Clinical trial NCT03711604
Conditions: Hematological Malignancies
Keywords: Hematological Malignancies Tenalisib RP6530 Compassionate Use
Sponsor: Rhizen Pharmaceuticals SA
Start date: 2018-11-28; Completion date: 2023-03-25
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Tenalisib has been evaluated as an investigational new drug in number of early clinical studies in patients with relapsed/refractory hematological malignancies and demonstrated acceptable safety and promising efficacy in these patients. Since these advanced relapsed/refractory patients have limited therapeutic options, it is reasonable to continue Tenalisib in responding patients post completion of their participation in previous clinical studies.

Detailed description:

Arms: arm 1: Participants receive Tenalisib (RP6530) BID Orally
Interventions: intervention 1: Tenalisib
Intervention descriptions: intervention 1: BID Orally

Protocol documents:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
Page 1 of 37 
                  PROTOCOL NO. RP6530-1803 
 
An Open label, Compassionate Use Study of Tenalisib (RP6530) 
in Patients currently receiving treatment on Tenalisib trials in 
Hematological Malignancies 
 
 
 
 
This document is a confidential communication of Rhizen Pharmaceuticals S.A.  Acceptance of this 
document constitutes agreement by the recipient that no unpublished information contained herein shall 
be published or disclosed without prior written approval.
PROTOCOL NUMBER 
RP6530-1803 
TRIAL DRUG 
Tenalisib (RP6530)  
 
 
SPONSOR  
Rhizen Pharmaceuticals S.A. 
Fritz-Courvoisier 40, 
Ch-2300 La Chaux-de-Fonds,  
Switzerland. 
 
SPONSOR’S 
REPRESENTATIVE  
Ajit Nair, PhD 
SVP, Clinical R&D  
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 
 
Version 2.0, Dated October 15, 2019 


Protocol No. RP6530-1803 
                                                     Rhizen Pharmaceuticals SA. 
Version: 2.0,  15 October 2019 
 
CONFIDENTIAL 
Page 6 of 37 
PROTOCOL SYNOPSIS 
Study Title 
An Open label, Compassionate Use Study of Tenalisib (RP6530) in Patients currently 
receiving treatment on Tenalisib trials in Hematological Malignancies. 
Study 
Sponsor 
Rhizen Pharmaceuticals S.A. 
Study 
Rationale 
Compassionate use provides an important avenue for patients with life-threatening 
conditions to gain access to unapproved investigational drugs, biologics and medical 
devices. Currently, Tenalisib has been evaluated as an investigational new drug in 
number of early clinical studies in patients with relapsed/refractory hematological 
malignancies. Tenalisib demonstrated acceptable safety and promising efficacy in these 
patients.  
 
Since these advanced relapsed/refractory patients have limited therapeutic options, it is 
reasonable to continue Tenalisib in responding patients post completion of their 
participation in previous clinical studies. It is anticipated that Tenalisib would not expose 
patients to an unreasonable and significant risk or injury. Therefore, this trial is designed 
to offer patients benefited by Tenalisib and who completed study without progression an 
opportunity to continue Tenalisib as compassionate medication and followed up on 
treatment for safety and disease progression. 
Study 
Objectives 
1. To evaluate the safety and tolerability of Tenalisib as single agent or in combination 
until the withdrawal of subject from the study due to disease progression, 
unacceptable toxicity or any other reason including consent withdrawal or 
investigator’s decision. 
2. Time to disease progression  
 
Endpoints 
1. Adverse Events (AEs), Grade 3/ 4 AEs and Serious Adverse Event (SAEs). 
2. Date of disease progression. 
Study Design  
This is an open label, compassionate use study in patients who have completed a clinical 
trial of Tenalisib sponsored by Rhizen Pharmaceuticals S.A. This trial offers an 
opportunity to patients who have responded (either have CR, PR or SD on Tenalisib 
treatment) to receive Tenalisib as compassionate medication following their completion 
of previous study. Patients will continue to receive Tenalisib (schedule and dose) as they 
received in previous protocols, unless dose adjustments or delays are necessary for 
toxicity management.  
 
Trials evaluating Tenalisib as a single agent or in combination with other therapies will 
be part of this compassionate study protocol. The patients of these studies will be rolled 
over to compassionate use study once they complete the participation in original study.   
No. of 
Patients 
Approximately 50 patients 
Inclusion 
Criteria 
Patients must meet all inclusion criteria to be eligible for participation in this study: 
1. Patients must be currently receiving treatment with Tenalisib either as monotherapy 
or in combination with another agent on a previously approved protocol for 
hematological malignancies including but not limited to indications DLBCL, iNHL, 
PTCL, CTCL, CLL and HL. 
2. Patients must have had at least one efficacy evaluation following the initiation of 
Tenalisib in previous study and should have achieved either SD, PR or CR. 
3. Patients must have completed at least 6 cycles of Tenalisib in previous study 
4. Ability to swallow and retain oral medication. 


Protocol No. RP6530-1803 
                                                     Rhizen Pharmaceuticals SA. 
Version: 2.0,  15 October 2019 
 
CONFIDENTIAL 
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5. Female patients of child-bearing potential must consent to use two medically 
acceptable methods of contraception throughout the study period and for 4 weeks 
after the last dose of Tenalisib. A barrier method of contraception must be included.  
6. Male patients must be willing to use adequate contraceptive measures throughout 
the study period and for 12 weeks after the last dose of Tenalisib. 
7. Willingness and ability to comply with trial and follow-up procedures. 
8. Willingness to provide new written informed consent. 
Exclusion 
Criteria 
Patients must meet none of the following exclusion criteria to be eligible for 
participation in this study: 
1. Patient has been discontinued from their previous Tenalisib study 4 weeks prior to 
entering the compassionate use trial. 
2. Patient progressed while receiving Tenalisib therapy in his/her previous study. 
3. Pregnant or lactating woman. 
4. Inability or unwillingness to comply with study and/or follow-up procedures 
outlined in the protocol. 
5. Concurrent condition that in the investigator’s opinion would jeopardize compliance 
with the protocol. 
Study 
Procedure 
Once rolled over to compassionate use study, patients will visit the study center every 3 
months until documented disease progression or treatment discontinuation due to 
toxicity or consent withdrawal. During these visits, Tenalisib will be dispensed and 
medication compliance will be monitored. In case of roll over from a combination study, 
the investigator has a choice to continue with the combination therapy or to maintain the 
patient on Tenalisib monotherapy. If combination agent is continued, it will be 
administered as a part of SOC.  
Safety and efficacy assessments will be done as mentioned below.  
• 
Safety assessments: Safety assessments will be done during these visits and AEs 
will be reported as required by the protocol. There are no specific safety labs or 
evaluations (including vitals, physical examinations, pregnancy tests and ECGs) 
required as per protocol. As part of SOC, laboratory tests or other evaluations will 
be done per Investigator’s discretion. Adverse events (AEs, SAEs and deaths) will 
be recorded and reported until 30 calendar days after last dose or until a new anti-
cancer treatment is initiated, whichever is earlier. After this period, only AEs, SAEs, 
or deaths assessed by the investigator as treatment related are to be reported. 
• 
Efficacy assessments: Disease assessments should be performed as part of SOC.  
Date of disease progression will be recorded in the CRF. 
• 
Drug dispensing: Patients will be given drug supply of 3 months.   
Estimated 
Study 
duration 
Approximately 5 years 
Assessment of 
Response  
Efficacy evaluations will be performed as per physician’s discretion as part of SOC. 
These evaluations (e.g. measurement of lymph node, mSWAT) will not be recorded in 
CRF, however the date of disease progression will be reported. 
Study 
Treatment  
 
Patients showing clinical benefit will continue to receive Tenalisib as they are currently 
receiving in previous protocols. The treatment plan will be the same dosing schedule 
unless dose adjustments or delays are necessary for toxicity management. In case of roll 
over from a combination study, the investigator has a choice to continue with the 
combination therapy or to maintain the patient on Tenalisib monotherapy. If combination 
agent is continued, it will be administered as a part of SOC.   


Protocol No. RP6530-1803 
                                                     Rhizen Pharmaceuticals SA. 
Version: 2.0,  15 October 2019 
 
CONFIDENTIAL 
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Statistical 
Analysis 
 
The primary purpose of this study is to offer patients who completed a Rhizen sponsored 
clinical study without progression the opportunity to continue to receive Tenalisib on a 
compassion basis.  The safety and progression status will be summarized as appropriate.  


Protocol No. RP6530-1803                                                                                             Rhizen Pharmaceuticals S.A. 
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List of Abbreviations 
AE 
ALT 
AST 
Adverse Event 
Alanine Aminotransferase 
Aspartate Aminotransferase 
BID 
Twice Daily 
Cmax 
Peak Drug Concentration 
CBC 
Complete Blood Count 
cHL 
Classical Hodgkin’s lymphoma  
CLL 
Chronic Lymphocytic Leukemia  
CR 
Complete Response 
CrCl 
Creatinine Clearance 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTCL 
Cutaneous T cell Lymphoma 
CYP 
Cytochrome P450 
DLBCL 
Diffuse Large B Cell Lymphoma  
ECG 
Electrocardiogram 
CRF 
Case Report Form 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EOS 
End of Study 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FSH 
Follicular Stimulating Hormone 
GCP 
Good Clinical Practices 
Hb 
Hemoglobin 
HDPE 
High-density Polyethylene 
IB 
Investigator brochure  
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee 
INR 
iNHL 
International Normalized Ratio 
Indolent non-Hodgkin’s Lymphoma 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
LMWH 
Low Molecular Weight Heparin 
ORR 
Objective Response Rate 
pAKT 
PhosphoAKT 
PCP 
Pneumocystis Carinii Pneumonia  
PET 
Positron Emission Tomography 
PTCL 
Peripheral T cell Lymphoma  
PI 
Principle Investigator 
PI3K 
Phosphoinositide-3-Kinase 
PR 
Partial Response 
SAE 
Serious Adverse Events 
SD 
Stable Disease  
SDV 
Source Document Verification 
SOC 
Standard of Care  


Protocol No. RP6530-1803                                                                                             Rhizen Pharmaceuticals S.A. 
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TABLE OF CONTENTS  
1 
Background Information ................................................................................................................... 14 
1.1 
Tenalisib (RP6530) ................................................................................................................. 14 
1.2 
Summary of Clinical Evaluation ............................................................................................ 14 
1.3 
Study Rationale ...................................................................................................................... 15 
1.4 
Benefit and Risk ..................................................................................................................... 15 
2 
TRIAL OBJECTIVES ...................................................................................................................... 15 
3 
TRIAL DESIGN ............................................................................................................................... 15 
3.1 
Trial End Point ....................................................................................................................... 15 
3.2 
Design of Trial ........................................................................................................................ 15 
3.3 
Randomization and Blinding .................................................................................................. 16 
3.4 
Investigational Medicinal Product .......................................................................................... 16 
3.4.1 Dosage form and strengths ........................................................................................... 16 
3.4.2 Labeling, packaging and supply ................................................................................... 16 
3.4.3 Preparation and administration of Investigational Products......................................... 16 
3.4.4 Accountability of Investigational Products .................................................................. 16 
3.4.5 Precautions and Risks associated with Investigational Product ................................... 17 
3.5 
The Expected Duration of Subject Participation and Follow-up ............................................ 17 
4 
SELECTION AND WITHDRAWAL of SUBJECTS ...................................................................... 18 
4.1 
Inclusion Criteria .................................................................................................................... 18 
4.2 
Exclusion Criteria ................................................................................................................... 18 
4.3 
Discontinuation from Trial Treatment .................................................................................... 18 
5 
TREATMENT OF SUBJECTS ........................................................................................................ 19 
5.1 
Administration of Tenalisib .................................................................................................... 19 
5.2 
Concomitant Medications ....................................................................................................... 19 
5.3 
Prohibited Medications ........................................................................................................... 19 
5.4 
Procedures for Monitoring Subject Compliance. ................................................................... 20 
6 
TRIAL ASSESSMENT AND PROCEDURE .................................................................................. 20 
6.1 
Overview ................................................................................................................................ 20 
6.2 
Screening Procedure ............................................................................................................... 20 
6.2.1 Informed Consent ......................................................................................................... 20 
6.2.2 Enrollment of patient.................................................................................................... 21 
6.2.3 Screening Procedure..................................................................................................... 21 
6.3 
Treatment and Study Procedures ............................................................................................ 21 


Protocol No. RP6530-1803                                                                                             Rhizen Pharmaceuticals S.A. 
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6.4 
End of Trial Treatment (EOT) ................................................................................................ 23 
6.5 
End of Study (EOS) ................................................................................................................ 23 
7 
ASSESSMENT OF SAFETY ........................................................................................................... 23 
7.1 
Adverse Events ....................................................................................................................... 23 
7.1.1 Definitions of adverse events ....................................................................................... 23 
7.1.2 Recording of adverse events ........................................................................................ 23 
7.2 
Adverse Event/Serious Adverse Event Causality Assessment ............................................... 24 
7.3 
Serious Adverse Events .......................................................................................................... 24 
7.3.1 Definitions of serious adverse events ........................................................................... 24 
7.3.2 Serious adverse event reporting by Investigators ......................................................... 24 
7.3.3 Sponsor SAE Reporting Requirements ........................................................................ 25 
7.3.4 Pregnancy, Abortion, Birth Defects/Congenital Anomalies ........................................ 25 
7.4 
Protocol-Defined Events of Special Interest .......................................................................... 25 
7.4.1 Pregnancy, Abortion, Birth Defects/Congenital Anomalies ........................................ 25 
7.4.2 Overdose ...................................................................................................................... 26 
7.5 
Dose Modifications ................................................................................................................ 26 
8 
ASSESSMENT OF EFFICACY ....................................................................................................... 29 
9 
STATISTICAL METHOD AND CONSIDERATIONS .................................................................. 29 
10 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS ........................................ 29 
10.1 IRB/IEC Approval .................................................................................................................. 30 
10.2 Regulatory Approval .............................................................................................................. 30 
10.3 Insurance and Indemnity ........................................................................................................ 30 
10.4 Financial Disclosure and Obligations ..................................................................................... 30 
10.5 Informed Consent ................................................................................................................... 30 
10.6 Confidentiality ........................................................................................................................ 31 
10.6.1 Patient confidentiality .................................................................................................. 31 
10.6.2 Investigator’s responsibilities ....................................................................................... 31 
10.6.3 Investigator and Staff training ...................................................................................... 32 
11 
RECORD RETENTION AND DOCUMENTATION OF THE TRIAL .......................................... 32 
11.1 Amendments to the Protocol .................................................................................................. 32 
11.2 Protocol Deviations ................................................................................................................ 32 
11.3 Documentation Required to Initiate Trial ............................................................................... 32 
12 
DATA HANDLING AND RECORD KEEPING ............................................................................. 32 
12.1 Data Collection ....................................................................................................................... 34 


Protocol No. RP6530-1803                                                                                             Rhizen Pharmaceuticals S.A. 
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12.2 Trial Monitoring, Auditing, and Inspecting............................................................................ 34 
12.3 Medical Monitoring ................................................................................................................ 34 
12.4 Quality Assurance and Quality Control ................................................................................. 34 
13 
Disclosure and Publication Policy..................................................................................................... 35 
14 
REFERENCES .................................................................................................................................. 35 
15 
APPENDICES................................................................................................................................... 36 
Appendix A: Contraceptive Guidelines and Pregnancy .................................................................... 36 
 
 
List of Tables 
Table 1:  Schedule of Events ...................................................................................................................... 22 
Table 2: Dose Modifications for Hematologic Toxicity ............................................................................. 26 
Table 3: Dose Modifications for Non-Hematologic Toxicities .................................................................. 27 
 
 
 
 


Protocol No. RP6530-1803                                                                                             Rhizen Pharmaceuticals S.A. 
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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. 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. Refer to Investigator’s Brochure (IB) for detailed 
background information on Tenalisib.1  
 
1.2 Summary of Clinical Evaluation 
In the clinical setting, Tenalisib demonstrated a promising single agent activity with 
objective response rate (ORR) of 19.4 % (CR: 6.5% and PR: 12.9 %) in patients with 
hematological malignancies; and 46% (CR: 8.5% and PR: 37%) in evaluable R/R TCL 
patients with a manageable safety profile.1 Below is the summary of clinical studies of 
Tenalisib.  
 
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 
(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 (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 (Protocol no: RP6530-1501). Status: Completed   
4. An Open label, Phase I/II study to evaluate the safety and efficacy of RP6530, a novel 
PI3K δ/γ dual inhibitor given in combination with an anti-PD-1 therapy, Pembrolizumab 
in adult patients with relapsed or refractory Classical Hodgkin’s lymphoma (cHL). 
(Protocol Number: RP6530+Pembrolizumab-1701). Status: Terminated. 
5. An Open label, Phase II study to evaluate the efficacy and safety of Tenalisib (RP6530), 
a novel PI3K δ/γ dual inhibitor in adult patients with relapsed/refractory indolent Non-
Hodgkin’s Lymphoma (iNHL). (Protocol number: RP6530-1802). Status: Ongoing. 
6. 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 number: RP6530+Romidepsin-1805). Status: Ongoing. 
7. 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). Status: Planned. 
 


Protocol No. RP6530-1803                                                                                             Rhizen Pharmaceuticals S.A. 
Version : 2.0, 15 October 2019 
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1.3 Study Rationale  
Compassionate use provides an important avenue for patients with life-threatening 
conditions to gain access to unapproved investigational drugs, biologics and medical 
devices.2 Currently, Tenalisib is being evaluated as an investigational new drug in number 
of early clinical studies in patients with relapsed/refractory hematological malignancies. 
Tenalisib demonstrated acceptable safety and promising efficacy in these patients.  
 
Since these advanced relapsed/refractory patients have limited therapeutic options, it is 
reasonable to continue Tenalisib in responding patients post completion of their participation 
in previous (original) clinical studies. It is anticipated that Tenalisib would not expose 
patients to an unreasonable and significant risk or injury. Therefore, this trial is designed to 
offer patients benefitted by Tenalisib and who completed previous study without progression 
an opportunity to continue Tenalisib as compassionate medication and followed up on 
treatment for safety and disease progression. 
 
1.4 Benefit and Risk 
It is anticipated that Tenalisib would not expose patients to an unreasonable and significant 
risk or injury. Additional details regarding specific benefits and risks for subjects 
participating in this clinical trial may be found in the accompanying IB and Informed 
Consent documents. 
 
2 TRIAL OBJECTIVES 
• To evaluate the safety and tolerability of Tenalisib as single agent or in combination until 
the withdrawal of subject from the study due to disease progression, unacceptable 
toxicity or any other reason including consent withdrawal or investigator’s decision. 
• Time to disease progression  
   
3 TRIAL DESIGN 
3.1 Trial End Point 
• Adverse Event (AE), Grade 3/ 4 AEs and Serious Adverse Event (SAE) 
• Date of disease progression  
 
3.2 Design of Trial 
This is an open label, compassionate use study in patients who have completed a clinical 
trial of Tenalisib sponsored by Rhizen Pharmaceuticals S.A. This trial offers an opportunity 
to patients who have responded (either have CR, PR or SD on Tenalisib treatment) to receive 
Tenalisib as compassionate medication following their completion of previous study. 
Patients will continue to receive Tenalisib (schedule and dose) as they received in previous 
protocols unless dose adjustments or delays are necessary for toxicity management.  
 
Trials evaluating Tenalisib as a single agent or in combination with other therapies will be 
part of this compassionate study protocol. The patients of these studies will be rolled over to 
compassionate use study once they complete their participation in original study.       
 


Protocol No. RP6530-1803                                                                                             Rhizen Pharmaceuticals S.A. 
Version : 2.0, 15 October 2019 
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3.3 Randomization and Blinding 
This is a non-randomized, open label study.  
 
3.4 Investigational Medicinal Product 
3.4.1 Dosage form and strengths 
 
Investigational Product 
Dosage form, strength 
 Tenalisib 
Tablets; 200 mg and 400 mg.  
Note: Please refer current Investigator’s brochure for additional information of Tenalisib.  
 
In case of roll over from the combination study, the combination agent (e.g. romidepsin) will be 
administered as part of SOC and will not be supplied/provided by Rhizen Pharmaceuticals SA.   
 
3.4.2 Labeling, packaging and supply 
Tenalisib will be supplied by through Rhizen Pharmaceuticals S.A. Tenalisib will be 
available in 30 tablets per bottle. All trial drugs must be kept in a secure place at below 25°C 
(77°F), protected from moisture. 
 
3.4.3 Preparation and administration of Investigational Products 
At each visit, patients will be dispensed sufficient quantity of Tenalisib until the next visit. 
Study drug compliance will be reviewed with the patient at the beginning of cycle.  Study 
drug compliance will be documented, including missed doses.   
Guidelines 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 will be 
given outside of protocol requirements. However, these medications may be 
administered for treatment of symptoms/adverse events. 
• 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. Please note, patients will continue to receive the same dose they were receiving 
in previous protocols. (e.g. If patient is receiving Tenalisib 400 mg BID while rolling 
over, he/she will continue to receive 400 mg BID dose in compassionate study 
protocol). 
• Tenalisib tablets should be taken at approximately same time each day. Tablets should 
be swallowed; and should NOT be crushed or chewed.   
• If a dose of Tenalisib is missed, it should be taken as soon as possible on same day with 
an interval of 8 hrs between two doses. If it is missed for the entire day, it should not be 
repeated. If vomiting occurs, no attempt should be made to replace the vomited dose.  
• Study drug compliance should be reviewed with the patient at the beginning of cycle. 
Missed doses should be documented. 
 
3.4.4 Accountability of Investigational Products 
The PI/ designee is responsible for accountability of all trial drug supplies (used/unused) at 
the site. The study monitor will verify receipt of investigational product at the site during 
monitoring visit(s), and will conduct an inventory of remaining clinical trial supplies at the 


Protocol No. RP6530-1803                                                                                             Rhizen Pharmaceuticals S.A. 
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site close-out visit. All trial drug inventories must be made available for inspection by the 
monitor, sponsor representatives and regulatory agency inspectors/monitor upon request.  
 
Following monitor verification, returned or expired trial drugs can be destroyed according 
to local institutional policy after sponsor approval. Certificate(s) of destructions must be filed 
at the site and in Trial Master File.  
 
3.4.5 Precautions and Risks associated with 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/drug reaction, 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, 
enteritis 
(colitis), 
pneumonia/pneumonitis as these events are reported with other PI3K inhibitors.  
• Tenalisib may cause serious infections that may include sepsis and other infections. 
Monitor patients for signs and symptoms of infection and interrupt Tenalisib for Grade 
3 or higher infection. 
• Tenalisib elicits no photo instability upon exposure to ultraviolet (UV) radiations. 
However, in absence of in vitro data, possibility of photo-toxicity with Tenalisib cannot 
be ruled out.  
• Tenalisib demonstrated moderate to high inhibition of CYP3A4 enzymes. Therefore, 
concomitant administration of Tenalisib with CYP3A4 substrates (e.g. calcium channel 
blockers, warfarin, carbamazepine, macrolide antibiotics, lovastatin, simvastatin, 
terfenadine) may reduce clearance of these drugs increasing the risk of adverse events.  
• Similarly, as Tenalisib is inhibited by CYP3A4/5 and CYP2C9, there is possibility of 
drug interaction with inhibitors or inducers of CYP3A4 and CYP2C9. If concomitant 
treatment of these drugs 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 is generally avoided. Low molecular weight heparin 
(LMWH) is advised for prophylaxis and treatment of venous thrombosis. 
• Strong inhibitor or inducers should be avoided as directed in Section on prohibited 
medication. Please refer to the recent Investigator Brochure for additional safety 
information. 
• In absence of reproductive toxicity and genotoxicity data, the study participants should 
be advised to follow post treatment contraceptive measures. 
  
3.5 The Expected Duration of Subject Participation and Follow-up 
The expected duration of subject participation in the study is variable. Participation in the 
study will be continued until withdrawal of the subject from the study due to disease 
progression, unacceptable toxicity or any other reason including consent withdrawal by 
patient or investigator’s decision. 
 
Sponsor reserves the right to terminate the study in the interest of patient safety, for non-
compliance with the protocol, lack of recruitment or any other administrative reasons. The 


Protocol No. RP6530-1803                                                                                             Rhizen Pharmaceuticals S.A. 
Version : 2.0, 15 October 2019 
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sponsor and PIs will notify the regulatory authority and IRBs 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 inclusion criteria to be eligible for participation in this study: 
1. Patients must be currently receiving treatment with Tenalisib either as monotherapy or 
in combination with another agent on a previously approved protocol for hematological 
malignancies including but not limited to indications DLBCL, iNHL, PTCL, CTCL, 
CLL and HL. 
2. Patients must have had at least one efficacy evaluation following the initiation of 
Tenalisib in previous study and should have achieved either SD, PR or CR. 
3. Patients must have completed at least 6 cycles of Tenalisib in previous study 
4. Ability to swallow and retain oral medication. 
5. Female patients of child-bearing potential must consent to use two medically acceptable 
methods of contraception throughout the study period and for 4 weeks after the last dose 
of Tenalisib. A barrier method of contraception must be included.   
6. Male patients must be willing to use adequate contraceptive measures throughout the 
study period and for 12 weeks after the last dose of Tenalisib. 
7. Willingness and ability to comply with trial and follow-up procedures. 
8. Willingness to provide new written informed consent. 
 
4.2 Exclusion Criteria 
Patients must meet none of the following exclusion criteria to be eligible for participation 
in this study: 
1. Patient has been discontinued from their previous Tenalisib study 4 weeks prior to 
entering the compassionate use trial. 
2. Patient progressed while receiving Tenalisib therapy in his/her previous study. 
3. Pregnant or lactating woman. 
4. Inability or unwillingness to comply with study and/or follow-up procedures outlined in 
the protocol. 
5. Concurrent condition that in the investigator’s opinion would jeopardize compliance 
with the protocol. 
 
4.3 Discontinuation from Trial Treatment 
The following events may be considered sufficient reason for discontinuing treatment with 
the study medication: 
- NCI CTCAE v4.0 Grade 3/4 non-hematological toxicity related to study drug that 
necessitate withdrawal in the opinion of investigator. 
- 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  


Protocol No. RP6530-1803                                                                                             Rhizen Pharmaceuticals S.A. 
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Page 19 of 37 
- Confirmed disease progression  
 
5 TREATMENT OF SUBJECTS  
5.1 Administration of Study drugs 
Patients showing clinical benefits (have achieved either SD, PR or CR) will continue to 
receive Tenalisib as they were receiving in previous protocols. The treatment plan will be 
the same dosing schedule unless dose adjustments or delays are necessary for toxicity 
management.   
In case of roll over from a combination study, the investigator has a choice to continue with 
the combination therapy or to maintain the patient on Tenalisib monotherapy. If combination 
agent is continued, it will be administered as a part of SOC.   
 
5.2 Concomitant Medications 
• Antimicrobial and anti-viral prophylaxis should be used according to local standard 
practice; PCP and Zoster prophylaxis is strongly recommended.   
• G-CSF and other hematopoietic growth factors may be used for the management of acute 
toxicity such as febrile neutropenia when clinically indicated or at the discretion of the 
investigator. 
• Transfusions (blood/platelets) may be given, based on standard criteria and clinical 
judgment.  
• Patient may receive prophylactic anti-emetics at the discretion of the investigator if 
required for a combination agent.    
• Patient may receive prophylactic allopurinol, in case risk of tumor lysis syndrome.  
• Low doses of steroids are allowed if it stabilized at < 20 mg per day of prednisone or 
equivalent.  
• Patients are permitted to use of topical, ocular, intra-articular, intranasal, and inhaled 
corticosteroids (with minimal systemic absorption). A brief (less than 3 weeks) course of 
corticosteroids for prophylaxis (e.g. contrast dye allergy) or for treatment of non-
autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by a contact 
allergen) and also for the treatment of drug-related AE is permitted. 
• Inactivated seasonal influenza vaccine can be given to subjects before treatment and while 
on therapy without restriction.  
• If concomitant treatment of drugs metabolized by CYP3A4/CYP2C9 enzymes are 
clinically warranted, careful observation of the patient is advised. Refer prohibited 
medication section [Sec 5.3]. Use of heparin or warfarin for prophylaxis and treatment of 
venous thrombosis is prohibited. Low molecular weight heparin (LMWH) is acceptable. 
• Patients should be warned about the possible photosensitivity and advised to be careful 
with the UV exposure while on Tenalisib treatment. Patients should be recommended to 
wear loose-fitting clothes that protect skin from sun exposure, in case they need to be 
outdoors. If sunburn like reaction or skin eruption occurs, patients should contact study 
physician. 
 
5.3 Prohibited Medications 
The following treatments are prohibited while on the compassionate study protocol:    
• Any other anti-lymphoma therapy (e.g. radiation therapy, hormonal therapy for cancer, 


Protocol No. RP6530-1803                                                                                             Rhizen Pharmaceuticals S.A. 
Version : 2.0, 15 October 2019 
CONFIDENTIAL 
Page 20 of 37 
cancer immunotherapy or other biologic therapy).  
• Herbal medications are not allowed throughout the trial. Patients should stop using these 
herbal medications at least 7 days prior to C1D1.  
• Strong inhibitors or inducers of CYP3A4 including grapefruit products, herbal 
medication. Patients should stop using these medications at least 7 days prior to C1D1.  
• Strong inhibitors or inducers of CYP2C9 including herbal medications. Patients should 
stop using these medications at least 7 days prior to C1D1. 
• Substrates of CYP3A4 enzyme with a narrow therapeutic range (e.g. Warfarin and 
phenytoin). Patients should stop using these medications at least 7 days prior to C1D1.    
• Steroids > 20 mg unless for management of toxicity. 
 
Discontinuation of patient who received concomitant/prohibited medication will be taken 
by the PI in consultation with medical monitor on case by case basis, after reviewing 
ongoing clinical benefit and risk. The decision to allow a patient to continue will be 
documented. 
 
5.4 Procedures for Monitoring Subject Compliance. 
The following measures will be employed to ensure treatment compliance. 
Subjects will be asked to bring any unused study drug to the study center at their next visit. 
Site 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 patient.  
 
6 TRIAL ASSESSMENT AND PROCEDURE  
 
6.1 Overview 
The Schedule of Events (Table 1) summarizes the trial procedures to be performed at each 
visit and is divided into following:  
1. 
Screening (Day -14 to Day C1D1) 
2. 
On treatment procedures (C1D1 to EOT) 
3. 
End of Treatment (EOT) 
4. 
End of Study (EOS) (Day +30 from last dose) 
 
6.2 Screening Procedure 
6.2.1 Informed Consent  
The investigator/qualified designee must obtain written informed 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 an IRB/IEC approved 
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.   
 


Protocol No. RP6530-1803                                                                                             Rhizen Pharmaceuticals S.A. 
Version : 2.0, 15 October 2019 
CONFIDENTIAL 
Page 21 of 37 
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.  
 
6.2.2 Enrollment of patient  
During the screening period, the investigator/designee will complete the patient enrollment 
form and submit to the Sponsor for review and approval prior to enrolling the patient in the 
study. 
 
6.2.3 Screening Procedure  
Medical history, ECOG status and weight will be taken. Information on prior medication 
use, prior therapies including Tenalisib treatment will also be obtained to confirm eligibility 
of the patient. 
 
6.3 Treatment and Study Procedures  
Patients will visit the study center every three months until documented disease progression 
or treatment discontinuation due to toxicity or consent withdrawal. During these visits, 
Tenalisib will be dispensed and medication compliance will be monitored. Safety and 
efficacy assessments will be done as mentioned below.  
• Safety assessments:  
- 
Safety assessment will be done during the visits and AEs will be reported as required 
by the protocol.  
- 
Concomitant medications may be administered as clinically indicated.  
- 
A medication history should be reviewed at each clinic visit to assure no potential 
adverse events are noted. 
- 
There are no specific safety labs or evaluations (including vitals, physical 
examinations, pregnancy tests and ECGs) required as per protocol. As part of SOC, 
laboratory tests or other evaluations can be done per Investigator’s discretion. 
Adverse events (AEs, SAEs and deaths) will be recorded and reported for 30 calendar 
days after last dose or until a new anti-cancer treatment is initiated, whichever is 
earlier. After this period, only AEs, SAEs, or deaths assessed by the investigator as 
treatment related are to be reported. 
• Efficacy assessments:  
- 
Disease assessments [e.g. radiological imaging (e.g. CT, PET-CT) or any other 
appropriate evaluation tool (e.g. mSWAT in case of skin involvement)] should be 
performed as part of SOC. These evaluations (e.g. measurement of lymph node, 
mSWAT) will not be recorded in the CRF, however, date of disease progression will 
be reported . 
• Drug dispensing:  
- 
Patients will be given drug supply for 3 months.   


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                                                    Rhizen Pharmaceuticals S.A. 
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Note: *There are no specific safety labs or evaluations (including vitals, physical examinations, pregnancy 
tests, ECGs and radiological evaluation/mSWAT scoring) required as per protocol. As part Standard of care 
(SOC), laboratory tests or any evaluations can be done per Investigator’s discretion.   
 
Foot notes: 
1. Depending on the feasibility, screening/eligibility assessment and dispensing of the study drug can be done on 
same day. Assessment performed in previous study (e.g. Medical history, vital signs demographics, Weigh and 
ECOG) can be used for eligibility evaluation. The first day of Tenalisib administration will be considered as C1D1  
2. Demographic profile will include age, sex and race. 
3. Medical history will include history of cancer, past history of Tenalisib, no of prior therapies and prior medication 
(last 4 weeks); and other medical history. Any medical significant history at subsequent visit will be captured as 
adverse event.  
4. Applicable only for women of child-bearing potential.  
5. Disease assessment may include evaluation of disease condition by radiological imaging (e.g. CT, PET, PET-CT 
or MRI) or by any other appropriate evaluation tool depending on the disease condition (e.g. mSWAT in case of 
skin involvement, bone marrow biopsy in case of marrow involvement). Disease evaluation will be performed at 
the discretion of study investigator.  
6. The day of the last dose of study drug will be considered as EOT.  
7. Tenalisib will be dispensed in a HDPE container having 30 tablets of Tenalisib. A 3-month supply of study drug 
will be dispensed at each visit. In case of roll over from the combination study, the combination agent (e.g. 
Table 1:  Schedule of Events   
 
Screening 
and 
Eligibility 
Cycle 1  
Cycle 4 
Cycle 7 
Through   
EOT  
     EOT  
EOS11  
Day  
D-14 to D1 
D1 
D1 
D1 
- 
- 
Window period  
-14  
- 
±7 
±7 
- 
+30 
Study Days  
D-14 to D1 
11 
85 
169 
- 
- 
Informed Consent 
X 
- 
- 
- 
- 
- 
Eligibility Confirmation 
X 
- 
- 
- 
- 
- 
Demographics2 
X 
- 
- 
- 
- 
- 
Medical history3 
X 
- 
- 
- 
- 
- 
Vitals 
- 
SOC* 
SOC* 
SOC* 
SOC* 
- 
Weight4 
X 
SOC* 
SOC* 
SOC* 
SOC* 
- 
Physical exam 
- 
SOC* 
SOC* 
SOC* 
SOC* 
- 
ECOG Performance 
X 
SOC* 
SOC* 
SOC* 
SOC* 
- 
Complete blood count 
- 
SOC* 
SOC* 
SOC* 
SOC* 
- 
Chemistry 
- 
SOC* 
SOC* 
SOC* 
SOC* 
- 
PT/INR 
- 
SOC* 
SOC* 
SOC* 
SOC* 
- 
Urinalysis (routine) 
- 
SOC* 
SOC* 
SOC* 
SOC* 
- 
Pregnancy test4 
- 
SOC* 
SOC* 
SOC* 
SOC* 
- 
12-lead ECGs 
- 
SOC* 
SOC* 
SOC* 
SOC* 
- 
Disease assessment5 
- 
SOC* 
SOC* 
SOC* 
SOC* 
- 
Date of discontinuation6 
- 
- 
- 
- 
X 
- 
Drug Dispensing7 
- 
X 
X 
X 
- 
- 
Tenalisib treatment8 
- 
X 
X 
X 
- 
- 
Drug compliance  
- 
- 
X 
X 
X 
- 
AE evaluation9 
X 
X 
X 
X 
X 
X 
SAE evaluation10  
X 
X 
X 
X 
X 
X 
Concomitant medication  
X 
X 
X 
X 
X 
X 


Protocol No. RP6530-1803 
                                                    Rhizen Pharmaceuticals S.A. 
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Page 23 of 37 
romidepsin) will be administered as part of SOC and will not be supplied/provided by Rhizen Pharmaceuticals 
S.A.   
8. Patients showing clinical benefit (have achieved either SD, PR or CR) will continue to receive Tenalisib as they 
are currently receiving in previous protocols. The treatment plan will be the same dosing schedule unless dose 
adjustments or delays are necessary for toxicity management.   
In case of roll over from a combination study, the investigator has a choice to continue with the combination 
therapy or to maintain the patient on Tenalisib monotherapy. If combination agent is continued, it will be 
administered as a part of SOC.   
9. All AEs should be recorded spanning from the informed consent drug until 30 calendar days after the last dose of 
study drug or till new anti-cancer treatment is initiated whichever is earlier.  
10. All events that meet the definition of serious but, in the opinion of the treating investigator, are clearly expected 
from the Patient’s disease or related to disease progression (i.e. there exists no reasonable possibility that they 
were caused by the study drug) should be reported on the case report forms and do not require expedited reporting. 
In addition, progression of malignancy (including fatal outcomes), if documented by use of appropriate method 
(e.g. CT/ PET) or clinically confirmed, should not be reported as a serious adverse event.  
11. Patients should be followed for AEs for 30 calendar days after the last dose of study treatment or till new anti-
cancer treatment is initiated whichever is earlier. 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.  
 
6.4 End of Trial Treatment (EOT) 
The day of the last dose of study drug will be considered as EOT. Reason of discontinuation should 
be recorded. 
 
6.5 End of Study (EOS) 
All patients will be followed for adverse events until 30 calendar days after the last dose of study 
drug or until new anti-cancer treatment is initiated whichever is earlier. Telephonic follow up is 
acceptable. In case of drug related AEs, further safety assessments will be performed as warranted, 
at the discretion of PI. The patient will be followed until resolution or stabilization of related 
adverse event.  
 
7 ASSESSMENT OF SAFETY 
7.1 Adverse Events 
 
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.   
 
7.1.2 Recording of adverse events 
All adverse events should be graded as per the CTCAE v5.0. and should be recorded in the case 
report form. 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 or till new anti-cancer treatment is initiated whichever is earlier. 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. After 30 days of completion of protocol-specific 


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                                                    Rhizen Pharmaceuticals S.A. 
Version : 2.0, 15 October 2019 
 
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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  
The causality assessment will be categorized as related and not related.  
• Related: All toxicities should be considered to be related to Tenalisib unless there is a clear 
alternative explanation.   
• Not related:  If there is no temporal association, or another etiology has been identified as the 
cause, or the trial treatment cannot be implicated based upon the current information. 
 
7.3 Serious Adverse Events 
7.3.1 Definitions of serious adverse events 
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, is a congenital 
anomaly/birth defect or an important medical event.  
 
All events that meet the definition of serious but, in the opinion of the treating investigator, are 
clearly expected from the Patient’s disease or related to disease progression (i.e. there exists no 
reasonable possibility that they were caused by the study drug) should be reported on the case 
report forms and do not require expedited reporting. In addition, progression of malignancy 
(including fatal outcomes), if documented by use of appropriate method (e.g. CT/ PET) or 
clinically confirmed, should not be reported as a serious adverse event.  
 
Treatment within or admission to the following facilities is not considered to meet the criteria of 
“in-patient hospitalization” (although if any other SAE criteria are met, the event must still be 
treated as an SAE and immediately reported): 
• Emergency Department or Emergency Room 
• Outpatient or same-day surgery units 
• Observation or short-stay unit 
• Rehabilitation facility 
• Hospice or skilled nursing facility 
• Nursing homes, Custodial care or Respite care facility 
 
Hospitalization during the trial for a pre-planned surgical or medical procedure (one which is 
planned prior to entry in the trial or planned in advance and not related to the study procedure/ 
drug), does not require reporting as a serious adverse event to the Sponsor. 
 
7.3.2 Serious adverse event reporting by Investigators 
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 study 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. 
The SAE report should be sent to the sponsor/sponsor representative via e-mail. Follow-up 


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                                                    Rhizen Pharmaceuticals S.A. 
Version : 2.0, 15 October 2019 
 
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Page 25 of 37 
information for SAEs and information on non-serious AEs that become serious should also be 
reported to Sponsor as soon as it is available. 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 guidelines, FDA regulations, and/or local regulatory requirements. 
 
Sponsor/sponsor representative is responsible for reporting unexpected fatal or life-threatening 
events associated with the use of the trial drugs to the regulatory agencies and competent authorities 
via fax/mail within 7 calendar days after being notified of the event.   
 
The Sponsor will report all related, unexpected SAEs, including non-death/non-life-threatening 
related unexpected SAEs associated with the use of the trial medications to the FDA by a written 
safety report within 15 calendar days of notification. Reporting to the IRB/IEC will be done 
according to institutional policy. 
 
7.3.4 Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
Pregnancy, abortion, birth defects, and congenital anomalies are events of special interest.  Please 
refer to pregnancy section 7.4.1 for specific instructions. 
 
7.4 Protocol-Defined Events of Special Interest 
The following are events of special interest and will need to be reported expeditiously. 
 
7.4.1 Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
Female patients of child-bearing potential (see Appendix A) must consent to use two medically 
acceptable method of contraception throughout the study period and for 4 weeks after the last dose 
of Tenalisib.  
 
During the course of the trial, all female patients of childbearing potential and pregnant partner of 
male subjects must contact the treating investigator immediately if they suspect that they may be 
pregnant (a missed or late menstrual period should be reported to the treating investigator).   
 
If an investigator suspects that a patient may be pregnant after the patient has been receiving trial 
drug(s), the trial drug(s) must immediately be withheld until the result of the pregnancy test is 
confirmed. If a pregnancy is confirmed, the trial drug(s) must be immediately and permanently 
stopped, the patient must be discontinued from the trial, and the investigator must notify the 
medical monitor and Sponsor Representative as soon as possible. If a patient becomes pregnant 
while enrolled in the trial, a Pregnancy Form should be completed and mailed to the Sponsor. The 
outcome of the pregnancy will be monitored as outlined in Appendix A. 
    
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be 
expeditiously reported as an SAE, using the previously described process for SAE reporting. A 
Pregnancy Form should also have been previously completed and will need to be updated to reflect 
the outcome of the pregnancy. 


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                                                    Rhizen Pharmaceuticals S.A. 
Version : 2.0, 15 October 2019 
 
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7.4.2 Overdose 
An overdose is defined as accidental or intentional administration of any dose of product that is 
considered both excessive and medically important. For purposes of this trial, an overdose will be 
defined as any dose exceeding the proposed dose of Tenalisib (e.g. > 800 mg twice a day).   
 
Symptomatic and non-symptomatic overdose must be recorded in the CRF.  Any accidental or 
intentional overdose with the trial treatment that is symptomatic, and if not fulfilling a seriousness 
criterion, is to be reported to the Sponsor immediately as an AE. All symptomatic overdose, 
fulfilling a seriousness criterion is to be reported as an SAE as per the SAE reporting procedure. 
For patients who experience overdose, treatment should consist of supportive therapy. A decision 
to interrupt treatment or dose reduction to be taken depending on the symptoms.  
 
7.5 Dose Modifications 
The dose modification should be performed for the drug toxicity or underlying disease conditions. 
Guidelines (Refer Table 2 and 3) are intended to be applied when the investigator determines the 
event related to Tenalisib. Please note the dose modifications provided below should be used as a 
guidance and should be determined as per PI’s clinical judgement. 
 
Patients may resume Tenalisib, provided that the toxicity has resolved to Grade ≤2 or baseline and 
there is no clinical or radiographic evidence of disease progression. If study drug is delayed >2 
weeks because of an adverse event, strategy of re-initiation of study drug should be discussed with 
medical monitor. 
 
At the discretion of the Investigator, a dose re-escalation may be permitted for patients who 
previously had a dose reduction. Holidays from study drug are discouraged. Any patient in whom 
similar toxicity recurs at the reduced dose should be discontinued from further Tenalisib treatment. 
Note: In exceptional case, a patient may be allowed following a careful assessment of benefit and 
risk by the investigator and with approval from the medical monitor. 
 
Table 2: Dose Modifications for Hematologic Toxicity 
Worst CTCAE Grade Toxicity 
Action to be Taken 
HEMATOLOGIC  
Neutropenia (ANC) 
Grade 3  
1.0 X 109/L<ANC ≥ 0.5 X 109 /L 
Maintain dose level. 
Monitor ANC at least weekly. 
Grade 4  
0.5 x 109 /L<ANC 
First incidence: 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 <1000/mm3 with a single 
temperature of > 38.3 0C (1010F) 
Withhold* dose until resolved to ≤ Grade 2 or baseline, consider growth 
factor support, then reduce by 1 dose level (Tenalisib 400 mg BID), if 


Protocol No. RP6530-1803 
                                                    Rhizen Pharmaceuticals S.A. 
Version : 2.0, 15 October 2019 
 
CONFIDENTIAL 
Page 27 of 37 
or a sustained temperature of ≥ 38 
0C (100.4 0F) for more than one 
hour. 
warranted. If the 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. 
 
 
Table 3: Dose Modifications for Non-Hematologic Toxicities  
NON-HEMATOLOGIC  
Action to be Taken 
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 


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Page 28 of 37 
• 
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 
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. 
 
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. 
• 
 
Cardiac 
If a QTcF >500 msec has been demonstrated, hold dose. 


Protocol No. RP6530-1803 
                                                    Rhizen Pharmaceuticals S.A. 
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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. 
 
8 ASSESSMENT OF EFFICACY 
Efficacy evaluations will be performed at the physician’s discretion as part of standard of care 
(SOC). These evaluations (e.g. measurement of lymph node, mSWAT) will not be reported in CRF, 
however the date of disease progression will be reported. 
 
9 STATISTICAL METHOD AND CONSIDERATIONS   
The primary purpose of this study is to offer patients who completed a Rhizen sponsored clinical 
study without progression the opportunity to continue to receive Tenalisib on a compassion basis.  
The safety and progression status will be summarized as appropriate. No formal sample is 
determined for this study and final sample size will depend on the number of patients who 
benefitted and completed the Tenalisib study. 
 
10 ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
This trial will be conducted according to the standards of Good Clinical Practice outlined in the 
ICH E6 Tripartite Guideline, and CFR Title 21 part 312, World Medical Association’s Declaration 
of Helsinki, applicable government regulations, institutional research policies and procedures and 
any other local applicable regulatory requirement(s).  
 
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.  
 
The patient will be closely monitored until the QTcF <500 msec and the 
QTcF has returned to <30 msec from baseline. Immediate attention to 
potassium and magnesium and other clinical factors such as oxygenation 
and ischemia should be addressed.   
All cardiac events should be treated as per the local standard of care and 
referral to a specialist if clinically indicated. Any final decisions concerning 
dose modifications or permanently discontinuing the patient from study drug 
due to QTcF prolongation will occur after discussion with medical monitor. 
OTHER NON-
HEMATOLOGIC  
Action to be Taken 
Grade 1 or 2 
None 
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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                                                    Rhizen Pharmaceuticals S.A. 
Version : 2.0, 15 October 2019 
 
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10.1  IRB/IEC Approval 
The trial documents (e.g, protocol, ICF, IB, available safety information, patient documents, patient 
recruitment procedures, information about payments (i.e., PI payments) and compensation 
available to the patients and documentation evidencing the PI’s qualifications) should be submitted 
to the IRB/IEC for ethical review and approval if required by local regulations, prior to the trial 
start.   
 
The PI/Rhizen and/or designee will follow all necessary regulations to ensure appropriate, initial, 
and ongoing, IRB/IEC trial review. The PI/Rhizen (as appropriate) must submit and, where 
necessary, obtain approval from the IRB/IEC for all subsequent protocol amendments and changes 
to the informed consent document.  Investigators will be advised by Rhizen/designee whether an 
amendment is considered substantial or non-substantial and whether it requires submission for 
approval or notification only to an IRB/IEC. 
 
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.  
 
10.3  Insurance and Indemnity 
Details of insurance and/or indemnity will be contained within the written agreement between the 
PI or site and Rhizen. Rhizen will reimburse the subject for all study-related injuries provided that 
the injury does not arise from the subject’s misuse of the study drug or failure to follow the 
Investigator’s instructions. 
 
10.4 Financial Disclosure and Obligations 
Principal Investigators and Sub-Investigators are required to provide financial disclosure 
information to allow Rhizen to submit the complete and accurate certification or disclosure 
statements required under Part 54 of Title 21 of the CFR. In addition, the Principal 
Investigator/Sub- Investigators must provide to the Sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 1 year 
following the completion of the study. 
 
10.5  Informed Consent 
The informed consent form will be submitted for approval to the IRB/IEC that is responsible for 
review and approval of the trial.  Each consent form must include all of the relevant elements 
currently required by the US FDA or state regulations and national requirements. Translation of 
the informed consent form is allowed if necessary. 
 
Before recruitment and enrollment into the trial, each prospective candidate will be given a full 
explanation of the trial. Once the essential information has been provided to the prospective 
candidate, and the investigator is sure that the individual candidate understands the implications of 
participating in this trial, the candidate will be asked to give consent to participate in the trial by 
signing an informed consent form. A notation that written informed consent has been obtained will 


Protocol No. RP6530-1803 
                                                    Rhizen Pharmaceuticals S.A. 
Version : 2.0, 15 October 2019 
 
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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 
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 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 named on the FDA Form 
1572. 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 


Protocol No. RP6530-1803 
                                                    Rhizen Pharmaceuticals S.A. 
Version : 2.0, 15 October 2019 
 
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that the study is conducted according to applicable health authorities (FDA), sound medical 
practices, and in compliance with applicable regulations (21 CFR, ICH). 
 
10.6.3 Investigator and Staff training  
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 
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. The written amendment must be 
submitted and approved by the IRB/IEC. 
 
11.2 Protocol Deviations 
The Principal Investigator is required to follow the protocol. A protocol deviation is an unintended 
and/or unanticipated departure from the protocol procedures. The Investigator/designee must 
document and explain in the subject’s source documentation any deviation from the approved 
protocol. Protocol deviations will be documented by the CRA/monitor throughout the course of 
monitoring visits. Principal Investigator will be notified of deviations in writing by the 
CRA/monitor. The IRB/IEC should be notified of all protocol violations and deviations according 
to their IRB/IEC reporting requirements.  
 
11.3  Documentation Required to Initiate Trial 
Before the trial may begin, documentation required by US FDA will be provided by the Sponsor.  
At minimum, documents required to begin a trial in the US include, but are not limited to: a signed 
protocol acceptance page, and contract; a copy of the official IRB/IEC approval of the trial and the 
IRB/IEC membership list; current Curricula Vita for the Principal Investigator and any sub-
investigator who will be involved in the trial; indication of appropriate accreditation for any 
laboratories to be used in the trial and a copy of the normal ranges for tests to be performed by that 
laboratory; completed signed Form FDA 1572 (Statement of Investigator), financial disclosure 
forms for all investigators listed on Form FDA 1572; site qualification reports, where applicable; 
verification of Principal Investigator acceptability from local and/or national debarment list(s).  
 
12 DATA HANDLING AND RECORD KEEPING  
The PI must maintain a list of appropriately qualified persons to whom he/she has delegated trial 
duties and should ensure that all persons assisting in the conduct of the trial are informed of their 
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 


Protocol No. RP6530-1803 
                                                    Rhizen Pharmaceuticals S.A. 
Version : 2.0, 15 October 2019 
 
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transcriptions certified after verification as being accurate and complete, photographic negatives, 
microfilm or magnetic media, X-rays, and correspondence. 
 
The PI and site staff are responsible for maintaining a comprehensive and centralized filing system 
(Site Trial File/SSF or Investigator Site File (ISF) of all trial-related (essential) documentation, 
suitable for inspection at any time by representatives from the Sponsor and/or applicable regulatory 
authorities.  The ISF/SSF must consist of those documents that individually or collectively permit 
evaluation of the conduct of the trial and the quality of the data produced. The ISF/SSF should 
contain as a minimum all relevant documents and correspondence as outlined in ICH GCP section 
E6 and 21 CFR Part 312.57, including key documents such as the IB and any amendments, protocol 
and any amendments, signed ICFs, copies of completed CRFs, IRB/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 drug accountability record, at a minimum, should contain PI name, date drug 
shipped/received, date, quantity and batch/code, or lot number for identity of each shipment. In 
addition, all original source documents supporting entries in the CRF must be maintained and be 
readily available. 
 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial and as required by the applicable regulatory 
requirement(s). The investigator/institution should take measures to prevent accidental or 
premature destruction of these documents 
 
The Investigator shall maintain adequate records of drug disposition, case histories and any other 
trial-related records as per 21 CFR Part 312.62 for no less than 2 years after the last marketing 
application has been approved by FDA; or, in the event that the marketing application has not been 
approved by FDA, for no less than 2 years after the last shipment / delivery of the drug for 
investigational use is discontinued and FDA 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 


Protocol No. RP6530-1803 
                                                    Rhizen Pharmaceuticals S.A. 
Version : 2.0, 15 October 2019 
 
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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 
Data will be captured via Case Record Form (CRF). 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. The Principal Investigator will sign and date each CRF 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 verifying errors and inconsistencies in 
the data which would otherwise impact on the analysis and reporting objectives, or the credibility 
of the Clinical Study Report. Adverse events, medical history and concomitant medications will be 
coded using industry standard dictionaries (MedDRA and WHO Drug).  
 
12.2   Trial Monitoring, Auditing, and Inspecting 
The study will be monitored by the Sponsor and/or Sponsor's representatives at all stages of study 
conduct from inception to completion in accordance with current GCPs. Monitoring will be done 
in the form of on-site visits, remote monitoring and other communication and will include review 
of original source documents and CRFs. 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 
or its representatives and government regulatory authorities 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. 
 
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 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. 


Protocol No. RP6530-1803 
                                                    Rhizen Pharmaceuticals S.A. 
Version : 2.0, 15 October 2019 
 
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13 DISCLOSURE AND PUBLICATION POLICY 
All information provided regarding the trial, as well as all information collected/documented 
during the course of the trial, will be regarded as confidential. The Sponsor reserves the right to 
release literature publications based on the results of the trial.  Results from the trial will be 
published/presented as per the Sponsor’s publication strategy. 
 
14 REFERENCES 
 
1. Tenalisib (RP6530) Investigator’s brochure. Version 10. Dated 15 October 2019.  
2. Expanded Access (Compassionate Use). 
https://www.fda.gov/NewsEvents/PublicHealthFocus/ExpandedAccessCompassionateUse/de
fault.htm#Expanded_Access_to_Investigational_Drugs_and_Biologics. Accessed on 23 
March 2018 
 
 
 
 
 
 
 


Protocol No. RP6530-1803 
                                                    Rhizen Pharmaceuticals S.A. 
Version : 2.0, 15 October 2019 
 
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Page 36 of 37 
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 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 
Fertile Males 


Protocol No. RP6530-1803 
                                                    Rhizen Pharmaceuticals S.A. 
Version : 2.0, 15 October 2019 
 
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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. 


Statistical analysis Plan 
Page | 1  
 
   
 
 
 
 
   
 
 
 
       STATISTICAL ANALYSIS PLAN 
 
PROTOCOL NO. RP6530-1803 
An Open label, Compassionate Use Study of Tenalisib 
(RP6530) in Patients currently receiving treatment on Tenalisib 
trials in Hematological Malignancies 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


Statistical analysis Plan 
Page | 2  
 
1 STATISTICAL METHOD AND CONSIDERATIONS   
The primary purpose of this study is to offer patients who completed a Rhizen sponsored 
clinical study without progression the opportunity to continue to receive Tenalisib on a 
compassion basis.  The safety and progression status will be summarized as appropriate. 
No formal sample is determined for this study and final sample size will depend on the 
number of patients who benefitted and completed the Tenalisib study. 
 
2 DISPOSITION OF PATIENTS  
A tabular presentation of the patient disposition will be provided by type of cancer and 
previous study protocol and dose of tenalisib. All patients’ data will be used for this 
analysis. 
 
3 ASSESSMENT OF EFFICACY 
3.1 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.   
 
All adverse events should be graded as per the CTCAE v5.0. and should be recorded in the case 
report form. 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 or till new anti-cancer treatment is initiated whichever is earlier. 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. 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. 
The causality assessment will be categorized as related and not related.  
• Related: All toxicities should be considered to be related to Tenalisib unless there is 
a clear alternative explanation.   
• Not related:  If there is no temporal association, or another etiology has been 
identified as the cause, or the trial treatment cannot be implicated based upon the 
current information. 
 


Statistical analysis Plan 
Page | 3  
 
3.2 Serious Adverse Events 
• 
Definitions of serious adverse events 
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, is a congenital 
anomaly/birth defect or an important medical event.  
 
All events that meet the definition of serious but, in the opinion of the treating investigator, are 
clearly expected from the Patient’s disease or related to disease progression (i.e. there exists no 
reasonable possibility that they were caused by the study drug) should be reported on the case 
report forms and do not require expedited reporting. In addition, progression of malignancy 
(including fatal outcomes), if documented by use of appropriate method (e.g. CT/ PET) or 
clinically confirmed, should not be reported as a serious adverse event.  
 
 
3.3 Protocol-Defined Events of Special Interest 
The following are events of special interest and will need to be reported expeditiously. 
• 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be 
expeditiously reported as an SAE, using the previously described process for SAE reporting. A 
Pregnancy Form should also have been previously completed and will need to be updated to 
reflect the outcome of the pregnancy. 
• 
Overdose 
An overdose is defined as accidental or intentional administration of any dose of product that is 
considered both excessive and medically important. For purposes of this trial, an overdose will 
be defined as any dose exceeding the proposed dose of Tenalisib (e.g. > 800 mg twice a day).   
 
The safety endpoints will include:  
• 
Incidence of AEs and related AEs 
• 
Incidence of grade 3, grade 4 and grade 5 AEs 
• 
Incidence of SAEs and deaths  
 
The analyses of safety will be based on the frequency of adverse events for patients who received 
at least one dose of study treatment. 


Statistical analysis Plan 
Page | 4  
 
 
4 ASSESSMENT OF EFFICACY 
Efficacy evaluations will be performed at the physician’s discretion as part of standard 
of care (SOC). These evaluations (e.g. measurement of lymph node, mSWAT) will not 
be reported in CRF, however, the date of disease progression will be reported. 
 
The duration of disease progression will be calculated for patients who received at least one 
dose of study treatment.