Conditions: Leukemia, Lymphocytic, Chronic, B-Cell
Keywords: Phosphoinositide 3-kinase Pi3k Delta and gamma inhibitor Tenalisib Leukemia, Lymphocytic, Chronic, B-Cell
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 21
Healthy volunteers: no

Brief summary:
The trial is a Phase II, open label, Simon's two stage study design to evaluate the efficacy and safety of Tenalisib in patients with CLL who have relapsed or are refractory after at least one prior therapy.

Detailed description:
Tenalisib is a highly specific and orally available dual PI3K δ/γ inhibitor. Pre-clinical experiments demonstrated that Tenalisib is highly effective in killing primary CLL cells in vitro. A Phase II study is planned to evaluate the efficacy and safety of Tenalisib in patients with relapsed/refractory CLL.

Arms:
arm 1: Patients receive Tenalisib 800 mg BID, Orally in 28-Day cycle for 7 cycles

Interventions: intervention 1: Tenalisib
Intervention descriptions: intervention 1: Tenalisib 800 mg BID, Orally

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL 
Page 1 of 61 
                  PROTOCOL NO. RP6530-1901 
 
A Phase 2, Open label Study to Assess the Efficacy and Safety of 
Tenalisib (RP6530), a Novel PI3K Dual δ/γ Inhibitor, in Patients 
with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) 
 
 
This is a confidential document 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agreement by the recipient that no unpublished information contained herein shall be published or 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 
 
 
 
RP6530-1901 
 
TRIAL DRUG 
 
Tenalisib (RP6530)  
SPONSOR 
 
Rhizen Pharmaceuticals S.A. 
Fritz-Courvoisier 40, 
Ch-2300 La Chaux-de-Fonds,  
Switzerland. 
SPONSOR’S MEDICAL 
EXPERT 
 
Prajak Barde, MD 
Senior Medical Director, Clinical R&D  
Rhizen Pharmaceuticals S.A. 
Fritz-Courvoisier 40, 
Ch-2300 La Chaux-de-Fonds,  
Switzerland. 
 
 
 
DOCUMENT VERSION 
 
 
Final, Version 1.0, Dated 12 September 2019 


Protocol No: RP6530-1901 
                                                 Rhizen Pharmaceuticals S.A. 
Version: 1.0, Dated 12 September 2019 
 
CONFIDENTIAL 
Page 2 of 61 
Clinical Trial Protocol Statement of Compliance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This clinical trial shall be conducted in compliance with the protocol, and all applicable 
local, and international regulatory requirements including 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) 
• 
European Commission - Detailed guidance on the collection, verification and 
presentation of adverse event/reaction reports arising from clinical trials on medicinal 
products for human use (‘CT-3’) (2011/C 172/01) 
• 
As the principal investigator (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. 
• 
As the Clinical Research Organization (CRO) Representative, I agree and accept the 
contracted sponsor responsibilities as defined by the protocol, applicable clinical trial 
agreements (CTA), and/or business contracts.  Additionally, I agree that any changes to 
the protocol, CTA, or contracts shall be implemented with the Sponsor’s review and 
approval prior to implementation.  
• 
As the Sponsor Representative, I understand that my signature constitutes agreement and 
understanding of acceptance of the defined and contracted sponsor responsibilities to the 
CRO as defined by the protocol, applicable clinical trial agreements (CTA), and/or 
business contracts, but does not in any capacity relieve me of my responsibilities as the 
Sponsor.  Additionally, my signature constitutes my understanding and agreement that 
any changes to the protocol, CTA, or contracts shall be implemented timely with my 
review and approval prior to implementation. 


Protocol No: RP6530-1901 
                                                 Rhizen Pharmaceuticals S.A. 
Version: 1.0, Dated 12 September 2019 
 
CONFIDENTIAL 
Page 3 of 61 
Protocol Approval Page 
A Phase 2, Open label, Study to Assess the Efficacy and Safety of Tenalisib 
(RP6530), a Novel PI3K Dual δ/γ Inhibitor, in Patients with 
Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) 
 
PROTOCOL NUMBER 
RP6530-1901  
TRIAL DRUG(S) 
Tenalisib (RP6530) 
DOCUMENT VERSION 
1.0, Dated 12 September 2019 
                
 
      
 
 
 
 
 
Prajak Barde, MD 
 
 
 
 
 
 
 
 September 12, 2019                 
_________________________ 
 
 
_________________________________ 
 
Sponsor’s Medical Expert   
 
 
Signature  
 
 
Date 
 
 
 
 
  
Ajit Nair, PhD  
                                    September 12, 2019 
_________________________ 
 
 
___________________________________  
Sponsor’s Representative   
 
 
Signature 
 
 
Date             
 
 
 
 
 
 
 
Michael Chen, PhD 
 
 
 
  
 
 
 
 
September 12, 2019 
_________________________ 
 
 
___________________________________  
Bio-statistician 
 
 
 
 
Signature 
 
 
Date             
 
                                     
 
 
 
 


Protocol No: RP6530-1901 
                                                 Rhizen Pharmaceuticals S.A. 
Version: 1.0, Dated 12 September 2019 
 
CONFIDENTIAL 
Page 4 of 61 
Protocol Acceptance Page 
 
 
 
A Phase 2, Open label, Study to Assess the Efficacy and Safety of Tenalisib 
(RP6530), a Novel PI3K Dual δ/γ Inhibitor, in Patients with 
Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) 
PROTOCOL NUMBER 
RP6530-1901 
TRIAL DRUG(S) 
Tenalisib (RP6530)  
DOCUMENT VERSION 
1.0, Dated 12 September 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator 
 Signature 
 
         Date       
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 


Protocol No: RP6530-1901 
                                                 Rhizen Pharmaceuticals S.A. 
Version: 1.0, Dated 12 September 2019 
 
CONFIDENTIAL 
Page 5 of 61 
PROTOCOL SYNOPSIS 
 
Study Title  
A Phase 2, Open label, Study to Assess the Efficacy and Safety of Tenalisib 
(RP6530), a Novel PI3K Dual δ/γ Inhibitor, in Patients with 
Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) 
Protocol Number: RP6530-1901 
Study Sponsor  
Rhizen Pharmaceuticals S.A. 
Study Sites  
Approximately 10-15 sites. 
Study Objectives  
Primary objective:  
• To assess the anti-tumor activity of Tenalisib as determined by the 
objective response rate (ORR) and duration of response (DoR) 
 
Secondary objectives:  
• To characterize safety and tolerability of Tenalisib.  
• To assess progression free survival (PFS) 
End points  
Efficacy:  
• Overall response rate (ORR): ORR is defined as sum of complete response 
(CR) and partial response (PR) rates as defined by iwCLL guideline for 
CLL (Hallek et al. 2018).  
• Duration of response (DoR): DoR is defined as the interval from the first 
documentation of CR/PR to first documentation of definitive disease 
progression or death from any cause.  
• Progression-free survival (PFS): PFS is defined as the interval from first 
dose to first documentation of definitive disease progression or death from 
any cause.  
 
Safety:  
• Adverse Event (AE), Grade 3/ 4 AEs, Serious Adverse Event (SAE).   
Study Design and 
procedure 
The trial is a Phase II, open label, Simon’s two stage study design to evaluate 
the efficacy and safety of Tenalisib in 61 patients with CLL who have relapsed 
or are refractory after at least one prior therapy. In stage 1, 20 patients will be 
enrolled. If eight or fewer responders are observed at this stage, the study will 
be terminated. Else, 41 additional patients will be enrolled into stage 2.   
 
The study treatment Tenalisib (800 mg BID) will be administered orally in 28-
days of cycle over a period of 7 months (C1D1 to C8D1) in absence of 
definitive disease progression or unacceptable toxicity. The study will end 
when all ongoing subjects have reached their third tumor assessment on Cycle 
8/Day 1 (C8D1) or have discontinued from the study for any reason, whichever 
is earlier. At the end of the study, all ongoing patients with no evident disease 
progression will be given an opportunity to enroll in an open-label 
compassionate medication use study [Protocol:RP6530-1803; NCT03711604] 
and will be followed up. The detailed study procedure is presented in Study 
assessment and Treatment schedule (Table 1). Anti-infective prophylaxis (e.g. 


Protocol No: RP6530-1901 
                                                 Rhizen Pharmaceuticals S.A. 
Version: 1.0, Dated 12 September 2019 
 
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for herpes simplex virus (HSV), pneumocyctis Jirovecii pneumonia (PJP), 
hepatitis B virus (HBV), cytomegalovirus (CMV) are recommeded and will be 
given at the discretion of study investigator. All safety laboratory assessments, 
electrocardiogram (ECG) and radiological assessments (e.g. CT) will be 
performed at the respective sites.  
Number of 
patients  
Approximately 61 patients with relapsed/refractory CLL will be enrolled.  
Eligibility 
Criteria 
Patients must meet all the following inclusion criteria to be eligible for 
participation in this study: 
1. Patients with diagnosis of B-cell CLL as confirmed by histopathology or 
flow cytometry.  
2. Disease status defined as refractory to or relapsed after at least one prior 
therapy. 
3. Presence of measurable lymphadenopathy, defined as the presence of > 1 
nodal lesion that measures ≥ 1.5 cm in the longest diameter (LD) as 
assessed by computed tomography (CT). 
4. ECOG performance status ≤ 2. 
5. Male or female ≥ 18 years of age. 
6. Life expectancy of at least 3 months.  
7. Adequate bone marrow (BM), liver, and renal function as assessed by the 
following laboratory requirements conducted within 14 calendar days 
before starting study treatment.  
a. Adequate bone marrow function.  
I. Haemoglobin ≥ 9 g/dl  
II. Absolute neutrophil count (ANC) ≥ 1 x 10^9/L  
III. Platelets ≥50 x 10^9/L  
Patients with hemoglobin, neutrophil and platelet counts below the 
above specified values will be eligible if it is due to tumor 
dissemination or infiltration to bone marrow and as per physician’s 
discretion. Hemoglobin and platelet requirements should not be met by 
use of recent transfusion or growth factor support (G-CSF or 
erythropoietin) within 3 weeks prior to assessment. 
b. Adequate liver function.  
I. Total bilirubin ≤1.5 times the upper limit of normal (ULN)  
II. ALT and AST should be ≤ 3 x ULN. ALT and AST ≤ 5 x ULN 
if known liver involvement.  
c. Adequate renal function: Calculated creatinine clearance ≥ 50 mL/min 
(as calculated by the Cockcroft-Gault method) or Creatinine ≤ 1.5 
mg/dl. 
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 should have a negative serum pregnancy test 
within 3 days prior to Cycle 1 Day 1 (C1D1). Female patients of child-
bearing potential must consent to use a medically acceptable method of 
contraception as defined in Appendix A , throughout the study period and 
for 30 days after the last dose of study drug. 


Protocol No: RP6530-1901 
                                                 Rhizen Pharmaceuticals S.A. 
Version: 1.0, Dated 12 September 2019 
 
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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 and 
give written informed consent. 
Exclusion criteria  1. Patient with Richter’s (large cell) transformation, or prolymphocytic 
leukemia (PLL) transformation. 
2. Patients receiving any cancer therapy (i.e., chemotherapy, radiation 
therapy, immunotherapy and biologic therapy) or any cancer 
investigational drug within 3 weeks (21 days) or 5 half-lives (whichever is 
shorter) prior to C1D1.  
3. Prior exposure to drug that specifically inhibits PI3K (e.g. idelalisib, 
copanlisib, duvelisib, umbralisib)  
4. Patient with autologous / allogeneic stem cell transplant (ASCT/Allo-
SCT) receiving treatment for active graft versus-host disease (GVHD). 
5. Evidence of ongoing severe systemic bacterial, fungal or viral infection 
as assessed by the investigator.  
6. Central nervous system (CNS) involvement of leukemia or lymphoma 
7. Ongoing immunosuppressive therapy including systemic corticosteroids 
except as allowed per concomitant medication (Section 5.2).  
8. Known history of severe liver injury including drug-induced liver injury 
(e.g. alcoholic liver disease, primary biliary cirrhosis, ongoing extrahepatic 
obstruction caused by stones, cirrhosis of the liver or portal hypertension) 
as judged by investigator; 
9. Any severe and/or uncontrolled medical conditions or other conditions that 
could affect patient participation in the study, as judged by investigator, 
such as: 
a. 
Symptomatic or history of documented congestive heart failure (New 
York heart association (NYHA) functional classification III-IV) 
b. Myocardial infarction within 6 months of C1D1 
c. 
QTcF >470 msec. 
d. Angina not well-controlled by medication. 
e. 
Poorly 
controlled 
atherosclerotic 
vascular 
disease 
(e.g. 
cerebrovascular accident, transient ischemic attack, angioplasty, 
cardiac/vascular stenting). 
10. Patient treated for other malignancy in last 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; and localized prostate cancer with PSA <1.0 mg/dL within 4 
weeks of C1D1. 
11. Women who are pregnant or lactating. 
12. Known 
seropositive 
requiring 
anti-viral 
therapy 
for 
human 
immunodeficiency virus (HIV) infection.  
13. Known seropositive requiring anti-viral therapy for hepatitis B virus 
(HBV) infection OR evidence of active hepatitis B infection as defined by 
detectable viral load if the antibody tests are positive. [Note: Subject with 


Protocol No: RP6530-1901 
                                                 Rhizen Pharmaceuticals S.A. 
Version: 1.0, Dated 12 September 2019 
 
CONFIDENTIAL 
Page 8 of 61 
a positive HBcAb with an undetectable/negative hepatitis B DNA test (e.g., 
polymerase chain reaction [PCR] test) can be enrolled].  
14. Known seropositive requiring anti-viral therapy for hepatitis c virus (HCV) 
infection OR patients with positive hepatitis C virus Ab with detectable 
viral 
load. 
[Note: 
Subject 
with 
a 
positive 
HCV 
with 
an 
undetectable/negative hepatitis C RNA test (e.g., PCR) can be enrolled].  
15. Known seropositive requiring anti-viral therapy for active CMV infection 
(Note: A serology positive CMV subject with negative CMV PCR test will 
be enrolled).   
16. Unresolved NCI-CTCAE grade 2 and above toxicity (except as mentioned 
in adequate organ function (Refer inclusion criteria #7) attributed to any 
prior therapy/procedure excluding alopecia.  
17. Inability or unwillingness to comply with study and/or follow-up 
procedures outlined in the protocol;  
18. Concurrent condition that in the investigator’s opinion would jeopardize 
compliance with the protocol.  
Concomitant 
medication  
• Antimicrobial and/or anti-viral prophylaxis should be used according to 
local standard practice; PJP and herpes zoster prophylaxis is strongly 
recommended. CMV carriers will be monitored per institutional guidelines 
and/or will be given anti-CMV therapy (e.g., ganciclovir, valganciclovir). 
Similarly, chronic carriers of HBV should receive prophylactic anti-viral 
therapy.  
• 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 administered at dose ≤ 20 mg per 
day of prednisone or equivalent. The dose should be stabilized for at least 
1 week or 5 half-lives (whichever is shorter) prior to C1D1.  
• Patients are permitted to use of topical, ocular, intra-articular, intranasal, 
and inhaled corticosteroids (with minimal systemic absorption).  
• 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.  
• Low molecular weight heparin (LMWH), Dabigatran or Edoxaban is 
acceptable for prophylaxis and/or treatment of venous thrombosis.  
Prohibited 
medication  
The following treatments are prohibited while on the clinical trial:    
• Any other anti-leukemia/lymphoma therapy  


Protocol No: RP6530-1901 
                                                 Rhizen Pharmaceuticals S.A. 
Version: 1.0, Dated 12 September 2019 
 
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• Herbal medications. Patients should stop using herbal medications at 
least 7 days prior to C1D1.  
• Strong inhibitors or inducers of CYP3A4. Patients should stop using 
these medications at least 7 days or 5 half-lives (whichever is shorter) 
prior to C1D1.  
• Strong inhibitors or inducers of CYP2C9. Patients should stop using 
these medications at least 7 days or 5 half-lives (whichever is shorter) 
prior to C1D1. 
• Substrates of CYP3A4 enzyme with a narrow therapeutic range. 
Patients should stop using these medications at least 7 days or 5 half-
lives (whichever is shorter) prior to C1D1.    
• Use of heparin, warfarin, apixaban or rivaroxaban for prophylaxis 
and/or treatment of venous thrombosis is prohibited. These drugs should 
be stopped at least 7 days or 5 half-lives (whichever is shorter) prior to 
C1D1.    
• Live attenuated vaccine (e.g. Flu vaccine, pneumovax, varicella) 
• Steroids > 20 mg unless it is required for management of toxicity (e.g., 
transaminitis) during the study. 
Estimated Study 
duration  
Approximately 10-12 months for patient accrual plus 7.5 months of treatment 
and follow up. Estimated clinical duration is about 20 months.   
Response 
assessment  
Efficacy will be evaluated by CT scan at C3D1±7 days, C5D1±7 days and 
C8D1±7 days or at End of the treatment (EOT) visit. The determination of 
response and progression will be based on iwCLL guidelines for diagnosis and 
treatment of CLL (Hallek et al. 2018).  
 
Unilateral bone marrow aspiration and/or biopsy will be performed at 
investigator discretion in patients for whom assessment of extent of CLL 
involvement and bone marrow cellularity is important in determining 
eligibility. However, bone marrow biopsy should be done to confirm potential 
CR. 
Radiographic and clinical tumor response as evaluated and confirmed by the 
site investigator (defined as PI-confirmed response) will be considered for 
analyses of ORR and other efficacy endpoints.  
Sample size 
The sample size is derived based on Simon's two stage design to achieve 90% 
power at alpha of 0.05 for the null hypothesis of ORR ≤ 40%, assuming 60% 
response rate.  Up to 61 patients will be enrolled.  In stage 1, 20 patients will 
be enrolled. If eight or fewer responders are observed in this stage, the study 
will be terminated without rejecting the null hypothesis. Else, 41 additional 
patients will be enrolled into stage 2. If 31 or more responders are observed in 
the study, the null hypothesis of ORR ≤ 40% will be rejected. 
Statistical Analysis 
 
Statistical methods to analyze efficacy and safety will be described in 
statistical analysis plan (SAP). 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 SAP that will be 


Protocol No: RP6530-1901 
                                                 Rhizen Pharmaceuticals S.A. 
Version: 1.0, Dated 12 September 2019 
 
CONFIDENTIAL 
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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. 


Protocol No: RP6530-1901 
                                                 Rhizen Pharmaceuticals S.A. 
Version: 1.0, Dated 12 September 2019 
 
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Page 11 of 61 
                                               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 
SPONSOR’S 
REPRESENTATIVE 
Ajit Nair, PhD 
SVP and Head 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 
Senior 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. RP6530-1901                                                     Rhizen Pharmaceuticals S.A. 
Version : 1.0, Dated 12 September 2019 
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Page 12 of 61 
List of Abbreviations 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT (SGOT) 
Alanine aminotransferase 
ANC 
Absolute Neutrophil Count 
aPTT 
Activated Partial Thromboplastin Time 
Allo-SCT 
Auto-SCT 
Allogeneic Hematopoietic Stem Cell Transplantation  
Autologous 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 
CFR 
CMV 
Complete Blood Count 
Code of Federal Regulation 
Cytomegalovirus 
CLL 
Chronic Lymphocytic Leukemia 
CNS 
Central Nervous System 
CR 
CRF 
Complete Response 
Case Report Form 
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 
DVT 
Data Review Committee 
Deep Vein Thrombosis 
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 
Hb 
Hemoglobin 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HDL 
High-Density Lipoprotein 
HEENT 
Head, Eyes, Ears, Nose and Throat 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immune Deficiency Virus 
IB 
Investigator brochure  
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee 
IRB/IEC 
IWCLL  
Institutional Review Board 
International Workshop on CLL 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
LDH 
Lactate Dehydrogenase 


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Version : 1.0, Dated 12 September 2019 
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LDL 
Low-Density Lipoprotein 
LLN 
Lower Limit of Normal  
LMWH 
Low Molecular Weight Heparin 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NOAEL 
No-Observed-Adverse Effect Level 
NYHA 
New York Heart Association 
ORR 
Objective Response Rate 
pAKT 
PhosphoAKT 
PJP 
PD 
Pneumocystis Jirovecii Pneumonia 
Progressive disease  
PFS 
Progression-Free Survival 
PI 
Principle Investigator 
PI3K 
Phosphoinositide-3-Kinase 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PR 
Partial Response 
QA 
Quality Assurance 
QTcF 
QTc Fredericia  
SAE 
Serious Adverse Events 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SD 
Stable Disease  
SDV 
Source Document Verification 
SOP 
Standard Operating Procedures 
SUV 
Standardized Uptake Value 
t1/2 
Plasma Half Life 
tmax 
Time to maximum plasma concentration  
TEAE 
Treatment-Emergent Adverse Event 
TG 
Triglyceride 
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  
 
 


Protocol No: RP6530-1901 
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14 
Confidential  
TABLE OF CONTENTS  
1 
Background Information ................................................................................................................... 18 
1.1 
Tenalisib (RP6530) ................................................................................................................. 18 
1.2 
Summary of pre-clinical evaluation ....................................................................................... 18 
1.3 
Summary of clinical evaluation .............................................................................................. 18 
1.4 
Study Rationale ...................................................................................................................... 19 
1.4.1 Rationale for study population ..................................................................................... 19 
1.4.2 Rationale for dose selection ......................................................................................... 20 
1.5 
Benefit and Risk ..................................................................................................................... 20 
2 
TRIAL OBJECTIVES ...................................................................................................................... 21 
2.1 
Primary Objective ................................................................................................................... 21 
2.2 
Secondary Objective ............................................................................................................... 21 
3 
TRIAL DESIGN ............................................................................................................................... 21 
3.1 
Trial End Points ...................................................................................................................... 21 
3.2 
Design of Trial ........................................................................................................................ 21 
3.3 
Data Review Committee (DRC) ............................................................................................. 21 
3.4 
Randomization and Blinding .................................................................................................. 22 
3.5 
Investigational Medicinal Product .......................................................................................... 22 
3.5.1 Dosage form and strengths ........................................................................................... 22 
3.5.2 Labeling, packaging and supply ................................................................................... 22 
3.5.3 Preparation and administration of the Investigational Product .................................... 22 
3.5.4 Accountability of Investigational Products .................................................................. 22 
3.5.5 Precautions and risks associated with the Investigational Product .............................. 23 
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 Study Drug .......................................................................................... 26 
5 
TREATMENT OF SUBJECTS ........................................................................................................ 26 
5.1 
Administration of Tenalisib .................................................................................................... 26 
5.2 
Concomitant Medications ....................................................................................................... 26 
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 ................................................................................ 32 


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Confidential  
6.2.1 Informed consent .......................................................................................................... 32 
6.2.2 Assignment of screening number ................................................................................. 32 
6.2.3 Medical history ............................................................................................................ 32 
6.2.4 Prior and concomitant medication ............................................................................... 33 
6.2.5 Prior therapies .............................................................................................................. 33 
6.2.6 Physical examination ................................................................................................... 33 
6.2.7 Vital signs .................................................................................................................... 33 
6.2.8 Laboratory safety evaluations ...................................................................................... 33 
6.2.9 ECG 
35 
6.3 
Eastern Cooperative Oncology Group (ECOG) Performance Status ..................................... 35 
6.4 
Disease assessment ................................................................................................................. 35 
6.5 
Radiological assessment ......................................................................................................... 36 
6.6 
Bone marrow biopsy .............................................................................................................. 36 
6.7 
Trial Treatment Period ........................................................................................................... 37 
6.8 
End of Trial Treatment (EOT) ................................................................................................ 37 
6.9 
End of Study (EOS) ................................................................................................................ 37 
6.10 Early Patient Termination / Patient Withdrawal ..................................................................... 37 
7 
ASSESSMENT OF SAFETY ........................................................................................................... 37 
7.1 
Adverse Events ....................................................................................................................... 37 
7.1.1 Definitions of adverse events ....................................................................................... 38 
7.1.2 Recording of adverse events ........................................................................................ 38 
7.1.3 Handling of adverse events .......................................................................................... 38 
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 
Severity of Adverse events ..................................................................................................... 40 
7.5 
Recording of Adverse Events and Serious Adverse Events ................................................... 41 
7.5.1 Diagnosis vs. signs and symptoms ............................................................................... 41 
7.5.2 Persistent or recurrent adverse events .......................................................................... 41 
7.5.3 Abnormal laboratory values ......................................................................................... 42 
7.5.4 Deaths 42 
7.5.5 Hospitalization, prolonged hospitalization, or surgery ................................................ 42 
7.5.6 Pre-Existing medical conditions .................................................................................. 42 
7.5.7 Pregnancy, abortion, birth defects/congenital anomalies ............................................. 42 
7.5.8 New Cancers ................................................................................................................ 42 


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7.5.9 Lack of efficacy ........................................................................................................... 43 
7.6 
Protocol-Defined Events of Special Interest .......................................................................... 43 
7.6.1 Pregnancy, abortion, birth defects/congenital anomalies ............................................. 43 
7.6.2 Overdose ...................................................................................................................... 43 
7.7 
Dose Modifications ................................................................................................................ 44 
8 
ASSESSMENT OF EFFICACY ....................................................................................................... 48 
8.1 
Specification of the Efficacy Parameters................................................................................ 48 
8.2 
Response Evaluations and Measurements .............................................................................. 49 
9 
STATISTICAL METHOD AND CONSIDERATIONS .................................................................. 50 
9.1 
General Considerations .......................................................................................................... 50 
9.2 
Determination of Sample Size ................................................................................................ 50 
9.3 
Study Population .................................................................................................................... 51 
9.4 
Statistical Analysis ................................................................................................................. 51 
9.4.1 Demographic and baseline characteristics ................................................................... 51 
9.4.2 Safety analyses ............................................................................................................. 51 
9.4.3 Efficacy analyses .......................................................................................................... 51 
10 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS ........................................ 52 
10.1 IRB/IEC Approval .................................................................................................................. 52 
10.2 Regulatory Approval .............................................................................................................. 52 
10.3 Insurance and Indemnity ........................................................................................................ 52 
10.4 Financial Disclosure and Obligations ..................................................................................... 52 
10.5 Informed Consent ................................................................................................................... 53 
10.6 Confidentiality ........................................................................................................................ 53 
10.6.1 Patient confidentiality .................................................................................................. 53 
10.6.2 Investigator’s responsibilities ....................................................................................... 54 
10.6.3 Investigator and staff training and information ............................................................ 54 
11 
RECORD RETENTION AND DOCUMENTATION OF THE TRIAL .......................................... 54 
11.1 Amendments to the Protocol .................................................................................................. 54 
11.2 Protocol Deviations ................................................................................................................ 54 
11.3 Documentation Required to Initiate Trial ............................................................................... 55 
12 
DATA HANDLING AND RECORD KEEPING ............................................................................. 55 
12.1 Data Collection ....................................................................................................................... 56 
12.2 Trial Monitoring, Auditing, and Inspecting............................................................................ 57 
12.3 Medical Monitoring ................................................................................................................ 57 
12.4 Quality Assurance and Quality Control ................................................................................. 57 
13 
Disclosure and Publication Policy..................................................................................................... 57 
14 
REFERENCES .................................................................................................................................. 59 


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15 
APPENDICES................................................................................................................................... 60 
Appendix A: Contraceptive Guidelines and Pregnancy .................................................................... 60 
 
List of Tables 
Table 1:  Study Assessments and Treatment Schedule ...............................................................................29 
Table 2: Laboratory Tests for Hematology, Chemistry and Urinalysis ......................................................34 
Table 3:Rai staging system .........................................................................................................................36 
Table 4: Dose Modifications for Hematologic Toxicity .............................................................................44 
Table 5: Dose Modifications for Non-Hematologic Toxicities ..................................................................45 
Table 6: Response Criteria for CLL (iwCLL) (Hallek et al, 2018) ............................................................49 
 
 
 
 


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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.  
 
1.2 
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 cutaneous T cell lymphoma (CTCL) cells isolated from patient donors.  
 
Pre-clinical experiments demonstrated that Tenalisib is highly effective at killing primary 
CLL cells in vitro. The effect appeared to be equal to the Bruton tyrosine kinase (BTK) 
inhibitor- ibrutinib.  In fact, the calculated IC50 was slightly lower for Tenalisib than ibrutinib 
(362 nM, versus 567 nM).  In comparison, the IC50 for Tenalisib was lower than IC50 for the 
conventional chemotherapy agents fludarabine (14.8 µM), bendamustine (382 µM), and 
chlorambucil (152 µM). Tenalisib also induced 50-60% reduction in chemokine induced 
migration of Daudi cells (in vitro surrogate for CLL patient B-cells), indicating the potential 
of the molecule in modulating tumor microenvironment [4]. 
 
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 [5].  
 
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. Refer to 
Investigator’s Brochure (IB) for detailed background information on Tenalisib [4].  
 
1.3 
Summary of clinical evaluation 
To date, Tenalisib has been evaluated in five clinical trials. Status of the studies as follows:  
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: Completed 
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   


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4. 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 no.: RP6530-1802). Status: Ongoing 
5. An Open label, Phase I/II study to evaluate the safety and efficacy of Tenalisib (RP6530), 
a novel PI3K δ/γ dual inhibitor given in combination with a histone deacetylase (HDAC) 
inhibitor, Romidepsin in adult patients with relapsed/refractory T-cell Lymphoma 
(Protocol no.: RP6530+Romidepsin-1805). Status: Ongoing 
 
In addition, an open-label compassionate medication use study [Protocol:RP6530-1803; 
NCT03711604] is opened to allow ongoing patients with no evident disease progression 
to continue Tenalisib treatment. 
 
•  Safety of Tenalisib:  
A total of 95 patients with relapsed/refractory hematologic malignancies were exposed to 
Tenalisib till date. In RP6530-1301 study, Tenalisib demonstrated acceptable safety profile 
up to 1200 mg BID and 800 mg TID without any dose limiting toxicity (DLT).  
 
In RP6530-1401 study, a total of 58 patients were treated at Tenalisib 200 mg BID, 400 mg 
BID, 800 mg BID (Fasting) and 800 mg BID (Fed) in both dose escalation and expansion 
cohorts. Tenalisib demonstrated acceptable safety and tolerability profile up to 800 mg BID 
(Fasting). Reported DLTs included Grade 3 transaminitis, and Grade 3 skin rash. Tenalisib 
800 mg BID (Fasting) was considered as maximum tolerated dose (MTD). Treatment related 
SAE were few and included pyrexia, raised international normalized ratio (INR), sepsis, skin 
infection, hypersensitivity, and diplopia secondary to neuropathy. Overall, Tenalisib has 
acceptable safety and tolerability profile up to 800 mg BID (Fasting).  
 
• Pharmacokinetics (PK):  
In RP6530-1301 study, maximum systemic exposures of Tenalisib were assessed on Cycle 
1 Day 1 at doses 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 exposures were observed 
beyond 400 mg. There was no change in tmax on increasing doses however there was change 
in t1/2. Steady state PK parameters of Tenalisib as determined on Cycle 2 Day 1 revealed no 
accumulation of Tenalisib. Similar PK profile was seen in RP6530-1401 study. 
 
• Efficacy:  
In RP6530-1301 study, Tenalisib demonstrated an ORR ≈ 20% (CR: 7% and PR: 13%) in 
heavily pre-treated R/R patients with hematological malignancies. In RP6530-1401 study, 
response assessments of the thirty-five evaluable patients receiving at least two cycles of 
Tenalisib showed an ORR of 46% (CR: 9% and PR: 37%). Indication specific analysis 
showed an ORR of 47% (CR: 20%, PR: 27%) in PTCL and 45% (PR: 45%) in CTCL. 
 
1.4 
Study Rationale  
1.4.1 Rationale for study population  
Chronic Lymphocytic Leukemia (CLL) is a myeloproliferative neoplasm characterized by 
an accumulation of monoclonal mature B-cells (CD5+CD23+) in the blood, bone marrow, 
and secondary lymphatic organs. CLL is the most common form of adulthood leukemia. 
 
The clinical course of CLL varies but it is typically a slowly progressing disease. The 
approximate 5-year survival rate for patients with CLL is 81.7% [6]. Due to infiltration of 
the bone marrow by lymphocytes, the principal complication of CLL is immunodeficiency 


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related to myelosuppression and as a result, infection is the major cause of death in these 
patients [7].  
 
Chromosomal abnormalities of 17p del, 11q del, and IGHV unmutated have been found to 
be markers of poor prognosis with a decrement in overall survival. Other markers of poor 
prognosis are β2-microglobulin >3.5 mg/L, lymphocyte doubling time <12 months, and age 
> 60 years [8]. Treatment-related factors associated with poor prognosis include fludarabine 
refractoriness and relapse after 3 or more prior therapies [9]. 
 
Despite high response rates to initial treatment, relapse is common in CLL and relapsed/ 
refractory disease is often characterized by resistance to chemotherapy. Among patients who 
either relapse or are refractory to first line treatment, the choice of subsequent therapy 
depends on age, duration of response to prior therapy, ability to tolerate treatment, disease 
related manifestations, and the presence of molecular poor-risk features. The majority of 
CLL patients receive intermittent treatment with periods of remission or stable disease. With 
each successive treatment regimen, many patients become refractory to treatment with 
diminished response rates and shorter response durations. Although newer agents Ibrutinib 
(BTK inhibitor), Venetoclax (BCL-2 inhibitor), Idelalisib (PI3K δ inhibitor), Duvelisib 
(PI3K δ/γ inhibitor) have become available for the treatment of CLL recently [10], CLL still 
remains an incurable disease for most patients and is still an unmet medical need.  
 
Further, the safety and tolerability of newer agents remains a concern as there are high 
incidence of adverse events with use of these agents (e.g., atrial fibrillation, neutropenia, 
colitis and pneumonitis) leading to discontinuation of drug therapy. Therefore, there is 
ongoing need for safer and better treatment options.  
 
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. Pre-clinical 
experiments demonstrated that Tenalisib is highly effective in killing primary CLL cells in 
vitro. The effect appeared to be equal to ibrutinib and higher than conventional 
chemotherapy agents. Tenalisib also demonstrated reduction in chemokine induced 
migration of Daudi cells, indicating its potential in modulating tumor microenvironment. 
Tenalisib has demonstrated clinical activity in patients with hematological malignancies 
with acceptable safety profile. Therefore, Tenalisib may offer a good treatment option for 
patient with relapsed/refractory CLL.  
 
1.4.2 Rationale for dose selection 
Maximum tolerated dose of Tenalisib (800 mg BID (Fasting)) was established in Phase I/Ib 
study and showed acceptable safety and promising efficacy in patients with peripheral and 
cutaneous T-cell lymphoma. Also, the same dose is being tested in a Phase II study in 
indolent NHL patients. Hence, 800 mg BID (Fasting) dose has been selected for CLL patient 
population. 
 
1.5 
Benefit and Risk 
It is expected that the proposed single agent Tenalisib therapy has the potential to improve 
response rates in the relapsed/refractory CLL 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 medicine. In addition, there are certain risk associated 
with Tenalisib treatment which are described in section 3.5.5 of protocol. Additional details 


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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) and duration of response (DoR) 
 
2.2 Secondary Objective 
• To characterize safety and tolerability of Tenalisib. 
• To assess progression free survival (PFS)          
 
3 TRIAL DESIGN 
3.1 
Trial End Points 
Efficacy: 
• Overall response rate (ORR): ORR is defined as sum of CR and PR rates as defined by 
iwCLL guideline for CLL (Hallek et al. 2018).  
• Duration of response (DOR): DOR is defined as the interval from the first 
documentation of CR/PR to first documentation of definitive disease progression or 
death from any cause.  
• Progression-free survival (PFS): PFS is defined as the interval from first dose to first 
documentation of definitive disease progression or death from any cause.  
 
Safety:  
• Adverse Event (AE), Grade 3/ 4 AEs, Serious Adverse Event (SAE) 
 
3.2 
Design of Trial 
The trial is a Phase II, open label, Simon’s two stage study design to evaluate the efficacy 
and safety of Tenalisib in 61 patients with CLL who have relapsed or are refractory after at 
least one prior therapy. In Stage 1, 20 patients will be enrolled and the study treatment 
Tenalisib (800 mg BID) will be administered orally in 28-days of cycle over a period of 7 
months (C1D1 to C8D1) in absence of definitive disease progression or unacceptable 
toxicity. If 8 or fewer responders are observed in this stage, the study will be 
terminated.  Else, 41 additional patients will be enrolled into stage 2.   
 
Patients will be evaluated for efficacy response by CT at C3D1±7 days, C5D1±7 days and 
C8D1±7 days and/or at End of the treatment (EOT) visit. The study will end when all 
ongoing subjects have reached their third tumor assessment on Cycle 8/Day 1 (C8D1) or 
have discontinued from the study for any reason, whichever is earlier. At the end of the 
study, all ongoing patients with no evident disease progression will be given the opportunity 
to enroll in an open-label compassionate medication use study [Protocol:RP6530-1803; 
NCT03711604] and will be followed up. The details of the study procedures are given in 
Study Assessments and Treatment Schedule (Table 1). 
 
3.3 
Data Review Committee (DRC) 
The DRC will be constituted by the sponsor to review the safety and efficacy data. The 
committee will consist of PI of respective sites, sponsor representative, sponsor’s medical 
expert, and a statistician. The DRC will meet and review the efficacy and safety data at 
regular intervals to assess the safety and efficacy of study drug and will provide 
recommendations.  


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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 
Two dose strengths of Tenalisib will be used in the study.  
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.  
 
3.5.2 Labeling, packaging and supply 
Tenalisib will be appropriately labeled and packaged as per local regulatory requirements 
and will be supplied by STA Pharma Co. Ltd through Rhizen Pharmaceuticals SA. Tenalisib 
will be available as 30 tablets per bottle. This must be kept in a secure place at below 25°C 
(77°F), protected from moisture”. 
 
3.5.3 Preparation and administration of the Investigational Product 
At each visit, patients will be dispensed enough quantity of Tenalisib until the next visit. 
Study drug compliance should be reviewed at the beginning of each new treatment cycle.  
Study drug compliance will 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 treatment of symptoms (see section 5.2). 
• 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 hours 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 cycle. Missed doses 
should be documented. 
 
3.5.4 Accountability of Investigational Products 
The site PI/ designee is responsible for accountability of all trial drug supplies (used/unused 
medication) 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.  
 


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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 will be filed at the site and in Trial Master File (TMF).  
 
3.5.5 Precautions and risks associated with the Investigational Product 
• 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 
Tenalisib for Grade 3 or higher event. In addition, monitor patients for diarrhea/ colitis 
and pneumonitis as these events are reported with agents of PI3K inhibitor class.  
• Patients with CLL are at increased risk for infection (including sepsis and/or 
opportunistic infection with Pneumocystis jirovecii or Herpesviridae (herpes simplex 
virus, varicella-zoster virus, CMV, Epstein-Barr virus)) because of compromised 
immune function, which might be related to the disease itself and/or to the consequences 
of therapy. Therefore, monitor patients for signs and symptoms of infection and interrupt 
Tenalisib for Grade 3 or higher infection. The severity of infections should be quantiﬁed 
as minor (requiring either oral antimicrobial therapy or symptomatic care alone), major 
(requiring hospitalization and systemic antimicrobial therapy), or fatal (death as a result 
of the infection). 
• Tenalisib shows 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 and CYP2C9, there is possibility of drug 
interaction with inhibitors or inducers of CYP3A4 and CYP2C9. If concomitant 
treatment of these drugs is clinically warranted, careful observation of the patient is 
advised. Raised INR has been reported with concomitant warfarin administration. 
Therefore, use of heparin or warfarin to be avoided. Low molecular weight heparin 
(LMWH), Dabigatran or Edoxaban is advised for prophylaxis and treatment of venous 
thrombosis. 
• Strong inhibitor or inducers should be avoided as directed in Section 5.3 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 is 7 months (C1D1 to C8D1). 
The study will end when all ongoing subjects have reached their third tumor assessment on 
Cycle 8/Day 1 (C8D1) or have discontinued from the study for any reason, whichever is 
earlier. At the end of the study, all ongoing patients with no evident disease progression will 
be given the opportunity to enroll in an open-label compassionate medication use study 
[Protocol:RP6530-1803] and will be followed up. 
 
3.7 
Study Stopping Rules 
The following study stopping rules based on the safety and efficacy will be used.  
• 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, 


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study accrual will be suspended pending further investigation, and will only be resumed 
at the recommendation of the DRC. In addition, the DRC may recommend for 
termination of the study in case of major safety concerns. 
• Efficacy: Once 20 patients are recruited in stage 1 of the study, the DRC will review the 
efficacy results and may recommend early termination of the study if there are 8 or fewer 
responders out of 20 patients. Else, 41 additional patients will be enrolled into stage 2.  
 
In addition, Sponsor reserves the right to terminate the study in the interest of patient safety, 
for noncompliance with the protocol, lack of recruitment or any other administrative reasons. 
The sponsor and PIs will notify the regulatory authority and respective IRB/IEC 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 the following inclusion criteria to be eligible for participation in 
this study: 
1. 
Patients with diagnosis of B-cell CLL as confirmed by histopathology or flow 
cytometry.  
2. 
Disease status defined as refractory to or relapsed after at least one prior therapy. 
3. 
Presence of measurable lymphadenopathy, defined as the presence of > 1 nodal lesion 
that measures ≥ 1.5 cm in the longest diameter (LD) as assessed by computed 
tomography (CT). 
4. 
ECOG performance status ≤ 2. 
5. 
Male or female ≥ 18 years of age. 
6. 
Life expectancy of at least 3 months.  
7. 
Adequate bone marrow (BM), liver, and renal function as assessed by the following 
laboratory requirements conducted within 14 calendar days before starting study 
treatment.  
a. 
Adequate bone marrow function:   
I. Haemoglobin ≥ 9 g/dl  
II. Absolute neutrophil count (ANC) ≥ 1 x 10^9/L  
III. Platelets ≥50 x 10^9/L  
Patients with hemoglobin, neutrophil and platelet counts below the above 
specified values will be eligible if it is due to tumor dissemination or infiltration 
to bone marrow and as per physician’s discretion. Hemoglobin and platelet 
requirements should not be met by use of recent transfusion or growth factor 
support (G-CSF or erythropoietin) within 3 weeks prior to assessment. 
b. Adequate liver function:   
I. Total bilirubin ≤1.5 times the upper limit of normal (ULN)  
II. ALT and AST should be ≤ 3 x ULN. ALT and AST ≤ 5 x ULN if known 
liver involvement.  
c. 
Adequate renal function: Calculated creatinine clearance ≥ 50 mL/min (as 
calculated by the Cockcroft-Gault method) or Creatinine ≤ 1.5 mg/dl. 
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 should have a negative serum pregnancy test within 3 days prior to 
Cycle 1 Day 1 (C1D1). Female patients of child-bearing potential must consent to use 
a medically acceptable method of contraception as defined in Appendix A, throughout 
the study period and for 30 days after the last dose of study drug. 


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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 and give 
written informed consent. 
 
4.2 
Exclusion Criteria 
Patients should not meet any one of the following exclusion criteria to be eligible for the 
study 
1. 
Patient with Richter’s (large cell) transformation, or prolymphocytic leukemia (PLL) 
transformation. 
2. 
Patients receiving any cancer therapy (i.e., chemotherapy, radiation therapy, 
immunotherapy and biologic therapy) or any cancer investigational drug within 3 
weeks (21 days) or 5 half-lives (whichever is shorter) prior to C1D1.  
3. 
Prior exposure to drug that specifically inhibits PI3K (e.g. idelalisib, copanlisib, 
duvelisib, umbralisib)  
4. 
Patient with autologous / allogeneic stem cell transplant (ASCT/Allo-SCT) receiving 
treatment for active graft versus-host disease (GVHD). 
5. 
Evidence of ongoing severe systemic bacterial, fungal or viral infection as assessed 
by the investigator.  
6. 
Central nervous system (CNS) involvement of leukemia or lymphoma 
7. 
Ongoing immunosuppressive therapy including systemic corticosteroids except as 
allowed per concomitant medication (Section 5.2).  
8. 
Known history of severe liver injury including drug-induced liver injury (e.g. 
alcoholic liver disease, primary biliary cirrhosis, ongoing extrahepatic obstruction 
caused by stones, cirrhosis of the liver or portal hypertension) as judged by 
investigator. 
9. 
Any severe and/or uncontrolled medical conditions or other conditions that could 
affect patient participation in the study, as judged by investigator, such as: 
a. Symptomatic or history of documented congestive heart failure (New York 
heart association (NYHA) functional classification III-IV) 
b.Myocardial infarction within 6 months of C1D1 
c. QTcF >470 msec. 
d.Angina not well-controlled by medication. 
e. Poorly controlled atherosclerotic vascular disease (e.g. cerebrovascular 
accident, transient ischemic attack, angioplasty, cardiac/vascular stenting). 
10. Patient treated for other malignancy in last 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; and localized prostate cancer with PSA <1.0 
mg/dL within 4 weeks of C1D1. 
11. 
Women who are pregnant or lactating. 
12. 
Known seropositive requiring anti-viral therapy for human immunodeficiency virus 
(HIV) infection.  
13. 
Known seropositive requiring anti-viral therapy for hepatitis B virus (HBV) infection 
OR evidence of active hepatitis B infection as defined by detectable viral load if the 
antibody tests are positive. [Note: Subject with a positive HBcAb with an 
undetectable/negative hepatitis B DNA test (e.g., polymerase chain reaction [PCR] 
test) can be enrolled].  
14. 
Known seropositive requiring anti-viral therapy for hepatitis c virus (HCV) infection 
OR patients with positive hepatitis C virus Ab with detectable viral load. [Note: 


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                                             Rhizen Pharmaceuticals S.A. 
Version: 1.0, Dated 12 September 2019 
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Subject with a positive HCV with an undetectable/negative hepatitis C RNA test (e.g., 
PCR) can be enrolled].  
15. 
Known seropositive requiring anti-viral therapy for active CMV infection (Note: A 
serology positive CMV subject with negative CMV PCR test will be enrolled).   
16. 
Unresolved NCI-CTCAE grade 2 and above toxicity (except as mentioned in adequate 
organ function (Refer inclusion criteria #7) attributed to any prior therapy/procedure 
excluding alopecia.  
17. 
Inability or unwillingness to comply with study and/or follow-up procedures outlined 
in the protocol;  
18. 
Concurrent condition that in the investigator’s opinion would jeopardize compliance 
with the protocol. 
 
Note: Relapse is deﬁned as evidence of disease progression in a patient who has previously 
achieved the criteria of a CR or partial remission for ≥ 6 months. Refractory disease is 
deﬁned as treatment failure or as progression within 6 months from the last dose of therapy. 
 
4.3 
Discontinuation from Study Drug 
The following events may be considered for discontinuation of the study drug.  
- 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  
- Lack of protocol compliance in the opinion of study investigator 
- 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 7 months (C1D1 to 
C8D1) unless progression of disease or toxicity warranting discontinuation of therapy. 
Please refer section 3.5.3 for administration of Tenalisib. Post completion of 7 months, if 
the patient shows clinical benefit, patient may be enrolled into a compassionate medication 
use study [Protocol:RP6530-1803] to receive further treatment with Tenalisib.  
 
5.2 
Concomitant Medications 
In general, patients should not to take any concomitant medications during the study, unless 
it is required as a standard of care (as necessary supportive care), prophylaxis or for the 
treatment of adverse event in the opinion of the treating investigator. The following guidance 
should be followed for concomitant medications and the information including blood 
transfusion should be recorded in CRF.  
• Antimicrobial and/or anti-viral prophylaxis should be used according to local standard 
practice; PJP and herpes zoster prophylaxis is strongly recommended. CMV carriers will 
be monitored per institutional guidelines and/or will be given anti-CMV therapy (e.g., 


Protocol No: RP6530-1901 
                                             Rhizen Pharmaceuticals S.A. 
Version: 1.0, Dated 12 September 2019 
27 
Confidential  
ganciclovir, valganciclovir). Similarly, chronic carriers of HBV should receive 
prophylactic anti-viral therapy.  
• 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 administered at dose ≤ 20 mg per day of 
prednisone or equivalent. The dose should be stabilized for at least 1 week or 5 half-
lives (whichever is shorter) prior to C1D1.  
• Patients are permitted to use of topical, ocular, intra-articular, intranasal, and inhaled 
corticosteroids (with minimal systemic absorption).  
• 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.  
• Low molecular weight heparin (LMWH), Dabigatran or Edoxaban is acceptable for 
prophylaxis and/or treatment of venous thrombosis. 
 
5.3 
Prohibited Medications 
The following treatments are prohibited while on the clinical trial and should be 
discontinued:    
• Any other anti- leukemia/lymphoma therapy  
• Herbal medications. Patients should stop using herbal medications at least 7 days prior to 
C1D1.  
• Strong inhibitors or inducers of CYP3A4. Patients should stop using these medications 
at least 7 days or 5 half-lives (whichever is shorter) prior to C1D1. Examples of the drugs 
include but not limited to:  
− Strong inhibitors: Boceprevir, cobicistat, conivaptan, danoprevir, elvitegravir, 
grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir, paritaprevir, 
ritonavir, 
posaconazole, 
saquinavir, 
telaprevir, 
tipranavir, 
troleandomycin, 
voriconazole, clarithromycin, diltiazem, idelalisib, nefazodone, nelfinavir. 
− Strong inducer: Carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. 
John’s wort(g) 
• Strong inhibitors or inducers of CYP2C9. Patients should stop using these medications 
at least 7 days or 5 half-lives (whichever is shorter) prior to C1D1. Examples of the drugs 
include but not limited to:  
− Carbamazepine, rifampin 
• Substrates of CYP3A4 enzyme with a narrow therapeutic range. Patients should stop 
using these medications at least 7 days or 5 half-lives (whichever is shorter) prior to 
C1D1. Examples of the drugs include but not limited to:  
− Cyclosporine, warfarin, phenytoin, theophylline, procainamide, tacrolimus, fentanyl, 
dofetilide and imipramine      
• Use of heparin, warfarin, apixaban or rivaroxaban for prophylaxis and/or treatment of 
venous thrombosis is prohibited. These drugs should be stopped at least 7 days or 5 half-
lives (whichever is shorter) prior to C1D1.    


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• Live attenuated vaccine (e.g. Flu vaccine, pneumovax, varicella). 
• Steroids > 20 mg unless it is required for management of toxicity (e.g., transaminitis) 
during the study. 
 
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 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 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 C8D1) 
3. 
End of Treatment (Day +7 from last dose) 
4. 
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, HBV, HCV and CMV), 
and thus local regulations may require that additional informed consent be obtained from 
the subject.  In these cases, such evaluations/testing will be performed in accordance with 
local regulations. 
 


Protocol No. RP6530-1901 
                                                        
Rhizen Pharmaceuticals SA 
Version : 1.0, Dated 12 September 2019 
CONFIDENTIAL 
 
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Table 1:  Study Assessments and Treatment Schedule 
Day  
Screening 
C1 
C2 
C3 
C4 
C5 
C6 
C7 
C8/ 
EOT18 
EOS19 
Day  
 
D1 
D15 
D1 
D15 
D1 
D1 
D1 
D1 
D1 
D1 
- 
Window period  
-28 
0 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
+7 
+30 
Study Days  
D-28 to 0 
1 
15 
29 
43 
57 
85 
113 
141 
169 
197 
227 
Informed consent1 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Demographics2 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Medical history3 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
Vitals4 
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 
- 
Complete physical exam6 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
Abbreviated physical exam6 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
ECOG Performance Status 
X 
X 
- 
- 
- 
X 
- 
X 
- 
- 
X 
- 
Rai Staging  
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Laboratory assessment  
 
 
 
 
 
 
 
 
 
 
 
 
Complete blood count7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
-
Chemistry panel I8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
-
Chemistry panel II9 
X 
X 
- 
- 
- 
X 
- 
X 
- 
- 
X 
-
Serology10  
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
PT and INR11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
-
Urinalysis (routine) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Pregnancy test12 
X 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
12-lead ECGs13 
X 
X 
- 
X 
- 
X 
- 
X 
- 
- 
X 
- 
Bone marrow biopsy/ aspirate14 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 


Protocol No. RP6530-1901 
                                                        
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Disease assessment  
 
 
 
 
 
 
 
 
 
 
 
 
Radiological scan/imaging15 
X 
- 
- 
- 
- 
X 
- 
X 
- 
- 
X 
- 
Treatment administration  
 
 
 
 
 
 
 
 
 
 
 
 
Tenalisib treatment16 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Tenalisib dispensing  
- 
X 
- 
X 
- 
X 
X 
X 
X 
X 
X 
- 
Drug compliance  
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Safety evaluation  
 
 
 
 
 
 
 
 
 
 
 
 
AE evaluation17 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAE evaluation  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Foot notes: 
1. Patient should be re-consented, if informed consent is obtained >30 days prior to the initiation of study drug.  
2. Demographic profile will include age, sex and race. 
3. Detailed history will be taken at screening that includes history of cancer, past history, no of prior therapies; prior medication 
(in last 4 weeks); and other medical history (history of transfusions). Any medical significant history at subsequent visit will 
be captured as adverse event.  
4. Vitals will be done prior to the administration of study drug (Pre-dose) at the days specified above.   
5. Weight will be measured at all visits. Height to be recorded at screening only; historical data is acceptable. 
6. Physical examination will include lymph node and systemic examination. Complete physical examination will be done at 
screening and EOT visits. At other visits, abbreviated examination (directed physical examination) will be done depending 
on the assessment of tumor. 
7. Complete blood count: hemoglobin, hematocrit, WBC (total and differential leucocyte count) and platelet count. Additional 
investigations will be performed if clinically indicated. Hematology should be done ≤ 14 days prior to C1D1. However, if 
screening assessments are performed within 72 hours of C1D1; these tests need not be repeated on C1D1.      
8. Chemistry Panel I include total bilirubin, ALP, AST, ALT, GGT, urea/ blood urea nitrogen (BUN), creatinine, sodium, 
potassium, chloride, calcium, phosphorus, CO2/bicarbonate and magnesium. The tests should be done ≤ 14 days prior to 
C1D1. However, if screening assessments are performed within 72 hours of C1D1; these tests need not be repeated on C1D1. 
These tests will be performed at supplementary (unscheduled) visits if clinically indicated.       


Protocol No. RP6530-1901 
                                                        
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CONFIDENTIAL 
 
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9. Chemistry Panel II includes blood glucose, LDH, albumin, total protein, TSH, T3 (total/free), T4 (free), total Cholesterol, 
TG, LDL and HDL. These tests will be performed at unscheduled visits if clinically indicated.       
10. Serology includes HIV, HBV, HCV and CMV. Historical results in last 12 weeks is acceptable.  
11. PT and INR. 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. Pregnancy test is required for women of childbearing potential. A serum pregnancy test will be performed at screening; and 
serum/urine pregnancy test at C1D1 (within 72 hours) of dosing. Urine pregnancy test will be performed at other visits as 
indicated. 
13. 12-lead ECG:  ECG will be done at Pre-dose on scheduled timepoints on the day of drug administration. Additional ECGs 
will be obtained if clinically indicated. Triplicate ECGs will be performed to confirm the significant changes of single ECG.  
14. A bone marrow biopsy/aspirate: Unilateral bone marrow aspiration and/or biopsy will be performed at investigator discretion 
in patients for whom assessment of extent of CLL involvement and bone marrow cellularity is important in determining 
eligibility.  However, post initiation of treatment, bone marrow biopsy should be done to confirm potential CR. 
15. Radiological assessment: “Diagnostic quality” CT scan of neck/chest/abdomen/pelvis, as applicable, will be done at the time 
of screening within 28 days of C1D1. The scan and other investigations to document measurable or evaluable disease should 
be performed ≤28 days prior to initiation of treatment or as approved by the medical monitor if it is out of 28-days window 
period. Following screening, CT scans should be repeated at C3D1 (± 7 days), C5D1 (± 7 days) and C8D1 (± 7 days) or at 
end of the treatment (EOT) visit.  
16. Tenalisib will be administered orally twice a day in 28-days of cycle for 7 cycles (C1D1 to C8D1) in absence of disease 
progression or toxicity warranting discontinuation of therapy.  
17. 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.  
18. Post C8D1, patient experiencing clinical benefit with no evident disease progression will be given the opportunity to enroll 
in an open-label compassionate medication use study and will be followed up. Excluding patients who participate in 
compassionate medication use study [Protocol:RP6530-1803], all other patients will undergo the end-of-treatment (EOT) 
assessments within 7 days after the last dose of study drug or discontinuation from the study.   
19. Patients should be followed for AEs for 30 calendar days after the last dose of study drug. 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. RP6530-1901 
                                                     Rhizen Pharmaceuticals S.A. 
Version: 1.0, Dated 12 September 2019 
 
CONFIDENTIAL 
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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 local 
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 study drug.  
 
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 
dosing 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   
Comprehensive medical history should be taken at least for period of minimum 6 months by the 
investigator/qualified designee. In addition, information on cytogenetics and immunophenotyping, 
if available at the screening will be noted. Investigator should note at least 1 of the following criteria 
to document active disease that warrants initiation of therapy; 
a. 
Evidence of progressive bone marrow failure as manifested by the onset or worsening of 
anemia (Hb <10 g/dL) and/or thrombocytopenia (count <100 X 109/L), OR 
b. Massive (lower edge of spleen ≥ 6 cm below the left costal margin) progressive, or 
symptomatic splenomegaly, OR 
c. 
Massive nodes (≥ 10 cm in the longest diameter), progressive, or symptomatic 
lymphadenopathy, OR 
d. Progressive lymphocytosis in the absence of infection, with an increase in blood absolute 
lymphocyte count (ALC) >50% over a 2-month period or lymphocyte doubling time of <6 
months (if initial ALC is ≥30,000/µL), OR 


Protocol No. RP6530-1901 
                                                     Rhizen Pharmaceuticals S.A. 
Version: 1.0, Dated 12 September 2019 
 
CONFIDENTIAL 
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e. 
Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or 
other standard therapy, OR 
f. 
Constitutional symptoms, defined as any one or more of the following disease-related 
symptoms or signs occurring in the absence of evidence of infection: 
i. Unintentional weight loss of ≥10% within the previous 6 months, or 
ii. Significant fatigue (≥ Grade 2), or 
iii. Fevers >100.5°F or 38.0°C for ≥2 weeks, or 
iv. Night sweats for >1 month. 
 
6.2.4 Prior and concomitant medication 
Prior medication history includes treatment received for disease condition/co-morbidities, 
supplements, prophylactic treatment, transfusions in last 4 weeks and should be recorded. Anti-
cancer-treatment for the disease (prior therapies) should be recorded separately and should not be 
listed as a prior medication. Concomitant medication includes treatment for disease condition/co-
morbidities, supplements, prophylactic treatment, transfusions, given after starting the study drug 
and should be recorded. 
 
6.2.5 Prior therapies  
Prior therapy includes systemic treatments, prior transplantation, radiation, and surgeries received 
for the treatment of cancer condition. Prior therapies should be recorded from the initial diagnosis 
and response to each therapy (relapse/refractory) should be noted. 
 
6.2.6 Physical examination 
Full physical examination should be performed during the screening period and as defined in Study 
Assessments and Treatment Schedule (Table 1). Full physical examination includes lymph node 
and systemic examination (e.g. General Appearance, neck, cardiovascular, lungs, abdomen, 
extremities, neurological, skin, and musculoskeletal). The bi-dimensional diameters of the largest 
palpable lymph nodes in each of the following sites should be recorded: cervical, axillary, and 
inguinal. The dimensions of the liver and spleen below their respective costal margins, as assessed 
by palpation, should also be recorded. 
 
For cycles that do not require a full physical exam per the Study Assessments and Treatment 
Schedule (Table 1), a directed physical examination (Abbreviated) as clinically indicated 
depending on assessment of tumor, prior to study drug administration should be performed. After 
the first dose of study drug new clinically significant abnormal findings should be recorded as AEs. 
 
6.2.7 Vital signs  
Vital signs will be taken at screening, prior to the administration of each dose of study drug and at 
treatment discontinuation as specified in the Study Assessments and Treatment Schedule. Vital 
signs should include temperature (oral/axillary/tympanic), 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 


Protocol No. RP6530-1901 
                                                     Rhizen Pharmaceuticals S.A. 
Version: 1.0, Dated 12 September 2019 
 
CONFIDENTIAL 
Page 34 of 61 
  
Table 2: Laboratory Tests for Hematology, Chemistry and Urinalysis 
Hematology  
Chemistry Panel I 
Chemistry Panel II 
Urinalysis 
Other Lab 
Hematocrit  
Total bilirubin 
Blood glucose  
Blood  
Serum β-hCG 
Hemoglobina 
Alkaline phosphatase  
LDH 
Glucose  
Urine 
pregnancy 
test 
Platelet count 
Alanine aminotransferase 
Albumin 
Protein  
PT 
White blood cell 
count 
Aspartate 
aminotransferase  
Total protein 
Specific 
gravity  
INR 
WBC (Total and 
differentials) 
Urea 
or 
blood 
urea 
nitrogenb 
Total Cholesterol 
Microscopic 
examd 
 
Red blood cell 
count 
Creatinine 
Triglyceride (TG) 
 
 
Absolute 
neutrophil count 
Gamma-glutamyl 
transferase 
LDL 
 
 
Absolute 
lymphocyte count 
Sodium 
HDL 
 
 
 
Potassium  
TSH 
 
 
 
Calcium 
T3 (Total or Free) 
 
 
 
Phosphorous 
T4 (free) 
 
 
 
Carbon Dioxide (CO2) or 
bicarbonateC  
 
 
 
 
Chloride  
 
 
 
 
Magnesium  
 
 
 
a Screening and subsequent Hb determinations should be performed before any given transfusions. 
b Blood Urea Nitrogen is preferred; if not available Urea may be tested. 
C One of these tests to be performed depending on standard of care practice followed at the institution.  
d Microscopic exam, if abnormal results are noted.  
 
Blood drawn for these tests will be specified in informed consent form (ICF). All laboratory 
investigations will be performed at local laboratory.  
 
Screening laboratory described in Table 2 will be performed, reviewed, and determined to be 
acceptable by the site PI/designee within ≤ 14 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. Re-screening can be done at the discretion of PI. The scan 
and other investigations to document measurable or evaluable disease should be performed ≤28 
days prior to initiation of treatment or as approved by the medical monitor if it is out of 28-days 
window period.  
 
During screening, active HBV, HCV, HIV and CMV infection should be ruled out. To be 
considered negative for active infection, following algorithm will be used:  


Protocol No. RP6530-1901 
                                                     Rhizen Pharmaceuticals S.A. 
Version: 1.0, Dated 12 September 2019 
 
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Page 35 of 61 
• 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, HCVRNA 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). 
• 
CMV: Negative for anti-CMV IgM antibody or if positive anti-CMV IgG antibody is 
positive, CMV DNA should be negative. [Note: Carriers will be monitored per institutional 
guidelines.] 
 
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 prophylaxis and should be closely monitored for HBV reactivation. CMV carriers will be 
monitored per institutional guidelines and/or will be given anti-CMV therapy (e.g., ganciclovir, 
valganciclovir). 
 
6.2.9 ECG     
A standard 12-lead ECG will be performed using local standard procedures as defined in Study 
Assessments and Treatment Schedule (Table 1). Additional ECGs will be obtained if clinically 
indicated. Triplicate ECGs will be performed to confirm the significant changes of single ECG. If 
ECG finding is considered as clinically significant, it should be recorded as medical history/adverse 
event appropriately. On the day of dosing, ECG will be performed prior to dose administration. 
 
6.3 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
ECOG performance status will be assessed as below at time points specified in the Schedule of 
Event. 
 
 
6.4 
Disease assessment  
The disease assessment will be done by an expert haemato-oncologist/oncologist by evaluating 
disease-related symptoms/cytopenias, physical examination, lymph nodes assessment, assessment 
of organomegaly and constitutional symptoms. Based on the disease assessment, Rai staging will be 
Score  Description  
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to 
carry out any work activities.  Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead 


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performed to define risk status of the patients (low risk disease, intermediate-risk disease and high-
risk disease) [11].   
          Table 3:Rai staging system  
Stage 
Description 
Modified Risk 
Status 
0 
Lymphocytosis, lymphocytes in blood >5 x 109/L clonal B-
cells and >40% lymphocytes in the bone marrow 
Low 
I 
Stage 0 with enlarged node (s) 
Intermediate 
II 
Stage 0-I with splenomegaly, hepatomegaly, or both 
Intermediate 
III 
Stage 0-II with hemoglobin <11.0 g/dL or hematocrit <33% 
High 
IVc 
Stage 0-III with platelets <100,000/µL 
High 
C Immune-mediated cytopenias are not the basis for these stage definitions. 
 
6.5 
Radiological assessment  
Initial disease assessment of relapsed/refractory CLL patient should be performed within 28 days 
prior to the first dose of study drug using CT scan of neck/chest/abdomen/pelvis, as applicable 
(This scan will be considered as baseline scan). The PI should review baseline scan images to 
confirm the subject has measurable disease as defined in the inclusion criteria. Scan performed as 
part of routine clinical management is acceptable for use as the baseline scan if it is of diagnostic 
quality and performed within 28 days prior to the C1D1 or as approved by the medical monitor if 
it is out of window period. Subsequently, CT scan should be done throughout the study at time-
points designated in Study Assessments and Treatment Schedule (Table 1). Other radiological 
evaluations (e.g. MRI/USG) will be performed if warranted. 
 
Disease response assessments should be performed at C3D1 (± 7 days), C5D1 (± 7 days) and C8D1 
(± 7 days), and/ or at the EOT or as clinically indicated (if clinical progression is suspected). If CT 
scan at Screening is negative for disease involvement in the neck, subsequent CT scan may not 
include neck. If CT scan at Screening are positive for disease involvement of the neck, subsequent 
CT scan must include neck. 
 
Note: Evaluation of radiological assessment will be performed and confirmed by the site 
investigator (defined as PI-confirmed response). The PI confirmed response will be considered for 
analyses of efficacy endpoints. 
 
6.6 
Bone marrow biopsy  
Unilateral bone marrow aspiration and/or biopsy will be performed at investigator discretion in 
patients for whom assessment of extent of CLL involvement and bone marrow cellularity is 
important in determining eligibility during screening period (within 28 days prior to the first dose 
of study drug). However, bone marrow biopsy should be done to confirm potential CR.  
 
To deﬁne a CR, the cytological or pathological evaluation of the bone marrow smear or biopsy 
must be at least normocellular for age, without evidence for typical CLL lymphocytes by 
morphological criteria. 


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Note: Bone marrow biopsy/aspirate will be performed at the site (local lab) as a diagnostic 
procedure as per the site practice.  
 
6.7 Trial Treatment Period 
Patients will visit the study center bi-weekly for the first two 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 7 cycles (C1D1 to C8D1). 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. 
 
6.8 
End of Trial Treatment (EOT) 
Patients are permitted to continue Tenalisib treatment until C8D1 unless there is disease 
progression, or discontinuation of patients due to unacceptable toxicity or decision to discontinue 
treatment by the patient (consent withdrawal)/PI. Follow-up evaluations required after treatment 
ends are specified in Table 1. 
 
Treatment Beyond Cycle 8: Post C8D1, patient experiencing clinical benefit with no evident 
disease progression will be given the opportunity to enroll in an open-label compassionate 
medication use study and will be followed up.  
 
All patients who discontinue Tenalisib will have an End of Treatment visit within 7 days from the 
last dose of the study drug. If treatment is discontinued because of toxicity or any other reason(s), 
the date of discontinuation will fulfill the End of Trial Treatment Visit. Patients who will be 
considered for compassionate use study protocol will have EOT assessment on C8D1. 
 
6.9 
End of Study (EOS) 
All patients must be followed for adverse events for 30 calendar days after the last dose of study 
drug. Telephonic follow up is acceptable. Patients who will be considered for compassionate use 
study protocol will have EOS visit on C8D1. 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.  
 
6.10 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 authorities. 
 


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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 related or unrelated 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 initiation of study drug 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 
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 adverse event to the study drug. For this study, the 
causality assessment will be categorized as related and not related.  
 
• Related: All toxicities should be considered 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 study drug 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. 
 


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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) 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 
 
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 during the course of study; 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 dose of drug. 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.   
 


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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 dose of study drug 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 dose of study drug 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 dose of study drug and 
not attributed to study drug (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 e-mail. The detailed SAE 
reporting process will be provided to the sites in the SAE reporting guidelines. 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. 
 
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 E6 guidelines, and 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 
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 local regulatory 
authorities (as applicable) 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 
Severity of Adverse events 
Severity of adverse events will be assessed according to National Cancer Institute (NCI)- CTCAE 
v5.0 with exceptions for platelet, hemoglobin and ANC that are recommended by iwCLL 
guidelines for the CLL (see below). 
 
Grade* 
Decrease in platelet† or Hb‡ (nadir) from 
baseline, % 
Absolute neutrophil count 
(nadir)§ x 109/L 
0 
No change to 10 
≥ 2 
1 
11-24 
≥1.5 and <2 
2 
25-49 
≥1 and <1.5 


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3 
50-74 
≥0.5 and <1 
4 
≥ 75 
<0.5 
* Grades: 1-mild; 2-moderate; 3-severe; 4-life-threatening; 5-fatal. Death occurring as a result of toxicity at any level 
of decrease from baseline will be recorded as grade 5. 
† Platelet counts must be below normal levels for grades 1-4. If, at any level of decrease the platelet count is <20 × 
109/L, this will be considered grade 4 toxicity unless a severe or life-threatening decrease in the initial platelet count 
(e.g., 20 × 109/L) is present at baseline, in which case the patient is not evaluable for toxicity referable to platelet 
counts. 
‡ Hb levels must be below normal levels for grades 1-4. Baseline and subsequent Hb determinations must be 
performed as per the schedule of events. The use of erythropoietin is irrelevant for the grading of toxicity but should 
be documented. 
§ If the absolute neutrophil count (ANC) reaches <1 × 109/L, it should be judged to be grade 3 toxicity. Other 
decreases in the white blood cell count or in circulating granulocytes are not to be considered because a decrease in 
the white blood cell count is a desired therapeutic end point. A gradual decrease in granulocytes is not a reliable 
index in CLL for stepwise grading of toxicity. If the ANC is <1 × 109/L before therapy, the patient is not evaluable 
for toxicity referable to the ANC. The use of G-CSF is irrelevant for the grading of toxicity but should be 
documented. 
 
7.5 
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.  
 
7.5.1 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. If a diagnosis is determined subsequent to the 
reporting of the constellation of symptoms, the signs/symptoms should be updated to reflect the 
diagnosis. 
 
7.5.2 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. If a persistent AE 
becomes more severe or lessens in severity, AE should be recorded separately with onset date as 
date of change of severity in CRF.    
A recurrent AE is one that occurs and resolves between patient evaluation time points, and 
subsequently recurs. All recurrent events should be recorded separately on an SAE Report Form 
and/or CRF.  
 


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7.5.3 Abnormal laboratory values 
Any grade 3/4 laboratory abnormalities or any clinically significant grade 1/2 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 
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. 
 
7.5.4 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.  
 
7.5.5 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 (See section 7.3) that do not require reporting as an SAE. 
 
7.5.6 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. 
 
7.5.7 Pregnancy, abortion, birth defects/congenital anomalies 
Pregnancy, abortion, birth defects, and congenital anomalies are events of special interest.  Please 
refer to pregnancy Section7.6.1 for specific instructions. 
 
7.5.8 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 as disease 
progression. 
 


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7.5.9 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 will be considered lack of efficacy and not an AE. 
 
7.6 
Protocol-Defined Events of Special Interest 
The following are events of special interest and will need to be reported expeditiously. 
 
7.6.1 Pregnancy, abortion, birth defects/congenital anomalies 
Female patients who are not of child-bearing potential (see Appendix A) and female patients of 
child-bearing potential who have a negative serum pregnancy test (within 72 hours prior to 
initiation of study drug) are eligible for the study. Female patients of child-bearing potential (see 
Appendix A), must consent to use a medically acceptable method of contraception throughout the 
study period and for 4 weeks after the last dose of Tenalisib. A barrier method of contraception 
must be included.    
 
During the course of the trial, all female patients of childbearing potential (the definition of “women 
of childbearing potential” is listed in Appendix A) 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.   
 
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 as soon as possible. A pregnancy Form should be completed and emailed to 
Sponsor.    
 
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 update to reflect the outcome of the pregnancy. 
 
7.6.2 Overdose 
Both intentional (misuse/abuse) and unintentional (accidental) overdose must be reported in the 
CRF. Symptomatic unintentional and intentional overdose must be reported as AE in the CRF (see 
below). Any accidental overdose with the study drug that is symptomatic, fulfilling a seriousness 
criterion, is to be reported to the Sponsor immediately (within 24 hrs) as SAE. Intentional overdose 
should be reported as an SAE irrespective of seriousness criteria.  
 


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Type of 
overdose 
Document 
in CRF 
Document in AE 
CRF 
Complete SAE form 
Unintentional 
(accidental) 
Yes 
Only if associated 
with an AE 
Only if associated with an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not associated with a SAE 
 
7.7 
Dose Modifications 
In case of the hematologic and non-hematologic toxicities, the dose modifications provided below 
(Table 4 and Table 5) should be used a guidance and should be determined as per PI’s clinical 
judgement. The dose modifications are intended to be applied when the investigator determines the 
events related to Tenalisib. If events (cytopenia) are deemed related to the underlying disease rather 
than Tenalisib, dose reduction will be done as per the investigator’s discretion. 
 
In case of drug withhold, Tenalisib treatment can be resumed if:  
• Patient recovered from grade 3-4 toxicity as defined in dose modification guidance below.   
• No clinical or radiographic evidence of disease progression.  
• Investigator believes the risk of progression outweighs the risk of further treatment. 
 
If treatment is delayed >2 weeks, treatment continuation should be discussed with Medical monitor. 
The treatment should be permanently discontinued if withhold of study drug due to drug related 
toxicity is for > 28-days unless approved by medical monitor.  
 
At the discretion of the investigator, a dose re-escalation may be permitted for patients who earlier 
has dose reduction. The decision should be taken after evaluating the emerging safety data and 
benefit and risk of re-escalation. Drug holidays are discouraged. Any patient in whom similar 
toxicity recurs at the reduced dose, it should be discussed with medical monitor to determine 
appropriate strategy on treatment continuation.  
      Table 4: Dose Modifications for Hematologic Toxicity  
CTCAE Grade Toxicity 
Action to be Taken 
Hematologic  
Neutropenia (ANC)  
Grade 3  
1.0 X 109/L<ANC ≥ 0.5 X 109 /L 
Maintain Tenalisib dose. Monitor ANC at least weekly.  
 
Grade 4  
0.5 x 109 /L<ANC 
First incidence: Withhold* dose until resolved to ≤ Grade 2 or baseline. Monitor 
ANC at least weekly. Resume treatment at the same dose level. 
Subsequent occurrence: Hold dose until resolved to ≤ Grade 2 or baseline. 
Consider growth factor support. Resume treatment at the reduced dose level 
(Tenalisib 400 mg BID) if warranted. 
Grade 3 Febrile neutropenia  
ANC <1.0 X 109/L with a single 
temperature of > 38.3 0C (101 0F) 
Withhold* dose until resolved to ≤ Grade 2 or baseline, consider growth factor 
support, then reduce by 1 dose level (Tenalisib 400 mg BID), if warranted. If the 


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or a sustained temperature of ≥ 
38 0C (100.4 0F) for more than 
one hour. 
ANC is <1 X 109/L (1000/µL) before therapy, the dose shall not be modified as 
long as ANC >0.5 X 109/L. 
Thrombocytopenia  
Grade 3 thrombocytopenia# with 
Grade 1 bleeding 
Maintain Tenalisib dose. Monitor platelet count at least weekly.  
 
Grade 3 thrombocytopenia# with 
Grade 2 bleeding 
 
OR  
Grade 4 thrombocytopenia#  
(20.0 X 109/L< PLT) 
1st occurrence: Withhold** dose until to ≤ Grade 2 or baseline or resolution of 
bleeding. Consider platelet transfusion as necessary. Resume treatment at the same 
dose level. 
Subsequent Occurrences: Withhold dose until to ≤ Grade 2 or baseline or 
resolution of bleeding. Consider platelet transfusion as necessary. Resume 
treatment at the reduced dose level (Tenalisib 400 mg BID) if warranted. 
Doses should not be modified if Grade 4 thrombocytopenia is present at baseline. 
* The treatment should be permanently discontinued if withhold of study drug due to drug related toxicity is for > 28-
days unless approved by medical monitor.  
  ** Patient receiving concomitant medication (e.g. anti-platelets, aspirin, or low molecular weight heparin) should be    
      discussed with the medical monitor for further management. 
  # Refer iwCLL criteria  
 
Table 5: Dose Modifications for Non-Hematologic Toxicities  
Non-
Hematologic  
Action to be Taken 
Infection 
Grade 3 or higher sepsis or pneumonia 
• 
Withhold Tenalisib until infection has resolved. 
• 
Restart at the same or at the reduced dose (Tenalisib 400 mg BID) 
Skin rash  
(Cutaneous 
reactions) 
Grade 1-2 
• 
Maintain Tenalisib dose. Initiate supportive care with emollients, antihistamines (for 
pruritus), or topical steroids 
• 
Monitor closely until resolved. 
Grade 3 
• 
Withhold Tenalisib dose. Initiate supportive care with emollients, antihistamines (for 
pruritus), or topical steroids 
• 
Monitor at least weekly until resolved. 
• 
Restart Tenalisib at the reduced dose level (Tenalisib 400 mg BID).  
• 
If severe cutaneous reaction does not improve, worsens, or recurs, discontinue 
Tenalisib 
 
Life threatening or SJS, TEN, DRESS (any grade) 
• Discontinue Tenalisib permanently. 
 
Pneumonitis 
without 
suspected 
infectious cause 
Moderate (Grade 2) symptomatic pneumonitis 
• 
Withhold Tenalisib dose. Initiate systemic steroid therapy. If pneumonitis recovers to 
Grade 0 or 1, Tenalisib may be resumed at reduced dose.  
• 
If non-infectious pneumonitis recurs or patient does not respond to steroid therapy, 
discontinue Tenalisib. 
 


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Severe (Grade 3) or life-threatening pneumonitis 
• 
Discontinue Tenalisib. Treat with systemic steroid therapy. 
Non-infectious 
Diarrhea 
Moderate diarrhea and responsive to antidiarrheal agents:   
• 
Maintain Tenalisib dose. Monitor at least weekly until resolved.  
 
Moderate diarrhea and unresponsive to antidiarrheal agents:   
• 
Withhold Tenalisib dose. Initiate supportive therapy with enteric acting steroids (e.g., 
budesonide). 
• 
Monitor at least weekly until resolved.  
• 
Restart Tenalisib at the reduced dose level (Tenalisib 400 mg BID).  
 
Severe diarrhea or hospitalization  
• 
Withhold Tenalisib dose. Initiate supportive therapy with enteric acting steroids (e.g., 
budesonide) or systemic steroids. 
• 
Monitor at least weekly until resolved.  
• 
Restart Tenalisib at the reduced dose level (Tenalisib 400 mg BID). 
  
Life threatening diarrhoea   
• Discontinue Tenalisib permanently. 
 
Hepatic* 
Transaminitis  
Grade 1-2 Transaminitis (ALT/AST >1-3 x ULN if baseline is normal; 1.5 - 3 x baseline 
if baseline is abnormal):  
• 
Maintain Tenalisib dose and initiate prednisone 40 mg daily.  
• 
Monitor AST/ALT weekly until resolved and then taper steroid.  
• 
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; >5-20 x baseline if baseline is 
abnormal):  
• 
Withhold Tenalisib and monitor ALT/AST twice a weekly until Grade 1; restart 
Tenalisib at one dose lower (Tenalisib 400 mg BID).  
• 
Initiate prednisone 1 mg/kg in case no improvement after withholding Tenalisib for 
1 week.  
• 
Monitor ALT/AST twice a weekly until Grade 1; restart Tenalisib at one dose lower 
(Tenalisib 400 mg BID). 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; >20 x baseline if baseline is abnormal):  
• 
Tenalisib should be permanently discontinued. 
Bilirubin: 
• 
Grade 2 (> 1.5-3 x ULN; >1.5- 3 x baseline if baseline is abnormal): Maintain 
Tenalisib dose. Monitor at least weekly until ≤ 1x ULN 
• 
Grade 3 (> 3-10 x ULN; >3 - 10 x baseline if baseline is abnormal): Withhold 
Tenalisib. Monitor at least weekly until bilirubin is≤ 1x ULN; Restart Tenalisib at 
one dose lower (Tenalisib 400 mg BID). 
Grade 4 (> 10 x ULN; >10 x baseline if baseline is abnormal): Discontinue Tenalisib 
permanently 
Other Non-
Hematologic  
Action to be Taken   
Grade 1 or 2 
None 


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* The treatment should be permanently discontinued if withhold of study drug due to drug related toxicity is for > 28-
days unless approved by medical monitor. 
 
 
Grade 3 
Withhold Tenalisib dose until toxicity Grade ≤2.  
Restart Tenalisib at one dose lower (Tenalisib 400 mg BID) if warranted. 
Recurrence of 
grade 3 toxicity 
Withhold Tenalisib dose until toxicity Grade ≤2;   
Restart Tenalisib at one dose lower or discontinue treatment 
Grade 4  
Withhold Tenalisib dose until toxicity Grade ≤2;   
Restart Tenalisib at one dose lower (Tenalisib 400 mg BID) or discontinue Tenalisib 
Recurrence of 
grade 4 toxicity 
Discontinue Tenalisib 
 


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8 ASSESSMENT OF EFFICACY 
Assessment of efficacy includes careful evaluation of blood, lymph nodes and bone marrow by 
medical history, physical examination, laboratory tests (e.g. CBC and differential count), bone 
marrow aspirate and/or biopsy (as applicable) and CT scans of neck/chest/abdomen/pelvis, as 
applicable.  Investigator assessed efficacy response will be considered in the study. 
 
8.1 
Specification of the Efficacy Parameters 
• ORR is defined as sum of CR and PR rates as defined by iwCLL guideline for CLL (Hallek et 
al. 2018) [12]. Only those patients who have had a pre-treatment baseline efficacy evaluation 
and at least one post-treatment efficacy evaluation (that includes confirmed disease 
progression) will be considered evaluable for response.  
• CR rate will be assessed by the investigator according to the iwCLL guideline for CLL. Only 
those patients who have had a pre-treatment baseline efficacy evaluation and at least one post-
treatment efficacy evaluation (that includes confirmed disease progression) will be considered 
evaluable for response.  
• 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. 
• Best Overall Response: The best overall response is the best response, as assessed and 
confirmed by site PI, from the start of the treatment until disease progression or discontinuation 
from the study.  
 
Disease parameters:  
• Measurable lesions: Measurable lesions are defined as those that can be accurately measured 
in at least two dimensions with conventional techniques with size ≥ 1.5 cm. All tumor 
measurements should be recorded in centimeters.   
 
• Non-measurable lesions (evaluable disease): All other lesions including small lesions (>1 cm) 
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 


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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 
Disease response assessments should be performed at C3D1 (± 7 days), C5D1 (± 7 days) and C8D1 
(± 7 days), and/ or at the EOT or as clinically indicated (if clinical progression is suspected). If CT 
scan at Screening is negative for disease involvement in the neck, subsequent CT scans may not 
include neck. If CT scan at Screening is positive for disease involvement of the neck, subsequent 
CT scans must include neck. Disease assessment will be performed as per iwCLL guideline for 
CLL (Hallek et al. 2018) [12].  
 
To define the response to treatment, 2 groups of parameters will be assessed and documented:  
• Group A parameters: assess the lymphoid tumor load and constitutional symptoms.  
• Group B parameters: assess the hematopoietic system (Table 6). 
 
For complete remission (CR), all criteria given below should be met. For progressive disease, at 
least 1 of the criteria of group A or group B should be  met; For partial remission, at least 2 of the 
parameters of group A and 1 parameter of group B need to improve if previously abnormal; if only 
1 parameter of both groups A and B is abnormal before therapy, only 1 needs to improve.; For 
stable disease, all of the criteria have to be met; constitutional symptoms alone do not define PD. 
         Table 6: Response Criteria for CLL (iwCLL) (Hallek et al, 2018) 
Group 
Parameter 
CR 
PR 
PD 
SD 
A 
Lymph nodes 
None ≥ 1.5 cm 
Decrease ≥ 50% 
(from baseline) * 
Increase ≥ 50% 
from baseline or 
from response 
Change of -49% 
to +49% 
Liver and/or 
spleen size$ 
Spleen size <13 
cm; liver size 
normal 
Decrease ≥ 50% 
(from baseline)  
Increase ≥ 50% 
from baseline or 
from response 
Change of -49% 
to +49% 
Constitutional 
symptoms 
None 
Any 
Any 
Any 
Circulating 
lymphocyte 
count 
Normal 
Decrease ≥ 50% 
from baseline 
Increase ≥ 50% 
over baseline  
Change of -49% 
to +49% 
B 
Platelet count 
≥ 100 x 109/L 
≥ 100 x 109/L or 
increase ≥ 50% 
over baseline 
Decrease of ≥ 
50% over baseline 
secondary to CLL 
Change of -49% 
to +49% 
Hemoglobin 
≥ 11.0 g/dL 
(untransfused and 
without 
erythropoietin) 
≥ 11.0 g/dL or 
increase ≥ 50% 
over baseline 
Decrease of ≥ 
50% over baseline 
secondary to CLL 
Increase <11.0 
g/dL or <50% 
over baseline, or 


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decrease <2 
g/dL 
Marrow 
Normocellular, 
no CLL cells, no 
B-lymphoid 
nodules 
Presence of CLL 
cells, or of B-
lymphoid 
nodules, or not 
done 
Increase of CLL 
cells by ≥ 50% on 
successive 
biopsies  
No change in 
marrow infiltrate 
 $spleen size is considered normal if <13cm. There is no firmly established international consensus of the size of a 
normal liver; therefore, liver size should be evaluated by imaging and manual palpation and be recorded in CRF. 
 
*Sum of the products of 6 or fewer lymph nodes (as evaluated by CT scans and physical examination). No increase in 
any lymph node and no new enlarged lymph node (diameter ≥1.5 cm). For small lymph nodes (longest diameter <1.5 
cm), an increase <25% is not considered signiﬁcant. 
 
Note: Certain therapies (e.g., kinase inhibitors) may cause lymphocytosis. In the setting of therapy 
with such agents, an increase in blood lymphocyte count by itself does not uniformly indicate an 
increased tumor burden but may reﬂect redistribution of leukemia cells from lymphoid tissues to 
the blood [12]. As Tenalisib is a kinase inhibitor, increased lymphocytosis alone will not be 
considered a sign of treatment failure or PD in this study. 
 
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. 
 
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.   
 
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 
The sample size is derived based on Simon's two stage design to achieve 90% power at alpha of 
0.05 for the null hypothesis of ORR≤40%, assuming 60% response rate.  Up to 61 patients will be 
enrolled.  In stage 1, 20 patients will be enrolled, if 08 or fewer responders are observed in this 
stage, the study will be terminated without rejecting the null hypothesis. Otherwise, 41 additional 


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patients will be enrolled into stage 2. If 31 or more responders are observed in the study, the null 
hypothesis of ORR ≤40% will be rejected. 
 
9.3 
Study Population 
The following 3 analysis populations are planned in the study.  
• 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: 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 AEs considered to be drug-related 
• 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 
per patient will be tabulated for select adverse events and laboratory measurements by using NCI 
CTCAE criteria v5.0 with exceptions for platelet, hemoglobin and ANC that are recommended by 
iwCLL guidelines for the CLL. 
 
9.4.3 Efficacy analyses 
The efficacy endpoints will include: 
• Objective Response Rate  
• Duration of response 
• Progression free survival (PFS) 
The analysis will be done as per the disease subtypes and overall. Additional analyses (e.g. CR 
rates) may also be performed as appropriate. These analyses will be performed from time to time 
for presentation/publication purposes. 
 


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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, World Medical Association’s Declaration of Helsinki, local 
regulatory requirement(s), institutional research policies and procedures.  
 
All potential serious breaches must be reported to Rhizen 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 or 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. 
 
10.2  Regulatory Approval 
As required by local regulations, Rhizen will ensure 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 for 
Tenalisib will be prepared by the Sponsor 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 
Rhizen and PI or site. 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/investigator undertaking to allow Rhizen to submit the complete and accurate 
certification or disclosure statements required as per local regulatory requirements. 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. 


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10.5  Informed Consent 
Informed consent is a process by which a subject voluntarily confirms his or her willingness to 
participate in a 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 the relevant elements required 
by the local regulatory 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. 
 
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, 
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 


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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 only a unique trial number and initials will identify 
patients on the CRF or other documents 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. Therefore, absolute 
confidentiality cannot be guaranteed. 
 
10.6.2 
Investigator’s responsibilities 
Medical supervision is the responsibility of the Principal Investigator. 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 Ethical principles that have their origins in the Declaration of Helsinki and local 
regulatory requirements and good clinical practice.  
 
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 or 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 


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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 initiation of study, sponsor will ensure that documentation required by the local 
regulatory authorities and IRB/IEC will be in place. Documents will include, but are not limited 
to: a signed protocol, copy of regulatory and IRB/IEC approval and; current curricula vitae of the 
principal investigator; copy of signed agreement, insurance certificate, form FDA 
1572/Investigator undertaking (as applicable), IRB-approved consent form; financial disclosure 
forms for all investigators; site qualification reports, where applicable and study contract.  
 
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 
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 local 
regulatory requirements. These documents include but not limited to 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 


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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 dispensing, medical records and any other 
trial-related records as per local regulatory requirements for no less than 2 years after the last 
marketing application has been approved by the regulatory agency; or, in the event that the 
marketing application has not been approved by local regulatory agency, for no less than 2 years 
after the last shipment / delivery of the drug for investigational use is discontinued and local 
regulatory agency 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 
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).  


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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 
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 information collected/documented during 
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. 


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                                                     Rhizen Pharmaceuticals S.A. 
Version: 1.0, Dated 12 September 2019 
 
CONFIDENTIAL 
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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 
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.  
 
 


Protocol No. RP6530-1901 
                                                     Rhizen Pharmaceuticals S.A. 
Version: 1.0, Dated 12 September 2019 
 
CONFIDENTIAL 
Page 59 of 61 
14 REFERENCES 
1. Okkenhaug K. Signaling 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(15):3037-3040. 
4. Tenalisib (RP6530) Investigator’s brochure. Version 9.1 Dated 09 May 2019.  
5. MOLT-4 Xenograft in Nude Mice (Incozen-CP-006). 
6. Gunawardana C., et al. South Asian chronic lymphocytic leukemia patients have more rapid 
disease progression in comparison to White patients. Br J Haematol. 2008; 142:606–9. 
7. Howlader N, et al., SEER Cancer Statistics Review, 1975-2012, National Cancer Institute. 
Bethesda, MD, http://seer.cancer.gov/csr/1975_2012. 
8. Francis, S., et al., The effect of immunoglobulin VH gene mutation status and other prognostic 
factors on the incidence of major infections in patients with chronic lymphocytic leukemia. 
Cancer, 2006; 107(5):1023-33. 
9. Stilgenbauer, S., Prognostic markers and standard management of chronic lymphocytic 
leukemia. Hematology Am Soc Hematol Educ Program, 2015(1):368-77. 
10. Stilgenbauer, S. and T. Zenz, Understanding and managing ultra-high-risk chronic 
lymphocytic leukemia. Hematology Am Soc Hematol Educ Program, 2010:481-8. 
11. National Comprehensive Cancer Network, NCCN Clinical Practice Guidelines in Oncology: 
Chronic Lymphocytic leukemia/Small Lymphocytic Lymphoma. Version 2, 2019. 
12. Hallek, M. et al. iwCLL guidelines for diagnosis, indications for treatment, response 
assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760 
 
 
 
 
 


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15 APPENDICES 
        Appendix A: 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  Follicular Stimulating Hormone (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. 


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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. 

SAP_001.pdf: 
  
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PROTOCOL NO. RP6530-1901 
 
 
 A Phase 2, Open label Study to Assess the Efficacy and Safety of Tenalisib 
(RP6530), a Novel PI3K Dual δ/γ Inhibitor, in Patients with Relapsed/Refractory 
Chronic Lymphocytic Leukemia (CLL) 
 
Statistical Analysis Plan 
 
 
 
Author and Designation: 
Arti Kanujia 
Senior Statistician II 
Covance Scientific Services & Solutions Pvt. Ltd. 
Version and Date 
FINAL 1.0, 14DEC2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
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Revision History: 
 
 
VERSION  
CHANGE DESCRIPTION 
AUTHOR 
DATE 
FINAL 1.0 
Not Applicable 
Arti Kanujia 
14DEC2020 
 
 
 


  
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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 
 
 


  
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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 Objectives .................................................................................................................................................................. 7 
4. 
Study Endpoints ............................................................................................................................... 7 
4.1 
Efficacy Endpoints ....................................................................................................................................................................... 7 
4.2 
Safety Endpoints ........................................................................................................................................................................... 8 
5. 
Study Design ..................................................................................................................................... 8 
5.1 
Study Stopping Rules .................................................................................................................................................................. 8 
6. 
Sample Size Considerations ............................................................................................................ 9 
7. 
Analysis Populations ........................................................................................................................ 9 
7.1 
Modified Intent-to-Treat Population (mITT) Set ............................................................................................................. 9 
7.2 
Per-Protocol (PP) Population Set ........................................................................................................................................... 9 
7.3 
Safety Population Set ................................................................................................................................................................ 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 ........................................................................................................................................................ 10 
9.3.1 
Missing Dates for Adverse Events and Concomitant Medications ........................................................................... 10 
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 ..................................................................................................................................................................... 12 
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 ........................................................................................................................................................................ 13 
10.5.1 
Objective Response Rate (ORR) ..................................................................................................................................... 14 
10.5.2 
Complete Response (CR) Rate ......................................................................................................................................... 14 


  
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10.5.3 
Duration of Response (DoR) ............................................................................................................................................. 14 
10.5.4 
Best Overall Response ......................................................................................................................................................... 14 
10.5.5 
Progression Free Survival (PFS) ..................................................................................................................................... 14 
10.6 Safety Analysis ............................................................................................................................................................................ 15 
10.6.1 
Treatment Exposure and Compliance........................................................................................................................... 15 
10.6.2 
Adverse Events ...................................................................................................................................................................... 15 
10.6.3 
Clinical Laboratory Tests .................................................................................................................................................. 17 
10.6.4 
Physical Examinations ........................................................................................................................................................ 17 
10.6.5 
Vital Signs ............................................................................................................................................................................... 18 
10.6.6 
Electrocardiogram ............................................................................................................................................................... 18 
10.6.7 
ECOG ....................................................................................................................................................................................... 18 
11. Protocol Deviations ........................................................................................................................ 18 
12. Listings ............................................................................................................................................ 19 
13. References ....................................................................................................................................... 19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
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List of Abbreviations 
 
Abbreviation 
Term 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical  
BID 
Twice Daily 
CI 
Confidence Interval 
CLL 
Chronic Lymphocytic Leukemia 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
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 
IEC/IRB 
Independent Ethics Committee/ Institutional Review Board 
iwCLL 
International Workshop on Chronic Lymphocytic Leukemia 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
NCI 
National Cancer Institute 
ND 
Not Done 
NE 
Not Evaluable 
ORR 
Objective Response Rate 
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 
TEAE 
Treatment-Emergent Adverse Event 
WHO 
World Health Organization 
 
 


  
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1. 
Amendments from Previous Version(s) 
Not Applicable. 
 
2. 
Introduction 
Note: In this document, any text taken directly from the protocol (Number RP6530-1901, Final, 
Version 1.0, Dated 29 August 2019) is italicized. 
 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study RP6530-1901. This document may modify the plans outlined in the final 
protocol. 
   
2.1 
Rationale 
Chronic Lymphocytic Leukemia (CLL) is a myeloproliferative neoplasm characterized by an 
accumulation of monoclonal mature B-cells (CD5+CD23+) in the blood, bone marrow, and 
secondary lymphatic organs. CLL is the most common form of adulthood leukemia. 
 
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. Pre-clinical 
experiments demonstrated that Tenalisib is highly effective in killing primary CLL cells in vitro. 
The effect appeared to be equal to ibrutinib and higher than conventional chemotherapy agents. 
Tenalisib also demonstrated reduction in chemokine induced migration of Daudi cells, indicating 
its potential in modulating tumor microenvironment. Tenalisib has demonstrated clinical activity 
in patients with hematological malignancies with acceptable safety profile. Therefore, Tenalisib 
may offer a good treatment option for patient with relapsed/refractory CLL. 
 
3. 
Study Objectives  
3.1 
Primary Objective 
• To assess the anti-tumor activity of Tenalisib as determined by the objective response rate 
(ORR) and duration of response (DoR)  
 
3.2 
Secondary Objectives 
• To characterize safety and tolerability of Tenalisib  
• To assess progression free survival (PFS)  
 
4. 
Study Endpoints 
4.1 
Efficacy Endpoints 
 
• Overall response rate (ORR): ORR is defined as sum of CR and PR rates as defined by iwCLL 
guideline for CLL (Hallek et al. 2018)2.  


  
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• Duration of response (DOR): DOR is defined as the interval from the first documentation of 
CR/PR to first documentation of definitive disease progression or death from any cause. 
  
• Progression-free survival (PFS): PFS is defined as the interval from first dose to first 
documentation of definitive disease progression or death from any cause.  
 
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 trial is a Phase II, open label, Simon’s two stage study design to evaluate the efficacy and 
safety of Tenalisib in 61 patients with CLL who have relapsed or are refractory after at least one 
prior therapy. In Stage 1, 20 patients will be enrolled and the study treatment Tenalisib (800 mg 
BID) will be administered orally in 28-days of cycle over a period of 7 months (C1D1 to C8D1) 
in absence of definitive disease progression or unacceptable toxicity. If 8 or fewer responders 
are observed in this stage, the study will be terminated. Else, 41 additional patients will be 
enrolled into stage 2.  
 
Patients will be evaluated for efficacy response by CT at C3D1±7 days, C5D1±7 days and 
C8D1±7 days and/or at End of the treatment (EOT) visit. The study will end when all ongoing 
subjects have reached their third tumor assessment on Cycle 8/Day 1 (C8D1) or have 
discontinued from the study for any reason, whichever is earlier.  
 
5.1 
Study Stopping Rules 
• Safety: The Data review Committee (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. In addition, the DRC may recommend for 
termination of the study in case of major safety concerns.  
 
• Efficacy: Once 20 patients are recruited in stage 1 of the study, the DRC will review the 
efficacy results and may recommend early termination of the study if there are 8 or fewer 
responders out of 20 patients. Else, 41 additional patients will be enrolled into stage 2.  
 
In addition, Sponsor reserves the right to terminate the study in the interest of patient safety, for 
noncompliance with the protocol, lack of recruitment or any other administrative reasons. The 
sponsor and PIs will notify the regulatory authority and respective IRB/IEC respectively if the trial 
terminates early, with a justification for the early termination. 
 


  
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Notes:  
• After reviewing the efficacy data, the study has been closed due to absence of clinically 
meaningful response to single agent Tenalisib in Stage 1 of the study. Therefore, Stage 2 
will not be performed. 
• 
The analysis proposed in this SAP is considering the available data at the time of 
completion of the study. 
  
6. 
Sample Size Considerations 
The sample size was derived based on Simon's two stage design to achieve 90% power at alpha 
of 0.05 for the null hypothesis of ORR≤40%, assuming 60% response rate. Up to 61 patients 
will be enrolled. In stage 1, 20 patients will be enrolled, if 08 or fewer responders are observed 
in this stage, the study will be terminated without rejecting the null hypothesis. Otherwise, 41 
additional patients will be enrolled into stage 2. If 31 or more responders are observed in the 
study, the null hypothesis of ORR ≤40% will be rejected. 
Stage 1: 21 patients with relapsed/refractory CLL is enrolled. 
 
Stage 2 will not be initiated as the study is closed due to absence of clinically meaningful 
response to single agent Tenalisib.  
 
7. 
Analysis Populations 
7.1 
Modified Intent-to-Treat Population (mITT) Analysis Set 
The mITT is the primary efficacy analysis population set 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 Analysis Set 
The PP Population set is a subset of the modified Intent-to-Treat Population set and will include 
patients without major protocol deviations. 
Major deviations shall include: 
- 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 of 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 prior to the study database lock. All deviations will be reviewed by the Medical 
monitor prior to database closure in order to decide whether to include the patient in a PP 
analysis population set. The PP population analysis set will also be used for efficacy assessment. 
 


  
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Note: If 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 Set 
The Safety Population set 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 reported 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 
The sample size was derived based on Simon's two stage design to achieve 90% power at alpha 
of 0.05 for the null hypothesis of ORR ≤ 40%, assuming 60% response rate. Up to 61 patients 
will be enrolled. In stage 1, 20 patients will be enrolled. If eight or fewer responders are observed 
in this stage, the study will be terminated without rejecting the null hypothesis. Else, 41 
additional patients will be enrolled into stage 2. If 31 or more responders are observed in the 
study, the null hypothesis of ORR ≤ 40% will be rejected.  
 
9.2 
Interim Analysis 
No formal interim analysis will be performed for this study; however, the study data will be 
reviewed periodically by DRC during the course of the study. Refer Section 5.1 for detailed 
information. 
 
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: 


  
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 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 
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. 
 


  
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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. 
 
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. 
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 the treatment, 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. 
 


  
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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, chromosomal 
abnormalities, gene mutations, Rai staging at the time of screening, number of prior therapies, 
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) or 
higher]. 
 
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 will be termed as ‘Concomitant’.  
 
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 or higher) and the non-drug treatments data will be coded using MedDRA 
dictionary [Version 23.0 (Hierarchy) or higher]. 
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 
• These analyses will be done for overall population. }  
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. 
 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1901   
 
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10.5.1 Objective Response Rate (ORR)  
It is defined as sum of CR and PR rates as defined by iwCLL guideline for CLL (Hallek et al. 
2018)2.  Only those patients who have had a pre-treatment baseline efficacy evaluation and at 
least one post-treatment efficacy evaluation (that includes confirmed disease progression) will 
be considered evaluable for response. 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 and the 95% CI (Using exact 
method based on binomial distribution, subject to availability of adequate data) for the Overall 
group.  
The corresponding listing will also be provided. 
 
10.5.2 Complete and Partial Response Rate 
The investigator assessed response, which is done as per the iwCLL guideline for CLL will be 
used. Only those patients who have had a pre-treatment baseline efficacy evaluation and at least 
one post-treatment efficacy evaluation (that includes confirmed disease progression) will be 
considered evaluable for response.  
This data will be summarized using frequency, and percentage. the 95% CI (Using exact method 
based on binomial distribution, subject to availability of adequate data) will be presented for the 
Overall only.  
 
10.5.3 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 descriptively using n, mean, median, standard deviation, minimum 
and maximum values for overall subjects. The DoR data will be listed for each patient. 
  
10.5.4 Best Overall Response 
It is the best response, as assessed and confirmed by site PI, 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 reported in the 
CRFs for overall subjects.. This data will also be listed. 
 
10.5.5 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 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1901   
 
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FINAL 1.0 Dated 14DEC2020 
 
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their death. Subjects who did not progress or die will be censored on the date of their last tumor 
assessment that will be assessed at End of Treatment visit for this study. End of treatment visit 
will be considered as the cut-off visit for the calculation of PFS. 
This data will be summarized using the Kaplan-Meier method and displayed graphically for 
overall subjects.  The following reports will be generated:  
• The Q1, median and Q3 PFS time will be provided along with95% CI for the Q1, median, 
and Q3 PFS time will be presented for the Overall subjects using Brookmeyer-Crowley 
method, subjected to availability of adequate data. 
• The number and % of patients with disease progression (further divided into disease 
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. 
 
10.6 
Safety Analysis 
Analysis Set: Safety 
 
The safety analyses will be reported for Overall patient data only. 
 
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 reported 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 
Note: If needed, adverse event data may be presented for all screened patients. 
The frequency of adverse events (AEs) will be computed by counting each patient only once per 
MedDRA [Version 23.0 (Hierarchy) or higher] preferred term and according to the maximum 
NCI CTCAE v.5.0 grade attained by the patient over the specified period. The percentage of 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1901   
 
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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 (TEAEs) 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 
• Treatment Related TEAEs 
• Serious non-TEAEs 
• Serious TEAEs 
• Treatment Related Serious TEAEs 
• Grade 3 or 4 TEAEs 
• Treatment Related Grade 3 or 4 TEAEs 
• TEAEs leading to discontinuation 
• Treatment Related TEAEs leading to discontinuation 
• Serious TEAEs leading to discontinuation 
• Treatment Related Serious TEAEs leading to discontinuation 
• TEAEs leading to dose interruptions/dose reductions 
• Fatal TEAEs 
• Treatment 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 (Related/ Not Related/ Total) 
• Grade 3, 4 and 5 TEAEs (Related/ Not Related/ Total) 
• Treatment-Emergent SAEs  (Related/ Not Related/ Total) 
• TEAE with maximum CTCAE grade 
• Treatment-Related TEAEs with maximum CTCAE grade 
• Deaths 
 
The adverse events data will also be listed for individual patients. 
• Any non-TEAE 
• AEs 
• Related TEAEs 
• Treatment Emergent Grade 3, 4 and 5 AEs 
• Treatment Related Grade 3, 4 and 5 AEs 
• SAEs 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1901   
 
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• 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 of Laboratory parameters will be presented using descriptive statistics (n, mean, 
median, standard deviation, minimum and maximum values) as appropriate.  
The laboratory data will also be listed. 
A separate listing of patients with abnormal laboratory test values will also be presented. 
 
Hematology 
Chemistry Panel I 
Chemistry Panel II Urinalysis 
Other 
Hematocrit 
Total bilirubin 
Blood glucose 
Blood 
PT 
Hemoglobin 
Alkaline 
phosphatase  
LDH 
Glucose 
INR 
Platelet count 
Alanine 
aminotransferase  
Albumin 
Protein 
 
White blood cell 
count 
Aspartate 
aminotransferase  
Total protein 
Specific 
gravity 
 
WBC (Total and 
differentials) 
Urea or blood urea 
nitrogen 
Total Cholesterol 
Microscopic 
exam 
Red blood cell 
count 
Creatinine 
Triglyceride (TG) 
Absolute 
neutrophil count 
Gamma-glutamyl 
transferase  
 
LDL 
Absolute 
lymphocyte count 
Sodium 
HDL 
 
Potassium 
TSH 
 
Calcium 
T3 (Total or Free) 
 
Phosphorous 
T4 (free) 
 
Carbon Dioxide 
(CO2) or bicarbonate  
 
Chloride 
 
 
Magnesium 
 
 
10.6.4 Physical Examinations 
Analysis Set: Safety 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1901   
 
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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 
Vital signs will include pulse rate, respiratory rate, blood pressure, and temperature 
(oral/axillary/tympanic). Weight will also be included here.  
 
The baseline measurement is the last pre-treatment measurement taken on or before Cycle1 
Day1. 
 
Absolute values of Vital Signs 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 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 reported 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 


  
Rhizen Pharmaceuticals S.A.                                                                                                                      RP6530-1901   
 
Rhizen Pharmaceuticals SA Confidential 
FINAL 1.0 Dated 14DEC2020 
 
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will be categorized as major and minor and a decision will be taken by the medical monitor whether 
to include the subject in a PP analysis population set. 
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: 
• Screened patients 
• Eligibility review 
• Study completion/Reasons for withdrawal of patient from the study 
• Analysis populations 
• Prior therapy 
• Baseline Serology assessment 
• Cancer diagnosis 
• Disease assessment at Screening visit 
• Follow-Up Cancer Overall Assessment 
• 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 
 
13. 
References  
1. Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. Biometrics. 
38: 29-41, 1982. 
2. Hallek, M. et al. iwCLL guidelines for diagnosis, indications for treatment, response 
assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760