Clinical trial NCT03770000
Conditions: T Cell Lymphoma
Keywords: T cell Lymphoma RP6530 Tenalisib Romidepsin
Sponsor: Rhizen Pharmaceuticals SA
Start date: 2019-03-12; Completion date: 2021-05-14
Enrollment: 33 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
To characterize safety, tolerability and to establish the maximum tolerated dose (MTD) of Tenalisib in combination with Romidepsin in patients with R/R T-cell lymphoma.

Detailed description:

Arms: arm 1: Participants receive Tenalisib in escalating doses daily Orally BID and Romidepsin in escalating doses intravenously on day 1, 8 and 15
Interventions: intervention 1: Tenalisib intervention 2: Romidepsin
Intervention descriptions: intervention 1: Tenalisib, BID orally daily intervention 2: Romidepsin IV

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
Page 1 of 88 
 
PROTOCOL NO. RP6530+Romidepsin-1805 
 
 
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 
 
 
Amendment version dated 30 November 2018 
 
 
 
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document constitutes agreement by the recipient that no unpublished information contained herein shall 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+Romidepsin-1805 
TRIAL DRUG 
RP6530 (Tenalisib) and Romidepsin 
IND NUMBER  
124584 
SPONSOR 
Rhizen Pharmaceuticals S.A. 
Fritz-Courvoisier 40, 
Ch-2300 La Chaux-de-Fonds,  
Switzerland 
 
PRINCIPAL INVESTIGATOR 
AND STUDY CHAIR 
 
Swaminathan P Iyer, MD 
Professor, Department of Lymphoma/Myeloma,  
Division of Cancer Medicine,  
The University of Texas MD Anderson Cancer Center, Houston,
TX, USA   
 
SPONSOR’S MEDICAL 
EXPERT 
Prajak Barde, MD 
Medical Director, Clinical R&D  
Rhizen Pharmaceuticals S.A. 
Fritz-Courvoisier 40, 
Ch-2300 La Chaux-de-Fonds,  
Switzerland 
 
DOCUMENT VERSION 
Amendment 1 to Version 1.0, Dated 16 August 2018 


Protocol No. RP6530+Romidepsin-1805 
                                                     Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018  
CONFIDENTIAL 
Page 2 of 88 
Clinical Trial Protocol Statement of Compliance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This clinical trial shall be conducted in compliance with the protocol, as referenced herein, 
and all applicable local, national, and international regulatory requirements to include, but 
not be limited to: 
 
 
• 
International Conference on Harmonization (ICH) Guidelines on Good Clinical 
Practice (GCP) 
• 
Ethical principles that have their origins in the Declaration of Helsinki  
• 
<Food and Drug Administration (FDA) Code of Federal Regulation (CFR): 
o 
Title 21CFR Part 50 & 45 CFR Part 46, Protection of Human Subjects 
o 
Title 21CFR Part 54, Financial Disclosure by Clinical Investigators 
o 
Title 21CFR Part 56, Institutional Review Boards 
o 
Title 21CFR Part 312, Investigational New Drug Application 
o 
Title 45 CFR Parts 160, 162, and 164, Health Insurance Portability and 
Accountability Act (HIPAA) 
 
 
As the PI, I understand that my signature on the protocol constitutes my agreement and 
understanding of PI responsibilities to conduct the clinical trial in accordance to the 
protocol and applicable regulations.  Furthermore, it constitutes my understanding and 
agreement that any changes initiated by myself, without prior agreement in writing from 
the Sponsor, shall be defined as a deviation from the protocol, and shall be formally 
documented as such. 
 
 


Protocol No. RP6530+Romidepsin-1805 
                                                     Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018  
CONFIDENTIAL 
Page 3 of 88 
Protocol Approval Page 
 
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 
TRIAL DRUG(S) 
Tenalisib and Romidepsin 
IND NUMBER 
124584 
DOCUMENT VERSION 
Amendment 1 to version 1.0, Dated 16 August 2018 
Amendment Version dated 30 November 2018 
                
 
 
 
 
 
Prajak Barde, MD 
 
 
 
 
 
______________________________________________________ 
 
 
________________________________________________________________________ 
Sponsor’s Medical Expert   
 
 
Signature  
 
 
Date 
 
 
 
 
Ajit Nair, PhD  
  
 
 
______________________________________________________ 
 
 
________________________________________________________________________ 
Sponsor’s Representative   
 
 
Signature 
 
 
Date             
 
 
 
 
Michael Chen, PhD 
 
 
 
 
             
______________________________________________________ 
 
 
_______________________________________________________________________  
Bio-statistician 
 
 
 
 
Signature 
 
 
Date             
 
                                     
 
 
 
 
 
 
 


Protocol No. RP6530+Romidepsin-1805 
                                                     Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018  
CONFIDENTIAL 
Page 4 of 88 
Protocol Acceptance Page 
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 
TRIAL DRUG(S) 
Tenalisib and Romidepsin 
IND NUMBER 
124584 
DOCUMENT VERSION 
Amendment 1 to version 1.0, Dated 16 August 2018 
Amendment Version dated 30 November 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator 
 Signature 
 
         Date       
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 


Protocol No. RP6530+Romidepsin-1805 
                                                     Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018  
CONFIDENTIAL 
Page 5 of 88 
Amendment History 
 
Amendment#/date 
Reference to section 
Summary 
Rationale 
Amendment 1 to 
version 1.0, Dated 16 
August 2018 
 
Amendment Version 
dated 30 November 
2018 
Section 4.1 Inclusion criteria  
Inclusion criteria #9 is 
clarified   
Protocol clarification  
Section 5.3  
Concomitant medication  
Concomitant 
medication section is 
updated as “Similarly, 
Dabigatran and 
Edoxaban, Direct-acting 
Oral Anti-Coagulants 
(DOAC) class of drugs 
are acceptable”. 
Protocol clarification.  
Dabigatran and 
Edoxaban are acceptable 
as they are not 
metabolized by 
CYP3A4/CYP2C9 
enzymes. 
Section 5.4  
Prohibited medication 
Prohibited medication 
section is updated as 
“Apixaban and 
Rivaroxaban, DOAC 
class of drugs, are 
prohibited.    
Protocol clarification. 
Apixaban and 
Rivaroxaban are 
prohibited as they are 
metabolized by CYP3A4 
enzymes. 
Section 6: Trial assessment 
and procedure  
The time points for 
vitals, ECGs and 
laboratory assessment 
and visits are clarified.  
Protocol clarification 
Section 7.7 dose 
modifications  
Dose modifications are 
clarified.  
Protocol clarification 
Throughout the document 
Minor protocol 
clarifications and 
administrative changes 
 
 
 
 


Protocol No. RP6530+Romidepsin-1805 
                                                     Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018  
CONFIDENTIAL 
Page 6 of 88 
PROTOCOL SYNOPSIS 
Study Title 
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. 
Phase 
Phase I/II 
Study Sponsor 
Rhizen Pharmaceuticals S.A. 
Study Centers  
Approximately about 15 study centers  
Study 
Objectives 
Primary Objectives 
• To characterize safety, tolerability and to establish the maximum tolerated 
dose (MTD) of Tenalisib in combination with Romidepsin in patients with 
R/R T-cell lymphoma. 
  
Secondary Objectives 
• To assess the preliminary anti-tumor activity of various dose levels of 
Tenalisib in combination with Romidepsin, as determined by the objective 
response rate (ORR) and Duration of Response (DoR)   
• To characterize the Pharmacokinetics (PK) of Tenalisib and Romidepsin 
when given in combination. 
 
Exploratory Objectives 
• To correlate clinical efficacy with markers that include but are not limited to 
quantitative and qualitative measurements of malignant cells, cytokines, and 
chemokines in blood/serum. 
 
Endpoints 
Safety: 
• Adverse Event (AE), Grade 3/ 4 AEs, Serious and fatal Adverse Event 
(SAE), graded using NCI CTCAE Version 5.0. 
 
Efficacy:  
• Objective response rate (ORR), defined as sum of CR and PR rates, 
assessed according to the Lugano Classification for initial evaluation, 
staging, and response assessment of Hodgkin/non-Hodgkin lymphoma in 
PTCL patients; and according to the modified Severity Weighted Assessment 
Tool (mSWAT) in CTCL patients.   
• Duration of Response (DoR), calculated as time from the initial response to 
documented disease progression. 
 
Pharmacokinetics:  
• PK Parameters [AUC (0-∞), AUC (0- t), Cmax, tmax, Kel, and t½] of Tenalisib and 
Romidepsin.  
 
 


Protocol No. RP6530+Romidepsin-1805 
                                                     Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018  
CONFIDENTIAL 
Page 7 of 88 
Correlative/Exploratory: 
• Correlative markers include baseline and on-treatment serum levels of 
chemokines, cytokines, antibodies to tumor antigens, and other immune 
mediators (e.g. sIL2R and CTACK for PTCL; CD30, IL-31 and IL-32 for 
CTCL) as deemed relevant by the sponsor. 
Study Design 
and Procedure 
This is a multi-center, open label, non-randomized, two-part Phase I/II study of 
Tenalisib in combination with Romidepsin in adult patients with 
relapsed/refractory TCL. The first part is an open label, 3+3 design, Phase I dose 
escalation for MTD determination. The second part is a Phase II, dose expansion 
to delineate the safety and anti-tumor activity of the combination at the 
MTD/optimal dose.  
 
In dose escalation, a minimum of 2 and maximum 18 patients will be enrolled in 
three dose levels unless additional dose levels are required to reach MTD/ 
optimal dose. In dose expansion, up to 24 TCL patients will be enrolled (Group 
1 = 12 PTCL patients and Group 2 = 12 CTCL patients).  
 
The study will end when all ongoing subjects have reached their third tumor 
assessment on Cycle 8/Day 1 (C8D1) or have discontinued from the study for 
any reason, whichever is earlier. At the end of the study, all ongoing patients 
with no evident disease progression will be given the opportunity to enroll in an 
open-label compassionate use study protocol and will be followed up. 
 
PHASE I (DOSE ESCALATION):  
Sequential dose escalation will begin with Cohort 1. A minimum of three patients 
will be enrolled at each dose level. Dose levels will be increased in successive 
increments according to the dose escalation cohorts mentioned in the table below. 
Escalation to the next cohort will occur if no patient within a three-patient cohort 
or one in six patients experiences a dose limiting toxicity (DLT). De-escalation 
to different lower doses in case DLT criteria is met, will be done as per the 
discretion of Safety Review Committee (SRC). The highest doses of the 
combination (Tenalisib at 800 mg BID plus Romidepsin IV 14 mg/m2) will be 
considered as optimal in case there is no DLT at this dose level.  
Dose escalation scheme: 
Cohort 
N 
Tenalisib1 
Romidepsin2 
Cohort 1 
3-6 
Tab. 400 mg PO twice a day 
IV 12 mg/m2 on Day 1, 8 and 15  
Cohort 2 
3-6 
Tab. 600 mg PO twice a day 
IV 12 mg/m2 on Day 1, 8 and 15  
Cohort 3 
3-6 
Tab. 800 mg PO twice a day 
IV 14 mg/m2 on Day 1, 8 and 15  
Note: Alternate dose levels/dosing schedules may be considered by the SRC if deemed 
essential based on emerging safety and PK data.  
1In case the dose (e.g. 800 mg BID) is leading to DLT of the combination, the dose of 
Tenalisib will be reduced to lower dose (e.g. 600 mg BID) and will be evaluated for 
safety in a separate cohort.  


Protocol No. RP6530+Romidepsin-1805 
                                                     Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018  
CONFIDENTIAL 
Page 8 of 88 
2In case the dose (e.g. 14 mg/m2) is leading to DLT of the combination, the dose of 
Romidepsin will be reduced to lower dose (e.g.12 mg/m2) and if required further to 10 
mg/m2 and will be evaluated for safety in a separate cohort.  
 
DLT assessment: The data of at least 3 patients will be required for DLT 
assessment. DLT assessment period will be 28-days (inclusive) (will begin on 
C1D1 and end on C2D1), unless extended by the medical monitor. In the first 
cycle, patients must have been treated with at least 2 doses of Romidepsin and 
minimum 14 days with Tenalisib to be considered eligible for safety analysis 
unless identified to have a DLT. Patients who experience a DLT will be 
considered evaluable regardless of the number of doses received.  
 
Individual patients will be considered for Intra-subject dose escalation at the 
discretion of investigator after discussion with medical monitor. 
 
PHASE II (DOSE EXPANSION):  
After establishing the MTD/optimal dose, the Phase II (expansion part) will be 
opened as approved by the SRC to enroll two groups of patients. 
Group 
N 
Patient population 
Tenalisib 
Romidepsin 
Group 1 
12 
Patients with R/R PTCL MTD/Optimal 
dose 
MTD/Optimal dose on 
Day 1, 8 and 15 
Group 2 
12 
Patients with R/R CTCL MTD/Optimal 
dose 
MTD/Optimal dose on 
Day 1, 8 and 15 
 
The details of the study procedures are given in the schedule of events. 
No. of Patients 
Phase I: Total 2-18 patients will be enrolled in 3 escalating cohorts unless 
additional dose levels are required to reach MTD/ optimal dose. 
 
Phase II: Total 24 patients with relapsed/refractory TCL will be enrolled.   
Inclusion 
Criteria 
Inclusion criteria  
1. Age ≥18 years on the day of signing informed consent. 
2. Pathologically confirmed T-cell lymphoma at the enrolling institution*.  
3. Disease status as defined as relapsed after or refractory to at least one 
systemic therapy.  
4. The patients should have received NOT more than three prior systemic 
combination chemotherapies.  
5. Must have ECOG performance status ≤ 2  
6. PTCL patients must have measurable disease defined as at least one bi-
dimensional measurable lesion with minimum measurement of > 1.5 cm in 
the longest diameter.  
7. Life expectancy of at least 3 months 
8. Toxicities related to prior therapy must have returned to Grade 1 or less, 
except for alopecia.  


Protocol No. RP6530+Romidepsin-1805 
                                                     Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018  
CONFIDENTIAL 
Page 9 of 88 
9. Adequate bone marrow, liver and renal function in line with below mentioned 
laboratory requirements. Hemoglobin and platelet requirements should not 
be met by use of recent transfusion or growth factor support (GCSF or 
erythropoietin) within 3 weeks prior to treatment initiation. 
• Hemoglobin ≥8.0 g/dL  
• Absolute neutrophil count (ANC) ≥1,000/µL 
• Platelet count ≥75,000/μL 
• Total bilirubin ≤1.5 times the ULN (or ≤3 x ULN, if patient has Gilbert 
syndrome) 
• AST (SGOT) and ALT (SGPT) ≤ 3 x ULN; ≤ 5 ULN in case of liver 
involvement  
• Calculated creatinine clearance (CrCl) > 50 ml/min by Cockcroft-Gault 
formula.  
10. Use of an effective means of contraception for women of childbearing 
potential and men with partners of childbearing potential. 
11. Female subject of childbearing potential should have a negative urine or 
serum pregnancy within 72 hours prior to receiving the first dose of study 
medication.  If the urine test is positive or cannot be confirmed as negative, 
a serum pregnancy test will be required.  
12. Provide written informed consent prior to any study-specific screening 
procedures. 
13. Willingness and capability to comply with the requirements of the study. 
 
*Note: The EORTC classification of CTCLs will be used to classify patients. 
CTCL includes other variants other than MF (e.g. Gamma delta cutaneous T-cell 
lymphoma or subcutaneous or panniculitic like T-cell lymphoma and CD8 
positive T-cell lymphoma). PTCL includes patients with predominantly nodal 
disease (systemic involvement) but some patients (e.g. AITCL or ATCL) may 
have skin lesions.  Patient having both skin and node lesions will be placed into 
one of the group (CTCL or PTCL) as approved by investigator. 
Exclusion 
Criteria 
1. Patient receiving anticancer therapy including any investigational therapy 
(e.g. chemotherapy, biologic therapy, hormonal therapy, radiotherapy 
(except limited field palliative radiation), surgery and/or tumor embolization) 
≤3 weeks or 5 half-lives (whichever is shorter) prior to C1D1. 
2. Patient who discontinued prior therapy with PI3K inhibitors or HDAC 
inhibitors due to drug toxicity.  
3. PTCL patients with Allo-SCT on active GVHD or immunosuppression 
therapy within 3 months prior to C1D1. CTCL patients with the history of 
Allo-SCT will be excluded.  
4. Patient with medical conditions requiring the use of systemic 
immunosuppressive medications (> 20 mg/day of prednisone or equivalent). 
5. Severe bacterial, viral or mycotic infection requiring systemic treatment. 
6. Pregnancy or lactation.   
7. History of chronic liver disease, hepatic veno-occlusive disease, or current 
alcohol abuse. 


Protocol No. RP6530+Romidepsin-1805 
                                                     Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018  
CONFIDENTIAL 
Page 10 of 88 
8. Known clinically active central nervous system (CNS) or meningeal 
involvement. (Note: In the absence of symptoms, investigation into CNS 
involvement is not required. Patients are eligible if metastases have been 
treated and patients are neurologically returned to baseline or neurologically 
stable for at least 4 weeks prior to C1D1).  
9. Known 
seropositive 
requiring 
anti-viral 
therapy 
for 
human 
immunodeficiency virus (HIV) infection.  
10. Known seropositive requiring anti-viral therapy for hepatitis B virus (HBV) 
infection OR evidence of active hepatitis B infection as defined by detectable 
viral load if the antibody tests are positive. [Note: A positive HBcAb subject 
with an undetectable/negative hepatitis B DNA test (e.g., polymerase chain 
reaction [PCR] test) can be enrolled].  
11. Known seropositive requiring anti-viral therapy for hepatitis c virus (HCV) 
infection OR patients with positive hepatitis C virus Ab. 
12. Subjects with active EBV unrelated to underlying lymphoma (positive 
serology for anti-EBV VCA IgM antibody and negative for anti-EBV EBNA 
IgG antibody, or clinical manifestations and positive EBV PCR consistent 
with active EBV infection. 
13. Subject with active CMV (positive serology for anti-CMV IgM antibody and 
negative for anti-CMV IgG antibody and positive CMV PCR with clinical 
manifestations consistent with active CMV infection) and requiring therapy. 
[Note: Carriers will be monitored per institutional guidelines.] 
14. Subjects with concomitant second malignancies (except adequately treated 
non-melanomatous skin cancers, ductal carcinoma in situ, superficial bladder 
cancer, prostate cancer or in situ cervical cancers) are excluded unless a 
complete remission is achieved at least 2 years prior to study entry and no 
additional therapy (except adjuvant or maintenance therapy to reduce the risk 
of recurrence) is required or anticipated to be required during the study 
period. 
15. Administration of any of the following within 1 week prior to C1D1: 
• Strong inhibitors or inducers of CYP3A4 including but not limited to 
grapefruit products, herbal supplements and drugs 
• Strong inhibitors or inducers of CYP2C9 including but not limited to 
herbal supplements and drugs 
• Substrates of CYP3A4 enzyme with a narrow therapeutic range. 
16. History of Grade 4 anaphylactic reaction. 
17. Administration of live vaccines within 6 weeks of C1D1.   
18. History of prior surgery or gastrointestinal dysfunction that may affect drug 
absorption (e.g., gastric bypass surgery, gastrectomy) 
19. Current history of a serious uncontrolled medical disorder, metabolic 
dysfunction, physical examination findings, or clinical laboratory findings 
giving reasonable suspicion of a disease or condition that contraindicates use 
of an investigational drugs or render the subject at high risk from treatment 
complications.  


Protocol No. RP6530+Romidepsin-1805 
                                                     Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018  
CONFIDENTIAL 
Page 11 of 88 
20. Uncontrolled or significant cardiovascular disease including, but not limited 
to: 
• Congenital long QT syndrome. 
• QTcF interval > 450 msec  
• Myocardial infarction or stroke/TIA within the past 6 months  
• Uncontrolled angina within the past 3 months   
• Significant ECG abnormalities including 2nd degree atrio- ventricular 
(AV) block (AV) block type II, 3rd degree AV block. 
• History of clinically significant arrhythmias (such as ventricular 
tachycardia, ventricular fibrillation or torsades de pointes),  
• History of other clinically significant heart disease (ie, cardiomyopathy, 
congestive heart failure with NYHA functional classification III-IV, 
pericarditis, significant pericardial effusion)  
• Requirement for daily supplemental oxygen therapy. 
Estimated 
Study 
Participation  
Dose Escalation:  Approximately 10 months for accrual and follow up 
Dose Expansion:  Approximately 18 months for accrual plus patient follow up. 
Assessment of 
Response  
Initial disease assessment will be performed at screening. The response to 
treatment will be done at C3D1 (± 7 days), C5D1 (± 7 days), C8D1 (± 7 days) 
and/ or at the EOT and or as clinically indicated (if clinical progression is 
suspected or for confirmation of complete response/disease progression). The 
following assessments will be done.  
 
PTCL:  
The response assessment will be done using CT scan as per the Lugano 
classification. PET-CT will be preferred for FDG-avid lymphomas. PET-CT will 
be performed at C3D1 (± 7 days) and to confirm the CR. Bone marrow biopsy 
will be performed to confirm complete response. 
 
CTCL:  
Response assessment in CTCL will be done as per the modified Severity 
Weighted Assessment Tool (mSWAT).  Additionally, CT scan will be done in 
the CTCL patients with lymph node and visceral involvement. CTCL patients 
with subcutaneous lesions which cannot be measured by mSWAT will be 
assessed by change in PET-CT avid lesions. Bone marrow biopsy will be 
performed in patients with B2 blood involvement. In these patients, Sezary cell 
count will be quantified by flow cytometry or morphology in blood/bone 
marrow. 
Study 
Treatment  
 
For purposes of this study, each cycle of therapy consists of 4 weeks.  
Tenalisib: 
Tenalisib will be administered from Day 1-28 in 28-days of cycle up to C8D1 in 
absence of disease progression and unacceptable toxicity. However, in Cycle 1 
of Dose Escalation, Tenalisib will be started from Day 3 to permit 
pharmacokinetic analysis of Romidepsin alone prior to combination treatment. 


Protocol No. RP6530+Romidepsin-1805 
                                                     Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018  
CONFIDENTIAL 
Page 12 of 88 
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. On the day of Romidepsin therapy, the morning dose of 
Tenalisib will be given in clinic one hour prior to Romidepsin infusion. 
 
Romidepsin:  
Romidepsin will be administered intravenously (IV) over a 4-hour period on 
days 1, 8 and 15 in a 28-day cycle. 
Statistical 
Analysis 
 
Part 1: In Dose Escalation, three patients per cohort are considered appropriate 
for the assessment of overall safety and tolerability and for providing adequate 
confidence for dose escalation. No formal sample size and power analysis is 
done. Accordingly, total 2-18 patients will be enrolled in 3 escalating cohorts 
unless additional dose levels are required to reach MTD/ optimal dose. Optimal 
dose will be determined by the SRC. 
Part 2:  Total 24 patients with relapsed/refractory TCL will be enrolled in two 
groups (12 patients in each group).   
 
The SRC may modify the sample size due to unforeseen clinical situations.  


Protocol No: RP6530+Romidepsin-1805 
                                                 Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018 
 
CONFIDENTIAL 
Page 13 of 88 
                                               GENERAL INFORMATION 
SPONSOR 
Rhizen Pharmaceuticals S.A. 
Fritz-Courvoisier 40, 
Ch-2300 La Chaux-de-Fonds,  
Switzerland. 
Tel: +41 32 580 0113 
Fax: +41 32 967 9596 
PRINCIPAL 
INVESTIGATOR AND 
STUDY CHAIR 
 
Swaminathan P Iyer, MD 
Professor, Department of Lymphoma/Myeloma,  
Division of Cancer Medicine,  
The University of Texas MD Anderson Cancer Center, 
Houston, TX, USA   
Tel: +1 713-441-9948  
CO- PRINCIPAL 
INVESTIGATOR  
Auris Huen, MD 
Assistant Professor, Department of Dermatology,  
Division of Internal Medicine, The University of Texas  
MD Anderson Cancer Center, Houston, TX, USA   
Tel: +1 713-745-1113 
SPONSOR’S 
REPRESENTATIVE 
Ajit Nair, PhD 
SVP Clinical R&D  
Rhizen Pharmaceuticals S.A. 
Fritz-Courvoisier 40, 
Ch-2300 La Chaux-de-Fonds,  
Switzerland. 
Tel: +41 32 580 0113 
Fax: +41 32 967 9596 
SPONSOR’S MEDICAL 
EXPERT  
Prajak Barde, MD 
Medical Director, Clinical R&D  
Rhizen Pharmaceuticals S.A. 
Fritz-Courvoisier 40, 
Ch-2300 La Chaux-de-Fonds,  
Switzerland. 
Tel: +41 32 580 0175 
Fax: +41 32 967 9596 
STATISTICIAN   
Michael Chen, PhD 
Consulting Statistician,  
Tel: (908) 500 9334 
Fax: +41 32 967 9596 
CLINICAL PK, 
BIOMARKER 
LABORATORY 
North East Bioanalytical Laboratories,  
925 Sherman Avenue,  
Hamden, CT 06514, USA 
 
Tel: +001 203 361 3768 
Fax: +001 203 407 0703 


Protocol No. RP6530+Romidepsin-1805 
                                                     Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 14 of 88 
List of Abbreviations 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT (SGOT) Alanine aminotransferase 
ANC 
Absolute Neutrophil Count 
aPTT 
Activated Partial Thromboplastin Time 
Allo-SCT 
Allogeneic Hematopoietic Stem Cell Transplantation  
AST (SGPT) 
Aspartate aminotransferase 
AUC0-t 
Area Under the plasma-concentration time curve from zero up to the last 
measurable concentration 
BID 
Twice Daily 
β-HCG 
β-human chorionic gonadotropin 
BSA  
Body Surface Area  
Cmax 
Peak Drug Concentration 
CBC 
Complete Blood Count 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
CR 
Complete Response 
CrCl 
Creatinine Clearance 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTCL 
Cutaneous T cell Lymphoma 
DLT 
Dose Limiting Toxicity 
DoR 
Duration of Response 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EORTC 
European Organization for Research and Treatment of Cancer   
EOS 
End of Study 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FSH 
Follicular Stimulating Hormone 
GCP 
Good Clinical Practices 
GGT 
Gamma Glutamyl Transpeptidase  
G-CSF 
Granulocyte Colony-Stimulating Factor 
GVHD 
Graft Versus Host Disease 
Hb 
Hemoglobin 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HDL 
High-Density Lipoprotein 
HDPE 
High-density Polyethylene 
HEENT 
Head, Eyes, Ears, Nose and Throat 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immune Deficiency Virus 
HPV 
Human Papilloma Virus 
IB 
Investigator’s brochure  


Protocol No. RP6530+Romidepsin-1805 
                                                     Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 15 of 88 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee 
INR 
International Normalized Ratio 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IRR 
Infusion related reactions 
ISCL  
International Society of Cutaneous Lymphoma  
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
Kel 
Elimination Constant 
LDH 
Lactate Dehydrogenase 
LDL 
Low-Density Lipoprotein 
LLN 
Lower Limit of Normal  
LMWH 
Low Molecular Weight Heparin 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
Mycosis fungoides  
mITT 
Modified Intent-to-Treat 
MRI 
Magnetic Resonance Imaging  
MTD 
Maximum Tolerated Dose 
mSWAT 
Modified Severity Weighted Assessment tool  
NCI 
National Cancer Institute 
NOAEL 
No-Observed-Adverse Effect Level 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
NYHA 
New York Heart Association 
ORR 
Objective Response Rate 
pAKT 
Phospho AKT 
PCP 
Pneumocystis Carinii 
PD 
Progressive Disease 
PD-1 
Programmed Death-1 
PET 
Positron Emission Tomography 
PFS 
Progression-Free Survival 
PI 
Principle Investigator 
PI3K 
Phosphoinositide-3-Kinase 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PR 
Partial Response 
PTCL 
Peripheral T-Cell Lymphoma 
QA 
Quality Assurance 
QTcF 
Frederica’s (QTcf)  
SAE 
Serious Adverse Events 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SD 
Stable Disease  
SDV 
Source Document Verification 
SLL 
Small Lymphocytic Lymphoma 
SOP 
Standard Operating Procedures 
SRC 
Safety Review Committee 
SS 
Sezary Syndrome  


Protocol No. RP6530+Romidepsin-1805 
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SUV 
Standardized Uptake Value 
t1/2 
Plasma Half Life 
tmax 
Time to maximum plasma concentration  
TAM 
Tumor Associated Macrophages 
TEAE 
Treatment-Emergent Adverse Event 
TG 
Triglyceride 
TIA 
Transient Ischemic Attack 
TID 
Thrice Daily 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
USP 
United States Pharmacopeia 
UV 
Ultra-violet 
WBC 
White Blood Cells 
WHO 
World Health Organization  


Protocol No. RP6530+Romidepsin-1805 
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Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018 
CONFIDENTIAL 
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TABLE OF CONTENTS  
1 
Background Information ...................................................................................................... 22 
1.1 
Tenalisib (RP6530) .................................................................................................... 22 
1.1.1 Summary of Pre-Clinical Evaluation ................................................................ 22 
1.1.2 Summary of Clinical Evaluation ...................................................................... 22 
1.2 
Romidepsin ................................................................................................................ 23 
1.3 
Study Rationale .......................................................................................................... 24 
1.3.1 Rationale for Study Population ........................................................................ 24 
1.3.2 Rationale for Combination of Tenalisib and Romidepsin ................................ 25 
1.3.3 Rationale for Dose Selection ............................................................................ 26 
1.4 
Benefit and Risk ......................................................................................................... 26 
2 
TRIAL OBJECTIVES ......................................................................................................... 27 
2.1 
Primary Objectives ..................................................................................................... 27 
2.2 
Secondary Objectives ................................................................................................. 27 
2.3 
Exploratory Objectives .............................................................................................. 27 
3 
TRIAL DESIGN .................................................................................................................. 27 
3.1 
Trial End Points ......................................................................................................... 27 
3.1.1 Primary Endpoint .............................................................................................. 27 
3.1.2 Secondary Endpoints ........................................................................................ 27 
3.1.3 Correlative/Exploratory End Points.................................................................. 27 
3.2 
Design of Trial ........................................................................................................... 27 
3.2.1 Phase I: Dose Escalation................................................................................... 28 
3.2.2 Phase II: Dose Expansion ................................................................................. 30 
3.3 
Randomization and Blinding ..................................................................................... 30 
3.4 
Investigational Medicinal Product ............................................................................. 30 
3.4.1 Dosage Form and Strengths .............................................................................. 30 
3.4.2 Labeling, Packaging and Supply ...................................................................... 30 
3.4.3 Preparation and Administration of Investigational Products ............................ 30 
3.4.4 Accountability of Investigational Products ...................................................... 32 
3.4.5 Precautions and Risks Associated with Investigational Products .................... 33 
3.5 
The Expected Duration of Subject Participation and Follow-up ............................... 34 
3.6 
Study Stopping Rules ................................................................................................. 34 


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3.6.1 Stopping Rule for Dose Escalation ................................................................... 34 
3.6.2 Suspension of Patient Enrollment .................................................................... 34 
3.6.3 Stopping Rule for Dose Expansion .................................................................. 34 
3.6.4 Study Stopping ................................................................................................. 34 
4 
SELECTION AND WITHDRAWAL of SUBJECTS ......................................................... 34 
4.1 
Inclusion Criteria........................................................................................................ 34 
4.2 
Exclusion Criteria ...................................................................................................... 35 
4.3 
Discontinuation from Trial Treatment ....................................................................... 37 
5 
TREATMENT OF SUBJECTS ........................................................................................... 37 
5.1 
Administration of Tenalisib ....................................................................................... 37 
5.2 
Administration of Romidepsin ................................................................................... 37 
5.3 
Concomitant Medications .......................................................................................... 37 
5.4 
Prohibited Medications .............................................................................................. 38 
5.5 
Procedures for Monitoring Subject Compliance. ....................................................... 39 
5.5.1 Tenalisib ........................................................................................................... 39 
5.5.2 Romidepsin ....................................................................................................... 39 
6 
TRIAL ASSESSMENT AND PROCEDURE ..................................................................... 39 
6.1 
Overview ................................................................................................................... 39 
6.2 
Informed Consent .................................................................................................... 39 
6.3 
Screening .................................................................................................................... 40 
6.3.1 Assignment of Subject Number ........................................................................ 41 
6.3.2 Medical history ................................................................................................. 42 
6.3.3 Prior and Concomitant Medication Review ..................................................... 42 
6.3.4 Prior Therapies Details ..................................................................................... 42 
6.3.5 Physical Examination ....................................................................................... 42 
6.3.6 Vital Signs ........................................................................................................ 42 
6.4 
Laboratory Investigations .......................................................................................... 43 
6.5 
12-Lead Electrocardiograms ...................................................................................... 44 
6.6 
Bone Marrow Biopsy ................................................................................................. 44 
6.7 
Radiological Evaluations ........................................................................................... 45 
6.8 
Skin Biopsy ................................................................................................................ 45 
6.9 
Skin Photograph ......................................................................................................... 45 


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6.10 Pharmacokinetic (PK) Assessments........................................................................... 45 
6.11 Correlative /Exploratory Markers .............................................................................. 46 
6.12 End of Trial Treatment (EOT) Visit .......................................................................... 46 
6.13 End of Study (EOS) Visit........................................................................................... 46 
7 
ASSESSMENT OF SAFETY .............................................................................................. 55 
7.1 
Adverse Events .......................................................................................................... 55 
7.1.1 Definitions of Adverse Events .......................................................................... 55 
7.1.2 Recording of Adverse Events ........................................................................... 55 
7.1.3 Handling of Adverse Events ............................................................................. 55 
7.2 
Adverse Event/Serious Adverse Event Causality Assessment .................................. 55 
7.3 
Serious Adverse Events ............................................................................................. 56 
7.3.1 Definitions of Serious Adverse Events ............................................................. 56 
7.3.2 SAE Reporting by Investigators ....................................................................... 56 
7.3.3 Sponsor’s SAE Reporting Requirements ......................................................... 57 
7.4 
Recording of AE and SAE ......................................................................................... 57 
7.4.1 Diagnosis vs. Signs and Symptoms .................................................................. 58 
7.4.2 Persistent or Recurrent Adverse Events ........................................................... 58 
7.4.3 Abnormal Laboratory Values ........................................................................... 58 
7.4.4 Deaths 58 
7.4.5 Hospitalization, Prolonged Hospitalization, or Surgery ................................... 59 
7.4.6 Pre-existing Medical Conditions ...................................................................... 59 
7.4.7 Pregnancy, Abortion, Birth Defects/Congenital Anomalies ............................ 59 
7.4.8 New Cancers ..................................................................................................... 59 
7.4.9 Lack of Efficacy ............................................................................................... 59 
7.5 
Protocol-Defined Events of Special Interest .............................................................. 59 
7.5.1 Pregnancy, Abortion, Birth defects/Congenital anomalies .............................. 59 
7.5.2 Overdose ........................................................................................................... 60 
7.6 
Dose-Limiting Toxicity.............................................................................................. 60 
7.6.1 Hematological DLTs ........................................................................................ 60 
7.6.2 Non-Hematological DLTs ................................................................................ 61 
7.6.3 Determination of Dose-limiting toxicity .......................................................... 61 
7.6.4 Maximum Tolerated Dose (MTD) ................................................................... 61 


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7.7 
Dose Modifications .................................................................................................... 62 
7.7.1 Criteria for Re-Starting Tenalisib after Drug toxicity ...................................... 62 
7.7.2 Dose modifications ........................................................................................... 62 
7.7.3 Romidepsin Dose Modifications ...................................................................... 65 
8 
ASSESSMENT OF EFFICACY ......................................................................................... 65 
8.1 
Specification of the Efficacy Parameters ................................................................... 65 
8.2 
Response Evaluations and Measurements ................................................................. 66 
9 
STATISTICAL METHOD AND CONSIDERATIONS ..................................................... 67 
9.1 
General Considerations .............................................................................................. 67 
9.2 
Determination of Sample Size ................................................................................... 67 
9.3 
Study Population ........................................................................................................ 67 
9.4 
Statistical Analysis ..................................................................................................... 68 
9.4.1 Demographic and Baseline Characteristics ...................................................... 68 
9.4.2 Safety Analyses ................................................................................................ 68 
9.4.3 Efficacy analyses .............................................................................................. 68 
9.4.4 Pharmacokinetic Analyses ................................................................................ 68 
9.4.5 Exploratory Analysis ........................................................................................ 69 
10 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS .......................... 69 
10.1 IRB/IEC Approval ..................................................................................................... 69 
10.2 Regulatory Approval .................................................................................................. 69 
10.3 Insurance and Indemnity ............................................................................................ 69 
10.4 Financial Disclosure and Obligations ........................................................................ 70 
10.5 Informed Consent ....................................................................................................... 70 
10.6 Confidentiality ........................................................................................................... 70 
10.6.1 Patient Confidentiality ................................................................................... 70 
10.6.2 Investigator’s Responsibilities ....................................................................... 71 
10.6.3 Investigator and Staff training and Information ............................................. 71 
11 
RECORD RETENTION AND DOCUMENTATION OF THE TRIAL ............................ 71 
11.1 Amendments to the Protocol ...................................................................................... 71 
11.2 Protocol Deviations .................................................................................................... 72 
11.3 Documentation Required to Initiate Trial .................................................................. 72 
12 
DATA HANDLING AND RECORD KEEPING ............................................................... 72 


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12.1 Data Collection .......................................................................................................... 73 
12.2 Trial Monitoring, Auditing, and Inspecting ............................................................... 74 
12.3 Medical Monitoring ................................................................................................... 74 
12.4 Quality Assurance and Quality Control ..................................................................... 75 
13 
Disclosure and Publication Policy ....................................................................................... 75 
14 
REFERENCES .................................................................................................................... 75 
15 
APPENDICES ..................................................................................................................... 77 
Appendix A: ECOG Performance Status Scale ................................................................ 77 
Appendix B: Contraceptive Guidelines and Pregnancy ....................................................... 78 
Appendix C: Response Criteria for NHL-The Lugano classification .................................. 80 
Appendix D: Recommended evaluation for MF/SS patients ............................................... 83 
Appendix E:  
ISCL/EORTC staging of MF and SS patients .................................................. 84 
Appendix F: Modified Severity Weighted Assessment Tool (mSWAT) ..................................... 86 
Appendix G : Ann Arbor Staging System ........................................................................... 87 
Appendix H: Romidepsin Prescribing Information ............................................................. 88 
 
List of Tables 
Table 1: Dose Escalation Scheme ..................................................................................................... 28 
Table 2: Dose Expansion .................................................................................................................. 30 
Table 3: Summary of Key Assessments at Screening ......................................................................... 41 
Table 4: Laboratory Tests for Hematology, Chemistry and Urinalysis ................................................. 43 
Table 5: Schedule of Events for Dose Escalation ............................................................................... 47 
Table 6: Schedule of Events for Dose Expansion ............................................................................... 51 
Table 7: Dose Modifications for Hematologic Toxicity ...................................................................... 63 
Table 8: Dose Modifications for Non-Hematologic Toxicities ............................................................ 63 
 
 
List of Figure 
 
Figure 1. Inhibition of Cell Growth in T-Cell Lymphoma Cell Lines ................................................... 25 
 
 


Protocol No. RP6530+Romidepsin-1805 
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1 BACKGROUND INFORMATION  
1.1 
Tenalisib (RP6530) 
The phosphoinositide-3-kinases (PI3Ks) are a family of enzymes involved in various cellular 
functions, including cell proliferation and survival, cell differentiation, intracellular 
trafficking and immunity.[1-3] Tenalisib is a highly specific and orally available dual PI3K 
δ/γ inhibitor with nano-molar inhibitory potency and several fold selectivity over α and β 
PI3K isoforms. The specificity of Tenalisib towards PI3K δ and γ is evidenced by >1000 
and >100-fold selectivity over α and β isoforms in an enzyme-based assay. Chemically, 
Tenalisib is an iso-flavone substituted adenine.  
 
1.1.1 Summary of Pre-Clinical Evaluation  
Tenalisib has equimolar potency against both PI3K δ/γ isoforms in enzyme, cell, and blood-
based assays. Additionally, the compound inhibited antigen-induced superoxide or cytokine 
release from primary human neutrophils or monocytes at nano-molar concentration 
indicating a potential in modulation of the tumor microenvironment. Studies using 
immortalized B and T lymphoma cell lines demonstrated the anti-proliferative effect of 
Tenalisib coupled with induction of apoptosis and a concomitant inhibition of the 
downstream biomarker, pAKT. Similarly, cytokine induced pAKT was inhibited in 
malignant primary CTCL cells isolated from patient donors. Tenalisib induced apoptosis of 
patient derived primary CTCL cells following 48 hr incubation.  
 
In vivo efficacy of Tenalisib was confirmed in a subcutaneous mouse MOLT-4 xenograft 
model representative of human T-cell acute lymphoblastic leukemia. Oral administration of 
50 mg/kg/BID over an 18-day period resulted in a significant delay in tumor growth.[4] In 
28-days toxicity studies in rat and dog, once daily oral administration of Tenalisib was well 
tolerated. Target organ effects were observed in thyroid and liver. The no-observed-adverse-
effect level (NOAEL) was 20 mg/kg/day in rat and 10 mg/kg/day in dog.  
 
Refer to the Investigator’s Brochure (IB) for detailed background information on 
Tenalisib.[5] 
 
1.1.2 Summary of Clinical Evaluation 
To date, Tenalisib has been evaluated in four clinical trials:  
1. A Phase I Dose Escalation Study Evaluating the Safety and Efficacy of RP6530, a dual 
PI3K δ/γ inhibitor, in Patients with Relapsed or Refractory Hematologic Malignancies 
(European study: Protocol Number RP6530-1301) Status: Completed   
2. A Phase I/Ib, Dose Escalation Study to Evaluate Safety and Efficacy of RP6530, a dual 
PI3K δ/γ inhibitor, in Patients with Relapsed or Refractory T-cell Lymphoma (US study: 
Protocol number RP6530-1401). Status: Recruitment completed. Study Ongoing 
3. An open label, randomized, single dose, crossover study to evaluate food effects on 
relative bioavailability of RP6530 administered in fasting and fed conditions in healthy 
volunteers (Food effect study, Protocol no: RP6530-1501). Status: Completed  
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). Status: 
Ongoing and currently recruiting. 


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• Safety:  
In RP6530-1401 study, a total of 58 patients were treated at 200 mg BID (n=4), 400 mg BID 
(n=4), 800 mg BID (Fasting) (n=44) and 800 mg BID (Fed) (n=6) in both dose escalation 
and dose expansion cohorts. Tenalisib demonstrated acceptable safety and tolerability profile 
up to 800 mg BID (fasting). Tenalisib 800 mg BID (Fasting) was considered as MTD dose 
in patients with T-cell lymphoma. Majority of AEs include transaminitis, skin rash. 
Treatment related Grade ≥ 3 includes AST/ALT elevation (n=12), rash (n=4), 
hypophosphatemia (n=2), neutropenia (n=1), INR Increase (n=1), sepsis (n=1), pyrexia 
(n=1), diplopia secondary to neuropathy (n=1), drug reaction (n=1), and bacteremia (n=1). 
Treatment related SAE reported were pyrexia (n=1), raised INR (n=1), sepsis (n=1), diplopia 
secondary to neuropathy (n=1), drug reaction (n=1) and bacteremia (n=1).  
  
• Pharmacokinetics:  
In RP6530-1401 study, at the 200 mg dose, AUC0-t and Cmax were 3713.94 h*ng/mL and 
1463.57 ng/mL at C1D1 respectively; corresponding levels at C2D1 were 3985.52 h*ng/mL 
and 1781.24 ng/mL. Similarly, at the 800 mg dose (fed), AUC0-t and Cmax were 13204.17 
h*ng/mL and 2988.66 ng/mL at C1D1 respectively; corresponding levels at C2D1 were 
12737.21 h*ng/mL and 3234.50 ng/mL. At the 800 mg dose (fasting), AUC0-t and Cmax were 
14033.67 h*ng/mL and 4174.71 ng/mL at C1D1 respectively; corresponding levels at C2D1 
were 13210.24 h*ng/mL and 3395.28 ng/mL. Based on Cmax and AUC, dose proportionality 
was observed up to the 800 mg dose. Upon increasing doses, no changes in Tmax were 
observed and while changes in T1/2 were observed, steady state PK parameters of Tenalisib 
as determined on C2D1 revealed no accumulation.  
 
• Efficacy:  
In RP6530-1401 study, response assessments of the thirty-five evaluable patients receiving 
at least two cycles of Tenalisib showed an ORR of 46% (16/35 patients) out of which 3 (9%) 
were CR and 13 (37%) were PR.  Eleven patients showed stable disease (31%). Indication 
specific analysis showed an ORR of 47% (7/15, 3 CR, 4 PR) in PTCL and 45% (9/20, 9 PR) 
in CTCL. Effect of RP6530 on associated correlative markers in PTCL (sIL-2R and CD30) 
and CTCL (IL-31, IL-32α, and CTACK) patients that were either a CR, PR, or SD on C3D1 
showed decreased plasma concentrations of markers with the reductions being most 
pronounced for CD30 (57%) and IL-31 (33%) in the respective patient populations.[6] 
 
1.2 
Romidepsin 
Romidepsin is a histone deacetylases (HDAC) inhibitor and was approved by FDA for the 
treatment of CTCL and PTCL in 2009 and 2011 respectively for the patients who have 
received at least one prior systemic therapy. A pivotal phase II study on Romidepsin in 131 
patients with relapsed or refractory PTCL showed an ORR of 26 % (CR rate of 15 %), 
progression free survival (PFS): 4 months and DoR of 13 months.[7] Similarly, Romidepsin 
was evaluated in 2 multicenter, single-arm clinical studies in patients with CTCL. 
Cumulative, response rate (ORR) in 167 patients was 35 % (CR rate of 6%) and DoR of 13 
months.[ 7] 
 


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1.3 
Study Rationale  
1.3.1 Rationale for Study Population  
T-cell lymphomas (TCL) comprise a heterogeneous group of lymphoid malignancies arising 
from mature T-cells. Peripheral T cell lymphoma (PTCL) constitute 10–12 % of non-
Hodgkin’s lymphomas (NHL) in Western countries but are relatively common in Eastern 
Asian, constituting about 20 % of mature NHL.[8] There is no consensus regarding optimal 
treatment for PTCL, especially in relapsed or refractory cases, which have very poor 
prognosis. High-dose chemotherapy followed by autologous stem cell transplantation 
(ASCT) has been accepted as a salvage treatment for eligible patients, although the evidence 
is unclear.[9] Moreover, the overall prognosis remains dismal in patients unsuitable for 
ASCT.  
 
Cutaneous T-cell lymphomas (CTCLs) represent a group of rare, clinically and 
pathologically heterogeneous diseases. The incidence of CTCL has been increasing and is 
currently 6.4 per million persons, with the highest incidence rates being reported among 
males and African-Americans. Mycosis fungoides (MF) is the most common primary CTCL 
variant and is closely related to a rare leukemic variant, Sézary syndrome (SS). Skin-directed 
therapies, such as psoralen plus ultraviolet A in combination with retinoids or interferon, are 
used in the early stage disease and generally produce good, long-term responses. Patients 
with advanced-stage disease require a multidisciplinary approach that includes combinations 
of skin-directed therapies, biologic-response modifiers and systemic chemotherapeutic 
agents. Although patients with early stages of disease have an excellent prognosis, ∼25% 
develop progressive disease.[10-12] The prognosis for patients presenting with advanced-stage 
disease is poor.[10, 11, 13, 14] 
 
Over recent years, several single-agent therapies have proven to be effective in 
relapsed/refractory PTCL. Pralatrexate, romidepsin, and belinostat are all approved broadly 
for PTCL with ORR’s in phase II studies of 29, 25, and 26 %, respectively. Brentuximab 
vedotin is also approved in relapsed ALCL with an ORR of 86 % in a small phase II trial.  
 
Despite recent progress, there are hurdles to overcome in managing patients with PTCL as 
responses with these therapies are not optimal (all approved therapies except brentuximab 
has response rate <30%). Given the aggressive nature of PTCL, which has a poor prognosis, 
this patient population represents an unmet medical need.  
 
CTCL patients are responsive to treatment in the early stages; patients have a long duration 
of survival but are rarely cured of the disease. For refractory early-stage and advanced-stage 
disease (IIB-IV), a multidisciplinary approach is used that include bexarotene, interferon α, 
extracorporeal photopheresis, histone deacetylase inhibitors (vorinostat and romidepsin), 
and antibody therapies such as alemtuzumab, systemic chemotherapy, and allogeneic 
transplantation. Though, these agents, alone or in combinations, are associated with high 
response rates, unfortunately response is often of limited duration (frequently measured in 
months) and especially in advanced cases, characterized by frequent recurrences, probably 
due to treatment resistance. Therefore, the prognosis for patients presenting with advanced-
stage disease generally poor[10, 11, 13, 14]. Hence, novel therapeutic agents, either alone or in 
combination, are needed to achieve better disease control in these patients.  


Protocol No. RP6530+Romidepsin-1805 
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1.3.2 Rationale for Combination of Tenalisib and Romidepsin    
Modification of histones by acetylation plays a key role in epigenetic regulation of gene 
expression and is controlled by the balance between histone deacetylases (HDAC) and 
histone acetyltransferases (HAT). HDAC inhibitors induce cancer cell cycle arrest, 
differentiation and cell death, reduce angiogenesis and modulate immune response.  
 
Recently it is recognized that TCL may be a disease characterized by epigenetic 
dysregulation, partly explained by TCL sensitivity to histone deacetylase (HDAC) 
inhibitors. Early phase clinical studies have demonstrated that combination therapy with 
epigenetic therapies such as HDAC inhibitors plus other agents known to have activity in T 
cell lymphoma have enhanced clinical benefit for this group of diseases. Therefore, HDAC 
inhibitors have been increasingly used as a platform to which other novel therapies or 
chemotherapy can be added.  
 
Pre-clinical experiments demonstrated the synergistic anti-tumor activity achieved by 
combining PI3K inhibitor with HDAC inhibitor in B-cell lymphoma cell lines and primary 
NHL/ CLL cells. These experiments indicated that interference with PI3K signalling 
dramatically increases HDAC inhibitor-mediated apoptosis in malignant haematopoietic 
cells - this might be through either AKT-dependent or AKT-independent mechanisms. 
Moreover, the dramatic increase in HDAC inhibitor-related apoptosis observed in PI3K 
inhibitor-treated cells appears to be related to the disruption of the ERK signalling 
pathway.[15]  
 
Synergistic potential of the combination of Tenalisib and Romidepsin in attenuating T-cell 
lymphoma cell proliferation was determined using HuT-78, HuT-102, MOLT-4, and Jurkat. 
Cells were incubated with desired concentrations of DMSO (Vehicle), Tenalisib (RP6530), 
or a combination of Tenalisib (RP6530) and Romidepsin for 72 hours cell viability estimated 
in the MTT-based assay. Combination effect was determined by calculating the Bliss score 
where scores >10 indicate synergism. Among the cell lines evaluated, synergism between 
RP6530 and Romidepsin was most evident in the CTCL cell lines, Hut-78 and HuT-102. 
 
Figure 1. Inhibition of Cell Growth in T-Cell Lymphoma Cell Lines 
 
A. HuT-78 
 
 
 
 
 
 


Protocol No. RP6530+Romidepsin-1805 
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Amendment 1, 30 November 2018 
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B. Hut-102 
 
 
 
 
 
 
In the clinical setting, individually, both Tenalisib and Romidepsin has shown good response 
rate of > 25 % (ORR) and durable response for >4 months in TCL patients in 
relapsed/refractory setting. It is therefore hypothesized that a Tenalisib/Romidepsin 
combination has the potential to synergize and improve depth and durability of responses in 
these patients. 
 
1.3.3 Rationale for Dose Selection 
The safety and tolerability of Tenalisib has been established at 800 mg BID in an ongoing 
study in patients with relapsed/refractory T-cell lymphoma. Given the fact that both 
Romidepsin and Tenalisib have non-overlapping toxicity profiles, half of the optimal dose 
of Tenalisib (400 mg BID) and one dose below the approved dose of Romidepsin (12 mg/m2) 
are considered reasonable as starting doses of the combination from safety point of view. In 
line with the approved prescribing information, Romidepsin will be administered at Day 1, 
8 and 15 in a 28-day cycle. The lower doses may be selected on the basis of emerging 
toxicities of each of the agents given the distinctive nature of toxicities. 
 
1.4 
Benefit and Risk 
It is expected that proposed combination of Tenalisib with Romidepsin has the potential to 
improve response rates and increase the durability of response. However, all the patients in 
clinical trials generally cannot expect to receive direct benefit from treatment during 
participation, as clinical trials are designed to provide information about the safety and 
effectiveness of an investigational medicine. 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. 
 
 


Protocol No. RP6530+Romidepsin-1805 
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2 TRIAL OBJECTIVES 
2.1 
Primary Objectives 
• 
To characterize safety, tolerability and to establish the maximum tolerated dose (MTD) 
of Tenalisib in combination with Romidepsin in patients with R/R T-cell lymphoma. 
 
2.2 
Secondary Objectives 
• 
To assess the preliminary anti-tumor activity of various dose levels of Tenalisib in 
combination with Romidepsin as determined by the Objective Response Rate (ORR) 
and Duration of Response (DoR).   
• 
To characterize the Pharmacokinetics (PK) of Tenalisib and Romidepsin when given in 
combination. 
 
2.3 
Exploratory Objectives 
• 
To correlate clinical efficacy with markers that include but are not limited to quantitative 
and qualitative measurements of malignant cells, cytokines, and chemokines in 
blood/serum. 
 
 
3 TRIAL DESIGN 
3.1 
Trial End Points 
3.1.1 Primary Endpoint  
•  Safety: 
Adverse Event (AE), Grade 3/ 4 AEs, Serious and fatal Adverse Event (SAE), graded 
using NCI CTCAE Version 5.0. 
 
3.1.2 Secondary Endpoints  
•  Efficacy:  
1. Objective Response Rate (ORR), defined as sum of CR and PR rates, assessed 
according to the Lugano Classification for initial evaluation, staging, and response 
assessment of Hodgkin/non-Hodgkin lymphoma in PTCL patients; and according to the 
modified Severity Weighted Assessment Tool (mSWAT) in CTCL patients.     
2. Duration of Response (DoR), calculated as time from the initial response to 
documented disease progression. 
 
•  Pharmacokinetics:  
PK Parameters [AUC (0-∞), AUC (0- t), Cmax, tmax, Kel, and t½] of Tenalisib and 
Romidepsin.  
 
3.1.3 Correlative/Exploratory End Points 
Correlative markers include baseline and on-treatment serum levels of chemokines, 
cytokines, antibodies to tumor antigens, and other immune mediators (e.g. sIL2R and 
CTACK for PTCL; CD30, IL-31 and IL-32 for CTCL) as deemed relevant by the sponsor. 
 
3.2 
Design of Trial 
This is a multi-center, open label, non-randomized, two-part Phase I/II study of Tenalisib in 


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combination with Romidepsin in adult patients with relapsed/refractory TCL. The first part 
is an open-label, 3+3 dose escalation, Phase I study for MTD determination. The second part 
is a Phase II, dose expansion to delineate the safety and anti-tumor activity of the 
combination at the MTD/optimal dose.  
 
In dose escalation, a minimum of 2 and maximum 18 patients will be enrolled in three dose 
levels unless additional dose levels are required to reach MTD/ optimal dose. In dose 
expansion, up to 24 TCL patients will be enrolled (Group 1= 12 PTCL patients and Group 
2= 12 CTCL patients).  
 
The study will end when all ongoing subjects have reached their third tumor assessment on 
Cycle 8/Day 1 (C8D1) or have discontinued from the study for any reason, whichever is 
earlier. At the end of the study, all ongoing patients with no evident disease progression will 
be given the opportunity to enroll in an open-label compassionate use study protocol and 
will be followed up. 
 
3.2.1 Phase I: Dose Escalation 
3.2.1.1 Dose Escalation Cohorts  
Sequential dose escalation will begin with Cohort 1. A minimum of three patients will be 
enrolled at each dose level. Dose levels will be increased in successive increments according 
to the dose escalation cohorts mentioned in Table 1. Escalation to the next cohort will occur 
if no patient within a three-patient cohort or one in six patients experiences a dose limiting 
toxicity (DLT). De-escalation to different lower doses in case of DLT criteria met will be 
done as per the discretion of the Safety Review Committee (SRC). The highest doses of the 
combination (Tenalisib at 800 mg BID plus Romidepsin IV 14 mg/m2) will be considered as 
optimal in case there is no DLT at this dose level.  
 
Table 1: Dose Escalation Scheme 
Cohort 
N 
Tenalisib1  
Romidepsin2  
Cohort 1 
3-6 
Tab. 400 mg PO twice a day 
IV 12 mg/m2 on Day 1, 8 and 15  
Cohort 2 
3-6 
Tab. 600 mg PO twice a day 
IV 12 mg/m2 on Day 1, 8 and 15  
Cohort 3 
3-6 
Tab. 800 mg PO twice a day 
IV 14 mg/m2 on Day 1, 8 and 15  
Note: Alternate dose levels/dosing schedules may be considered by the SRC if deemed essential based on 
emerging safety and PK data.  
1In case the dose (e.g. 800 mg BID) is leading to DLT of the combination, the dose of Tenalisib will be 
reduced to lower dose (e.g. 600 mg BID) and will be evaluated for safety in a separate cohort.  
2In case the dose (e.g. 14 mg/m2) is leading to DLT of the combination, the dose of Romidepsin will be reduced 
to lower dose (e.g.12 mg/m2) and if required further to 10 mg/m2 and will be evaluated for safety in a separate 
cohort.  
 
Notes:  
• For dose escalation decision, safety data of the first 28-days follow up and PK data of 
C1D1 and C1D8 is essential.  
• The dose escalation may occur if no patient within a three-patient cohort experiences a 
DLT as defined in Section 7.6 If one of three patients within a 3-patient cohort experiences 


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a DLT, an additional three patients will be treated at the same dose level. If one of six 
patients within a dose level experiences a DLT, dose escalation will continue. If two or 
more of six patients within a dose level experience a DLT, that dose level will be defined 
as exceeding MTD, no further dose escalation will occur. The previous dose level will be 
considered the MTD or de-escalation to lower dose level will be done as per the discretion 
of the Safety Review Committee (SRC). Once the MTD/optimal dose of the combination 
is established; the same doses will be expanded to further elucidate safety and efficacy. 
Multiple expansion cohorts will be opened at different dose levels, if deemed necessary.  
• If two of the first 3 patients in a cohort experience a DLT, that dose level will be defined 
as exceeding MTD, no further dose escalation will occur. The previous dose level will be 
considered the MTD and will be expanded to further elucidate safety and to evaluate 
efficacy. 
• The actual number of dose cohorts explored will depend upon the MTD and the safety 
profile observed during the conduct of the trial. Intermediate dose levels and dosing 
schedules may be explored if deemed appropriate. 
• An optimal dose of combination is defined as the threshold doses of individual drugs at 
which Tenalisib/Romidepsin combination shows clinical activity/efficacy (shows 
complete response or partial response) in the disease population and is at or below the 
maximum tolerated dose.  
 
3.2.1.1 Intra-subject Dose Escalation  
During dose escalation, individual patients may be considered for treatment at a dose level 
of Tenalisib/Romidepsin higher than the dose to which they are initially assigned at 
investigator’s discretion after discussion with Medical Monitor. For a patient to be treated at 
a higher dose level of Tenalisib/Romidepsin, the patient must not have experienced a DLT 
at the assigned dose and tolerated the lower dose for at least one cycle of therapy. The patient 
must have undergone a disease evaluation and been found appropriate to continue on study. 
(e.g. A patient on Tenalisib 400 mg can be escalated to 600 mg dose once the safety of 600 
mg dose is established. For a patient to be treated at 600 mg dose level, the patient must not 
have experienced a DLT at 400 mg dose and tolerated the dose for at least one cycle of 
therapy. Similar is the case for Romidepsin)  
 
The new higher dose must be a dose that has completed evaluation and has not exceeded the 
MTD. The dose escalation can occur at the start of a new cycle. At the discretion of 
investigator, dose escalation may be done in patient who received lower doses (de-
escalation) due to safety reasons. 
 
3.2.1.2 Alternative Dosing Cohorts 
Depending on nature and timing of the toxicities, pharmacokinetic data of 
Tenalisib/Romidepsin, alternative dosing regimens and schedules may be examined. If in 
the opinion of the SRC, observed toxicities (DLTs and/or non-dose limiting adverse events 
of concern) are likely to have resulted from a continuous exposure to the study drug or 
cumulative effect, alternative dosing regimens or schedules may be explored. The SRC will 
determine an alternative schedule, based on PK data, nature and timing of toxicities, and the 


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recovery periods of the observed toxicities. Dose escalation will be continued with an 
alternative schedule till determination of the MTD/optimal dose of the combination.   
 
3.2.2 Phase II: Dose Expansion  
After establishing the MTD/optimal dose, the Phase II (Dose Expansion) will be opened as 
approved by the SRC to enroll two groups of patients. 
          
 
Table 2: Dose Expansion  
Group 
N 
Patient 
population 
Tenalisib 
Romidepsin 
Group 1 
12 
R/R PTCL 
MTD/Optimal dose 
MTD/Optimal dose on 
Day 1, 8 and 15 
Group 2 
12 
R/R CTCL 
MTD/Optimal dose 
MTD/Optimal dose on 
Day 1, 8 and 15 
 
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(s) 
Dosage form, strength 
Manufacturer 
 Tenalisib 
Tablets; 200 mg and 400 mg.  STA Pharma Co., Ltd 
Romidepsin  
10 mg single-dose vial 
For 
Romidepsin, 
please 
refer 
to 
prescribing information.  
Note: Please refer Investigator’s Brochure for additional information of Tenalisib. For Romidepsin, please 
refer to prescribing information.  
 
3.4.2 Labeling, Packaging and Supply 
• Tenalisib 
Tenalisib will be supplied through Rhizen Pharmaceuticals SA. Tenalisib will be available 
in 30 tablets per High-density Polyethylene (HDPE) bottle. All trial drugs must be kept in a 
secure place at below 25°C (77°F), protected from moisture”. 
 
• Romidepsin  
Commercially available Romidepsin will be used. Please refer to Appendix H for storage 
conditions and handling of Romidepsin. 
 
3.4.3 Preparation and Administration of Investigational Products 
3.4.3.1 Tenalisib  
At the start of each cycle, sufficient quantity of Tenalisib will be dispensed. Study drug 
compliance should be reviewed with the patient at the beginning of each new treatment 
cycle. Study drug compliance must be documented, including missed doses and subject re-
education and dose administration.   
 


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Guideline for Administration of Tenalisib: 
• Method of Administration:  Tenalisib will be administered orally twice daily in a 28-day 
cycle (Day 1-28). Only during Cycle 1 of Dose Escalation, Tenalisib will be given 
starting from Day 3 (i.e. C1D3) to permit PK assessment of Romidepsin alone. Patients 
will be, therefore, instructed to start Tenalisib treatment on C1D3 and will be informed 
that they will receive Tenalisib for only 25 days in the first cycle.  
• Pre-medications: None for Tenalisib. However, routine prophylactic anti-emetics or pre-
medications may be required for Romidepsin.  
• Tenalisib tablets will be self-administered orally twice daily one hour before a major 
meal (e.g. breakfast and dinner). Patients should not consume food during this one-hour 
period. 
• Tenalisib tablets should be taken at approximately same time each day. Tablets should 
be swallowed; and should NOT be crushed or chewed.   
• If a dose of Tenalisib is missed, it should be taken as soon as possible on same day with 
an interval of 8 hours between two doses. If it is missed for the entire day, it should not 
be repeated. If vomiting occurs, no attempt should be made to replace the vomited dose.  
• Study drug compliance should be reviewed with the patient at the beginning of each new 
treatment cycle. Missed doses should be documented. 
• On the day of Romidepsin administration, the morning dose of Tenalisib should be given 
in clinic one hour prior to Romidepsin infusion. 
 
3.4.3.2 Romidepsin 
Romidepsin will be supplied as a standard kit. Below is the general outline of preparation 
and administration of Romidepsin. However, please refer the Prescribing information for 
these instructions.  
 
•  Preparation of Romidepsin  
o Romidepsin must be reconstituted with the supplied diluent and further diluted with 
0.9% Sodium Chloride Injection, USP before intravenous infusion. 
o Romidepsin and diluent vials contain an overfill to ensure the recommended volume 
can be withdrawn at a concentration of 5 mg/mL 
 
• Preparation for Intravenous Administration  
o Each 10 mg single-dose vial of Romidepsin must be reconstituted with 2.2 mL of the 
supplied diluent. 
o With a suitable syringe, aseptically withdraw 2.2 mL from the supplied diluent vial, 
and slowly inject it into the Romidepsin for injection vial.  Swirl the contents of the 
vial until there are no visible particles in the resulting solution.   
o The reconstituted solution will contain Romidepsin 5 mg/mL. The reconstituted 
Romidepsin vial will contain 2 mL of deliverable volume of drug product. The 


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reconstituted Romidepsin solution is chemically stable for up to 8 hours at room 
temperature.  
o Extract the appropriate amount of Romidepsin from the vials to deliver the desired 
dose, using proper aseptic technique. 0Before intravenous infusion, further dilute 
Romidepsin in 500 mL 0.9% Sodium Chloride Injection, USP. 
o Infuse over 4 hours. 
 
Guideline for Administration of Romidepsin: 
• Method of administration: Romidepsin will be administered as an intravenous infusion 
in outpatient basis/ hospital setting. 
• Pre-medications:  
o 
Nausea and vomiting are common following treatment with Romidepsin, therefore 
prophylactic antiemetics are recommended for all patients.  Advise patients to 
report these symptoms so that appropriate treatment can be instituted the earliest. Due 
to potential for CYP3A4 interaction, administration of a neurokinin-1 receptor 
inhibitor antiemetics (e.g. aprepitant, fosaprepitant) is not permitted. 
o 
Patients with advanced stage disease and/or high tumor burden are at the risk of tumor 
lysis syndrome, therefore these patients are advised to maintain high fluid intake for 
at least 72 hours after each dose.  
• Serum potassium and magnesium should be ≤ ULN before Romidepsin treatment.  
• Trial treatment should be administered on Day 1, Day 8 and Day 15 of each cycle of 28 
days. Interruptions from the treatment plan may be allowed for toxicity management, but 
require consultation between the investigator and Sponsor, and written documentation of 
the collaborative decision on subject management.  
• All trial treatments will be administered on an outpatient basis. 
• Romidepsin should be infused over 4 hours. Sites should make every effort to target 
infusion timing to be as close to 4 hours as possible. However, given the variability of 
infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted. 
• Romidepsin must be stored as per prescribing information. . 
• Prescribing information should be referred for specific instructions for Romidepsin 
reconstitution, preparation of the infusion fluid, and administration. 
 
3.4.4 Accountability of Investigational Products 
The PI/ designee are responsible for accountability of all trial drug supplies (used/unused) at 
the site. During on-site monitoring visit, the study monitor/CRA will verify receipt of 
investigational product, returned and empty vials/cartons, batch numbers of used vials, and 
will conduct an inventory of remaining clinical trial supplies at the site close-out visit. All 
trial drug inventories must be made available for inspection by the monitor, sponsor 
representatives and regulatory agency inspectors/monitor upon request.  
 
Following monitor/CRA verification and instruction, expired or unused trial drugs can be 
return to the sponsor or destroyed according to local institutional policy with sponsor pre-
approval of a site-specific destruction policy. Certificate(s) of destruction or documentation 
of destruction must be filed at the site and in Trial Master File.  Used, returned trial drugs 
can be destroyed according to local institutional policy with sponsor pre-approval of a site-


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specific destruction policy. Certificate(s) of destruction or documentation of destruction 
must be filed at the site and in the Trial Master File. 
 
3.4.5 Precautions and Risks Associated with Investigational Products 
3.4.5.1 Tenalisib 
Monitoring of liver enzymes and levels of TSH, T3, and T4 in subjects receiving Tenalisib 
is recommended based on target organ toxicity. Patients will be monitored for increased 
ALT/AST, skin rash, neutropenia as these are reported with Tenalisib. In addition, enteritis 
(colitis), pneumonia/pneumonitis as these events are reported with other PI3K inhibitors.  
 
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 shows inhibition of CYP3A4 enzyme. Therefore, concomitant administration of 
Tenalisib with predominant CYP3A4 substrates (e.g. calcium channel blockers, warfarin, 
carbamazepine, macrolide antibiotics, lovastatin, simvastatin, terfenadine) may reduce 
clearance of these drugs increasing the risk of adverse events. Similarly, as Tenalisib is 
inhibited by CYP3A4/5 and CYP2C9, there is possibility of drug interaction with inhibitors 
or inducers of CYP3A4 and CYP2C9. If concomitant treatment of these drugs are clinically 
warranted, careful observation of the patient is advised. 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.  
 
3.4.5.2 Romidepsin 
The following adverse events have been reported in patients receiving Romidepsin: 
o 
Myelosuppression: Romidepsin can cause thrombocytopenia, leukopenia (neutropenia 
and lymphopenia), and anemia; monitor blood counts during treatment with 
Romidepsin; interrupt and/or modify the dose as necessary. 
o 
Fatal and serious infections, including pneumonia, sepsis, and viral reactivation, 
including Epstein Barr and Hepatitis B viruses, have been reported in clinical trials with 
Romidepsin.  These can occur during treatment and within 30 days after treatment. The 
risk of life-threatening infections may be greater in patients with a history of prior 
treatment with monoclonal antibodies directed against lymphocyte antigens and in 
patients with disease involvement of the bone marrow. 
o 
Several treatment-emergent morphological changes in ECGs (including T-wave and ST-
segment changes) have been reported in clinical studies.  The clinical significance of 
these changes is unknown. 
o 
Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor 
stage CTCL and 2% of patients with Stage III/IV PTCL.  Patients with advanced stage 
disease and/or high tumor burden are at greater risk, should be closely monitored, and 
managed as appropriate. 
o 
Since Romidepsin is a substrate of CYP3A4 enzymes, concomitant administration of 
CYP3A4 inhibitor or inducer may interact with Romidepsin. If concomitant treatment 
of these drugs is clinically warranted, careful observation of the patient is advised. 


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Strong inhibitor or inducers should be avoided as directed in Section on prohibited 
medication.  
 
Please refer to the full prescribing information of Romidepsin for additional safety 
information.  
 
3.5 
The Expected Duration of Subject Participation and Follow-up 
The expected duration of subject participation in the study will be about 8 months. Post 
C8D1, patients with no evident disease progression will be given the opportunity to enroll 
in an open-label compassionate use study protocol and will be followed up. 
 
3.6 
Study Stopping Rules 
3.6.1 Stopping Rule for Dose Escalation 
The SRC will be in charge of reviewing safety data following the final treatment dose (Day 
28 of Cycle 1) of the last patient in each cohort and will decide whether or not it is possible 
to proceed to the next cohort according to the dose escalation procedure described in Section 
3.2.1.1. In order to ensure safety and limit toxicity for enrolled patients, dose modifications 
will be performed according to the procedure described in Section 7.7.  
 
3.6.2 Suspension of Patient Enrollment 
In the event of one (1) death attributed to the study drug, study accrual will be suspended 
pending further investigation, and will only be resumed at the recommendation of the SRC.  
The SRC will have discretion to terminate the trial if an additional death occurs that can be 
attributed to the study drug. 
  
3.6.3 Stopping Rule for Dose Expansion 
After establishing the MTD/optimal dose, the Phase II expansion part will be opened as 
approved by the SRC. The SRC will continue to monitor safety of the combination (or 
toxicity trends that may be of concern) at interval of 3 months from initiation of expansion 
cohort till the completion of the study. Safety/toxicity will be monitored across cohorts 
combined together. The SRC will have discretion to terminate the trial if there are major 
safety concerns. 
 
3.6.4 Study Stopping  
Sponsor reserves the right to terminate the study in the interest of patient safety, for non-
compliance with the protocol, lack of recruitment or any other administrative reasons. The 
sponsor and PIs will notify the regulatory authority and respective IRB(s) respectively if the 
trial terminates early with a justification for the early termination. 
 
 
4 SELECTION AND WITHDRAWAL OF SUBJECTS  
4.1 
Inclusion Criteria 
1. Age ≥18 years on the day of signing informed consent. 
2. Pathologically confirmed T-cell lymphoma at the enrolling institution*.  
3. Disease status as defined as relapsed after or refractory to at least one systemic therapy. 


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4. The patients should have received NOT more than three prior systemic combination 
chemotherapies.   
5. Must have ECOG performance status ≤ 2.  
6. PTCL patients must have measurable disease as defined at least one bi-dimensional 
measurable lesion with minimum measurement of > 1.5 cm in the longest diameter.  
7. Life expectancy of at least 3 months. 
8. Toxicities related to prior therapy must have returned to Grade 1 or less, except for 
alopecia.  
9. Adequate bone marrow, liver and renal function in line with below mentioned laboratory 
requirements. Hemoglobin and platelet requirements should not be met by use of recent 
transfusion or growth factor support (GCSF or erythropoietin) within 3 weeks prior to 
treatment initiation. 
• Hemoglobin ≥8.0 g/dL  
• Absolute neutrophil count (ANC) ≥1,000/µL 
• Platelet count ≥75,000/μL 
• Total bilirubin ≤1.5 times the ULN (or ≤3 x ULN, if patient has Gilbert syndrome) 
• AST (SGOT) and ALT (SGPT) ≤ 3 x ULN; ≤ 5 ULN in case of liver involvement 
• Calculated creatinine clearance (CrCl) > 50 ml/min by Cockcroft-Gault formula. 
10. Use of an effective means of contraception for women of childbearing potential and men 
with partners of childbearing potential. 
11. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required.  
12. Provide written informed consent prior to any study-specific screening procedures. 
13. Willingness and capability to comply with the requirements of the study. 
 
*Note: The EORTC classification of CTCLs will be used to classify patients. CTCL includes 
other variants other than MF (e.g. Gamma delta cutaneous T-cell lymphoma or subcutaneous 
or panniculitis like T-cell lymphoma and CD8 positive T-cell lymphoma). PTCL includes 
patients with predominantly nodal disease (systemic involvement) but some patients (e.g. 
AITCL or ATCL) may have skin lesions.  Patient having both skin and node lesions will be 
placed into one of the group (CTCL or PTCL) as approved by investigator. 
 
4.2 
Exclusion Criteria 
1. Patient receiving anticancer therapy including any investigational therapy (e.g. 
chemotherapy, biologic therapy, hormonal therapy, surgery, radiotherapy (except limited 
field palliative radiation) and/or tumor embolization) ≤3 weeks or 5 half-lives (whichever 
is shorter) prior to C1D1. 
2. Patient who discontinued prior therapy with PI3K inhibitors or HDAC inhibitors due to 
drug toxicity.  
3. PTCL patients with Allo-SCT on active GVHD or immunosuppression therapy within 3 
months prior to C1D1. CTCL patients with the history of Allo-SCT will be excluded.  
4. Patient with any medical conditions requiring the use of systemic immunosuppressive 
medications (> 20 mg/day of prednisone or equivalent). 


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5. Severe bacterial, viral or mycotic infection requiring systemic treatment. 
6. Pregnancy or lactation.   
7. History of chronic liver disease, hepatic veno-occlusive disease, or current alcohol abuse. 
8. Known clinically active central nervous system (CNS) or meningeal involvement. (Note: 
In the absence of symptoms, investigation into CNS involvement is not required. Patients 
are eligible if metastases have been treated and patients are neurologically returned to 
baseline or neurologically stable for at least 4 weeks prior to C1D1).  
9. Known seropositive requiring anti-viral therapy for human immunodeficiency virus 
(HIV) infection.  
10. Known seropositive requiring anti-viral therapy for hepatitis B virus (HBV) infection 
OR evidence of active hepatitis B infection as defined by detectable viral load if the 
antibody tests are positive. [Note: A positive HBcAb subject with an 
undetectable/negative hepatitis B DNA test (e.g., polymerase chain reaction [PCR] test) 
can be enrolled] 
11. Known seropositive requiring anti-viral therapy for hepatitis c virus (HCV) infection OR 
patients with positive hepatitis C virus Ab. 
12. Subjects with active EBV unrelated to underlying lymphoma (positive serology for anti-
EBV VCA IgM antibody and negative for anti-EBV EBNA IgG antibody), or clinical 
manifestations and positive EBV PCR consistent with active EBV infection. 
13. Subject with active CMV (positive serology for anti-CMV IgM antibody and negative 
for anti-CMV IgG antibody and positive CMV PCR with clinical manifestations 
consistent with active CMV infection) and requiring therapy. [Note: Carriers will be 
monitored per institutional guidelines.] 
14. Subjects with concomitant second malignancies (except adequately treated non-
melanomatous skin cancers, ductal carcinoma in situ, superficial bladder cancer, prostate 
cancer or in situ cervical cancers) are excluded unless a complete remission is achieved 
at least 2 years prior to study entry and no additional therapy (except adjuvant or 
maintenance therapy to reduce the risk of recurrence) is required or anticipated to be 
required during the study period. 
15. Administration of any of the following within 1 week prior to C1D1: 
• Strong inhibitors or inducers of CYP3A4 including but not limited to grapefruit 
products, herbal supplements and drugs 
• Strong inhibitors or inducers of CYP2C9 including but not limited to herbal 
supplements and drugs 
• Substrates of CYP3A4 enzyme with a narrow therapeutic range. 
16. History of Grade 4 anaphylactic reaction. 
17. Administration of live vaccines within 6 weeks of C1D1.   
18. History of prior surgery or gastrointestinal dysfunction that may affect drug absorption 
(e.g., gastric bypass surgery, gastrectomy) 
19. Current history of a serious uncontrolled medical disorder, metabolic dysfunction, 
physical examination findings, or clinical laboratory findings giving reasonable 
suspicion of a disease or condition that contraindicates use of an investigational drugs or 
render the subject at high risk from treatment complications.  
20. Uncontrolled or significant cardiovascular disease including, but not limited to: 


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• Congenital long QT syndrome. 
• QTcF interval > 450 msec  
• Myocardial infarction or stroke/TIA within the past 6 months  
• Uncontrolled angina within the past 3 months   
• Significant ECG abnormalities including 2nd degree atrio- ventricular (AV) block 
(AV) block type II, 3rd degree AV block 
• History of clinically significant arrhythmias (such as ventricular tachycardia, 
ventricular fibrillation or torsades de pointes) 
• History of other clinically significant heart disease (ie, cardiomyopathy, congestive 
heart failure with NYHA functional classification III-IV, pericarditis, significant 
pericardial effusion) 
• Requirement for daily supplemental oxygen therapy. 
 
4.3 
Discontinuation from Trial Treatment 
The following events may be considered sufficient reason for discontinuing treatment with 
the study medication: 
- NCI CTCAE v5.0 Grade 3/4 non-hematological toxicity related to study drug that 
necessitate withdrawal in the opinion of investigator 
- 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  
- Disease progression during therapy  
- Study completion 
 
 
5 TREATMENT OF SUBJECTS  
5.1 
Administration of Tenalisib 
Tenalisib will be administered orally twice daily in 28-days cycle (Day 1-28) up to C8D1 
unless progression of disease or toxicity warranting discontinuation of therapy. Only during 
Cycle 1 of Dose Escalation, Tenalisib will be given starting from Day 3. Thus, patients will 
receive Tenalisib for 25 days in the first cycle of Dose Escalation. Please refer to Section 
3.4.3 for administration of Tenalisib.  
 
5.2 
Administration of Romidepsin 
Romidepsin will be administered intravenously (IV) over a 4-hour period on days 1, 8 and 
15 of a 28-day cycle. Please refer to Section 3.4.3 for administration of Romidepsin. 
 
5.3 
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 


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toxicity such as febrile neutropenia when clinically indicated or at the discretion of the 
investigator. 
• Transfusions may be given, based on standard criteria and clinical judgment.  
• No prophylaxis will be given for Tenalisib. However, patient may receive prophylactic 
anti-emetics for Romidepsin at the discretion of the investigator.  
• 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 and started at least 7 days prior to first dose.  
• Patients are permitted to use of topical, ocular, intra-articular, intranasal, and inhaled 
corticosteroids (with minimal systemic absorption). A brief (less than 4 weeks) course of 
corticosteroids for treatment 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 enzymes are clinically 
warranted, careful observation of the patient is advised. Use of heparin or warfarin for 
prophylaxis and treatment of venous thrombosis is prohibited. Low molecular weight 
heparin (LMWH) is acceptable. Similarly, Dabigatran and Edoxaban, Direct-acting Oral 
Anti-Coagulants (DOAC) class of drugs, are acceptable as they are not metabolized by 
CYP3A4/CYP2C9 enzymes. 
• Patients should be warned about the possible photosensitivity and advised to be careful 
with the UV exposure while on Tenalisib treatment. Patients should be recommended to 
wear loose-fitting clothes that protect skin from sun exposure, in case they need to be 
outdoors. If sunburn like reaction or skin eruption occurs, patients should contact study 
physician. 
 
5.4 
Prohibited Medications 
The following treatments are prohibited while on the clinical trial:    
• Any other anti-lymphoma therapy (e.g. radiation therapy, hormonal therapy for cancer, 
cancer immunotherapy or other biologic therapy).  
• Herbal preparations/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 
supplements and drugs (e.g. atazanavir, clarithromycin, indinavir, itraconazole, 
ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and 
rifampicin). Patients should stop using these medications at least 7 days prior to C1D1.  
• Strong inhibitors or inducers of CYP2C9, including herbal supplements and drugs (e.g. 
fluconazole and rifampicin). Patients should stop using these medications at least 7 days 
prior to C1D1. 
• Substrates of CYP3A4 enzyme with a narrow therapeutic range (e.g. Warfarin and 
phenytoin, alfentanil, astemizole, cisapride, cyclosporine, diergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus, tacrolimus, terfenadine). Patients should stop 
using these medications at least 7 days prior to C1D1.    
• Use of heparin or warfarin for prophylaxis and treatment of venous thrombosis is 
prohibited. Similarly, Apixaban and Rivaroxaban, DOAC class of drugs, are also 
prohibited they are metabolized by CYP3A4 enzymes. These drugs should be stopped at 


Protocol No. RP6530+Romidepsin-1805 
                                                     Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 39 of 88 
least 7 days prior to C1D1. 
• Live attenuated vaccine (e.g. Flu vaccine, pneumovax, varicella) 
• Steroids > 20 mg unless for management of toxicity. 
Discontinuation of patient who received concomitant/prohibited medication will be taken 
by the PI in consultation with Medical Monitor on case to case basis, after reviewing 
ongoing clinical benefit and risk. The decision to allow a patient to continue will be 
documented and archived at the site and at Rhizen. 
 
5.5 
Procedures for Monitoring Subject Compliance. 
The following measures will be employed to ensure treatment compliance. 
 
5.5.1 Tenalisib 
Subjects will be instructed to bring any unused study drug to the site at each visit.  Research 
personnel will count and record the number of used and unused study drug tablets at each 
visit. The study coordinator will question the patient regarding adherence to the dosing 
regimen, record the number of tablets and strengths returned, the date returned and determine 
treatment compliance before dispensing new medication to the study patient. Compliance 
below 80% will require counseling of the patient by study site personnel.  
 
5.5.2 Romidepsin 
Administration of trial medication will be documented by the investigator and/or trial staff 
as per institutional practice. The total volume of treatment infused will be compared to the 
total volume prepared to determine compliance with each dose administered. Compliance 
with trial treatment will be measured by number of Romidepsin infusion.  
 
 
6 TRIAL ASSESSMENT AND PROCEDURE  
6.1 
Overview 
The Schedule of Event (Table 5 and Table 6) summarizes the trial procedures to be performed 
at each visit and is divided into following.  
1. 
Screening (Day -28 to Day 0) 
2. 
On treatment procedures (C1D1 to C7D28) 
3. 
End of Treatment (C8D1 or within 7 days from the last dose) 
4. 
End of Study (Day +30 from the last dose) 
 
Individual trial procedures are described in detail below. It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. Multiple procedures may be scheduled at the same time point relative to 
Tenalisib. Priority should be given to PK collection at the time specified and vital signs 
should be performed prior to blood collections. 
 
6.2 
Informed Consent   
The investigator or qualified designee must obtain documented written 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 


Protocol No. RP6530+Romidepsin-1805 
                                                     Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 40 of 88 
subject’s legally acceptable representative’s dated signature on an IRB-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.   
 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/IEC’s 
approval/favorable opinion in advance of use. The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial. The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. Specifics about a trial 
and the trial population will be added to the consent form template at the protocol level. The 
informed consent will adhere to IRB/IEC requirements, applicable laws and regulations and 
Sponsor requirements. 
 
6.3 
Screening 
Written informed consent must be obtained ≤30 days prior to the initiation of trial treatment 
and before any protocol-specific procedures are performed. (The first day of trial treatment 
will be considered as C1D1.) Patients should be re-consented in the case that informed 
consent is obtained >30 days prior to the initiation of trial treatment. Screening vitals, 
laboratory tests, as described in the Schedule of Events, will be performed as per institutional 
practice and will be reviewed by the site PI/designee. The laboratory tests should be done 
≤7 calendar days prior to the initiation of trial treatment. Re-screening can be done at the 
discretion of PI. Scans and other investigations to document measurable disease should be 
performed within 28 days prior to C1D1. 
 
Lymphoma diagnosis should be made on the basis of morphology, immunohistochemistry, 
and flow cytometry reviewed by an experienced lymphoma pathologist. Appropriate, 
molecular studies should be considered to accurately categorize the lymphoma. For CTCL, 
the histopathologic diagnosis should be confirmed in a skin biopsy representative of current 
disease by a pathologist with expertise in cutaneous lymphoma. For Sezary patients, the 
diagnosis should be based on skin and blood criteria (defined as meeting T4 plus B2 criteria) 
(Appendix D). 
 
Clinical assessments of patients will include ECOG performance status (Appendix A), lymph 
nodes, organomegaly, and “B” symptoms. The staging of NHL/HL and CTCL patients will 
be done according to Ann Arbor (Appendix G) and ISCL/EORTC criteria (Appendix E) 
respectively [10]. CTCL patients will have half body global and up to 5 selected 
representative index lesions photographed at baseline.  
 
 
 
 


Protocol No. RP6530+Romidepsin-1805 
                                                     Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 41 of 88 
         Table 3: Summary of Key Assessments at Screening 
Procedures  
PTCL 
CTCL 
Lab investigation 
 
 
ECG 
 
 
Bone marrow biopsy  
 1 
In case of patients with blood 
involvement (B2)2  
Radiological assessment3  
 
In case of nodal/visceral 
involvement 
Skin assessment (mSWAT) 
- 
 
Skin biopsy  
- 
 
Skin photograph  
- 
 
Biomarker  
 
 
1. A bone marrow biopsy and/or aspirate should be collected ≤3 months prior to C1D1. 
2. A bone marrow biopsy will be done unless it has been shown to be negative within the 
last 6 months. 
3. The scan and other investigations to document measurable disease should be performed 
within 28 days prior to C1D1.  
 
During screening, active infection with HBV, HCV, CMV, EBV or HIV should be ruled out.  
To be considered negative for active infection, following algorithm will be used:  
• HBV: HBc antibody should be negative or if HBc antibody is positive, HBVDNA 
should be undetectable 
• HCV: HCV antibody should be negative or if HCV antibody is positive, HCVDNA 
should be undetectable 
• HIV: HIV antibody should be negative. (HIV 1/ 2 antibody should be negative unless 
positive result is considered false positive by PI) 
• EBV: Negative for anti-EBV VCA IgM antibody or if anti-EBV VCA IgG antibody is 
positive, EBV DNA should be negative. 
• CMV: Negative for anti-CMV IgM antibody or if positive anti-CMV IgG antibody is 
positive, CMV DNA should be negative. [Note: Carriers will be monitored per 
institutional guidelines.] 
Note: Patients who show evidence of hepatitis B infection (HBsAg positive [regardless of 
antibody status] or HBsAg negative but anti-HBc positive), need to be evaluated for initiation 
of HBV antiviral prophylaxis and should be closely monitored for HBV reactivation.  
  
6.3.1 Assignment of Subject Number 
All consented subjects who undergo at least one post-consent procedure will be given a 
unique subject number that will be used to identify the subject for all procedures that occur 
prior to enrollment. Each subject will be assigned only one subject number. Subject numbers 
must not be re-used for different subjects. Any subject who is screened multiple times will 
retain their original subject number assigned at the initial screening visit.  
 


Protocol No. RP6530+Romidepsin-1805 
                                                     Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 42 of 88 
6.3.2 Medical history   
Medical history will be obtained by the investigator or qualified designee. A comprehensive 
history includes but is not limited to age; sex; absence/presence of fevers to more than 101°F 
(38.3°C), chills, drenching night sweats, or unexplained weight loss more than 10% of body 
mass over 6 months; and history of malignancy. Fatigue, pruritus, and alcohol-induced pain 
should also be noted. 
 
6.3.3 Prior and Concomitant Medication Review 
Prior medication: The investigator/qualified designee will review prior medication use, 
including any protocol-specified washout requirement, and record prior medication taken by 
the subject within 28 days before starting the trial (i.e. C1D1). Treatment for the disease for 
which the subject has enrolled in the study will be recorded separately and not listed as a 
prior medication. 
 
Concomitant medication: The investigator or qualified designee will record medication, if 
any, taken by the subject during the trial.  
 
6.3.4 Prior Therapies Details  
The investigator or qualified designee will record all prior cancer treatments including 
systemic treatments, prior transplantation, radiation, and surgeries received for the treatment 
of TCL. 
 
6.3.5 Physical Examination 
Full physical examination: The investigator/qualified designee will perform a complete 
physical exam during the screening period and as defined in Schedule of Events. Physical 
examination will include lymph node and systemic examination (General Appearance, 
HEENT, neck, cardiovascular, lungs, abdomen, lymph nodes, genitourinary, extremities, 
neurological, skin, and musculoskeletal). Physical examination also includes measurement 
of accessible nodal groups and the size of the spleen and liver. Clinically significant 
abnormal findings should be recorded as medical history.  
 
Abbreviated (Directed) physical examination: For cycles that do not require a full 
physical exam per the Schedule of Events, the investigator or qualified designee will perform 
a directed physical exam as clinically indicated depending on assessment of tumor, prior to 
trial treatment administration. After the first dose of trial treatment new clinically significant 
abnormal findings should be recorded as AEs. 
 
6.3.6 Vital Signs  
Vital signs include temperature (oral/axillary), pulse, respiratory rate, weight and blood 
pressure and should be recorded as per institutional practice. Historical data can be used for 
height. Vitals will be done prior to the administration of study treatments (Pre-dose and Pre-
infusion), during infusion and post-infusion as applicable, at the time points specified below.  
• In the first cycle, vitals will be taken prior to the administration of study treatments (15 min 
before Tenalisib dose and 5 min prior to infusion). During the infusion, vitals should be 
done at every 15 min (± 5 min) during first hour and at every 30 min (± 10 min) for next 3 
hours and 1 hr (± 15 min) post infusion. All time points will be recorded in the CRF.  


Protocol No. RP6530+Romidepsin-1805 
                                                     Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 43 of 88 
• In subsequent cycles, vitals will be done as per the institutional practice. Pre-dose; and Pre- 
and Post-infusion vitals will be recorded in the CRF. 
• When slowing or re-starting an infusion due to an infusion reaction, vital signs should be 
monitored at every 15 minutes or as directed by the investigator until the infusion is 
completed and 15, 30 and 60 min post-infusion and longer if necessary until the subject is 
stabilized. In such case, the event of infusion reaction should be recorded as an adverse 
event.  
• The window periods for vitals will be ±5 min for 15 min interval time points during first 
hour of infusion; ±10 minutes for 30 min interval time points during the next three hours 
and ± 15 min for 1 hr post infusion time point.  
 
6.4 
Laboratory Investigations 
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 4. 
 
Table 4: Laboratory Tests for Hematology, Chemistry and Urinalysis 
Hematology  
Chemistry Panel I 
Chemistry Panel 
II 
Urinalysis 
Other  
Hematocrit  
Total bilirubin 
Blood glucose  
Blood  
Serum β-hCG 
Hemoglobin 
Alkaline 
phosphatase 
(ALP) 
Urea or blood urea 
nitrogen a 
Glucose  
Urine 
pregnancy 
test 
CBC with 
differentials 
Alanine 
aminotransferase (ALT) 
Creatinine 
Protein  
PT/INR 
Platelet count 
Aspartate 
aminotransferase (AST)  
Albumin 
Specific 
gravity  
Serology (Only at 
Screening) 
(Hepatitis 
B, 
Hepatitis C, HIV, 
EBV and CMV) 
WBC (Total and 
differentials) 
Lactate dehydrogenase 
(LDH) 
Total protein 
Microscopic 
examb 
Red blood cell 
count 
Gamma-glutamyl 
transferase (GGT) 
Total Cholesterol 
 
 
Absolute 
neutrophil count 
Sodium 
Triglyceride (TG) 
 
 
Absolute 
lymphocyte count 
Potassium  
LDL 
 
 
 
Calcium 
HDL 
 
 
 
Phosphorous 
TSH 
 
 
 
Bicarbonate or Carbon 
dioxide (CO2) 
T3 (Total or Free) 
 
 
 
Chloride  
T4 (free) 
 
 
 
Magnesium  
 
 
 
a Blood Urea Nitrogen is preferred; if not available Urea may be tested. 
b Microscopic exam, if abnormal results are noted 
 
Blood drawn for these tests will be specified in informed consent form (ICF). The 
investigations will be performed at each local laboratory. Additional details will be provided 
in the study-specific Laboratory Manual.  
 
Screening labs will be done within 7 calendar days prior to the initiation of trial treatment. 
If these initial examinations are obtained within 72 hours of Cycle 1 Day 1, the labs need not 
be repeated. Re-screening can be done at the discretion of PI. Scans and other investigations 


Protocol No. RP6530+Romidepsin-1805 
                                                     Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 44 of 88 
to document measurable disease should be performed ≤28 weeks prior to initiation of 
treatment.  
6.5 
12-Lead Electrocardiograms 
An ECG will be performed at the time points mentioned below table. Additional ECGs will 
be obtained if clinically indicated. A single ECG will be performed at all-time points unless 
specified. Triplicate ECGs only need to be performed at other time points to confirm the 
significant changes of single ECG (e.g. If QTcF > 450msec on single EKG at screening or 
>500 msec during treatment). All ECGs will be performed on local equipment. Window 
period of ± 5 minutes will be applicable to 30 min time point. For all time 1 hr time points, 
± 15 minutes window period will be applicable.   
 
Dose Escalation  
Days  
Time points  
Note 
Screening  
Within last 28 days  
- 
C1D1 
All PK matched time points 
(Pre-infusion (0), 1, 2, 3, 5, 7, 9, 10 
hrs). 
Time points are with respect 
to Romidepsin infusion.  
C1D8 
All PK matched time points 
(Pre-dose (0), 0.5, 1 (pre-infusion of 
Romidepsin), 2, 3, 4, 6, 8, 10, 11 hrs 
post-dose). 
Time points are with respect 
to Tenalisib dosing 
C1D15 
Before-infusion and immediately after 
infusion.  
Time points are with respect 
to Romidepsin infusion. 
Rest of the 
cycles (Day 1 
of each cycle)  
Before-infusion and immediately after 
infusion. 
Time points are with respect 
to Romidepsin infusion. 
 
Dose Expansion  
Days  
Time points  
Note 
Screening  
Within last 28 days  
- 
Day 1 of each 
cycle  
Before Romidepsin infusion. 
 
 
6.6 
Bone Marrow Biopsy 
• PTCL:  
A bone marrow biopsy and/or aspirate should be collected ≤3 months prior to C1D1 and/or 
to confirm a complete response to the study drug. If patient has negative bone marrow at 
baseline, there is no need to have it repeated to confirm CR. Additional biopsy will be 
obtained if clinically indicated.  
 
• CTCL patients with predominantly blood involvement (B2): 
Patients with predominantly blood involvement (B2) will have a bone marrow biopsy at 
screening (unless it has been shown to be negative within the last 6 months) and as indicated 
to confirm a complete response. 
 


Protocol No. RP6530+Romidepsin-1805 
                                                     Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 45 of 88 
6.7 
Radiological Evaluations 
Initial disease assessment by tumor imaging (baseline scan) must be performed within 28 
days prior to C1D1. The site investigator/designee must review radiological images to 
confirm the subject has measurable disease as defined in the inclusion criteria. Disease 
assessments or scans performed as part of routine clinical management are acceptable for use 
as the screening scan if they are of diagnostic quality and performed within 28 days prior to 
the first dose of trial treatment.  
 
• PTCL and CTCL patients with lymph node/visceral involvement:  
Computed tomography (CT) scan (chest/abdomen/pelvis/neck as appropriate) will be 
performed at screening for disease assessment. PET-CT is preferred for FDG-avid 
lymphomas. Other radiological evaluations (e.g. X-ray/MRI/USG) will be performed if 
warranted.   
 
• CTCL patients with skin and blood involvement:  
CT scan will be performed at screening for disease assessment.  
o In patients with clinically early disease (maximum/current T1-2N0M0B0-1), repeat scans 
should not be performed except in cases of an objective response (OR) in the skin. 
o In those patients with more advanced disease at baseline (TNMB > T1-2N0M0B0-1), CT 
scan should be performed at the time of PR and CR in the skin; any time there is a 
question of new or PD in the lymph nodes or viscera; and at end of study. 
 
6.8 
Skin Biopsy 
In CTCL patients, skin biopsy should be taken at screening, and to confirm a complete 
response. Biopsy should be performed at the most indurated area if only one biopsy. Skin 
biopsy will not be done in other patients.  
 
6.9 
Skin Photograph 
CTCL patients will have half body global and up to 5 selected representative index 
lesions photographed at screening (baseline), at the time of response (PR/CR/PD) and at 
other time points as required by the PI.  
 
6.10 Pharmacokinetic (PK) Assessments 
Blood samples will be collected for PK analysis of Tenalisib and its metabolites/Romidepsin 
in the Dose Escalation part of the study at the timepoints indicated in the below table. PK 
will not be performed in Dose Expansion. Blood will be collected, processed and stored at   
-70 °C at the site and shipped to the sponsor’s central bioanalytical laboratory: NorthEast 
Bioanalytical Laboratories, 925 Sherman Avenue, Hamden, CT 06514, USA. See 
laboratory manual for PK processing instructions.  
 
The window periods for PK blood collection will ±5 min for 30 min time points; ±10 minutes 
for one-hour time points up to 3 hrs (1-3 hrs); and ±15 minutes for subsequent one-hour time 
points (4-11 hrs).  
 
 
 
 


Protocol No. RP6530+Romidepsin-1805 
                                                     Rhizen Pharmaceuticals S.A. 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 46 of 88 
C1D1 
C1D8 
C2D1, C3D1, C4D1 
Romidepsin 
Tenalisib 
Romidepsin 
Tenalisib 
- 
0 (Pre-dose) 
- 
0 (Pre-dose) 
- 
0.5 
- 
- 
Pre-infusion 
1 
Pre-infusion 
- 
1 
2 
1 
- 
2 
3 
2 
- 
3 
4 
3 
- 
5 
6 
5 
- 
7 
8 
7 
- 
9 
10 
9 
- 
10 
11 
10 
- 
   All time points are in hours.  
Patient may be hospitalized on C1D1 and C1D8 at the discretion of the PI and site staff in 
order to facilitate multiple procedures (e.g. PK blood draws, ECGs) that required to be 
performed on C1D1 and C1D8. 
On C2D1, C3D1, C4D1, patients should consume their morning dose at the clinic after the 
pre-dose sample. 
 
6.11 Correlative /Exploratory Markers 
The analyses of correlative markers (e.g. CTACK, sILR2 (PTCL) and IL-30, IL-31 (CTCL) 
in plasma or blood are exploratory and will not be used to guide treatment decisions. During 
treatment, blood samples may be taken for correlative/exploratory marker evaluation in the 
dose escalation and expanded cohort of the study. Plasma aliquots will be prepared and shall 
be stored at below -700C until analysis of correlative markers. The decision to analyze the 
plasma samples will be taken at a later stage at the discretion of sponsor.  
 
6.12 End of Trial Treatment (EOT) Visit 
Post C8D1, patients experiencing clinical benefit with no evident disease progression will be 
given the opportunity to enroll in an open-label compassionate use study protocol and will 
be followed up. Excluding patients who participate in the compassionate use study protocol, 
all other patients will undergo the end-of-treatment (EOT) assessments within 7 days after 
the last dose of study drug or discontinuation from the study. Radiological assessment and 
bone marrow biopsy will not be performed if done earlier within 28 days. 
 
6.13 End of Study (EOS) Visit 
All patients must be followed up telephonically for adverse events for 30 calendar days after 
the last dose of study drug. In case of drug related SAE/AE or treatment discontinuation due 
to adverse event, the subjects will be followed till the resolution/stabilization of the AE or 
30 days after the last study dose whichever is the earlier


Protocol No. RP6530+Romidepsin-1805 
                                                        
Rhizen Pharmaceuticals SA 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018 
CONFIDENTIAL 
 
Page 47 of 88 
Table 5: Schedule of Events for Dose Escalation 
 
Screening  
Cycle 1  
Cycle 2 
Cycle 3 
Cycle 4-7 
EOT24 
/C8D1 
EOS25 
Day  
D-28 to 0 
D1 
D3 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D1 
D8 
D15 
D1 
- 
Window period  
-28 
0 
- 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
+7 
+30 
Study Days  
D-28 to 0 
1 
3 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
- 
- 
- 
197 
227 
Informed Consent1 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Demographics2 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Medical history3 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
Vitals4 
X 
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Height and weight5 
X 
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Complete Physical exam6 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
Abbreviated Physical exam6 
- 
X 
- 
X 
X 
- 
X 
X 
X 
- 
X 
X 
X 
X 
X 
X 
- 
- 
ECOG Performance Status 
X 
X 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
- 
X 
- 
Tumor staging  
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Laboratory assessment  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete blood count7 
X 
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Chemistry panel I8 
X 
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Chemistry panel II9 
X 
X 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
X 
- 
- 
X 
- 
Serology10  
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
PT and INR11 
X 
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Urinalysis (routine) 
X 
X 
- 
 
X 
- 
X 
- 
X 
- 
X 
- 
X 
X 
- 
X 
X 
- 
Pregnancy test12 
X 
X 
- 
- 
- 
- 
X 
- 
- 
- 
X 
- 
- 
X 
- 
- 
X 
- 
12-lead ECGs13 
X 
X 
- 
X 
X 
- 
X 
- 
- 
- 
X 
- 
- 
X 
- 
- 
X 
- 
Pharmacokinetic samples14 
- 
X 
- 
X 
- 
- 
X 
- 
- 
- 
X 
- 
- 
X 
- 
- 
- 
- 
Bone marrow biopsy15  
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 


Protocol No. RP6530+Romidepsin-1805 
                                                        
Rhizen Pharmaceuticals SA 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018 
CONFIDENTIAL 
 
Page 48 of 88 
Skin biopsy16  
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Disease assessment  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiological 
scan/imaging17 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
- 
X 
- 
mSWAT18 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
- 
X 
- 
Skin photographs19  
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Correlative markers20  
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
- 
- 
- 
Treatment administration  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tenalisib21 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
Romidepsin infusion22 
- 
X 
- 
X 
X 
- 
X 
X 
X 
- 
X 
X 
X 
X 
X 
X 
- 
- 
Drug compliance  
- 
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Safety evaluation  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE evaluation23 
X 
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAE evaluation  
X 
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication  
X 
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Foot notes: 
1. Patient should be re-consented, if informed consent is obtained >30 days prior to the initiation of trial treatment. The first day of Romidepsin administration 
will be considered the initiation of treatment (C1D1).  
2. Demographic profile will include age, sex and race. 
3. Detailed history will be taken at screening that includes history of cancer, past history, no of prior therapies and prior medication (in last 4 weeks); and 
other medical history. Any medical significant history at subsequent visit will be captured as adverse event.  
4. Vitals will be done prior to the administration of study treatments (Pre-dose and Pre-infusion), during infusion and post-infusion as applicable, at the time 
points specified above.  
• In the first cycle, vitals will be taken prior to the administration of study treatments (15 min before Tenalisib dose and 5 min prior to infusion). 
During the infusion, vitals should be done at every 15 min (± 5 min) during first hour and at every 30 min (± 10 min) for next 3 hours and 1 hr (± 
15 min) post infusion. All time points will be recorded in the CRF.  
• In subsequent cycles, vitals will be done as per the institutional practice. Pre-dose; and Pre- and Post-infusion vitals will be recorded in the CRF. 
• When slowing or re-starting an infusion due to an infusion reaction, vital signs should be monitored at every 15 minutes or as directed by the 
investigator until the infusion is completed and 15, 30 and 60 min post-infusion and longer if necessary until the subject is stabilized. In such case, 
the event of infusion reaction should be recorded as an adverse event.  
5. Weight will be measured at all visits. Height to be recorded at screening only; historical data is acceptable. 
6. Physical examination will include lymph node and systemic examination. Complete physical examination will be done at screening and EOT visits. At 
other visits, abbreviated examination (directed physical examination) will be done depending on the assessment of tumor. 


Protocol No. RP6530+Romidepsin-1805 
                                                        
Rhizen Pharmaceuticals SA 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018 
CONFIDENTIAL 
 
Page 49 of 88 
7. Complete blood count: Hb, complete blood count, total leucocyte and differential count and platelet count. Additional investigations will be performed if 
clinically indicated. Hematology must be done ≤7 days prior to C1D1. However, if these initial examinations are obtained within 72 hours of C1D1; 
they do not have to be repeated.      
8. Chemistry Panel I must be done ≤7 days prior to C1D1. However, if these initial examinations are obtained within 72 hours of C1D1; they do not have to 
be repeated. These tests will be performed at supplementary (unscheduled) visits if clinically indicated.       
9. Chemistry Panel II must be done ≤7 days prior to C1D1. However, if these initial examinations are obtained within 72 hours of C1D1; they do not have 
to be repeated. During treatment, the labs will be performed at C3D1 (± 1 days), C5D1 (± 1 days) and C8D1 (± 7 days) and/ or at the EOT. These tests 
will be performed at supplementary (unscheduled) visits if clinically indicated.       
10. Serology includes HIV, HBV, HCV and CMV. Historical evidence in last 12 weeks is acceptable.  
11. PT/INR: PT and INR test must be done ≤7 days prior to C1D1. However, if initial examination is obtained within 72 hours of C1D1; this do not have 
to be repeated. In case of abnormality, additional tests including aPTT to be done as per investigator discretion. This test will be performed at 
supplementary visits if clinically indicated.       
12. Pregnancy test is required for women of child bearing potential. A serum/urine pregnancy test will be performed at screening and C1D1 (within 72 
hours) of dosing. Urine pregnancy test will be performed at other visits as indicated. 
13. 12-lead ECG:  PK matching ECG will be done on C1D1 and C1D8. Please refer ECG table for detailed time points. Additional ECGs will be obtained 
if clinically indicated. Triplicate ECGs will be performed to confirm the significant changes of single ECG. Refer Section 6.5.  
14. PK: The blood will be collected for PK on following time points: C1D1: Pre-infusion (0), 1, 2, 3, 5, 7, 9, 10 hrs post-infusion. C1D8: Sampling with 
respect to Tenalisib dosing. Pre-dose (0), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 11 post-dose. Pre-dose sample will be taken on C2D1, C3D1 and C4D1. Patient will 
be hospitalized on C1D1 and C1D8 at the discretion of the site in order to facilitate multiple procedures (e.g. PK blood draws, ECGs) that required to 
be performed on C1D1 and C1D8. On C2D1, C3D1, C4D1, patients should consume their morning dose at the clinic after the pre-dose sample. Refer 
Section 6.10. 
15. A bone marrow biopsy: PTCL:  Bone marrow biopsy should be collected ≤12 weeks prior to C1D1 and/or to confirm a complete response to the study 
drug. If patient has negative bone marrow at baseline, there is no need to have it repeated to confirm CR. Additional biopsy will be obtained if clinically 
indicated. CTCL patients with predominantly blood involvement (B2) will have a bone marrow biopsy at screening (unless it has been shown to be 
negative within the last 6 months) and as indicated to confirm a complete response. 
16. Skin biopsy: In CTCL patients, skin biopsy should be performed at screening, and to confirm a complete response. Historical data of 12 weeks is 
acceptable.  
17. Radiological scan: In PTCL and CTCL patients with nodal and visceral involvement, PET and “diagnostic quality” CT scan will be performed at the 
time of screening within 28 days of screening. Following screening, CT scans should be repeated at C3D1 (± 7 days), C5D1 (± 7 days) and C8D1 (± 7 
days). PET should be done at C3D1 (± 7 days) and to confirm CR.  
18. Skin assessment: In all CTCL patients, mSWAT will be performed at the time of screening within 28 days of screening and at C3D1 (± 7 days), C5D1 
(± 7 days) and C8D1 (± 7 days). Disease response assessment will be performed at C3D1 (± 7 days), C5D1 (± 7 days) and C8D1 (± 7 days) and/ or at 
the EOT or as clinically indicated using mSWAT.  
19. Skin photograph: In CTCL patients, skin lesion photograph will be taken at screening, at the time of response (PR/CR/PD) and at other time points as 
required by the PI.  
20. Blood will be collected for biomarkers (e.g. sIL2R and CTACK for PTCL; CD30, IL-31 and IL-32 for CTCL).  
21. Tenalisib will be administered orally twice a day from Day 3 (C1D3) onward in 28-days of cycle for 7 cycles in absence of disease progression or 
toxicity warranting discontinuation of therapy. On the day of Romidepsin administration, the morning dose of Tenalisib should be given in clinic one 
hour prior to Romidepsin infusion. Tenalisib will be dispensed at the start of each cycle (C1D1, C2D1, C3D1 …). Only in Cycle 1, Tenalisib will be 


Protocol No. RP6530+Romidepsin-1805 
                                                        
Rhizen Pharmaceuticals SA 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018 
CONFIDENTIAL 
 
Page 50 of 88 
given starting from Day 3 (i.e. C1D3). Patients will be, therefore, be instructed to start the treatment on C1D3 and will be informed that they will receive 
Tenalisib for 25 days in the first cycle.  
22. Romidepsin will be administered as an intravenous infusion over 4 hours unless progression of disease or toxicity warranting discontinuation of therapy.  
23. All AEs regardless of seriousness or relationship to study drug should be recorded spanning from the informed consent drug until 30 calendar days after 
the last dose of study drug.  
24. Post C8D1, patient experiencing clinical benefit with no evident disease progression will be given the opportunity to enroll in an open-label 
compassionate use study protocol and will be followed up. Excluding patients who participate in compassionate use study protocol, all other patients 
will undergo the end-of-treatment (EOT) assessments within 7days after the last dose of study drug or discontinuation from the study.   
25. Patients should be followed for AEs for 30 calendar days after the last dose of study treatment. Telephonic follow up during this period is acceptable. 
All new AEs occurring during this period should be reported and followed until resolution unless, in the opinion of the investigator, the adverse event 
or laboratory abnormality/ies are not likely to improve because of the underlying disease.  
 
 
 
 


Protocol No. RP6530+Romidepsin-1805 
                                                        
Rhizen Pharmaceuticals SA 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018 
CONFIDENTIAL 
 
Page 51 of 88 
Table 6: Schedule of Events for Dose Expansion  
 
Screening 
C1 
C2 
C3 
C4-C7 
EOT22 
/C8D1 
EOS23 
Day  
D-28 to 0 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D1 
D8 
D15 
D1 
 
Window period  
-28 
0 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
+7 
+30 
Study Days  
D-28 to 0 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
- 
- 
- 
197 
227 
Informed Consent1 
X 
- 
- 
- 
 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Demographics2 
X 
- 
- 
- 
 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Medical history3 
X 
- 
- 
- 
 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
Vitals4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Height and weight5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  X 
- 
Complete Physical exam6 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
Abbreviated Physical exam6 
- 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
- 
- 
ECOG Performance Status 
X 
X 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
- 
X 
- 
Tumor staging  
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Laboratory assessment  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete blood count7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Chemistry panel I8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Chemistry panel II9 
X 
X 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
X 
- 
- 
X 
- 
Serology10  
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
PT and INR11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Urinalysis (routine) 
X 
X 
 
X 
 
X 
- 
X 
 
X 
 
X 
X 
 
X 
X 
- 
Pregnancy test12 
X 
X 
- 
- 
- 
X 
- 
- 
- 
X 
- 
- 
X 
- 
- 
X 
- 
12-lead ECGs13 
X 
X 
- 
- 
- 
X 
- 
- 
- 
X 
- 
- 
X 
- 
- 
X 
- 
Bone marrow biopsy14  
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 


Protocol No. RP6530+Romidepsin-1805 
                                                        
Rhizen Pharmaceuticals SA 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018 
CONFIDENTIAL 
 
Page 52 of 88 
 
 
Foot notes: 
1. Patient should be re-consented, if informed consent is obtained >30 days prior to the initiation of trial treatment. The first day of Romidepsin administration 
will be considered as C1D1.  
2. Demographic profile will include age, sex and race. 
3. Detailed history will be taken at screening that includes history of cancer, past history, no of prior therapies and prior medication (in last 4 weeks); and 
other medical history. Any medical significant history at subsequent visit will be captured as adverse event.  
4. Vitals will be done prior to the administration of study treatments (Pre-dose and Pre-infusion), during infusion and post-infusion as applicable, at the time 
points specified above.  
• 
In the first cycle, vitals will be taken prior to the administration of study treatments (15 min before Tenalisib dose and 5 min prior to infusion). During 
the infusion, vitals should be done at every 15 min (± 5 min) during first hour and at every 30 min (± 10 min) for next 3 hours and 1 hr (± 15 min) 
post infusion. All time points will be recorded in the CRF.  
• 
In subsequent cycles, vitals will be done as per the institutional practice. Pre-dose; and Pre- and Post-infusion vitals will be recorded in the CRF. 
• 
When slowing or re-starting an infusion due to an infusion reaction, vital signs should be monitored at every 15 minutes or as directed by the 
investigator until the infusion is completed and 15, 30 and 60 min post-infusion and longer if necessary until the subject is stabilized. In such case, 
the event of infusion reaction should be recorded as an adverse event.  
5. Weight will be measured at all visits. Height to be measured at screening only; historical data is acceptable.  
6. Physical examination will include lymph node and systemic examination. Complete physical examination will be done at screening and EOT visits. At 
other visits, abbreviated examination (directed physical examination) will be done depending on the assessment of tumor. 
Skin biopsy15  
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Disease assessment  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiological 
scan/imaging16 
X 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
- 
X 
- 
mSWAT17 
X 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
- 
X 
- 
Skin photographs18  
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Treatment administration  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tenalisib19 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
Romidepsin infusion20 
- 
X 
X 
X 
- 
X 
X 
X 
- 
X 
X 
X 
X 
X 
X 
- 
- 
Drug compliance  
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Safety evaluation  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE evaluation 21 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAE evaluation  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol No. RP6530+Romidepsin-1805 
                                                        
Rhizen Pharmaceuticals SA 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018 
CONFIDENTIAL 
 
Page 53 of 88 
7. Complete blood count: Hb, complete blood count, total leucocyte and differential count and platelet count. Additional investigations will be performed if 
clinically indicated. Hematology must be done ≤7 days prior to C1D1. However, if these initial examinations are obtained within 72 hours of C1D1; they 
do not have to be repeated.      
8. Chemistry Panel I: These tests must be done ≤7 days prior to C1D1. However, if these initial examinations are obtained within 72 hours of C1D1; they do 
not have to be repeated. These tests will be performed at supplementary (unscheduled) visits if clinically indicated.       
9. Chemistry Panel II: These tests must be done ≤7 days prior to C1D1. However, if these initial examinations are obtained within 72 hours of C1D1; they 
do not have to be repeated. During treatment, the labs will be performed at C3D1 (± 1 days), C5D1 (± 1 days) and C8D1 (± 7 days) and/ or at the EOT. 
These tests will be performed at supplementary visits if clinically indicated.       
10. Serology includes HIV, HBV, HCV and CMV. Historical evidence in last 12 weeks is acceptable.  
11. PT/INR: PT and INR test must be done ≤7 days prior to C1D1. However, if initial examination is obtained within 72 hours of C1D1; this do not have to 
be repeated. In case of abnormality, additional tests including aPTT to be done as per investigator discretion. This test will be performed at supplementary 
visits if clinically indicated.       
12. Pregnancy test is required for women of child bearing potential. A serum/urine pregnancy test will be performed at screening and C1D1 (within 72 hours) 
of dosing. Urine pregnancy test will be performed at other visits as indicated.  
13. 12-lead ECG: Please refer ECG table for detailed time points. Additional ECGs will be obtained if clinically indicated. Triplicate ECGs will be performed 
to confirm the significant changes of single ECG.  
14. A bone marrow biopsy: PTCL:  Bone marrow biopsy should be collected ≤12 weeks prior to C1D1 and/or to confirm a complete response to the study 
drug. If patient has negative bone marrow at baseline, there is no need to have it repeated to confirm CR. Additional biopsy will be obtained if clinically 
indicated. The CTCL patients with predominantly blood involvement (B2) will have a bone marrow biopsy at screening (unless it has been shown to be 
negative within the last 6 months) and as indicated to confirm a complete response. 
15. Skin biopsy: In CTCL patients, skin biopsy should be performed at screening, and to confirm a complete response. Historical data of 12 weeks is 
acceptable.  
16. Radiological scan: In PTCL and CTCL patients with nodal and visceral involvement, PET and “diagnostic quality” CT scan will be performed at the time 
of screening within 28 days of screening. Following screening, CT scans should be repeated at C3D1 (± 7 days), C5D1 (± 7 days) and C8D1 (± 7 days). 
PET should be done at C3D1 (± 7 days) and to confirm CR. Tumor imaging should remain consistent throughout study and should include those thought 
by investigator to best capture status of disease. Baseline scans, if already available as SOC within 28-days of screening is accepted as part of study 
protocol.  
17. Skin assessment: In all CTCL patients, mSWAT will be performed at the time of screening within 28 days of screening and at C3D1 (± 7 days), C5D1 (± 
7 days) and C8D1 (± 7 days). Disease response assessment will be performed at C3D1 (± 7 days), C5D1 (± 7 days) and C8D1 (± 7 days) and/ or at the 
EOT or as clinically indicated using mSWAT.  
18. Skin photograph: In CTCL patients, skin lesion photograph will be taken at screening, at the time of response (PR/CR/PD) and at other time points as 
required by the PI.  
19. Tenalisib will be administered orally twice a day in 28-days of cycle for 7 Cycles in absence of disease progression or toxicity warranting discontinuation 
of therapy. On the day of Romidepsin administration, the morning dose of Tenalisib should be given in clinic one hour prior to Romidepsin infusion. 
Patient will receive Tenalisib at the start of each cycle (C1D1, C2D1, C3D1 …). 
20. Romidepsin will be administered as an intravenous infusion over 4 hours unless progression of disease or toxicity warranting discontinuation of therapy.  
21. All AEs regardless of seriousness or relationship to study drug should be recorded spanning from the informed consent drug until 30 calendar days after 
the last dose of study drug.  


Protocol No. RP6530+Romidepsin-1805 
                                                        
Rhizen Pharmaceuticals SA 
Amendment 1, 30 November 2018 
Original Version : 1.0, 16 August 2018 
CONFIDENTIAL 
 
Page 54 of 88 
22. Post C8D1, patient experiencing clinical benefit with no evident disease progression will be given the opportunity to enroll in an open-label compassionate 
use study protocol and will be followed up. Excluding patients who participate in compassionate use study protocol, all other patients will undergo the 
end-of-treatment (EOT) assessments within 7 days after last dose of study drug or discontinuation from the study.   
23. Patients should be followed for AEs for 30 calendar days after the last dose of study treatment. Telephonic follow up during this period is acceptable. All 
new AEs occurring during this period should be reported and followed until resolution unless, in the opinion of the investigator, the adverse event or 
laboratory abnormality/ies are not likely to improve because of the underlying disease.  
 


Protocol No. RP6530+Romidepsin-1805 
                                                       Rhizen Pharmaceuticals SA 
Amendment 1: 30 November 2018 
Original version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 55 of 88 
7 ASSESSMENT OF SAFETY 
7.1 
Adverse Events 
The PI is responsible for collecting and reporting adverse events (see Section 7.1.2).  It is Sponsor 
responsibility to report relevant SAEs to the applicable regulatory body. 
 
7.1.1 Definitions of Adverse Events  
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational product, whether or not related to the investigational product.   
 
7.1.2 Recording of Adverse Events 
All adverse events of any patient during the course of the trial will be reported in the case report 
form, and the investigator will give his or her opinion as to the relationship of the adverse event to 
trial drug treatment (i.e., whether the event is related or unrelated to trial drug administration). If 
the adverse event is serious, it should be reported immediately to Sponsor. Other untoward events 
occurring in the framework of a clinical trial are also to be recorded as AEs (i.e., AEs that occur 
prior to assignment of trial treatment that are related to a protocol-mandated intervention, including 
invasive procedures such as biopsies, medication washout, or no treatment run-in). 
 
All AEs regardless of seriousness or relationship to Tenalisib/Romidepsin, spanning from the 
informed consent drug until 30 calendar days after the last dose of study drug, discontinuation or 
completion of protocol-specific treatment as defined by the protocol for that patient, are to be 
recorded in the electronic Case Record Form (eCRF).  
 
7.1.3 Handling of Adverse Events 
All adverse events resulting in discontinuation from the trial should be followed until resolution or 
stabilization. Patients must be followed for AEs for 30 calendar days after the last dose of study 
treatment. All new AEs occurring during this period must be reported and followed until resolution 
unless, in the opinion of the investigator, the adverse event or laboratory abnormality/ies are not 
likely to improve because of the underlying disease. In this case, the investigators must record his 
or her reasoning for this decision in the patient’s medical record and as a comment on the eCRF. 
After 30 days of completion of protocol-specific treatment or discontinuation, only AEs, SAEs, or 
deaths assessed by the investigator as treatment related are to be reported. 
 
7.2 
Adverse Event/Serious Adverse Event Causality Assessment  
Causality is assessing the relationship of the trial treatment to the adverse event. For this study, the 
causality assessment will be categorized as related and not related.  
 
• Related: All toxicities should be considered to be related to Tenalisib/Romidepsin 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. 
 


Protocol No. RP6530+Romidepsin-1805 
                                                       Rhizen Pharmaceuticals SA 
Amendment 1: 30 November 2018 
Original version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 56 of 88 
7.3 
Serious Adverse Events 
7.3.1 Definitions of Serious Adverse Events 
The definitions of serious adverse events (SAEs) are given below. The principal investigator is 
responsible for ensuring that all staff involved in the trial is familiar with the content of this section. 
 
An SAE or reaction is defined as any untoward medical occurrence that: results in death, is 
immediately life-threatening, requires at least a 24-hour in-patient hospitalization or prolongation 
of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital 
anomaly/birth defect. 
 
The definition of SAE also includes any important medical event. Medical and scientific judgment 
should be exercised in deciding whether expedited reporting is appropriate in other situations, such 
as important medical events that may not be immediately life-threatening or result in death or 
hospitalization, but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the previous definition.  These should also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. Progression of malignancy (including fatal 
outcomes), if documented by use of appropriate method (for example, as per Lugano 
classification 2014), 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 in unit or short stay to facilitate PK blood draws 
• 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 SAE Reporting by Investigators 
It is important to distinguish between “serious” and “severe” adverse events, as the terms are not 
synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need not 
necessarily be considered serious.  For example, nausea which persists for several hours may be 
considered severe nausea, but may not be considered an SAE.  On the other hand, a stroke which 
results in only a limited degree of disability may be considered only a mild stroke, but would be 
considered an SAE. Severity and seriousness should be independently assessed when recording 
AEs on the eCRF and SAEs on the SAE Report Form. 
 
Adverse events classified by the treating investigator as serious require expeditious handling and 
reporting to sponsor in order to comply with regulatory requirements.  Serious adverse events may 


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occur at any time from the signing of the informed consent form through the 30-day follow-up 
period after the last trial treatment. Sponsor/sponsor representative must be notified of all SAEs, 
regardless of causality, within 1 day of the first knowledge of the event by the investigator.   
 
To report an SAE, the SAE Report Form should be completed with the necessary information.  All 
SAEs occurring from the signing of consent until 30 calendar days of last trial treatment must be 
reported to the Sponsor as SAEs on the SAE Report and followed until resolution (with autopsy 
report if applicable). 
 
Deaths and other SAEs occurring >30 calendar days after last trial treatment that are deemed related 
to Tenalisib/Romidepsin must be reported as SAEs on the SAE Report within 1 day of first 
knowledge of the event by the treating physician or research personnel (with an autopsy report if 
available). Deaths occurring >30 calendar days after last trial treatment and not attributed to trial 
treatment (e.g., disease progression) need not be reported as SAEs, but simply captured on the 
appropriate eCRF. 
 
The SAE Report Form should be sent to the sponsor/sponsor representative via fax or e-mail within 
24 hours of becoming aware of the event. The detailed SAE reporting process will be reviewed 
with sites during the site initiation visit as well as provided on the SAE report itself. Transmission 
of the SAE report should be confirmed by the site personnel submitting the report. Follow-up 
information for SAEs and information on non-serious AEs that become serious should also be 
reported to Sponsor as soon as it is available; these reports should be submitted using the SAE 
Report Form.   
 
Investigators must report SAEs and follow-up information to their responsible IRB/IEC according 
to the policies of the responsible IRB/IEC. 
 
7.3.3 Sponsor’s SAE Reporting Requirements 
Sponsor/Sponsor representative is responsible for reporting relevant SAEs to the competent 
authority, other applicable regulatory authorities, and participating investigators, in accordance 
with ICH guidelines, FDA regulations, and/or local regulatory requirements. 
 
Sponsor/sponsor representative is responsible for reporting unexpected fatal or life-threatening 
events associated with the use of the trial drugs to the regulatory agencies and competent authorities 
via telephone or fax within 7 calendar days after being notified of the event.   
 
The Sponsor will report all related, unexpected SAEs, including non-death/non-life-threatening 
related unexpected SAEs associated with the use of the trial medications to the FDA by a written 
safety report within 15 calendar days of notification. Reporting to the IRB/IEC will be done 
according to institutional policy. 
 
7.4 
Recording of AE and SAE 
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on 
the SAE Report Forms and AE eCRF. Avoid colloquialisms and abbreviations. All AEs, including 
those that meet SAE reporting criteria, should be recorded on the AE eCRF; AEs that meet the 


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definition of an SAE should additionally be reported following the procedures noted in above 
sections.  
 
7.4.1 Diagnosis vs. Signs and Symptoms 
All AEs should be recorded individually in the patient’s own words (verbatim) unless, in the 
opinion of the Coordinating Investigator or designated physician, the AEs constitute components 
of a recognized condition, disease, or syndrome.  In the latter case, the condition, disease, or 
syndrome should be named rather than each individual sign or symptom.  If a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at the time 
of reporting, each individual event should be recorded as an AE or SAE as appropriate on the 
relevant form(s) (SAE Report Form and/or AE eCRF). If a diagnosis is subsequently established, 
it should be reported as follow-up information is available. If a diagnosis is determined subsequent 
to the reporting of the constellation of symptoms, the signs/symptoms should be updated to reflect 
the diagnosis. 
 
7.4.2 Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points. Such events should only be recorded once on the SAE Report Form and/or the 
AE eCRF, irrespective of severity. (E.g. If a persistent AE becomes more severe or lessens in 
severity, it should be recorded once with highest grade of severity on a SAE Report Form and/or 
AE eCRF).   
A recurrent AE is one that occurs and resolves between patient evaluation time points, and 
subsequently recurs. All recurrent events should be recorded separately on an SAE Report Form 
and/or AE eCRF. 
 
7.4.3 Abnormal Laboratory Values 
Any grade 3 or 4 laboratory abnormalities or any clinically significant grade 1 or 2 hematology or 
biochemistry laboratory value(s) should be recorded as an AE. Isolated laboratory abnormality 
without clinical significance should not be captured as AE if confirmed by the investigator. If an 
abnormal laboratory value or vital sign is associated with clinical signs and/or symptoms, the sign 
or symptom should be reported as an AE, and the associated laboratory value or vital sign should 
be considered additional information that must be collected on the relevant eCRF. If the laboratory 
abnormality is a sign of a disease or syndrome, only the diagnosis needs to be recorded on the SAE 
Report Form or AE eCRF. 
 
7.4.4 Deaths 
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
investigator solely to progression of disease will be recorded on the “Trial Discontinuation” eCRF 
and should not be reported as a SAE. All other on- trial deaths, regardless of attribution, will be 
recorded on an SAE Report and expeditiously reported to the Sponsor. 
 
When recording a serious adverse event with an outcome of death, the event or condition that 
caused or contributed to the fatal outcome should be recorded as the single medical concept on the 
SAE report and Adverse Event page of the eCRF. If the cause of death is unknown and cannot be 
ascertained at the time of reporting, record “Death NOS” on the CRF Adverse Event page.  
 


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7.4.5 Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization of >24 hours or prolonged hospitalization should be 
documented and reported as an SAE unless specifically instructed otherwise in this protocol. There 
are some hospitalization scenarios that do not require reporting as an SAE when there is no 
occurrence of an AE. (See section 7.3)  
 
7.4.6 Pre-existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the trial.  Such conditions 
should be recorded on the General Medical History eCRF. A pre-existing medical condition should 
be recorded as an AE or SAE only if the frequency, severity, or character of the condition worsens 
during the trial. When recording such events on an SAE Report Form and/or AE eCRF, it is 
important to convey the concept that the pre-existing condition has changed by including applicable 
description. 
 
7.4.7 Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
Pregnancy, abortion, birth defects, and congenital anomalies are events of special interest.  Please 
refer to pregnancy Section 7.5.1 for specific instructions. 
 
7.4.8 New Cancers 
The development of a new primary cancer should be regarded as an AE and will generally meet at 
least one of the serious criteria. New primary cancers are those that are not the primary reason for 
the administration of the study treatment and have developed after the inclusion of the patient into 
the study. They do not include new lesions of the original cancer. Symptoms of metastasis or the 
new lesions itself should not be reported as an AE/SAE, as they are considered to be disease 
progression. 
 
7.4.9 Lack of Efficacy 
When there is deterioration in the condition for which the study treatment is being used, there may 
be uncertainty as to whether this is lack of efficacy or an AE. In such cases, unless the sponsor or 
reporting physician considers the study treatment contributed to the deterioration of the condition, 
the deterioration should be considered lack of efficacy and not an AE. 
 
7.5 
Protocol-Defined Events of Special Interest 
The following are events of special interest, and will need to be reported expeditiously. 
 
7.5.1 Pregnancy, Abortion, Birth defects/Congenital anomalies 
Female patients who are not of child-bearing potential (see Appendix B) and female patients of 
child-bearing potential who have a negative pregnancy test within 72 hours prior to C1D1 are 
eligible for the study. Female patients of child-bearing potential (see Appendix B)), and all male 
partners must consent to use a medically acceptable method of contraception throughout the study 
period and for 4 weeks after the last dose of Tenalisib. An approved barrier method of contraception 
must be discussed with the investigator and documented in source note.    
 
During the course of the trial, all female patients of childbearing potential and pregnant partner of 
male subjects must contact the treating investigator immediately if they suspect that they may be 
pregnant (a missed or late menstrual period should be reported to the treating investigator).   


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If an investigator suspects that a patient may be pregnant prior to administration of trial drug(s), 
the trial drug(s) must be withheld until the result of the pregnancy test is confirmed. If a pregnancy 
is confirmed, the patient must not receive any trial drug(s), and must be discontinued from the trial. 
The outcome of the pregnancy will be monitored as outlined in Appendix B. 
 
If an investigator suspects that a patient may be pregnant after the patient has been receiving trial 
drug(s), the trial drug(s) must immediately be withheld until the result of the pregnancy test is 
confirmed. If a pregnancy is confirmed, the trial drug(s) must be immediately and permanently 
stopped, the patient must be discontinued from the trial, and the investigator must notify the 
Medical Monitor and Sponsor Representative as soon as possible. If a patient becomes pregnant 
while enrolled in the trial, a Pregnancy Form should be completed and faxed to the Sponsor. The 
outcome of the pregnancy will be monitored as outlined in Appendix B. 
    
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be 
expeditiously reported as an SAE, using the previously described process for SAE reporting. A 
Pregnancy Form should also have been previously completed, and will need to be updated to reflect 
the outcome of the pregnancy. 
 
7.5.2 Overdose 
An overdose is defined as accidental or intentional administration of any dose of product that is 
considered both excessive and medically important. For purposes of this trial, an overdose will be 
defined as any dose exceeding the proposed dose of Tenalisib (e.g. > 400 mg in first cohort) and/or 
prescribed dose for Romidepsin.   
 
Symptomatic and non-symptomatic overdose must be reported in the CRF.  Any accidental or 
intentional overdose with the trial treatment that is symptomatic, even if not fulfilling a seriousness 
criterion, is to be reported to the Sponsor immediately as an AE. All symptomatic overdose, 
fulfilling a seriousness criterion, is to be reported as an SAE as per the SAE reporting procedure. 
For patients who experience overdose, treatment should consist of supportive therapy. A decision 
to interrupt treatment or dose reduction to be taken depending on the symptoms.  
 
7.6 
 Dose-Limiting Toxicity  
All toxicities should be considered to be related to either Tenalisib/ Romidepsin combination or 
to either Tenalisib or Romidepsin individually unless there is a clear alternative explanation.  
Toxicity will be considered dose-limiting if it occurs during the first cycle (28 days) treatment 
and is considered related to the combination. Toxicity will be assessed utilizing the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. Dose-
limiting toxicities are defined as the following: 
 
7.6.1 Hematological DLTs 
• Grade 4 neutropenia that does not resolve to ≤ Grade 3 within 14 days with supportive treatment 
(e.g. growth factors) OR Grade ≥3 Febrile neutropenia (ANC <1000/µL with fever >38.5ºC 
[101ºF] that does not resolve to ≤ Grade 2 within 14 days with supportive treatment. 


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• Grade 4 thrombocytopenia that does not resolve to ≤ Grade 3 within 14 days with supportive 
treatment OR Grade ≥3 thrombocytopenia associated with Grade >2 bleeding that does not 
resolve to ≤ Grade 2 within 14 days with supportive treatment. 
 
7.6.2 Non-Hematological DLTs 
• Grade ≥3 non-hematologic toxicity that could not be controlled or prevented by supportive care 
including corticosteroids with exception of:  
• Grade ≥3 ALT/AST elevation that resolves to ≤ Grade 2 within 14 days; 
• Grade ≥3 diarrhea that improves ≤ Grade 2 within 48 hours or Grade ≥3 diarrhea in patients 
who have not received optimal treatment with anti-diarrhoeal drugs.  
• Grade ≥3 vomiting in patients who have not received the highest therapeutic dose of 
antiemetics (e.g. steroids, 5HT3 antagonists, prochlorperazine, lorazepam) 
• Single episode of Grade ≥3 infusion reaction. 
• Grade 3 nausea, Grade 3 asthenia or Grade 2 alopecia.  
• Treatment delay of ≥14 days due to unresolved toxicity. 
Adverse events meeting the above definitions but unrelated to study drug will not be considered 
DLTs. In some instances (e.g. in case of pre-existent Grade 2 toxicity), an event may fall within 
the protocol definition of a DLT but will not be considered a DLT (i.e., not clinically 
meaningful/significant or relevant to the combination). In such cases, the SRC will thoroughly 
review the event, supporting data, and the reasons for not considering the event a DLT will be 
clearly documented with supporting rationale. Conversely, other events which do not meet the 
definition of a DLT but are concerning to the SRC may be considered as DLTs. 
 
7.6.3 Determination of Dose-limiting toxicity 
The patient population used for determination of MTD will consist of patients who have met the 
minimum safety evaluation requirements of the study, and/or who have experienced a DLT. The 
data of at least 3 patients will be required for DLT assessment. 
• DLT assessment period will be 28-days (inclusive) (will begin on C1D1 and end on C2D1), 
unless extended by the medical monitor.  
• Patients must have been treated with at least 2 doses of Romidepsin and minimum 14 days 
with Tenalisib in the first cycle to be considered eligible for safety assessment unless 
identified to have a DLT.  
• Patients experiencing DLT after initiating combination will be considered evaluable 
regardless of the number of doses received (Please note Romidepsin alone will be 
administered on Day 1, therefore patient will not be considered for MTD assessment if 
patient develops DLT on these days).  
If a patient withdraws from the study during Cycle 1 due to any reason other than DLT (e.g. 
disease progression or consent withdrawal) and does not meet the minimum requirements for 
inclusion in the MTD-determining population described above will be replaced.  
 
7.6.4 Maximum Tolerated Dose (MTD) 
The MTD is the highest dose of the combination at which 0 of 3 patients or 1 of 6 patients 
experience a DLT during 1 cycle (28 days) of therapy. If 2 or more patients in a dosing group 
experience a DLT, the MTD has been exceeded. 
 


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7.7 
 Dose Modifications 
All dose modifications are graded by the CTCAE v5.0.  
Note:  If cytopenia events are deemed related to the underlying disease rather than either 
Tenalisib or Romidepsin, dose reduction will be done as per the investigator’s discretion. 
Patients who experience either a DLT or an adverse event meeting DLT criteria (that occurs after 
the DLT assessment window) will be allowed to delay dosing in order to recover from the toxicity. 
Patients may resume Tenalisib, provided that the toxicity has resolved to Grade ≤2 or baseline. If 
study drug is delayed >2 weeks due to drug toxicity, treatment initiation should be discussed and 
agreed with the Medical Monitor. 
 
Dose reductions will be permanent. A dose re-escalation are not permitted for patients who 
previously had a dose reduction. Holidays from study drug are discouraged. Any patient in whom 
similar toxicity recurs at the reduced dose should be discontinued from further Tenalisib treatment. 
Note: In exceptional case, a patient may be allowed following a careful assessment of benefit and 
risk by the investigator and with approval from the Medical Monitor. 
 
7.7.1 Criteria for Re-Starting Tenalisib after Drug toxicity 
Treatment continuation in the study is at the discretion of the treating Investigator. In the absence 
of unacceptable toxicities or disease progression, patients may continue treatment with Tenalisib 
as long as:  
• 
Absolute neutrophil count has returned to baseline, or >750/µL.  Platelet count is >50,000/µL.  
• 
Recovered from grade 3-4 non-hematologic toxicity to grade 2 or baseline (excluding 
alopecia). Treatment may be delayed for up to 2 weeks to recover from toxicity.  
• 
No clinical or radiographic evidence of disease progression.  
• 
If treatment is delayed > 2 weeks due to toxicity, because of an adverse event, treatment 
initiation should be discussed and agreed with the Medical Monitor. 
 
7.7.2 Dose modifications 
The dose modification guidelines are intended to be applied when the investigator determines 
the events to be related to either one of the investigational product.  
• In case the investigator determines the events to be related to Romidepsin, Tenalisib can be 
continued depending on toxicity at discretion of investigator.  
• Similarly, in case the investigator determines the events to be related to Tenalisib, 
Romidepsin can be continued depending on toxicity at discretion of investigator.  
• In case the event is possibly related to Romidepsin as well as Tenalisib, the most conservative 
approach of dose modification should be used.  
 
 


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7.7.2.1 Tenalisib Dose Modifications for Hematologic Toxicity 
The dose modification guidelines are intended to be applied when the investigator determines 
the events related to Tenalisib.  
 Table 7: 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. Restart Tenalisib when the event resolved 
to ≤ Grade 2 or baseline. 
Grade 4  
0.5 x 109 /L<ANC 
First incidence: Hold* dose until resolved to ≤ Grade 2 or baseline, 
Restart Tenalisib at one dose lower . 
Subsequent occurrence: Hold dose until resolved to ≤ Grade 2 or 
baseline, consider growth factor support. 
Discontinue if further dose modification required. 
Grade 3 Febrile neutropenia  
ANC <1000/mm3 with a single 
temperature of > 38.3 0C (101 0F) 
or a sustained temperature of ≥ 38 
0C (100.4 0F) for more than one 
hour. 
Hold* dose until resolved to ≤ Grade 2 or baseline, consider growth factor 
support, then restart Tenalisib at one dose lower .  
Thrombocytopenia 
Grade 3 (50.0 X 109 /L< PLT ≥ 
25.0 X 109 /L) 
Maintain dose level. 
Monitor ANC at least weekly. Restart Tenalisib when the event resolved 
to ≤ Grade 2 or baseline. 
Grade 4  
25.0 X 109/L< PLT 
Or thrombocytopenia that requires 
platelet transfusion 
1st occurrence: Hold** dose until to ≤ Grade 2 or baseline, Restart 
Tenalisib at one dose lower. 
Subsequent Occurrences: Hold dose until to ≤ Grade 2 or baseline, 
consider platelet transfusion as necessary.  
Discontinue if further dose modification required. 
*If study drug is delayed >2 weeks because of an adverse event, treatment strategy should be discussed with medical 
monitor. 
** Patient receiving concomitant medication (e.g. anticoagulants, anti-platelets, aspirin, or low molecular weight 
heparin) must be discussed with the medical monitor for continued management. 
 
 
Table 8: Dose Modifications for Non-Hematologic Toxicities  
NON-HEMATOLOGIC  
Action to be Taken 
Renal* 
If serum creatinine is Grade 3 (>3 x baseline or >3 x ULN), hold dose 
until ≤ grade 2. Monitor serum creatinine at least twice a week until 
resolution to ≤ grade 2, and then at least one week until it resolves to ≤ 
grade 1. 
Hepatic* 
Transaminitis  
Grade ≥ 1 Transaminitis (ALT/AST > 1-3 X ULN):  
• 
Maintain Tenalisib dose and initiate prednisone 40 mg daily.  


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• 
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):  
• 
Withhold Tenalisib and monitor ALT/AST twice a weekly until Grade 
1; restart Tenalisib at one dose lower. . 
• 
Initiate prednisone 1 mg/kg in case no improvement with 
discontinuation of Tenalisib in 1 week.  
• 
Monitor ALT/AST twice a weekly until Grade 1; restart Tenalisib at 
one dose lower. and taper steroid.  
• 
If no immediate response to steroids within 7 days, initiate 
mycophenolate mofetil.                                   
• 
In case of recurrence of transaminitis at reduced doses, discontinue 
Tenalisib permanently after assessing risk versus benefit.  
 
Grade ≥ 4 Transaminitis (ALT/AST >20 X ULN):  
• 
Tenalisib should be permanently discontinued. 
 
Bilirubin: 
• 
Grade ≥ 2 (> 1.5-3 X ULN): Maintain Tenalisib dose. Monitor at 
least weekly until ≤ 1X ULN 
• 
Grade ≥ 3 (> 3-10 X ULN): Withhold Tenalisib. Monitor at least 
weekly until bilirubin is≤ 1X ULN; restart Tenalisib at one dose 
lower. 
• 
Grade ≥ 4 (> 10 X ULN): Discontinue Tenalisib permanently 
Infection  
Grade 3 or higher sepsis or pneumonia 
• 
Interrupt Tenalisib until infection has resolved. 
Diarrhea  
Moderate:  
• 
Maintain Tenalisib dose. Monitor at least weekly until resolved. 
Severe diarrhoea or hospitalization 
• 
Withhold Tenalisib dose. Monitor at least weekly until resolved. 
• 
Restart Tenalisib at one dose lower . 
Life threatening diarrhoea  
• 
Discontinue Tenalisib permanently. 
Cardiac 
If a QTcF >500 msec has been demonstrated, hold dose. 
The patient will be monitored hourly with ECGs until the QTcF <500 msec 
and the QTcF has returned to “<30 msec from baseline”. Immediate 
attention to potassium and magnesium and other clinical factors such as 
oxygenation and ischemia should be addressed.   
All cardiac events should be treated as per the local standard of care and 
referral to a specialist if clinically indicated. Any final decisions concerning 
dose modifications or permanently discontinuing the patient from study drug 
due to QTcF prolongation will occur after discussion with medical monitor. 
OTHER NON-
HEMATOLOGIC  
Action to be Taken 
Grade 3/4 CTCAE  
First occurrence:  
Hold* dose until toxicity Grade ≤2; restart Tenalisib at one dose lower.  
Subsequent Occurrences: Hold dose until to ≤ Grade 2 or baseline.  
Discontinue if further dose modification required. 


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* If study drug is delayed >2 weeks because of an adverse event, treatment strategy should be discussed with 
medical monitor. 
 
7.7.3 Romidepsin Dose Modifications  
If toxicity, in the opinion of the investigator, is attributable to Romidepsin, the guideline for 
Romidepsin dose modification should be followed. Final discretion is with the treating investigator 
in regards to aggressive dose reductions, as well as the number of dose reductions.  
 
7.7.3.1 Hematologic Toxicity 
• Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed 
until the specific cytopenia returns to ANC ≥1.5×109/L and platelet count ≥75×109/L or 
baseline, then therapy may be restarted at same dose. 
• Grade 4 febrile (≥ 38.5ºC) neutropenia or thrombocytopenia that requires platelet transfusion: 
Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤ Grade 1 
or baseline, and then the dose should be permanently reduced to 10 mg/m2 or lower dose. 
 
7.7.3.2 Non-Hematologic Toxicities 
Nonhematologic toxicities except alopecia  
• Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤ 
Grade 1 or baseline, then therapy may be restarted at same dose. If Grade 3 toxicity recurs, 
treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline and 
the dose should be permanently reduced to 10 mg/m2 or lower.  
• Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 
1 or baseline, then the dose should be permanently reduced to 10 mg/m2 or lower dose.  
• Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction.  
 
 
8 ASSESSMENT OF EFFICACY 
8.1 
Specification of the Efficacy Parameters 
Evaluable for objective response:  Patients who have had a pre-treatment baseline efficacy 
evaluation and at least one post-treatment efficacy evaluation will be considered evaluable for 
response. “Investigator assessed response” will be used in the study. These patients will have 
their response classified according to the definitions stated below.  
 
Disease parameters:  
• Measurable disease: Measurable lesions are defined as those that can be accurately measured 
in at least two dimensions with conventional techniques (PET/CT, MRI, x-ray) or as >1.5 cm 
with spiral CT scan. All tumor measurements should be recorded in centimeters.   
 
• Non-measurable disease (evaluable disease): All other lesions (or sites of disease) including 
small lesions, (<1 cm using spiral CT scan) are considered non-measurable disease. Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis, and cystic 
lesions are all non-measurable. 
 
 
• Target lesions: All measurable lesions up to a maximum of 6 lesions total, representative of all 
involved organs, should be identified as target lesions and recorded and measured at baseline. 


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Target lesions should be selected on the basis of their size (lesions with the longest SPD 
diameter), and the highest SUV avidity (high SUV lesions may be prioritized even if not the 
largest lesions, and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). A baseline sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum 
diameters. The baseline sum of the diameters will be used as reference to further characterize 
any objective tumor regression in the measurable dimension of the disease. 
 
• Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over 
and above the 6 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
Evaluation of best objective response: The best objective response is the best response recorded 
from the start of the treatment until disease progression/recurrence.  
 
8.2 
Response Evaluations and Measurements 
In all patients (PTCL and CTCL), the response will be assessed approximately at 8 weeks interval 
for the first two assessments [(e.g. C3D1 (± 7 days), C5D1 (± 7 days)] and then at C8D1 (± 7 days) 
and/ or at the EOT or as clinically indicated (if clinical progression is suspected).  
 
• PTCL  
PTCL patients will be evaluated according to Lugano classification Cheson 2014)[16] (Appendix C) 
using the CT scan. PET-CT will be preferred for FDG-avid lymphomas. The modality chosen 
should be the same throughout the duration of the study. In addition, PET-CT will be performed at 
C3D1 (± 7 days) and to confirm CR. If PET and CT scan at Screening are negative for disease 
involvement in the neck, subsequent CT scans may not include neck. If PET and CT scans at 
Screening are positive for disease involvement of the neck, subsequent CT scans must include neck. 
Disease assessments and imaging should not be delayed for delays in cycle starts.  Disease 
assessments and imaging should be continued until documented disease progression, the start of 
new anti-cancer treatment, withdrawal of consent, death, or the end of the study, whichever occurs 
first.  
 
Each participating site will be responsible for radiological review and confirmation of response as 
per standard efficacy guidelines. The frequency outlined is the minimum required for study 
participation. Patients who progress according to the corresponding criteria will receive no further 
treatment. Patients who respond to the treatment (i.e., CR, PR or SD) may remain on trial. All 
disease specific assessments are to be completed as applicable to disease type.  
 
• CTCL:  
CTCL patients will be evaluated as per modified Severity Weighted Assessment Tool (mSWAT) 
(Appendix F). [17]  Additionally, CT scan will be done in the CTCL patients with lymph node and 
visceral involvement. CTCL patients with subcutaneous lesions which cannot be measured by 
mSWAT will be assessed by change in PET-CT avid lesions. Bone marrow biopsy will be 
performed in patients with B2 blood involvement. In these patients, Sezary cell count will be 
quantified by flow cytometry or morphology in blood/bone marrow. 


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In CTCL patients with other than presumed stage IA disease, or selected patients with limited T2 
disease and the absence of adenopathy or blood involvement, CT scans of chest, abdomen, and 
pelvis alone ± FDG-PET scan will be done to further evaluate any potential lymphadenopathy, 
visceral involvement, or abnormal laboratory tests. MRI may be substituted if clinically indicated.  
 
9 STATISTICAL METHOD AND CONSIDERATIONS   
This section describes the statistical methods to be used to analyze efficacy and safety. These 
methods may be revised and updated due to reasons such as regulatory requirements or need for 
further clarifications. The final analysis plan will be documented in a formal statistical analysis 
plan (SAP) that must be finalized before database lock. The SAP will include details on how 
variables will be derived, how missing data will be handled, and how data will be presented as well 
as the details on statistical methods to be used for safety and efficacy analyses. The final clinical 
study report will discuss deviations from the SAP, if any. 
 
9.1 
General Considerations 
Unless otherwise stated, all statistical analyses will be performed using a two-sided hypothesis test 
at the overall 5% level of significance.  The primary efficacy endpoint for the Phase II trial will be 
evaluated at a one-sided 5% level.  No adjustment for Type I error rate will be required because 
the study has only one primary endpoint with one comparison.  P-values will be rounded to three 
decimal places.  If a p-value is less than 0.001 it will be reported as “<0.001”.  
 
Continuous data will be described using the following descriptive statistics: n, mean, median, 
minimum and maximum. Data will be displayed in all listings sorted by phase, group and patient 
number.  When count data are presented, the percentage will be suppressed when the count is zero 
in order to draw attention to the non-zero counts.  A row denoted “Missing” will be included in 
count tabulations where necessary to account for dropouts and missing values.  Unless otherwise 
specified, the denominator for percentages will be the number of patients with a non-missing 
assessment in a given treatment group within the analysis population of interest. 
All statistical analyses will be performed using SAS 9.1 or higher. 
 
9.2 
Determination of Sample Size 
Part 1: In Dose Escalation, three patients per cohort are considered appropriate for the assessment 
of overall safety and tolerability and for providing adequate confidence for dose escalation. No 
formal sample size and power analysis is done. Accordingly, total 2-18 patients will be enrolled in 
3 escalating cohorts unless additional dose levels are required to reach MTD/ optimal dose. Optimal 
dose will be determined by the SRC. 
 
Part 2:  Total 24 patients with relapsed/refractory TCL will be enrolled in two groups (12 patients 
in each group). Twelve patients per group is considered appropriate for assessment of preliminary 
anti-tumor activity of the combination. However, the SRC may modify the sample size due to 
unforeseen clinical situations.  
 
9.3 
Study Population 
The following 3 analysis populations are planned for this study:  


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• Modified Intent-to-Treat Population (mITT): the mITT is the primary efficacy analysis 
population and will include data from all patients who received at least 1 dose of study 
medication and provide at least 1 post-baseline efficacy assessment.  
• Per-Protocol (PP) Population: the PP Population is a subset of the modified Intent-to-Treat 
Population and will include patients without major protocol deviations.  
• Safety Population: The Safety Population will include all subjects who receive at least 1 
dose of the study drug. 
Membership in the analysis populations will be determined before database lock. 
 
9.4 
Statistical Analysis 
9.4.1 Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized using descriptive statistics for 
continuous variables, and frequencies and percentages for categorical variables. 
 
9.4.2 Safety Analyses 
The safety endpoints will include: 
• Incidence of DLTs   
• Incidence of AEs and related AEs  
• Incidence of grade 3 and grade 4 AEs  
• Incidence of SAEs and death 
• Laboratory values 
• ECG/vital signs 
The safety endpoints will be listed and/or summarized by dose cohort. No inferential statistical 
analyses will be performed. 
 
The analyses of safety will be based on the frequency of adverse events and their severity for 
patients in each portion who received at least one dose of study treatment. Worst toxicity grades 
per patient will be tabulated for select adverse events and laboratory measurements by using NCI 
CTCAE criteria v5.0. 
 
9.4.3 Efficacy analyses 
The efficacy endpoints will include: 
• ORR: The percentages of CR, CR+PR, and CR+PR+SD as well as Conversion Rate for Group 
2 will be presented, as will the median duration of response. The 95% confidence intervals of 
these percentages may also be presented.    
• DOR: DOR is defined as time from the initial response to documented disease progression. This 
variable will be analyzed via Kaplan-Meier methodology. 
Additional analyses may also be performed as appropriate. 
These analyses will be performed from time to time for presentation/publication purposes. 
 
9.4.4 Pharmacokinetic Analyses 
The PK parameters (e.g. AUC(0-∞), AUC(0- t), Cmax, tmax, λz, and t½) will be assessed by analysis of 
Tenalisib and its metabolite; and Romidepsin plasma concentrations during the dose escalation 
phase of the study. These variables will be summarized by n, mean (both arithmetic and geometric 
if applicable), standard deviation, median, minimum, and maximum by dose.   
 


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9.4.5 Exploratory Analysis 
The analyses of correlative markers are exploratory and will not be used to guide treatment 
decisions.  
10 ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
 
This trial will be conducted according to the standards of Good Clinical Practice outlined in the 
ICH E6 Tripartite Guideline, and CFR Title 21 part 312, World Medical Association’s Declaration 
of Helsinki, applicable government regulations, institutional research policies and procedures and 
local applicable regulatory requirement(s).  
 
All potential serious breaches must be reported to Rhizen Pharmaceuticals SA immediately. A 
serious breach is a breach of the conditions and principles of GCP in connection with the study or 
the protocol, which is likely to affect, to a significant degree, the safety or physical or mental 
integrity of the subjects of the study or the scientific value of the study.  
 
10.1  IRB/IEC Approval 
The study protocol, ICF, IB, available safety information, patient documents, patient recruitment 
procedures (e.g., advertisements), information about 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 study start.   
 
The PI/Rhizen and/or designee will follow all necessary regulations to ensure appropriate, initial, 
and ongoing, IRB/IEC trial review. The PI/Rhizen (as appropriate) must submit and, where 
necessary, obtain approval from the IRB/IEC for all subsequent protocol amendments and changes 
to the informed consent document.  Investigators will be advised by Rhizen or designee whether 
an amendment is considered substantial or non-substantial and whether it requires submission for 
approval or notification only to an IRB/IEC. 
 
Safety updates for Tenalisib will be prepared by Rhizen or its representative as required, for 
submission to the relevant IRB/IEC. 
 
10.2  Regulatory Approval 
As required by local regulations, Rhizen will ensure that all legal aspects are covered, and approval 
of the appropriate regulatory bodies obtained, prior to trial initiation. If required, Rhizen will also 
ensure that the implementation of substantial amendment to the protocol and other relevant trial 
documents happen only after approval by the relevant regulatory authorities. Safety updates will be 
prepared by the Rhizen or its representative as required, for submission to the relevant regulatory 
authority.  
 
10.3  Insurance and Indemnity 
Details of insurance and/or indemnity will be contained within the written agreement between the 
PI/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. 
 


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10.4 Financial Disclosure and Obligations 
Principal Investigators and Sub-Investigators are required to provide financial disclosure 
information to allow Rhizen to submit the complete and accurate certification or disclosure 
statements required under Part 54 of Title 21 of the CFR. In addition, the Principal Investigator or 
Sub- Investigators must provide to the Sponsor a commitment to promptly update this information 
if any relevant changes occur during the course of the investigation and for 1 year following the 
completion of the study. 
 
10.5  Informed Consent 
Informed consent is a process by which a subject voluntarily confirms his or her willingness to 
participate in a particular trial, after having been informed of all aspects of the trial that are relevant 
to the subject's decision to participate. Informed consent is documented by means of a written, 
signed and dated informed consent form. 
 
The informed consent form will be submitted for approval to the IRB/IEC that is responsible for 
review and approval of the trial.  Each consent form must include all of the relevant elements 
currently required by the regulatory authorities or state regulations and national requirements. 
Translation of the informed consent form is allowed if necessary. 
 
Before recruitment and enrollment into the trial, each prospective candidate will be given a full 
explanation of the trial. Once the essential information has been provided to the prospective 
candidate, and the investigator is sure that the individual candidate understands the implications of 
participating in this trial, the candidate will be asked to give consent to participate in the trial by 
signing an informed consent form. A notation that written informed consent has been obtained will 
be made in the patient’s medical record. A copy of the signed informed consent form will be 
provided by the investigator to the patient.   
 
If an amendment to the protocol substantially alters the trial design or the potential risks to the 
patients, the patient’s re-consent to continue participation in the trial should be obtained. 
 
10.6   Confidentiality 
10.6.1 
Patient Confidentiality 
Confidentiality of patient’s personal data will be protected in accordance with the Health  
Insurance Portability and Accountability Act of 1996 (HIPAA) and national data protection laws 
or specific country requirements, as applicable. HIPAA regulations require that, in order to 
participate in the trial, a patient must sign an authorization from the trial that he or she has been 
informed of following: 
a. What protected health information (PHI) will be collected from patients in this trial; 
b. Who will have access to that information and why;  
c. Who will use or disclose that information;  
d. The information collected about the research trial will be kept separate from the patient’s 
medical records, but the patient will be able to obtain the research records after the conclusion 
of the trial;  
e. Whether the authorization contains an expiration date;   
f. The rights of a research patient to revoke his or her authorization.  
 


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In the event that a patient revokes authorization to collect or use his or her PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization.  For patients that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e., that the patient is alive) at the end 
of their scheduled trial period. 
 
In compliance with ICH GCP guidelines and applicable parts of 21 CFR, it is a requirement that 
the investigator and institution permit authorized representatives of Sponsor, the regulatory 
authorities and the IRB/IEC direct access to review the patient’s original medical records at the site 
for verification of trial-related procedures and data.  
 
Measures to protect confidentiality include mentioning of only a unique trial number and initials 
will identify patients on the CRF or other documents that will be submitted to Rhizen. This 
information, together with the patient’s date of birth, will be used in the database for patient 
identification. Patient names or addresses will not be entered in the CRF or database. No material 
bearing a patient’s name will be kept on file by Sponsor. Patients will be informed of their rights 
within the ICF.  
 
10.6.2 
Investigator’s Responsibilities 
Medical supervision is the responsibility of the Principal Investigator named on the FDA Form 
1572/country specific forms. The Investigator may delegate day-to-day activities to a sub-
investigator listed on these forms but retains overall responsibility for ensuring that the study is 
conducted properly and in accordance with the study protocol.  The Investigator is required to 
provide the Sponsor with his/her own CV and applicable licensure, as well as those of the personnel 
assuming significant responsibility in the study (e.g., sub-investigators).  The Investigator is 
responsible for ensuring that the study is conducted according to applicable health authorities (e.g. 
FDA), sound medical practices, and in compliance with applicable regulations (e.g. 21 CFR, ICH). 
 
10.6.3 
Investigator and Staff training and Information 
Personal data of the investigators and sub-investigators may be included in the site database, and 
shall be treated in compliance with all applicable laws and regulations. When archiving or 
processing personal data pertaining to the investigator or sub-investigator, the site shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized party. 
 
All Investigators and their study personnel will receive training regarding the study procedures and 
GCP/regulations specific to the conduct of clinical trials. This training will be documented and will 
take place prior to enrollment and throughout the study as necessary. 
 
 
11 RECORD RETENTION AND DOCUMENTATION OF THE TRIAL 
11.1 Amendments to the Protocol 
Amendments to the protocol shall be planned, documented and signature authorized prior to 
implementation. If an amendment to the protocol is required, the amendment will be originated and 
documented by Rhizen. All amendments require review and approval of Rhizen and the Principal 
Investigator supporting the trial. The written amendment must be reviewed and submitted to the 
IRB/IEC at the investigator’s facility for the board’s approval. 


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11.2 Protocol Deviations  
The Principal Investigator is required to follow the protocol. The Investigator or designee must 
document and explain in the subject’s source documentation any deviation from the approved 
protocol. A deviation from the protocol is an unintended and/or unanticipated departure from the 
procedures and/or processes approved by the Sponsor and the IRB/IEC and agreed to by the 
Principal Investigator. Protocol deviations will be documented by the clinical monitor throughout 
the course of monitoring visits. Principal Investigator will be notified of deviations in writing by 
the monitor. The IRB/IEC should be notified of all protocol deviations according to IRB/IEC 
reporting requirements.  
 
11.3  Documentation Required to Initiate Trial 
Before the trial may begin, documentation required by the health authorities will be provided by 
the Sponsor.  Documents at a minimum required to begin a trial include, but are not limited to: a 
signature-authorized protocol and contract; a copy of the official IRB/IEC approval of the trial and 
the IRB/IEC members list; current Curricula Vita for the principal investigator and any associate 
investigator(s) who will be involved in the trial; indication of appropriate accreditation for any 
laboratories to be used in the trial and a copy of the normal ranges for tests to be performed by that 
laboratory; appropriately completed and signed Form FDA 1572 (Statement of Investigator); a 
copy of the IRB-approved consent form containing permission for audit by representatives of 
Sponsor, the IRB, and the FDA/health authorities; financial disclosure forms for all investigators 
listed on Form FDA 1572; site qualification reports, where applicable; verification of Principal 
Investigator acceptability from local and/or national debarment list(s).  
 
12 DATA HANDLING AND RECORD KEEPING  
The PI must maintain a list of appropriately qualified persons to whom he/she has delegated trial 
duties and should ensure that all persons assisting in the conduct of the trial are informed of their 
obligations. All persons authorized to make entries and/or corrections on the CRFs are to be 
included on this document. All entries in the patient’s CRF are to be supported by source 
documentation where appropriate. 
 
Source documents are the original documents, data, records and certified copies of original records 
of clinical findings, observations and activities from which the patient’s CRF data are obtained. 
These can include, but are not limited to, hospital records, clinical and office charts, laboratory, 
medico-technical department and pharmacy records, diaries, microfiches, ECG traces, copies or 
transcriptions certified after verification as being accurate and complete, photographic negatives, 
microfilm or magnetic media, X-rays, and correspondence. 
 
The PI and study staff are responsible for maintaining a comprehensive and centralized filing 
system (Investigator Site File/ISF or Regulatory Binder) of all trial-related (essential) 
documentation, suitable for inspection at any time by representatives from the Sponsor and/or 
applicable regulatory authorities. The ISF 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 should contain as a minimum all relevant documents and correspondence as outlined in ICH 
GCP section E6 and 21 CFR Part 312.57, including key documents such as the IB and any 
amendments, protocol and any amendments, signed ICFs, copies of completed CRFs, IEC approval 


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documents, Financial Disclosure forms, patient identification lists, enrollment logs, delegation of 
authority log, staff qualification documents, laboratory normal ranges, records relating to the trial 
drug including accountability records. Drug accountability records should, at a minimum, contain 
information regarding receipt, shipment, and disposition.   
 
Each form of drug accountability record, at a minimum, should contain PI name, date drug 
shipped/received, date, quantity and batch/code, or lot number for identity of each shipment. In 
addition, all original source documents supporting entries in the CRF must be maintained and be 
readily available. 
 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial and as required by the applicable regulatory 
requirement(s). The investigator/institution should take measures to prevent accidental or 
premature destruction of these documents 
 
The Investigator shall maintain adequate records of drug disposition, case histories and any other 
trial-related records as per 21 CFR Part 312.62 for no less than 2 years after the last marketing 
application has been approved by FDA/health authority; or, in the event that the marketing 
application has not been approved by FDA/health authority, for no less than 2 years after the last 
shipment / delivery of the drug for investigational use is discontinued and FDA/health authority 
has been notified of the discontinuation. 
 
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the investigator additionally agrees to keep records, including the identity of all 
participating patients (sufficient information to link records e.g., eCRFs and medical records), all 
original, signed informed consent forms, and copies of all eCRFs, SAE Reporting forms, source 
documents, detailed records of treatment disposition, and related essential regulatory 
documents.  The documents listed above must be retained by the investigator for as long as needed 
to comply with national and international regulations (generally 2 years after discontinuing clinical 
development 
or 
after 
the 
last 
marketing 
approval).  
Sponsor 
will 
notify 
the 
investigator(s)/institutions(s) when the trial-related records are no longer required.   
 
If the investigator relocates, retires, or for any reason withdraws from the trial, both site and sponsor 
should be prospectively notified.  The trial records must be transferred to an acceptable designee, 
such as another investigator, another institution, or to sponsor.  The investigator must obtain the 
sponsor written permission before disposing of any records, even if retention requirements have 
been met.  All trial files will be maintained by the Sponsor/Sponsor Representative/CRO 
throughout the trial, and will be transferred to the Sponsor at the conclusion of the trial. 
 
12.1   Data Collection 
The data will be captured in electronic Case Record Form (eCRF) via an Electronic Data Capture 
(EDC) system. The eCRF is clinical trials data management tool that provides investigational sites 
a standardized and validated, remote, electronic data capture system for the collection of clinical 
trial data.  All data requested on the eCRF must be supported by and be consistent with the patient’s 
source documentation. All missing data must be explained. When a required laboratory test, 
assessment, or evaluation has not been done or an “Unknown” box is not an option on the eCRF, 


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a note should be created verifying that the field is “Not Done” or “Unknown”. For any entry errors 
made, the error(s) must be corrected, and a note explaining the reason for change should be 
provided.  
 
The Principal Investigator will sign and date each eCRF casebook attesting to his/her responsibility 
for the quality of all data included therein, and that the data represent a complete and accurate 
record of each subject's participation in the study.  
 
Clinical data management will be performed in accordance with applicable standards. Data 
cleaning procedures will be performed with the objective of removing errors and inconsistencies 
in the data which would otherwise impact on the analysis and reporting objectives, or the credibility 
of the Clinical Study Report. Adverse events, medical history and concomitant medications will be 
coded using industry standard dictionaries (MedDRA and WHO Drug).  
 
12.2   Trial Monitoring, Auditing, and Inspecting 
The study will be monitored by the Sponsor and/or Sponsor's representatives at all stages of study 
conduct from inception to completion in accordance with current GCPs. This monitoring will be 
in the form of site visits and other communication and will include review of original source 
documents and eCRFs. The Sponsor's monitor or representative will notify the Principal 
Investigator prior to conducting any investigational site visit.  The frequency of these visits will 
depend upon the progress of the study, and will include monitoring to assess facilities and 
equipment, recruiting, record-keeping, protocol adherence, data collection, AE reporting and other 
factors. 
 
The investigator will permit trial-related monitoring, quality audits, and inspections by the sponsor, 
government regulatory authorities, the Sponsor or its representative(s) of all trial-related 
documents (e.g., source documents, regulatory documents, data collection instruments, case report 
forms). The investigator will ensure the capability for inspections of applicable trial-related 
facilities. The investigator will ensure that the trial monitor or any other compliance or QA reviewer 
is given access to all trial-related documents and trial-related facilities.   
 
Participation as an investigator in this trial implies the acceptance of potential inspection by 
government regulatory authorities, the sponsor or its representative(s). At the Sponsor’s discretion 
Source Document Verification (SDV) may be performed on all data items or a percentage thereof. 
 
The Investigator is responsible for notifying Rhizen in advance of an impending regulatory 
inspection. He/she may request that Rhizen provide support for preparation, if necessary, and is 
required to provide updates on the ongoing activities during the inspection and submit any 
citations/objectionable findings (i.e., FDA 483) and is required to share any follow up responses to 
the outcome. 
 
12.3 Medical Monitoring 
The sponsor will provide a Medical Monitor, a medical expert who advises the study investigators 
and monitors participant safety. The role of the Medical Monitor is to review all AEs/SAEs on a 
regular basis throughout the study, to advise the investigators on study-related medical questions 


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or problems as needed, and to evaluate cumulative participant safety data and make 
recommendations regarding the safe continuation of the study.  
 
12.4 Quality Assurance and Quality Control 
Each trial site shall be required to have Standard Operating Procedures (SOP’s) to define and 
ensure quality assurance/control processes for trial conduct, data generation & collection, recording 
of data/documentation and reporting according to the protocol, GCP and any applicable local, 
national or international regulations. 
 
13 DISCLOSURE AND PUBLICATION POLICY 
All information provided regarding the trial, as well as all information collected/documented 
during the course of the trial, will be regarded as confidential. The Sponsor reserves the right to 
release literature publications based on the results of the trial.  Results from the trial will be 
published/presented as per the Sponsor’s publication strategy. 
 
Inclusion of the investigator in the authorship of any multi-center publication will be based upon 
substantial contribution to the design, analysis, interpretation of data, drafting and/or critically 
revising any manuscript(s) derived from the trial. The investigator acknowledges that the trial is 
part of a multi-center trial and agrees that any publication by the investigator of the results of the 
trial conducted at research site shall not be made before the first multi-center publication. In the 
event there is no multi-center publication within fifteen (15) months after the trial has been 
completed or terminated at all trial sites, and all data has been received, the investigator shall have 
the right to publish its results from the trial, subject to the notice requirements described herein and 
subject to acknowledgement of the Sponsor as appropriate.  Investigator shall provide the Sponsor 
thirty days to review a manuscript or any poster presentation, abstract or other written or oral 
material which describes the results of the trial for the purpose only of determining if any 
confidential or patentable information is disclosed thereby. If the Sponsor requests in writing, the 
investigator shall withhold any publication or presentation an additional sixty (60) days solely to 
permit the Sponsor to seek patent protection and to remove any site Confidential Information from 
all publications.  
 
14 REFERENCES 
 
1. 
Okkenhaug K. Signalling by the phosphoinositide 3-kinase family in immune cells. Annual 
review of immunology. 2013;31:675-704. 
2. 
Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase (PI3K) 
pathway in cancer. Nature reviews Drug discovery. 2009;8(8):627-644. 
3. 
Foster FM, Traer CJ, Abraham SM, Fry MJ. The phosphoinositide (PI) 3-kinase family. J 
Cell Sci. 2003;116(Pt 15):3037-3040. 
4. 
MOLT-4 Xenograft in Nude Mice (Incozen-CP-006). 
5. 
Tenalisib Investigator’s brochure. Version 9, Dated 05 October 2018. 
6. 
Huen A. Tenalisib, a dual PI3K δ/γ inhibitor: Safety and efficacy results from an on-going 
Phase I/Ib study in relapsed/refractory T -cell Lymphoma.ASCO 2018. 
7. 
Romidepsin prescribing information. 
8. 
Yoon SO, Suh C, Lee DH, et al. Distribution of lymphoid neoplasms in the Republic of 
Korea: analysis of 5318 cases according to the World Health Organization classification. Am 
J Hematol. 2010;85(10):760–764. 


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9. 
d’Amore F, Relander T, Lauritzsen GF, et al. Up-front autologous stem-cell transplantation 
in peripheral T-cell lymphoma: NLG-T-01. J Clin Oncol. 2012;30(25):3093–3099. 
10. 
Kim YH, Liu HL, Mraz-Gernhard S, Varghese A, Hoppe RT. Long-term outcome of 525 
patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk 
for disease progression. Arch Dermatol. 2003;139(7):857-866. 
11. 
Zackheim HS, Amin S, Kashani-Sabet M, McMillan A. Prognosis in cutaneous T-cell 
lymphoma by skin stage: long-term survival in 489 patients. J Am Acad Dermatol. 
1999;40(3):418-425. 
12. 
van Doorn R, Van Haselen CW, van Voorst Vader PC, et al. Mycosis fungoides: disease 
evolution and prognosis of 309 Dutch patients. Arch Dermatol. 2000;136(4):504-510. 
13. 
Diamandidou E, Cohen PR, Kurzrock R. Mycosis fungoides and Sezary syndrome. Blood. 
1996;88(7):2385-2409. 
14. 
Arulogun SO, Prince HM, Ng J, et al. Long-term outcomes of patients with advanced-stage 
cutaneous T-cell lymphoma and large cell transformation. Blood. 2008;112(8):3082-3087. 
15. 
Bodo J, Zhao X, Sharma A, et al. The phosphatidylinositol 3-kinases (PI3K) inhibitor GS-
1101 synergistically potentiates histone deacetylase inhibitor-induced proliferation inhibition 
and apoptosis through the inactivation of PI3K and extracellular signal-regulated kinase 
pathways. Br J Haematol. 2013 Oct;163(1):72-80. 
16. 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for Initial Evaluation, 
Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano 
Classification. J Clin Oncol. 2014;32(27):3059-3067. 
17.  Olsen EA, Whittaker S, Kim YH, Duvic M, Prince HM, Lessin SR, et al; International 
Society for Cutaneous Lymphomas; United States Cutaneous Lymphoma Consortium; 
Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment 
of Cancer. Clinical end points and response criteria in mycosis fungoides and Sézary 
syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the 
United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force 
of the European Organisation for Research and Treatment of Cancer. J Clin Oncol. 2011 Jun 
20;29(18):2598-607. 
 
 
 


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15 APPENDICES 
        Appendix A: 
ECOG Performance Status Scale 
         
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to 
carry out any work activities.  Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead 


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Appendix B: Contraceptive Guidelines and Pregnancy 
Women Not of Childbearing Potential are defined as Follows 
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with 
serum FSH levels > 40 mIU/mL] or have had surgical bilateral oophorectomy (with or without 
hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level assessment 
is she considered not of child bearing potential. 
Contraceptive Guidelines for Women of Child-Bearing Potential 
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, must use highly effective contraception during the study and for 5 T1/2 (48 hrs) plus 
an additional 4 weeks after stopping treatment. The highly effective contraception is defined as 
either: 
1. True abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
2. Sterilization:  have had surgical bilateral oophorectomy (with or without hysterectomy) or 
tubal ligation at least six weeks ago.  In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment. 
3. Male partner sterilization (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate). For female subjects on the study, the vasectomised male 
partner should be the sole partner for that patient. 
4. Use of a combination of any two of the following (a+b): 
a. Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
b. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or   
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. 
The following are unacceptable forms of contraception for women of childbearing potential:  
• 
Oral contraception, injected or implanted hormonal methods are not allowed as Tenalisib 
may potentially decrease the effectiveness of hormonal contraceptives. 
• 
IUD progesterone T  
• 
Female condom  
• 
Natural family planning (rhythm method) or breastfeeding  
• 
Fertility awareness  
• 
Withdrawal  
• 
Cervical shield 
 
Women of child-bearing potential must have a negative serum or urine pregnancy test ≤ 72 
hours prior to initiating treatment. 
 


Protocol No. RP6530+Romidepsin-1805 
                                                       Rhizen Pharmaceuticals SA 
Amendment 1: 30 November 2018 
Original version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 79 of 88 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fertile Males 
Fertile males, defined as all males physiologically capable of conceiving offspring must use 
condom during treatment, plus additional 12 weeks after stopping treatment and should not 
father a child in this period.   
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to 
Rhizen Pharmaceuticals SA within 24 hours of learning of its occurrence. The pregnancy should 
be followed up for 3 months after the termination of the pregnancy to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or absence 
of any birth defects, congenital abnormalities, or maternal and/or newborn complications. 
Consent to report information regarding these pregnancy outcomes should be obtained from the 
mother. 
Pregnancy is not considered a SAE. Initial and follow up information should be recorded on a 
Clinical Study Pregnancy Form and reported by the investigator to Rhizen Pharmaceuticals SA. 
Pregnancy follow-up should be recorded on the same form and should include an assessment of 
the possible relationship to the investigational drugs to any pregnancy outcome will also be 
captured on the pregnancy form. Any SAE experienced during pregnancy must be reported on 
the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 


Protocol No. RP6530+Romidepsin-1805 
                                                       Rhizen Pharmaceuticals SA 
Amendment 1: 30 November 2018 
Original version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 80 of 88 
Appendix C: Response Criteria for NHL-The Lugano classification  
 
Response and Site 
PET-CT–Based Response 
CT-Based Response 
COMPLETE 
Complete metabolic response 
Complete radiologic response (all of 
the following) 
Lymph nodes and extra 
lymphatic sites 
Score 1, 2, or 3* with or without a residual 
mass on 5PS† 
Target 
nodes/nodal 
masses 
must 
regress to ≤ 1.5 cm in LDi 
It is recognized that in Waldeyer's ring or 
extra-nodal sites with high physiologic 
uptake or with activation within spleen or 
marrow (e.g., with chemotherapy or 
myeloid colony-stimulating factors), uptake 
may be greater than normal mediastinum 
and/or liver. In this circumstance, complete 
metabolic response may be inferred if 
uptake at sites of initial involvement is no 
greater than surrounding normal tissue even 
if the tissue has high physiologic uptake 
No extra lymphatic sites of disease 
Nonmeasured lesion 
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in 
marrow 
Normal 
by 
morphology; 
if 
indeterminate, IHC negative 
 
 
 
PARTIAL 
Partial metabolic response 
Partial remission (all of the following) 
Lymph nodes and extra 
lymphatic sites 
Score 4 or 5† with reduced uptake 
compared with baseline and residual 
mass(es) of any size 
≥ 50% decrease in SPD of up to 6 
target measurable nodes and 
extra-nodal sites 
At 
interim, 
these 
findings 
suggest 
responding disease 
When a lesion is too small to measure 
on CT, assign 5 mm × 5 mm as the 
default value 
At end of treatment, these findings indicate 
residual disease 
When no longer visible, 0 × 0 mm 
For a node > 5 mm × 5 mm, but smaller 
than normal, use actual measurement 
for calculation 
Nonmeasured lesions 
Not applicable 
Absent/normal, regressed, 
but no 
increase 
Organ enlargement 
Not applicable 
Spleen must have regressed by > 50% 
in length beyond normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in 
normal marrow but reduced compared with 
baseline (diffuse uptake compatible with 
reactive 
changes 
from 
chemotherapy 
allowed). If there are persistent focal 
changes in the marrow in the context of a 
nodal response, consideration should be 
given to further evaluation with MRI or 
biopsy or an interval scan 
Not applicable 
 
 
 


Protocol No. RP6530+Romidepsin-1805 
                                                       Rhizen Pharmaceuticals SA 
Amendment 1: 30 November 2018 
Original version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 81 of 88 
NO 
RESPONSE 
OR 
STABLE DISEASE 
No metabolic response 
Stable disease 
Target nodes/nodal masses, 
extranodal lesions 
Score 4 or 5 with no significant change in 
FDG uptake from baseline at interim or end 
of treatment 
< 50% decrease from baseline in SPD 
of up to 6 dominant measurable nodes 
and extranodal sites; no criteria for 
progressive disease are met 
Nonmeasured lesions 
Not applicable 
No 
increase 
consistent 
with 
progression 
Organ enlargement 
Not applicable 
No 
increase 
consistent 
with 
progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
 
 
 
PROGRESSIVE 
DISEASE 
Progressive metabolic disease 
Progressive disease requires at least 1 
of the following 
Individual 
target 
nodes/nodal masses 
Score 4 or 5 with an increase in intensity of 
uptake from baseline and/or 
PPD progression: 
Extranodal lesions 
New FDG-avid foci consistent with 
lymphoma at interim or end-of-treatment 
assessment 
An individual node/lesion must be 
abnormal with: 
LDi > 1.5 cm and 
Increase by ≥ 50% from PPD nadir 
and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions ≤ 2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, the 
splenic length must increase by > 50% 
of the extent of its prior increase 
beyond baseline (eg, a 15-cm spleen 
must increase to > 16 cm). If no prior 
splenomegaly, must increase by at 
least 2 cm from baseline 
New or recurrent splenomegaly 
Nonmeasured lesions 
None 
New or clear progression of pre-
existing Nonmeasured lesions 
New lesions 
New FDG-avid foci consistent with 
lymphoma rather than another etiology (eg, 
infection, inflammation). If uncertain 
regarding etiology of new lesions, biopsy 
or interval scan may be considered 
Regrowth of previously resolved 
lesions 
A new node > 1.5 cm in any axis 
A new extra nodal site > 1.0 cm in any 
axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and 
must be attributable to lymphoma 
Assessable disease of any size 
unequivocally attributable to 
lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
Abbreviations: 
5PS, 
5-point 
scale; 
CT, 
computed 
tomography; 
FDG, 
fluorodeoxyglucose; 
IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance imaging; PET, 
positron emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, shortest axis 
perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions.  
 


Protocol No. RP6530+Romidepsin-1805 
                                                       Rhizen Pharmaceuticals SA 
Amendment 1: 30 November 2018 
Original version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 82 of 88 
* A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an 
interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to consider 
a score of 3 as inadequate responses (to avoid under treatment). Measured dominant lesions: Up to six of the largest 
dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two diameters. Nodes 
should preferably be from disparate regions of the body and should include, where applicable, mediastinal and 
retroperitoneal areas. Non-nodal lesions include those in solid organs (eg, liver, spleen, kidneys, and lungs), GI 
involvement, cutaneous lesions, or those noted on palpation. Non measured lesions: Any disease not selected as 
measured, dominant disease and truly assessable disease should be considered not measured. These sites include 
any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not meet the 
requirements for measurability but are still considered abnormal, as well as truly assessable disease, which is any 
site of suspected disease that would be difficult to follow quantitatively with measurement, including pleural 
effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be 
confirmed and followed by imaging. In Waldeyer's ring or in extranodal sites (eg, GI tract, liver, bone marrow), 
FDG uptake may be greater than in the mediastinum with complete metabolic response, but should be no higher 
than surrounding normal physiologic uptake (eg, with marrow activation as a result of chemotherapy or myeloid 
growth factors).  
† PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, 
uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely 
to be related to lymphoma. 
 
 
 


Protocol No. RP6530+Romidepsin-1805 
                                                       Rhizen Pharmaceuticals SA 
Amendment 1: 30 November 2018 
Original version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 83 of 88 
Appendix D: Recommended evaluation for MF/SS patients 
 
Recommended evaluation/initial staging of the patient with MF/Sézary syndrome 
 
Complete physical examination including 
• Determination of type(s) of skin lesions 
o If only patch/plaque disease or erythroderma, then estimate percentage of body surface area involved 
and note any ulceration of lesions 
o If tumors are present, determine total number of lesions, aggregate volume, largest size lesion, and 
regions of the body involved 
• Identification of any palpable lymph node, especially those >1.5 cm in largest diameter or firm, 
irregular, clustered, or fixed 
• Identification of any organomegaly 
 
Skin biopsy 
• Most indurated area if only one biopsy 
• Immunophenotyping to include at least the following markers: CD2, CD3, CD4, CD5, CD7, CD8, 
and a B-cell marker such as CD20. CD30 may also be indicated in cases where lymphomatoid 
papulosis, anaplastic lymphoma, or large-cell transformation is considered. 
• Evaluation for clonality of TCR gene rearrangement 
 
Blood tests 
• CBC with manual differential, liver function tests, LDH, comprehensive chemistries 
• TCR gene rearrangement and relatedness to any clone in skin 
• Analysis for abnormal lymphocytes by either Sézary cell count with determination absolute number 
of Sézary cells and/or flow cytometry (including CD4+/CD7- or CD4+/CD26-) 
 
Radiologic tests 
• In patients with T1N0B0stage disease who are otherwise healthy and without complaints directed to a 
specific organ system, and in selected patients with T2N0B0disease 
• with limited skin involvement, radiologic studies may be limited to a chest X-ray or ultrasound of the 
peripheral nodal groups to corroborate absence of adenopathy 
• In all patients with other than presumed stage IA disease, or selected patients with limited T2 disease 
and the absence of adenopathy or blood involvement, CT scans of chest, abdomen, and pelvis 
alone±FDG-PET scan are recommended to further evaluate any potential lymphadenopathy, visceral 
involvement, or abnormal laboratory tests. In patients unable to safely undergo CT scans, MRI may 
be substituted. 
 
Lymph node biopsy  
• Excisional biopsy is indicated in those patients with a node that is either ≥1.5 cm in diameter and/or 
is firm, irregular, clustered, or fixed 
• Site of biopsy 
o Preference is given to the largest lymph node draining an involved area of the skin or if FDG-PET 
scan data are available, the node with highest standardized uptake value (SUV). 
o If there is no additional imaging information and multiple nodes are enlarged and otherwise equal in 
size or consistency, the order of preference is cervical, axillary, and inguinal areas. 
• Analysis: pathologic assessment by light microscopy, flow cytometry, and TCR gene rearrangement. 
 
 


Protocol No. RP6530+Romidepsin-1805 
                                                       Rhizen Pharmaceuticals SA 
Amendment 1: 30 November 2018 
Original version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 84 of 88 
 Appendix E:  ISCL/EORTC staging of MF and SS patients 
 
TNMB 
Stages 
 
Description of TNMB 
Skin* 
    
T1 
Limited patches, papules, and/or plaques covering < 10% of the skin surface; may further 
stratify into T1a (patch only) v T1b(plaque ± patch) 
    
T2 
Patches, papules, or plaques covering ≥ 10% of the skin surface; may further stratify into 
T2a (patch only) v T2b (plaque ± patch) 
T3 
One or more tumors (≥ 1 cm diameter) 
T4 
Confluence of erythema covering ≥ 80% body surface area 
Node† 
N0 
No clinically abnormal lymph nodes; biopsy not required 
N1 
Clinically abnormal lymph nodes; histopathology Dutch grade 1 or NCI LN0-2 
N1a 
Clone negative 
N1b 
Clone positive 
N2 
Clinically abnormal lymph nodes; histopathology Dutch Grade 2 or NCI LN3 
N2a 
Clone negative 
N2b 
Clone positive 
N3 
Clinically abnormal lymph nodes; histopathology Dutch grade 3-4 or NCI LN4; clone 
positive or negative 
    
Nx 
Clinically abnormal lymph nodes without histologic confirmation or inability to fully 
characterize the histologic subcategories 
Visceral 
M0 
No visceral organ involvement 
M1 
Visceral involvement (must have pathology confirmation and organ involved should be 
specified) 
Blood 
B0 
Absence of significant blood involvement: ≤ 5% of peripheral blood lymphocytes are 
atypical (Sézary) cells 
B0a 
Clone negative 
B0b 
Clone positive 
B1 
Low blood tumor burden: > 5% of peripheral blood lymphocytes are atypical (Sézary) cells 
but does not meet the criteria of B2 
B1a 
Clone negative 
B1b 
Clone positive 
    
B2 
High blood tumor burden: ≥ 1,000/μL Sézary cells with positive clone‡; one of the 
following can be substituted for Sézary cells: CD4/CD8 ≥ 10, CD4+CD7- cells ≥ 40% or 
CD4+CD26- cells ≥ 30% 


Protocol No. RP6530+Romidepsin-1805 
                                                       Rhizen Pharmaceuticals SA 
Amendment 1: 30 November 2018 
Original version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 85 of 88 
• 
Abbreviations: ISCL, International Society for Cutaneous Lymphomas; EORTC, European 
Organisation for Research and Treatment of Cancer; MF, mycosis fungoides; SS, Sézary syndrome; 
NCI, National Cancer Institute. 
• 
↵* Patch = any size lesion without induration or significant elevation above the surrounding 
uninvolved skin: pokiloderma may be present. Plaque = any size lesion that is elevated or indurated: 
crusting or poikiloderma may be present. Tumor = any solid or nodular lesion ≥ 1 cm in diameter with 
evidence of deep infiltration in the skin and/or vertical growth. 
• 
↵† Lymph node classification has been modified from 2007 ISCL/EORTC consensus revisions1 to 
include central nodes. Lymph nodes are qualified as abnormal if > 1.5 cm in diameter. 
• 
↵‡ The clone in the blood should match that of the skin. The relevance of an isolated clone in the 
blood or a clone in the blood that does not match the clone in the skin remains to be determined. 
 
 
Modified ISCL/EORTC Revisions to the Staging of MF/SS 
Stage  
T 
N 
M 
B 
IA 
1 
0 
0 
0,1 
IB 
2 
0 
0 
0,1 
IIA 
1.2 
1,2X 
0 
0,1 
IIb 
3 
0-2X 
0 
0,1 
IIIA 
4 
0-2X 
0 
0 
IIIB 
4 
0-2X 
0 
1 
IVA1 
1-4 
0-2X 
0 
2 
IVA2 
1-4 
3 
0 
0-2 
IVB 
1-4 
0-3X 
1 
0-2 
 
X clinically abnormal lymph nodes without histologic confirmation or inability to fully characterize 
histologic subcategories. 
 
  
 
 


Protocol No. RP6530+Romidepsin-1805 
                                                       Rhizen Pharmaceuticals SA 
Amendment 1: 30 November 2018 
Original version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 86 of 88 
Appendix F: Modified Severity Weighted Assessment Tool (mSWAT) 
 
Body Region 
% BSA in Body Region 
Assessment of Involvement in Patient's Skin 
Patch* 
Plaque† 
Tumor‡ 
Head 
7 
Neck 
2 
Anterior trunk 
13 
Arms 
8 
Forearms 
6 
Hands 
5 
Posterior trunk 
13 
Buttocks 
5 
Thighs 
19 
Legs 
14 
Feet 
7 
Groin 
1 
Subtotal of lesion BSA 
    Weighting factor 
×1 
×2 
×4 
Subtotal lesion BSA × 
weighting factor 
• NOTE. mSWAT score equals summation of each column line. 
• Abbreviations: BSA, body surface area; mSWAT, modified Severity Weighted Assessment 
Tool. 
• ↵* Any size lesion without induration or significant elevation above the surrounding uninvolved 
skin; poikiloderma may be present. 
• ↵† Any size lesion that is elevated or indurated; crusting, ulceration, or poikiloderma may be 
present. 
• ↵‡ Any solid or nodular lesion ≥ 1 cm in diameter with evidence of deep infiltration in the skin 
and/or vertical growth. 
 
 
 
 
 
 
 


Protocol No. RP6530+Romidepsin-1805 
                                                       Rhizen Pharmaceuticals SA 
Amendment 1: 30 November 2018 
Original version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 87 of 88 
Appendix G : Ann Arbor Staging System 
 
Stage I 
Either of the following means the disease is stage I: 
• 
The lymphoma is in only 1 lymph node area or lymphoid organ such as the thymus 
(I). 
• 
The cancer is found only in 1 area of a single organ outside of the lymph system 
(IE). 
 
Stage II 
Either of the following means the disease is stage II: 
• 
The lymphoma is in 2 or more groups of lymph nodes on the same side of (above 
or below) the diaphragm (the thin band of muscle that separates the chest and 
abdomen). For example, this might include nodes in the underarm and neck area 
but not the combination of underarm and groin nodes (II). 
• 
The lymphoma extends from a single group of lymph node(s) into a nearby organ 
(IIE). It may also affect other groups of lymph nodes on the same side of the 
diaphragm. 
 
Stage III 
Either of the following means the disease is stage III: 
• 
The lymphoma is found in lymph node areas on both sides of (above and below) 
the diaphragm. 
• 
The cancer may also have spread into an area or organ next to the lymph nodes 
(IIIE), into the spleen (IIIS), or both (IIISE). 
 
Stage IV 
Either of the following means the disease is stage IV: 
• 
The lymphoma has spread outside of the lymph system into an organ that is not 
right next to an involved node. 
• 
The lymphoma has spread to the bone marrow, liver, brain or spinal cord, or the 
pleura (thin lining of the lungs). 
Other modifiers may also be used to describe the lymphoma stage: 
 
 
 
 
 
 
 
 
 


Protocol No. RP6530+Romidepsin-1805 
                                                       Rhizen Pharmaceuticals SA 
Amendment 1: 30 November 2018 
Original version : 1.0, 16 August 2018 
CONFIDENTIAL 
Page 88 of 88 
 
Appendix H: Romidepsin Prescribing Information 
 
 

SAP_001.pdf: 
  
Rhizen Pharmaceuticals AG.                                                                                                               RP6530+Romidepsin-1805   
 
Rhizen Pharmaceuticals AG                                                         Confidential 
FINAL 1.0 Dated 09AUGL2021 
 
                                                                                                                                                                               Page 1 of 22 
 
 
 
 
 
PROTOCOL NO. RP6530+Romidepsin-1805 
 
  
 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 
 
Statistical Analysis Plan 
 
 
 
Author and Designation: 
Arti Kanujia 
Senior Manager, Biostatistics 
Labcorp Scientific Services & Solutions Pvt. Ltd. 
Version and Date 
FINAL 1.0, 09AUG2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
Rhizen Pharmaceuticals AG.                                                                                                               RP6530+Romidepsin-1805   
 
Rhizen Pharmaceuticals AG                                                         Confidential 
FINAL 1.0 Dated 09AUGL2021 
 
                                                                                                                                                                               Page 2 of 22 
 
 
Revision History: 
 
 
VERSION  
CHANGE DESCRIPTION 
AUTHOR 
DATE 
FINAL 1.0  
Not Applicable 
Arti Kanujia 
09AUG2021 
 
 
 


  
Rhizen Pharmaceuticals AG.                                                                                                               RP6530+Romidepsin-1805   
 
Rhizen Pharmaceuticals AG                                                         Confidential 
FINAL 1.0 Dated 09AUGL2021 
 
                                                                                                                                                                               Page 3 of 22 
 
Signature Page  
 
 
Signature above indicates approval of this plan, for the analysis and reporting of this study. Approval of the SAP 
and approval of any subsequent amendments is the responsibility of the Head of Statistics function or equivalent.   
The approver serves as a single point of accountability for approval and must ensure that all relevant functions are 
in agreement with the final SAP. 
 
TITLE  
NAME 
SIGNATURE 
DATE 
Authoring Statistician 
Arti Kanujia 
 
 
Reviewing Statistician 
Anup Banerjee 
 
 
Manager Statistics  
(or equivalent) 
Sponsor Representative 
Dr Prajak Barde 
 
 


  
Rhizen Pharmaceuticals AG.                                                                                                               RP6530+Romidepsin-1805   
 
Rhizen Pharmaceuticals AG                                                         Confidential 
FINAL 1.0 Dated 09AUGL2021 
 
                                                                                                                                                                               Page 4 of 22 
 
Table of Contents 
 
1. 
Amendments from Previous Version(s) ......................................................................................... 7 
2. 
Introduction ...................................................................................................................................... 7 
2.1 
Rationale ......................................................................................................................................................................................... 7 
3. 
Study Objectives .............................................................................................................................. 7 
3.1 
Primary Objective ........................................................................................................................................................................ 7 
3.2 
Secondary Objectives .................................................................................................................................................................. 7 
3.3 
Exploratory Objective ................................................................................................................................................................ 8 
4. 
Study Endpoints ............................................................................................................................... 8 
4.1 
Primary Endpoint ........................................................................................................................................................................ 8 
4.2 
Secondary Endpoints .................................................................................................................................................................. 8 
4.3 
Correlative/ Exploratory Endpoints ...................................................................................................................................... 8 
5. 
Study Design ..................................................................................................................................... 8 
5.1 
Phase I: Dose escalation ............................................................................................................................................................. 9 
5.2 
Phase II: Dose Expansion .......................................................................................................................................................... 9 
5.2.1 
Number of subjects.................................................................................................................................................................... 10 
5.3 
Study Stopping Rules ................................................................................................................................................................ 10 
6. 
Sample Size Considerations .......................................................................................................... 10 
7. 
Analysis Populations ...................................................................................................................... 11 
7.1 
All Enrolled Patients ................................................................................................................................................................. 11 
7.2 
Safety Population Set ................................................................................................................................................................ 11 
7.3 
Modified Intent-to-Treat Population (mITT) Analysis Set ......................................................................................... 11 
7.4 
Per-Protocol (PP) Population Analysis Set ....................................................................................................................... 11 
8. 
Randomization and Blinding ........................................................................................................ 12 
9. 
Method of Analysis ........................................................................................................................ 12 
9.1 
Statistical Hypotheses ............................................................................................................................................................... 12 
9.2 
Interim Analysis ......................................................................................................................................................................... 12 
9.3 
Handling of Missing Data ........................................................................................................................................................ 12 
9.3.1 
Missing Dates for Adverse Events and Concomitant Medications ........................................................................... 12 
9.3.2 
Missing Dates for Efficacy Endpoints................................................................................................................................. 13 
9.3.3 
Missing dates for Primary Diagnosis/Prior therapy ...................................................................................................... 13 
10. Statistical Analysis ......................................................................................................................... 13 
10.1 Patient Disposition ..................................................................................................................................................................... 14 
10.2 Demographic and Baseline Characteristics ...................................................................................................................... 14 


  
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Rhizen Pharmaceuticals AG                                                         Confidential 
FINAL 1.0 Dated 09AUGL2021 
 
                                                                                                                                                                               Page 5 of 22 
 
10.3 Medical and Surgical History ................................................................................................................................................ 14 
10.4 Prior and Concomitant Medications ................................................................................................................................... 15 
10.5 Efficacy Analysis ........................................................................................................................................................................ 15 
10.5.1 
Objective Response Rate (ORR) ..................................................................................................................................... 15 
10.5.2 
Duration of Response (DoR) ............................................................................................................................................. 16 
10.5.3 
Best Overall Response (BOR) .......................................................................................................................................... 16 
10.6 Safety Analysis ............................................................................................................................................................................ 16 
10.6.1 
Treatment Exposure and Compliance........................................................................................................................... 16 
10.6.2 
Adverse Events ...................................................................................................................................................................... 17 
10.6.3 
Clinical Laboratory Tests .................................................................................................................................................. 18 
10.6.4 
Physical Examinations ........................................................................................................................................................ 19 
10.6.5 
Vital Signs ............................................................................................................................................................................... 20 
10.6.6 
Electrocardiogram ............................................................................................................................................................... 20 
10.6.7 
ECOG ....................................................................................................................................................................................... 20 
11. Pharmacokinetic (PK) Analysis .................................................................................................... 21 
12. Exploratory analysis ...................................................................................................................... 21 
13. Protocol Deviations ........................................................................................................................ 21 
14. Listings ............................................................................................................................................ 21 
15. References ....................................................................................................................................... 22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
Rhizen Pharmaceuticals AG.                                                                                                               RP6530+Romidepsin-1805   
 
Rhizen Pharmaceuticals AG                                                         Confidential 
FINAL 1.0 Dated 09AUGL2021 
 
                                                                                                                                                                               Page 6 of 22 
 
List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical  
BID 
Twice Daily 
CI 
Confidence Interval 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTCL 
Cutaneous T cell lymphoma 
DCR 
Disease Control Rate 
DLT 
Dose Limiting Toxicity 
DoR 
Duration of Response 
DRC 
Data Review Committee 
ECG 
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
HDAC 
histone deacetylases  
IEC/IRB 
Independent Ethics Committee/ Institutional Review Board 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
mSWAT 
Modified Severity-Weighted Assessment Tool 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ND 
Not Done 
NE 
Not Evaluable 
ORR 
Objective Response Rate 
P13K 
phosphoinositide-3-kinase 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PR 
Partial Response 
PT 
Preferred Term 
PTCL 
Peripheral T-cell lymphoma 
Q1 
First Quartile 
Q3 
Third Quartile 
QTcF 
QT interval with Fridericia's correction 
SAE 
Serious Adverse Events 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SD 
Stable Disease 
SOC 
System Organ Class 
SRC 
Scientific Review Committee 
TCL 
T-cell lymphoma 
TEAE 
Treatment-Emergent Adverse Event 
WHO 
World Health Organization 


  
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Rhizen Pharmaceuticals AG                                                         Confidential 
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1. 
Amendments from Previous Version(s) 
Not Applicable. 
 
2. 
Introduction 
Note: In this document, any text taken directly from the protocol (Number: RP6530+Romidepsin 
-1805, Amendment 1 to Version 1.0 Dated 16 August 2018, Amendment version dated 30 
November 2018) is italicized. 
 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study RP6530+Romidepsin-1805. This document may modify the plans outlined in 
the final protocol. 
   
2.1 
Rationale 
Tenalisib is a highly specific and orally available dual kinase PI3K (phosphoinositide-3-kinase) 
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. 
 
Romidepsin is a histone deacetylases (HDAC) inhibitor and was approved by FDA for the 
treatment of CTCL and PTCL in 2009 and 2011 respectively for the patients who have received 
at least one prior systemic therapy. 
 
Given the fact that both Romidepsin and Tenalisib have non-overlapping toxicity profiles, half of 
the optimal dose of Tenalisib (400 mg BID) and one dose below the approved dose of 
Romidepsin (12 mg/m2) are considered reasonable as starting doses of the combination from 
safety point of view. It is expected that proposed combination of Tenalisib with Romidepsin has 
the potential to improve response rates and increase the durability of response. 
 
3. 
Study Objectives  
3.1 
Primary Objective 
• To characterize safety, tolerability and to establish the maximum tolerated dose (MTD) of 
Tenalisib in combination with Romidepsin in patients with R/R T-cell lymphoma.  
 
3.2 
Secondary Objectives 
• To assess the preliminary anti-tumor activity of various dose levels of Tenalisib in 
combination with Romidepsin as determined by the Objective Response Rate (ORR) and 
Duration of Response (DoR).  
 


  
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Rhizen Pharmaceuticals AG                                                         Confidential 
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• To characterize the Pharmacokinetics (PK) of Tenalisib and Romidepsin when given in 
combination.  
 
3.3 
Exploratory Objective 
• To correlate clinical efficacy with markers that include but are not limited to quantitative 
and qualitative measurements of malignant cells, cytokines, and chemokines in blood/serum.  
 
4. 
Study Endpoints 
4.1 
Primary Endpoint 
• Safety 
o Adverse Event (AE), Grade 3/ 4 AEs, Serious and fatal Adverse Event (SAE), graded 
using NCI CTCAE Version 5.0. 
 
4.2 
Secondary Endpoints 
• Efficacy 
o Objective Response Rate (ORR), defined as sum of CR and PR rates, assessed 
according to the Lugano Classification for initial evaluation, staging, and response 
assessment of Hodgkin/non-Hodgkin lymphoma in PTCL patients; and according to 
the modified Severity Weighted Assessment Tool (mSWAT) in CTCL patients. 
  
o Duration of Response (DoR), calculated as time from the initial response to 
documented disease progression.  
 
• Pharmacokinetics 
o PK Parameters [AUC (0-∞), AUC (0- t), Cmax, tmax, Kel, and t½] of Tenalisib and 
Romidepsin. 
 
4.3 
Correlative/ Exploratory Endpoints 
• Correlative markers include baseline and on-treatment serum levels of chemokines, cytokines, 
antibodies to tumor antigens, and other immune mediators (e.g. sIL2R and CTACK for PTCL; 
CD30, IL-31 and IL-32 for CTCL) as deemed relevant by the sponsor. 
 
5. 
Study Design 
This is a multi-center, open label, non-randomized, two-part Phase I/II study of Tenalisib in 
combination with Romidepsin in adult patients with relapsed/refractory TCL. The first part is an 
open-label, 3+3 dose escalation, Phase I study for MTD determination. The second part is a 
Phase II, dose expansion to delineate the safety and anti-tumor activity of the combination at the 
MTD/optimal dose.  
 
In dose escalation, a minimum of 2 and maximum 18 patients will be enrolled in three dose 
levels unless additional dose levels are required to reach MTD/ optimal dose. In dose expansion, 


  
Rhizen Pharmaceuticals AG.                                                                                                               RP6530+Romidepsin-1805   
 
Rhizen Pharmaceuticals AG                                                         Confidential 
FINAL 1.0 Dated 09AUGL2021 
 
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up to 24 TCL patients will be enrolled (Group 1= 12 PTCL patients and Group 2= 12 CTCL 
patients).  
 
The study will end when all ongoing subjects have reached their third tumor assessment on 
Cycle 8/Day 1 (C8D1) or have discontinued from the study for any reason, whichever is 
earlier. At the end of the study, all ongoing patients with no evident disease progression will 
be given the opportunity to enroll in an open-label compassionate use study protocol and will 
be followed up.  
 
5.1 
Phase I: Dose escalation 
Sequential dose escalation will begin with Cohort 1. A minimum of three patients will be 
enrolled at each dose level. Dose levels will be increased in successive increments according to 
the dose escalation cohorts mentioned in the table below. Escalation to the next cohort will 
occur if no patient within a three-patient cohort or one in six patients experiences a dose limiting 
toxicity (DLT). De-escalation to different lower doses in case DLT criteria is met, will be done as 
per the discretion of Safety Review Committee (SRC). The highest doses of the combination 
(Tenalisib at 800 mg BID plus Romidepsin IV 14 mg/m2) will be considered as optimal in case 
there is no DLT at this dose level.  
 
Dose escalation scheme: 
Cohort 
N 
Tenalisib1 
Romidepsin2 
Cohort 1 
3-6 
Tab. 400 mg PO twice a day 
IV 12 mg/m2 on Day 1, 8 and 15 
Cohort 2 
3-6 
Tab. 600 mg PO twice a day 
IV 12 mg/m2 on Day 1, 8 and 15 
Cohort 3 
3-6 
Tab. 800 mg PO twice a day 
IV 14 mg/m2 on Day 1, 8 and 15 
Note: Alternate dose levels/dosing schedules may be considered by the SRC if deemed essential based on emerging 
safety and PK data.  
1In case the dose (e.g. 800 mg BID) is leading to DLT of the combination, the dose of Tenalisib will be reduced to 
lower dose (e.g. 600 mg BID) and will be evaluated for safety in a separate cohort.  
2In case the dose (e.g. 14 mg/m2) is leading to DLT of the combination, the dose of Romidepsin will be reduced to 
lower dose (e.g.12 mg/m2) and if required further to 10 mg/m2 and will be evaluated for safety in a separate cohort.  
 
DLT assessment: The data of at least 3 patients will be required for DLT assessment. DLT 
assessment period will be 28-days (inclusive) (will begin on C1D1 and end on C2D1), unless 
extended by the medical monitor. In the first cycle, patients must have been treated with at least 
2 doses of Romidepsin and minimum 14 days with Tenalisib to be considered eligible for safety 
analysis unless identified to have a DLT. Patients who experience a DLT will be considered 
evaluable regardless of the number of doses received.  
Individual patients will be considered for Intra-subject dose escalation at the discretion of 
investigator after discussion with medical monitor.  
 
5.2 
Phase II: Dose Expansion 
After establishing the MTD/optimal dose, the Phase II (expansion part) will be opened as 
approved by the SRC to enroll two groups of patients.  
 
Group 
N 
Patient Population  
Tenalisib 
Romidepsin 


  
Rhizen Pharmaceuticals AG.                                                                                                               RP6530+Romidepsin-1805   
 
Rhizen Pharmaceuticals AG                                                         Confidential 
FINAL 1.0 Dated 09AUGL2021 
 
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Group 1 
12 
Patients with R/R PTCL 
MTD/ Optimal dose  MTD/ Optimal dose on 
Day 1, 8 and 15 
Group 2 
12 
Patients with R/R CTCL 
MTD/ Optimal dose MTD/ Optimal dose on 
Day 1, 8 and 15 
 
5.2.1 Number of subjects 
• Phase I: Total 2-18 patients will be enrolled in 3 escalating cohorts unless additional dose 
levels are required to reach MTD/ optimal dose. 
  
• 
Phase II: Total 24 patients with relapsed/refractory TCL will be enrolled.  
5.3 
Study Stopping Rules 
• Stopping Rule for Dose Escalation: The SRC will be in charge of reviewing safety data 
following the final treatment dose (Day 28 of Cycle 1) of the last patient in each cohort and 
will decide whether or not it is possible to proceed to the next cohort. 
 
• Suspension of Patient Enrollment: In the event of one (1) death attributed to the study drug, 
study accrual will be suspended pending further investigation, and will only be resumed at 
the recommendation of the SRC. The SRC will have discretion to terminate the trial if an 
additional death occurs that can be attributed to the study drug. 
 
• Stopping Rule for Dose Expansion: After establishing the MTD/optimal dose, the Phase II 
expansion part will be opened as approved by the SRC. The SRC will continue to monitor 
safety of the combination (or toxicity trends that may be of concern) at interval of 3 months 
from initiation of expansion cohort till the completion of the study. Safety/toxicity will be 
monitored across cohorts combined together. The SRC will have discretion to terminate the 
trial if there are major safety concerns. 
 
• Study Stopping: Sponsor reserves the right to terminate the study in the interest of patient 
safety, for noncompliance with the protocol, lack of recruitment or any other administrative 
reasons. The sponsor and PIs will notify the regulatory authority and respective IRB/IEC 
respectively if the trial terminates early, with a justification for the early termination. 
  
6. 
Sample Size Considerations 
Part 1: In Dose Escalation, three patients per cohort are considered appropriate for the 
assessment of overall safety and tolerability and for providing adequate confidence for dose 
escalation. No formal sample size and power analysis is done. Accordingly, total 2-18 patients 
will be enrolled in 3 escalating cohorts unless additional dose levels are required to reach MTD/ 
optimal dose. Optimal dose will be determined by the SRC.  
 
Part 2: Total 24 patients with relapsed/refractory TCL will be enrolled in two groups (12 patients 
in each group). Twelve patients per group is considered appropriate for assessment of preliminary 
anti-tumor activity of the combination. However, the SRC may modify the sample size due to 
unforeseen clinical situations. 


  
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Rhizen Pharmaceuticals AG                                                         Confidential 
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7. 
Analysis Populations 
7.1 
All Enrolled Patients 
The enrolled patients are those who have consented and screened with eligibility verified as per 
the Inclusion-Exclusion criteria mentioned in study protocol. 
 
7.2 
Safety Population Set 
The Safety Population set will include all subjects who receive at least 1 dose of the study 
medication. This set will be used for reporting safety data, patient demographic data and any 
available patient baseline characteristics as reported in the Case Report Form (CRF). 
 
7.3 
Modified Intent-to-Treat Population (mITT) Analysis Set 
The mITT is the primary efficacy analysis population and will include data from all patients who 
received at least 1 dose of study medication and provide at least 1 post-baseline efficacy 
assessment. 
 
Note: In order to offer sufficient time for assessing the effectiveness of the study medications, 
patients who provide the post-baseline efficacy assessment; at least on Cycle 3 Day 1 or are 
discontinued from study at Cycle 3 Day 1 shall be evaluated for mITT analysis set. 
Programmatically, if the patient received at least 1 dose of study medication and have provided 
at least Cycle 2 Day 22 efficacy assessment, then he/she will be qualified for mITT analysis set. 
 
7.4 
Per-Protocol (PP) Population Analysis Set 
The PP Population is a subset of the modified Intent-to-Treat Population and will include 
patients without major protocol deviations.  
 
 Major deviations shall include: 
- Deviation from an IEC/IRB approved protocol which compromise the safety and welfare of 
participating subjects or compromise the integrity of the study and /or the completeness, 
accuracy and reliability of study data.  Examples of deviations included but not limited to: 
o Failure to obtain informed consent from the enrolled subject (e.g., there is no 
documentation of informed consent);  
o Informed consent is obtained after initiation of study procedure;  
o Enrollment of subject who has failed to meet the eligibility criteria. 
 
The list of protocol deviations with categorization with respect to major and minor deviations 
will be generated prior to the study database lock. Sponsor’s Medical monitor will review all 
deviations prior to database lock and decide whether to include the patient in a PP analysis 
population set. The PP population analysis set will also be used for efficacy assessment. 
 
Note: If the patients qualifying for mITT set are same as the patients qualifying for PP set, the 
respective tables and figures proposed using PP set will not be produced to avoid the duplication 
of the results. 


  
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Rhizen Pharmaceuticals AG                                                         Confidential 
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Membership in the analysis populations will be determined before database lock.  
 
8. 
Randomization and Blinding 
This is a non-randomized, open label study. 
 
9. 
Method of Analysis 
9.1 
Statistical Hypotheses 
There are no formal statistical hypotheses tested in this study. 
 
9.2 
Interim Analysis 
No formal interim analysis is planned for this study. 
 
9.3 
Handling of Missing Data 
9.3.1 Missing Dates for Adverse Events and Concomitant Medications 
Missing dates (either completely or partially) of adverse events and concomitant medications 
will be imputed as explained below for the purposes of calculation of durations. 
 
For end of concomitant medications or adverse events: 
 
• If only Day of end date is missing: 
 The last date of the month and year reported or the date of the final contact with the subject, 
whichever is earlier, will be used as the end date. 
 
• If Day and Month of end date are missing:  
The last date of year i.e. December 31 of the year reported or the date of the last study 
contact with the subject, whichever is earlier, will be used as the end date. 
 
• If Year of end date or complete end date is missing:  
If the year of end of medication/event is missing or end date is completely missing, then no 
end date will be imputed. 
 
For the start of a concomitant medication or adverse event: 
 
• If only Day of start date is missing: 
o If the start year and month of medication/event are the same as that for the first dose 
date, then following approach will be used: 
▪ If the end date of medication/event is NOT before the first dose date or end 
date of medication/event is completely missing, then impute the start day as 
the day of first dose date. 
▪ Otherwise, impute the start day as 1. 
 


  
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Rhizen Pharmaceuticals AG                                                         Confidential 
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o If the start year and month of medication/event are NOT same as that for the first 
dose date, then 
▪ Impute the start day as 1. 
 
• If Day and Month of start date are missing: 
 
o If start year of medication/event is same as first dose year, then following approach 
will be used: 
i. 
For medication, impute the start Month as January and the Day as 1 
ii. 
For adverse event, 
▪ If the end date of event is NOT before the first dose date or end date of event is 
completely missing, then impute the start Month and Day as the Month and Day of 
first dose date; 
▪ Otherwise, impute the start Month as January and the Day as 1. 
 
o If start year of medication/event is NOT same as first dose year, then 
▪ Impute start Month as January and the Day as 1. 
 
• If Year of start date or complete start date is missing: 
 
If the year of start of medication/event is missing or start date is completely missing, then no 
start date will be imputed. 
 
9.3.2 Missing Dates for Efficacy Endpoints  
For time-to-event endpoints (Objective Response Rate and Duration of Response), if the last 
objective response date is completely missing, no imputation will be performed. 
 
However, the incomplete/partial dates will be handled following the general conventions as 
detailed in Section 9.3.1. 
 
9.3.3 Missing dates for Primary Diagnosis/Prior therapy 
Partial primary diagnosis and prior therapy dates will have imputation performed as explained 
below for the purposes of calculation of relativity to study medication. 
• If only Day is missing, impute the day 1 
• If Day and Month are missing, impute the Month as January and the Day as 1. 
• If the year of primary diagnosis is missing or the date of primary diagnosis is completely 
missing, then no date will be imputed. 
10. 
Statistical Analysis 
Unless otherwise stated, all statistical analyses will be performed using a two-sided hypothesis 
test at the overall 5% level of significance.  
 


  
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Rhizen Pharmaceuticals AG                                                         Confidential 
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Data will be displayed in all listings sorted by phase, group and patient number. When count 
data are presented, the percentage will be suppressed when the count is zero in order to draw 
attention to the non-zero counts. A row denoted “Missing” will be included in count tabulations 
where necessary to account for dropouts and missing values. Unless otherwise specified, the 
denominator for percentages will be the number of patients with a non-missing assessment in a 
given treatment group within the analysis population of interest.  
 
All the patient data including, demographics, medical history, prior/concomitant medications, 
safety data (where appropriate) and efficacy data will be summarized by following two modes of 
representation: 
 
1. Dose Escalation (Cohort 1, Cohort 2, Cohort 3, All Cohorts), Dose Expansion (Group 1, 
Group 2, Both Groups) and Overall.  
2. PTCL, CTCL and Overall 
 
All statistical analyses will be performed using SAS 9.4 or higher. 
 
10.1 
Patient Disposition 
A tabular presentation of the patient disposition will be provided. It will include the number of 
patients screened, enrolled, dosed, completed the treatment, as well as the number of dropouts, 
with reasons for dropouts, number in each population sets, number of patients with dose 
reduction, drug interruptions (transient discontinuation) and dose discontinuation (permanent 
discontinuation) etc. All patients’ data will be used for this analysis. This data will also be listed. 
 
10.2 
Demographic and Baseline Characteristics 
Analysis set: Safety 
Demographic and baseline characteristics data will be summarized using descriptive statistics (n, 
mean, standard deviation, median, minimum, and maximum) for continuous variables, and using 
frequencies and percentages for categorical variables.  
Demographic characteristics will include age, race, gender, height, etc. 
 
Disease characteristics will include time from initial diagnosis to treatment, subtype of PTCL, 
subtype of CTCL, staging at screening,  number of prior therapies, number of subject relapsed or 
refractory to the last therapy, time from date of last therapy to study treatment, ECOG 
performance status at screening, etc. 
 
10.3 
Medical and Surgical History  
Analysis set: Safety 
This data will be summarized using frequencies and percentages by System Organ Class and 
Preferred Term. A listing will also be provided. 


  
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Rhizen Pharmaceuticals AG                                                         Confidential 
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The medical history data will be coded using MedDRA dictionary [Version 24.0]. 
 
10.4 
Prior and Concomitant Medications 
Analysis set: Safety 
Concomitant medications are those that were taken while on study drug. Also, the medications / 
non-drug treatments which start after study treatment will be termed as ‘Concomitant’.  
 
Prior medications are those that were taken prior to the first dose of study drug. 
 
The medication data will be coded using WHO-Drug dictionary (WHODRUG GLOBAL B3 
March, 2021) and the non-drug treatments data will be coded using MedDRA dictionary 
[Version 24.0]. 
A summary of frequencies and percentages by ATC level 2 and Preferred Terms and the listing 
of the prior and concomitant treatments taken will be provided.  
 
10.5 
Efficacy Analysis 
Analysis Set: mITT and PP 
All the efficacy analyses will be based on the data collected in the Dose escalation and Dose 
Expansion Phase of the study. 
Note:  The analyses outlined below are subject to availability of adequate data.  
 
10.5.1 Objective Response Rate (ORR)  
It is defined as sum of CR and PR rates, assessed according to the Lugano Classification for 
initial evaluation, staging, and response assessment of Hodgkin/non-Hodgkin lymphoma in 
PTCL patients; and according to the modified Severity Weighted Assessment Tool (mSWAT) in 
CTCL patients.  
Additionally, Disease Control Rate (DCR= CR+PR+SD) will be presented. 
This data will be summarized using frequency, and percentage and the 95% CI (Using exact 
method based on binomial distribution, subject to availability of adequate data). The 
corresponding listing will also be provided.  
Also, the Conversion rate, defined as the conversion from partial response (PR) to CR or from 
SD to PR/CR that occurs during the first 7 months of treatment (till Cycle 8 Day 1) will be 
summarized for the Overall group of patients using frequency, percentage and the 95% CI 
(Using exact method based on binomial distribution, subject to availability of adequate data). 
This data will not be listed. 
 
𝐶𝑜𝑛𝑣𝑒𝑟𝑠𝑖𝑜𝑛 𝑅𝑎𝑡𝑒 = 
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑜𝑛𝑣𝑒𝑟𝑠𝑖𝑜𝑛𝑠∗100
𝑆𝐷 𝑜𝑟 𝑃𝑅 𝑎𝑡 𝑡ℎ𝑒 𝑓𝑖𝑟𝑠𝑡 𝑒𝑓𝑓𝑖𝑐𝑎𝑐𝑦 𝑎𝑠𝑠𝑒𝑠𝑠𝑚𝑒𝑛𝑡
 
 


  
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Rhizen Pharmaceuticals AG                                                         Confidential 
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Note: First efficacy assessment = Cycle 3 Day 1. 
 
10.5.2 Duration of Response (DoR) 
It is defined as time from the initial response to documented disease progression.  
 
The DoR will be presented for patients with confirmed complete response or partial response. 
 
This data will be summarized using the Kaplan-Meier method. Also, data will be displayed 
graphically for: PTCL subjects in dose escalation and dose expansion together, CTCL subjects in 
dose escalation and dose expansion together, and overall.   
The patients who did not progress or die without disease progression will be censored at the date 
of their last disease assessment. The following reports will be generated:  
• The Q1, median and Q3 DoR time will be provided along with 95% CI for the Q1, 
median, and Q3 DoR time will be presented using Brookmeyer-Crowley method (subject 
to availability of adequate data). 
• The number and % of patients with progressive disease will be provided. 
• The number and % of patients censored (further divided by reasons for censoring) will be 
provided. 
• Kaplan-Meier curves will be produced. 
• DoR data will be listed. 
10.5.3 Best Overall Response (BOR) 
It is the best response, as assessed and confirmed by site PI, from the start of the treatment until 
disease progression or discontinuation from the study.  
This data will be summarized using frequency and percentage for CR, PR, SD, and PD, as 
reported in the CRFs for overall subjects. This data will also be listed. 
 
10.6 
Safety Analysis 
10.6.1 Treatment Exposure and Compliance 
Analysis set: Safety 
The treatment exposure and Treatment compliance will be summarized descriptively (n, mean, 
median, standard deviation, minimum and maximum values) and will also be listed. 
• The treatment exposure to the study medication for patient will be calculated as: 
Exposure (day) = Last day of dosing – First Day of dosing + 1  
 
o A summary of duration of treatment (days) will be provided. In addition, a swimmer 
plot for duration on treatment will be provided individually for the patients with 
PTCL, CTCL and Overall. The BOR (CR/ PR/ SD/ PD) obtained for each patient at 
Cycle 3 Day 1 efficacy assessment will be used for representing the responses for 
each patient in graphical representation. 


  
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Rhizen Pharmaceuticals AG                                                         Confidential 
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• The treatment compliance as reported for each patient in the eCRF, will be summarized 
descriptively for each cycle. This data will be listed for individual patient. 
 
Note: If the patient fails to return the study treatment on the scheduled return cycle, then 
that patient data will be not be considered for calculating the compliance at the respective 
return cycle. This approach will be applied for both the summary table and the listing 
presentation of treatment compliance. 
 
10.6.2 Adverse Events 
Analysis set: Safety 
Note: 
• If needed, adverse event data may be presented for all patients. 
• The dose reduction information will be compiled using the treatment exposure page and 
AE page of eCRF through common AE number. 
 
The frequency of adverse events (AEs) will be computed by counting each patient only once per 
MedDRA [Version 24.0] preferred term and according to the maximum NCI CTCAE v.5.0 grade 
attained by the patient over the specified period. The percentage of patients with an event will be 
calculated using the number of patients in the safety analysis set as the denominator. 
 
Standard Summaries of Adverse Events 
 
Treatment Emergent Adverse Events (TEAEs) are those that start on or after the date of first 
dose of study medication. 
 
An overall summary of TEAEs (number and percentage of patients along with the number of 
events) will be presented with the following: 
• Any TEAE 
• Treatment Related TEAEs  
• Serious TEAEs 
• Treatment Related Serious TEAEs 
• Grade 3 or 4 TEAEs 
• Treatment Related Grade 3 or 4 TEAEs 
• DLTs (Note: Applicable for dose escalation phase only) 
• TEAEs leading to drug interruptions 
• Related TEAEs leading to drug interruptions  
• Serious TEAEs leading to drug interruptions  
• Treatment Related Serious TEAEs leading to drug interruptions  
• TEAEs leading to dose reduction 
• Related TEAEs leading to dose reduction  
• Serious TEAEs leading to dose reduction  
• Treatment Related Serious TEAEs leading to dose reductions 


  
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Rhizen Pharmaceuticals AG                                                         Confidential 
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• TEAEs leading to drug withdrawn permanently  
• Treatment Related TEAEs leading to drug withdrawn permanently 
• Serious TEAEs leading to drug withdrawn permanently 
• Treatment Related Serious TEAEs leading to drug withdrawn permanently 
• Fatal TEAEs 
• Treatment Related Fatal TEAEs 
• Protocol-Defined Adverse Events of Special Interest: 
- Pregnancy, abortion, birth defects/congenital anomalies 
- Overdose 
 
Summaries showing the number of patients (n, %) along with number of events by SOC and PT 
will be provided for the following: 
• DLTs (Note: Applicable for dose escalation phase only) 
• TEAEs  
• Related TEAEs 
• Non-TEAEs 
• Grade 3, 4 and 5 TEAEs  
• Related Grade 3, 4 and 5 TEAEs 
• Treatment-Emergent SAEs   
• Related Treatment –Emergent SAEs 
• TEAE with maximum CTCAE grade 
• Treatment-Related TEAEs with maximum CTCAE grade per suspected drug(s) 
[Tenalisib, Romidepsin or Combination] 
• Deaths 
• TEAEs leading to drug interruptions  
• TEAEs leading to dose reduction 
• TEAE leading to drug withdrawn permanently 
 
The adverse events data will also be listed for individual patients. 
• Any non-TEAE 
• TEAEs 
• Related TEAEs  
• SAEs 
• Treatment Emergent Grade 3, 4 and 5 AEs 
• Treatment Related Grade 3, 4 and 5 AEs 
• Treatment Related SAEs  
• TEAEs leading to drug interruptions 
• TEAEs leading to dose reduction 
• TEAE leading to drug withdrawn permanently 
 
10.6.3 Clinical Laboratory Tests 
Analysis Set: Safety 
Laboratory data will be presented per cycle for each phase.  


  
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Baseline will be defined in each phase of the study. The baseline measurement will be the last 
pre-treatment measurement taken on or before Cycle1 Day1 in respective phase. For Dose 
Escalation phase, the baseline will be the last pre-treatment measurement taken on or before the 
Cycle 1 Day 1 dose for Romidepsin, and for Dose Expansion phase, the baseline will be the last 
pre-treatment measurement taken on or before Cycle 1 Day 1 dose of Romidepsin or Tenalisib 
whichever is earlier. 
Absolute values of laboratory parameters will be presented at each visit using descriptive 
statistics (n, mean, median, standard deviation, minimum and maximum values).  
The laboratory data will also be listed. 
A separate listing of patients with abnormal laboratory test values will also be presented. 
 
Hematology 
Chemistry Panel I 
Chemistry Panel II Urinalysis 
Other 
Hematocrit 
Total bilirubin 
Blood glucose 
Blood 
PT 
Hemoglobin 
Alkaline 
phosphatase (ALP) 
Urea or blood urea 
nitrogen 
Glucose 
INR 
CBC with 
differentials 
Alanine 
aminotransferase 
(ALT) 
Albumin 
Protein 
 
Platelet count 
Aspartate 
aminotransferase  
(AST) 
Total protein 
Specific 
gravity 
 
WBC (Total and 
differentials) 
Lactate 
dehydrogenase 
(LDH)  
Total Cholesterol 
Microscopic 
exam 
Red blood cell 
count 
Gamma-glutamyl 
transferase  
 
Triglyceride (TG) 
Absolute 
neutrophil count 
Sodium 
LDL 
Absolute 
lymphocyte count 
Potassium 
HDL 
 
Calcium 
TSH 
 
Phosphorous 
T3 (Total or Free) 
 
Bicarbonate or          
Carbon Dioxide 
(CO2)  
T4 (free) 
 
Chloride 
Creatinine 
 
Magnesium 
 
 
10.6.4 Physical Examinations 
Analysis Set: Safety 
Physical examination data will be listed for Screening visit in each phase of the study. 
A separate listing of patients with abnormal findings will also be presented. 
 


  
Rhizen Pharmaceuticals AG.                                                                                                               RP6530+Romidepsin-1805   
 
Rhizen Pharmaceuticals AG                                                         Confidential 
FINAL 1.0 Dated 09AUGL2021 
 
                                                                                                                                                                               Page 20 of 22 
 
10.6.5 Vital Signs 
Analysis Set: Safety 
Vital signs will include pulse rate, respiratory rate, blood pressure, and temperature 
(oral/axillary). Weight will also be included here.  
 
Baseline will be defined in each phase of the study. The baseline measurement will be the last 
pre-treatment measurement taken on or before Cycle1 Day1 in respective phase. For Dose 
Escalation phase, the baseline will be the last pre-treatment measurement taken on or before the Cycle 1 
Day 1 dose for Romidepsin, and for Dose Expansion phase, the baseline will be the last pre-treatment 
measurement taken on or before Cycle 1 Day 1 dose of Romidepsin or Tenalisib whichever is earlier.  
 
Absolute values of Vital Signs data will be summarized descriptively (n, mean, median, standard 
deviation, minimum and maximum) per cycle for every scheduled timepoint. A listing will also 
be provided. 
 
A separate listing of patients with abnormal vital signs findings will also be presented. 
10.6.6 Electrocardiogram 
Analysis Set: Safety 
• Baseline will be defined in each phase of the study. The baseline measurement will be the 
last pre-treatment measurement taken on or before Cycle1 Day1 in respective phase. For 
Dose Escalation phase, the baseline will be the last pre-treatment measurement taken on or before 
the Cycle 1 Day 1 dose for Romidepsin, and for Dose Expansion phase, the baseline will be the last 
pre-treatment measurement taken on or before Cycle 1 Day 1 dose of Romidepsin or Tenalisib 
whichever is earlier. 
• Absolute values of ECG parameters [PR Interval, HR (heart rate), QT interval, QTcF (QT 
interval with Fridericia's correction), QRS Duration] as collected on CRF will be 
presented through n, mean, median, standard deviation, minimum, and maximum per 
cycle for every scheduled timepoint. 
• A summary of abnormal ECG results will also be provided per cycle in each phase 
including baseline visit using frequencies and percentages. 
• A listing of this data will also be provided.  
• A separate listing for the abnormal ECG values will also be presented. 
 
10.6.7 ECOG 
Analysis Set: Safety 
Baseline will be defined in each phase of the study. The baseline measurement will be the last 
pre-treatment measurement taken on or before Cycle1 Day1 in respective phase. For Dose 
Escalation phase, the baseline will be the last pre-treatment measurement taken on or before the 
Cycle 1 Day 1 dose for Romidepsin, and for Dose Expansion phase, the baseline will be the last 
pre-treatment measurement taken on or before Cycle 1 Day 1 dose of Romidepsin or Tenalisib 
whichever is earlier. 
 


  
Rhizen Pharmaceuticals AG.                                                                                                               RP6530+Romidepsin-1805   
 
Rhizen Pharmaceuticals AG                                                         Confidential 
FINAL 1.0 Dated 09AUGL2021 
 
                                                                                                                                                                               Page 21 of 22 
 
ECOG performance status (0=Normal activity, 1=Symptoms, but ambulatory, 2=In bed < 50% of 
the time, 3 and above=In bed > 50% of the time or 100% bedridden or are Dead), as reported in 
the eCRF, will be summarized per cycle in each phase with number and percentage for each 
status category. This data will also be listed. 
 
11. 
Pharmacokinetic (PK) Analysis 
PK analysis is not applicable for this SAP. The same will be prepared by a Clinical 
pharmacology Clinical Research Organization appointed by Rhizen and the analysis results will 
be shared for inclusion in the study report. 
 
12. 
Exploratory analysis 
The analyses of correlative markers are exploratory and will not be used to guide treatment 
decisions. 
This is not applicable for this SAP. The same will be prepared by Rhizen and the analysis results 
will be shared for inclusion in the study report. 
 
13. 
Protocol Deviations 
Analysis set: Safety 
A full list of protocol deviations for the study report will be compiled prior to database lock.  All 
deviations will be reviewed by the Medical monitor prior to database lock. Each deviation will be 
categorized as major and minor and a decision will be taken by the medical monitor whether to 
include the subject in a PP analysis population set. 
Protocol deviations will be presented as number and percentage of patients with minor and major 
deviations in the study. This data will also be listed as appropriate. 
 
14. 
Listings 
In addition to all the listings mentioned above, separate listings will be presented for the following: 
• Screened patients 
• Patients Eligibility 
• Patient visits 
• Study completion/Reasons for discontinuation/withdrawal of patient from the study 
• Analysis populations 
• Cancer Diagnosis  
• Prior therapy 
• mSWAT assessment 
• Serology Assessment 
• Study drug exposure 
• Study drug accountability 
• Target lesion assessment 
• Non-target lesion assessment 


  
Rhizen Pharmaceuticals AG.                                                                                                               RP6530+Romidepsin-1805   
 
Rhizen Pharmaceuticals AG                                                         Confidential 
FINAL 1.0 Dated 09AUGL2021 
 
                                                                                                                                                                               Page 22 of 22 
 
• Disease Response assessment 
• Overall tumor assessment 
• Pregnancy test 
• Investigator’s Comments 
 
15. 
References  
1. Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. Biometrics. 
38: 29-41, 1982.