2 
Per-Protocol (PP) Population 
The PP Population is a subset of the modified Intent-to-Treat Population and will include 
patients without major protocol deviations. 
Major deviations shall include: 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1802   
 
Rhizen Pharmaceuticals SA Confidential 
FINAL 1.0 Dated 07AUG2020 
 
                                                                                                                                                                               Page 10 of 20 
 
- Deviation from an IEC/IRB approved protocol which compromise the safety and welfare of 
participating subjects or the integrity of the study and /or the completeness, accuracy and 
reliability of study data.  Examples deviations included but not limited to: 
o Failure to obtain informed consent (e.g., there is no documentation of informed 
consent) for a subject;  
o Informed consent is obtained after initiation of study procedures;  
o Enrollment of subject who has failed to meet the inclusion/exclusion criteria. 
 
The list of protocol deviations with categorization with respect to major and minor deviations 
will be generated. This population will also be used for efficacy assessment. 
 
Note: In situation, the patients qualifying for mITT set are same as the patients qualifying for PP 
set, the respective tables and figures proposed using PP set will not be produced to avoid the 
duplication of the results. 
 
7.3 
Safety Population 
The Safety Population will include all subjects who receive at least 1 dose of the study drug. 
 
7.4 
Full Analysis Set (FAS) 
The FAS includes all the patients who sign the Informed Consent Document and are enrolled 
into the study. This set will be used for reporting patient demographic data and any available 
patient baseline characteristics as captured in the Case Report Form (CRF). 
 
Membership in the analysis populations will be determined before database lock.  
 
8. 
Randomization and Blinding 
This is a non-randomized, open label study. 
 
9. 
Method of Analysis 
9.1 
Statistical Hypotheses 
There are no formal statistical hypotheses. 
 
9.2 
Interim Analysis 
After all patients enrolled in Part 1 have had the opportunity to provide at least three tumor 
outcome assessments, the DRC will evaluate the efficacy (anti-tumor activity) and safety 
results for each of the subtypes. If the committee believes there are potential clinically 
meaningful responses for certain subtype, the committee will recommend initiation of Part 2 
to evaluate efficacy and safety for that subtype. Else, the study will be terminated. 
 
The DRC will continue to monitor safety of Tenalisib (or toxicity trends that may be of concern) 
at interval of approximately 3 months from initiation of study until the completion of the study. In 
the event of one (1) death attributed to the study drug, study accrual will be suspended pending 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1802   
 
Rhizen Pharmaceuticals SA Confidential 
FINAL 1.0 Dated 07AUG2020 
 
                                                                                                                                                                               Page 11 of 20 
 
further investigation, and will only be resumed at the recommendation of the DRC. The DRC will 
have discretion to terminate the trial if an additional death occurs that can be attributed to the 
study drug. 
 
9.3 
Handling of Missing Data 
 
9.3.1 Missing Dates for Adverse Events and Concomitant Medications 
Adverse events and concomitant medications with completely or partially missing assessment 
dates will have imputation performed as explained below for the purposes of calculation of 
durations or relativity to study medication. 
 
For the end of a concomitant medication or adverse event: 
 
• If only Day of end date is missing: 
 The last date of the month and year reported or the date of the final contact with the subject, 
whichever is earlier, will be used as the end date. 
 
• If Day and Month of end date are missing:  
The last date of year i.e. December 31 of the year reported or the date of the last study contact with 
the subject, whichever is earlier, will be used as the end date. 
 
• If Year of end date or complete end date is missing:  
If the year of end of medication/event is missing or end date is completely missing, then no end 
date will be imputed. 
 
For the start of a concomitant medication or adverse event: 
 
• If only Day of start date is missing: 
o If the start year and month of medication/event are the same as that for the first dose 
date, then following approach will be used: 
▪ If the end date of medication/event is NOT before the first dose date or end 
date of medication/event is completely missing, then impute the start day as 
the day of first dose date 
▪ Otherwise, impute the start day as 1. 
 
o If the start year and month of medication/event are NOT same as that for the first 
dose date, then 
▪ Impute the start day as 1. 
 
• If Day and Month of start date are missing: 
 
o If start year of medication/event is same as first dose year, then following approach 
will be used: 
i. 
For medication, impute the start Month as January and the Day as 1 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1802   
 
Rhizen Pharmaceuticals SA Confidential 
FINAL 1.0 Dated 07AUG2020 
 
                                                                                                                                                                               Page 12 of 20 
 
ii. 
For adverse event, 
▪ If the end date of event is NOT before the first dose date or end date of event is 
completely missing, then impute the start Month and Day as the Month and Day of 
first dose date; 
▪ Otherwise, impute the start Month as January and the Day as 1. 
 
o If start year of medication/event is NOT same as first dose year, then 
▪ Impute start Month as January and the Day as 1. 
 
• If Year of start date or complete start date is missing: 
 
If the year of start of medication/event is missing or start date is completely missing, then no 
start date will be imputed. 
 
9.3.2 Missing Dates for Efficacy Endpoints  
For time-to-event endpoints (Progression Free Survival, Overall Response and Duration of 
response), if the date is completely missing, no imputation will be performed. 
 
However, the incomplete/partial dates will be handled following the general conventions as 
detailed in Section 9.3.1. 
 
Patient without measurable and/or assessable lesions will not be assessed for response. 
 
Measurable lesions are defined as those that can be accurately measured in at least two 
dimensions with conventional techniques (CT/PET/PET-CT, MRI, x-ray) or as >1.5 cm with CT 
scan. 
 
9.3.3 Missing dates for Primary Diagnosis/Prior therapy 
Partial Primary diagnosis and prior therapy dates will have imputation performed as explained 
below for the purposes of calculation of relativity to study medication. 
• If only Day is missing, impute the day 1 
• If Day and Month are missing, impute the Month as January and the Day as 1. 
• If the year of primary diagnosis is missing or the date of primary diagnosis is completely 
missing, then no date will be imputed. 
10. 
Statistical Analysis 
Due to early closure of the study, the analysis proposed in the SAP is based on the available data 
at the time of study closure.  
The safety endpoints will be listed and/or summarized. No inferential statistical analyses will be 
performed. 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1802   
 
Rhizen Pharmaceuticals SA Confidential 
FINAL 1.0 Dated 07AUG2020 
 
                                                                                                                                                                               Page 13 of 20 
 
Unless otherwise stated, all statistical analyses will be performed using a two-sided hypothesis 
test at the overall 5% level of significance.  
 
When count data are presented, the percentage will be suppressed when the count is zero in 
order to draw attention to the non-zero counts. A row denoted “Missing” will be included in 
count tabulations where necessary to account for dropouts and missing patients. Unless 
otherwise specified, the denominator for percentages will be the number of patients with a non-
missing assessment in a given treatment group within the analysis population of interest. 
All statistical analyses will be performed using SAS 9.4 or higher. 
 
10.1 
Patient Disposition 
A tabular presentation of the patient disposition data will be provided. It will include the number 
of patients screened, enrolled, assigned treatment, completed, as well as the number of dropouts, 
with reasons for discontinuation, number in each population sets, number of patients with dose 
reductions or interruptions (if applicable), etc. All patients’ data will be used for this report. 
 
10.2 
Demographic and Baseline Characteristics 
Analysis set: FAS 
Demographic and baseline characteristics data will be summarized using descriptive statistics (n, 
mean, Standard Deviation, median, minimum, maximum) for continuous variables, and using 
frequencies and percentages for categorical variables.  
Demographic characteristics will include age, race, gender, height, weight, etc. 
 
Disease characteristics will include time from initial diagnosis to enrollment, Subtype of iNHL, 
Staging, number of prior therapies, (systemic therapy, radiotherapy and cancer surgery), number 
of subject relapsed or refractory to the last therapy, time from date of last therapy to enrollment, 
ECOG performance status, etc. 
 
10.3 
Medical and Surgical History  
Analysis set: FAS 
This data will be summarized using frequencies and percentages by System Organ Class and 
Preferred Term. A listing will also be provided. 
The medical history data will be coded using MedDRA dictionary [Version 23.0 (Hierarchy)]. 
 
10.4 
Prior and Concomitant Medications 
Analysis set: FAS 
Concomitant medications are those that were taken while on study drug. Also, the medications / 
non-drug treatments which start after study treatment end date will be termed as ‘Concomitant’.  


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1802   
 
Rhizen Pharmaceuticals SA Confidential 
FINAL 1.0 Dated 07AUG2020 
 
                                                                                                                                                                               Page 14 of 20 
 
 
Prior medications are those that were taken prior to the initial dose of study drug. 
 
The medication data will be coded using WHO-Drug dictionary (WHODRUG GLOBAL B3 
March 1, 2020) and the non-drug treatments data will be coded using MedDRA dictionary 
[Version 23.0 (Hierarchy)]. 
A summary of frequencies and percentages by ATC level 2 and Preferred Terms and the listing 
of the prior and concomitant treatments taken will be provided.  
 
10.5 
Efficacy Analysis 
Analysis Set: mITT and PP 
• The analysis will be done as per the disease subtypes [Follicular lymphoma (FL), 
Marginal zone lymphoma (MZL), Waldenstrom’s macroglobulinemia (WM) and Small 
lymphocytic lymphoma (SLL)] and overall. 
Note:  The analyses outlined below are subject to availability of adequate data. In absence of 
adequate data, some of the efficacy endpoints discussed below will be presented with basic 
summaries and/or plots and listings, as appropriate. 
 
10.5.1 Objective Response Rate (ORR)  
It is defined as sum of CR and PR rates. Only those patients who have had a pre-treatment 
baseline efficacy evaluation and at least one post-treatment efficacy evaluation or confirmed 
disease progression will be considered evaluable for response. Subtype specific and overall ORR 
will be calculated. 
Additionally, Disease Control Rate (DCR= CR+PR+SD) will be presented. 
This data will be summarized using frequency, and percentage. Due to low number of patients 
observed in each of the disease subtype, the 95% CI (Using exact method based on binomial 
distribution, subject to availability of adequate data) will be presented for the Overall group only.  
 The corresponding listing will also be provided. 
 
10.5.2 Complete Response (CR) Rate 
For assessment of CR, only those patients who have had a pre-treatment baseline efficacy 
evaluation and at least one post-treatment efficacy evaluation or confirmed disease progression 
will be considered evaluable for response.  
This data will be summarized using frequency, and percentage. Due to low number of patients 
observed in each of the disease subtype, the 95% CI (Using exact method based on binomial 
distribution, subject to availability of adequate data) will be presented for the Overall group only.  
 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1802   
 
Rhizen Pharmaceuticals SA Confidential 
FINAL 1.0 Dated 07AUG2020 
 
                                                                                                                                                                               Page 15 of 20 
 
10.5.3 Progression Free Survival (PFS) 
It is defined as time of the first dose of Tenalisib to disease progression or death. Subjects who 
die without a reported prior progression will be considered to have progressed on the date of 
their death. Subjects who did not progress or die will be censored on the date of their last tumor 
assessment. 
This data will be summarized using the Kaplan-Meier method and displayed graphically per the 
disease subtype and Overall.  The following reports will be generated:  
• The Q1, median and Q3 PFS time will be provided. Due to low number of patients observed 
in each of the disease subtype, 95% CI for the Q1, median, and Q3 PFS time will be 
presented for the Overall group only using Brookmeyer-Crowley method subject to 
availability of adequate data. 
• The number and % of patients with disease progressive events (further divided into 
progression or death) will be provided. 
• The number and % of patients censored (further divided by reasons for censoring) will be 
provided. 
• Kaplan-Meier curves will be produced. 
• A listing of PFS data will be provided. 
 
10.5.4 Duration of Response (DoR) 
It is defined as the time when the measurement criteria are first met for PR or CR (whichever is 
reported first) until the date of documented disease progression or death. For subjects who 
neither progress nor die, the duration of response will be censored at the date of their last 
disease assessment. 
This data will be summarized using the Kaplan-Meier method and displayed graphically per the 
disease subtype and overall.  The following reports will be generated:  
• The Q1, median, and Q3 DoR time will be provided. Due to low number of patients 
observed in each of the disease subtype, 95% CI for the Q1, median, and Q3 DoR time will 
be presented for the Overall group only using Brookmeyer-Crowley method subject to 
availability of adequate data. 
• A plot of duration of response will be provided and include each responding patient 
(subject to availability of adequate data). 
 
10.5.5 Best Overall Response 
It is the best response recorded from the start of the treatment until disease progression or 
discontinuation from the study. 
This data will be summarized using frequency and percentage for Complete Response (CR), 
Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD), as captured in the 
CRFs, per the disease subtype and overall. This data will also be listed. 
 
10.6 
Safety Analysis 
Analysis Set: Safety 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1802   
 
Rhizen Pharmaceuticals SA Confidential 
FINAL 1.0 Dated 07AUG2020 
 
                                                                                                                                                                               Page 16 of 20 
 
 
The safety analyses will be reported for Overall patient data only. However, when necessary, 
adverse event data may be reported by disease subtype. 
 
10.6.1 Treatment Exposure and Compliance 
Analysis set: Safety 
Treatment compliance and the treatment exposure will be summarized descriptively (n, mean, 
median, standard deviation, minimum and maximum values) and will also be listed. 
• The treatment exposure to the study medication for subject will be calculated as: 
Exposure (day) = Last day of dosing – First Day of dosing + 1  
 
o A summary of duration of treatment (days) will be provided. In addition, a plot for 
duration on treatment will be provided per patient. 
  
• The treatment compliance percentage (per patient), which is captured in the eCRF, will 
be summarized descriptively per Cycle. This data will be listed for individual patient. 
 
10.6.2 Adverse Events 
Analysis set: Safety 
The frequency of adverse events (AEs) will be computed by counting each patient only once per 
MedDRA [Version 23.0 (Hierarchy)] preferred term and according to the maximum NCI 
CTCAE v.5.0 grade attained by the patient over the specified period. The percentage of patients 
with an event will be calculated using the number of patients in the safety analysis set as the 
denominator. 
 
Standard Summaries of Adverse Events 
 
Treatment Emergent Adverse Events are those that start on or after the date of first dose of study 
medication. 
 
An overall summary of TEAEs (number and percentage of patients along with the number of 
events) will be presented with the following: 
• Any non-TEAE 
• Any TEAE 
• Related TEAEs 
• Serious TEAEs 
• Related Serious TEAEs 
• Grade 3 or Grade 4 TEAEs 
• Related Grade 3 or Grade 4 TEAEs 
• TEAEs leading to discontinuation 
• Related TEAEs leading to discontinuation 
• Serious TEAEs leading to discontinuation 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1802   
 
Rhizen Pharmaceuticals SA Confidential 
FINAL 1.0 Dated 07AUG2020 
 
                                                                                                                                                                               Page 17 of 20 
 
• Related Serious TEAEs leading to discontinuation 
• TEAEs leading to dose interruptions 
• Fatal TEAEs 
• Related Fatal TEAEs 
• Protocol-Defined Adverse Events of Special Interest: 
- Pregnancy, abortion, birth defects/congenital anomalies 
- Overdose 
 
Summaries showing the number of patients (n, %) along with number of events by SOC and PT 
will be provided for the following: 
• TEAEs 
• Grade 3, 4 and 5 TEAEs  
• TEAE by disease subtype 
• Treatment-related TEAEs  
• TEAE with maximum CTCAE grade 
• Treatment-Emergent SAEs  
• Treatment-Related SAEs 
• Treatment-related TEAEs with maximum CTCAE grade 
• Deaths 
 
The adverse events data will also be listed for individual patients. 
• AEs 
• Related TEAEs 
• Treatment Emergent Grade 3, 4 and 5 AEs 
• Treatment Related Grade 3, 4 and 5 AEs 
• Treatment Emergent SAEs 
• Treatment Related SAEs 
• TEAE leading to discontinuation 
 
10.6.3 Clinical Laboratory Tests 
Analysis Set: Safety 
Laboratory data will be presented per cycle. 
The baseline measurement is the last pre-treatment measurement taken on or before Cycle1 
Day1. 
Absolute values and change from baseline values of Laboratory parameters will be presented 
using descriptive statistics (n, mean, median, standard deviation, minimum and maximum 
values).  
The laboratory data will also be listed. 
A separate listing of patients with abnormal laboratory test values will also be presented. 
 
Based on the available data which is captured in the database, the laboratory data will be 
summarized for the following clinical laboratory parameters: 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1802   
 
Rhizen Pharmaceuticals SA Confidential 
FINAL 1.0 Dated 07AUG2020 
 
                                                                                                                                                                               Page 18 of 20 
 
 
Hematology 
Chemistry Panel I 
Chemistry Panel II Urinalysis 
Other 
Hematocrit 
Total bilirubin 
Blood glucose 
Blood 
PT 
Hemoglobin 
Alkaline phosphatase 
(ALP) 
Urea or blood urea 
nitrogen  
Glucose 
INR 
CBC with 
differentials 
Alanine 
aminotransferase 
(ALT) 
Creatinine 
Protein 
 
Platelet count 
Aspartate 
aminotransferase 
(AST) 
Albumin 
Specific gravity 
 
WBC (Total 
and 
differentials) 
Lactate 
dehydrogenase 
(LDH) 
Total protein 
Microscopic 
exam 
Red blood 
cell count 
Gamma- 
glutamyl 
transferase 
GGT) 
Total Cholesterol 
Absolute 
neutrophil 
count 
Sodium 
Triglyceride (TG) 
Absolute 
lymphocyte 
count 
Potassium 
LDL 
 
Calcium 
HDL 
 
Phosphorous 
TSH 
 
Carbon Dioxide 
(CO2) or bicarbonate 
T3 (Total or Free) 
 
Chloride 
T4 (free) 
 
Magnesium 
 
 
10.6.4 Physical Examinations 
Analysis Set: Safety 
Physical examination data will be listed for Screening visit. 
A separate listing of patients with abnormal findings will also be presented. 
 
10.6.5 Vital Signs 
Analysis Set: Safety 
Vitals will include pulse rate, blood pressure, respiratory rate and oral temperature. Weight will 
also be included here.  
 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1802   
 
Rhizen Pharmaceuticals SA Confidential 
FINAL 1.0 Dated 07AUG2020 
 
                                                                                                                                                                               Page 19 of 20 
 
The baseline measurement is the last pre-treatment measurement taken on or before Cycle1 
Day1. 
 
Absolute values and change from baseline values of Vital data will be summarized descriptively 
(n, mean, median, standard deviation, minimum and maximum) per cycle. A listing will also be 
provided. 
 
A separate listing of patients with abnormal vital signs findings will also be presented. 
10.6.6 Electrocardiogram 
Analysis Set: Safety 
• The baseline measurement is the last pre-treatment measurement taken on or before 
Cycle1 Day1. 
• Absolute values and changes from baseline values of ECG parameters [PR Interval, HR 
(heart rate), QT interval, QTcF (QT interval with Fridericia's correction), QRS Duration] 
as collected on CRF will be presented through n, mean, median, standard deviation, 
minimum, and maximum per cycle. 
• A summary of abnormal ECG results will also be provided per cycle including baseline 
visit using frequencies and percentages. 
• A listing of this data will also be provided.  
• A separate listing for the abnormal ECG values will also be presented. 
 
10.6.7 ECOG 
Analysis Set: Safety 
ECOG performance status as captured in the eCRF will be summarized per cycle with number 
and percentage for each status category. This data will also be listed. 
 
The baseline measurement is the last pre-treatment measurement taken on or before Cycle1 
Day1. 
 
11. 
Protocol Deviations 
Analysis set: FAS 
A full list of protocol deviations for the study report will be compiled prior to database closure.  
All deviations will be reviewed by the Medical monitor prior to database closure. Each deviation 
will be categorized as major and minor and a decision will be taken by medical monitor whether 
to include the subject in a PP analysis population. 
Protocol deviations will be presented as number and percentage of patients with minor and major 
deviations in the study. This data will also be listed as appropriate. 
 
12. 
Listings 
In addition to all the listings mentioned above, separate listings will be presented for the following: 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1802   
 
Rhizen Pharmaceuticals SA Confidential 
FINAL 1.0 Dated 07AUG2020 
 
                                                                                                                                                                               Page 20 of 20 
 
• Screened patients 
• Eligibility review 
• Reasons for withdrawal of patient from the study 
• Analysis populations 
• Prior therapy 
• Baseline Serology assessment 
• Cancer diagnosis 
• Study drug exposure 
• Study drug accountability 
• Target lesion assessment 
• Non-target lesion assessment 
• Disease Response assessment 
• Overall tumor assessment 
• Pregnancy test 
• Investigator Comments 
• Patient visits 
• Laboratory IgM levels in LPL/WM patients 
 
13. 
References  
1. Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. Biometrics. 
38: 29-41, 1982. 
 

Prot_000.pdf: 
CONFIDENTIAL 
Page 1 of 62 
                  PROTOCOL NO. RP6530-1802 
 
An Open label, Phase II study to evaluate the efficacy and safety 
of Tenalisib (RP6530), a novel PI3K δ/γ dual inhibitor in adult 
patients with relapsed/refractory indolent Non-Hodgkin’s 
Lymphoma (iNHL) 
 
 
 
This document is a confidential communication of Rhizen Pharmaceuticals S.A.  Acceptance of this 
document constitutes agreement by the recipient that no unpublished information contained herein shall 
be published or disclosed without prior written approval.
PROTOCOL NUMBER 
RP6530-1802 
TRIAL DRUG 
Tenalisib (RP6530)  
IND NUMBER  
124584 
SPONSOR 
Rhizen Pharmaceuticals S.A. 
Fritz-Courvoisier 40, 
Ch-2300 La Chaux-de-Fonds,  
Switzerland. 
PRINCIPAL INVESTIGATOR 
AND STUDY CHAIR  
 
Ian W. Flinn, MD, PhD 
Tennessee Oncology, PLLC 
250 25th Avenue North, Suite 412 
Nashville, TN, USA 
SPONSOR’S MEDICAL 
EXPERT 
Prajak Barde, MD 
Medical Director, Clinical R&D  
Rhizen Pharmaceuticals S.A. 
Fritz-Courvoisier 40, 
Ch-2300 La Chaux-de-Fonds,  
Switzerland. 
DOCUMENT VERSION 
Amendment 1 to Version 1.0, Dated 15 March 2018 
Amendment Version dated 04 December 2018 


Protocol No. RP6530-1802 
                                                     Rhizen Pharmaceuticals SA. 
Amendment 1, 04 December 2018 
Original Version: 1, 15 March 2018 
 
CONFIDENTIAL 
Page 2 of 62 
Clinical Trial Protocol Statement of Compliance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This clinical trial shall be conducted in compliance with the protocol, as referenced herein, 
and all applicable local, national, and international regulatory requirements to include, but 
not be limited to: 
 
 
• 
International Conference on Harmonization (ICH) Guidelines on Good Clinical 
Practice (GCP) 
• 
Ethical principles that have their origins in the Declaration of Helsinki  
• 
<Food and Drug Administration (FDA) Code of Federal Regulation (CFR): 
o 
Title 21CFR Part 50 & 45 CFR Part 46, Protection of Human Subjects 
o 
Title 21CFR Part 54, Financial Disclosure by Clinical Investigators 
o 
Title 21CFR Part 56, Institutional Review Boards 
o 
Title 21CFR Part 312, Investigational New Drug Application 
o 
Title 45 CFR Parts 160, 162, and 164, Health Insurance Portability and 
Accountability Act (HIPAA) 
 
 
As the PI, I understand that my signature on the protocol constitutes my agreement and 
understanding of PI responsibilities to conduct the clinical trial in accordance to the 
protocol and applicable regulations.  Furthermore, it constitutes my understanding and 
agreement that any changes initiated by myself, without prior agreement in writing from 
the Sponsor, shall be defined as a deviation from the protocol, and shall be formally 
documented as such. 
 
 


Protocol No. RP6530-1802 
                                                     Rhizen Pharmaceuticals SA. 
Amendment 1, 04 December 2018 
Original Version: 1, 15 March 2018 
 
CONFIDENTIAL 
Page 3 of 62 
Protocol Approval Page 
An Open label, Phase II study to evaluate the efficacy and safety of 
Tenalisib (RP6530), a novel PI3K δ/γ dual inhibitor in adult patients with 
relapsed/refractory indolent Non-Hodgkin’s Lymphoma (iNHL) 
 
PROTOCOL NUMBER 
RP6530-1802  
TRIAL DRUG(S) 
Tenalisib (RP6530)  
IND NUMBER 
124584 
DOCUMENT VERSION 
Amendment 1 to Version 1.0, Dated 15 March 2018 
Amendment Version dated 04 December 2018 
                     
 
 
 
Prajak Barde, MD 
 
 
 
 
            
_________________________ 
 
 
_________________________________ 
 
Sponsor’s Medical Expert   
 
 
Signature  
 
 
Date 
 
 
Ajit Nair, PhD  
                 
  _________________________                              ___________________________________  
Sponsor’s Representative   
 
 
Signature 
 
 
Date             
 
 
 
 
 
Michael Chen, PhD 
 
 
 
  
          
_________________________ 
 
           ___________________________________  
Bio-statistician 
 
 
 
 
Signature 
 
 
Date             
 
                                     
 
 
 
 
 
 
 
 


Protocol No. RP6530-1802 
                                                     Rhizen Pharmaceuticals SA. 
Amendment 1, 04 December 2018 
Original Version: 1, 15 March 2018 
 
CONFIDENTIAL 
Page 4 of 62 
 
Protocol Acceptance Page 
An Open label, Phase II study to evaluate the efficacy and safety of Tenalisib 
(RP6530), a novel PI3K δ/γ dual inhibitor in adult patients with 
relapsed/refractory indolent Non-Hodgkin’s Lymphoma (iNHL) 
PROTOCOL NUMBER 
RP6530-1802 
TRIAL DRUG(S) 
Tenalisib (RP6530)  
IND NUMBER 
124584 
DOCUMENT VERSION 
Amendment 1 to Version 1.0, Dated 15 March 2018 
Amendment Version dated 04 December 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator 
 Signature 
 
         Date       
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 


Protocol No. RP6530-1802 
                                                     Rhizen Pharmaceuticals SA. 
Amendment 1, 04 December 2018 
Original Version: 1, 15 March 2018 
 
CONFIDENTIAL 
Page 5 of 62 
Amendment History 
 
Amendment#/date 
Reference to 
section 
Summary 
Rationale 
Amendment 1 to 
Version 1.0, Dated 
15 March 2018 
Amendment Version 
dated 04 December 
2018 
 
 
 
General 
information  
Change 
of 
Principal 
investigator 
and 
study 
chair 
Administrative change 
Section 
4.1 
Inclusion criteria  
Inclusion criteria # 7 is 
updated as “The ALT and 
AST should be ≤ 1.5 X 
ULN in absence of liver 
involvement/ metastasis.”   
Patients with history of prior 
chemotherapy may have altered 
liver 
function 
and 
therefore 
inclusion 
criterion 
has 
been 
defined to set an upper limit of 
AST/ALT 
acceptable 
in 
this 
patient population.   
Section 
4.2 
Exclusion 
criteria 
Inclusion criteria # 9 is 
updated 
as 
“Known 
history of severe drug-
induced liver injury…… 
Patient with history of prior 
chemotherapy may have altered 
liver 
function 
and 
therefore 
patients with only severe drug-
induced liver injury will be 
excluded from the study.   
Section 5.2  
Concomitant 
medication  
Concomitant medication 
section is updated as 
“Similarly, 
Dabigatran 
and Edoxaban, Direct-
acting 
Oral 
Anti-
Coagulants (DOAC) class 
of drugs are acceptable”. 
Protocol clarification.  
Dabigatran and Edoxaban are 
acceptable 
as 
they 
are 
not 
metabolized by CYP3A4/CYP2C9 
enzymes. 
Section 5.3  
Prohibited 
medication 
Prohibited 
medication 
section is updated as 
“Apixaban 
and 
Rivaroxaban, DOAC class 
of drugs, are prohibited.    
Protocol clarification. 
Apixaban and Rivaroxaban are 
prohibited as they are metabolized 
by CYP3A4 enzymes. 
Section 6: Trial 
assessment and 
procedure  
The time points of vitals 
and visits are clarified.  
Protocol clarification 
Section 7.6 dose 
modifications  
Dose modifications are 
clarified.  
Protocol clarification 
Throughout the 
document 
Minor 
protocol 
clarifications 
and 
administrative changes 
 
 
 


Protocol No. RP6530-1802 
                                                     Rhizen Pharmaceuticals SA. 
Amendment 1, 04 December 2018 
Original Version: 1, 15 March 2018 
 
CONFIDENTIAL 
Page 6 of 62 
PROTOCOL SYNOPSIS 
Study Title 
An Open label, Phase II study to evaluate the efficacy and safety of Tenalisib 
(RP6530), a novel PI3K δ/γ dual inhibitor in adult patients with 
relapsed/refractory indolent Non-Hodgkin’s Lymphoma (iNHL) 
Phase 
Phase II 
Study 
Sponsor 
Rhizen Pharmaceuticals S.A. 
Study Centers  Approximately 10 sites.  
Study 
Objectives 
Primary objective 
• 
To assess the anti-tumor activity of Tenalisib, as determined by the Objective 
Response Rate (ORR), Duration of Response (DoR) and Progression Free 
Survival (PFS).   
  
Secondary objective 
• 
To characterize safety and tolerability of Tenalisib in patients with iNHL. 
 
Endpoints 
Efficacy:  
• 
ORR is defined as sum of CR and PR rates and will be assessed according to the 
Lugano Classification for initial evaluation, staging, and response assessment of 
Non-Hodgkin lymphoma. (Cheson-2014)  
• 
CR rate will be assessed according to the Lugano Classification for initial 
evaluation, staging, and response assessment of non-Hodgkin lymphoma.  
• 
DoR is calculated as time from the initial response to disease progression or death. 
• 
PFS is calculated as time of the first dose of Tenalisib to disease progression or 
death. 
 
Safety: 
• 
Adverse Event (AE), Grade 3/ 4 AEs, Serious and fatal Adverse Event (SAE), 
graded using NCI CTCAE Version 5.0. 
Study Design 
and 
Procedure 
The study is designed as a Phase II, open label, two parts study in relapsed/refractory 
iNHL patients. The mandatory Part 1 of the study will assess the efficacy and safety of 
Tenalisib in 20 patients with iNHL. After all patients enrolled in Part 1 have had the 
opportunity to provide at least three tumor outcome assessments, the Data Review 
Committee (DRC) will evaluate the efficacy (anti-tumor activity) and safety results for 
each of the subtypes [e.g. follicular lymphoma (FL) or marginal zone lymphoma (MZL) 
or Waldenstrom macroglobulinemia (WM)]. If the committee believes there are 
potential clinically meaningful responses for certain subtype, the committee will 
recommend initiation of Part 2 to evaluate efficacy and safety for that subtype. If not, 
the study will be terminated without initiating Part 2. The sample size for Part 2 will be 
derived based on the outcome from Part 1. Data from Part 1 will not be included in the 
analysis of Part 2 of the study.     
 
The study treatment Tenalisib (800 mg BID) will be administered orally in 28-days of 
cycle over a period of 8 months in absence of definitive disease progression or 
unacceptable toxicity. Treatment will be continued in patients experiencing clinical 
benefit until the occurrence of definitive disease progression, unacceptable toxicity, or 


Protocol No. RP6530-1802 
                                                     Rhizen Pharmaceuticals SA. 
Amendment 1, 04 December 2018 
Original Version: 1, 15 March 2018 
 
CONFIDENTIAL 
Page 7 of 62 
withdrawal from the study due to investigator decision or other reasons; maximum for 
up to 24 months.  
The efficacy response will be evaluated on Weeks 8 (C3D1± 7 days), Weeks 16 (C5D1± 
7 days) and then every 12 weeks thereafter, and/ or at the EOT or as clinically indicated 
(if clinical progression is suspected or for confirmation of complete response/disease 
progression). The details of the study procedures are given in Schedule of Events.  
Group 
N 
Patient population 
Tenalisib 
Part 1 
20 
Refractory/ relapsed iNHL  800 mg BID in 28-Days 
Cycle for 8 Cycles1  
Part 2 (If 
initiated) 
The sample 
size will be 
derived based 
on the outcome 
from Part 1 
Refractory/ relapsed iNHL 
patients of one of the 
specific subtypes (e.g. FL, 
MZL, WM) 
800 mg BID in 28-Days 
Cycle for 8 Cycles1 
 
1Post cycle 8, treatment will be continued in patients experiencing clinical benefit up to 
24 months unless progression of disease or toxicity warranting discontinuation of 
therapy. The decision to continue the treatment will be determined by the PI after 
consultation with Sponsor on case to case basis. 
 
The details of the study procedures are given Schedule of Events. 
No. of 
Patients 
Part 1: 20 patients with relapsed/refractory iNHL will be enrolled.   
Part 2:  The sample size for Part 2 will be determined by the DRC after the committee 
has completed Part 1 analysis. 
Inclusion 
Criteria 
Patients must meet all of the following inclusion criteria to be eligible for participation 
in this study: 
1. Patients with histologically confirmed diagnosis of indolent B-cell NHL, with 
histological subtype limited to: 
• Follicular lymphoma (FL) G1, G2, or G3a 
• Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal) 
• Lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM)  
• Small lymphocytic lymphoma (SLL) with absolute lymphocyte count < 5 x 10^9 
/L at the time of diagnosis and at study entry. 
2. Relapsed or refractory after ≥ 2 prior lines of therapy (refractory defined as not 
responding to a standard regimen or progressing within 6 months of the last course 
of a standard regimen). Patients must have received rituximab and alkylating 
agents.  
3. Patients must have at least one bi-dimensionally measurable lesion (that has not 
been previously irradiated) with the longest diameter ≥ 1.5 cm.  
4. Male or female patients > 18 years of age. 
5. ECOG performance status ≤ 2. 
6. Life expectancy of at least 3 months. 
7. Adequate bone marrow, liver, and renal function as assessed by the following 
laboratory requirements conducted within 7 days before starting study treatment:  
a. Hemoglobin ≥ 9 g/dl 
b. Absolute neutrophil count (ANC) ≥ 1 x 10^9/L 


Protocol No. RP6530-1802 
                                                     Rhizen Pharmaceuticals SA. 
Amendment 1, 04 December 2018 
Original Version: 1, 15 March 2018 
 
CONFIDENTIAL 
Page 8 of 62 
c. Platelets ≥50 x 10^9/L (patient without BM involvement) and 30 x 10^9/L 
(patient with BM involvement) 
d. Total bilirubin ≤1.5 times the upper limit of normal (ULN) 
e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x 
ULN if known liver involvement. The ALT and AST should be ≤ 1.5 X ULN 
in absence of liver involvement/metastasis.  
f.  Calculated creatinine clearance ≥ 50 mL/min (as calculated by the Cockcroft-
Gault method) 
8. Ability to swallow and retain oral medication 
9. Female patients who are not of child-bearing potential, and female patients of child-
bearing potential who have a negative serum pregnancy test within 72 hours prior to 
initial trial treatment. Female patients of child-bearing potential, and all male 
partners must consent to use a medically acceptable two methods of contraception 
throughout the study period and for 4 weeks after the last dose of Tenalisib. A barrier 
method of contraception must be included.    
10. Male patients willing to use adequate contraceptive measures throughout the study 
period and for 12 weeks after the last dose of Tenalisib. 
11. Willingness and ability to comply with trial and follow-up procedures, give written 
informed consent 
Exclusion 
Criteria 
1. Histologically confirmed diagnosis of follicular lymphoma grade 3b or transformed 
disease or chronic lymphocytic leukemia (CLL).  
2. Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy, 
immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumor 
embolization) or any cancer investigational drug within 3 weeks (21 days) or 5 half-
lives (whichever is shorter) prior to C1D1. Corticosteroids (prednisone or 
equivalent) at a dose of < 20 mg daily are allowed. Corticosteroid should be 
stabilized for at least 1 week prior to C1D1.  
3. Autologous hematologic stem cell transplant (Auto-SCT) within 3 months from 
C1D1. Patients must not have active graft versus-host disease; 
4. History of an allogeneic bone marrow transplant (Allo-SCT) 
5. Active hepatitis B or C infection. (All subjects must be screened for hepatitis B and 
C up to 28 days prior to C1D1 using the hepatitis viral panel. Subject positive for 
HBsAg or HBcAb will be eligible if they are negative for HBV-DNA. Subject 
positive for HCV IgG will be eligible if they are negative for HCV-RNA);  
6. Known history of human immunodeficiency virus (HIV) infection; 
7. Evidence of ongoing severe systemic bacterial, fungal or viral infection;   
8. Known primary central nervous system lymphoma or known intracranial 
involvement, leptomeningeal metastases or spinal cord compression due to disease 
or any preexisting neurologic manifestations; 
9. Known history of severe drug-induced liver injury; alcoholic liver disease, primary 
biliary cirrhosis, ongoing extrahepatic obstruction caused by stones, cirrhosis of the 
liver or portal hypertension; 
10. Patient with any severe and/or uncontrolled medical conditions or other conditions 
that could affect their participation in the study as per investigator’s judgment;  
11. Patient with symptomatic or history of documented congestive heart failure (NY 
Heart Association functional classification III-IV).  
12. Patient with angina not well-controlled by medication 


Protocol No. RP6530-1802 
                                                     Rhizen Pharmaceuticals SA. 
Amendment 1, 04 December 2018 
Original Version: 1, 15 March 2018 
 
CONFIDENTIAL 
Page 9 of 62 
13. Patient with poorly controlled or clinically significant atherosclerotic vascular 
disease (including cerebrovascular accident, transient ischemic attack or have 
angioplasty, cardiac or vascular stenting) in the past 6 months; 
14. Prior exposure to drug that specifically inhibits PI3K (e.g. Idelalisib, Copanlisib, 
Duvelisib and Umbralisib) 
15. Previous or concurrent malignancy that is distinct in primary site or histology from 
indolent B-cell NHL within 3 years of study enrollment EXCEPT for adequately 
treated basal, squamous cell carcinoma or non-melanomatous skin cancer, 
carcinoma in situ of the cervix, superficial bladder cancer not treated with 
intravesical chemotherapy or BCG within 6 months, localized prostate cancer with 
PSA <1.0 mg/dL on 2 consecutive measurements at least 3 months apart with the 
most recent one being within 4 weeks of study entry;  
16. Patients with seizure disorder requiring medication. 
17. Unresolved toxicity higher than CTCAE grade 1 (NCI-CTCAE version 5.0) 
attributed to any prior therapy/procedure excluding alopecia. 
18. Myeloid growth factors or red blood cells/ platelet transfusion within 14 days prior 
to C1D1. 
19. Administration of any of the following within 1 week prior to C1D1: 
a. Strong inhibitors or inducers of CYP3A4, including grapefruit products, herbal 
medications. 
b. Strong inhibitors or inducers of CYP2C9, including herbal medications. 
c. Substrates of CYP3A4 enzyme with a narrow therapeutic range (e.g. Warfarin 
and phenytoin)  
20. Pregnant or lactating woman; 
21. Inability or unwillingness to comply with study and/or follow-up procedures 
outlined in the protocol; 
22. Concurrent condition that in the investigator’s opinion would jeopardize compliance 
with the protocol. 
Estimated 
Study 
duration 
Part 1:  Approximately 12 months for accrual plus 8 months of follow up 
Part 2:  To be determined. 
Assessment of 
Response  
Response assessments will be performed as per Lugano Classification (Cheson criteria 
2014) at C3D1 (± 7 days), C5D1 (± 7 days) and approximately every 12 weeks thereafter 
(± 7 days), and/ or at the EOT. 
Study 
Treatment  
 
For purposes of this study, each cycle of therapy consists of 4 weeks. Tenalisib will be 
administered in a cycle of 28 days in absence of disease progression and unacceptable 
toxicity.  
Tenalisib tablets will be self-administered orally twice daily one hour before a major 
meal (e.g. breakfast and dinner). Patients should not consume food during this one-hour 
period. 
Statistical 
Analysis 
 
The sample size for Part 1 is not based on statistical consideration.  The sample size for 
Part 2 will be derived based on ORR data from Part 1. 


Protocol No: RP6530-1802 
                                                 Rhizen Pharmaceuticals S.A. 
Amendment 1, 04 December 2018 
Original Version: 1, 15 March 2018 
 
CONFIDENTIAL 
Page 10 of 62 
                                               GENERAL INFORMATION 
SPONSOR 
Rhizen Pharmaceuticals S.A. 
Fritz-Courvoisier 40, 
Ch-2300 La Chaux-de-Fonds,  
Switzerland. 
Tel: +41 32 580 0113 
Fax: +41 32 967 9596 
PRINCIPAL 
INVESTIGATOR AND 
STUDY CHAIR  
 
Ian W. Flinn, MD, PhD 
Tennessee Oncology, PLLC 
250 25th Avenue North, Suite 412 
Nashville, TN, USA 
Tel: +01-615-329-7274 
       +01-615-986-7600 
SPONSOR’S 
REPRESENTATIVE 
Ajit Nair, PhD 
SVP Clinical R&D  
Rhizen Pharmaceuticals S.A. 
Fritz-Courvoisier 40, 
Ch-2300 La Chaux-de-Fonds,  
Switzerland. 
Tel: +41 32 580 0113 
Fax: +41 32 967 9596 
SPONSOR’S MEDICAL 
EXPERT  
Prajak Barde, MD 
Medical Director,  
Rhizen Pharmaceuticals S.A. 
Fritz-Courvoisier 40, 
Ch-2300 La Chaux-de-Fonds,  
Switzerland. 
Tel: +41 32 580 0175 
Fax: +41 32 967 9596 
STATISTICIAN   
Michael Chen, PhD 
Consultant Statistician,  
Tel: +01 908 500 9334 
Fax: +41 32 967 9596 


Protocol No. RP6530-1802                                                                                             Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
CONFIDENTIAL 
Page 11 of 62 
List of Abbreviations 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT (SGOT) 
Alanine aminotransferase 
ANC 
Absolute Neutrophil Count 
aPTT 
Activated Partial Thromboplastin Time 
Allo-SCT 
Allogeneic Hematopoietic Stem Cell Transplantation  
AST (SGPT) 
Aspartate aminotransferase 
AUC 
Area Under the plasma-concentration time curve 
BID 
Twice Daily 
β-HCG 
β-human chorionic gonadotropin 
Cmax 
Peak Drug Concentration 
CBC 
Complete Blood Count 
CLL 
Chronic Lymphocytic Leukemia 
CNS 
Central Nervous System 
CR 
Complete Response 
CrCl 
Creatinine Clearance 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTCL 
Cutaneous T cell Lymphoma 
DLT 
Dose Limiting Toxicity 
DoR 
Duration of Response 
DRC 
Data Review Committee   
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EOS 
End of Study 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FL 
Follicular lymphoma 
FSH 
Follicular Stimulating Hormone 
GCP 
Good Clinical Practices 
GGT 
Gamma Glutamyl Transpeptidase  
G-CSF 
Granulocyte Colony-Stimulating Factor 
GVHD 
Graft Versus Host Disease 
Hb 
Hemoglobin 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HDL 
High-Density Lipoprotein 
HDPE 
High-density Polyethylene 
HEENT 
Head, Eyes, Ears, Nose and Throat 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immune Deficiency Virus 
HPV 
Human Papilloma Virus 
IB 
Investigator brochure  
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee 
INR 
iNHL 
International Normalized Ratio 
Indolent non-Hodgkin’s Lymphoma 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
LDH 
Lactate Dehydrogenase 
LDL 
Low-Density Lipoprotein 


Protocol No. RP6530-1802                                                                                             Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
CONFIDENTIAL 
Page 12 of 62 
LLN 
Lower Limit of Normal  
LMWH 
Low Molecular Weight Heparin 
LPL 
Lymphoplasmacytic lymphoma 
MCL 
Mantle Cell Lymphoma  
MM 
Multiple Myeloma  
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MRI 
Magnetic Resonance Imaging  
MZL 
Marginal Zone Lymphoma 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NOAEL 
No-Observed-Adverse Effect Level 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
NYHA 
New York Heart Association 
ORR 
Objective Response Rate 
pAKT 
PhosphoAKT 
PCP 
Pneumocystis Carinii 
PET 
Positron Emission Tomography 
PFS 
Progression-Free Survival 
PI 
Principle Investigator 
PI3K 
Phosphoinositide-3-Kinase 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PR 
Partial Response 
PTCL 
Peripheral T-Cell Lymphoma 
QA 
Quality Assurance 
QTcF 
Frederica’s (QTcf)  
SAE 
Serious Adverse Events 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SD 
Stable Disease  
SDV 
Source Document Verification 
SLL 
Small Lymphocytic Lymphoma 
SOP 
Standard Operating Procedures 
SUV 
Standardized Uptake Value 
t1/2 
Plasma Half Life 
tmax 
Time to maximum plasma concentration  
TAM 
Tumor Associated Macrophages 
TEAE 
Treatment-Emergent Adverse Event 
TG 
Triglyceride 
TIA 
Transient Ischemic Attack 
TID 
Thrice Daily 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
USP 
United States Pharmacopeia 
UV 
Ultra-violet 
WBC 
White Blood Cells 
WHO 
World Health Organization  
WM 
Waldenstrom macroglobulinemia  


Protocol No. RP6530-1802                                                                                             Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
CONFIDENTIAL 
Page 13 of 62 
TABLE OF CONTENTS  
1 
Background Information ...................................................................................................... 17 
1.1 
Tenalisib (RP6530) .................................................................................................... 17 
1.1.1 Summary of pre-clinical evaluation ................................................................. 17 
1.1.2 Summary of clinical evaluation ........................................................................ 17 
1.2 
Study Rationale .......................................................................................................... 19 
1.2.1 Rationale for study population ......................................................................... 19 
1.2.2 Rationale for dose selection for Tenalisib ........................................................ 19 
1.3 
Benefit and Risk ......................................................................................................... 19 
2 
TRIAL OBJECTIVES ......................................................................................................... 20 
2.1 
Primary Objective ...................................................................................................... 20 
2.2 
Secondary Objective ................................................................................................ 20 
3 
TRIAL DESIGN .................................................................................................................. 20 
3.1 
Trial End Points ......................................................................................................... 20 
3.2 
Design of Trial ........................................................................................................... 20 
3.3 
Data Review Committee (DRC) ................................................................................ 21 
3.4 
Randomization and Blinding ..................................................................................... 21 
3.5 
Investigational Medicinal Product ............................................................................. 21 
3.5.1 Dosage form and strengths ............................................................................... 21 
3.5.2 Labeling, packaging and supply ....................................................................... 22 
3.5.3 Preparation and administration of Investigational Products ............................. 22 
3.5.4 Accountability of Investigational Products ...................................................... 22 
3.5.5 Precautions and risks associated with Investigational Products ....................... 22 
3.6 
The Expected Duration of Subject Participation and Follow-up ............................... 23 
3.7 
Study Stopping Rules ................................................................................................. 23 
4 
SELECTION AND WITHDRAWAL of SUBJECTS ......................................................... 24 
4.1 
Inclusion Criteria........................................................................................................ 24 
4.2 
Exclusion Criteria ...................................................................................................... 25 
4.3 
Discontinuation from Trial Treatment ....................................................................... 26 
5 
TREATMENT OF SUBJECTS ........................................................................................... 26 
5.1 
Administration of Tenalisib ....................................................................................... 26 
5.2 
Concomitant Medications .......................................................................................... 26 


Protocol No. RP6530-1802                                                                                             Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
CONFIDENTIAL 
Page 14 of 62 
5.3 
Prohibited Medications .............................................................................................. 27 
5.4 
Procedures for Monitoring Subject Compliance. ....................................................... 28 
6 
TRIAL ASSESSMENT AND PROCEDURE ..................................................................... 28 
6.1 
Overview ................................................................................................................... 28 
6.2 
Screening and on Treatment Procedures............................................................... 33 
6.2.1 Informed consent .............................................................................................. 33 
6.2.2 Assignment of screening number ..................................................................... 33 
6.2.3 Medical history ................................................................................................. 33 
6.2.4 Prior and concomitant medication review ........................................................ 33 
6.2.5 Prior therapies details ....................................................................................... 34 
6.2.6 Physical examination ........................................................................................ 34 
6.2.7 Vital signs ......................................................................................................... 34 
6.2.8 Laboratory safety evaluations ........................................................................... 34 
6.2.9 ECG 35 
6.3 
Eastern Cooperative Oncology Group (ECOG) Performance Status ........................ 35 
6.4 
Radiological Evaluation ............................................................................................. 36 
6.5 
Trial Treatment Period ........................................................................................... 36 
6.6 
Treatment Beyond Cycle 8 (Cycle 9 onward up to Cycle 26) .............................. 36 
6.7 
End of Trial Treatment (EOT) ............................................................................... 36 
6.8 
End of Study (EOS) ................................................................................................... 37 
6.9 
Early Patient Termination / Patient Withdrawal ................................................. 37 
7 
ASSESSMENT OF SAFETY .............................................................................................. 37 
7.1 
Adverse Events .......................................................................................................... 37 
7.1.1 Definitions of adverse events ........................................................................... 37 
7.1.2 Recording of adverse events ............................................................................. 37 
7.1.3 Handling of adverse events .............................................................................. 37 
7.2 
Adverse Event/Serious Adverse Event Causality Assessment .................................. 38 
7.3 
Serious Adverse Events ............................................................................................. 38 
7.3.1 Definitions of serious adverse events ............................................................... 38 
7.3.2 Serious adverse event reporting by Investigators ............................................. 39 
7.3.3 Sponsor SAE reporting requirements ............................................................... 40 
7.4 
Recording of Adverse Events and Serious Adverse Events ...................................... 40 


Protocol No. RP6530-1802                                                                                             Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
CONFIDENTIAL 
Page 15 of 62 
7.4.1 Diagnosis vs. signs and symptoms ................................................................... 40 
7.4.2 Persistent or recurrent adverse events .............................................................. 40 
7.4.3 Abnormal laboratory values ............................................................................. 40 
7.4.4 Deaths 41 
7.4.5 Hospitalization, prolonged hospitalization, or surgery ..................................... 41 
7.4.6 Pre-Existing medical conditions ....................................................................... 41 
7.4.7 Pregnancy, abortion, birth defects/congenital anomalies ................................. 41 
7.4.8 New Cancers ..................................................................................................... 41 
7.4.9 Lack of efficacy ................................................................................................ 42 
7.5 
Protocol-Defined Events of Special Interest .............................................................. 42 
7.5.1 Pregnancy, abortion, birth defects/congenital anomalies ................................. 42 
7.5.2 Overdose ........................................................................................................... 42 
7.6 
Dose Modifications .................................................................................................... 43 
7.6.1 Criteria for starting Tenalisib new cycle .......................................................... 43 
7.6.2 Dose modifications ........................................................................................... 43 
8 
ASSESSMENT OF EFFICACY ......................................................................................... 45 
8.1 
Specification of the Efficacy Parameters ................................................................... 45 
8.2 
Response Evaluations and Measurements ................................................................. 47 
9 
STATISTICAL METHOD AND CONSIDERATIONS ..................................................... 47 
9.1 
General Considerations .............................................................................................. 47 
9.2 
Determination of Sample Size ................................................................................... 48 
9.3 
Study Population ........................................................................................................ 48 
9.4 
Statistical Analysis ..................................................................................................... 48 
9.4.1 Demographic and baseline characteristics ........................................................ 48 
9.4.2 Safety analyses ................................................................................................. 48 
9.4.3 Efficacy analyses .............................................................................................. 49 
10 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS .......................... 49 
10.1 IRB/IEC Approval ..................................................................................................... 49 
10.2 Regulatory Approval .................................................................................................. 50 
10.3 Insurance and Indemnity ............................................................................................ 50 
10.4 Financial Disclosure and Obligations ........................................................................ 50 
10.5 Informed Consent ....................................................................................................... 50 


Protocol No. RP6530-1802                                                                                             Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
CONFIDENTIAL 
Page 16 of 62 
10.6 Confidentiality ........................................................................................................... 51 
10.6.1 Patient confidentiality .................................................................................... 51 
10.6.2 Investigator’s responsibilities ......................................................................... 51 
10.6.3 Investigator and staff training and information .............................................. 52 
11 
RECORD RETENTION AND DOCUMENTATION OF THE TRIAL ............................ 52 
11.1 Amendments to the Protocol ...................................................................................... 52 
11.2 Protocol Deviations .................................................................................................... 52 
11.3 Documentation Required to Initiate Trial .................................................................. 52 
12 
DATA HANDLING AND RECORD KEEPING ............................................................... 52 
12.1 Data Collection .......................................................................................................... 54 
12.2 Trial Monitoring, Auditing, and Inspecting ............................................................... 54 
12.3 Medical Monitoring ................................................................................................... 55 
12.4 Quality Assurance and Quality Control ..................................................................... 55 
13 
Disclosure and Publication Policy ....................................................................................... 55 
14 
REFERENCES .................................................................................................................... 56 
15 
APPENDICES ..................................................................................................................... 57 
Appendix A: ECOG Performance Status Scale ................................................................ 57 
Appendix B: Contraceptive Guidelines and Pregnancy ....................................................... 58 
Appendix C: Response Criteria for iNHL- (Cheson et. al. 2014) ........................................ 60 
 
List of Tables 
Table 1: Schedule of Events for Part 1 .............................................................................................. 30 
Table 2: Laboratory Tests for Hematology, Chemistry and Urinalysis ................................................. 34 
Table 3: Dose Modifications for Hematologic Toxicity ...................................................................... 43 
Table 4: Dose Modifications for Non-Hematologic Toxicities ............................................................ 44 
 
 
 
 


Protocol No. RP6530-1802                                                                                             Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
CONFIDENTIAL 
Page 17 of 62 
1 BACKGROUND INFORMATION  
1.1 Tenalisib (RP6530) 
The phosphoinositide-3-kinases (PI3Ks) are a family of enzymes involved in various cellular 
functions, including cell proliferation and survival, cell differentiation, intracellular 
trafficking and immunity [1,2,3]. Tenalisib is a highly specific and orally available dual PI3K 
δ/γ inhibitor with nano-molar inhibitory potency and several fold selectivity over α and β 
PI3K isoforms. The specificity of Tenalisib towards PI3K δ and γ is evidenced by >1000 
and >100 fold selectivity over α and β isoforms in an enzyme based assay. Chemically, 
Tenalisib is an iso-flavone substituted adenine.  
 
1.1.1 Summary of pre-clinical evaluation  
Tenalisib has equimolar potency against both PI3K δ/γ isoforms in enzyme, cell, and blood-
based assays. Additionally, the compound inhibited antigen-induced superoxide or cytokine 
release from primary human neutrophils or monocytes at nano-molar concentration 
indicating a potential in modulation of the tumor microenvironment. Studies using 
immortalized B and T lymphoma cell lines demonstrated the anti-proliferative effect of 
Tenalisib coupled with induction of apoptosis and a concomitant inhibition of the 
downstream biomarker, pAKT. Similarly, cytokine induced pAKT was inhibited in 
malignant primary CTCL cells isolated from patient donors. Tenalisib induced apoptosis of 
patient derived primary CTCL cells following 48 hr incubation.  
 
In vivo efficacy of Tenalisib was confirmed in a subcutaneous mouse MOLT-4 xenograft 
model representative of human T-cell acute lymphoblastic leukemia. Oral administration of 
50 mg/kg/BID over an 18-day period resulted in a significant delay in tumor growth [4]. 
 
In 28-days toxicity studies in rat and dog, once daily oral administration of Tenalisib was 
well tolerated. Target organ effects were observed in thyroid and liver. The no-observed-
adverse-effect level (NOAEL) was 20 mg/kg/day in rat and 10 mg/kg/day in dog.  
 
PI3K δ/γ isoforms are known to play a role in modulating the tumor microenvironment. PI3K 
γ is also important for migration and differentiation of tumor-associated myeloid cells. 
Published data has demonstrated that Tumor-Associated Macrophages (TAMs) are reduced 
in PI3Kγ deficient mice resulting in reduced tumor growth. Pre-clinical models demonstrated 
that selective inactivation of macrophage PI3Kγ stimulates and prolongs NFκB activation 
and inhibits C/EBPβ activation, thus promoting an immuno-stimulatory transcriptional 
program that restores CD8+ T cell activation and cytotoxicity. Refer to Investigator’s 
Brochure (IB) for detailed background information on Tenalisib [5].  
 
1.1.2 Summary of clinical evaluation 
To date, Tenalisib has been evaluated in three clinical trials:  
1. A Phase I Dose Escalation Study Evaluating the Safety and Efficacy of RP6530, a dual 
PI3K δ/γ inhibitor, in Patients with Relapsed or Refractory Hematologic Malignancies 
(European study: Protocol Number RP6530-1301) Status: Completed   
2. A Phase I/Ib, Dose Escalation Study to Evaluate Safety and Efficacy of RP6530, a dual 
PI3K δ/γ inhibitor, in Patients with Relapsed or Refractory T-cell Lymphoma (US study: 
Protocol number RP6530-1401). Status: Ongoing 


Protocol No. RP6530-1802                                                                                             Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
CONFIDENTIAL 
Page 18 of 62 
3. An open label, randomized, single dose, crossover study to evaluate food effects on 
relative bioavailability of RP6530 administered in fasting and fed conditions in healthy 
volunteers (Food effect study, Protocol no: RP6530-1501). Status: Completed   
 
• Safety:  
In RP6530-1301 study, Tenalisib demonstrated acceptable safety and tolerability profile up 
to 1200 mg BID and 800 mg TID without any dose limiting toxicity (DLT) in 35 patients 
with relapsed/refractory haematological malignancies. Treatment related Grade ≥ 3 Aes 
were hypertriglyceridemia, neutropenia and diarrhea. Reported SAEs were assessed to be 
not related to Tenalisib but attributed to disease under study/concomitant disease conditions. 
Reported events were consistent with co-morbidities/disease burden in patients with 
relapsed/refractory hematological malignancies.  
 
In an ongoing RP6530-1401 study, a total of 49 patients were treated at 200 mg BID (n=4), 
400 mg BID (n=4), 800 mg BID (Fasting) (n=35) and 800 mg BID (Fed) (n=6) in both dose 
escalation and dose expansion cohorts. Tenalisib demonstrated acceptable safety and 
tolerability profile up to 800 mg BID (fasting). Tenalisib 800 mg BID (Fasting) is considered 
as a MTD dose in patients with T-cell lymphoma. Majority of Aes include transaminitis, 
skin rash and fatigue and nausea. Treatment related Grade ≥ 3 includes AST/ALT elevation 
(n=11), rash (n=3), neutropenia (n=3), hypophosphatemia (n=1), INR Increase (n=1), sepsis 
(n=1) and diplopia secondary to neuropathy (n=1). Treatment related SAE reported were 
fever (n=1), raised INR (n=1), sepsis (n=1) and diplopia secondary to neuropathy (n=1).  
  
• Pharmacokinetics (PK):  
In RP6530-1301 study, maximum systemic exposures were assessed by AUC0-t and Cmax as 
determined on Cycle 1 Day 1 (C1D1) at 25 mg to 1200 mg BID; 600 and 800 mg TID. Based 
on Cmax and AUC dose proportionality was observed up to 400 mg dose. Dose related 
exposure were observed beyond 400 mg. Up on increasing doses, there is no change in 
Tmax   were observed and while there was change in T1/2. Steady state PK parameters of 
Tenalisib as determined on Cycle 2 Day 1 (C2D1) revealed no accumulation. Similar findings 
were seen in ongoing RP6530-1401 study. 
 
• Efficacy:  
In RP6530-1301 study, Tenalisib was evaluated as single agent in 35 heavily pre-treated 
patients with relapsed/refractory (R/R) hematological malignancies (CLL, DLBCL, FL, 
MZL, WM, MCL, HL, TCL and MM). Tenalisib demonstrated an ORR ≈ 20% (CR: 7% and 
PR: 13%).   
 
In RP6530-1401 study, response assessments of the twenty-eight evaluable patients 
receiving at least two cycles of Tenalisib showed an ORR of 57% (16/28 patients) out of 
which 3 (11%) were CR and 13 (46%) were PR.  Seven patients showed stable disease 
(25%). Indication specific analysis showed an ORR of 58% (7/12, 3 CR, 4 PR) in PTCL and 
56% (9/16, 9 PR) in CTCL. 


Protocol No. RP6530-1802                                                                                             Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
CONFIDENTIAL 
Page 19 of 62 
1.2 Study Rationale  
1.2.1 Rationale for study population  
Approximately one third of NHLs are indolent. These indolent NHLs (iNHLs) are slow-
growing tumors with a prolonged natural history, and most patients present with advanced 
disease. iNHLs are highly treatable but rarely cured. [6]  
 
Though iNHLs remain incurable, treatment is markedly advanced after the advent of the 
anti-CD20 monoclonal antibody rituximab, which now has widespread use both as 
monotherapy and in chemo-immunotherapy regimens for first-line and relapsed or refractory 
(R/R) diseases. Recommended first-line regimens for grade 1–2 FL include rituximab 
monotherapy; rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-
CHOP/CHOP); 
CHOP-obinutuzumab; 
rituximab, 
cyclophosphamide, 
vincristine, 
prednisone (RCVP/CVP); bendamustine-obinutuzumab and rituximab in combination with 
bendamustine or lenalidomide. [7] 
 
With advances in treatment, iNHL death rates have declined. Although the increased 
response rates and prolonged progression-free survival (PFS) with rituximab monotherapy 
and combination therapy are encouraging, as noted earlier, ~20% of patients relapse within 
2 years of first-line chemo-immunotherapy, and these patients have lower survival rates 
compared with patients who did not relapse in the first 2 years (OS at 2 years, 68% vs 97%, 
respectively). [8] Moreover, responses to second-line therapies are often suboptimal, 
suggesting that salvage regimens are poorly effective after first-line rituximab. [9]  
 
An analysis of data from the National LymphoCare Study revealed that patients older than 
80 years were most likely to be treated with first-line rituximab monotherapy or observation 
only instead of chemo-immunotherapy, and when combination therapy was used, it was 
generally RCVP. [10] Although current practice supports the use of rituximab-based 
regimens in younger, medically fit patients, rituximab monotherapy or watchful waiting is 
generally recommended for elderly or frail patients. In the National Comprehensive Cancer 
Network guidelines, recommendations for first-line therapy in the elderly or infirm are 
limited to rituximab monotherapy, single-agent alkylators, and radio-immunotherapy. [7] 
Taken together, it is clear that there is a substantial unmet need for effective, well-tolerated 
treatments in R/R patients and elderly or frail patients with iNHL, despite the recent 
approvals of Idelalisib and Copanlisib.  
 
1.2.2 Rationale for dose selection for Tenalisib 
The safety and tolerability of Tenalisib has been established up to doses of 1200 mg BID 
and 800 mg TID. In an ongoing US study, Tenalisib 800 mg BID (Fasting) is established as 
a MTD dose in patients with T-cell lymphoma. Therefore, Tenalisib (800 mg BID) is 
considered for this study. 
 
1.3 Benefit and Risk 
It is expected that proposed monotherapy has the potential to improve response rates in the 
proposed patient population. However, all the patients in clinical trials generally cannot 
expect to receive direct benefit from treatment during participation, as clinical trials are 
designed to provide information about the safety and effectiveness of an investigational 


Protocol No. RP6530-1802                                                                                             Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
CONFIDENTIAL 
Page 20 of 62 
medicine. Additional details regarding specific benefits and risks for subjects participating 
in this clinical trial may be found in the accompanying IB and Informed Consent documents. 
 
2 TRIAL OBJECTIVES 
2.1 Primary Objective 
• To assess the anti-tumor activity of Tenalisib, as determined by the Objective 
Response Rate (ORR), Duration of Response (DoR) and Progression Free Survival 
(PFS).   
 
2.2 Secondary Objective 
• To characterize safety and tolerability of Tenalisib in patients with iNHL. 
          
 
3 TRIAL DESIGN 
3.1 Trial End Points 
• Efficacy: 
• ORR is defined as sum of CR and PR rates and will be assessed according to the 
Lugano Classification for initial evaluation, staging, and response assessment of 
Non-Hodgkin lymphoma. (Cheson-2014)  
• CR rate will be assessed according to the Lugano Classification for initial 
evaluation, staging, and response assessment of non-Hodgkin lymphoma.  
• DoR is measured from the initial response to disease progression or death. 
• PFS is defined as the time of the first dose of Tenalisib to disease progression or 
death. 
 
• Safety:  
• Adverse Event (AE), Grade 3/ 4 AEs, Serious and fatal Adverse Event (SAE), 
graded using NCI CTCAE Version 5.0. 
 
3.2 Design of Trial 
The study is designed as a Phase II, open label, two parts study in relapsed/refractory iNHL 
patients. The mandatory Part 1 of the study will assess the efficacy and safety of Tenalisib 
in 20 patients with iNHL. After all patients enrolled in Part 1 have had the opportunity to 
provide at least three tumor outcome assessments, the Data Review Committee (DRC) will 
evaluate the efficacy (anti-tumor activity) and safety results for each of the subtypes (e.g. 
FL, MZL or WM). If the committee believes there are potential clinically meaningful 
responses for certain subtype, the committee will recommend initiation of Part 2 to evaluate 
efficacy and safety for that subtype. If not, the study will be terminated without initiating 
Part 2. The sample size for Part 2 will be derived based on the outcome from Part 1. Data 
from Part 1 will not be included in the analysis of Part 2 of the study.  
 
The study treatment Tenalisib (800 mg BID) will be administered orally in 28-days of cycle 
over a period of 8 months in absence of definitive disease progression or unacceptable 
toxicity. Treatment will be continued in patients experiencing clinical benefit until the 


Protocol No. RP6530-1802                                                                                             Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
CONFIDENTIAL 
Page 21 of 62 
occurrence of definitive disease progression, unacceptable toxicity, or withdrawal from the 
study due to investigator decision or other reasons; maximum for up to 24 months.  
 
The efficacy response will be evaluated on Weeks 8 (C3D1± 7 days), Weeks 16 (C5D1± 7 
days) and then every 12 weeks thereafter, and/ or at the EOT or as clinically indicated (if 
clinical progression is suspected or for confirmation of complete response/disease 
progression). The details of the study procedures are given in Schedule of Events.  
 
 
 
 
 
 
 
 
 
 
 
 
1Post cycle 8, treatment will be continued in patients experiencing clinical benefit up to 24 months 
unless progression of disease or toxicity warranting discontinuation of therapy. The decision to 
continue the treatment will be determined by the PI after consultation with Sponsor on case to case 
basis. 
 
3.3 Data Review Committee (DRC) 
The DRC will be constituted by the sponsor in consultation with PI and will consist of PI, 
sponsor representative, sponsor’s medical expert, medical monitor, and a statistician. The 
DRC will meet and review the safety and efficacy data at regular interval and as required by 
the sponsor/investigator to assess the safety and tolerability of study drug.   
  
After all patients enrolled in Part 1 have had the opportunity to provide at least three tumor 
outcome assessments, the DRC will evaluate the efficacy (anti-tumor activity) and safety 
results for each of the subtypes. If the committee believes there are potential clinically 
meaningful responses for certain subtype, the committee will recommend initiation of Part 
2 to evaluate efficacy and safety for that subtype. 
 
3.4 Randomization and Blinding 
This is a non-randomized, open label study.  
 
3.5 Investigational Medicinal Product 
3.5.1 Dosage form and strengths 
 
Investigational 
Product 
Dosage form, strength 
Manufacturer 
 Tenalisib 
Tablets; 200 mg and 400 mg.  
STA Pharma Co. Ltd. 
Note: Please refer Investigator’s brochure for additional information of Tenalisib.  
 
Group 
N 
Patient population 
Tenalisib 
Part 1 
20 
Refractory/ relapsed iNHL. 
800 mg BID in 28-Days 
Cycle for 8 Cycles1  
Part 2 
The sample 
size will be 
derived based 
on the outcome 
from Part 1 
Refractory/ relapsed iNHL patients of 
one of the specific subtype (e.g. FL, 
MZL, WM) 
800 mg BID in 28-Days 
Cycle  for 8 Cycles1 


Protocol No. RP6530-1802                                                                                             Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
CONFIDENTIAL 
Page 22 of 62 
3.5.2 Labeling, packaging and supply 
Tenalisib will be supplied by STA Pharma Co. Ltd. through Rhizen Pharmaceuticals S.A. 
Tenalisib will be available as 30 tablets per bottle. All trial drugs must be kept in a secure 
place at below 25°C (77°F), protected from moisture. 
 
3.5.3 Preparation and administration of Investigational Products 
At each visit, patients will be dispensed sufficient quantity of Tenalisib until the next visit. 
Study drug compliance should be reviewed with the patient at the beginning of each new 
treatment cycle.  Study drug compliance must be documented, including missed doses and 
subject re-education and dose administration.   
 
Guideline for administration of Tenalisib: 
• Method of Administration:  Tenalisib will be administered orally twice daily. 
• Pre-medications: None. No routine prophylactic anti-emetics or pre-medications should 
be given outside of protocol requirements. However, these medications may be 
administered for the treatment of symptoms (see Section 5.3). 
• Tenalisib tablets will be self-administered orally twice daily one hour before a major 
meal (e.g. breakfast and dinner). Patients should not consume food during this one-hour 
period. 
• Tenalisib tablets should be taken at approximately same time each day. Tablets should 
be swallowed; and should NOT be crushed or chewed.   
• If a dose of Tenalisib is missed, it should be taken as soon as possible on same day with 
an interval of 8 hrs between two doses. If it is missed for the entire day, it should not be 
repeated. If vomiting occurs, no attempt should be made to replace the vomited dose.  
• Study drug compliance should be reviewed at the beginning of each new treatment cycle. 
Missed doses should be documented. 
 
3.5.4 Accountability of Investigational Products 
The PI/ designee are responsible for accountability of all trial drug supplies (used/unused) at 
the site. The study monitor will verify receipt of investigational product at the sites during 
monitoring visit(s), and will conduct an inventory of remaining clinical trial supplies at the 
site close-out visit. All trial drug inventories must be made available for inspection by the 
monitor, sponsor representatives and regulatory agency inspectors/monitor upon request.  
 
Following monitor verification, returned or expired trial drugs can be destroyed according 
to local institutional policy with sponsor pre-approval of a site-specific destruction policy. 
Certificate of destructions must be filed at the site and in Trial Master File.  
 
3.5.5 Precautions and risks associated with Investigational Products 
• Monitoring of liver enzymes and levels of TSH, T3, and T4 in subjects receiving 
Tenalisib is recommended based on target organ toxicity. Patients should be monitored 
for increased ALT/AST, skin rash, neutropenia as these events are reported with 
Tenalisib. Monitor patients for signs and symptoms of these events and interrupt 


Protocol No. RP6530-1802                                                                                             Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
CONFIDENTIAL 
Page 23 of 62 
Tenalisib 
for 
Grade 
3 
or 
higher 
event. 
In 
addition, 
enteritis 
(colitis), 
pneumonia/pneumonitis as these events are reported with other PI3K inhibitors.  
• Tenalisib  may  cause  serious  infections  that  may  include  sepsis  and  other  infections. 
Monitor patients for signs and symptoms of infection and interrupt Tenalisib for Grade 
3 or higher infection. 
• Tenalisib elicits no photo instability upon exposure to ultraviolet (UV) radiations. 
However, in absence of in vitro data, possibility of photo-toxicity with Tenalisib cannot 
be ruled out.  
• Tenalisib demonstrated moderate to high inhibition of CYP3A4 enzymes. Therefore, 
concomitant administration of Tenalisib with CYP3A4 substrates (e.g. calcium channel 
blockers, warfarin, carbamazepine, macrolide antibiotics, lovastatin, simvastatin, 
terfenadine) may reduce clearance of these drugs increasing the risk of adverse events. 
Similarly, as Tenalisib is inhibited by CYP3A4/5 and CYP2C9, there is possibility of 
drug interaction with inhibitors or inducers of CYP3A4 and CYP2C9. If concomitant 
treatment of these drugs are clinically warranted, careful observation of the patient is 
advised. Raised INR has been reported with concomitant warfarin administration. 
Therefore, use of heparin or warfarin is generally avoided. Low molecular weight heparin 
(LMWH) is advised for prophylaxis and treatment of venous thrombosis. 
• Strong inhibitor or inducers should be avoided as directed in Section on prohibited 
medication. Please refer to the recent Investigator Brochure for additional safety 
information. 
• In absence of reproductive toxicity and genotoxicity data, the study participants should 
be advised to follow post treatment contraceptive measures. 
  
3.6 The Expected Duration of Subject Participation and Follow-up 
The expected duration of subject participation in the study will be 8 months. Treatment will 
be continued in patients experiencing clinical benefit up to 2 years unless progression of 
disease or toxicity warranting discontinuation of therapy. The decision to continue the 
treatment will be taken by PI after consultation with sponsor on case to case basis. 
 
3.7 Study Stopping Rules 
Efficacy:  
After all patients enrolled in Part 1 have had the opportunity to provide at least three tumor 
outcome assessments, the DRC will evaluate the efficacy (anti-tumor activity) and safety 
results for each of the subtypes. If the committee believes there are potential clinically 
meaningful responses for certain subtype, the committee will recommend initiation of Part 
2 to evaluate efficacy and safety for that subtype. Else, the study will be terminated. 
 
Safety: The DRC will continue to monitor safety of Tenalisib (or toxicity trends that may 
be of concern) at interval of approximately 3 months from initiation of study until the 
completion of the study. In the event of one (1) death attributed to the study drug, study 
accrual will be suspended pending further investigation, and will only be resumed at the 
recommendation of the DRC. The DRC will have discretion to terminate the trial if an 
additional death occurs that can be attributed to the study drug. 
  


Protocol No. RP6530-1802                                                                                             Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
CONFIDENTIAL 
Page 24 of 62 
Sponsor reserves the right to terminate the study in the interest of patient safety, for non-
compliance with the protocol, lack of recruitment or any other administrative reasons. The 
sponsor and PIs will notify the regulatory authority and respective IRB respectively if the 
trial terminates early, with a justification for the early termination. 
 
4 SELECTION AND WITHDRAWAL OF SUBJECTS  
4.1 Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for participation in 
this study: 
1. Patients with histologically confirmed diagnosis of indolent B-cell NHL, with 
histological subtype limited to: 
• Follicular lymphoma (FL) G1, G2, or G3a 
• Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal) 
• Lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM)  
• Small lymphocytic lymphoma (SLL) with absolute lymphocyte count < 5 x 10^9 /L 
at the time of diagnosis and at study entry. 
2. Relapsed or refractory after ≥ 2 prior lines of therapy (refractory defined as not 
responding to a standard regimen or progressing within 6 months of the last course of a 
standard regimen). Patients must have received rituximab and alkylating agents.  
3. Patients must have at least one bi-dimensionally measurable lesion (that has not been 
previously irradiated) with the longest diameter ≥ 1.5 cm.  
4. Male or female patients > 18 years of age. 
5. ECOG performance status ≤ 2. 
6. Life expectancy of at least 3 months. 
7. Adequate bone marrow, liver, and renal function as assessed by the following laboratory 
requirements conducted within 7 days before starting study treatment:  
a. 
Hemoglobin ≥ 9 g/dl 
b. 
Absolute neutrophil count (ANC) ≥ 1 x 10^9/L 
c. 
Platelets ≥50 x 10^9/L (patient without BM involvement) and 30 x 10^9/L (patient 
with BM involvement) 
d. 
Total bilirubin ≤1.5 times the upper limit of normal (ULN) 
e. 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x 
ULN if known liver involvement. The ALT and AST should be ≤1.5 X ULN in 
absence of liver involvement/metastasis. 
f. 
Creatinine ≤ 1.5 mg/dL OR calculated creatinine clearance ≥ 50 mL/min (as 
calculated by the Cockcroft-Gault method) 
8. Ability to swallow and retain oral medication. 
9. Female patients who are not of child-bearing potential, and female patients of child-
bearing potential who have a negative serum pregnancy test within 72 hours prior to 
initial trial treatment. Female patients of child-bearing potential, and all male partners 
must consent to use a medically acceptable two methods of contraception throughout 


Protocol No. RP6530-1802                                                                                             Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
CONFIDENTIAL 
Page 25 of 62 
the study period and for 4 weeks after the last dose of Tenalisib. A barrier method of 
contraception must be included.    
10. Male patients willing to use adequate contraceptive measures throughout the study 
period and for 12 weeks after the last dose of Tenalisib. 
11. Willingness and ability to comply with trial and follow-up procedures, give written 
informed consent. 
 
4.2 Exclusion Criteria 
1. Histologically confirmed diagnosis of follicular lymphoma grade 3b or transformed 
disease or chronic lymphocytic leukemia (CLL).  
2. Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, 
biologic therapy, hormonal therapy, surgery and/or tumor embolization) or any cancer 
investigational drug within 3 weeks (21 days) or 5 half-lives (whichever is shorter) prior 
to C1D1. Corticosteroids (prednisone or equivalent) at a dose of < 20 mg daily are 
allowed. Corticosteroid should be stabilized for at least 1 week prior to C1D1.  
3. Autologous hematologic stem cell transplant (Auto-SCT) within 3 months from C1D1. 
Patients must not have active graft versus-host disease; 
4. History of an allogeneic bone marrow transplant (Allo-SCT) 
5. Active hepatitis B or C infection. (All subjects must be screened for hepatitis B and C 
up to 28 days prior to C1D1 using the hepatitis viral panel. Subject positive for HBsAg 
or HBcAb will be eligible if they are negative for HBV-DNA. Subject positive for HCV 
IgG will be eligible if they are negative for HCV-RNA);  
6. Known history of human immunodeficiency virus (HIV) infection; 
7. Evidence of ongoing severe systemic bacterial, fungal or viral infection;   
8. Known primary central nervous system lymphoma or known intracranial involvement, 
leptomeningeal metastases or spinal cord compression due to disease or any preexisting 
neurologic manifestations; 
9. Known history of severe drug-induced liver injury, alcoholic liver disease, primary 
biliary cirrhosis, ongoing extrahepatic obstruction caused by stones, cirrhosis of the liver 
or portal hypertension; 
10. Patient with any severe and/or uncontrolled medical conditions or other conditions that 
could affect their participation in the study as per investigator’s judgement;  
11. Patient with symptomatic, or history of documented congestive heart failure (NY Heart 
Association functional classification III-IV);  
12. Patient with angina not well-controlled by medication; 
13. Patient with poorly controlled or clinically significant atherosclerotic vascular disease 
(including cerebrovascular accident, transient ischemic attack or have angioplasty, 
cardiac or vascular stenting) in the past 6 months; 
14. Prior exposure to drug that specifically inhibits PI3K (e.g. Idelalisib, Copanlisib, 
Duvelisib and Umbralisib); 
15. Previous or concurrent malignancy that is distinct in primary site or histology from 
indolent B-cell NHL within 3 years of study enrollment EXCEPT for adequately treated 
basal, squamous cell carcinoma or non-melanomatous skin cancer, carcinoma in situ of 
the cervix, superficial bladder cancer not treated with intravesical chemotherapy or BCG 
within 6 months, localized prostate cancer with PSA <1.0 mg/dL on 2 consecutive 


Protocol No. RP6530-1802                                                                                             Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
CONFIDENTIAL 
Page 26 of 62 
measurements at least 3 months apart with the most recent one being within 4 weeks of 
study entry;  
16. Patients with seizure disorder requiring medication; 
17. Unresolved toxicity higher than CTCAE grade 1 (NCI-CTCAE version 5.0) attributed to 
any prior therapy/procedure excluding alopecia; 
18. Myeloid growth factors or red blood cells/ platelet transfusion within 14 days prior to 
C1D1; 
19. Administration of any of the following within 1 week prior to C1D1: 
a. Strong inhibitors or inducers of CYP3A4, including grapefruit products, herbal 
medications. 
b. Strong inhibitors or inducers of CYP2C9, including herbal medications. 
c. Substrates of CYP3A4 enzyme with a narrow therapeutic range (e.g. Warfarin 
and phenytoin)  
20. Pregnant or lactating woman; 
21. Inability or unwillingness to comply with study and/or follow-up procedures outlined in 
the protocol; 
22. Concurrent condition that in the investigator’s opinion would jeopardize compliance 
with the protocol. 
 
4.3 Discontinuation from Trial Treatment 
The following events may be considered sufficient reason for discontinuing treatment with 
the study medication: 
- NCI CTCAE v5.0 Grade 3/4 non-hematological toxicity related to study drug that 
necessitate withdrawal in the opinion of investigator. 
- Withhold of study drug for > 28 days due to adverse event, unless approved by medical 
monitor.  
- Development of an intercurrent illness, condition or procedural complication, which 
could interfere with the patient’s continued participation.  
- Voluntary patient withdrawal from study treatment (all patients are free to withdraw from 
participation in this study at any time, for any reasons, specified or unspecified, and 
without prejudice). 
- Any other situation where, in the opinion of the investigator, continued participation in 
the study would not be in the best interest of the patient  
- Confirmed disease progression  
- Study completion. 
 
5 TREATMENT OF SUBJECTS  
5.1 Administration of Tenalisib 
Tenalisib will be dosed continuously twice a day in 28-days cycle up to 24 months unless 
progression of disease or toxicity warranting discontinuation of therapy. Please refer section 
3.4.3 for administration of Tenalisib. Post completion of 24 months, if the patient shows 
clinical benefit, patient may be enrolled into a compassionate use study protocol to receive 
Tenalisib.  
 
5.2 Concomitant Medications 
• Antimicrobial and anti-viral prophylaxis should be used according to local standard 


Protocol No. RP6530-1802                                                                                             Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
CONFIDENTIAL 
Page 27 of 62 
practice; PCP and Zoster prophylaxis is strongly recommended.   
• G-CSF and other hematopoietic growth factors may be used for the management of acute 
toxicity such as febrile neutropenia when clinically indicated. 
• Transfusions (blood/platelets) may be given, based on standard criteria and clinical 
judgment.  
• No routine prophylactic anti-emetics or pre-medications should be given outside of 
protocol requirements. However, these medications may be administered for the 
treatment of symptoms.  
• Patient may receive prophylactic allopurinol, in case the risk of tumor lysis syndrome.  
• Low doses of steroids are allowed if it stabilized at < 20 mg per day of prednisone or 
equivalent. If initiated before starting treatment, corticosteroid should be stabilized for at 
least 1 week prior to C1D1.  
• Patients are permitted to use of topical, ocular, intra-articular, intranasal, and inhaled 
corticosteroids (with minimal systemic absorption). A brief (less than 3 weeks) course of 
corticosteroids for prophylaxis (e.g. contrast dye allergy) or for treatment of non-
autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by a contact 
allergen) and also for the treatment of drug-related AE is permitted. 
• Inactivated seasonal influenza vaccine can be given to subjects before treatment and while 
on therapy without restriction.  
• If concomitant treatment of drugs metabolized by CYP3A4/CYP2C9 enzymes are 
clinically warranted, careful observation of the patient is advised. Use of heparin or 
warfarin for prophylaxis and treatment of venous thrombosis is prohibited. Low 
molecular weight heparin (LMWH) is acceptable. Similarly, Dabigatran and Edoxaban, 
Direct-acting Oral Anti-Coagulants (DOAC) class of drugs, are acceptable as they are not 
metabolized by CYP3A4/CYP2C9 enzymes. 
• Patients should be warned about the possible photosensitivity and advised to be careful 
with the UV exposure while on Tenalisib treatment. Patients should be recommended to 
wear loose-fitting clothes that protect skin from sun exposure, in case they need to be 
outdoors. If sunburn like reaction or skin eruption occurs, patients should contact study 
physician. 
 
5.3 Prohibited Medications 
The following treatments are prohibited while on the clinical trial:    
• Any other anti-lymphoma therapy (e.g. radiation therapy, hormonal therapy for cancer, 
cancer immunotherapy or other biologic therapy).  
• Herbal medications are not allowed throughout the trial. Patients should stop using these 
herbal medications at least 7 days prior to C1D1.  
• Strong inhibitors or inducers of CYP3A4, including grapefruit products, herbal 
medication (e.g. atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, 
nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and rifampicin). Patients 
should stop using these medications at least 7 days prior to C1D1.  
• Strong inhibitors or inducers of CYP2C9, including herbal medications (e.g. 
fluconazole and rifampicin). Patients should stop using these medications at least 7 days 
prior to C1D1. 
• Substrates of CYP3A4 enzyme with a narrow therapeutic range (e.g. Warfarin and 


Protocol No. RP6530-1802                                                                                             Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
CONFIDENTIAL 
Page 28 of 62 
phenytoin, alfentanil, astemizole, cisapride, cyclosporine, diergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus, tacrolimus, terfenadine). Patients should stop 
using these medications at least 7 days prior to C1D1.    
• Use of heparin or warfarin for prophylaxis and treatment of venous thrombosis is 
prohibited. Similarly, Apixaban and Rivaroxaban, DOAC class of drugs, are also 
prohibited they are metabolized by CYP3A4 enzymes. These drugs should be stopped at 
least 7 days prior to C1D1.   Live attenuated vaccine (e.g. Flu vaccine, pneumovax, 
varicella) 
• Steroids > 20 mg unless for management of toxicity. 
 
Discontinuation of patient who received concomitant/prohibited medication will be taken 
by the PI in consultation with medical monitor on case to case basis, after reviewing 
ongoing clinical benefit and risk. The decision to allow a patient to continue will be 
documented and archived at the site and at Rhizen. 
 
5.4 Procedures for Monitoring Subject Compliance. 
The following measures will be employed to ensure treatment compliance. 
Subjects will be asked to bring any unused study drug to the research center at their next 
visit.  Research personnel will count and record the number of used and unused study drug 
tablets at each visit. The study coordinator will question the patient regarding adherence to 
the dosing regimen, record the number of tablets and strengths returned, the date returned 
and determine treatment compliance before dispensing new medication to the study patient. 
Compliance below 80% will require counseling of the patient by study site personnel.  
 
6 TRIAL ASSESSMENT AND PROCEDURE  
6.1 Overview 
Schedule of Event (Table 1) summarizes the trial procedures to be performed at each visit 
and is divided into following.  
1. 
Screening (Day -28 day to Day 0) 
2. 
On treatment procedures (C1D1 to C8D28) 
3. 
Treatment beyond Cycle 9 (C9D1 to C26) 
4. 
End of Treatment (Day +7 from last dose) 
5. 
End of Study (Day +30 from last dose) 
 
Individual trial procedures are described in detail below. It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.  
 
Furthermore, additional evaluations/testing may be deemed necessary by the investigator 
and or the Sponsor for reasons related to subject safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and 
thus local regulations may require that additional informed consent be obtained from the 


Protocol No. RP6530-1802                                                                                             Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
CONFIDENTIAL 
Page 29 of 62 
subject.  In these cases, such evaluations/testing will be performed in accordance with those 
regulations. 
 
 
 


Protocol No. RP6530-1802 
                                                        
Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
 
Page 30 of 62 
Table 1: Schedule of Events for Part 1  
 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
C4 
C5 
C6 
C7 
C8 
C9-26  
EOT20 
EOS21 
Day  
D-28 to 0 
D1 
D15 
D1 
D15 
D1 
D15 
D1 
D1 
D1 
D1 
D1 
D1 
- 
- 
Window period  
-28  
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
+14 
+30 
Study Days  
D-28 to 0 
1 
15 
29 
43 
57 
71 
85 
113 
141 
169 
197 
- 
- 
- 
Informed Consent1 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Demographics2 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Medical history3 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
Vitals4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
- 
Height and weight5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
- 
Complete Physical exam6 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
Abbreviated Physical exam6 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
- 
ECOG Performance Status 
X 
X 
- 
- 
- 
X 
- 
- 
X 
X 
X 
X 
- 
X 
- 
Complete blood count7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X19 
X 
- 
Chemistry panel I8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X19 
X 
- 
Chemistry panel II9 
X 
X 
- 
- 
- 
X 
- 
- 
X 
- 
- 
X 
- 
X 
- 
Serology10  
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
PT and INR11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
- 
Urinalysis (routine) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X19 
X 
- 
Pregnancy test12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
- 
12-lead ECGs13 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
- 
X 
- 
X 
- 
Radiological scan/imaging 
X 
- 
- 
- 
- 
X 
- 
- 
X 
- 
- 
X 
X19 
X 
- 
CT scan14 
X 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
X 
X19 
X 
- 
PET/PET-CT14 
X 
- 
- 
- 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Disease Response 
Assessment15 
X 
- 
- 
- 
- 
X 
- 
- 
X 
- 
- 
X 
X19 
X 
- 
Drug Dispensing16 
- 
X 
- 
X 
- 
X 
- 
X 
X 
X 
X 
X 
X19 
X 
- 


Protocol No. RP6530-1802 
                                                        
Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
 
Page 31 of 62 
Foot notes: 
1. Patient should be re-consented, if informed consent is obtained >30 days prior to the initiation of trial treatment. The first day of Tenalisib administration 
will be considered as C1D1.   
2. Demographic profile will include age, sex and race. 
3. Detailed history will be taken at screening that includes history of cancer, past history, number of prior therapies; and prior medication (in last 4 weeks); 
and other medical history. Any medical significant history at subsequent visit will be captured as adverse event.  
4. Vitals will include pulse; blood pressure; respiratory rate and oral temperature that should be done at screening, C1D1 (within 30 minutes prior to 
dosing) and at the time of clinic visit at all other time points. Supine or sitting position is acceptable depending on the patient condition.  
5. Weight will be measured at all visits. Height to be measured at screening only.  
6. Physical examination will include lymph node and systemic examination (General Appearance, HEENT, neck, cardiovascular, lungs, abdomen, lymph 
nodes, genitourinary, extremities, neurological, skin, and musculoskeletal). Complete physical examination will be done at screening visit and EOT. At 
all other visits, abbreviated examination (directed physical examination) will be done depending on the assessment of tumor. 
7. This will include hemoglobin, complete blood count, total leucocyte and differential count and platelet count. Additional investigations will be performed 
if clinically indicated. Hematology must be done ≤7 days prior to C1D1. However, if these initial examinations are obtained within 72 hours of C1D1; 
they do not have to be repeated.      
8. Chemistry Panel I includes total bilirubin, ALP, AST, ALT, GGT, LDH, sodium, potassium, chloride, calcium, phosphorus, CO2/bicarbonate and 
magnesium. These tests must be done ≤7 days prior to C1D1. However, if these initial examinations are obtained within 72 hours of C1D1; they do not 
have to be repeated. These tests will be performed at supplementary visits if clinically indicated.       
9. Chemistry Panel II includes blood glucose, urea/ blood urea nitrogen (BUN), creatinine, albumin, total protein, TSH, T3 (total/free), T4 (free), total 
Cholesterol, TG, LDL and HDL. These tests must be done ≤7 days prior to C1D1. However, if these initial examinations are obtained within 72 hours 
of C1D1; they do not have to be repeated. These tests will be performed at supplementary (unscheduled) visits if clinically indicated.       
10. Serology includes HIV, HBV and HCV. Historical evidence in the last 4 weeks is acceptable.  
11. PT and INR test must be done ≤7 days prior to C1D1. However, if initial examination is obtained within 72 hours of C1D1; this do not have to be 
repeated. In case of abnormality, additional tests including aPTT to be done as per investigator discretion. This test will be performed at supplementary 
visits if clinically indicated.       
12. This is required for women of child bearing potential. A serum pregnancy test will be performed at screening and C1D1 (within 72 hours) of dosing. 
Urine pregnancy test will be performed at other visits as indicated.  
13. A standard 12-lead ECG will be performed at the defined time points. Additional ECGs will be obtained if clinically indicated. Triplicate ECGs will be 
performed to confirm significant changes of a single ECG.  
 
Tenalisib treatment17 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X19 
X 
- 
Drug compliance  
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
- 
AE evaluation 18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X19 
X 
X 
SAE evaluation  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X19 
X 
X 
Concomitant medication  
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X19 
X 
X 


Protocol No. RP6530-1802 
                                                        
Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
 
Page 32 of 62 
 
14. PET/PET-CT and “diagnostic quality” CT scan will be performed at the time of screening within 28 days of screening. Following screening, CT scans 
should be repeated at C5D1 and at every 12-Weeks thereafter. PET/PET-CT should be repeated at C3D1 and to confirm CR/PD; and as clinically 
indicated. Tumor imaging should remain consistent throughout study, and should include those thought by investigator to best capture the status of 
disease. Baseline scans if already available as SOC within 28-days of screening, is accepted as part of study protocol.  
15. Disease response assessment will be performed at C3D1 (± 7 days), C5D1 (± 7 days) and approximately every 12 weeks thereafter (± 7 days), and/ or 
at the EOT or as clinically indicated (if clinical progression is suspected or for confirmation of complete response/disease progression) using Cheson 
Criteria 2014.  
16. Tenalisib will be dispensed in a HDPE container having 30 tablets of Tenalisib.  
17. Tenalisib will be administered orally twice a day in 28-days of cycle in absence of disease progression or toxicity warranting discontinuation of therapy. 
Post cycle 8, Tenalisib will be continued in patients experiencing clinical benefit up to 24 months unless progression of disease or toxicity warranting 
discontinuation of therapy. The decision to continue the treatment will be taken by PI after consultation with Sponsor on case to case basis.   
18. All AEs regardless of seriousness or relationship to study drug should be recorded spanning from the informed consent drug until 30 calendar days after 
the last dose of study drug.  
19. Post cycle 8, all visits will occur monthly. During these monthly visits, Tenalisib will be dispensed, medication compliance will be monitored. Safety 
and efficacy assessments will be done as mentioned below. An EOT visit will be performed within 14 days after treatment ends. 
• 
Safety assessments: Safety assessment will be done during the monthly visits and AEs will be reported as required by the protocol. There is no 
specific safety labs or evaluations to be done as per protocol. As part Standard of care, laboratory evaluations will be done and recorded per 
Investigator’s discretion. Adverse events (AEs, SAEs and deaths) will be recorded and reported for 30 calendar days after discontinuation or 
completion of protocol-specific treatment. After the 30 day reporting period, only AEs, SAEs, or deaths assessed by the investigator as treatment 
related are to be reported. 
• 
Efficacy assessments: Disease assessments should be performed at 12 weekly intervals (± 7 days), and/ or at the EOT. For example, the appropriate 
radiological investigation (e.g. CT scan, PET-CT/PET) will be performed patients at C11D1, C14D1, C17D1, C20D1, etc.  
• 
Drug dispensing: Patients will be given 30 days of drug supply at the beginning of each cycle.   
20. All patients will undergo the end-of-treatment (EOT) assessments within 14 days after last dose of study drug or discontinuation.   
21. Patients should be followed for AEs for 30 calendar days after the last dose of study treatment. Telephonic follow up during this period is acceptable. 
All new AEs occurring during this period should be reported and followed until resolution unless, in the opinion of the investigator, the adverse event 
or laboratory abnormality/ies are not likely to improve because of the underlying disease.  


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 33 of 62 
6.2  Screening and on Treatment Procedures  
6.2.1 Informed consent   
The investigator/qualified designee must obtain documented consent from each potential subject 
or each subject’s legally acceptable representative prior to participating in a clinical trial. Consent 
must be documented by the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature on a consent form along with the dated signature of the person 
conducting the consent discussion. A copy of the signed and dated consent form should be given 
to the subject before participation in the trial.   
 
The initial informed consent form, any subsequent revised written informed consent form and any 
written information provided to the subject must receive the IRB/IEC’s approval/favorable opinion 
in advance of use. The subject or his/her legally acceptable representative should be informed in a 
timely manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the trial. The communication of this information will be 
provided and documented via a revised consent form or addendum to the original consent form that 
captures the subject’s dated signature or by the subject’s legally acceptable representative’s dated 
signature. Specifics about a trial and the trial population will be added to the consent form template 
at the protocol level. The informed consent will adhere to IRB/IEC requirements, applicable laws 
and regulations and Sponsor requirements. 
 
The informed consent must be obtained ≤30 days prior to initiation of treatment before any 
protocol-specific procedures are performed. Patient should be re-consented in case informed 
consent is not obtained ≤30 days prior to the initiation of trial treatment.  
 
6.2.2 Assignment of screening number 
All consented subjects who undergo at least one post-consent procedure will be given a unique 
screening number that will be used to identify the subject for all procedures that occur prior to 
randomization or allocation. Each subject will be assigned only one screening number. Screening 
numbers must not be re-used for different subjects. Any subject who is screened multiple times 
will retain the original screening number assigned at the initial screening visit.  
 
6.2.3 Medical history   
A medical history will be obtained by the investigator/qualified designee. Comprehensive history 
will include but not limited to age; sex; absence/presence of fever more than 101°F (38.3°C), chills, 
drenching night sweats, or unexplained weight loss more than 10% of body mass over 6 months; 
and history of malignancy. Medical history should be taken for period of minimum 6 months.  
 
6.2.4 Prior and concomitant medication review 
Prior medication: The investigator/qualified designee will review prior medication use, including 
any protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial. Treatment for the disease for which the subject has enrolled 
in the study will be recorded separately and not listed as a prior medication. 
 
Concomitant medication: The investigator/qualified designee will record medication, if any, 
taken by the subject during the trial.  


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 34 of 62 
6.2.5 Prior therapies details  
The investigator/qualified designee will review all prior cancer treatments including systemic 
treatments, prior transplantation, radiation, and surgeries received for the treatment of cancer 
condition from the initial diagnosis and record in the source document. 
 
6.2.6 Physical examination 
Full physical examination: The investigator/qualified designee will perform a complete physical 
exam during the screening period and as defined in Schedule of Events. Physical examination will 
include lymph node and systemic examination (General Appearance, HEENT, neck, 
cardiovascular, lungs, abdomen, lymph nodes, genitourinary, extremities, neurological, skin, and 
musculoskeletal).  
 
Abbreviated (Directed) physical examination: For cycles that do not require a full physical exam 
per the Schedule of Event, the investigator/qualified designee will perform a directed physical 
exam as clinically indicated depending on assessment of tumor, prior to trial treatment 
administration. After the first dose of trial treatment new clinically significant abnormal findings 
should be recorded as AEs. 
 
6.2.7 Vital signs  
Vital signs will be taken at screening, C1D1 (within 30 minutes prior to dosing) and at the time of 
clinic visit at all other time points  as specified in the Schedule of Event. Vital signs should include 
temperature (oral/axillary), pulse, respiratory rate, weight and blood pressure. Supine or sitting 
position is acceptable depending on the patient condition. The window periods for vitals will ±30 
min for the specified time points. 
 
6.2.8 Laboratory safety evaluations 
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 2. 
 
 
Table 2: Laboratory Tests for Hematology, Chemistry and Urinalysis 
 
Hematology  
Chemistry Panel I 
Chemistry Panel II 
Urinalysis 
Other  
Hematocrit  
Total bilirubin 
Blood glucose  
Blood  
Serum β-hCG 
Hemoglobin 
Alkaline 
phosphatase 
(ALP) 
Urea or blood urea 
nitrogen a 
Glucose  
Urine 
pregnancy 
test 
CBC with 
differentials 
Alanine aminotransferase 
(ALT) 
Creatinine 
Protein  
PT 
Platelet count 
Aspartate 
aminotransferase (AST)  
Albumin 
Specific 
gravity  
INR 
WBC (Total and 
differentials) 
Lactate 
dehydrogenase 
(LDH) 
Total protein 
Microscopic 
exam 
 
Red blood cell 
count 
Gamma-glutamyl 
transferase (GGT) 
Total Cholesterol 
 
 
Absolute 
neutrophil count 
Sodium 
Triglyceride (TG) 
 
 
Absolute 
lymphocyte count 
Potassium  
LDL 
 
 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 35 of 62 
 
Calcium 
HDL 
 
 
 
Phosphorous 
TSH 
 
 
 
Carbon Dioxide (CO2) 
or bicarbonateC 
T3 (Total or Free)d 
 
 
 
Chloride  
T4 (free) 
 
 
 
Magnesium  
 
 
 
a Blood Urea Nitrogen is preferred; if not available Urea may be tested. 
b Microscopic exam, if abnormal results are noted.  
C One of these tests to be performed depending on standard of care practice followed at the institution.  
d Free or total T3 to be performed depending on standard of care practice followed at the institution.  
 
Blood drawn for these tests will be specified in informed consent form (ICF). The investigations 
will be performed at the local laboratory as decided by the sponsor and investigator. .  
 
Screening laboratory described in Table 2 will be performed, reviewed, and determined to be 
acceptable by the site PI/designee after obtaining informed consent and ≤7 calendar days prior to 
the initiation of treatment. If these initial examinations are obtained within 72 hours (or as 
otherwise noted) of Cycle 1 Day 1, the investigations need not be repeated. Rescreening can be 
done at the discretion of PI. The scan and other investigations to document measurable or evaluable 
disease should be performed ≤28 weeks prior to initiation of treatment.  
 
During screening, active HBV, HCV or HIV infection should be ruled out. To be considered 
negative for active infection, following algorithm will be used:  
• HBV: HBc antibody should be negative or if HBc antibody is positive, HBVDNA should be 
undetectable 
• HCV: HCV antibody should be negative or if HCV antibody is positive, HCVDNA should be 
undetectable 
• HIV: HIV antibody should be negative. (HIV 1/ 2 antibody should be negative unless positive 
result is considered false positive by PI) 
 
Note: Patients  who  show  evidence  of  hepatitis  B  infection  (HBsAg positive  [regardless  of  
antibody  status]  or  HBsAg  negative  but  anti-HBc  positive),  need to be evaluated for initiation 
of HBV antiviral therapy and should be closely monitored for HBV reactivation.  
 
6.2.9 ECG     
A standard 12-lead ECG will be performed using local standard procedures as defined in Schedule 
of Events. Additional ECGs will be obtained if clinically indicated. Triplicate ECGs will be 
performed to confirm the significant changes of single ECG. Clinically significant abnormal 
findings should be recorded as an adverse event. 
 
6.3 Eastern Cooperative Oncology Group (ECOG) Performance Status 
The investigator/qualified designee will assess ECOG status (see Appendix A) at screening; prior 
to the administration of each dose of trial treatment and discontinuation of trial treatment as 
specified in the Schedule of Event. 
 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 36 of 62 
6.4 Radiological Evaluation  
Initial disease assessment by tumor imaging (baseline scan) must be performed within 28 days 
prior to the first dose of trial treatment.  The site study team must review pre-trial images to confirm 
the subject has measurable disease as defined in the inclusion criteria. Disease assessments or scans 
performed as part of routine clinical management are acceptable for use as the screening scan if 
they are of diagnostic quality and performed within 28 days prior to the first dose of trial 
treatment. The CT/ PET/PET-CT should be done throughout the study at local imaging centre at 
time-points designated in Schedule of Events.  
 
6.5 Trial Treatment Period 
Patients will visit the study center bi-weekly for the first three cycles and thereafter every month. 
All visits should occur as close as possible to the protocol specified time. Complete listings of the 
assessments that will be performed at each visit during the trial treatment period are specified in 
Table 1.  
 
Trial treatment period is of 8 cycles. Assessments will be performed thereafter if warranted, at the 
discretion of PI. Patients with progressive disease or unacceptable toxicity should be discontinued 
from the trial; patients with stable disease or response to therapy will continue treatment. The 
assessments to be performed are specified in Table 1.  
 
6.6  Treatment Beyond Cycle 8 (Cycle 9 onward up to Cycle 26) 
Post cycle 8, all visits will occur monthly in responding patients. During these monthly visits, 
Tenalisib will be dispensed, medication compliance will be monitored. Safety and efficacy 
assessments will be done as mentioned below. An EOT visit will be performed within 14 days after 
treatment ends. 
• Safety assessments: Safety assessment will be done during the monthly visits and AEs will 
be reported as required by the protocol. There is no specific safety labs or evaluations to be 
done as per protocol. As part Standard of care, laboratory evaluations will be done and 
recorded per Investigator’s discretion. Adverse events (AEs, SAEs and deaths) will be 
recorded and reported for 30 calendar days after discontinuation or completion of protocol-
specific treatment. After the 30 day reporting period, only AEs, SAEs, or deaths assessed by 
the investigator as treatment related are to be reported. 
• Efficacy assessments: Disease assessments should be performed at 12 weekly intervals (± 7 
days), and/ or at the EOT. For example, the appropriate radiological investigation (e.g. CT 
scan, PET-CT/ PET) will be performed patients at C11D1, C14D1, C17D1, C20D1, etc.  
• Drug dispensing: Patients will be given 30 days of drug supply at the beginning of each cycle.   
 
6.7 End of Trial Treatment (EOT) 
Patients are permitted to continue treatment with Tenalisib until disease progression, or the patient 
is discontinued due to unacceptable toxicity or decision to discontinue treatment by the patient or 
the trial physician. Follow-up evaluations required after treatment ends are specified in Table 1. 
 
All patients who discontinue study drugs will have an End of Treatment visit within 14 days from 
the last dose of study drug. If treatment is discontinued because of toxicity or any other reason(s) 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 37 of 62 
at a treatment visit and no trial treatment is administered, that visit may fulfill the End of Trial 
Treatment Visit. 
 
6.8 End of Study (EOS) 
All patients must be followed for adverse events for 30 calendar days after the last dose of study 
drug. A telephonic follow up is acceptable. In case of drug related AEs, further safety assessments 
will be performed as warranted, at the discretion of PI. The patient will be followed till resolution 
or stabilization of related adverse event.  
 
6.9 Early Patient Termination / Patient Withdrawal 
Patients who discontinue treatment early due to disease progression or withdrawal will be asked to 
have all end-of-treatment safety evaluations performed as described in the protocol (see Table 1).  
 
7 ASSESSMENT OF SAFETY 
7.1 Adverse Events 
The PI is responsible for collecting and reporting adverse events (see Section 7.1.2).  It is Sponsor 
responsibility to report relevant SAEs to the applicable regulatory body. 
 
7.1.1 Definitions of adverse events  
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational product, whether or not related to the investigational product.   
 
7.1.2 Recording of adverse events 
All adverse events of any patient during the course of the trial will be reported in the case report 
form, and the investigator will give his or her opinion as to the relationship of the adverse event to 
trial drug treatment (i.e., whether the event is related or unrelated to trial drug administration). If 
the adverse event is serious, it should be reported immediately to Sponsor. Other untoward events 
occurring in the framework of a clinical trial are also to be recorded as AEs (i.e., AEs that occur 
prior to assignment of trial treatment that are related to a protocol-mandated intervention, including 
invasive procedures such as biopsies, medication washout, or no treatment run-in). 
 
All AEs regardless of seriousness or relationship to Tenalisib, spanning from the informed consent 
drug until 30 calendar days after the last dose of study drug, discontinuation or completion of 
protocol-specific treatment as defined by the protocol for that patient, are to be recorded in the 
electronic Case Record Form (CRF).  
 
7.1.3 Handling of adverse events 
All adverse events resulting in discontinuation from the trial should be followed until resolution or 
stabilization. Patients must be followed for AEs for 30 calendar days after the last dose of study 
treatment. All new AEs occurring during this period must be reported and followed until resolution 
unless, in the opinion of the investigator, the adverse event or laboratory abnormality/ies are not 
likely to improve because of the underlying disease. In this case, the investigators must record his 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 38 of 62 
or her reasoning for this decision in the patient’s medical record and as a comment on the CRF. 
After 30 days of completion of protocol-specific treatment or discontinuation, only AEs, SAEs, or 
deaths assessed by the investigator as treatment related are to be reported. 
 
7.2 Adverse Event/Serious Adverse Event Causality Assessment  
Causality is assessing the relationship of the trial treatment to the adverse event. For this study, the 
causality assessment will be categorized as related and not related.  
 
• Related: All toxicities should be considered to be related to Tenalisib unless there is a clear 
alternative explanation.   
• Not related:  If there is no temporal association, or another etiology has been identified as the 
cause, or the trial treatment cannot be implicated based upon the current information. 
 
7.3 Serious Adverse Events 
7.3.1 Definitions of serious adverse events 
The definitions of serious adverse events (SAEs) are given below. The principal investigator is 
responsible for ensuring that all staff involved in the trial is familiar with the content of this section. 
 
An SAE or reaction is defined as any untoward medical occurrence that: results in death, is 
immediately life-threatening, requires at least a 24-hour in-patient hospitalization or prolongation 
of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital 
anomaly/birth defect. 
 
The definition of SAE also includes any important medical event. Medical and scientific judgment 
should be exercised in deciding whether expedited reporting is appropriate in other situations, such 
as important medical events that may not be immediately life-threatening or result in death or 
hospitalization, but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the previous definition. These should also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. Progression of malignancy (including fatal 
outcomes), if documented by use of appropriate method (e.g. CT/ PET) or clinically confirmed, 
should not be reported as a serious adverse event.  
 
Treatment within or admission to the following facilities is not considered to meet the criteria of 
“in-patient hospitalization” (although if any other SAE criteria are met, the event must still be 
treated as an SAE and immediately reported): 
• Emergency Department or Emergency Room 
• Outpatient or same-day surgery units 
• Observation or short-stay unit 
• Rehabilitation facility 
• Hospice or skilled nursing facility 
• Nursing homes, Custodial care or Respite care facility 
 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 39 of 62 
Hospitalization during the trial for a pre-planned surgical or medical procedure (one which is 
planned prior to entry in the trial or planned in advance and not related to the study procedure/ 
drug), does not require reporting as a serious adverse event to the Sponsor. 
 
7.3.2 Serious adverse event reporting by Investigators 
It is important to distinguish between “serious” and “severe” adverse events, as the terms are not 
synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need not 
necessarily be considered serious.  For example, nausea which persists for several hours may be 
considered severe nausea, but may not be considered an SAE.  On the other hand, a stroke which 
results in only a limited degree of disability may be considered only a mild stroke, but would be 
considered an SAE. Severity and seriousness should be independently assessed when recording 
AEs on the CRF and SAEs on the SAE Report Form. 
 
Adverse events classified by the treating investigator as serious require expeditious handling and 
reporting to sponsor in order to comply with regulatory requirements.  Serious adverse events may 
occur at any time from the signing of the informed consent form through the 30-day follow-up 
period after the last trial treatment. Sponsor/sponsor representative must be notified of all SAEs, 
regardless of causality, within 1 day of the first knowledge of the event by the investigator.   
 
To report an SAE, the SAE Report Form should be completed with the necessary information.  All 
SAEs occurring from the signing of consent until 30 calendar days of last trial treatment must be 
reported to the Sponsor as SAEs on the SAE Report and followed until resolution (with autopsy 
report if applicable). 
 
Deaths and other SAEs occurring >30 calendar days after last trial treatment that are deemed 
‘possibly’ or ‘probably’ related to Tenalisib must be reported as SAEs on the SAE Report within 
1 day of first knowledge of the event by the treating physician or research personnel (with an 
autopsy report if available). Deaths occurring >30 calendar days after last trial treatment and not 
attributed to trial treatment (e.g., disease progression) need not be reported as SAEs, but simply 
captured on the appropriate CRF. 
 
The SAE report should be sent to the sponsor/sponsor representative via fax or e-mail within 24 
hours of becoming aware of the event. The detailed SAE reporting process will be reviewed with 
sites during the site initiation visit as well as provided on the SAE report itself.. Transmission of 
the SAE report should be confirmed by the site personnel submitting the report. Follow-up 
information for SAEs and information on non-serious AEs that become serious should also be 
reported to Sponsor as soon as it is available; these reports should be submitted using the SAE 
Report Form.   
 
Investigators must report SAEs and follow-up information to their responsible IRB/IEC according 
to the policies of the responsible IRB/IEC. 
 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 40 of 62 
7.3.3 Sponsor SAE reporting requirements 
Sponsor/Sponsor representative is responsible for reporting relevant SAEs to the competent 
authority, other applicable regulatory authorities, and participating investigators, in accordance 
with ICH guidelines, FDA regulations, and/or local regulatory requirements. 
 
Sponsor/sponsor representative is responsible for reporting unexpected fatal or life-threatening 
events associated with the use of the trial drugs to the regulatory agencies and competent authorities 
via telephone or fax within 7 calendar days after being notified of the event.   
 
The Sponsor will report all related, unexpected SAEs, including non-death/non-life-threatening 
related unexpected SAEs associated with the use of the trial medications to the FDA by a written 
safety report within 15 calendar days of notification. Reporting to the IRB/IEC will be done 
according to institutional policy. 
 
7.4 Recording of Adverse Events and Serious Adverse Events 
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on 
the SAE Report Forms and AE CRF. Avoid colloquialisms and abbreviations. All AEs, including 
those that meet SAE reporting criteria, should be recorded on the AE CRF; AEs that meet the 
definition of an SAE should additionally be reported following the procedures noted in above 
sections.  
 
7.4.1 Diagnosis vs. signs and symptoms 
All AEs should be recorded individually in the patient’s own words (verbatim) unless, in the 
opinion of the Coordinating Investigator or designated physician, the AEs constitute components 
of a recognized condition, disease, or syndrome.  In the latter case, the condition, disease, or 
syndrome should be named rather than each individual sign or symptom.  If a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at the time 
of reporting, each individual event should be recorded as an AE or SAE as appropriate on the 
relevant form(s) (SAE Report Form and/or AE CRF). If a diagnosis is subsequently established, it 
should be reported as follow-up information is available. If a diagnosis is determined subsequent 
to the reporting of the constellation of symptoms, the signs/symptoms should be updated to reflect 
the diagnosis. 
 
7.4.2 Persistent or recurrent adverse events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points. Such events should only be recorded once on the SAE Report Form and/or the 
AE CRF, irrespective of severity. (E.g. If a persistent AE becomes more severe or lessens in 
severity, it should be recorded once with highest grade of severity in CRF/SAE Report Form).  A 
recurrent AE is one that occurs and resolves between patient evaluation time points, and 
subsequently recurs. All recurrent events should be recorded separately in CRF/SAE Report Form. 
 
7.4.3 Abnormal laboratory values 
Any grade 3 or 4 laboratory abnormalities or any clinically significant grade 1 or 2 hematology or 
biochemistry laboratory value(s) should be recorded as an AE. Isolated laboratory abnormality 
without clinical significance should not be captured as AE if confirmed by the investigator. If an 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 41 of 62 
abnormal laboratory value or vital sign is associated with clinical signs and/or symptoms, the sign 
or symptom should be reported as an AE, and the associated laboratory value or vital sign should 
be considered additional information that must be collected on the relevant CRF. If the laboratory 
abnormality is a sign of a disease or syndrome, only the diagnosis needs to be recorded on the SAE 
Report Form or AE CRF. 
 
7.4.4 Deaths 
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
investigator solely to progression of disease will be recorded on the “Trial Discontinuation” CRF 
and should not be reported as a SAE. All other on- trial deaths, regardless of attribution, will be 
recorded on an SAE Report and expeditiously reported to the Sponsor. 
 
When recording a serious adverse event with an outcome of death, the event or condition that 
caused or contributed to the fatal outcome should be recorded as the single medical concept on the 
SAE report and Adverse Event page of the CRF. If the cause of death is unknown and cannot be 
ascertained at the time of reporting, record “Death NOS” on the CRF Adverse Event page.  
 
7.4.5 Hospitalization, prolonged hospitalization, or surgery 
Any AE that results in hospitalization of >24 hours or prolonged hospitalization should be 
documented and reported as an SAE unless specifically instructed otherwise in this protocol. There 
are some hospitalization scenarios that do not require reporting as an SAE when there is no 
occurrence of an AE. (See section 7.3)  
 
7.4.6 Pre-Existing medical conditions 
A pre-existing medical condition is one that is present at the start of the trial.  Such conditions 
should be recorded on the General Medical History CRF. A pre-existing medical condition should 
be recorded as an AE or SAE only if the frequency, severity, or character of the condition worsens 
during the trial. When recording such events on an SAE Report Form and/or AE CRF, it is 
important to convey the concept that the pre-existing condition has changed by including applicable 
description. 
 
7.4.7 Pregnancy, abortion, birth defects/congenital anomalies 
Pregnancy, abortion, birth defects, and congenital anomalies are events of special interest.  Please 
refer to pregnancy section 7.5.1 for specific instructions. 
 
7.4.8 New Cancers 
The development of a new primary cancer should be regarded as an AE and will generally meet at 
least one of the serious criteria. New primary cancers are those that are not the primary reason for 
the administration of the study treatment and have developed after the inclusion of the patient into 
the study. They do not include new lesions of the original cancer. Symptoms of metastasis or the 
new lesions itself should not be reported as an AE/SAE, as they are considered to be disease 
progression. 
 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 42 of 62 
7.4.9 Lack of efficacy 
When there is deterioration in the condition for which the study treatment is being used, there may 
be uncertainty as to whether this is lack of efficacy or an AE. In such cases, unless the sponsor or 
reporting physician considers the study treatment contributed to the deterioration of the condition, 
the deterioration should be considered lack of efficacy and not an AE. 
 
7.5 Protocol-Defined Events of Special Interest 
The following are events of special interest, and will need to be reported expeditiously. 
 
7.5.1 Pregnancy, abortion, birth defects/congenital anomalies 
Female patients who are not of child-bearing potential (see Appendix B) and female patients of 
child-bearing potential who have a negative serum pregnancy test within 72 hours prior to C1D1 
are eligible for the study. Female patients of child-bearing potential (see Appendix B)), and all 
male partners must consent to use a medically acceptable method of contraception throughout the 
study period and for 4 weeks after the last dose of Tenalisib. An approved barrier method of 
contraception must be discussed with the investigator and documented in source note.    
 
During the course of the trial, all female patients of childbearing potential and pregnant partner of 
male subjects must contact the treating investigator immediately if they suspect that they may be 
pregnant (a missed or late menstrual period should be reported to the treating investigator).   
 
If an investigator suspects that a patient may be pregnant prior to administration of trial drug(s), 
the trial drug(s) must be withheld until the result of the pregnancy test is confirmed. If a pregnancy 
is confirmed, the patient must not receive any trial drug(s), and must be discontinued from the trial. 
The outcome of the pregnancy will be monitored as outlined in Appendix B. 
 
If an investigator suspects that a patient may be pregnant after the patient has been receiving trial 
drug(s), the trial drug(s) must immediately be withheld until the result of the pregnancy test is 
confirmed. If a pregnancy is confirmed, the trial drug(s) must be immediately and permanently 
stopped, the patient must be discontinued from the trial, and the investigator must notify the 
medical monitor and Sponsor Representative as soon as possible. If a patient becomes pregnant 
while enrolled in the trial, a Pregnancy Form should be completed and faxed to the Sponsor. The 
outcome of the pregnancy will be monitored as outlined in Appendix B. 
    
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be 
expeditiously reported as an SAE, using the previously described process for SAE reporting. A 
Pregnancy Form should also have been previously completed, and will need to be updated to reflect 
the outcome of the pregnancy. 
 
7.5.2 Overdose 
An overdose is defined as accidental or intentional administration of any dose of product that is 
considered both excessive and medically important. For purposes of this trial, an overdose will be 
defined as any dose exceeding the proposed dose of Tenalisib (e.g. > 800 mg).   
 
Symptomatic and non-symptomatic overdose must be reported in the CRF.  Any accidental or 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 43 of 62 
intentional overdose with the trial treatment that is symptomatic, even if not fulfilling a seriousness 
criterion, is to be reported to the Sponsor immediately as an AE. All symptomatic overdose, 
fulfilling a seriousness criterion is to be reported as an SAE as per the SAE reporting procedure. 
For patients who experience overdose, treatment should consist of supportive therapy. A decision 
to interrupt treatment or dose reduction to be taken depending on the symptoms.  
 
7.6 Dose Modifications 
All dose modifications are graded by the CTCAE v5.0.  
Note:  If cytopenia events are deemed related to the underlying disease rather than Tenalisib, 
dose reduction will be done as per the investigator’s discretion. 
Patients may resume Tenalisib, provided that the toxicity has resolved to Grade ≤2 or baseline. If 
study drug is delayed >2 weeks because of an adverse event, re-initiation of treatment need to be 
discussed with the medical monitor. 
 
At the discretion of the Investigator, a dose re-escalation may be permitted for patients who 
previously had a dose reduction. Holidays from study drug are discouraged. Any patient in whom 
similar toxicity recurs at the reduced dose should be discontinued from further Tenalisib treatment. 
Note: In exceptional case, a patient may be allowed following a careful assessment of benefit and 
risk by the investigator and with approval from the medical monitor. 
7.6.1 Criteria for starting Tenalisib new cycle  
If treatment is delayed > 2 weeks due to AE or any other reason, treatment to be resumed with new 
cycle after discussion with medical monitor as long as:  
• 
Absolute neutrophil count has returned to baseline, or >750/µL. Platelet count is >50,000/µL.  
• 
Recovered from grade 3-4 non-hematologic toxicity to grade 2 or baseline (excluding 
alopecia). Treatment may be delayed for up to 2 weeks to recover from toxicity.  
• 
No clinical or radiographic evidence of disease progression.  
 
7.6.2 Dose modifications 
The dose modification guidelines are intended to be applied when the investigator determines 
the events related to Tenalisib.  
 Table 3: Dose Modifications for Hematologic Toxicity 
Worst CTCAE Grade Toxicity 
Action to be Taken 
HEMATOLOGIC  
Neutropenia (ANC) 
Grade 3  
1.0 X 109/L<ANC ≥ 0.5 X 109 /L 
Maintain dose level. 
Monitor ANC at least weekly. 
Grade 4  
0.5 x 109 /L<ANC 
First incidence: Hold* dose until resolved to ≤ Grade 2 or baseline, 
Restart Tenalisib at 400 mg BID dose level. 
Subsequent occurrence: Hold dose until resolved to ≤ Grade 2 or 
baseline, consider growth factor support. 
Discontinue if further dose modification required. 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 44 of 62 
Grade 3 Febrile neutropenia  
ANC <1000/mm3 with a single 
temperature of > 38.3 0C (101 0F) 
or a sustained temperature of ≥ 38 
0C (100.4 0F) for more than one 
hour. 
Hold* dose until resolved to ≤ Grade 2 or baseline, consider growth factor 
support, then reduce by 1 dose level.  
Thrombocytopenia 
Grade 3 (50.0 X 109 /L< PLT ≥ 
25.0 X 109 /L) 
Maintain dose level. 
Monitor platelet count at least weekly. 
Grade 4  
25.0 X 109/L< PLT 
1st occurrence: Hold** dose until resolved to ≤ Grade 2 or baseline, 
Restart Tenalisib at 400 mg BID dose level. 
Subsequent Occurrences: Hold dose until to ≤ Grade 2 or baseline, 
consider platelet transfusion as necessary.  
Discontinue if further dose modification required. 
Note: If the count is <50 X 109/L before initiation of therapy (e.g. in case 
of marrow involvement), the dose reduction should be done as per 
investigator’s judgement. 
*If study drug is delayed >2 weeks because of an adverse event, treatment strategy should be discussed with medical 
monitor. 
** Patient receiving concomitant medication (e.g. anticoagulants, anti-platelets, aspirin, or low molecular weight 
heparin) must be discussed with the medical monitor for continued management. 
 
 
Table 4: Dose Modifications for Non-Hematologic Toxicities  
NON-HEMATOLOGIC  
Action to be Taken 
Renal* 
If serum creatinine Grade ≥3 ( >3 x baseline or >3 x ULN), hold dose 
until ≤ grade 2. Monitor serum creatinine at least twice a week until 
resolution to ≤ grade 2, and then at least one week until it resolves to ≤ 
grade 1. 
Hepatic* 
Transaminitis  
Grade ≥ 1 Transaminitis (ALT/AST > 1-3 X ULN):  
• 
Maintain Tenalisib dose and initiate prednisone 40 mg daily.  
• 
Monitor AST/ALT weekly until resolved.  
• 
Withhold Tenalisib in case of development of grade 2 transaminitis or 
worsening of Grade 1 transaminitis while on steroids.  
 
Grade ≥ 3 Transaminitis (ALT/AST >5–20 X ULN):  
• 
Withhold Tenalisib and monitor ALT/AST twice a weekly until Grade 
1; restart Tenalisib at 400 mg BID dose level. 
• 
Initiate prednisone 1 mg/kg in case no improvement with 
discontinuation of Tenalisib in 1 week.  
• 
Monitor ALT/AST twice a weekly until Grade 1; restart Tenalisib at 
400 mg BID dose level and taper steroid.  
• 
If no immediate response to steroids within 7 days, initiate 
mycophenolate mofetil.                                   
• 
In case of recurrence of transaminitis at reduced doses, discontinue 
Tenalisib permanently after assessing risk versus benefit.  
 
Grade ≥ 4 Transaminitis (ALT/AST >20 X ULN):  
• 
Tenalisib should be permanently discontinued. 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 45 of 62 
 
 
 
 
 
 
 
* If study d*If the drug is delayed >2 weeks because of an adverse event, treatment strategy should be discussed 
with medical monitor. 
 
 
8 ASSESSMENT OF EFFICACY 
8.1 Specification of the Efficacy Parameters 
• ORR is defined as sum of CR and PR rates, as assessed by the Investigator according to the 
Lugano Classification for initial evaluation, staging, and response assessment of Non-Hodgkin 
lymphoma. Only those patients who have had a pre-treatment baseline efficacy evaluation and 
at least one post-treatment efficacy evaluation or confirmed disease progression will be 
considered evaluable for response. Subtype specific and overall ORR will be calculated in Part 
 
Bilirubin: 
• 
Grade ≥ 2 (> 1.5-3 X ULN): Maintain Tenalisib dose. Monitor at 
least weekly until ≤ 1X ULN 
• 
Grade ≥ 3 (> 3-10 X ULN): Withhold Tenalisib. Monitor at least 
weekly until bilirubin is≤ 1X ULN; restart Tenalisib at 400 mg BID 
dose level. 
• 
Grade ≥ 4 (> 10 X ULN): Discontinue Tenalisib permanently 
Infection  
Grade 3 or higher sepsis or pneumonia 
• 
Interrupt Tenalisib until infection has resolved. 
Diarrhea  
Moderate:  
• 
Maintain Tenalisib dose. Monitor at least weekly until resolved. 
Severe diarrhoea or hospitalization 
• 
Withhold Tenalisib dose. Monitor at least weekly until resolved. 
• 
Restart Tenalisib at 400 mg BID dose level. 
Life threatening diarrhoea  
• 
Discontinue Tenalisib permanently. 
Cardiac 
If a QTcF >500 msec has been demonstrated, hold dose. 
The patient will be monitored hourly with ECGs until the QTcF <500 msec 
and the QTcF has returned to “<30 msec from baseline”. Immediate 
attention to potassium and magnesium and other clinical factors such as 
oxygenation and ischemia should be addressed.   
All cardiac events should be treated as per the local standard of care and 
referral to a specialist if clinically indicated. Any final decisions concerning 
dose modifications or permanently discontinuing the patient from study drug 
due to QTcF prolongation will occur after discussion with medical monitor. 
OTHER NON-
HEMATOLOGIC  
Action to be Taken 
Grade 3/4 CTCAE  
First occurrence:  
Hold* dose until toxicity Grade ≤2; restart Tenalisib at 400 mg BID dose 
level.  
Subsequent Occurrences: Hold dose until to ≤ Grade 2 or baseline.  
Discontinue if further dose modification required. 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 46 of 62 
1 of the study. Criteria for evaluable subjects for Part 2 will be re-defined based on the results 
of Part 1.  
 
• CR rate will be assessed by the investigator according to the Lugano Classification for initial 
evaluation, staging, and response assessment of non-Hodgkin lymphoma. For assessment of 
CR, a post-treatment residual mass of any size is permitted if it is negative on positron emission 
tomography imaging. Only those patients who have had a pre-treatment baseline efficacy 
evaluation and at least one post-treatment efficacy evaluation or confirmed disease progression 
will be considered evaluable for response. Subtype specific and overall CR will be calculated 
in Part 1 of the study.  
 
• PFS is defined as time of the first dose of Tenalisib to disease progression or death. Subjects 
who die without a reported prior progression will be considered to have progressed on the date 
of their death. Subjects who did not progress or die will be censored on the date of their last 
tumor assessment.  
 
• DoR 
is 
defined 
as 
the 
time 
when 
the 
measurement 
criteria 
are 
first 
met for PR or CR (whichever is reported first) until the date of documented disease 
progression or death. For subjects who neither progress nor die, the duration of response 
will be censored at the date of their last disease assessment. 
 
• Evaluation of Best Overall Response: The “best overall response” is the best response 
recorded from the start of the treatment until disease progression or discontinuation from the 
study.  
 
Disease parameters:  
• Measurable disease: Measurable lesions are defined as those that can be accurately measured 
in at least two dimensions with conventional techniques (CT/PET/PET-CT, MRI, x-ray) or 
as >1.5 cm with CT scan. All tumor measurements should be recorded in centimeters.   
 
• Non-measurable disease (evaluable disease): All other lesions (or sites of disease) including 
small lesions, (<1 cm using spiral CT scan) are considered non-measurable disease. Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis, and cystic 
lesions are all non-measurable. 
 
 
• Target lesions: All measurable lesions up to a maximum of 6 lesions total, representative of all 
involved organs, should be identified as target lesions and recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest SPD 
diameter), and the highest SUV avidity (high SUV lesions may be prioritized even if not the 
largest lesions, and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). A baseline sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 47 of 62 
diameters. The baseline sum of the diameters will be used as reference to further characterize 
any objective tumor regression in the measurable dimension of the disease. 
 
• Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over 
and above the 6 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
8.2 Response Evaluations and Measurements 
During Screening, the disease will be staged and confirmed by an expert hematologist as per the 
appropriate staging. Ann-Arbor staging or Follicular Lymphoma International Prognostic Index 
(FLIPI) will be performed as appropriate. Clinical assessments will include ECOG performance 
status (Appendix A), lymph nodes, organomegaly and “B” symptoms.  
 
Disease response assessments should be performed at C3D1 (± 7 days), C5D1 (± 7 days) and 
approximately every 12 weeks thereafter (± 7 days), and/ or at the EOT or as clinically indicated 
(if clinical progression is suspected). If PET/PET-CT and CT scan at Screening are negative for 
disease involvement in the neck, subsequent CT scans may not include neck. If PET/PET-CT and 
CT scans at Screening are positive for disease involvement of the neck, subsequent CT scans must 
include neck. Disease assessments and imaging should continue to be performed until documented 
disease progression, the start of new anti-cancer treatment, withdrawal of consent, death, or the end 
of the study, whichever occurs first. Disease assessment will be performed as per the Lugano 
Classification (Cheson criteria 2014) [11] (refer Appendix C). 
 
 
9 STATISTICAL METHOD AND CONSIDERATIONS   
This section describes the statistical methods to be used to analyze efficacy and safety. These 
methods may be revised and updated due to reasons such as regulatory requirements or need for 
further clarifications. The final analysis plan will be documented in a formal statistical analysis 
plan (SAP) that must be finalized before database lock. The SAP will include details on how 
variables will be derived, how missing data will be handled, and how data will be presented as well 
as the details on statistical methods to be used for safety and efficacy analyses. The final clinical 
study report will discuss deviations from the SAP, if any. 
 
After all patients enrolled in Part 1 had the opportunity to provide at least three tumor outcome 
assessments, the DRC will evaluate the efficacy (anti-tumor activity) and safety results for each of 
the subtypes. If the committee believes there are potential clinically meaningful benefits for certain 
subtype, the committee will recommend initiation of Part 2 to evaluate efficacy and safety for that 
subtype. Data from Part 1 will not be included in the analysis of Part 2 of the study. 
 
9.1 General Considerations 
Unless otherwise stated, all statistical analyses will be performed using a two-sided hypothesis test 
at the overall 5% level of significance. Continuous data will be described using the following 
descriptive statistics: n, mean, median, minimum and maximum. Data will be displayed in all 
listings sorted by phase, group and patient number.   


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 48 of 62 
 
When count data are presented, the percentage will be suppressed when the count is zero in order 
to draw attention to the non-zero counts. A row denoted “Missing” will be included in count 
tabulations where necessary to account for dropouts and missing values. Unless otherwise 
specified, the denominator for percentages will be the number of patients with a non-missing 
assessment in a given treatment group within the analysis population of interest. 
All statistical analyses will be performed using SAS 9.1 or higher. 
 
9.2 Determination of Sample Size 
Since study Part 1 was exploratory in nature.  The sample size for Part 1 is not based on statistical 
considerations. After all patients enrolled in Part 1 had the opportunity to provide at least three 
tumor outcome assessments, the DRC will evaluate the efficacy and safety results for each of the 
subtypes. If the committee believes there are potential clinically meaningful benefits for certain 
subtype, the committee will recommend initiation of Part 2 to evaluate efficacy and safety for that 
subtype. The sample size for Part 2 will be derived based on ORR data from Part 1. 
 
9.3 Study Population 
The following 3 analysis populations are planned for Part 1 of the study. Analysis population for 
Part 2 will be redefined based on the results of Part 1.  
• Modified Intent-to-Treat Population (mITT): the mITT is the primary efficacy analysis 
population and will include data from all patients who received at least 1 dose of study 
medication and provide at least 1 post-baseline efficacy assessment.  
• Per-Protocol (PP) Population: the PP Population is a subset of the modified Intent-to-Treat 
Population and will include patients without major protocol deviations.  
• Safety Population: the Safety Population will include all subjects who receive at least 1 
dose of the study drug. 
Membership in the analysis populations will be determined before database lock. 
 
9.4 Statistical Analysis 
9.4.1 Demographic and baseline characteristics 
Demographics and baseline characteristics will be summarized using descriptive statistics for 
continuous variables, and frequencies and percentages for categorical variables. 
 
9.4.2 Safety analyses 
The safety endpoints will include: 
• Incidence of AEs and related AEs  
• Incidence of grade 3, grade 4 AEs  
• Incidence of SAEs and death 
• Laboratory values 
• ECG/vital signs 
The safety endpoints will be listed and/or summarized. No inferential statistical analyses will be 
performed. 
 
The analyses of safety will be based on the frequency of adverse events and their severity for 
patients in each portion who received at least one dose of study treatment. Worst toxicity grades 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 49 of 62 
per patient will be tabulated for select adverse events and laboratory measurements by using NCI 
CTCAE criteria v5.0. 
 
9.4.3 Efficacy analyses 
The efficacy endpoints will include: 
• Objective Response Rate  
• CR rates   
• Duration of response 
• Progression free survival (PFS) 
The analysis will be done as per the disease subtypes and overall. Additional analyses may also be 
performed as appropriate. These analyses will be performed from time to time for 
presentation/publication purposes. 
 
 
10 ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
This trial will be conducted according to the standards of Good Clinical Practice outlined in the 
ICH E6 Tripartite Guideline, and CFR Title 21 part 312, World Medical Association’s Declaration 
of Helsinki, applicable government regulations, institutional research policies and procedures and 
local applicable regulatory requirement(s).  
 
All potential serious breaches must be reported to Rhizen Pharmaceuticals SA immediately. A 
serious breach is a breach of the conditions and principles of GCP in connection with the study or 
the protocol, which is likely to affect, to a significant degree, the safety or physical or mental 
integrity of the subjects of the study or the scientific value of the study.  
 
10.1  IRB/IEC Approval 
The trial protocol, ICF, IB, available safety information, patient documents, patient recruitment 
procedures (e.g., advertisements), information about payments (i.e., PI payments) and 
compensation available to the patients and documentation evidencing the PI’s qualifications should 
be submitted to the IRB/IEC for ethical review and approval if required by local regulations, prior 
to the trial start.   
 
The PI/Rhizen and/or designee will follow all necessary regulations to ensure appropriate, initial, 
and ongoing, IRB/IEC trial review. The PI/Rhizen (as appropriate) must submit and, where 
necessary, obtain approval from the IRB/IEC for all subsequent protocol amendments and changes 
to the informed consent document.  Investigators will be advised by Rhizen/designee whether an 
amendment is considered substantial or non-substantial and whether it requires submission for 
approval or notification only to an IRB/IEC. 
 
Safety updates for Tenalisib will be prepared by Rhizen or its representative as required, for 
submission to the relevant IRB/IEC. 
 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 50 of 62 
10.2  Regulatory Approval 
As required by local regulations, Rhizen will ensure that all legal aspects are covered, and approval 
of the appropriate regulatory bodies obtained, prior to trial initiation. If required, Rhizen will also 
ensure that the implementation of substantial amendment to the protocol and other relevant trial 
documents happen only after approval by the relevant regulatory authorities. Safety updates will be 
prepared by the Rhizen or its representative as required, for submission to the relevant regulatory 
authority.  
 
10.3  Insurance and Indemnity 
Details of insurance and/or indemnity will be contained within the written agreement between the 
PI or site and Rhizen. Rhizen will reimburse the subject for all study-related injuries provided that 
the injury does not arise from the subject’s misuse of the study drug or failure to follow the 
Investigator’s instructions. 
 
10.4 Financial Disclosure and Obligations 
Principal Investigators and Sub-Investigators are required to provide financial disclosure 
information to allow Rhizen to submit the complete and accurate certification or disclosure 
statements required under Part 54 of Title 21 of the CFR. In addition, the Principal Investigator or 
Sub- Investigators must provide to the Sponsor a commitment to promptly update this information 
if any relevant changes occur during the course of the investigation and for 1 year following the 
completion of the study. 
 
10.5  Informed Consent 
Informed consent is a process by which a subject voluntarily confirms his or her willingness to 
participate in a particular trial, after having been informed of all aspects of the trial that are relevant 
to the subject's decision to participate. Informed consent is documented by means of a written, 
signed and dated informed consent form. 
 
The informed consent form will be submitted for approval to the IRB/IEC that is responsible for 
review and approval of the trial.  Each consent form must include all of the relevant elements 
currently required by the regulatory authorities or state regulations and national requirements. 
Translation of the informed consent form is allowed if necessary. 
Before recruitment and enrollment into the trial, each prospective candidate will be given a full 
explanation of the trial. Once the essential information has been provided to the prospective 
candidate, and the investigator is sure that the individual candidate understands the implications of 
participating in this trial, the candidate will be asked to give consent to participate in the trial by 
signing an informed consent form. A notation that written informed consent has been obtained will 
be made in the patient’s medical record. A copy of the signed informed consent form will be 
provided by the investigator to the patient.   
 
If an amendment to the protocol substantially alters the trial design or the potential risks to the 
patients, the patient’s re-consent to continue participation in the trial should be obtained. 
 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 51 of 62 
10.6   Confidentiality 
10.6.1 Patient confidentiality 
Confidentiality of patient’s personal data will be protected in accordance with the Health  
Insurance Portability and Accountability Act of 1996 (HIPAA) and national data protection laws 
or specific country requirements, as applicable. HIPAA regulations require that, in order to 
participate in the trial, a patient must sign an authorization from the trial that he or she has been 
informed of following: 
a. What protected health information (PHI) will be collected from patients in this trial; 
b. Who will have access to that information and why;  
c. Who will use or disclose that information;  
d. The information collected about the research trial will be kept separate from the patient’s 
medical records, but the patient will be able to obtain the research records after the conclusion 
of the trial;  
e. Whether the authorization contains an expiration date;   
f. The rights of a research patient to revoke his or her authorization.  
 
In the event that a patient revokes authorization to collect or use his or her PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization.  For patients that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e., that the patient is alive) at the end 
of their scheduled trial period. 
 
In compliance with ICH GCP guidelines and applicable parts of 21 CFR, it is a requirement that 
the investigator and institution permit authorized representatives of Sponsor, the regulatory 
authorities and the IRB/IEC direct access to review the patient’s original medical records at the site 
for verification of trial-related procedures and data.  
 
Measures to protect confidentiality include mentioning of only a unique trial number and initials 
will identify patients on the CRF or other documents that will be submitted to Rhizen. This 
information, together with the patient’s date of birth, will be used in the database for patient 
identification. Patient names or addresses will not be entered in the CRF or database. No material 
bearing a patient’s name will be kept on file by Sponsor. Patients will be informed of their rights 
within the ICF.  
 
10.6.2 Investigator’s responsibilities 
Medical supervision is the responsibility of the Principal Investigator named on the FDA Form 
1572/country specific forms. The Investigator may delegate day-to-day activities to a sub-
investigator listed on these forms but retains overall responsibility for ensuring that the study is 
conducted properly and in accordance with the study protocol.  The Investigator is required to 
provide the Sponsor with his/her own CV and applicable licensure, as well as those of the personnel 
assuming significant responsibility in the study (e.g., sub-investigators).  The Investigator is 
responsible for ensuring that the study is conducted according to applicable health authorities (e.g. 
FDA), sound medical practices, and in compliance with applicable regulations (e.g. 21 CFR, ICH). 
 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 52 of 62 
10.6.3 Investigator and staff training and information 
Personal data of the investigators and sub-investigators may be included in the site database, and 
shall be treated in compliance with all applicable laws and regulations. When archiving or 
processing personal data pertaining to the investigator or sub-investigator, the site shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized party. 
 
All Investigators and their study personnel will receive training regarding the study procedures and 
GCP/regulations specific to the conduct of clinical trials. This training will be documented and will 
take place prior to enrollment and throughout the study as necessary. 
 
11 RECORD RETENTION AND DOCUMENTATION OF THE TRIAL 
 
11.1 Amendments to the Protocol 
Amendments to the protocol shall be planned, documented and signature authorized prior to 
implementation. If an amendment to the protocol is required, the amendment will be originated and 
documented by Rhizen. All amendments require review and approval of Rhizen and the Principal 
Investigator supporting the trial. The written amendment must be reviewed and submitted to the 
IRB/IEC at the investigator’s facility for the board’s approval. 
 
11.2 Protocol Deviations  
The Principal Investigator is required to follow the protocol. The Investigator/designee must 
document and explain in the subject’s source documentation any deviation from the approved 
protocol. A deviation from the protocol is an unintended and/or unanticipated departure from the 
procedures and/or processes approved by the Sponsor and the IRB/IEC and agreed to by the 
Principal Investigator. Protocol deviations will be documented by the clinical monitor throughout 
the course of monitoring visits. Principal Investigator will be notified of deviations in writing by 
the monitor. The IRB/IEC should be notified of all protocol deviations according to IRB/IEC 
reporting requirements.  
 
11.3  Documentation Required to Initiate Trial 
Before the trial may begin, documentation required by the health authorities will be provided by 
the Sponsor.  Documents at a minimum required to begin a trial include, but are not limited to: a 
signature-authorized protocol and contract; a copy of the official IRB/IEC approval of the trial and 
the IRB/IEC members list; current Curricula Vita for the principal investigator and any associate 
investigator(s) who will be involved in the trial; indication of appropriate accreditation for any 
laboratories to be used in the trial and a copy of the normal ranges for tests to be performed by that 
laboratory; original Form FDA 1572 (Statement of Investigator), appropriately completed and 
signed; a copy of the IRB-approved consent form containing permission for audit by 
representatives of Sponsor, the IRB, and the FDA/health authorities; financial disclosure forms for 
all investigators listed on Form FDA 1572; site qualification reports, where applicable; verification 
of Principal Investigator acceptability from local and/or national debarment list(s).  
 
12 DATA HANDLING AND RECORD KEEPING  
The PI must maintain a list of appropriately qualified persons to whom he/she has delegated trial 
duties and should ensure that all persons assisting in the conduct of the trial are informed of their 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 53 of 62 
obligations. All persons authorized to make entries and/or corrections on the CRFs are to be 
included on this document. All entries in the patient’s CRF are to be supported by source 
documentation where appropriate. 
 
Source documents are the original documents, data, records and certified copies of original records 
of clinical findings, observations and activities from which the patient’s CRF data are obtained. 
These can include, but are not limited to, hospital records, clinical and office charts, laboratory, 
medico-technical department and pharmacy records, diaries, microfiches, ECG traces, copies or 
transcriptions certified after verification as being accurate and complete, photographic negatives, 
microfilm or magnetic media, X-rays, and correspondence. 
 
The PI and trial staffs are responsible for maintaining a comprehensive and centralized filing 
system (Site Trial File/SSF or ISF) of all trial-related (essential) documentation, suitable for 
inspection at any time by representatives from the Sponsor and/or applicable regulatory authorities.  
The ISF/SSF must consist of those documents that individually or collectively permit evaluation 
of the conduct of the trial and the quality of the data produced. The ISF/SSF should contain as a 
minimum all relevant documents and correspondence as outlined in ICH GCP section E6 and 21 
CFR Part 312.57, including key documents such as the IB and any amendments, protocol and any 
amendments, signed ICFs, copies of completed CRFs, IEC approval documents, Financial 
Disclosure forms, patient identification lists, enrollment logs, delegation of authority log, staff 
qualification documents, laboratory normal ranges, records relating to the trial drug including 
accountability records. Drug accountability records should, at a minimum, contain information 
regarding receipt, shipment, and disposition.   
 
Each form of drug accountability record, at a minimum, should contain PI name, date drug 
shipped/received, date, quantity and batch/code, or lot number for identity of each shipment. In 
addition, all original source documents supporting entries in the CRF must be maintained and be 
readily available. 
 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial and as required by the applicable regulatory 
requirement(s). The investigator/institution should take measures to prevent accidental or 
premature destruction of these documents 
 
The Investigator shall maintain adequate records of drug disposition, case histories and any other 
trial-related records as per 21 CFR Part 312.62 for no less than 2 years after the last marketing 
application has been approved by FDA/health authority; or, in the event that the marketing 
application has not been approved by FDA/health authority, for no less than 2 years after the last 
shipment / delivery of the drug for investigational use is discontinued and FDA/health authority 
has been notified of the discontinuation. 
 
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the investigator additionally agrees to keep records, including the identity of all 
participating patients (sufficient information to link records e.g., CRFs and medical records), all 
original, signed informed consent forms, and copies of all CRFs, SAE Reporting forms, source 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 54 of 62 
documents, detailed records of treatment disposition, and related essential regulatory 
documents.  The documents listed above must be retained by the investigator for as long as needed 
to comply with national and international regulations (generally 2 years after discontinuing clinical 
development 
or 
after 
the 
last 
marketing 
approval).  
Sponsor 
will 
notify 
the 
investigator(s)/institutions(s) when the trial-related records are no longer required.   
 
If the investigator relocates, retires, or for any reason withdraws from the trial, both site and sponsor 
should be prospectively notified.  The trial records must be transferred to an acceptable designee, 
such as another investigator, another institution, or to sponsor.  The investigator must obtain the 
sponsor written permission before disposing of any records, even if retention requirements have 
been met.  All trial files will be maintained by the Sponsor/Sponsor Representative/CRO 
throughout the trial, and will be transferred to the Sponsor at the conclusion of the trial. 
 
12.1   Data Collection 
The data will be captured in electronic Case Record Form (CRF). The CRF is clinical trials data 
management tool that provides investigational sites a standardized and validated, remote, electronic 
data capture system for the collection of clinical trial data.  All data requested on the CRF must be 
supported by and be consistent with the patient’s source documentation. All missing data must be 
explained. When a required laboratory test, assessment, or evaluation has not been done or an 
“Unknown” box is not an option on the CRF, a note should be created verifying that the field is 
“Not Done” or “Unknown”. For any entry errors made, the error(s) must be corrected, and a note 
explaining the reason for change should be provided.  
 
The principal investigator will sign and date each casebook attesting to his/her responsibility for 
the quality of all data included therein, and that the data represent a complete and accurate record 
of each subject's participation in the study.  
 
Clinical data management will be performed in accordance with applicable standards. Data 
cleaning procedures will be performed with the objective of removing errors and inconsistencies 
in the data which would otherwise impact on the analysis and reporting objectives, or the credibility 
of the Clinical Study Report. Adverse events, medical history and concomitant medications will be 
coded using industry standard dictionaries (MedDRA and WHO Drug).  
 
12.2   Trial Monitoring, Auditing, and Inspecting 
The study will be monitored by the Sponsor and/or Sponsor's representatives at all stages of study 
conduct from inception to completion in accordance with current GCPs. This monitoring will be 
in the form of site visits and other communication and will include review of original source 
documents and eCRFs. The Sponsor's monitor or representative will notify the Principal 
Investigator prior to conducting any investigational site visit.  The frequency of these visits will 
depend upon the progress of the study, and will include monitoring to assess facilities and 
equipment, recruiting, record-keeping, protocol adherence, data collection, AE reporting and other 
factors. 
 
The investigator will permit trial-related monitoring, quality audits, and inspections by the sponsor, 
government regulatory authorities, the Sponsor or its representative(s) of all trial-related 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 55 of 62 
documents (e.g., source documents, regulatory documents, data collection instruments, case report 
forms). The investigator will ensure the capability for inspections of applicable trial-related 
facilities. The investigator will ensure that the trial monitor or any other compliance or QA reviewer 
is given access to all trial-related documents and trial-related facilities.   
 
Participation as an investigator in this trial implies the acceptance of potential inspection by 
government regulatory authorities, the sponsor or its representative(s). At the Sponsor’s discretion 
Source Document Verification (SDV) may be performed on all data items or a percentage thereof. 
 
The Investigator is responsible for notifying Rhizen in advance of an impending regulatory 
inspection. He/she may request that Rhizen provide support for preparation, if necessary, and is 
required to provide updates on the ongoing activities during the inspection and submit any 
citations/objectionable findings (i.e., FDA 483) and is required to share any follow up responses to 
the outcome. 
 
12.3 Medical Monitoring 
The sponsor will provide a medical monitor, a medical expert who advises the study investigators 
and monitors participant safety. The role of the medical monitor is to review all AEs/SAEs on a 
regular basis throughout the study, to advise the investigators on study-related medical questions 
or problems as needed, and to evaluate cumulative participant safety data and make 
recommendations regarding the safe continuation of the study.  
 
12.4 Quality Assurance and Quality Control 
Each trial site shall be required to have Standard Operating Procedures (SOP’s) to define and 
ensure quality assurance/control processes for trial conduct, data generation & collection, recording 
of data/documentation and reporting according to the protocol, GCP and any applicable local, 
national or international regulations. 
 
13 DISCLOSURE AND PUBLICATION POLICY 
All information provided regarding the trial, as well as all information collected/documented 
during the course of the trial, will be regarded as confidential. The Sponsor reserves the right to 
release literature publications based on the results of the trial.  Results from the trial will be 
published/presented as per the Sponsor’s publication strategy. 
 
Inclusion of the investigator in the authorship of any multi-center publication will be based upon 
substantial contribution to the design, analysis, interpretation of data, drafting and/or critically 
revising any manuscript(s) derived from the trial. The investigator acknowledges that the trial is 
part of a multi-center trial and agrees that any publication by the investigator of the results of the 
trial conducted at research site shall not be made before the first multi-center publication. In the 
event there is no multi-center publication within fifteen (15) months after the trial has been 
completed or terminated at all trial sites, and all data has been received, the investigator shall have 
the right to publish its results from the trial, subject to the notice requirements described herein and 
subject to acknowledgement of the Sponsor as appropriate.  Investigator shall provide the Sponsor 
thirty days to review a manuscript or any poster presentation, abstract or other written or oral 
material which describes the results of the trial for the purpose only of determining if any 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 56 of 62 
confidential or patentable information is disclosed thereby. If the Sponsor requests in writing, the 
investigator shall withhold any publication or presentation an additional sixty (60) days solely to 
permit the Sponsor to seek patent protection and to remove any site Confidential Information from 
all publications.  
 
14 REFERENCES 
1. Okkenhaug K. Signalling by the phosphoinositide 3-kinase family in immune cells. Annual 
review of immunology. 2013;31:675-704. 
2. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase (PI3K) 
pathway in cancer. Nature reviews Drug discovery. 2009;8(8):627-644. . 
3. Foster FM, Traer CJ, Abraham SM, Fry MJ. The phosphoinositide (PI) 3-kinase family. J 
Cell Sci. 2003;116(Pt 15):3037-3040. 
4. MOLT-4 Xenograft in Nude Mice (Incozen-CP-006). 
5. Tenalisib (RP6530) Investigator’s brochure. Version 9, Dated 05  October 2018.   
6. Jaffe ES. Relationship of classification to biologic behavior of non-Hodgkin’s 
lymphomas. Semin Oncol. 1986;13(4 suppl 5):3–9 
7. National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in 
Oncology: Non-Hodgkin’s Lymphomas (version 2.2018) 2018. 
8. Casulo C, Byrtek M, Dawson KL, et al. Early relapse of follicular lymphoma after rituximab 
plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high 
risk for death: an analysis from the National LymphoCare Study. J Clin 
Oncol. 2015;33(23):2516–2522 
9. Chao MP. Treatment challenges in the management of relapsed or refractory non-
Hodgkin’s lymphoma – novel and emerging therapies. Cancer Manage Res. 2013;5:251–
269. 
10. Nabhan C, Byrtek M, Rai A, Dawson K, Zhou X, Link BK et al. Disease characteristics, 
treatment patterns, prognosis, outcomes and lymphoma-related mortality in elderly 
follicular lymphoma in the United States. Br J Haematol. 2015 Jul;170 (1):85-95. 
11. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for Initial Evaluation, 
Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano 
Classification. J Clin Oncol. 2014;32(27):3059-3067 
 
 
 
 
 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 57 of 62 
15 APPENDICES 
        Appendix A: 
ECOG Performance Status Scale 
         
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to 
carry out any work activities.  Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 58 of 62 
Appendix B: Contraceptive Guidelines and Pregnancy 
Women Not of Childbearing Potential are defined as Follows 
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with 
serum FSH levels > 40 mIU/mL] or have had surgical bilateral oophorectomy (with or without 
hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level assessment 
is she considered not of child bearing potential. 
Contraceptive Guidelines for Women of Child-Bearing Potential 
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, must use highly effective contraception during the study and for 5 T1/2 plus an 
additional 4 weeks after stopping treatment. The highly effective contraception is defined as 
either: 
1. 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. 
2. Sterilization:  have had surgical bilateral oophorectomy (with or without hysterectomy) or 
tubal ligation at least six weeks ago.  In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment. 
3. Male partner sterilization (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate). For female subjects on the study, the vasectomised male 
partner should be the sole partner for that patient. 
4. Use of a combination of any two of the following (a+b): 
a. Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
b. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or   
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. 
 
The following are unacceptable forms of contraception for women of childbearing potential:  
• 
Oral contraception, injected or implanted hormonal methods are not allowed as Tenalisib 
may potentially decrease the effectiveness of hormonal contraceptives. 
• 
IUD progesterone T  
• 
Female condom  
• 
Natural family planning (rhythm method) or breastfeeding  
• 
Fertility awareness  
• 
Withdrawal  
• 
Cervical shield 
Women of child-bearing potential must have a negative serum or urine pregnancy test ≤ 72 
hours prior to initiating treatment. 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 59 of 62 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fertile Males 
Fertile males, defined as all males physiologically capable of conceiving offspring must use 
condom during treatment, plus additional 12 weeks after stopping treatment and should not 
father a child in this period.   
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to 
Rhizen Pharmaceuticals SA within 24 hours of learning of its occurrence. The pregnancy should 
be followed up for 3 months after the termination of the pregnancy 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. 
Consent to report information regarding these pregnancy outcomes should be obtained from the 
mother. 
Pregnancy is not considered a SAE. Initial and follow up information should be recorded on a 
Clinical Study Pregnancy Form and reported by the investigator to Rhizen Pharmaceuticals SA. 
Pregnancy follow-up should be recorded on the same form and should include an assessment of 
the possible relationship to the investigational drugs to any pregnancy outcome will also be 
captured on the pregnancy form. Any SAE experienced during pregnancy must be reported on 
the SAE Report Form. 
Pregnancy outcomes must 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. 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 60 of 62 
Appendix C: Response Criteria for iNHL- (Cheson et. al. 2014)  
 
Response and Site 
PET-CT–Based Response 
CT-Based Response 
COMPLETE 
Complete metabolic response 
Complete radiologic response (all of 
the following) 
Lymph nodes and extra 
lymphatic sites 
Score 1, 2, or 3* with or without a residual 
mass on 5PS† 
Target nodes/nodal masses must 
regress to ≤ 1.5 cm in LDi 
It is recognized that in Waldeyer's ring or 
extra-nodal sites with high physiologic 
uptake or with activation within spleen or 
marrow (e.g., with chemotherapy or 
myeloid colony-stimulating factors), 
uptake may be greater than normal 
mediastinum and/or liver. In this 
circumstance, complete metabolic response 
may be inferred if uptake at sites of initial 
involvement is no greater than surrounding 
normal tissue even if the tissue has high 
physiologic uptake 
No extra lymphatic sites of disease 
Nonmeasured lesion 
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in 
marrow 
Normal by morphology; if 
indeterminate, IHC negative 
 
 
 
PARTIAL 
Partial metabolic response 
Partial remission (all of the following) 
Lymph nodes and extra 
lymphatic sites 
Score 4 or 5† with reduced uptake 
compared with baseline and residual 
mass(es) of any size 
≥ 50% decrease in SPD of up to 
6 target measurable nodes and 
extra-nodal sites 
At interim, these findings suggest 
responding disease 
When a lesion is too small to measure 
on CT, assign 5 mm × 5 mm as the 
default value 
At end of treatment, these findings indicate 
residual disease 
When no longer visible, 0 × 0 mm 
For a node > 5 mm × 5 mm, but 
smaller than normal, use actual 
measurement for calculation 
Nonmeasured lesions 
Not applicable 
Absent/normal, regressed, but no 
increase 
Organ enlargement 
Not applicable 
Spleen must have regressed by > 50% 
in length beyond normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in 
normal marrow but reduced compared with 
baseline (diffuse uptake compatible with 
reactive changes from chemotherapy 
allowed). If there are persistent focal 
changes in the marrow in the context of a 
nodal response, consideration should be 
given to further evaluation with MRI or 
biopsy or an interval scan 
Not applicable 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 61 of 62 
 
 
 
NO 
RESPONSE 
OR 
STABLE DISEASE 
No metabolic response 
Stable disease 
Target nodes/nodal masses, 
extranodal lesions 
Score 4 or 5 with no significant change in 
FDG uptake from baseline at interim or 
end of treatment 
< 50% decrease from baseline in SPD 
of up to 6 dominant measurable nodes 
and extranodal sites; no criteria for 
progressive disease are met 
Nonmeasured lesions 
Not applicable 
No increase consistent with 
progression 
Organ enlargement 
Not applicable 
No increase consistent with 
progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
 
 
 
PROGRESSIVE 
DISEASE 
Progressive metabolic disease 
Progressive disease requires at least 1 
of the following 
Individual 
target 
nodes/nodal masses 
Score 4 or 5 with an increase in intensity of 
uptake from baseline and/or 
PPD progression: 
Extranodal lesions 
New FDG-avid foci consistent with 
lymphoma at interim or end-of-treatment 
assessment 
An individual node/lesion must be 
abnormal with: 
LDi > 1.5 cm and 
Increase by ≥ 50% from PPD nadir 
and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions ≤ 2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, the 
splenic length must increase by > 50% 
of the extent of its prior increase 
beyond baseline (eg, a 15-cm spleen 
must increase to > 16 cm). If no prior 
splenomegaly, must increase by at 
least 2 cm from baseline 
New or recurrent splenomegaly 
Nonmeasured lesions 
None 
New or clear progression of pre-
existing Nonmeasured lesions 
New lesions 
New FDG-avid foci consistent with 
lymphoma rather than another etiology (eg, 
infection, inflammation). If uncertain 
regarding etiology of new lesions, biopsy 
or interval scan may be considered 
Regrowth of previously resolved 
lesions 
A new node > 1.5 cm in any axis 
A new extra nodal site > 1.0 cm in any 
axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and 
must be attributable to lymphoma 
Assessable disease of any size 
unequivocally attributable to 
lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance imaging; 
PET, positron emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, 


Protocol No. RP6530-1802 
                                                    Rhizen Pharmaceuticals S.A. 
Amendment 1: 04 December 2018 
Original version : 1.0, 15 March 2018 
 
CONFIDENTIAL 
Page 62 of 62 
shortest axis perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for multiple 
lesions.  
* A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the 
time of an interim scan. However, in trials involving PET where de-escalation is investigated, it may be 
preferable to consider a score of 3 as inadequate responses (to avoid under treatment). Measured dominant 
lesions: Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly 
measurable in two diameters. Nodes should preferably be from disparate regions of the body and should 
include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid 
organs (eg, liver, spleen, kidneys, and lungs), GI involvement, cutaneous lesions, or those noted on 
palpation. Non measured lesions: Any disease not selected as measured, dominant disease and truly 
assessable disease should be considered not measured. These sites include any nodes, nodal masses, and 
extranodal sites not selected as dominant or measurable or that do not meet the requirements for 
measurability but are still considered abnormal, as well as truly assessable disease, which is any site of 
suspected disease that would be difficult to follow quantitatively with measurement, including pleural 
effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot 
be confirmed and followed by imaging. In Waldeyer's ring or in extranodal sites (eg, GI tract, liver, bone 
marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but 
should be no higher than surrounding normal physiologic uptake (eg, with marrow activation as a result of 
chemotherapy or myeloid growth factors).  
† PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 
4, uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of 
uptake unlikely to be related to lymphoma.