Clinical trial NCT04028388
Conditions: Prostate Cancer Metastatic Castration-resistant Prostate Cancer
Sponsor: Modra Pharmaceuticals
Start date: 2019-07-17; Completion date: 2021-11-29
Enrollment: 135 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter phase 2b study to evaluate the efficacy and tolerability of ModraDoc006 in combination with ritonavir (denoted ModraDoc006/r) in patients with metastatic castration-resistant prostate cancer, suitable for treatment with a taxane.

Detailed description:
This is an open label 1:1 randomized Phase 2b trial to determine the efficacy and tolerability of oral ModraDoc006/r versus i.v. docetaxel in mCRPC subjects. Cohort 1 will receive i.v. docetaxel at 75 mg/m2 every 3 weeks (Q3W). Cohort 2 will receive 30 mg ModraDoc006 in combination with 200 mg ritonavir in the morning and 20 mg ModraDoc006 in combination with 100 mg ritonavir in the evening (7-12 hours after the morning dose), on Day 1, 8 and 15 of a 21-day cycle (BIDW). All patients will also receive 5 mg oral prednisone twice daily. Treatment in both cohorts will continue until disease progression, unacceptable toxicity, or discontinuation for any other reason. The end of the trial is defined as the time point when all subjects have discontinued trial treatment and have been given follow-up for safety measurements according to the trial assessment schedule.

Arms: arm 1: This study arm will receive docetaxel at 75 mg/m2 given i.v. as a one-hour infusion on day 1 every 21 days plus 5 mg oral prednisone twice daily. arm 2: This cohort will receive ModraDoc006/r 30 mg oral docetaxel in combination with 200 mg ritonavir in the morning and 20 mg oral docetaxel in combination with 100 mg ritonavir in the evening (7-12 hours after the morning dose), on Day 1, 8 and 15 of a 21-day cycle, plus 5 mg oral prednisone twice daily.
Interventions: intervention 1: Docetaxel in Parenteral Dosage Form intervention 2: ModraDoc006/r
Intervention descriptions: intervention 1: Treatment with IV docetaxel at 75 mg/m2 given as a one-hour infusion on day 1 every 21 days plus 5 mg oral prednisone twice daily intervention 2: Treatment with twice daily once weekly (BIDW) ModraDoc006 (oral docetaxel) 10mg tablets in combination with ritonavir 100mg tablets

Protocol documents:
Prot_000.pdf: 
Modra Pharmaceuticals 
Clinical Trial Protocol, Amendment 2 
 Final Version V3.0  
ModraDoc006/r 
M18MDP 
31 Mar 2020 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
Protocol Title  
“A multicentre Phase IIb trial to evaluate the efficacy and 
tolerability of ModraDoc006/r in subjects with metastatic 
Castration Resistant Prostate Cancer (mCRPC), suitable for 
treatment with a taxane” 
EudraCT / IND  
2019-000582-21 / IND 140355 
Clinical Phase  
IIb 
Protocol No. 
M18MDP 
Compound 
ModraDoc006/r 
Sponsor  
Modra Pharmaceuticals 
Barbara Strozzilaan 201 
1083 HN Amsterdam, The Netherlands 
Phone:   +31 (0) 20-205 0188 
 
Version 
Final Version 3.0 
Date  
31 Mar 2020 
 
Confidential 
This document contains Modra Pharmaceuticals information that is confidential, a trade–secret and/or 
proprietary in nature. It is provided to you for your confidential review on behalf of Modra 
Pharmaceuticals and is not to be photocopied, disclosed or transmitted to any other person or party 
who is not covered by a Confidential Disclosure Agreement with Modra Pharmaceuticals except that 
the document may be disclosed to appropriate Institutional Review Boards (IRB) or Ethics 
Committees (EC) as long as they are required to maintain its confidentiality. As the Principal 
Investigator you are responsible for the safekeeping and return of this document to Modra 
Pharmaceuticals upon request. You will be sent updated information and/or amendments as they 
become available. 


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M18MDP 
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PROTOCOL SIGNATURE PAGE SPONSOR 
 
Protocol No.: 
M18MDP 
Compound: 
ModraDoc006/r 
Title: 
“A multicentre Phase IIb trial to evaluate the efficacy and 
tolerability of ModraDoc006/r in subjects with metastatic 
Castration Resistant Prostate Cancer (mCRPC), suitable for 
treatment with a taxane” 
Issue Date / Version 
31 Mar 2020 / Final V3.0 
Sponsor name: 
Modra Pharmaceuticals 
Sponsor address: 
Barbara Strozzilaan 201 
1083 HN Amsterdam, The Netherlands 
Phone: +31 (0) 20-205 0188 
 
 
By signing below, the Sponsor agrees to the content of the Protocol as outlined. 
 
 
J.H.M. Schellens, MD, PhD 
 
01-Apr-2020 
Chief Medical Officer  
 
Signature 
 
Date 
[PRINT IN BLOCK CAPITAL LETTERS] 
 
 
C. Freund, MA 
 
01-Apr-2020 
Chief Executive Officer  
 
Signature 
 
Date 
[PRINT IN BLOCK CAPITAL LETTERS] 
 
 
 


Modra Pharmaceuticals 
Clinical Trial Protocol, Amendment 2 
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ModraDoc006/r 
M18MDP 
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Confidential 
 
 
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PROTOCOL SIGNATURE PAGE INVESTIGATOR  
 
Protocol No.: 
M18MDP 
Compound: 
ModraDoc006/r 
Title: 
“A multicentre Phase IIb trial to evaluate the efficacy and 
tolerability of ModraDoc006/r in subjects with metastatic 
Castration Resistant Prostate Cancer (mCRPC), suitable for 
treatment with a taxane” 
Issue Date / Version: 
31 Mar 2020 / Final V3.0 
Institution Name (Site #): 
 
Institution Address:  
 
 
I have read this protocol and agree to conduct this trial in accordance with all stipulations of the 
protocol and in accordance with all relevant local regulations, the current International 
Conference on Harmonization (ICH) of Technical Requirements for Registration of 
Pharmaceuticals for Human Use Guideline for Good Clinical Practice (GCP), and with the 
principles of the most recent version of the Declaration of Helsinki. 
 
 
 
 
Investigator Name  
 
Signature 
 
Date 
[PRINT IN BLOCK CAPITAL LETTERS] 
 
 
 
 
 


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DOCUMENT HISTORY  
 
M18MDP* 
Document 
Protocol 
version 
Issue date 
Amendment 
type 
Comments 
Clinical Trial 
Protocol 
1.2 
31 Jan 2019 
- 
New Protocol 
Amendment 1 
2.0 
05 Mar 2019 
 
Includes clarifications on exclusion 
criteria, dose modifications and 
administrative aspects. 
Amendment 2 
3.0 
31 Mar 2020 
 
Includes change from Objective Response 
Rate (ORR) to radiographic Progression 
Free Survival (rPFS) as primary endpoint; 
adaption of starting dose for 
ModraDoc006/r (arm B); harmonization of 
assessments for both arms; widening of 
screening window; minor clarifications 
and corrections. 
 
 
 
 
 
 
 
 
 
 
*This overview only lists general amendments to the protocol. Site- and country-specific amendments to the protocol 
are not included. 
 
 


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CONTACT DETAILS 
At Modra Pharmaceuticals (Sponsor) 
 
Company Address 
Barbara Strozzilaan 201 
1083 HN Amsterdam 
The Netherlands 
Phone: +31 (0) 20-205 0188 
Email: info@modrapharmaceuticals.com 
 
Head of Oncology 
Development 
Edwin de Wit, MD 
Mobile phone: +41 79 672 2865 
Email: edwin.dewit@modrapharmaceuticals.com 
Project Director 
Marianne Keessen 
Mobile phone: +31 629 025 013 
Email: marianne.keessen@modrapharmaceuticals.com 
Chief Medical Officer 
Jan Schellens, MD PhD 
Mobile phone: +31 651 294 436 
Email: jan.schellens@modrapharmaceuticals.com 
Chief Executive Officer 
Colin Freund 
Mobile phone: +1 (609) 933 8008 
Email: colin.freund@modrapharmaceuticals.com  
 
 
At Covance (Contract Research Organisation) 
 
Project Management 
Covance Inc. 
www.covance.com  
Pharmacovigilance 
 
 
Szymon Wroblewski 
Drug Safety Project Manager 
Phone: +48 667 000 075 
E-mail : Szymon.Wroblewski@covance.com 
www.covance.com 
Covance (Polska) Sp. z o.o., Wspólna 47/49, 00-684 Warsaw, 
Poland 
Medical Monitoring 
 
 
Oxana Bzhadug, MD 
Tel. +7 495 787-16-41 
E-mail: Oxana.Bzhadug@covance.com 
www.covance.com 
Millenium House Business Center, 4th Floor, Office A, 
12 Trubnaya St., 107045 Moscow, Russian Federation 
 
A list of all participating investigators is available in the Trial Master File and Investigator File. 


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TABLE OF CONTENTS 
 
PROTOCOL SIGNATURE PAGE INVESTIGATOR ...................................................................3 
DOCUMENT HISTORY.................................................................................................................4 
CONTACT DETAILS .....................................................................................................................5 
TABLE OF CONTENTS .................................................................................................................6 
LIST OF TABLES ...........................................................................................................................9 
LIST OF FIGURES .......................................................................................................................10 
LIST OF APPENDICES ................................................................................................................10 
LIST OF TERMS AND ABBREVIATIONS ................................................................................11 
PROTOCOL SYNOPSIS...............................................................................................................14 
1. 
INTRODUCTION ......................................................................................................23 
1.1. 
Description of the Investigational Medicinal Product (IMP) .....................................26 
1.1.1. 
ModraDoc006 .............................................................................................................26 
1.1.2. 
Ritonavir .....................................................................................................................27 
1.1.3. 
Pre-Clinical Information .............................................................................................27 
1.2. 
Clinical Data ...............................................................................................................27 
1.2.1. 
Trial 1: Once daily, once weekly ModraDoc006/r .....................................................27 
1.2.2. 
Trial 2: Bi-daily, once weekly ModraDoc006/r..........................................................28 
1.2.3. 
Trial 3: Bi-daily, once weekly ModraDoc006/r in patients with mCRPC..................28 
1.3. 
Trial and Dosing Rationale .........................................................................................32 
1.3.1. 
Ritonavir .....................................................................................................................32 
1.3.2. 
ModraDoc006/r ...........................................................................................................32 
1.3.3. 
ModraDoc006/r in mCRPC ........................................................................................33 
1.4. 
Potential Benefits and Risks .......................................................................................34 
1.4.1. 
Benefits of IMP ...........................................................................................................34 
1.4.2. 
Management of Risks .................................................................................................34 
1.4.3. 
Benefit/Risk Ratio ......................................................................................................35 
2. 
TRIAL OBJECTIVES AND ENDPOINTS ...............................................................36 
2.1. 
Primary Objectives .....................................................................................................36 
2.2. 
Secondary Objectives .................................................................................................36 
2.3. 
Endpoints ....................................................................................................................36 


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2.3.1. 
Efficacy .......................................................................................................................36 
2.3.2. 
Safety ..........................................................................................................................37 
2.3.3. 
Health Related Quality of Life (HRQoL) ...................................................................37 
3. 
TRIAL DESIGN .........................................................................................................39 
3.1. 
Overall Trial Design ...................................................................................................39 
3.2. 
Sample Size ................................................................................................................40 
3.3. 
End of Trial .................................................................................................................40 
4. 
SELECTION OF PATIENTS .....................................................................................42 
4.1. 
Trial Population ..........................................................................................................42 
4.2. 
Inclusion Criteria ........................................................................................................42 
4.3. 
Exclusion Criteria .......................................................................................................43 
5. 
TRIAL TREATMENT ...............................................................................................45 
5.1. 
Identity of Investigational Medicinal Product (Trial Drug) .......................................45 
5.1.1. 
Description of the IMP ...............................................................................................45 
5.1.2. 
Formulation, preparation and labelling of ModraDoc006 ..........................................45 
5.1.3. 
Preparation and labelling of i.v. docetaxel .................................................................45 
5.2. 
Drug accountability ....................................................................................................45 
5.3. 
Compliance and handling of study drug .....................................................................46 
5.3.1. 
Accountability Procedures ..........................................................................................46 
5.4. 
Administration of i.v. docetaxel .................................................................................46 
5.4.1. 
Dose and Schedule of i.v. docetaxel according to standard of care............................46 
5.4.2. 
Dose Modifications i.v. docetaxel ..............................................................................47 
5.5. 
Administration of ModraDoc006/r .............................................................................47 
5.5.1. 
Dose and Schedule of ModraDoc006/r .......................................................................47 
5.5.2. 
Premedication and supportive care for ModraDoc006/r.............................................48 
5.5.3. 
Dose Modifications of ModraDoc006/r ......................................................................51 
5.6. 
End of Treatment ........................................................................................................55 
5.7. 
Prior and Concomitant Treatments .............................................................................55 
5.8. 
Contraception ..............................................................................................................57 
5.9. 
Drug accountability ....................................................................................................58 
6. 
INVESTIGATIONAL PLAN .....................................................................................59 
6.1. 
Trial Assessment Specifications .................................................................................59 
6.2. 
Screening Visit(s) and Registration of Patients ..........................................................61 


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6.2.1. 
Screening Visit(s) .......................................................................................................61 
6.3. 
Patient Registration and Randomization ....................................................................62 
6.4. 
Treatment Visit(s) .......................................................................................................62 
6.5. 
End of Treatment Visit ...............................................................................................62 
6.6. 
Follow-up Visit ...........................................................................................................62 
6.7. 
Assessment of Safety ..................................................................................................63 
6.8. 
Withdrawal, Discontinuation and Replacement of Patients .......................................65 
6.8.1. 
Withdrawal .................................................................................................................65 
6.8.2. 
Discontinuation ...........................................................................................................65 
6.8.3. 
Replacement of Patients .............................................................................................65 
6.9. 
Assessment of Efficacy ...............................................................................................66 
6.9.1. 
Clinical efficacy assessments......................................................................................66 
6.9.2. 
Determination of Radiographic Disease Progression .................................................67 
7. 
ADVERSE EVENTS ..................................................................................................68 
7.1. 
Definitions ..................................................................................................................68 
7.1.1. 
Adverse Event (AE) ....................................................................................................68 
7.1.2. 
Adverse Drug Reaction (ADR) ..................................................................................69 
7.1.3. 
Unexpected Adverse Drug Reaction...........................................................................69 
7.1.4. 
Serious Adverse Event (SAE) ....................................................................................69 
7.1.5. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) .....................................69 
7.1.6. 
Toxic Death ................................................................................................................70 
7.2. 
Monitoring, Reporting, and Documentation of Adverse Events ................................70 
7.2.1. 
Monitoring of AEs ......................................................................................................70 
7.2.2. 
Documentation of AEs ...............................................................................................70 
7.2.3. 
Reporting of Serious Adverse Events .........................................................................71 
7.2.4. 
Pharmacovigilance Contact for Reporting SAEs........................................................72 
8. 
STATISTICAL METHODS .......................................................................................73 
8.1. 
Data Analysis Considerations .....................................................................................73 
8.2. 
Population for Analysis ..............................................................................................75 
8.2.1. 
Safety analysis ............................................................................................................75 
8.2.2. 
Population evaluable for radiological response ..........................................................75 
8.3. 
Clinical Efficacy .........................................................................................................75 
8.4. 
Safety ..........................................................................................................................76 


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8.5. 
Interim Analysis ..........................................................................................................76 
9. 
DATA MANAGEMENT AND MONITORING .......................................................77 
9.1. 
Data Collection, Validation and Handling ..................................................................77 
9.2. 
Data Review ................................................................................................................77 
9.3. 
Medical Coding ..........................................................................................................78 
9.4. 
Quality Control and Quality Assurance ......................................................................78 
10. 
ADMINISTRATIVE ASPECTS ................................................................................79 
10.1. 
Maintenance of Patient Records .................................................................................79 
10.2. 
Investigator Site File (ISF) .........................................................................................79 
10.3. 
Handling of Investigational Product ...........................................................................79 
10.4. 
Drug Accountability ...................................................................................................79 
10.5. 
Protocol Deviations ....................................................................................................80 
10.6. 
Procedures for Protocol Amendments ........................................................................80 
11. 
ETHICAL AND LEGAL CONSIDERATIONS ........................................................81 
11.1. 
Regulatory Authority / Independent Ethics Committees ............................................81 
11.2. 
Site Review .................................................................................................................81 
11.3. 
Informed Consent .......................................................................................................81 
11.4. 
Confidentiality ............................................................................................................82 
11.5. 
Insurance .....................................................................................................................82 
11.6. 
Publication Policy .......................................................................................................83 
12. 
REFERENCES .........................................................................................................124 
 
LIST OF TABLES 
Table 1: 
Overall and progression free survival and PSA response in mCRPC patients 
treated with first line docetaxel in different studies. ...................................................24 
Table 2 
Adverse Events Reported During ModraDoc006/r Study with BIDW (Twice 
Daily, Once Weekly) Dosing in mCRPC patients ......................................................29 
Table 3 
Pharmacokinetic results of ModraDoc006/r (docetaxel and ritonavir) with 
BIDW (Twice Daily, Once Weekly) dosing in mCRPC ............................................31 
Table 4: 
Dose modifications for i.v. docetaxel .........................................................................47 
Table 5: 
ModraDoc006/r treatment ..........................................................................................48 
Table 6: 
Premedication before ModraDoc006/r .......................................................................49 
Table 7: 
Anti-emetic therapy ....................................................................................................49 


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Table 8: 
Diarrhea - Supportive treatment and Dose Modifications ..........................................50 
Table 9: 
Dose modifications for ModraDoc006/r in case of hematological toxicity................52 
Table 10: Dose modifications for ModraDoc006/r in case of non-hematological 
toxicity ........................................................................................................................53 
Table 11: Dose modifications for ModraDoc006/r .....................................................................54 
Table 12: Dose modifications for ModraDoc006/r under amendment 1 ....................................54 
Table 13: Trial Assessments .......................................................................................................60 
Table 14: Overview of Safety Assessments ................................................................................63 
Table 15:  Overview of Clinical Efficacy Assessments ...............................................................66 
Table 16:  Protocol-Specified Documentation for Radiographic Evidence of Disease 
Progression .................................................................................................................67 
 
LIST OF FIGURES 
Figure 1: 
Structural formula of docetaxel. .................................................................................26 
Figure 2 
Efficacy of ModraDoc006/r in mCRPC patients ........................................................32 
Figure 3: 
Schematic of study design. .........................................................................................39 
Figure 4: 
Study schedule cohort 1 ..............................................................................................47 
Figure 5:  Study schedule cohort 2 ..............................................................................................48 
 
LIST OF APPENDICES 
Appendix I: Assessments ............................................................................................................84 
Appendix II: WHO Performance Status Scale............................................................................86 
Appendix III: Common Terminology Criteria for Adverse Events (CTCAE) v5.0 ...................87 
Appendix IV: RECIST v1.1 - Tumor Evaluation Criteria ..........................................................88 
Appendix V: PCWG3 Recommendations ..................................................................................93 
Appendix VI: Quality of life Questionnaires ............................................................................101 
Appendix VII: Structured Risk Analysis ..................................................................................114 
Appendix VIII: Drug-Drug Interactions ...................................................................................116 
 


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LIST OF TERMS AND ABBREVIATIONS 
ADR 
Adverse Drug Reaction 
ADT 
Androgen Deprivation Therapy 
AE 
Adverse Event 
ALAT 
Alanine Amino Transferase 
ANC 
Absolute Neutrophil Count 
ASAT 
Aspartate Amino Transferase 
ASI 
Additional Safety Information 
AUC 
Area Under the Plasma Concentration-Time Curve 
BID 
Bis In Die (twice daily) 
BIDW 
Twice daily once weekly 
Cmax 
Maximum Concentration in Plasma Concentration-Time Curve 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CR  
Complete Response 
CRA 
Clinical Research Associate 
CRF 
Case Record Form 
CRO 
Contract Research Organisation 
CRPC 
Castration Resistant Prostate Cancer 
CYP 
Cytochrome P450 – main drug metabolizing enzyme system 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
ECG  
Electrocardiogram 
EEA 
European Economic Area 
EMA 
European Medicines Agency 
eCRF 
Electronic Case Report Form 
EOT 
End of Treatment 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FAS 
Full Analysis Set 
FDA 
US Food and Drug Administration 
GCP  
Good Clinical Practice 
GDPR 
General Data Protection Regulations 


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GGT 
Gamma-Glutamyl Transferase 
GI 
Gastro-intestinal 
GMP 
Good Manufacturing Practice 
HNPC 
Hormone Naïve Prostate Cancer 
HRQoL 
Health Related Quality of Life 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Central Ethical Committee 
IMP 
Investigational Medicinal Product 
IV (or i.v.) 
Intravenous 
LDH 
 
Lactate Dehydrogenase 
LPLV 
Last Patient Last Visit 
m (in mCRPC) 
metastatic 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI  
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria of Adverse 
Events 
ORR 
Objective Response Rate 
OS  
Overall Survival 
PCWG3 
Prostate Cancer Clinical Trials Working Group 3  
PD 
Progressive disease (or also Pharmacodynamics) 
PFS 
Progression-Free Survival 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PR 
Partial Response 
PSA 
Prostate Specific Antigen 
PSA RR 
PSA Response Rate 
QW 
Once every week 
r (in rPFS) 
radiographic 
/r (in ModraDoc006/r) 
ritonavir 


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RA 
Regulatory Authority 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE  
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SC 
Subcutaneous 
SD 
Stable Disease 
SNP 
Single Nucleotide Polymorphism 
SOP 
Standard Operating Procedure 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Biological or terminal Half-Life 
tmax 
Time after Which the Peak Plasma Concentration is Achieved 
ULN 
Upper Limit of Normal 
WBC  
White Blood Cell 
WHO  
World Health Organisation 


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PROTOCOL SYNOPSIS 
Protocol Title 
“A multicentre Phase IIb trial to evaluate the efficacy and tolerability 
of ModraDoc006/r in subjects with metastatic Castration Resistant 
Prostate Cancer (mCRPC), suitable for treatment with a taxane” 
Protocol Number 
M18MDP 
Clinical Phase 
IIb 
Trial Background 
Modra Pharmaceuticals has developed an oral tablet formulation of 
docetaxel, which is called ModraDoc006. ModraDoc006 is 
co-administered with ritonavir (/r), a CYP3A4 and P-glycoprotein 
(P-gp) inhibitor, to increase the bioavailability of docetaxel. This 
results in increased exposure, as measured by area under the plasma 
concentration-time curve (AUC). The combination is denoted 
ModraDoc006/r. By the nature of its disposition after oral absorption 
the ModraDoc006/r combination is designed to have a lower toxicity 
than i.v.  docetaxel, but at least comparable efficacy. The lower 
toxicity of ModraDoc006/r can be explained by its >10-fold lower 
maximum plasma concentration (Cmax) compared with i.v. 
docetaxel at a comparable AUC over a time period of three weeks, 
which is defined as one cycle. ModraDoc006/r has been evaluated in 
several clinical trials in which patients have been treated for up to 72 
weeks. 
The proposed Phase IIb trial aims to investigate the efficacy and 
tolerability of the ModraDoc006/r combination in subjects with 
metastatic Castration Resistant Prostate Cancer (mCRPC) versus i.v. 
docetaxel. 
Trial Rationale 
For patients with mCRPC, prognosis remains poor with a median 
survival of between 9 and 13 months. According to current 
guidelines, docetaxel is given in 3-weekly i.v. administrations as first 
line systemic chemotherapy, with a survival benefit of 2.4 months. 
Considering the milder safety profile of oral ModraDoc006/r, with 
less neurotoxicity and less neutropenia than docetaxel i.v., together 
with comparable systemic exposure and higher patient convenience, 
oral docetaxel in the form of ModraDoc006/r may offer a better 
treatment option to these patients. 
Primary Objective 
To determine the efficacy of ModraDoc006/r, as measured by 
radiographic Progression Free Survival (rPFS), compared to standard 
treatment with i.v. docetaxel in subjects with mCRPC. 
Secondary Objectives 
• 
To evaluate the efficacy of ModraDoc006/r, as measured by 
PCWG3-modified RECIST v1.1 criteria of objective response 
rate (ORR), disease control rate (DCR) and duration of response 
(DOR) compared to standard treatment with i.v. docetaxel in 
subjects with mCRPC. 
• 
To evaluate the clinical outcome in terms of rPFS at 6 months 
and time to progression (TTP) of ModraDoc006/r compared to 
i.v. docetaxel 


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• 
To evaluate the outcome in terms of PSA tumor marker 
evaluation for PSA response, PSA-PFS and time to PSA 
progression of ModraDoc006/r compared to i.v. docetaxel 
• 
To compare the time to first skeletal-related event between 
ModraDoc006/r and i.v. docetaxel 
• 
To determine the safety and tolerability of ModraDoc006/r 
compared to i.v. docetaxel 
• 
To compare subject’s Health Related Quality of Life (HRQoL) 
response of ModraDoc006/r and docetaxel i.v.  
Trial Design 
This is an open label 1:1 randomized Phase IIb trial to determine the 
efficacy and tolerability of oral ModraDoc006/r versus i.v. docetaxel 
in mCRPC subjects. Cohort 1 will receive i.v. docetaxel at 75 mg/m2 
Q3W. Cohort 2 will receive 20 mg ModraDoc006 in combination 
with 200 mg ritonavir in the morning and 20 mg ModraDoc006 in 
combination with 100 mg ritonavir in the evening (7-12 hours after 
the morning dose), on Day 1, 8 and 15 of a 21-day cycle. All patients 
will also receive 5 mg oral prednisone twice daily. Treatment in both 
cohorts will continue until disease progression, unacceptable 
toxicity, or discontinuation for any other reason. The end of the trial 
is defined as the time point when all subjects have discontinued trial 
treatment and have been given follow-up for safety measurements 
according to the trial assessment schedule. 
Trial Endpoints 
Primary endpoints: 
• 
Radiographic Progression Free Survival (rPFS) according to 
PCWG3 criteria 
Secondary endpoints:  
Efficacy endpoints: 
• 
Objective Response Rate (ORR)  
• 
Disease control rate (DCR) 
• 
Duration of response (DOR)  
• 
Radiographic Progression Free Survival (rPFS) at 6 months 
according to PCWG3 criteria 
• 
Time to progression (TTP)  
• 
PSA response rate according to PCWG3 criteria 
• 
Progression free survival (PFS) at 6 months  
• 
PSA-PFS according to PCWG3 criteria  
• 
Time to PSA progression 
• 
Time to first skeletal event 
Safety endpoints:  
• 
Adverse events (AEs) and serious adverse events (SAEs), 
according to the current National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) 
v5.0 
• 
Assessments of e.g.: physical examinations, body weight, vital 
signs, WHO performance status, changes in hematology and 
biochemistry, electrocardiogram (ECG) 
HRQoL endpoints: 


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• 
Health Related Quality of Life (HRQoL) as assessed by FACT 
global, FACT-P and FACT-taxane, Treatment Satisfaction and 
EQ-5D questionnaires: 
• 
Overall HRQoL improvement  
• 
Improvements in the individual HRQoL domains  
• 
Time to HRQoL deterioration 
• 
Overall Health Related Utility 
Number of Subjects 
A total of 100 subjects evaluable for radiological response according 
to PCWG3 will be included in the trial and randomized 1:1 into 
cohort 1 and cohort 2. 
Subjects will not be replaced unless they fail to receive any 
administration of docetaxel i.v./ oral ModraDoc006/r or they fail to 
undergo any efficacy assessment after baseline measurement. 
Trial Population 
This trial will include subjects with metastatic castration resistant 
prostate cancer (mCRPC) eligible for first line systemic 
chemotherapy with docetaxel according to standard of care, 
following progression on hormonal therapies.   
Inclusion Criteria 
To be eligible to participate in this trial, subjects must meet all of the 
following eligibility criteria: 
1. 
Age ≥ 18 years 
2. 
Histologically or cytologically proven prostate cancer with 
evidence of progressive mCRPC, defined as:  
a. 
Castrate levels of testosterone, defined as ≤ 50 ng/dL (or ≤ 
0.50 ng/mL or 1.73 nmol/L) 
b. Evidence of progressive metastatic disease as defined by 
radiographic disease progression or PSA progression   
c. 
With an indication for systemic treatment with docetaxel 
according to the standard of care 
3. 
Evaluable disease, defined as nodal or visceral lesions as 
evaluated with CT-scan or MRI, and measured according to 
RECIST v1.1. and/or bone metastasis as evaluated with 
99mTc-methylene diphosphonate (MDP) radionuclide bone 
scintigraphy by PCWG3 criteria 
4. 
Resolution of toxicity of prior therapy to < grade 2 (except 
for alopecia), as defined by CTCAE v5.0. For any pre-
existing gastro-intestinal toxicities (diarrhea or 
nausea/vomiting) and mucositis, full resolution is required 
prior to study start. 
5. 
Adequate haematological, renal and hepatic functions: 
a. Haemoglobin   mmol/l (>9.6 g/dL) 
b. ANC ≥ 1.5 x 109 /L 
c. Platelet count ≥ 100 x 109 /L 
d. Hepatic function defined by serum bilirubin  ULN, 
ALAT and ASAT  1.5 x ULN concomitant with 
alkaline phosphatase  2.5 × ULN. 


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e. Renal function defined by serum creatinine  1.5 x 
ULN or creatinine clearance  50 ml/min (by 
Cockcroft-Gault formula, or MDRD). 
6. 
WHO performance status of 0-2 
7. 
Estimated life expectancy of at least 12 weeks 
8. 
Able and willing to swallow oral medication 
9. 
Able and willing to undergo radiologic scans (CT scan) 
10. 
Able and willing to give written informed consent according 
to local guidelines 
Exclusion Criteria 
Subjects who meet ANY of the following criteria at screening will 
be excluded from trial entry: 
1. Any treatment with investigational drugs, chemotherapy or 
immunotherapy within 4 weeks prior to receiving the first dose 
of investigational treatment. Palliative radiotherapy (1x8 Gy 
dose) is allowed before and during the study, but not in the week 
prior to start of study treatment.  
2. Subjects who have had prior treatment with taxanes. 
3. Subjects with symptomatic brain metastases. Subjects 
asymptomatic in the absence of corticosteroids and 
anticonvulsant therapy for ≥6 weeks are eligible. Radiotherapy 
for brain metastasis must have been completed ≥6 weeks prior to 
start of trial. Brain metastasis must be stable with verification by 
imaging (e.g. brain MRI or CT completed at screening, 
demonstrating no current evidence of progressive brain 
metastases). Subjects are not permitted to receive anti-epileptic 
drugs or corticosteroid treatment indicated for brain metastasis. 
Subjects with a history of leptomeningeal metastases are not 
eligible.  
4. Current malignancies other than mCRPC with exception of 
adequately treated basal or squamous cell carcinoma of the skin, 
or adequately treated non-muscular invasive bladder cancer. 
5. Absence of highly effective method of contraception as of cycle 
one day one (C1D1). Men enrolled in this trial must agree to use 
a highly effective contraceptive method throughout the study. 
6. Uncontrolled hypertension (systolic > 150 mm Hg and/or 
diastolic > 100 mm Hg) 
7. Grade ≥ 2 motor or sensory neuropathy symptoms (as defined by 
CTCAE version 5.0)  
8. Known hypersensitivity to any of the study drugs or excipients 
or taxanes 
9. Concomitant use of P-glycoprotein (P-gp , MDR), CYP3A, 
OATP1B1, OATP1B3 and MRP2 modulating drugs such as 
Ca+- entry blockers (verapamil, dihydropyridines), cyclosporine, 


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quinidine and grapefruit juice, concomitant use of HIV 
medications, other protease inhibitors, (non) nucleoside 
analogues, or St. John’s wort 
10. Bowel obstruction or motility disorder that may influence the 
resorption of drugs as judged by the treating physician 
11. Major surgical procedures within 21 days prior to providing 
informed consent 
12. Active acute or chronic infection, which is not controlled by 
appropriate medication (at the discretion of the treating 
physician) 
13. Known positivity for Human Immunodeficiency Virus HIV-1 or 
HIV-2 type 
14. Patients with known active infection of hepatitis B, C, or E 
(patients who are anti-HBC positive but HBsAg negative are 
eligible to participate in this study) 
15. Clinically significant (i.e. active) cardiovascular disease defined 
as stroke, transient ischemic attack (TIA), myocardial infarction, 
unstable angina, or congestive heart failure within ≤ 6 months 
prior to first trial treatment  
16. Evidence of any other medical conditions (such as treatment-
resistant peptic ulcer disease, erosive oesophagitis or gastritis, 
infectious or inflammatory bowel disease, diverticulitis, or 
pulmonary embolism within 4 weeks of randomization, or 
psychiatric illness, drug or alcohol abuse, physical examination 
or laboratory findings) that may interfere with the planned 
treatment, affect subject compliance or place the subject at high 
risk of treatment-related complications 
17. Legal incapacity 
Trial Duration 
The trial will include four weeks of screening (max.) and three 
weeks per treatment cycle in both trial cohorts. Subjects may 
continue to receive study medication until the subject experiences 
disease progression, unacceptable toxicity, request by subject or 
physician to discontinue treatment, death, or termination of the trial 
by the Sponsor. The duration of the trial for each individual subject 
may therefore be different. Each subject should attend an end of 
treatment (EOT) visit and a follow up (FU) visit as described in the 
trial schedule. The end of trial will be reached when all subjects have 
discontinued trial treatment, or 10 months after last patient enrolled, 
whichever comes first.  
Dosage and Schedule 
Subjects eligible for the trial will receive: 
• 
Cohort 1: on Day 1 of each cycle docetaxel i.v. Q3W at 
75 mg/m2. Each treatment cycle consists of 21 days. 
Recommended premedication with dexamethasone 8 mg at 12h, 
3h, and 1h before infusion, though local hospital standard will be 
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• 
Cohort 2: twice daily on Day 1, 8 and 15 of each cycle 
ModraDoc006/r at 20/20 mg (morning/evening) in combination 
with ritonavir 200/100 mg (morning/evening). Each treatment 
cycle consists of 21 days. Premedication with dexamethasone is 
not necessary. 
• 
Continuous prednisone 2dd 5mg will be given in both cohorts. 
 
Note: Patients enrolled under protocol amendment 1, who are dosed 
with 30 mg of ModraDoc006 combined with 200 mg ritonavir in the 
morning and 20 mg of ModraDoc006 combined with 100 mg 
ritonavir in the evening, will, at the investigator’s discretion, be able 
to continue at this dose. 
Dose Modification Criteria 
Dose reductions should be implemented due to toxicities as defined 
in section 5.4.2 and 5.5.3, which have been assessed by the 
Investigator as possibly, probably or definitely related to study drug. 
These toxicities may occur during the study despite adequate 
supportive care.  
One dose reduction of i.v. docetaxel is allowed from 75 mg/m2 to 
60 mg/m2, as described in Section 4.4. If a patient requires more 
than the allowed dose-reduction, study treatment needs to be 
discontinued. 
One dose reduction of ModraDoc006/r is allowed according to the 
step described in the table below. If a patient requires more than the 
allowed dose-reduction, study treatment needs to be discontinued. 
  
Dose 
Standard dose 
Dose reduction 
Morning dose 
ModraDoc006 
20 mg 
20 mg 
Ritonavir 
200 mg 
200 mg 
Evening dose 
ModraDoc006 
20 mg 
10 mg 
Ritonavir 
100 mg 
100 mg 
 
Note: For patients enrolled under protocol amendment 1, two dose 
reductions of ModraDoc006/r will be allowed, see Table 12. 
Safety Assessments 
Safety will be assessed by means of physical examination, weight, 
vital signs, WHO performance status, laboratory evaluations 
(haematology, biochemistry), electrocardiograms (ECG), and 
recording of concurrent illness/ therapy and adverse events (using 
CTCAE v5.0, Appendix III). All assessments will be performed as 
indicated in the Schedule of Assessments (Appendix I). Additional 
assessments may be performed as clinically indicated. 
Efficacy Assessments 
Efficacy measurements will include tumor assessments, consisting of 
clinical examination and appropriate imaging techniques (computed 
tomography [CT] scans per RECIST v1.1, Appendix IV and bone 


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scan per PCWG3, Appendix V). Other imaging tests (magnetic 
resonance imaging [MRI] and X-ray) may be performed, if required, 
and if compliant with RECIST v1.1 and PCWG3. 
Tumor assessments will be performed at screening; every 8 weeks 
for first 24 weeks (i.e. during week 9, 17 and 25) and thereafter 
every 12 weeks during active treatment; and at the End of Treatment 
(EOT) visit, if disease progression has not been documented 
previously. Imaging will follow PCWG3 recommendations to 
include nodal/visceral and bone metastatic variables. A radiological 
response will be confirmed after ≥ 4-6 weeks. Analysis of PSA blood 
levels will also be used for efficacy assessment as per PCWG3 
criteria at screening, Day 1 of every cycle and at the EOT visit. A 
PSA response will be confirmed after 3-4 weeks.  
Additional Assessments 
Health Related Quality of Life (HRQoL) endpoints will be assessed 
by FACT global, FACT-P and FACT-taxane and EQ-5D-5L 
questionnaires at baseline and at the end of cycle 3, 6 and 10, or at 
End of Treatment (EOT) if this would occur earlier; HRQoL 
assessment by Treatment Satisfaction questionnaire will be done at 
the end of cycle 3, 6 and 10, or at End of Treatment (EOT) if this 
would occur earlier (Appendix VII). 
Statistical Procedures 
Analysis Populations: 
• 
Safety Population (SAF): All subjects receiving at least one 
dose of trial medication in either study arm will be included 
in the evaluation of safety.  
• 
Efficacy Population (Full Analysis Set (FAS)): All subjects 
who received at least one dose of docetaxel i.v. (cohort 1) or 
one full three-week cycle of ModraDoc006/r (cohort 2) and 
have at least one post-baseline tumour assessment (+PSA 
levels) will be included in the evaluation of efficacy and 
HRQoL evaluation.  
• 
Per Protocol (PP) population includes all subjects in the FAS 
population with the exclusion of subjects who are not 
compliant to study treatment or have at least one major 
protocol deviation that will affect the interpretation of 
efficacy. 
Safety Analysis: 
Safety data will be summarized for the safety population. 
Efficacy Analysis: 
Radiographic Progression-Free Survival: Defined as time from 
randomization to the first objective evidence of radiologic 
progression or death due to any cause after treatment 
discontinuation, whichever occurs first will be assessed, per PCWG3 
criteria. 
Objective Response Rate: The best overall soft tissue response as 
assessed by investigators using RECIST 1.1 will be summarized. 
Only patients with measurable soft tissue disease at screening (i.e., at 
least 1 target lesion per RECIST 1.1) will be included in this 
analysis. Tumor response for target lesions will be assessed at 


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baseline and specified time points throughout the study. The tumor 
response will be evaluated according to RECIST version 1.1. The 
calculation of ORR as primary endpoint is based on disease status as 
determined by tumor assessments.  
Disease Control Rate: Defined as proportion of patients who have 
achieved complete response, partial response and stable disease 
using RECIST 1.1. 
Duration of Response: Defined as time from documentation of 
tumor response using RECIST 1.1 to the first objective evidence of 
radiologic progression. 
Radiographic Progression-Free Survival at 6 months: Defined as 
probability of rPFS at 6 month based on the time from randomization 
to the first objective evidence of radiologic progression or death due 
to any cause. 
Time To Progression: Defined as time from randomization to the 
first objective evidence of radiologic progression 
PSA Response: Confirmed PSA responses will be defined as ≥50% 
reductions in PSA from baseline to lowest postbaseline PSA result, 
with a consecutive assessment conducted at least 3 weeks later 
required to confirm the PSA response. PSA response ≥50% will be 
calculated by treatment group for patients with PSA values at the 
baseline assessment and at least 1 postbaseline assessment. The 
analysis of the tumor marker PSA will be performed on the efficacy 
population as per PCWG3 criteria81. The variables will be evaluated 
using appropriate descriptive statistics for each assessment point and 
for the changes from baseline. 
PSA Progression-Free Survival / Time to PSA Progression: PSA 
progression according to PCWG3 criteria is defined as the first PSA 
increase that is ≥25% and ≥2 ng/mL, either above the nadir (if PSA 
decline after baseline) or from baseline beyond 12 weeks (if no PSA 
decline from baseline), and which is confirmed by a second value ≥ 
3 weeks later. 
Time to First Skeletal-Related Event: Time from randomization to 
first skeletal-related event will be assessed. A skeletal-related event 
is defined as radiation therapy or surgery to bone, pathologic bone 
fracture, spinal cord compression. 
Health Related Quality of Life Endpoints: 
FACT Quality of Life: The FACT global, FACT-P and FACT-
taxane data will be summarized descriptively by study visit. 
Treatment Satisfaction Questionnaire for Medication: TSQM 
data will be summarized descriptively by study visit. 
EQ-5D-5L Quality of Life: The EQ-5D-5L data will be summarized 
descriptively by study visit. 
Planned Data Analysis: 
All data collected in this trial will be documented using summary 
tables, figures, and patient data listings.  


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• 
Continuous variables will be summarized using descriptive 
statistics (N, mean, standard deviation, quartiles, median, 
minimum, and maximum).  
• 
Categorical variables will be summarized using counts, 
frequencies and percentages.  
• 
ORR will be reported as proportion of subjects per cohort who 
have presented response at fixed time intervals and separately at 
the end of trial 
• 
Response rates and 95% CIs will be calculated for the ORR and 
DCR by treatment group 
• 
PSA values will be reported as percentage change from baseline 
every cycle and as absolute change in PSA over time from 
baseline to best response  
• 
Differences between the cohorts will be compared using 
parametric techniques for continuous variables (only in case of 
severe deviations of normality will the Wilcoxon-Mann Whitney 
test be used) and Fisher’s exact test for categorical variables.  
PFS, TTP-DOR, PSA-PFS and time to PSA progression will be 
summarized using Kaplan-Meier estimates and differences will be 
determined via the log-rank test. Univariate Cox proportional 
hazards models, multivariate models, and propensity score-weighted 
multivariate models may be constructed to evaluate the effect of 
confounding variables on PSA-PFS, PFS and time to PSA 
progression. All tests will be two-sided and considered significant 
at P<0.05. With the design that compares treatment with 
ModraDoc006/r versus standard i.v. docetaxel, the treatment 
outcome will be estimated and used as the basis for the design of the 
future pivotal trial. The sample size of 50 evaluable patients per 
cohort will provide a sufficiently precise point estimate of the 
primary endpoint rPFS in both groups to calculate the sample size 
for the pivotal study.  
Number of Centres 
Approximately 40 centres in the US and Europe. 
 
 


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1. 
INTRODUCTION 
Prostate cancer 
Prostate cancer (PCa) is the most frequently occurring malignancy in men in the Western world, 
with more than 1,000,000 newly diagnosed cases per year worldwide 1. The multimodal 
therapeutic management of PCa varies greatly depending on the risk classification and whether 
disease is localized, or metastases have been identified 2,3. After progression on hormonal 
therapy in the metastatic castration resistant prostate cancer (mCRPC) setting, the prognosis is 
poor (OS of 9 to 13 months) and morbidity can be severe because of pain or complications 
related to bone metastases4. The presence of anaemia, development of new bone metastatic 
lesions, significant pain and the presence of visceral metastases were identified as pre-treatment 
risk factors that predict for PSA declines and survival in men with mCRPC 5. 
First line docetaxel treatment 
According to current guidelines, systemic therapy with docetaxel should be reserved for the 
metastatic castration resistant setting 2,3, although increasingly, based on recent trial outcomes, 
docetaxel is applied earlier in metastatic high-volume hormone sensitive prostate cancer 
(HSPC) 6,7. Treatment with docetaxel every three weeks in combination with prednisone, led to a 
survival benefit of 2.4 months, improved rates of response in terms of pain, serum PSA level and 
quality of life, as compared with mitoxantrone plus prednisone8.  For docetaxel plus 
estramustine, comparison with a similar control group showed an improvement in median 
survival of nearly two months in patients with mCRPC 9. Table 1 describes the median PFS and 
OS in patients with mCRPC with docetaxel treatment in several studies. Because of current 
longer prior treatment before start of docetaxel (with abiraterone and enzalutamide), the PFS for 
mCRPC patients may be shorter than the estimated PFS of 7 to 8 months in Table 1. 


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Table 1: 
Overall and progression free survival and PSA response in mCRPC patients 
treated with first line docetaxel in different studies.   
Study 
N 
Median 
OS 
docetaxel 
arm (mo) 
Median PFS 
docetaxel 
arm (mo) 
Response rate Docetaxel arm 
Total 
number 
in trial 
Number in 
Docetaxel 
arm 
(75 mg/m²  
cycle 3 wks.) 
>50% PSA 
decline 
RECIST 
Tumor 
response 
Tannock 8 
Docetaxel/P vs 
mitoxantrone/P 
1006 
335 
18.9 
Not reported 
 
45% 
12% 
 
Petrylak10 
Docetaxel/P +/- 
lenalinomide 
1046 
526 
Not 
reported 
10.6 
58% 
25% 
Kelly11 
Docetaxel/P 
+/- bevacizumab 
1052 
526 
21.5 
7.5 
57.9% 
35.5% 
Fizazi 12 
Docetaxel/P  
+/- zibotentan 
1052 
 
528 
19.2 
7.9 
56.4% 
Not reported 
Meulenbeld 13 
Docetaxel/P +/- 
risedronate 
592 
301 
18.4 
6.5 
66.3% 
20.8% 
Sonpavde 14 
Docetaxel/P +/- 
risedronate 
220 
110 
17.8 
10.3 
46% 
27% 
Quinn15 
Docetaxel/P +/- 
atrasentan 
994 
496 
17.6 
9.1 
49% 
14% 
Tannock16 
Docetaxel/P +/- 
aflibercept 
1224 
612 
21.2 
6.2 
63% 
28.1% 
Oudard17 
Docetaxel/P vs 
cabazitaxel 
1168 
391 
24.3 
5.3 
68.4% 
30.9% 
Araujo18 
Docetaxel/P +/- 
dasatinib 
1522 
760 
21.2 
11.1 
Not reported 
31.9 
Total 
9876 
4585 
 
 
 
 
Mean 
 
 
20.0 
8.3 
57% 
25% 
Abbreviations: N = number of patients, OS = overall survival, PFS = progression free survival, PSA = prostate 
specific antigen, P = prednisolone 


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Treatment in the field of prostate cancer is currently changing, after recent trials have shown 
benefit from earlier treatment with docetaxel in the non-castrate setting, with an improvement in 
overall survival in the metastatic hormone-sensitive group  6,7,19-28.  
Weekly vs 3-weekly docetaxel 
Weekly administration of i.v. docetaxel seems safe and effective in patients with androgen-
independent prostate cancer 29-37. The phase III study leading to the initial approval for i.v. 
docetaxel in metastatic castration resistant prostate cancer was designed to compare a weekly 
regimen of docetaxel with treatment every three weeks. Although no direct statistical comparison 
was performed between weekly and 3-weekly docetaxel, they found no evidence of a lower rate 
of adverse events or improved outcomes with the weekly schedule. The authors concluded that 
treatments given at intervals of three weeks are more convenient for most patients and should 
remain the standard with docetaxel 8.  
A recent randomized phase III study compared the efficacy and safety of 2-weekly vs 3-weekly 
docetaxel administration. Docetaxel administered every 2 weeks was associated with longer time 
to treatment failure (TTTF) and fewer occurrences of neutropenia and neutropenic infections 
than was 3-weekly administration in patients with castration-resistant advanced prostate cancer. 
The authors stated that somewhat unexpectedly, median overall survival was longer by 2.5 
months in the 2-weekly docetaxel group than in the 3-weekly group. They found the reasons for 
this difference are unclear, but more frequent docetaxel dosing might improve treatment 
tolerability, efficacy, or both 38.  
Based on these studies, it can be expected that the efficacy will at least be non-inferior and 
possibly superior, and that the safety will be better with weekly treatment with docetaxel. 
Because of the improved convenience in comparison to i.v. docetaxel, a weekly schedule for oral 
docetaxel seems acceptable for patients, and this will be evaluated in this study in the form of 
ModraDoc006/r.  
Prednisone treatment 
After the FDA approval for i.v. docetaxel in combination with prednisone, based on trials that 
used combined docetaxel and prednisone treatment in CRPC, the combination of i.v. docetaxel 
with prednisone has become the standard of care 8,9. Importantly however, there is no convincing 
evidence for improvement of treatment efficacy in terms of overall survival with addition of 
corticosteroids to docetaxel in patients with mCRPC 39,40. Earlier studies reported a relief of pain, 
associated with suppression of adrenal androgens in patients with symptomatic metastatic 
prostate cancer 41. PSA declines during prednisone treatment were reported, but only declines 
above 50% were correlated with improvement of overall survival and the effect of anti-androgen 
withdrawal may have influenced the results 42-44. Administration of 20 mg dexamethasone orally 
every 6 hours for 3 doses every 3 weeks did not significantly improve the PSA response rate of 
estramustine and docetaxel 45.  
A significant improvement in overall survival was achieved in patients with hormone naïve 
metastatic prostate cancer without addition of prednisone to the docetaxel treatment in the 
CHAARTED study 46. 


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1.1. 
Description of the Investigational Medicinal Product (IMP) 
1.1.1. 
ModraDoc006 
Docetaxel is a chemotherapeutic agent from the drug class of taxanes. It is a semi-synthetic 
analogue of paclitaxel. Docetaxel can be is manufactured through two methods, a Taxus Baccata 
tree-dependent or -independent method. The Taxus Baccata tree-independent method fabricates 
docetaxel through a cell fermentation process that generates a primary taxane mixture. This 
primary taxane mixture is then chemically converted into docetaxel, see Figure 1 for the 
structural formula). ModraDoc006 contains the docetaxel from the tree-independent method. 
It stimulates the polymerization of tubulin proteins into unusually stable, dysfunctional 
microtubules, consequently interfering with cell cycle division. Docetaxel is clinically effective 
in multiple tumor types, for instance breast cancer, prostate cancer, ovarian cancer, gastric 
cancer, head and neck cancer and non-small cell lung cancer. 
Figure 1: 
Structural formula of docetaxel. 
 
Docetaxel is known to be metabolized into four major metabolites: M1, M2, M3 and M4 formed by successive oxidation 
followed by spontaneous cyclization. The four metabolites are primarily excreted via the bile into the faeces. Docetaxel 
metabolism is primarily catalysed by the CYP3A4 enzymes in hepatocytes and human liver microsomes. The metabolites of 
docetaxel are inactive and have no anti-tumor activity47. 
 
Oral formulation of docetaxel 
For patients, oral administration of anticancer drugs has several advantages over i.v. 
administration48-50. Besides the need for hospital admission, i.v. administration of docetaxel has 
the drawback of frequently observed infusion-related reactions essentially related to the excipient 
Tween-80 that is present in its formulation. For this reason, dexamethasone is given 
prophylactically to all patients receiving i.v. docetaxel and paclitaxel. With oral docetaxel 
(ModraDoc006) treatment, toxicity of premedication with corticosteroids can be omitted, as the 
tablets of docetaxel do not contain Tween-80. In addition to increased patient convenience, there 
is the potential for longer treatment duration due to improved tolerability.  
However, the oral route is often hampered by low oral bioavailability. The low bioavailability of 
docetaxel is the result of the poor water-solubility of the drug, as the drug does not sufficiently 
dissolve in water when administered in the crystalline form, therefore ModraDoc006 uses an  
amorphous form to improve water-solubility. Furthermore, affinity for drug transporters highly 
expressed in the epithelial layer of the gastro-intestinal (GI) tract (e.g., P-glycoprotein (P-gp, 


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MDR1, ABCB1) and extensive first-pass metabolism by the cytochrome P450 (CYP) metabolic 
enzymes, especially CYP3A4 in the gut wall, hamper the oral bioavailability of docetaxel47,51.  
To improve the bioavailability of oral docetaxel (ModraDoc006), a specific CYP3A4 and P-
glycoprotein (P-gp) blocker such as ritonavir (/r) is co-administered (combination denoted as 
ModraDoc006/r).  
1.1.2. 
Ritonavir 
Ritonavir is a viral protease inhibitor that has been approved as a combination treatment to 
increase the bioavailability of other protease inhibitors including saquinavir, nelfinavir, indinavir 
and lopinavir52,53. It is a potent inhibitor of CYP3A and also inhibits CYP2D6 mediated 
reactions; ritonavir also exhibits P-gp inhibiting properties.  
1.1.3. 
Pre-Clinical Information 
Preclinical studies showed that first-pass metabolism is the most important factor determining 
the low bioavailability of orally administered docetaxel. Low oral bioavailability is determined 
by both P-gp and CYP3A4 metabolizing enzymes. In preclinical studies the CYP3A4 and P-gp  
inhibitor ritonavir was used in combination with oral docetaxel to examine the oral 
bioavailability of docetaxel47,51,54. Ritonavir markedly increased the area under the plasma 
concentration time curve (AUC) of docetaxel in mice, primarily due to inhibition of CYP3A455. 
1.2. 
Clinical Data 
Two phase I dose escalating trials in patients with solid tumors investigating the 
pharmacokinetics, maximum tolerated dose (MTD) and safety of ModraDoc006/r (i.e. oral 
docetaxel as tablets of 10 mg each co-administered with one single dose of ritonavir (Norvir®) 
of 100 mg) as once daily once weekly (QW) dosing and bi-daily once weekly dosing (BIDW), 
respectively, have been performed56,57 (Section 1.2.1 and 1.2.2). In these phase I trials, patients 
have been treated with ModraDoc006/r for a duration of up to 72 weeks. In addition, a phase Ib 
trial was conducted to assess the safety, pharmacokinetics and efficacy of ModraDoc006/r in 
mCRPC patients (Section 1.2.3). 
All three trials were conducted using a classic 3+3 dose escalation schedule. 
1.2.1. 
Trial 1: Once daily, once weekly ModraDoc006/r 
In this study, several oral formulations of docetaxel were tested once daily, once weekly (QW), 
starting with a drinking solution and ending up with the tablet form known as ModraDoc006. 
Dose-escalation with ModraDoc006/r was performed up to a weekly dose of 80 mg 
ModraDoc006/100 mg ritonavir. 
Adverse events (AEs) were collected according to the National Cancer Institute’s Common 
Terminology Criteria for AEs version 3.0 (NCI-CTCAE v3.0). Most frequently occurring AEs 
with an incidence ≥10% in ModraDoc006/r QW dosing were diarrhea (76%), fatigue/malaise 
(67%), nausea (61%), vomiting (61%), alopecia (33%), dysgeusia (33%), abdominal cramps 
(28%), abdominal pain (22%), mucositis (22%), weight loss (22%) and anorexia (11%). Most 
AEs were of low grade (i.e. grade 1-2) and easily manageable with standard-of-care.  


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The MTD was 60 mg ModraDoc006/100 mg ritonavir administered weekly. Dose Limiting 
Toxicities (DLTs) reported in the study were grade 2 nausea, diarrhea and mucositis, resulting in 
inability to restart within three weeks (1x), grade 3 neutropenic fever and mucositis (1x) and 
grade 3 diarrhea (1x).  
1.2.2. 
Trial 2: Bi-daily, once weekly ModraDoc006/r 
Dose-escalation of ModraDoc006/r administered bi-daily once weekly (BIDW) was performed 
starting from bi-daily 20 mg ModraDoc006/100 mg ritonavir up to bi-daily 30 mg 
ModraDoc006/100 mg ritonavir.  
The AEs during this study were collected according to the National Cancer Institute’s Common 
Terminology Criteria for AEs version 3.0 (NCI-CTCAE v3.0). The safety profile of the BIDW 
schedule follows the observations of the QW schedule. AEs with an incidence ≥10% in 
ModraDoc006/r BIDW dosing were diarrhea (64%), nausea (61%), vomiting (43%), fatigue 
(39%), mucositis (32%), alopecia (21%), anorexia (21%), dysgeusia (21%), nail toxicity (21%), 
abdominal cramps (14%), aspartate aminotransferase (AST) increased, (16%), alanine 
aminotransferase (ALT) increased (16%), constipation (14%) and weight loss (14%), mostly of 
grade 1 and 2 severity. 
For both the QW (Trial 1) and BIDW (Trial 2) dosing schedules, the reported AEs are not 
unexpected based on experience with i.v. docetaxel, but appear to be less severe with 
ModraDoc006/r. AEs frequently seen with i.v. docetaxel, (i.e. leukocytopenia, neutropenic fever, 
nail toxicity, and neurotoxicity) were uncommon with ModraDoc006/r. Allergic reactions were 
not observed. Alopecia, mostly grade 1, occurred much less frequently than would be expected 
with i.v. docetaxel. The severity of the AEs was most commonly CTC grade 1-2 and 
occasionally grade 3-4. Diarrhea was reported approximately twice as frequently as reported in 
the docetaxel package insert. 
The MTD and the recommended dose for further clinical development in this trial was 
determined to be 30/20 mg ModraDoc006 (morning/evening dose, respectively) with bi-daily 
100 mg ritonavir. Docetaxel AUC observed with this dose was comparable to the AUC of a 
weekly i.v. docetaxel dose of 35 mg/m²  
DLTs reported in the study were grade 3 nausea (2x), mucositis (2x), dehydration (1x), 
neutropenic fever (1x) and inability to restart treatment within 3 weeks due to treatment related 
toxicity (1x). 
Because of the lower interpatient variation in pharmacokinetics as compared to the once daily 
dosing the bi-daily weekly dosing of 30/20mg ModraDoc006/r was selected for further 
development in solid tumors. Keeping in mind the limitations related to inter-study comparison, 
the interpatient variation in pharmacokinetics of oral and i.v. docetaxel appears similar in 
patients with normal liver function when compared with historical data.  
1.2.3. 
Trial 3: Bi-daily, once weekly ModraDoc006/r in patients with mCRPC 
 
Dose-escalation of ModraDoc006/r administered bi-daily once weekly was performed starting 
from bi-daily 20 mg ModraDoc006/100 mg ritonavir in Cohort 1. The second dose cohort of 
30/20 mg ModraDoc006 (morning/evening dose, respectively) with bi-daily 200 mg ritonavir 
resulted in a too high docetaxel exposure (1687 ng/mL*h) with 2 dose limiting toxicities (DLTs) 


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in 6 patients. In the third cohort, simultaneous evaluation of  Cohort 3A: 30/20 mg 
ModraDoc006 (morning/evening dose, respectively) with 200/100 mg ritonavir 
(morning/evening dose, respectively) and Cohort 3B: 20/20 mg ModraDoc006 (morning/evening 
dose, respectively) with 200/100 mg ritonavir (morning/evening dose, respectively) was 
performed.  
 
The most common toxicities (see Table 2) observed with the bi-daily, once weekly treatment 
schedule, all doses, consisted of diarrhea, nausea, vomiting, anorexia and fatigue. In cohort 2 
some patients experienced severe toxicities of which 2 were considered DLTs (grade 3 diarrhea 
and mucositis). One patient in this cohort experienced grade 3 febrile neutropenia, mucositis and 
fatigue, which was considered non-evaluable toxicity, given the concomitant use of mirabegron 
(also a CYP3A4 inhibitor). In cohort 3A 2 patients experienced severe toxicity, of which one 
was considered a DLT (grade 3 diarrhea) and one a grade 3 febrile neutropenia and grade 2 
mucositis, which was considered non-evaluable toxicity, given the concomitant use of oral 
methotrexate. In cohort 3B no DLTs were observed. The MTD was established at weekly 30/20 
mg ModraDoc006 (morning/evening dose, respectively) in combination with 200/100 mg 
ritonavir. 
 
Table 2 
Adverse Events Reported During ModraDoc006/r Study with BIDW (Twice 
Daily, Once Weekly) Dosing in mCRPC patients 
  
Cohort 1:  
M: 30-20 mg/  
R: 100-100 mg    
(N=5) 
Cohort 2:  
M: 30-20 mg/  
R: 200-200 mg  
(N=8) 
Cohort 3A:  
M: 30-20 mg/ 
R: 200-100 mg  
(N=7) 
Cohort 3B:  
M: 20-20 mg/ 
R: 200-100 mg 
(N=3) 
All 
AEs 
 
(N=23) 
All 
AEs  
 
(N=23) 
Mild 
AEs  
Severe 
AEs 
Adverse Events 
Gr 
1 
Gr 
2 
Gr 
3 
Gr 
1 
Gr 
2 
Gr 
3 
Gr 
1 
Gr 
2 
Gr 
3 
Gr 
1 
Gr 
2 
Gr 
3 
N 
% 
% 
% 
Diarrhea 
5 
  
  
4 
1 
2 
3 
2 
2 
1 
1 
  
21 
91% 
74% 
17% 
Nausea 
2 
2 
  
5 
1 
  
4 
1 
  
  
  
  
15 
65% 
65% 
  
Fatigue 
  
2 
  
1 
3 
1 
1 
3 
  
  
1 
  
12 
52% 
48% 
4% 
Anorexia 
1 
  
  
1 
3 
  
2 
1 
1 
1 
1 
  
11 
48% 
43% 
4% 
Vomiting 
1 
1 
  
3 
  
  
2 
1 
  
2 
  
  
10 
43% 
43% 
  
Dysgeusia 
  
  
  
4 
  
  
2 
1 
  
  
  
  
7 
30% 
30% 
  
Alanine aminotransferase 
increased 
  
  
1 
1 
  
  
2 
1 
  
1 
  
  
6 
26% 
22% 
4% 
Dyspepsia 
  
  
  
1 
1 
  
1 
2 
  
1 
  
  
6 
26% 
26% 
  
Oral mucositis 
  
  
  
1 
  
1 
3 
1 
  
  
  
  
6 
26% 
22% 
4% 
Alopecia 
  
  
  
1 
1 
  
3 
  
  
  
  
  
5 
22% 
22% 
  
Gastro-intestinal mucositis2 
  
  
  
2 
  
1 
2 
  
  
  
  
  
5 
22% 
17% 
4% 
Abdominal pain 
  
  
  
2 
  
  
  
2 
  
  
  
  
4 
17% 
17% 
  
Aspartate aminotransferase 
increased 
1 
  
  
  
  
  
1 
1 
  
1 
  
  
4 
17% 
17% 
  
Eructation 
  
  
  
2 
  
  
1 
  
  
1 
  
  
4 
17% 
17% 
  
Nail toxicity 
  
  
  
1 
1 
  
  
2 
  
  
  
  
4 
17% 
17% 
  
Weight loss 
1 
  
  
3 
  
  
  
1 
  
  
  
  
4 
17% 
22% 
  
Anemia 
  
  
  
1 
  
  
  
  
1 
  
1 
1 
3 
13% 
9% 
9% 
Constipation 
  
  
  
  
1 
  
1 
  
  
  
1 
  
3 
13% 
13% 
  
Dry skin 
  
  
  
1 
1 
  
1 
  
  
  
  
  
3 
13% 
13% 
  
Myalgia 
  
  
  
1 
  
  
2 
  
  
  
  
  
3 
13% 
13% 
  


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Peripheral sensory 
neuropathy 
  
  
  
  
  
  
1 
1 
  
1 
  
  
3 
13% 
13% 
  
Rhinitis 
  
  
  
2 
  
  
  
1 
  
  
  
  
3 
13% 
13% 
  
Dry mouth 
  
  
  
1 
  
  
1 
  
  
  
  
  
2 
9% 
9% 
  
Febrile neutropenia1-2 
  
  
  
  
  
1 
  
  
1 
  
  
  
2 
9% 
  
9% 
Fever (non-neutropenic) 
  
  
  
1 
  
  
1 
  
  
  
  
  
2 
9% 
9% 
  
Hypotension 
  
  
  
  
2 
  
  
  
  
  
  
  
2 
9% 
9% 
  
Rectal hemorrhage 
1 
  
  
  
  
  
  
  
  
1 
  
  
2 
9% 
9% 
  
Thrombocytopenia 
  
  
  
1 
  
  
  
  
  
1 
  
  
2 
9% 
9% 
  
Ascites 
  
  
  
  
1 
  
  
  
  
  
  
  
1 
4% 
4% 
  
Balanitis 
  
  
  
  
  
  
  
1 
  
  
  
  
1 
4% 
4% 
  
Dizziness 
  
  
  
1 
  
  
  
  
  
  
  
  
1 
4% 
4% 
  
Dry eye 
  
  
  
1 
  
  
  
  
  
  
  
  
1 
4% 
4% 
  
Headache 
  
  
  
1 
  
  
  
  
  
  
  
  
1 
4% 
4% 
  
Leucopenia 
  
  
  
  
  
1 
  
  
  
  
  
  
1 
4% 
  
4% 
Localized edema 
  
  
  
  
  
  
  
  
  
1 
  
  
1 
4% 
4% 
  
Malaise 
  
  
  
  
1 
  
  
  
  
  
  
  
1 
4% 
4% 
  
Paronychia 
  
  
  
  
  
  
  
1 
  
  
  
  
1 
4% 
4% 
  
Rash 
  
  
  
  
  
  
1 
  
  
  
  
  
1 
4% 
4% 
  
Restless legs 
  
  
  
  
  
  
  
  
  
1 
  
  
1 
4% 
4% 
  
Skin fissures 
  
  
  
  
1 
  
  
  
  
  
  
  
1 
4% 
4% 
  
*All CTCAE grade (Gr) adverse events (AEs) that were possibly, probably or definitely related to ModraDoc006/r. In case of 
multiple grades of the same AE, the worst grade was reported per patient. DLTs are high-lighted in bold. ¹including a non-
evaluable patient using mirabegron, ²including a non-evaluable patient using methotrexate 
Abbreviations: N = number of patients, ALAT = serum alanine aminotransferase, ASAT = serum aspartate aminotransferase 
 
The pharmacokinetic results of patients with mCRPC are presented in Table 3 below. In the 5 
patients in cohort 1 the mean docetaxel AUC0-inf was (399 ng/mL*h (coefficient of variation 
(CV) 49.6%) in cycle 1 and 524 ng/mL*h (CV 55.5%) in cycle 2. Doubling of the ritonavir dose 
in cohort 2 resulted in an increase of the docetaxel AUC0-inf (1554 (CV 67.9%) and 1821 (CV 
56.5%) ng/mL*h in cycle 1 and 2, respectively) in 6 evaluable patients. In cohort 3A, a mean 
AUC0-inf of docetaxel of 1342 (CV 39.6%) ng/mL*h was observed in cycle 1 and 1692 (CV 
40.0%) ng/mL*h in cycle 2. In cohort 3B, a mean docetaxel AUC0-inf of 526 ng/mL*h in cycle 
1 (CV 33.2%) and 590 ng/mL*h (CV 12.1%) ng/mL*h in cycle 2 was achieved. Treatment with 
ModraDoc006/r has previously been evaluated in patients with miscellaneous advanced solid 
tumors in two Phase I trials (see above). The ritonavir dose in the morning is higher (200 instead 
of 100 mg as in the two phase I studies in patients with solid tumors) as in the dose-finding trial 
in mCRPC with ModraDoc006/r it was observed that the systemic exposure to docetaxel as well 
as to ritonavir was lower than in the phase I studies in which no patients with mCRPC had taken 
part. 


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Table 3 
Pharmacokinetic results of ModraDoc006/r (docetaxel and ritonavir) with 
BIDW (Twice Daily, Once Weekly) dosing in mCRPC 
Para-
meter 
 
 
 
Pt 
Cohort 1 
M:30-20mg 
R: 100-100mg 
(n=5) 
Cohort 2 
M: 30-20mg 
R: 200-100mg 
(n=6) 
Cohort 3A 
M: 30-20mg 
R: 200-200mg   
(n=6) 
Cohort 3B 
M: 20-20mg 
R: 200-100mg   
(n=3) 
 
 
Docetaxel 
Ritonavir 
Docetaxel 
Ritonavir 
Docetaxel 
Ritonavir 
Docetaxel 
Ritonavir 
Cycle 
 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
AUC0-
inf  
1 
485 
611 
5721 
7402 
679 
877 
21010 
23222 
289 
332 
18135 
14934 
435 
666 
14432 21242 
2 
283 
256 
14918 
12503 
1325 1764 
22847 
27540 
3418 
3131 
85263 
98185 
728 
578 
23054 15971 
3 
108 
187 
7713 
9972 
1029 1391 
41171 
78579 
1468 
1458 
41959 
45979 
416 
525 
8941 
12920 
4 
565 
862 
8773 
9550 
1116 1158 
34188 
35659 
1644 
2239 
52893 
44609 
 
 
5 
553 
702 
11042 
11547 
2148 2478 
43635 
45072 
1629 
2611 
50113 
64784 
6 
 
 
1756 2484 
26354 
27372 
873 
1157 
35037 
44734 
 
399 
 
CV% 
49.6 
524 
 
CV% 
55.5 
9514 
 
CV%    
38.0 
10195 
 
CV% 
19.3 
1342 
 
CV% 
39.6 
1692 
 
CV% 
40.0 
31534 
 
CV% 
30.4 
39574 
 
CV% 
52.1 
1554 
 
CV% 
67.9 
1821 
 
CV% 
56.5 
47233 
 
CV% 
47.4 
52204 
 
CV% 
52.9 
526 
 
CV% 
33.2 
590 
 
CV% 
12.1 
15476 
 
CV% 
46.0 
16711 
 
CV% 
25.2 
Cmax 
1 
38.6 
47.4 
873 
847 
226 
84.3 
1750 
2430 
39.9 
37.8 
1930 
1830 
63.3 
78.6 
2130 
4210 
2 
24.5 
14.7 
1050 
500 
148 
155 
2740 
2830 
263 
204 
8380 
9720 
53 
43.7 
3400 
1990 
3 
6.21 
19.9 
1010 
2270 
97 
128 
4620 
5710 
134 
156 
4450 
5260 
21.9
33.3 
467 
1080 
4 
41.8 
94.6 
507 
807 
130 
150 
6620 
5650 
159 
170 
6470 
4090 
 
 
5 
54.1 
54.1 
733 
1320 
214 
267 
6070 
5290 
205 
230 
11000 
9890 
6 
 
 
170 
235 
4020 
3170 
74.8 
104 
2650 
3880 
 
33.0 
 
CV% 
55.5 
46.1 
 
CV% 
69.3 
835 
 
CV% 
26.5 
1149 
 
CV% 
60.2 
164 
 
CV% 
30.2 
170 
 
CV% 
40.2 
4303 
 
CV% 
43.6 
4180 
 
CV% 
36.5 
146 
 
CV% 
56.3 
150.3 
 
CV% 
46.5 
5813 
 
CV% 
60.0 
5578 
 
CV% 
57.3 
46.1 
 
CV% 
46.8 
51.9 
 
CV% 
45.7 
1999 
 
CV% 
73.6 
2427 
 
CV% 
66.3 
Abbreviations: M = ModraDoc006, R = ritonavir, n = number of patients, Pt = patient number, AUC0-inf  = area under the plasma 
concentration versus time curve from 0 to infinity, in ng/ml*h, Cmax = maximum plasma concentration in ng/ml, = mean, CV% 
= coefficient of variation (percentage) 
 
The MTD of ModraDoc006/r in mCRPC patients is different than in patients with other solid 
tumors, which is in line with the observed higher docetaxel clearance in i.v. treated mCRPC 
patients65. This might be caused by induction of CYP3A4 in mCRPC patients, associated with 
low testosterone levels.  
 
ModraDoc006/r has demonstrated efficacy in mCRPC patients as shown in 2. A PSA decrease of  
≥50% was observed in 6 out of 10 evaluable patients (after ≥9 ModraDoc006/r cycles). Five 
patients had measurable disease, of which one in cohort 2 and two in cohort 3A achieving stable 
disease (SD) and 2 patients in cohort 3B with a confirmed partial response. One patient in cohort 
3A with radiological SD discontinued in the study because of clinical and biochemical 
progression. 
 


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Figure 2 
Efficacy of ModraDoc006/r in mCRPC patients 
Duration of treatment with ModraDoc006/r in weeks, the reason for early discontinuation if indicated and treatment response. 
Each bar represents one individual patient. Patients with PSA responses are depicted on the left. The striped bars indicate that the 
patient has measurable disease according to RECIST, the corresponding evaluation (SD or PR) is depicted at the end of the bar 
on the right. Each dose level is represented by one color, as stated in the legend.  
 
1.3. 
Trial and Dosing Rationale 
1.3.1. 
Ritonavir 
In this study, 300 mg of ritonavir will be administered maximally per week: it will be 
administered as two separate doses of 200 mg in the morning and 100 mg in the evening 
(concomitant with the two doses of ModraDoc006). With this schedule, no or only minor side 
effects are expected of ritonavir, due to the low total dose given. As context, ritonavir is 
administered in HIV treatment, because of its ability to inhibit CYP3A4 activity in the intestinal 
luminal cells, and it has been proven that ritonavir can be administered safely at doses up to 400 
mg daily for prolonged periods of time63, resulting maximally in a weekly dose of 2800 mg. 
Ritonavir has also been administered to healthy volunteers in doses of up to 600 mg at 12-hour 
intervals. Vomiting, nausea, and abdominal pain do occur frequently, especially during the first 
few weeks of therapy, at these higher doses, and they are correlated with ritonavir plasma 
levels63. Since ritonavir in our study is administered at much lower doses and frequencies, no 
serious side effects are expected from ritonavir in this study. Furthermore, the safety of ritonavir 
was favorable at daily doses of 100-200 mg in clinical studies with multiple combinations with 
protease inhibitors52,53,64 – a frequency which is far higher than will be used in this study. 
1.3.2. 
ModraDoc006/r 
Frequently occurring toxicities of i.v. docetaxel, such as neutropenia and peripheral 
polyneuropathy, have rarely been observed with ModraDoc006/r in the phase I studies 
performed to date. The lower toxicity of ModraDoc006, in combination with ritonavir can be 
explained by the pharmacokinetic observation of a more than 10-fold lower maximum 


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concentration (Cmax) as compared to i.v. docetaxel. The AUC is comparable to i.v. docetaxel over 
the time course of a treatment cycle of 3 weeks. Observed tumor responses in the phase I trials, 
in a heavily pre-treated patient population, seem to suggest effectiveness of ModraDoc006 in 
combination with ritonavir. Therefore, it is speculated that for each malignant disease in which 
docetaxel treatment has become standard of care, toxicity of ModraDoc006/r will be lower, but 
the efficacy will be at least similar and potentially better when compared to i.v. docetaxel. 
 
1.3.3. 
ModraDoc006/r in mCRPC 
The MTD of ModraDoc006/r in mCRPC has been established in the Phase Ib trial in this 
population (Section 1.2.3). However, this study demonstrated that based on pharmacokinetics, 
safety and efficacy data, two dose regimens could be selected for further studies in mCRPC: 
ModraDoc006 30/20 mg (morning/evening dose, respectively) with 200/100 mg ritonavir 
(morning/evening dose, respectively) and  ModraDoc006  20/20 mg (morning/evening dose, 
respectively) with 200/100 mg ritonavir (morning/evening dose, respectively). Both 
ModraDoc006/r dose levels provide a level of AUC that is in the range (or moderately above) of 
that achieved with 75 mg/m2 docetaxel by i.v. administration, with ModraDoc006  30/20 mg on 
the high end and 20 ModraDoc006  20/20 mg on the low end of the docetaxel i.v. AUC. Both 
dose levels demonstrated sufficient safety and tolerance, although the number of adverse events 
at the ModraDoc006 20/20mg dose was less compared to the 30/20mg dose. In regards to 
efficacy, both dose levels have demonstrated encouraging response rates in PSA and in tumor 
reduction where measurable, in addition to clinical improvement. The ModraDoc006 20/20mg 
dose level appeared remarkably well tolerated and effective, with all patients achieving the 
maximum treatment length of 30 weeks. 
 
Initially, as clinical data demonstrated that dose level ModraDoc006 30/20mg was the MTD, this 
dose was selected for further phase II evaluation in mCRPC patients. Preliminary tolerability 
information from the current study however, shows that this ModraDoc006 30/20 mg with 
200/100 mg ritonavir regimen has higher rates of (low grade) GI adverse events than aimed for 
as a convenient and tolerable oral treatment. Supported by the data from the phase Ib study, 
demonstrating both good tolerance and good efficacy, a reduction to the ModraDoc006 20/20 mg 
with 200/100 mg ritonavir dose level in the current study is indicated as the RP2D . 
 
In the Phase Ib trial in mCRPC encouraging PSA responses have been observed. However, 
efficacy has not yet been explored sufficiently in patients with mCRPC. Therefore, the current 
trial is proposed with the primary aim to determine the efficacy of ModraDoc006/r as measured 
by radiographic Progression Free Survival (rPFS) based on the Prostate Cancer Clinical Trials 
Working Group 3 (PCWG3) recommendations81 compared to standard treatment with i.v. 
docetaxel in subjects with mCRPC. Furthermore, the safety, tolerability and HRQoL of 
ModraDoc006/r in the target population will be assessed and compared to standard i.v. 
docetaxel. In addition, Overall Response Rate (ORR) based on PCWG3-modified RECIST 1.1 
criteria, Time to progression (TTP), Duration of response (DOR), PSA-PFS, Time to PSA 
progression and Disease Control Rate (DCR) based on PCWG3-modified RECIST v1.1 criteria 
will be determined and compared with standard i.v. docetaxel. 


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If comparable efficacy - or trends of superior efficacy - as well as improved safety, quality of life 
and patient convenience can be demonstrated, ModraDoc006/r treatment will have advantages 
for patients with mCRPC. Depending upon the outcome of this trial a pivotal study will be 
initiated incorporating the data of this trial. 
1.4. 
Potential Benefits and Risks  
The patient risk of this study is qualified as ‘low’. This is motivated by the following: 
1. The study drug has been tested in two prior phase I trials 56,57 and one dose-finding study 
in the target population of mCRPC (NCT03136640). Based on the results of these trials, 
the toxicity of ModraDoc006/r is expected to be lower than standard i.v. docetaxel 
treatment. 
2. The benefit-risk profile of ModraDoc006/r is expected to improve with a starting dose of 
ModraDoc006 from 20/20 mg (morning/evening dose, respectively) with 200/100 mg 
ritonavir (morning/evening dose, respectively), to allow for a better tolerability, while 
keeping a sufficient level of exposure, enabling longer treatment duration and associated 
treatment activity. 
3. The safety profile of docetaxel as an i.v. formulation in the patient population is well 
known. 
4. With this schedule, no or only minor side effects are expected of ritonavir, due to the low 
total dose given.  
5. Treatment guidelines to decrease dose or interrupt treatment when side-effects occur will 
be followed as specified in this protocol, based on the experience in the two prior phase I 
trials.  
Considering the broad experience with i.v. docetaxel and the observed lower toxicity of the study 
treatment, the remaining risks are acceptable for the patients participating in the study. A 
structured risk analysis including all study details can be found in Appendix VIII. 
1.4.1. 
Benefits of IMP 
The principal aim of this trial is to compare safety and efficacy data on administration of 
ModraDoc006/r with standard i.v. docetaxel as therapy in patients with mCRPC suitable to 
receive docetaxel monotherapy. This information, together with data of HRQoL, will help in 
establishing the pivotal study design in the target population, and may result in an improvement 
of this disease state.  
1.4.2. 
Management of Risks 
To minimize the risk to patients and maximize safety, the following factors have been 
incorporated into the trial design: 
• Detailed safety and laboratory assessments will be performed as outlined in 
Section 6.7 of this protocol. 


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• Patients will be provided with diet and hydration instructions and a home prescription 
for loperamide, with instructions on how to use this medication in case diarrhea 
occurs at home 
• All clinical observations will be evaluated by the Investigator on an ongoing basis. 
• The trial will be planned to minimize the time interval which would influence routine 
procedure to the patient.  
1.4.3. 
Benefit/Risk Ratio 
The anticipated risks are based on ModraDoc006/r non-clinical and clinical experiences and are 
not expected to be significant. Patients will be monitored closely for the occurrences of any 
significant clinical events, and treatment will only continue if it is considered safe and 
appropriate to do so. 
The early clinical development of ModraDoc006/r demonstrated that its use is generally safe and 
well tolerated, and can justify evaluation in a larger patient population. These studies also 
demonstrated that IMP has a strong potential for anti-tumor activity. 
In summary, the expected benefit outweighs the expected risks for patients.  


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2. 
TRIAL OBJECTIVES AND ENDPOINTS  
2.1. 
Primary Objectives 
To determine the efficacy of ModraDoc006/r, as measured by radiographic Progression Free 
Survival (rPFS), compared to standard treatment with i.v. docetaxel in subjects with mCRPC. 
2.2. 
Secondary Objectives  
• To evaluate the efficacy of ModraDoc006/r, as measured by PCWG3-modified 
RECIST v1.1 criteria of objective response rate (ORR), disease control rate (DCR) 
and duration of response (DOR) compared to standard treatment with i.v. docetaxel in 
subjects with mCRPC. 
• To evaluate the clinical outcome in terms of rPFS at 6 months and time to progression 
(TTP) of ModraDoc006/r compared to i.v. docetaxel 
• To evaluate the outcome in terms of PSA tumor marker evaluation for PSA response, 
PSA-PFS and time to PSA progression of ModraDoc006/r compared to i.v. docetaxel 
• To compare the time to first skeletal-related event between ModraDoc006/r and i.v. 
docetaxel 
• To determine the safety and tolerability of ModraDoc006/r compared to i.v. docetaxel 
• To compare subject’s Health Related Quality of Life (HRQoL) response of 
ModraDoc006/r and docetaxel i.v. 
2.3. 
Endpoints 
2.3.1. 
Efficacy 
The primary efficacy endpoint for this study is: 
• Radiographic Progression Free Survival (rPFS) according to PCWG3 criteria 
Secondary efficacy endpoints (based on PCWG3-modified RECIST v1.1 criteria where 
applicable) are: 
• Objective Response Rate (ORR)  
• Disease control rate (DCR) 
• Duration of response (DOR)  
• Radiographic Progression Free Survival (rPFS) at 6 months according to PCWG3 
criteria 
• Time to progression (TTP)  
• PSA response rate according to PCWG3 criteria 
• Progression free survival (PFS) at 6 months  
• PSA-PFS according to PCWG3 criteria  


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• Time to PSA progression 
• Time to first skeletal event 
• HRQoL as assessed by FACT global, FACT-P and FACT-taxane, Treatment 
Satisfaction and EQ-5D-5L questionnaire 
2.3.2. 
Safety 
The following secondary safety and tolerability endpoints will be assessed: 
• Adverse events (AEs) and serious adverse events (SAEs), according to the current 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0 
• Assessments of e.g.: physical examinations, body weight, vital signs, WHO 
performance status, changes in hematology and biochemistry, electrocardiogram 
(ECG) 
2.3.3. 
Health Related Quality of Life (HRQoL) 
Health Related Quality of Life (HRQoL) will be measured using the FACT global, FACT-P, 
FACT-taxane, Treatment Satisfaction and EQ-5D-5L questionnaires. The FACT-P is a validated 
and frequently used questionnaire in metastatic prostate cancer trials which has led to HRQoL-
based approvals by the European Medicines Agency 67-73. A limited number of studies has 
compared HRQoL between oral and i.v. anticancer treatment 74. In this study, the validated 
FACT-taxane questionnaire will be used to compare the HRQoL related to toxicities of 
ModraDoc006/r and i.v. docetaxel 75. The Treatment Satisfaction questionnaire is also a 
validated tool to compare different treatments76. 
The following questionnaires will be employed to assess HRQoL (see also Appendix VII): 
• FACT global  
• FACT-P  
• FACT-taxane  
• Treatment Satisfaction  
• EQ-5D-5L 
Overall health related quality of life (HRQoL) improvement will be evaluated with weekly 
ModraDoc006/r as compared to the standard treatment with i.v. docetaxel. HRQoL response is 
defined as a 10-point or greater increase in the global FACT score at a post-baseline assessment 
compared with baseline. 
Improvements in individual HRQoL domains will be investigated with weekly ModraDoc006/r 
as compared to the standard treatment with i.v. docetaxel. Improvements that are considered 
significant are in subscales of FACT: 
• ≥3 for physical wellbeing (7 items; score range 0–28) 
• ≥3 for social or family wellbeing (7 items; score range 0–28) 


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• ≥3 for emotional wellbeing (6 items; score range 0–24) 
• ≥3 for functional wellbeing (7 items; score range 0–28) 
• ≥3 for prostate cancer subscale (12 items; score range 0–48) 
• ≥3 for taxane treatment subscale (16 items; score range 0–64) 
The time to HRQoL deterioration with weekly ModraDoc006/r will be investigated as compared 
to the standard treatment with i.v. docetaxel. Time from date of randomization to the date of first 
HRQoL deterioration (defined as a ≥10-point decrease in the global FACT score at a 
post-baseline assessment compared with baseline) or death from any cause, whichever occurs 
first, is considered significant. 
The overall Health Related Utility with weekly ModraDoc006/r as compared to the standard 
treatment with i.v. docetaxel will be assessed by the EQ-5D-5L (Appendix VII). 


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3. 
TRIAL DESIGN 
3.1. 
Overall Trial Design 
This is an open label 1:1 randomized Phase IIb trial to determine the efficacy and tolerability of 
ModraDoc006/r (i.e. ModraDoc006 in combination with ritonavir therapy) versus standard i.v. 
docetaxel in mCRPC subjects (Figure 3). 
Cohort 1 will receive docetaxel at 75 mg/m2 given i.v. as a one-hour infusion on day 1 every 21 
days plus 5 mg oral prednisone twice daily.  
Cohort 2 will receive ModraDoc006/r 20 mg oral docetaxel in combination with 200 mg 
ritonavir in the morning and 20 mg oral docetaxel in combination with 100 mg ritonavir in the 
evening (7-12 hours after the morning dose), on Day 1, 8 and 15 of a 21-day cycle, plus 5 mg 
oral prednisone twice daily.   
Treatment in both cohorts will continue until disease progression, unacceptable toxicity, or 
discontinuation for any other reason. The end of the trial is defined as the timepoint when all 
subjects have discontinued trial treatment and have been given follow-up for safety 
measurements according to the trial assessment schedule. After 10 months of the last enrolled 
patient, the sponsor may terminate the study. Any patient still under treatment in Cohort 1 can be 
switched to commercially available i.v. docetaxel. Patients still treated in Cohort 2 and who 
experience clinical benefit, will be offered the opportunity for compassionate use 
ModraDoc006/r. 
Figure 3: 
Schematic of study design.  
 
Metastatic Castration Resistant Prostate Cancer (mCRPC) patients for whom treatment with i.v. docetaxel is indicated according 
to the standard of care will be randomized 1:1 to one of the two cohorts depicted above. Abbreviations: BIDW = bi-daily once 
weekly, Q 21 days = once every 21 days (Q3W)  
Tumor assessment will be performed (following PCWG3) by PSA every cycle and radiological 
assessment (i.e. CT/MRI and bone scan) after every 8 weeks for first 24 weeks (i.e. during week 
9, 17 and 25), thereafter every 12 weeks and at End Of Treatment (EOT), according to the 
RECIST v1.1 criteria. Both PSA response and radiological response (PR/CR) must be confirmed 
either after 3-4 weeks for PSA and after 4-6 weeks for RECIST v1.1. in patients with measurable 
disease. Confirmation of changes in bone lesions by PCWG3 criteria will occur after a minimum 
of 16 weeks (i.e. scheduled assessments during week 17 and beyond). 


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3.2. 
Sample Size 
In total 100 patients with evaluable disease according to RECIST 1.1. and PCWG3 criteria will 
be treated in this trial. Patients may be replaced (see Section 6.8.3), therefore the total number of 
treated patients may be higher than the anticipated number of evaluable patients. This phase II 
study is conducted to gather preliminary efficacy and safety information on the new oral 
treatment. The sample size is not based on a formal hypothesis testing. However, sample size 
sensitivity assessments were performed based on precision (width of 95% confidence interval) 
for the difference in the proportions of radiographic progression free survival (rPFS) between 
treatment at time of the 6 months follow-up. The average median rPFS in patients with mCRPC 
with docetaxel treatment in previous studies (Table 1) was 8.3 months, corresponding to the 
proportion of patients with rPFS at 6 months of  around 61% (assuming rPFS  
follows an exponential distribution). It is expected that ModraDoc006/r will be at least as 
effective as i.v. docetaxel.  The following table provides 95% confidence intervals for the 
treatment differences in proportion of rPFS at 6 month follow-up. 
 
Docetaxel  
Response 
ModraDoc006/r 
Response 
Treatment Difference 
(ModraDoc006/r  - Docetaxel ) 
Median 
PFS 
% rPFS at 
6 Month 
Median 
PFS 
% rPFS at 6 
Month 
Difference 
Lower  
95% CI 
Upper 
95%CI 
8.3 
61% 
8.3 
61% 
0% 
-19.1% 
19.1% 
8.3 
61% 
9.1 
63% 
2% 
-17.0% 
21.0% 
7 
55% 
7 
55% 
0% 
-19.5% 
19.5% 
7 
55% 
7.7 
58% 
3% 
-16.4% 
22.4% 
6 
50% 
6 
50% 
0% 
-19.6% 
19.6% 
6 
50% 
6.6 
53% 
3% 
-16.6% 
22.6% 
 
Trial Stopping Rules 
Conditions that warrant termination of or holding of the trial include, but are not limited to, the 
following: 
• The incidence or severity of (S)AEs in this trial posing an unacceptable risk to the patients 
enrolled in the trial. 
• A decision by the Sponsor to suspend or discontinue testing, evaluation, or development 
of the product in this indication.  
The Investigator will be notified by the Sponsor, if the trial is terminated or placed on hold. The 
relevant Institutional Ethics Committee (IEC) and health authorities will also be informed 
according to appropriate regulatory requirements. 
3.3. 
End of Trial 
The end of the trial is defined as the last patient last visit (LPLV). For the purpose of data 
summarisation, data analyses will be performed after the last patient has completed their End of 
Trial (EOT) visit or the last enrolled patient has completed six (6) months of treatment, 
whichever occurs first. Patients may still be on trial at the time of data summarisation, as all 


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patients may continue to receive trial treatment until disease progression, unacceptable toxicity, 
or discontinuation for any other reason, according to the standard of care. 
After 10 months of the last enrolled patient, the sponsor may terminate the study. Any patient 
still under treatment in Cohort 1 can be switched to commercially available i.v. docetaxel. 
Patients still treated in Cohort 2 and who experience clinical benefit, will be offered the 
opportunity for compassionate use ModraDoc006/r. 


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4. 
SELECTION OF PATIENTS 
4.1. 
Trial Population 
This study will enrol patients with mCRPC for whom treatment with i.v. docetaxel is indicated 
according to the standard of care. These patients will be randomized to Cohort 1 or Cohort 2 as 
described in Section 3.1 above. They will be randomized to standard i.v. docetaxel 75 mg/m2, q 
3 weeks or to ModraDoc006/r BIDW.  
Only patients who meet all of the eligibility criteria will be enrolled. 
4.2. 
Inclusion Criteria 
To be eligible to participate in this trial, subjects must meet all of the following eligibility 
criteria: 
1. 
Age ≥ 18 years 
2. 
Histologically or cytologically proven prostate cancer with evidence of progressive 
mCRPC, defined as:  
a. Castrate levels of testosterone, defined as ≤ 50 ng/dL (or ≤ 0.50 ng/mL or 1.73 
nmol/L) 
b. Evidence of progressive metastatic disease as defined by radiographic disease 
progression or PSA progression   
c. With an indication for systemic treatment with docetaxel according to the standard 
of care 
3. 
Evaluable disease, defined as nodal or visceral lesions as evaluated with CT-scan or MRI, 
and measured according to RECIST v1.1. and/or bone metastasis as evaluated with 99mTc-
methylene diphosphonate (MDP) radionuclide bone scintigraphy by PCWG3 criteria 
4. 
Resolution of toxicity of prior therapy to < grade 2 (except for alopecia), as defined by 
CTCAE 
v5.0. 
For 
any 
pre-existing 
gastro-intestinal 
toxicities 
(diarrhea 
or 
nausea/vomiting) and mucositis, full resolution is required prior to study start. 
5. 
Adequate hematological, renal and hepatic functions: 
a. Hemoglobin   mmol/l (>9.0 g/dL) 
b. ANC ≥ 1.5 x 109 /L 
c. Platelet count ≥ 100 x 109 /L 
d. Hepatic function defined by  
i. Total bilirubin ≤ 1.5 x ULN, except for patients with familial 
bilirubinemia (Gilbert’s disease) 


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ii. Serum ASAT and ALAT ≤ 2.5 x ULN (≤ 5 x ULN with liver 
metastases) 
e. Renal function defined by serum creatinine  1.5 x ULN or creatinine clearance  
50 ml/min (by Cockcroft-Gault formula, or MDRD [Modification of Diet in Renal 
Disease]). 
6. 
WHO performance status of 0-2 
7. 
Estimated life expectancy of at least 12 weeks 
8. 
Able and willing to swallow oral medication 
9. 
Able and willing to undergo radiologic scans (CT-scan, or MRI and bone scintigraphy) 
10. 
Able and willing to give written informed consent according to local guidelines 
 
4.3. 
Exclusion Criteria 
Subjects who meet ANY of the following criteria at screening will be excluded from trial entry: 
1. Any treatment with investigational drugs, chemotherapy or immunotherapy within 4 weeks 
prior to receiving the first dose of investigational treatment. Palliative radiotherapy (1x8 Gy 
dose) is allowed before and during the study, but not in the week prior to start of study 
treatment.  
2. Subjects who have had prior treatment with taxanes. 
3. Subjects with symptomatic brain metastases. Subjects asymptomatic in the absence of 
corticosteroids and anticonvulsant therapy for ≥6 weeks are eligible. Radiotherapy for brain 
metastasis must have been completed ≥6 weeks prior to start of trial. Brain metastasis must 
be stable with verification by imaging (e.g. brain MRI or CT completed at screening, 
demonstrating no current evidence of progressive brain metastases). Subjects are not 
permitted to receive anti-epileptic drugs or corticosteroid treatment indicated for brain 
metastasis. Subjects with a history of leptomeningeal metastases are not eligible.  
4. Current malignancies other than mCRPC with exception of adequately treated basal or 
squamous cell carcinoma of the skin, or adequately treated non-muscular invasive bladder 
cancer. 
5. Absence of highly effective method of contraception as of cycle one day one (C1D1). Men 
enrolled in this trial must agree to use a highly effective contraceptive method throughout the 
study. 
6. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) 
7. Grade ≥ 2 motor or sensory neuropathy symptoms (as defined by CTCAE version 5.0) 
8. Known hypersensitivity to any of the study drugs or excipients or taxanes 


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9. Concomitant use of MDR, CYP3A, OATP1B1, OATP1B3 and MRP2 modulating drugs 
such as Ca+- entry blockers (verapamil, dihydropyridines), cyclosporine, quinidine and 
grapefruit juice, concomitant use of HIV medications, other protease inhibitors, (non) 
nucleoside analogues, or St. John’s wort 
10. Bowel obstruction or motility disorder that may influence the resorption of drugs as judged 
by the treating physician 
11. Major surgical procedures within 21 days prior to providing informed consent 
12. Active acute or chronic infection, which is not controlled by appropriate medication (at the 
discretion of the treating physician) 
13. Known positivity for Human Immunodeficiency Virus HIV-1 or HIV-2 type 
14. Patients with known active infection of hepatitis B, C, or E (patients who are anti-HBC 
positive but HBsAg negative are eligible to participate in this study) 
15. Clinically significant (i.e. active) cardiovascular disease defined as stroke, transient ischemic 
attack (TIA), myocardial infarction, unstable angina, or congestive heart failure within ≤ 6 
months prior to first trial treatment  
16. Evidence of any other medical conditions (such as treatment-resistant peptic ulcer disease, 
erosive oesophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, or 
pulmonary embolism within 4 weeks of randomization, or psychiatric illness, drug or alcohol 
abuse, physical examination or laboratory findings) that may interfere with the planned 
treatment, affect subject compliance or place the subject at high risk of treatment-related 
complications 
17. Legal incapacity 
 
 


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5. 
TRIAL TREATMENT 
5.1. 
Identity of Investigational Medicinal Product (Trial Drug) 
5.1.1. 
Description of the IMP 
Modra Pharmaceuticals developed a spray-dried solid dispersion formulation of docetaxel 
pressed into tablets (ModraDoc006 10 mg tablets), containing 10 mg docetaxel. The formulation 
excipients are polyvinyl pyrrolidone K30, sodium dodecyl sulphate, lactose monohydrate, 
croscarmellose, silica colloidalis anhydrica and magnesium stearate. All excipients are included 
in the FDA guide for inactive compounds (oral capsules and tablets).  
The stability studies of ModraDoc006 10 mg are ongoing and according to relevant International 
Council of Harmonization (ICH) guidelines. Interim data shows that ModraDoc006 10 mg 
tablets in the current package form are stable for at least 18 months at room temperature and 
protected from light. Shelf life will be set based on ICH Q1E guideline. 
5.1.2. 
Formulation, preparation and labelling of ModraDoc006 
ModraDoc006 is manufactured and packaged at the pharmacy Netherlands Cancer Institute 
according to good manufacturing practice (GMP) regulations. Final clinical labelling will be 
conducted by a clinical logistics service organisation. Ritonavir is commercially available as 
100 mg tablets for oral consumption (Norvir®). This tablet has been granted market approval in 
1996 in the EU (EU/1/96/016/005) by the European Commission and in 2010 in the USA (NDA 
022417).  Norvir® bottles will be overlabelled with appropriate clinical label. Both drugs will be 
distributed by a clinical logistics service organisation. 
Plasma concentrations of ritonavir after administration of a single 100 mg dose tablet are similar 
to the 100 mg soft gelatine capsule under fed conditions, although the absorption of the tablet 
may be more efficient52. Norvir® tablets and Norvir® capsules have not been compared under 
fasting conditions. 
All clinical labels will comply with GMP regulations and local regulatory requirements and will 
state that the drug is for clinical use only and should be kept out of reach of children.  
5.1.3. 
Preparation and labelling of i.v. docetaxel 
All labels will comply with good manufacturing practice regulations and will state that the drug is 
for clinical use only and should be kept out of reach of children. Information regarding the patient, 
for example enrolment number, contents, expiry date, dosing instructions as well as a space for the 
date of dispensing will be included on the labels.   
5.2. 
Drug accountability 
Modra Pharmaceuticals will provide the study drugs ModraDoc006, ritonavir (Norvir®) and i.v. 
docetaxel. All other medications will be taken from the Pharmacy’s own stock at the 
investigational site. The study drugs will be stored and handled according to the manufacturer’s 
instructions. The site will acknowledge receipt of the study drugs indicating shipment content 
and condition. Damaged supplies will be quarantined and replaced. Until dispensed to the 
patients, all study drugs will be stored in a secure locked area, accessible to authorised personnel 
only. The Investigator agrees to use the study drugs only in accordance with this study protocol.  


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5.3. 
Compliance and handling of study drug 
Patients will be instructed to take their study drug dose at approximately the same time on the 
same day of each week. Patients will report their medication intake and possible symptoms on a 
personal registration list (medication diary) that will be reviewed in an outpatient setting. In 
addition, during the first cycle on Day 3 and Day 10 (+/- 1 day), patients will be contacted by 
telephone to check on compliance. 
Patients will be instructed to return any unused tablets during each visit, including empty boxes, 
to enable the site staff to check compliance. Tablets that are not taken will not be reallocated but 
returned to the pharmacy.  
5.3.1. 
Accountability Procedures 
Accurate records of all study drugs (ModraDoc006, ritonavir and i.v. docetaxel) dispensed to the 
investigational site are to be maintained, including the amount (number of vials) and lot 
numbers, according to site-specific Standard Operating Procedures (SOPs). Records will include 
overall accountability of the bulk product shipped to the investigational sites, and details of the 
dosing vials dispensed to patients for traceability. Drug accountability will be monitored 
throughout the study.  
Upon termination of the study, and after inventory by a Modra Pharmaceuticals monitor or 
designated representative, all study drugs are to be returned to Modra Pharmaceuticals or 
designee in the original vials unless there is agreement to destroy it on site. The site must supply 
a copy of their study drug destruction policy to Modra Pharmaceuticals before authorisation for 
destruction will be considered. Full documentation of study drug destruction will be provided for 
the Trial Master File.  
5.4. 
Administration of i.v. docetaxel 
5.4.1. 
Dose and Schedule of i.v. docetaxel according to standard of care 
All patients in Cohort 1 will be treated with i.v. docetaxel 75 mg/m2 as a one-hour infusion on 
day 1 every 21 days plus oral prednisone 2dd 5 mg until disease progression or intolerable 
toxicity, according to standard of care77 (see Figure 4:). Per the FDA label for docetaxel, 
premedication with dexamethasone is required in order to reduce the incidence and severity of 
fluid retention as well as the severity of hypersensitivity reactions.”77. The recommended 
premedication regimen is oral dexamethasone 8 mg, at 12 hours, 3 hours and 1 hour before 
docetaxel infusion. Adherence to this schedule is recommended, however, use of dexamethasone 
according to the local hospital standard will be allowed. Anti-emetic premedication may be 
applied as per local practice standard of care. 
Under all circumstances accurate documentation of dose and schedule of dexamethasone and all 
other co-medication in the medical record of the patient is essential. 
On a predefined day of the first and every subsequent cycle, the patient will receive i.v. 
docetaxel. This regimen will be continued 3-weekly until disease progression (specifically meant 
as radiographic disease progression, not biochemical or PSA progression only), unacceptable 
toxicity, or discontinuation for any other reason.  
 


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Figure 4: 
Study schedule cohort 1  
Week 
1 
2 
3 
Day 
1 
 
 
 
 
 
 
8 
 
 
 
 
 
 
15 
 
 
 
 
 
Docetaxel i.v. 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prednisone 
twice daily 
x 
x x x x x x 
x 
x x x x x x 
x 
x x x x x 
ADT* 
 
Patients will be treated with i.v. docetaxel on day 1 every 21 days with prednisone 5 mg twice daily every day. *Patients will also 
be treated with androgen deprivation therapy (ADT) according to the standard of care, for example gosereline (Zoladex) 10.8 mg 
s.c. every 12 weeks. 
 
5.4.2. 
Dose Modifications i.v. docetaxel 
Toxicities for patients with mCRPC treated with docetaxel and prednisone are described in the 
FDA label 77 and Summary of Product Characteristics (SPC) 78. 
One dose reduction of i.v. docetaxel is allowed from 75 mg/m2 to 60 mg/m2 (see Table 44).  If a 
patient requires more than the allowed dose-reduction, study treatment needs to be discontinued. 
Patients should permanently discontinue study treatment for all grade 4 toxicities with the 
exception of:  laboratory values which resolve to CTCAE < grade 1, alopecia, or inadequately 
treated nausea, vomiting, or diarrhea. 
 
Table 4: 
Dose modifications for i.v. docetaxel 
Treatment 
Standard dose 
First dose reduction 
i.v. docetaxel 
75 mg/m² 
60 mg/m² 
 
5.5. 
Administration of ModraDoc006/r 
5.5.1. 
Dose and Schedule of ModraDoc006/r 
All patients in Cohort 2 will take ModraDoc006/r orally bi-daily on day 1 of every week (see 
Figure 5), in the morning and in the afternoon on an empty stomach, either 1 hour before or 2 
hours after meals (see Table 55). The time allowed between morning and afternoon dosage is at 
least 7 hours, up to 12 hours. Depending on the treatment schedule, administration may take 
place in an outpatient setting. ModraDoc006 is administered simultaneously with 200 mg 
ritonavir in the morning and 100 mg ritonavir in the afternoon and a glass of tap water 
(approximately 150 mL). Patients will report their medication intake and possible symptoms on a 
personal registration list that will be reviewed in an outpatient setting. In case of vomiting after 


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intake, the patient should not take another dose. The patient should ensure that the whole dose is 
taken.  
On a predefined day of the first and every subsequent weekly cycle, the patient will receive 
ModraDoc006/r. This regime will be continued weekly until disease progression (specifically 
meant as radiographic disease progression, not biochemical or PSA progression only), 
unacceptable toxicity, or discontinuation for any other reason. There is no maximum duration of 
ModraDoc006/r administration. 
Figure 5:  
Study schedule cohort 2  
Week 
1 
2 
3 
Day 
1 
 
 
 
 
 
 
1 
 
 
 
 
 
 
1 
 
 
 
 
 
 
Morning
Evening
 
Morning
Evening
 
Morning
Evening
 
ModraDoc006 x x  
 
 
 
 
 
x x  
 
 
 
 
 
x x  
 
 
 
 
Ritonavir x x  
 
 
 
 
 
x x  
 
 
 
 
 
x x  
 
 
 
 
Prednisone  
twice daily 
x x x x x x x x x x x x x x x x x x x x x x x 
ADT*  
Patients will be treated with ModraDoc006 and ritonavir twice a day, once every week and with prednisone 5 mg twice daily 
every day. *Patients will also be treated with androgen deprivation therapy (ADT) according to the standard of care, for 
example gosereline (Zoladex) 10.8 mg s.c. every 12 weeks. 
 
Table 5: 
ModraDoc006/r treatment 
Schedule: Once weekly (on the same day) 
Treatment 
Dosing 
Administration 
ModraDoc006 
 
 
Ritonavir  
20 mg in the morning 
20 mg in the evening 
 
200 mg in the morning (i.e. 2*100 mg) 
100 mg in the evening 
oral tablets of 10 mg each 
 
 
oral tablets of 100 mg each 
 
Note: Patients enrolled under protocol amendment 1, who are dosed with 30 mg of ModraDoc006 
combined with 200 mg ritonavir in the morning and 20 mg of ModraDoc006 combined with 100 
mg ritonavir in the evening, will, at the investigator’s discretion, be able to continue at this dose. 
5.5.2. 
Premedication and supportive care for ModraDoc006/r 
 
Anti-emetic therapy 
As anti-emetic therapy, all patients will be given bi-daily a 5HT3 antagonist prior to oral 
ModraDoc006/r administration during the first two weeks (see Table 66). In subsequent cycles, 
5HT3 antagonist premedication may be given if indicated. All patients should be provided by the 


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site with a home prescription for anti-emetics (metoclopramide 10 mg maximum 4 times daily) 
and should receive instructions on how to use this medication in case nausea/vomiting occurs at 
home. In case metoclopramide (or domperidone) proves insufficient, a 5HT3 antagonist may be 
taken on days of study medication, granisetron 1-hour prior or ondansetron 2 hours prior to study 
medication, and this may be continued for up to 3 days after the intake of study medication. 
Should this prove insufficient, dexamethasone and lorazepam may be added as anti-emetic 
treatment according to step 3 in the schedule provided in Table 77. Dexamethasone may be used 
as outlined in table 7 as a third step only and at a low dose of 1 mg, because as has been 
explained in Appendix VIIII, concomitantly used ritonavir may increase exposure to 
dexamethasone.   
In case of vomiting after intake, the patient should not take any new study drug. 
Table 6: 
Premedication before ModraDoc006/r 
Premedication (standard during first two cycles, thereafter according to standard practice of the 
treating physician) 
Treatment 
Dose 
Day 
Administration 
Granisetron (preferred) 
1 mg 
morning dose, one hour before treatment 
evening dose, one hour before treatment 
oral tablet 
Ondansetron* 
8 mg 
morning dose, two hours before treatment 
evening dose, two hours before treatment 
oral tablet 
*If ondansetron is prescribed, it has to be taken at least 2 hours in advance of the study treatment to avoid 
drug-drug interactions. 
Table 7: 
Anti-emetic therapy 
Step 1 
Step 2 
Step 3 
Metoclopramide (preferred) 
4 dd 10 mg as needed 
or 
Domperidone 
4 dd 10 mg as needed 
Granisetron (preferred) 
2 dd 1 mg  
or 
Ondansetron* 
2 dd 8 mg  
Dexamethasone 
1 dd 1 mg, increase as needed 
or 
Lorazepam 
1 dd 1 mg, increase as needed 
*If ondansetron is prescribed, it has to be taken at least 2 hours in advance of the study treatment to avoid 
drug-drug interactions. 
Supportive care for diarrhea 
All patients should be provided by the site with diet and hydration instructions and a home 
prescription for loperamide, with instructions on how to use this medication in case diarrhea 
occurs at home. Of note, loperamide is not allowed on the day of administration of 
ModraDoc006/r, due to metabolism by the CYP3A isoenzyme.  
In case of diarrhea and the presence of nausea and/or vomiting, treatment with metoclopramide 
should be altered to a 5HT3 antagonist.  
Instructions on AE management and dose modifications for diarrhea are provided in Table 88. 
Patients will be instructed that if they miss a day’s dose, they must not double up the next dose 
but skip this dose instead and resume the dosing schedule as planned. If a dose or doses are 
missed, the reason(s) and the number of doses not taken will be noted and recorded in the eCRF, 
just as all administered doses are documented. 


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Table 8: 
Diarrhea - Supportive treatment and Dose Modifications  
CTCAE Grade  
Adverse Event Management 
Dose Modification 
Uncomplicated 
diarrhea¹  
Grade 1 or Grade 2  
 
Diet: Stop all lactose-containing products; 
eat small meals, BRAT diet (bananas, 
apples, rice, toast) is recommended.  
 
Hydration: 8 to 10 large glasses of clear 
liquids per day (e.g., Gatorade or broth).  
 
Medication (Grade 2): 
- stop metoclopramide, in case of 
nausea/vomiting: start ondansetron or 
granisetron. 
 
- Loperamide³, initially 4 mg, followed by 
2 mg every 4 hours or after every unformed 
stool, to a maximum of 16 mg/ day. 
Continue until diarrhea-free for 12 hours.  
Loperamide is NOT allowed on the day of 
administration of ModraD006/r. 
 
Diarrhea > 24 hours: Loperamide 2 mg 
every two hours to a maximum of 16 mg/ 
day. Consider adding oral antibiotics.  
Diarrhea > 48 hours: Loperamide 2 mg 
every two hours to a maximum of 16 mg/ 
day. Add budesonide or other 2nd line 
therapies (octreotide, or tincture of opium) 
and oral antibiotics.  
Grade 1 (despite optimal 
supportive treatment): No dose 
reduction, unless unacceptable to 
patient or medically concerning. 
 
Grade 2 (despite optimal 
supportive treatment):  
Hold or omit4 ModraDoc006/r 
until recovery to ≤ grade 1. 
Restart with a dose reduction of 
ModraDoc006/r. 
Any complicated 
diarrhea²  
Grade 3 or Grade 4 
 
Clinical evaluation is mandatory.  
 
Stop metoclopramide, in case of 
nausea/vomiting: start ondansetron or 
granisetron. 
 
Loperamide³: initially 4 mg, followed by 
2 mg every 4 hours or after every unformed 
stool, to a maximum of 16 mg/ day. 
Continue until diarrhea-free for 12 hours.  
2nd line therapies should be implemented if 
clinically indicated. Loperamide is NOT 
allowed on the day of administration of 
ModraD006/r. 
 
Hydration: IV fluids should be administered 
if clinically indicated.  
 
Antibiotics (oral or IV) should be 
administered if clinically indicated.  
 
≥ Grade 3 (despite optimal 
supportive treatment):  
Hold or omit4 ModraDoc006/r 
until recovery to ≤ grade 1, and 
then restart with a dose reduction 
of ModraDoc006/r if in the best 
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CTCAE Grade  
Adverse Event Management 
Dose Modification 
Interventions should be continued until 
the patient is diarrhea-free for ≥ 24 
hours.  
Intervention may require hospitalization 
for patients at risk of life-threatening 
complications.  
¹ Uncomplicated diarrhea is defined by the absence of other symptoms such as cramping, nausea/vomiting ≥ Grade 2, 
decreased performance status, pyrexia, sepsis, neutropenia ≥ Grade 3, frank bleeding, and/or dehydration requiring 
IV fluid substitution.  
² Complicated diarrhea is defined by the presence of symptoms such as cramping, nausea/vomiting ≥ Grade 2, 
decreased performance status, pyrexia, sepsis, neutropenia ≥ Grade 3, frank bleeding, and/or dehydration requiring 
IV fluid substitution.  
³ Loperamide should be made available prior to the start of study treatment so that loperamide administration can 
begin when indicated. Loperamide is NOT allowed on the day of administration of ModraDoc006/r. 
4 Hold or omit = Hold dose in case of Day 1; Omit dose in case of Day 8 or Day 15. Patients should be assessed 
weekly until recovery. Up to a maximum of 28 days in between doses is permitted. 
5.5.3. 
Dose Modifications of ModraDoc006/r 
Toxicities leading to dose modification are defined as any of the following occurring during the 
treatment despite adequate supportive care and by the Investigator assessed as possibly, probably 
or definitely related to ModraDoc006/r (see Table 99 for hematological toxicities and  


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Table 10 for non-hematological toxicities): 


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Table 9: 
Dose modifications for ModraDoc006/r in case of hematological toxicity 
NCI Common Toxicity Criteria: Hematological toxicity 
Toxicity 
Definition 
Dose modification 
Anaemia 
Grade 1-4 
No dose reduction, but blood transfusions or other 
medical intervention aimed at resolving bleeding 
focus, when present, are allowed as needed. 
Neutropenia 
Grade 1-2 
No intervention or dose reduction. 
Grade 3 without 
fever (< 38.5 ᵒC) 
Hold or omit* ModraDoc006/r and repeat blood 
count twice weekly until resolution to CTCAE < 
grade 2. Resume at the same dose-level when ANC 
≥ 1.0 x10⁹/L. 
Grade 3 with fever (
≥ 38.5 ᵒC) or 
Grade 4 
Hold or omit* ModraDoc006/r and repeat blood 
count every other day until resolution to CTCAE < 
grade 2. Resume when ANC ≥ 1.0 x10⁹/L with a 
dose reduction if in the best interest of the patient. 
Thrombocytopenia 
Grade 1 
No intervention or dose reduction. 
Grade 2 
Hold or omit* ModraDoc006/r and repeat blood 
count after one week. Resume treatment at the same 
dose-level when platelets ≥ 75 x10⁹/L. 
Grade 3 
Hold or omit* ModraDoc006/r and repeat blood 
count twice weekly until resolution to CTCAE < 
grade 2. Resume treatment at the same dose-level 
when platelets ≥ 75 x10⁹/L. If grade 3 is associated 
with bleeding, hold ModraDoc006/r and repeat blood 
count after one week. Resume treatment when 
platelets ≥ 75 x10⁹/L with a dose reduction of 
ModraDoc006 if in the best interest of the patient. 
Grade 4 
Hold or omit* ModraDoc006/r and repeat blood 
count every other day until grade 3. Resume when 
platelets ≥ 75 x10⁹/L with a dose reduction if in the 
best interest of the patient. 
All grading will be done according to CTCAE v5.0 (Appendix III). 
*Hold or omit = Hold dose in case of Day 1; Omit dose in case of Day 8 or Day 15. Patients should be assessed weekly 
until recovery. Up to a maximum of 28 days in between doses is permitted. 
 
If a second episode of ≥ grade 3 hematological toxicity occurs after dose reduction, patients will 
be taken off study. 
 
 
 
 


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Table 10: 
Dose modifications for ModraDoc006/r in case of non-hematological toxicity 
NCI Common Toxicity Criteria: Non-Hematological toxicity 
Toxicity 
Definition 
Dose modification 
Diarrhea 
Grade 1-4 
See Table 88 
Nausea and vomiting 
(failing optimal 
dopamine antagonist, 
5HT3 antagonist, 
dexamethasone, or 
benzodiazepine therapy) 
Grade 1 
No intervention or dose reduction. 
≥ Grade 2 
Hold or omit* until recovery to ≤ grade 1, up to 21 
days, and then restart with a dose reduction if in the 
best interest of the patient. 
Mucositis 
Grade 1 
 
Grade 2-3 
Dose reduce if G1 mucositis appears in Cycle 1 or 2. 
No intervention or dose reduction in Cycle 3 or more. 
Hold or omit* until recovery to ≤ grade 1, up to 21 
days, and then restart with a dose reduction. 
Peripheral neuropathy 
Grade 1 
No intervention or dose reduction. 
Grade 2 
No intervention or dose reduction, but if 
unacceptable to patient or medically concerning, then 
treatment should be discussed with PI. 
≥ Grade 3 
Permanent discontinuation of study treatment.. 
Fatigue 
Grade 1 
No intervention or dose reduction. 
Grade 2 
Dose reduce if G2 fatigue appears in Cycle 1 or 2. 
If unacceptable to patient or medically concerning, 
then hold or omit* until recovery to ≤ grade 1, up to 
21 days. Restart at the same dose or consider dose 
reduction if in the best interest of the patient. 
Grade 3 
Hold or omit* until recovery to ≤ grade 1, up to 21 
days and then restart with a dose reduction if in the 
best interest of the patient. 
Other non-
hematological toxicity 
Grade 1 
No intervention or dose reduction. 
Grade 2 
Dose reduce if G2 appears in Cycle 1 or 2. 
If unacceptable to patient or medically concerning, 
then hold or omit* until recovery to ≤ grade 1, up to 
21 days. Restart at the same dose or consider dose 
reduction if in the best interest of the patient. 
Grade 3 
 
Hold or omit* until non-hematological toxicity has 
resolved to ≤ grade 1, up to 21 days, and then restart 
with a dose reduction if in the best interest of the 
patient. 
Any non-hematological 
toxicity  
Grade 4 
Permanent discontinuation of study treatment, except 
in case of laboratory values which resolve to CTCAE 
≤ grade 1, alopecia, or inadequately treated nausea, 
vomiting, or diarrhea. 
All grading will be done according to CTCAE v5.0 (Appendix III). 
*Hold or omit = Hold dose in case of Day 1; Omit dose in case of Day 8 or Day 15. Patients should be assessed weekly 
until recovery. Up to a maximum of 28 days in between doses is permitted. 


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In case of grade 4 toxicities, patients should permanently discontinue study treatment with the 
exception of:  laboratory values which resolve to CTCAE ≤ grade 1, alopecia, or inadequately 
treated nausea, vomiting, or diarrhea. 
Patients who develop grade 3-4 peripheral neuropathy should permanently discontinue study. 
One dose reduction of ModraDoc006/r as described in Table 1111 is allowed. If a patient 
requires more than the allowed dose-reduction, study treatment needs to be discontinued. 
 
Table 11: 
Dose modifications for ModraDoc006/r 
Dose 
Standard dose 
Dose reduction 
Morning dose 
ModraDoc006 
20 mg 
20 mg 
Ritonavir 
200 mg 
200 mg 
Evening dose 
ModraDoc006 
20 mg 
10 mg 
Ritonavir 
100 mg 
100 mg 
 
 
Note: For patients enrolled under protocol amendment 1, two dose reductions of ModraDoc006/r 
will be allowed. In these patients, if a second episode of ≥ grade 3 hematological toxicity occurs, 
treatment will be stopped until toxicity resolves to ANC ≥ 1.0 x10⁹//L and/or platelets ≥ 75 
x10⁹/L. If a second episode of ≥ unacceptable grade 2 or grade 3 non-hematological toxicity 
occurs, treatment will be stopped until toxicity resolves to ≤ grade 1. When treatment is resumed, 
patients will receive a second dose reduction of ModraDoc006, according to the dose reduction 
scheme in Table 12. If a third episode of ≥ grade 3 hematological toxicity or ≥ unacceptable 
grade 2 or grade 3 non-hematological toxicity occurs, patients will be taken off study. 
 
Table 12: 
Dose modifications for ModraDoc006/r under amendment 1 
Dose 
Standard dose 
First 
dose reduction 
Second 
dose reduction 
Morning dose 
ModraDoc006 
30 mg 
20 mg 
20 mg 
Ritonavir 
200 mg 
200 mg 
200 mg 
Evening dose 
ModraDoc006 
20 mg 
20 mg 
10 mg 
Ritonavir 
100 mg 
100 mg 
100 mg 
 
 


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5.6. 
End of Treatment 
In this trial, end of treatment (EOT) is defined as the moment at which trial treatment is 
permanently discontinued. 
Patients are scheduled to continue to receive treatment with ModraDoc006/r until any of the 
following occurs:  
• Unacceptable toxicity (even after the allowed dose modification has been applied, 
refer to Section 6.8) 
• Progressive disease as defined in RECIST v1.1 (Appendix IV) and/or PCWG3 
(Appendix V) 
• Initiation of any other anti-cancer treatment  
• Inability or unwillingness of the patient to comply with trial procedures 
• Significant protocol violations, as judged by the Investigator 
• Withdrawal of consent by the patient 
• Changes in the medical status of the patient such that the Investigator believes that the 
safety of the patient will be compromised 
• Patient lost to follow-up 
• Death 
The Investigator is ultimately responsible for the safety and wellbeing of the patient. If at any 
time participation in this protocol is detrimental to the patient's health, the patient may be taken 
off treatment or off trial.  
The CRO must be notified and the reason(s) for treatment withdrawal/trial drop-out should be 
documented in the electronic Case Report From (eCRF). 
5.7. 
Prior and Concomitant Treatments 
All prior therapies (beginning and stopped within 4 weeks prior to, and/or ongoing at the time of 
the screening visit until Cycle 1 Day 1) and concomitant treatment, blood products, as well as 
interventions (e.g. analgesic use, radiotherapy) received by the patients from signing Informed 
Consent until EOT visit will be recorded in the eCRF. This includes start and stop date, dose, 
unit, frequency, route of administration and indication. 
The following rules should be considered when prescribing other treatments prior to or during 
the patient’s participation in the trial: 
• Ancillary treatments will be given as medically indicated; they should be recorded in 
the patient’s medical chart and on the appropriate eCRF. 
• Radiotherapy may be given concomitantly for control of bone pain or other reasons, 
however may not be given within one week prior to start of the trial treatment. If 
possible, not all evaluable lesions should be included in the irradiated field. If this 
cannot be realised, the patient will be removed from the trial and will not be evaluable 
for response from that moment on. Any lesion within the irradiated area cannot be 


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used as a parameter for response assessment. The area should therefore be as small as 
possible. 
• Patients will not receive other anticancer treatments or other investigational agents 
from start of trial treatment until last trial treatment. 
• Prior treatment with ADT is allowed. Treatment with ADT such as an agonist of 
luteinising-hormone-releasing hormone may be continued in participants who are 
receiving it.  
• Patients are allowed to take bisphosphonate drugs if they commenced treatment at 
least two months before registration and they continued them as per the 
manufacturer’s guidelines or as per institutional practice. Patients not taking 
bisphosphonate treatment are not permitted to start such therapy until they have 
completed 12 weeks of study treatment. 
Standard use of growth factors (G-CSF, epo) is not allowed, unless a ≥ grade 4 febrile 
neutropenia, neutropenic infection or a ≥ grade 4 anemia has occurred in the previous 
treatment cycle. In this case, if in alignment with local practice, G-CSF or epo 
prevention in subsequent cycles is indicated, this will be allowed for IV docetaxel 
(cohort 1) only. According to the FDA label G-CSF is recommended in case of 
accidental overdose of docetaxel Injection as it reads in paragraph 10 of the 
PRESCRIBING INFORMATION: “Anticipated complications of overdosage 
include: bone marrow suppression, peripheral neurotoxicity, and mucositis. Patients 
should receive therapeutic G-CSF as soon as possible after discovery of overdose."77 
There is no experience with overdose of ModraDoc006/r and in case of such accident 
the sponsor should be notified without delay to discuss supportive measures to ensure 
optimal safety of the involved patient. 
Prohibited concomitant therapy within 6 weeks prior to the first dose of ModraDoc006/r or i.v. 
docetaxel until after completion of study treatment (i.e., after EOT visit) is defined as follows (a 
list of commonly used drugs of below drug types is provided in Appendix VIIII): 
• Systemic chemotherapy, or any other investigational agent within the last 4 weeks 
prior to the first dose of ModraDoc006/r, or i.v. docetaxel. Single dose palliative 
radiation (1*8Gy) for pain relieve is allowed during the study, but not within one 
week prior to start (these lesions are not to be included as target lesions).  
• Corticosteroids and anticonvulsive treatment for brain metastasis are prohibited 
and should have been discontinued at least 6 weeks prior to proposed first dose of 
ModraDoc006/r, or i.v. docetaxel. 
Drugs that show interaction with ModraDoc006/r, or i.v. docetaxel, need to have been stopped at 
least 5 times the terminal half-life (according to SPC) or 7 days, whichever is longest, in order to 
prevent interaction with the drug (see also Appendix VIIII): 
• CYP3A4 inducers / inhibitors: all strong inducers and inhibitors of CYP3A4 may 
not be used during this trial, since this might prevent uptake or could result in 
significant toxicity 


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• CYP3A4 substrates: all substrates of CYP3A4 should be used with great caution. If 
administration of a CYP3A4 substrate is deemed necessary, dose-reductions of this 
drug might be needed.  
• OATP1B1, OATP1B3 inhibitors: all other strong inducers and inhibitors of 
OATP1B1 and OATP1B3 may not be used during this trial, since this might prevent 
uptake or could result in significant toxicity.  
• OATP1B1, OATP1B3 substrates: all substrates of OATP1B1 and OATP1B3 should 
be used with great caution. If administration of an OATP1B1 or OATP1B3 substrate 
is deemed necessary, dose-reductions of this drug might be needed.  
• P-glycoprotein (P-gp, ABCB1, MDR1) inducers/inhibitors: all other strong 
inducers and inhibitors of P-gp may not be used during this trial, since this might 
prevent uptake or could result in significant toxicity.  
• P-glycoprotein (P-gp, ABCB1, MDR1) substrates:  
Loperamide is widely used to treat acute and chronic diarrhea, irritable bowel 
syndrome, and faecal incontinence. Despite that loperamide is a full agonist at the 
opioid μ-receptor, it is not associated with the induction of typical systemic opioid 
effects. It acts only peripherally because it is a substrate for the MDR1 efflux 
protein P-gp in the blood–brain barrier. Despite the fact that the short-term use of 
loperamide most likely does not significantly affect the PK of ModraDoc006/r or 
the central toxicity of the therapy, patients may NOT take loperamide on the day 
of ModraDoc006/r administration. On other days, loperamide is allowed, if 
needed. 
all other substrates of P-gp should be used with great caution. If administration of a P-
gp substrate is deemed necessary, dose-reductions of this drug might be needed.  
• MRP2 (ABCC2) inducers/inhibitors: all other strong inducers and inhibitors of MRP2 may 
not be used during this trial, since this might prevent uptake or could result in significant 
toxicity.  
• MRP2 (ABCC2) substrates: all substrates of MRP2 should be used with great caution. If 
administration of a MRP2 substrate is deemed necessary, dose-reductions of this drug might 
be needed.  
Dietary limitations 
Grapefruit, grapefruit juice, other grapefruit products and St. John’s wort are not to be used 
during this trial because of the interaction with CYP3A4 (see Appendix VIIII). 
5.8. 
Contraception 
Patients with a female partner of childbearing potential will be informed that taking the study 
medication may involve unknown risks to the foetus, if pregnancy were to occur during the 
study. In order to participate in the study, they must adhere to the study contraception 
requirements during the study from the time of screening until 12 weeks after the last dose of 
study medication. Adequate contraceptive methods are: condom, male sterilization, other barrier 
contraceptive measures preferably in combination with condoms, true abstinence. 


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If a female partner of a patient inadvertently becomes pregnant while on treatment, a Pregancy 
Report will need to be filled out. Every effort will be made to obtain permission to follow the 
outcome of the pregnancy and report the condition of the foetus or newborn to the sponsor. A 
Health Report of the infant will need to be filled out at 4 weeks of age. 
5.9. 
Drug accountability 
For the shipment, receipt, disposition, return and destruction of the investigational medicinal 
products the procedures are depicted in the Pharmacy Manual. 
 
 


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6. 
INVESTIGATIONAL PLAN 
In this section, a description is given of all assessments that need to be performed during the trial 
visit. These assessments have been divided into screening, visits during treatment, safety 
assessments and clinical efficacy assessments. Appendix I provides an overview of all 
assessments to be carried out throughout the trial. 
6.1. 
Trial Assessment Specifications 
The following Table 13 provides an overview of the specifications of each of the assessments. 
All regular laboratory safety assessments will be analysed at the local hospital laboratory. All 
additional lab assessments (i.e. outside regular visits), may be performed at local labs (at the 
discretion of the treating physician). See also Appendix I. 


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Table 13: 
Trial Assessments 
Assessment 
Specification 
Physical examination 
(incl. Height in cm & 
Weight in kg) 
Includes the following: head/neck/oral cavity, respiratory system/chest, 
cardiovascular system/ heart, abdomen, skin, lymph nodes, extremities and 
(at the Investigator’s discretion) genitourinary system/pelvis. The 
Investigator (or qualified designee) should evaluate all items of the 
examination either as normal or abnormal, and in case of the latter, whether 
clinically significant or not.  Information about the physical examination 
must be present in the source documentation at the investigational site. 
Significant findings that are present prior to the signing of the ICF must be 
included on the Medical History eCRF. Significant findings which meet the 
definition of an AE, must be recorded on the AE eCRF. 
Medical History & 
Demographics 
• Medical history: patient demographics, current medical conditions, 
including those symptoms related to the advanced cancer condition leading 
to trial participation and any associated symptoms thereof.  
• Prior anti-neoplastic medications, radiotherapy, and surgeries.  
• Dates of initial diagnosis of primary cancer and advanced/metastatic 
disease. 
• Medication history for the past 4 weeks prior to signing Informed Consent.  
WHO Performance 
Status 
Assessment using scale of 0 to 5 (Appendix II) prior to ModraDoc006/r or 
i.v. docetaxel administration. Only patients with a WHO Performance Status 
score of 0, 1 or 2 are allowed to enter the trial. A score of ≥3 during 
treatment is not a criterion for withdrawing the patient from the trial. 
HRQoL assessment 
Health Related Quality of Life (HRQoL) endpoints will be assessed by 
FACT global, FACT-P and FACT-taxane and EQ-5D-5L questionnaires at 
baseline and at the end of cycle 3, 6 and 10, or at End of Treatment (EOT) if 
this would occur earlier; HRQoL assessment by Treatment Satisfaction 
questionnaire will be done at the end of cycle 3, 6 and 10, or at End of 
Treatment (EOT) if this would occur earlier (Appendix VII). 
Electrocardiogram 
(ECG) &  
Vital signs 
A single 12-lead ECG will be made as per local practice and assessed by the 
Investigator (or qualified designee) at screening, week 6 and EOT. The 
ECGs should be assessed at the investigational site as soon as possible after 
recording and prior to ModraDoc006/r or i.v. docetaxel administration. 
Vital signs (blood pressure, temperature and heart rate) will be obtained at all 
visits and should be taken pre-dose. Blood pressure may be measured in a 
sitting position.  
Hematology1  
Includes the following: haemoglobin, hematocrit, red blood cell count, white 
blood cell count and differential (including neutrophil, lymphocyte, 
monocyte, basophil and eosinophil counts) and platelet count. 
Biochemistry1 
Includes the following: sodium (Na), potassium (K), calcium (Ca), glucose, 
urea, creatinine, total bilirubin, alkaline phosphatase, gamma-glutamyl 
transferase (GGT), aspartate aminotransferase (ASAT), alanine 
aminotransferase (ALAT), lactate dehydrogenase (LD), total protein, 
albumin. Creatinine clearance is calculated using the Cockcroft-Gault or 
MDRD formula. 
Urinalysis1 
A dipstick analysis will be performed on urine to test the following: protein, 
glucose, blood, pH, and ketones. If dipstick findings are abnormal according 
to local reference ranges, then a microscopic evaluation may be performed to 
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Assessment 
Specification 
Tumor marker1 
PSA according to the assessment scheme (Appendix I). Please record in the 
eCRF. 
(S)AEs 
Assessed at screening and then continuously until follow-up visit. Grading of 
(S)AEs will be according to CTCAE v5.0. 
Concomitant 
medications/procedures  
Will be assessed at screening and then at each visit until follow-up visit. 
Compliance 
Triage by telephone at Cycle 1, Day 3 and 10 for compliance assessment of 
administration of ModraDoc006/r (cohort 2 only) and optimal supportive 
treatment (cohort 1 and 2) 
CT/MRI/ Bone Scans  
Patients will undergo repeated tumor imaging to evaluate disease progression 
per PCWG3 (Appendix V) and assess tumor responses per RECIST v1.1 
(Appendix IV). RECIST v1.1 evaluation will be performed every 8 weeks 
for first 24 weeks (i.e. during week 9, 17 and 25) timepoint beginning after 
Cycle 1, thereafter every 12 weeks and at End Of Treatment (EOT) of 
ModraDoc006/r or i.v. docetaxel. Scans will include the thorax, abdomen 
and pelvis (preferably CT-scans with appropriate slice thickness per RECIST 
v1.1). In case CT is contraindicated (e.g. due to contrast allergy), then an 
MRI of the abdomen needs to be performed with a chest CT without contrast. 
The modality selected should be the same throughout the study.  
1All laboratory tests to be done at the local lab of the institution 
6.2. 
Screening Visit(s) and Registration of Patients 
6.2.1. 
Screening Visit(s) 
At the screening visit, the trial will be explained to the patient and informed consent will be 
obtained before any trial procedures are conducted. This procedure should be thoroughly 
described in the source documents. Screening may be performed over more than one day as long 
as all tasks are completed within the maximum allowable visit window of 14 days. 
Screening/baseline laboratory assessments done within 3 days of the first ModraDoc006/r or i.v. 
docetaxel administration do not need to be repeated at Day 1. All procedures as described in the 
Schedule of Assessments (Appendix I) should be completed and patient eligibility should be 
confirmed before trial treatment can take place. Patients who do not meet all inclusion criteria or 
who meet any of the exclusion criteria are not eligible for the trial. As soon as a patient is 
deemed ineligible during the screening phase, all further trial evaluations will be cancelled for 
this patient. Patient numbers assigned to patients who fail screening will not be reused. Patients 
failing the screening assessments will be replaced. 
Re-screening may be allowed on a case-by-case basis. In the case of out-of-range laboratory 
results during the screening period, a re-test may be allowed within the screening period. The 
Investigator must contact the Medical Monitor to discuss each re-screening case. 
In case of a re-screening after the initial screening period, a new ICF must be signed by the 
patient and (sub-)Investigator, a new patient number will be assigned, and all screening 
assessments must be repeated. 


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6.3. 
Patient Registration and Randomization 
Patients considered eligible for the trial may only enter the trial after the patient has been 
properly informed about the study and the Informed Consent Form has been signed.  
Eligible patients will be registered in the electronic CRF for details about the patient’s 
randomized treatment arm and the patient’s trial number. 
6.4. 
Treatment Visit(s) 
Evaluations and procedures for all visits are shown in the Assessment Schedule (Appendix I). 
Cohort 1 i.v. docetaxel: 
I.v. docetaxel will be administered Day 1 of 21 day cycles. Safety will be monitored at day 3 and 
10 during the first cycle and once every cycle thereafter, i.e. once every 21 days. Additional 
safety visits are, when indicated, left to the discretion of the treating physician. Patients may 
continue to receive additional cycles of treatment until the patient experiences disease 
progression, unacceptable toxicity, request by patient or physician to discontinue treatment, 
death, or termination of the trial by the Sponsor. The duration of patient participation may 
therefore vary per patient.  
 
Cohort 2 ModraDoc006/r: 
Each treatment cycle is a time-period of 21 days. ModraDoc006/r will be administered Day 1 of 
each week (i.e. Day 1, 8 and 15 of each cycle). Safety will be monitored at day 3 and 10 during 
the first cycle and once every cycle thereafter, i.e. once every 21 days. In the absence of 
progressive disease (PD) or unacceptable toxicity, patients may receive additional cycles of 
treatment. It should be the intention to treat a patient in all cycles at the dose level assigned at 
cycle 1 day 1. 
 
6.5. 
End of Treatment Visit  
Patients are scheduled to continue to receive treatment with ModraDoc006/r, or i.v. docetaxel, 
until any of the reasons as specified in Section 6.8 occurs. Patients should visit the hospital as 
soon as possible after treatment discontinuation, preferably within 7 days of last ModraDoc006/r 
or i.v. docetaxel administration.  
6.6. 
Follow-up Visit 
Following withdrawal from treatment, patients should visit the hospital 30 days after the last 
ModraDoc006/r or i.v. docetaxel administration.  
Patients that withdraw from the trial due to withdrawal of consent, inability or unwillingness of 
the patient to comply with trial procedures or lost to follow-up are considered as trial drop-outs 
and will not have to perform this follow-up visit. 
All patients with any remaining adverse events at this 30-day follow-up visit should be followed 
as indicated in Section 7.2.1 (Adverse Events). 


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6.7. 
Assessment of Safety 
Safety will be assessed by means of physical examination, weight, vital signs, performance 
status, laboratory evaluations (hematology, biochemistry and urinalysis), electrocardiograms 
(ECG), and recording of concurrent illness/therapy and adverse events.  
An overview of the assessments to be performed during each visit is provided in Table 14. For 
more detailed information about the assessments itself, please refer to Table 13.  
 
 
Table 14: 
Overview of Safety Assessments 
Moment in trial 
Required safety assessment 
Screening/Baseline  
Note: ≤ 3 days before 1st dose. These can 
therefore also be performed on day 1 of cycle 
1 before administration of ModraDoc006/r or 
i.v. docetaxel. 
• 
Physical examination 
• 
Weight 
• 
Vital signs 
• 
WHO performance status 
• 
Hematology 
• 
Biochemistry 
• 
Urinalysis 
• 
ECG 
• 
Recording concurrent illness/therapy 
• 
Recording AE 
Once every cycle, i.e. once every 21 days, 
within 3 days before administration  
 
Note: before ModraDoc006/r or i.v. docetaxel 
administration.  
*Baseline measurements ≤ 3 days before 
administration can also be used for this. 
** For patients with grade 3-4 neutropenia 
and/or thrombocytopenia blood counts should 
be determined twice weekly (grade 3) or 
every other day (grade 4) until resolution to 
CTCAE < grade 2. 
• 
Physical examination 
• 
Weight 
• 
Vital signs  
• 
WHO performance status* 
• 
Hematology*/** 
• 
Biochemistry* 
• 
Recording concurrent illness/therapy 
• 
Recording AE 
Cycle 1, Day 3 and Day 10 
Note: window of +/- 1 day allowed 
• 
Recording AE 
• 
Compliance  
End of treatment 
• 
Physical examination 
• 
Weight 
• 
Vital signs 
• 
WHO performance status 
• 
Hematology 
• 
Biochemistry 
• 
Urinalysis 
• 
ECG 
• 
Recording concurrent illness/therapy 
• 
Recording AE 
30-day follow up 
• 
Physical examination 


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Moment in trial 
Required safety assessment 
• 
Weight 
• 
Vital signs 
• 
WHO performance status 
• 
Hematology 
• 
Biochemistry 
• 
Recording concurrent illness/therapy 
• 
Recording AE 
 


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6.8. 
Withdrawal, Discontinuation and Replacement of Patients 
6.8.1. 
Withdrawal 
Patients should be withdrawn from the trial, if the patient:  
• Withdraws consent. It is recommended that the Investigator attempts to perform EOT 
visit evaluations on the date a patient withdraws consent; 
• Is non-compliant with the trial treatments; 
• Is non-compliant with the trial visits and procedures;  
The primary reason for patient withdrawal will be noted on the eCRF. The Investigator should 
attempt to follow withdrawn patients until resolution of any AEs, or at least 30 days after the last 
dose of ModraDoc006/r, or i.v. docetaxel.  
Upon withdrawal, no further dosing, or follow-up visits should be performed for these patients. 
Investigators shall make reasonable attempts to contact lost-to-follow-up patients for evaluation 
of overall response and/or PFS.  
6.8.2. 
Discontinuation  
Patients should discontinue treatment with ModraDoc006/r or i.v. docetaxel, if: 
• The patient has clinically significant lab abnormalities or AEs that, in the 
Investigator’s judgment, would preclude continued treatment.  
• Patients should permanently discontinue study treatment for all grade 4 toxicities with 
the exception of:  laboratory values which resolve to CTCAE < grade 1, alopecia, or 
inadequately treated nausea, vomiting, or diarrhea. 
• Patients who develop grade 3-4 peripheral neuropathy should permanently 
discontinue study. 
• Any other reason including withdrawal of consent. 
If a patient fails to return for a scheduled visit/follow up, attempts should be made to contact the 
patient to ensure that the reason for not returning is not a (serious) adverse event ((S)AE).  
Likewise, if a patient declares his/her wish to discontinue from the study, e.g. for personal 
reasons, an attempt should be made to establish that the true reason is not an AE (bearing in 
mind that the patient is not obliged to state his/her reasons). If the study drug therapy is 
prematurely discontinued, the primary reason for discontinuation must be recorded in the eCRF 
and all efforts will be made to complete and report the observations as thoroughly as possible.  
A complete final evaluation following the patient’s withdrawal should be made, and any AEs 
followed up until resolution or a period of 30 days from the last dose of ModraDoc006/r or i.v. 
docetaxel has elapsed, whichever is the shorter. 
6.8.3. 
Replacement of Patients  
• Patients who fail to receive any administration of docetaxel i.v./ oral ModraDoc006/r 
• Patients who fail to undergo any efficacy assessment after baseline measurement 


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• Patients who discontinue due to toxicity related to study drug will NOT be replaced. 
6.9. 
Assessment of Efficacy 
6.9.1. 
Clinical efficacy assessments 
Preliminary clinical efficacy will be assessed according to RECIST v1.1 and PCWG3 criteria 
(Appendix IV and Appendix V). An overview of the schedule of preliminary clinical efficacy 
assessments is provided in Table 15. 
Table 15:  
Overview of Clinical Efficacy Assessments 
Moment in trial 
Required assessment 
Baseline 
Note: Radiological assessment needs to be 
done < 28 days prior to start of intake of study 
medication  
• CT-scan (or MRI-scan if CT contraindicated)  
• Tumor marker PSA* 
• Bone scintigraphy 
Prior to every cycle 
• Tumor markers PSA* 
After every 8 weeks for first 24 weeks (i.e. 
during week 9, 17 and 25), thereafter every 
12 weeks# – 4-6 weeks later again if PR/CR 
for confirmation   (interval of minimally 4 
weeks) 
• CT-scan (or MRI-scan if CT contraindicated)#  
• Bone scintigraphy 
End of Treatment 
 
• CT-scan (or MRI-scan if CT contraindicated)  
• Tumor markers PSA* 
• Bone scintigraphy 
# In this randomized comparative trial, the scheduled assessments should not be affected by delays in therapy, drug   
holidays or any other events that might lead to imbalance in a treatment arm in the timing of disease assessment.  
*Tumor marker: PSA. Please record in eCRF when measured during the course of the study. 
 
In order to evaluate efficacy, appropriate imaging procedures to accurately assess the tumor stage 
need to be performed.  
All lesions identified at screening/baseline will be consistently followed using the unique lesion 
number assigned at screening/baseline. All tumor measurements are to be obtained using the 
same diagnostic procedure used at screening/baseline.  
Each time a tumor assessment is made, standard RECIST v1.1 and PCWG3 criteria are to be 
applied. All responses need to be documented in the patient eCRF. 
If there is a reduction in tumor size consistent with a complete or partial response (CR or PR), 
tumor assessment will be repeated after 4-6 weeks for confirmation. If the response is 
maintained, then subsequent tumor assessments will be repeated according to the schedule in the 
Assessment table in Appendix I. If a patient goes off trial with an unconfirmed PR or CR, 
follow-up measurement must be done 4 weeks later to confirm the response. 
All lesions must be followed during and after treatment (i.e. target lesions as well as non-target 
lesions) until progression of disease or subjects’ end of study.  
 


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6.9.2. 
Determination of Radiographic Disease Progression 
 
The consensus guidelines of the Response Evaluation Criteria in Solid Tumors, version 1.1 
(RECIST 1.1) (Appendix IV) and the Prostate Cancer Clinical Trials Working Group 3 
(PCWG3) (Appendix V) have been taken into consideration for the determination of 
radiographic disease progression. Radiographic disease progression is defined by RECIST 1.1 
for soft tissue disease, or the appearance of two or more new bone lesions on bone scan (               
PCWG3). The documentation required for the determination of radiographic disease progression 
is listed in Table 16. 
 
Table 16:  
Protocol-Specified Documentation for Radiographic Evidence of Disease 
Progression 
Date 
Progression 
Detected 
(Visit)a 
Criteria for Progression 
Criteria for Confirmation 
of Progression 
(requirement 
and timing) 
Criteria for 
Documentation of Disease 
Progression on 
Confirmatory Scan 
Week 9 
Bone lesions: 2 or more 
new lesions compared to 
baseline bone scan by 
PCWG3. 
Timing: at least 6 weeks 
after progression identified or 
at Week 17 visit.b 
Two or more new bone 
lesions on bone scan 
(compared to Week 9 
scan) 
Soft tissue lesions: 
Progressive disease on CT 
or MRI by RECIST 1.1 
Confirmation required for 
soft tissue disease (scan of 
same modality as 
demonstrated progression)b 
Confirmation of 
progressive soft tissue 
disease by RECIST 1.1 
Week 17 
Bone lesions: Two or 
more new lesions on bone 
scan compared to Week 9 
bone scan. 
Timing: at least 6 weeks 
after progression identified or 
at Week 25 visit. Required 
for bone lesions observed on 
bone scanb 
Persistentc or increase in 
number of bone lesions 
on bone scan compared 
to Week 17 scan 
Soft tissue lesions: 
Progressive disease on CT 
or MRI by RECIST 1.1 
No confirmatory scan 
required for soft tissue 
disease progression. 
n/a 
Week 25 and 
Later 
 
Bone lesions: Two or 
more new lesions 
compared to Week 9 bone 
scan. 
Timing: at least 6 weeks 
after progression identified. 
Required for bone lesions 
observed on bone scanb 
Persistentc or increase in 
number of lesions on 
bone scan compared to 
prior scan 
Soft tissue lesions: 
Progressive disease on CT 
or MRI by RECIST 1.1 
No confirmatory scan 
required for soft tissue 
disease progression 
n/a 
a Progression detected by bone scan at an unscheduled visit either prior to Week 9 or between scheduled visits will 
require a confirmatory scan at least 6 weeks later and should follow confirmation criteria outlined in the table for the 
next scheduled scan. Progression detected by CT/MRI at an unscheduled visit prior to Week 13 will require a 
confirmatory scan at least 6 weeks later whereas progression on or after Week 13 does not require confirmation. 
b Confirmation must occur at the next available scan. 
c For confirmation, at least two of the lesions first identified as new must be present at that next available scan 
(confirmation scan). 
n/a, not applicable. 


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7. 
ADVERSE EVENTS 
All adverse events in this trial will be collected and processed in accordance with ICH-GCP and 
national and local laws and regulations. In line with these, the Investigator is responsible for 
reporting Serious Adverse Events (SAEs) to the CRO within the appropriate timelines (see 
below). If required, the Investigator is also responsible for notifying the appropriate local ethics 
committee of SAEs per the guidelines of the Institution and in accordance with aforementioned 
laws and regulations. 
7.1. 
Definitions 
7.1.1. 
Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. When 
there are reasonable grounds for suspicion that the event is caused by the investigational product 
(i.e. there are facts or arguments to suggest a causal relationship), it must be considered as 
adverse drug reaction (ADR). 
Worsening of the patient’s condition for which the trial treatment is being used, is not considered 
an AE. 
All AEs reported by the patient or observed by the Investigator or his staff will be recorded. AEs  
should be followed until resolution or until judged to be permanent. Assessments should be made 
at each visit. Information about common side effects already know about the IMP can be found 
within the IB or will be communicated between IB updates in the form of Investigator 
Notifications. 
The investigator should also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician believes might 
reasonably be related to the study treatment. 
Each AE will be described by: 
• Description of the event 
• Its duration (start and end dates) 
• The severity Grade (according to CTCAE v5.0 criteria for toxicity; Section 7.2.2.1) 
• Its relationship to the study drugs separately (Section 7.2.2.2) 
• Treatment of the event 
• The outcome 
• Consequences (actions taken) for study medication 


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7.1.2. 
Adverse Drug Reaction (ADR) 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered as adverse drug reactions (ADRs). The phrase “responses to medicinal product” 
means that a causal relationship between a medicinal product and an adverse event is at least a 
reasonable possibility, i.e., a relationship cannot be ruled out. ADRs are also referred to as 
toxicity. 
7.1.3. 
Unexpected Adverse Drug Reaction 
An unexpected adverse drug reaction is an adverse drug reaction of which the nature or severity 
is not consistent with the available product information, e.g. IB for an unapproved investigational 
product. ADRs that are more specific or more severe than described in the Investigator’s 
brochure should also be considered unexpected. 
7.1.4. 
Serious Adverse Event (SAE) 
A SAE is an occurrence that at any dose of any of the following: 
• Results in death. If death results from (progression of) the disease, it should be 
reported as an event (SAE) itself; or 
• Is life threatening (the patient was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe); 
or 
• Requires patient hospitalisation or prolongation of existing hospitalisation; or 
• Results in persistent or significant disability/incapacity; or 
• Is a congenital anomaly/birth defect in case of pregnancy outcome of partner. 
Any event that does not meet the above criteria may also be considered by the Investigator to be 
an SAE, based on appropriate medical and scientific judgment. This includes important medical 
events that may not be immediately life-threatening, or result in death or hospitalisation, but may 
jeopardise the patient or may require intervention to prevent one of the other outcomes listed in 
the definition above.  
Severity grade for adverse events  is based on an organ toxicity grading scale as described in 
CTCAE v5.0 (Appendix III), provided separately in the Investigator File. The relationship 
between the administration of trial drug and the occurrence of the adverse event is described as 
belonging to one of only two categories, either suspected by the Investigator or not suspected by 
the Investigator. 
7.1.5. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Any SAE for which there is a reasonable possibility that it is related to the study drug and where 
the nature or severity is not consistent with the product information mentioned in the IB or the 
study protocol.  


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7.1.6. 
Toxic Death 
Any death to which drug toxicity is thought to have contributed should be notified to the CRO at 
once (within 24 hours of learning of the event) in case of toxic death. The CRO will notify the 
Sponsor immediately. 
7.2. 
Monitoring, Reporting, and Documentation of Adverse Events 
7.2.1. 
Monitoring of AEs 
Patients will be monitored for AEs from ICF Signature until 30 days after last ModraDoc006/r or 
i.v. docetaxel administration.  
In addition, for all patients with any remaining SAEs at the 30-day follow-up visit, regardless of 
its relationship to trial medication, AE information need to be collected every 3 weeks, until:  
• the symptom subsides or stabilizes;  
• any clinically relevant abnormal laboratory value has returned to baseline;  
• there is a satisfactory explanation other than the trial medication for the change(s) 
observed; or 
• death, in which case an autopsy report should be supplied to the CRO, if performed. 
AEs occurring 30 days after EOT and coming to the attention of the Investigator must be 
recorded only if they are considered (in the opinion of the Investigator) unexpected and related to 
ModraDoc006/r, or i.v. docetaxel. 
7.2.2. 
Documentation of AEs 
All AEs are to be evaluated for duration, intensity and relationship to (association with) the trial 
treatment or alternatively due to other causes. 
All non-laboratory AEs (problems, complaints, signs, and symptoms and clinically relevant 
laboratory abnormalities), both those observed by trial site personnel and those spontaneously 
reported by the trial patients, must be recorded on the AE page in the eCRF, as well as in the 
patient’s medical record using standard medical terminology, regardless of causality. Required 
information includes the type of adverse event, an estimate of its severity, date and time of 
occurrence, date of resolution, actions required, and an assessment of its causal relationship to 
trial medication. AEs resulting from concurrent illnesses, reactions to concurrent medications, or 
progression of disease states are also to be recorded. Progression of disease itself is not 
considered to be an AE. 
All AEs must be recorded on the AE page in the eCRF, as well as in the patient’s medical record. 
If an AE occurred after signing informed consent, but the patient withdraws trial participation 
before trial treatment, the AE should be recorded on the Screening Log (instead of on the AE 
page in the eCRF).  
7.2.2.1. 
Severity of Adverse Events 
Each AE is to be classified and graded according to CTCAE criteria (v5.0, Appendix III). A 
copy of these will be provided in the Investigator File. Dates of onset and resolution, including 


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dates at which the grade of an AE changes, are to be recorded in the patient file. If no CTC 
grading is available, the severity of an AE is graded as follows:  
• Mild: the event causes discomfort without disruption of normal daily activities. 
• Moderate: the event causes discomfort that affects normal daily activities. 
• Severe: the event makes the patient unable to perform normal daily activities or significantly 
affects the clinical status. 
• Life-threatening: the patient was at risk of death at the time of the event, or the event caused 
death. 
7.2.2.2. 
Relationship to Trial Treatment 
Relationship with the study drug is generally caused by systemic exposure to the active 
ingredient (docetaxel), and therefore due to the combination of ModraDoc006 and ritonavir. In 
rare cases relationship may be attributed to only one of both drugs (i.e. ModraDoc006 alone or 
ritonavir alone), if suspected it is advised to discuss with sponsor.  
The relationship of an adverse event to trial medication will be recorded on the CRF and defined 
as following:  
• Not Related: the event is definitely not associated with trial drug administration, but is judged 
clearly and incontrovertibly to be due to causes other than the trial medication. 
• Unlikely: an event that follows such a temporal sequence from administration of the trial 
medication that a relationship is not likely, and is likely to be due to causes such as (known 
characteristics of) the patient’s clinical state or other treatment. 
• Possibly: an event that follows a reasonable temporal sequence from administration of the trial 
medication, but that may be due to another cause. 
• Probably: an event that follows a reasonable temporal sequence from administration of the 
trial medication, and that is not easily explained by another cause such as known characteristics 
of the patient’s clinical state or other treatment. 
• Definitively: an event that follows an established temporal sequence from administration of 
the trial medication (e.g. re-challenge), or that cannot be explained by any other cause. 
7.2.3. 
Reporting of Serious Adverse Events 
Information on SAEs, like all AEs, will be collected from the time of Inform Consent Form 
Signature until 30 days after the last administration of the trial medication.  
SAEs occurring within 30 days after EOT must only be reported when they are considered (in 
the opinion of the Investigator) unexpected and related to ModraDoc006/r, or i.v. docetaxel.  
All AEs that meet the criteria for SAE require the completion of a trial-specific SAE Form (or 
Additional Safety Information (ASI) Form). This applies to all SAEs, whether or not they were 
considered to be related to the trial treatment.  
The Investigator must report all SAEs to the CRO immediately, i.e. within 24 hours (in the 
eCRF) of learning of their occurrence. For this reporting, an SAE Form (provided in the 
Investigator File) needs to be completed in English. Follow-up information about a previously 
reported SAE must also be reported to the CRO within 24 hours of receiving the information. 
This follow-up data must be provided on an ASI Form.  


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If a SAE occurred after signing informed consent, but before trial treatment and the patient 
continues on trial, a SAE must also be entered on the relevant Medical History page of the eCRF. 
The SAE report should provide a detailed description of the AE and should include anonymised 
copies of hospital records and other relevant documents. Autopsy results, if applicable, should 
also be sent to the CRO as soon as they become available. Copies of each report will be kept in 
the Investigator File.  
All SAEs will need to be followed actively until resolution or stabilisation. The above is also 
applicable to follow-up SAE information. 
The CRO, on behalf of Sponsor, is required by law to report to the health authorities in a written 
safety report: 1) all fatal or life-threatening SUSARs within seven (7) calendar days of initial 
notification; and 2) all other SUSARs within fifteen (15) calendar days of initial notification. 
7.2.4. 
Pharmacovigilance Contact for Reporting SAEs 
CRO:   
Covance Clinical & Periapproval Services Limited 
Street:   
Osprey House, Maidenhead Office Park, Westacott Way 
Postal code:  SL6 3QH 
Place:  
Maidenhead 
Country:  
United Kingdom 
Tel:    
+44 (0)1628 548000 
Fax:   
+44 (0)1628 540028 
E-mail:  
SAEIntake@covance.com 
 
 


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8. 
STATISTICAL METHODS 
The full statistical methodology and presentation of data will be described in a Statistical 
Analysis Plan separate from this protocol. 
All data collected in this trial will be documented using summary tables, figures, and patient data 
listings. Continuous variables will be summarized using descriptive statistics (N, mean, standard 
deviation, quartiles, median, minimum and maximum). Categorical variables will be summarized 
using counts and percentages.  
8.1. 
Data Analysis Considerations 
Analysis Populations: 
• Safety Population (SAF): All subjects receiving at least one dose of trial medication in 
either study arm will be included in the evaluation of safety.  
• Efficacy Population (Full Analysis Set (FAS)): All subjects who received at least one 
dose of i.v. docetaxel (Cohort 1) or one full cycle of ModraDoc006/r (Cohort 2) and have 
at least one post-baseline tumor assessment (+PSA levels) will be included in the 
evaluation of efficacy and the QoL evaluation.  
• Per Protocol (PP) population includes all subjects in the FAS population with the 
exclusion of subjects who are not compliant to study treatment or have at least one major 
protocol deviation that will affect the interpretation of efficacy. 
Safety Analysis: 
Safety data will be summarized for the safety population.  
 
Efficacy Analysis: 
Radiographic Progression-Free Survival: Defined as time from randomization to the first 
objective evidence of radiologic progression or death due to any cause after treatment 
discontinuation, whichever occurs first will be assessed, per PCWG3 criteria. 
 
Objective Response Rate: The best overall soft tissue response as assessed by investigators 
using RECIST 1.1 will be summarized. Only patients with measurable soft tissue disease at 
screening (i.e., at least 1 target lesion per RECIST 1.1) will be included in this analysis. Tumor 
response for target lesions will be assessed at baseline and specified time points throughout the 
study. The tumor response will be evaluated according to RECIST version 1.1. The calculation 
of ORR as primary endpoint is based on disease status as determined by tumor assessments.  
 
Disease Control Rate: Defined as proportion of patients who have achieved complete response, 
partial response and stable disease using RECIST 1.1. 
 
Duration of Response: Defined as time from documentation of tumor response using RECIST 
1.1 to the first objective evidence of radiologic progression. 
 


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Radiographic Progression-Free Survival at 6 months: Defined as probability of rPFS at 6 
month based on the time from randomization to the first objective evidence of radiologic 
progression or death due to any cause. 
 
Time To Progression: Defined as time from randomization to the first objective evidence of 
radiologic progression 
 
PSA Response: Confirmed PSA responses will be defined as ≥50% reductions in PSA from 
baseline to lowest postbaseline PSA result, with a consecutive assessment conducted at least 3 
weeks later required to confirm the PSA response. PSA response ≥50% will be calculated by 
treatment group for patients with PSA values at the baseline assessment and at least 1 
postbaseline assessment. The analysis of the tumor marker PSA will be performed on the 
efficacy population as per PCWG3 criteria81. The variables will be evaluated using appropriate 
descriptive statistics for each assessment point and for the changes from baseline. 
 
PSA Progression-Free Survival / Time to PSA Progression: PSA progression according to 
PCWG3 criteria is defined as the first PSA increase that is ≥25% and ≥2 ng/mL, either above the 
nadir (if PSA decline after baseline) or from baseline beyond 12 weeks (if no PSA decline from 
baseline), and which is confirmed by a second value ≥ 3 weeks later. 
 
Time to First Skeletal-Related Event: Time from randomization to first skeletal-related event 
will be assessed. A skeletal-related event is defined as radiation therapy or surgery to bone, 
pathologic bone fracture, spinal cord compression. 
 
Health Related Quality of Life Endpoints: 
FACT Quality of Life: The FACT global, FACT-P and FACT-taxane data will be summarized 
descriptively by study visit. 
 
Treatment Satisfaction Questionnaire for Medication: TSQM data will be summarized 
descriptively by study visit. 
 
EQ-5D-5L Quality of Life: The EQ-5D-5L data will be summarized descriptively by study 
visit. 
 
Planned Data Analysis: 
All data collected in this trial will be documented using summary tables, figures, and patient data 
listings.  
• Continuous variables will be summarized using descriptive statistics (N, mean, 
standard deviation, quartiles, median, minimum, and maximum).  
• Categorical variables will be summarized using counts, frequencies and percentages.  
• ORR will be reported as proportion of subjects per cohort who have presented 
response at fixed time intervals and separately at the end of trial. 


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• Response rates and 95% CIs will be calculated for the ORR and DCR by treatment 
group 
• PSA values will be reported as percentage change from baseline every cycle and as 
absolute change in PSA over time from baseline to best response.  
• Differences between the cohorts will be compared using parametric techniques for 
continuous variables (only in case of severe deviations of normality will the 
Wilcoxon-Mann Whitney test be used) and Fisher’s exact test for categorical 
variables.  
PFS, TTP-DOR, PSA-PFS and time to PSA progression will be summarized using Kaplan-Meier 
estimates and differences will be determined via the log-rank test. Univariate Cox proportional 
hazards models, and multivariate models may be constructed to evaluate the effect of 
confounding variables on PSA-PFS, PFS and time to PSA progression. All tests will be two-
sided and considered significant at P<0.05. With the design that compares treatment with 
ModraDoc006/r versus standard i.v. docetaxel, the treatment outcome will be estimated and used 
as the basis for the design of the future pivotal trial.  
8.2. 
Population for Analysis 
For analysis of trial results, the following populations will be defined and analysed: 
8.2.1. 
Safety analysis 
To be considered evaluable for safety, patients should have received at least one administration 
of ModraDoc006/r or i.v. docetaxel (all administrations on day 1). 
8.2.2. 
Population evaluable for radiological response  
To be considered evaluable for radiological response:  
• Patients should have received at least 6 weekly administrations of ModraDoc006/r or 
2 standard three-weekly cycles of i.v. docetaxel 
• Patients should have measurable lesions according to RECIST v1.1 
• Response should be evaluated according to RECIST v1.1 and PCWG3 as described in 
Appendix IV and Appendix V and as described in Section 6.9. 
8.3. 
Clinical Efficacy 
Response to therapy will be presented as the numbers and proportions of the patients evaluable 
for radiological response who had a progressive disease, stable disease, a partial radiological 
response or a complete radiological response as best response. ORR will be summarised with 
95% confidence intervals. PFS and time-to-event endpoints will be summarised and illustrated 
graphically using a Kaplan-Meier plot. Median survival and associated 95% confidence interval 
will be provided for each time to event endpoint. The proability of event free and 95% 
Confidence interval at 6 and 12 months will also be provided by treatment group. The between 
treatment hazard ratio and 95% confidence interval will be provided based on Cox proportional 
hazards models. Tumor sizes (volumes) will be summarised by assessment point and for changes 
during the study. 


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8.4. 
Safety 
Toxicity will be scored according to the CTCAE v5.0. (see Appendix III). Individual safety data, 
as well as the absolute and relative incidence of toxicities, will be presented in tables. The worst 
grades of these toxicities will be given for all patients who were evaluable for toxicity 
measurements. These toxicities will be scored from the moment the patients received their first 
dose of study medication until end of treatment. The toxicities might be classified and presented 
in different tables, based on the nature of the toxicities (hematological or non-hematological) or 
the causality of the toxicities (treatment related, or all observed toxicities).  
The number of adverse events (AEs) that start or worsen after first dose of study drug will be 
summarised, as well as related AEs, AEs of each severity (CTCAE grade), SAEs, deaths, related 
SAEs, and discontinuations due to AEs. AEs and SAEs will further be summarised by system 
organ class and preferred term. 
The AEs and SAEs by preferred term, grade (according to CTCAE v.5.0), and relationship to the 
study drug, will be presented in a table.  
Specifically, the incidence will be tested of: 
• grade 3-4 neutropenia with weekly ModraDoc006/r as compared to the standard 
treatment with i.v. docetaxel 
• febrile neutropenia with weekly ModraDoc006/r as compared to the standard 
treatment with i.v. docetaxel 
• toxicity-related hospital admissions with weekly ModraDoc006/r as compared to 
the standard treatment with i.v. docetaxel 
• grade 3-4 diarrhea with weekly ModraDoc006/r as compared to the standard 
treatment with i.v. docetaxel 
• grade 3-4 fatigue with weekly ModraDoc006/r as compared to the standard 
treatment with i.v. docetaxel 
• grade 3-4 neuropathy with weekly ModraDoc006/r as compared to the standard 
treatment with i.v. docetaxel 
• grade 3-4 treatment-related allergic reactions with weekly ModraDoc006/r as 
compared to the standard treatment with i.v. docetaxel. 
Other safety data will be summarised by assessment point and for changes during the study.  
8.5. 
Interim Analysis  
No formal interim analysis is planned. However, after in total 50% of evaluable patients have 
been treated efficacy endpoints will be reviewed in both treatment arms to obtain a first 
impression about the effect of ModraDoc006/r and standard i.v. docetaxel. 
   
 


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9. 
DATA MANAGEMENT AND MONITORING 
9.1. 
Data Collection, Validation and Handling 
Data management and handling of data will be conducted according to the trial specific Data 
Management Plan and SOPs of the CRO. 
Data for this trial will be captured using eCRFs. Data collection and entry into the eCRF is the 
responsibility of the clinical trial staff at the investigational site, under the supervision of the 
Principal Investigator. The data will be subject to validation according to the Data Validation and 
Medical Review Plans, in order to ensure the information in the eCRF is complete, consistent 
and accurate. The clinical trial site staff are responsible for resolving data queries issued by 
CRAs, Medical Monitor(s) and Data Management team at the CRO. A system audit trail will 
maintain a record of initial entries and changes made; reasons for change; time and date of entry; 
and user name of trial personnel authorizing entry or change.  
Prior to the database lock, the eCRF must be completed and electronically signed by the 
Principal Investigator or authorized delegate from the clinical trial site staff. A complete eCRF 
package will be transferred to Sponsor, and the Investigator will receive a copy at the end of the 
trial. 
All external data will be electronically transferred to the CRO for further data handling. 
Quality control audits of all key safety and efficacy data in the database will be made prior to 
locking the database. Protocol deviations will be monitored throughout the trial and a final 
assessment of major/minor deviations will be made at the end of the trial. 
9.2. 
Data Review 
This trial will be monitored by appropriate staff from the CRO, and may also be 
audited/inspected by the CRO, Sponsor, or by an independent body and/or authority. By agreeing 
to this Protocol, the Investigator agrees to fully co-operate with compliance checks by allowing 
access for authorised individuals to all relevant trial documents. 
CRAs will conduct regular monitoring visits. The CRA may be accompanied by a representative 
of Sponsor on that occasion. Amongst other things, the following will be reviewed during those 
visits: 
• Trial progress; 
• Compliance with the Protocol; 
• Consent procedures, including date of consent and signatures; 
• Medical history, concomitant medication; 
• Completion of CRFs and verification of data against the source data; 
• Adverse events; 
• Storage, dispensing and accountability of trial medication; 
• Archiving of trial documentation. 


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It is the Investigator’s responsibility to assure that adequate time for these visits will be made 
available by him/her and other trial personnel. 
It is a prerequisite of the Investigator’s participation in this trial that the CRA has direct access to 
source data for data verification. All information on eCRFs must be traceable to these source 
documents in the patient's file (permission will be sought from the patient as part of the consent 
process). Direct access to source documents will also be required for representatives of the 
Sponsor and for regulatory authorities.  
The audit or inspection may include, for example, a review of all source documents, drug 
records, original clinical medical notes, some or all of the facilities used in the trial. 
In addition, participation and personal information will be treated as strictly confidential to the 
extent the applicable law permits, and will not be made publicly available. 
9.3. 
Medical Coding 
Coding of prior and concomitant medications will be performed using World Health 
Organization (WHO) Drug Dictionary. AEs and medical history will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). 
9.4. 
Quality Control and Quality Assurance 
The Sponsor or its designee will perform the quality assurance and quality control activities for 
this trial. However, responsibility for the accuracy, completeness and reliability of the trial data 
presented to the Sponsor lies with the Principal or qualified Investigator generating the data. 
 
 


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10. 
ADMINISTRATIVE ASPECTS 
10.1. 
Maintenance of Patient Records 
The Principal Investigator will maintain adequate records, including flow sheets, laboratory 
reports, signed patient consent forms, drug disposition records, and information on AEs, patient 
treatment discontinuation and reasons for treatment discontinuation. All records will be signed 
and dated by the Investigator. All records are to be retained for a period of 15 years following the 
date the entire clinical investigation is completed, terminated or discontinued. 
10.2. 
Investigator Site File (ISF) 
At trial initiation, each Investigator will be provided with an Investigator Site File (ISF) 
containing information as specified in Section 8.2-4 of ICH GCP79. It is the Investigator's 
responsibility to keep the Investigator Site File up to date. 
10.3. 
Handling of Investigational Product 
The trial medication must be received by a designated person at the trial site, handled and stored 
safely and properly, and kept in a secured location to which only the Investigator, Pharmacist 
and designated assistants have access. Upon receipt, the trial medication and all supplies should 
be stored according to the instructions specified on the drug labels. 
Medication labels will comply with the legal requirements of the country. In addition, they will 
include storage conditions for the drug, but no information about the trial. 
For drug accountability, the Investigator must maintain an accurate record of the shipment and 
dispensing of trial drug. 
The trial medication must be used only as directed in the Protocol and for patients enrolled in 
this trial. 
For more information, see Section 5.3. 
10.4. 
Drug Accountability 
Each time trial medication is dispensed to a patient, this must be recorded on a drug 
dispensing/accountability log. Copies of this form will be supplied in the ISF. 
At regular intervals the CRA(s) will perform a ‘drug reconciliation visit’, verifying if all trial 
medication that has been shipped to the institute can be accounted for by records of receipt, 
dispensing and destruction. 
Unused study drug that is not dispensed may only be destroyed following authorisation by a 
representative of the CRO, and destruction shall be fully documented. Alternatively, the study 
drug may be returned to Sponsor. 
At the end of the trial, it must be possible to reconcile delivery records with records of usage and 
destroyed or returned stock. It is essential that the Investigator or institute account for all trial 
treatment, and that any discrepancies are explained and documented. 


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10.5. 
Protocol Deviations 
Major protocol deviations are any deviations that might significantly affect the completeness, 
accuracy, and/or reliability of the trial data, or that might significantly affect a patient's rights, 
safety, or well-being. This includes deviations related to patient eligibility, informed consent, 
study drug dosing errors, or failing to perform assessments required to interpret the primary 
endpoint. Additional categories may be identified as deemed necessary by the Medical Monitor.  
All protocol deviations will be reported by the CRAs or other trial-involved personnel. The 
protocol deviations will be reviewed by the Medical Monitor. The Medical Monitor determines 
whether a deviation is major or not. Major deviations are reported to the Sponsor as part of 
regular reporting. Important protocol deviations will be summarized in the clinical trial report. In 
accordance with applicable regulatory authority mandates, the Investigator is responsible for 
reporting protocol deviations to the IRB/ IEC. 
In case of a deviation, the Investigator enters a comment in the source documents, and the non-
compliance will be documented in a Monitoring Visit Report by the CRA. All non-compliance 
will be followed up and reported to RA and IEC as per local regulations.  
In parallel, corrective and/or preventive actions will be undertaken and documented, including 
any retraining of the Investigator and site staff. 
No waivers for inclusion or exclusion criteria will be given. 
10.6. 
Procedures for Protocol Amendments 
Should any change be required to the approved Protocol, a Protocol Amendment will be 
prepared. Any amendment is to be approved by the same people approving the original Protocol. 
Upon approval, the final Protocol amendment will be incorporated into the Protocol. In case of a 
substantial Protocol amendment, it must be submitted to the IEC/IRB and competent authorities, 
detailing the reasons necessitating the amendment. Approval by an IEC/IRB and competent 
authorities is required for all substantial amendments, in accordance with international and local 
regulations. Notwithstanding the need for approval before implementation of formal Protocol 
amendments, the Investigator is expected to take any immediate action required for the safety of 
any patient included in this trial, even if this action represents a deviation from the Protocol.  
 
 


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11. 
ETHICAL AND LEGAL CONSIDERATIONS 
The Investigator will ensure that this trial is conducted in full conformance with the principles of 
the “Declaration of Helsinki” (64th WMA General Assembly, Fortaleza, Brazil, October 2013) 
or with the laws and regulations of the country in which the research is conducted, whichever 
affords the greater protection to the individual. The trial must fully adhere to the principles 
outlined in “Guideline for Good Clinical Practice” ICH Tripartite Guideline, or with local law if 
it affords greater protection to the patient. As this trial is conducted in the EU/EEA countries, the 
Investigator will ensure compliance with the EU Clinical Trial Directive [2001/20/EC]. 
11.1. 
Regulatory Authority / Independent Ethics Committees 
The protocol and any accompanying material provided to the patient (such as patient information 
sheets or descriptions of the trial used to obtain informed consent, as well as any recruitment 
materials or compensation given to the patient) will be submitted to the Regulatory Authority 
(RA) and Independent Ethics Committees (IEC).  
Approval from the committee must be obtained before starting the trial and should be 
documented in a letter to the Investigator specifying the date on which the committee met and 
granted the approval.  
Any modifications made to the protocol after receipt of the RAs/IECs approval must be re-
submitted in the European Economic Area (EEA) member states in accordance with local 
procedures and regulatory requirements. 
11.2. 
Site Review 
The Investigator will submit this Protocol, the site-specific informed consent form, and any 
required documents for site review and approval. A letter confirming approval must be 
forwarded to the CRO prior to initiation of this trial at each Investigational site.  
Prior to trial start, the Investigator is required to sign a Protocol signature page confirming 
his/her agreement to conduct the trial in accordance with these documents and all of the 
instructions and procedures found in this Protocol and to give access to all relevant data and 
records to CRAs, auditors, and regulatory authorities as required. Investigators ascertain they 
will apply due diligence to avoid Protocol deviations. 
The Investigator will make appropriate reports on the progress of this trial to the CRO in 
accordance with applicable government regulations and their agreement with the CRO.  
11.3. 
Informed Consent 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, the 
Data Protection Directive (Directive 95/46/EC), and local regulations. The Investigator will 
prepare the informed consent form (ICF) and provide the documents to the RA and IEC for 
approval.  
Before enrolment in the trial, the Investigator or an authorized member of the investigational 
staff must explain to potential trial patients and/or his legal representative the aims, methods, 
reasonably anticipated benefits, and potential hazards of the trial, and any discomfort 
participation in the trial may entail. Patients will be informed that their participation is voluntary 


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and they may withdraw consent to participate at any time. They will be informed that choosing 
not to participate will not affect the care the patient will receive for the treatment of his disease. 
Patients will be told that alternative treatments are available if they refuse to take part and that 
such refusal will not prejudice future treatments. Finally, they will be told by the Investigator 
that health authorities and authorized Sponsor staff may access a patient identification register 
and their medical records for the purposes of long-term follow-up if needed, without violating 
the confidentiality of the patient, to the extent permitted by the applicable law(s) or regulation.  
By signing the ICF the patient is authorizing such access and agrees to allow his or her trial 
physician to re-contact the patient for obtaining consent for additional safety evaluations if 
needed, or to obtain information about his or her vital status.  
The patient will be given sufficient time to read the ICF, and the opportunity to ask questions. 
After this explanation and before entry into the trial, consent should be appropriately recorded by 
means of the patient’s personally dated signature and authorized trial staff’s personally dated 
signature. After obtaining the consent, a copy of the ICF must be given to the patient.  
If the patient is unable to read or write, an impartial witness should be present for the entire ICF 
process (which includes reading and explaining all written information) and should personally 
date and sign the ICF after the oral consent of the patient is obtained. 
Copies of the signed ICF will be given to the patient, and the original will be maintained with the 
patient’s records. If new safety information results in significant changes in the risk/benefit 
assessment, the ICF should be reviewed and updated as necessary. All patients should be 
informed of the new information and give their consent to continue the trial. 
11.4. 
Confidentiality 
By conducting this trial, the Investigator affirms to the CRO that all information regarding this 
trial and ModraDoc006/r will be maintained in strict confidence. Such information can be 
communicated to the Investigator's local review and approval authority under an appropriate 
understanding of confidentiality. Updated General Data Protection Regulations (GDPR) 
procedures are covered in the ICF and in site agreements.  
Every effort will be made to maintain the anonymity and confidentiality of patients during this 
clinical trial. However, because of the experimental nature of this treatment, the Investigator 
agrees to allow representatives of the CRO, the Sponsor, as well as authorized employees of the 
regulatory authorities, to inspect the facilities used in this trial as well as to review, for purposes 
of verification, the hospital or clinic records of all patients enrolled into this trial. A statement to 
this effect is to be included in the patient consent form. 
11.5. 
Insurance 
Insurance is detailed in the Investigator contracts.  
The Investigator/institution is required to have adequate current insurance to cover claims for 
negligence and/or malpractice according to applicable national regulations. The Sponsor will 
provide insurance coverage for the clinical study as required by applicable national regulations.  


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11.6. 
Publication Policy 
Both the use of data and the publication policy are detailed within the clinical trial agreement. 
The Investigator should be aware that intellectual property rights (and related matters) generated 
by the Investigator and others performing the clinical trial will be subject to the terms of a 
clinical trial agreement that will be agreed upon between the institution and the Sponsor or 
designee. With respect to such rights, the Sponsor or designee will solely own all rights and 
interest in any materials, data, and intellectual property rights developed by any party performing 
the clinical trial described in this protocol, subject to the terms of any such agreement. In order to 
facilitate such ownership, the relevant party will be required to assign all such inventions either 
to the relevant institution or directly to the sponsor or their designee, as will be set forth in the 
clinical trial agreement. Further specifics are detailed in the study contract. 


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Appendix I: Assessments 
Trial procedures 
Baseline 
 
Cohort 1: 
Docetaxel 75 mg/m² iv 
Once every 3 weeks 
(cycle = 21 days with infusion on day 1) 
Premedication with oral dexamethasone 8mg, 12 hrs, 3 hrs and 1 hr before 
infusion, or according to local standard of care.  
Prednisone 2dd 5 mg continuously 
 
Cohort 2:  
ModraDoc006/r 20/20mg + 200/100mg 
Once every week twice daily  
(cycle = 21 days with ModraDoc006/r intake on day 1, 8, 15) 
Prednisone 2dd 5 mg continuously 
 
 
≤ Day 28 
Cycle 1  
Subsequent 
Cycles 
EOT*** 
FU**** 
Day 1* 
Day 3 ** 
Day 10 ** 
Day 1* 
 
 
Visit outpatient clinic 
X 
X 
 
 
X 
X 
X 
Compliance 
assessments 
 
 
X 
X 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Randomization 1 
X 
 
 
 
 
 
 
In-/exclusion criteria  
X 
X 
 
 
 
 
 
Demographic Data 1 
X 
 
 
 
 
 
 
Medical History2 
X 
 
 
 
 
 
 
Physical examination3 
X 
X 
 
 
X 
X 
X 
Vital Signs4 
X 
X 
 
 
X 
X 
X 
Hematology5 
X 
X 
 
 
X 
X 
X 
Clinical chemistry6 
X 
X 
 
 
X 
X 
X 
Serum testosterone 
X 
 
 
 
 
 
 
Urinalysis7 
X 
 
 
 
 
X 
 
Creatinine Clearance8 
X 
X 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
X 
 
CT-scan /MRI9 
X 
 
 
 
 
X 
X13 
Bone scintigraphy9 
X 
 
 
 
 
X 
X13 
PSA 
X 
X 
 
 
X 
X 
X 
Safety assessments10 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication11 
X 
X 
 
 
X 
X 
X 
HRQoL 
questionnaires and  
EQ-5D12 
X 
 
 
 
X12 
X 
X 
* Assessments may be performed within 3 days of day 1 
**Day 3 and 10 (+/- 1 day) safety (AEs) and compliance assessments via triage by telephone during cycle 1 only 
*** End Of Treatment (EOT) visit as soon as possible after discontinuation  
**** Follow Up visit (FU) 30 days after the last administration of ModraDoc006/r or i.v. docetaxel  
 
1. Randomization ≤ 3 days; Demographic data: age, ethnic origin 
2. Medical History: (including details of malignancy, stage of cancer, radiotherapy and other therapies, with start and 
stop dates of therapy, number of cycles, cumulative doses, (cancer related) surgery etc., if applicable)). 
3. Physical examination: WHO Performance Status, weight in kg, height in cm (height: baseline only). 


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4. Vital Signs: blood pressure, pulse rate and temperature. 
5. Hematology: hemoglobin, hematocrit, RBC, WBC with differential (differential should include: neutrophil, 
lymphocyte, monocyte, basophil and eosinophil counts), platelet count. 
6. Clinical Chemistry: ASAT, ALAT, GGT, LD, alkaline phosphatase, total and direct bilirubin, Na, K, Ca, Mg, 
glucose, urea, total protein, albumin, serum creatinine,. 
7. Urinalysis: dipstick for protein, glucose, blood, pH, and ketones. 
8. Creatinine Clearance: will be measured using Cockcroft-Gault formula or MDRD formula. 
 
For items 3) – 8): Assessments during screening less than 3 days before dosing need not to be repeated at day 1 of 
Cycle 1. 
 
9. Tumor assessment (following PCWG3) by PSA prior to every cycle and imaging/radiological assessment (i.e. 
CT/MRI + bone scan) at baseline (≤ 28 days prior to administration of study medication), every 8 weeks for first 
24 weeks (i.e. during week 9, 17 and 25), thereafter every 12 weeks and at End of Treatment (EOT), according to 
the RECIST v1.1 and PCWG3 criteria. Both PSA response and radiological response must be confirmed either 
after at least 3 weeks for PSA and after 4-6 weeks for RECIST v1.1. Of note: In this randomized comparative 
trial, the scheduled assessments should not be affected by delays in therapy, drug holidays or any other events that 
might lead to imbalance in a treatment arm in the timing of disease assessment (see Table 15 in par. 6.9 for further 
details).  
10. Toxicity assessments: baseline signs and symptoms and all related and unrelated adverse events will be assessed 
using the NCI-CTCAE criteria Version 5.0, including start and stop dates, severity, relationship to study drug, 
outcome and action taken. 
11. Concomitant medication: including start and stop dates, dose, frequency, route of administration and indication. 
12. Baseline, at the end of cycle 3, 6 and 10 or at EOT (if this would occur earlier): FACT global, FACT-P and 
FACT-taxane, Treatment Satisfaction (excluding baseline) and EQ-5D-5L questionnaire. 
13. Imaging to be performed in the Follow Up visit, in case of unconfirmed PR or CR. 


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Appendix II: WHO Performance Status Scale 
KARNOFSKY 
ZUBROD-ECOG-WHO 
Status 
Scales    
Status 
Normal, no complaints 
100 
0 
Normal activity 
Able to carry on normal activities 
Minor signs of symptoms of disease 
90 
1 
Symptoms, but nearly ambulatory 
Normal activity with effort 
80 
 
 
Cares for self. Unable to carry on normal 
activity or to do active work 
70 
2 
Symptomatic, but in bed <50% of the day 
Requires occasional assistance, but able to 
care for most of his needs 
60 
 
 
Requires considerable assistance and 
frequent medical care 
50 
3 
Needs to be in bed >50% of the day, but not 
bedridden 
Disabled, requires special care and 
assistance 
40 
 
 
Severely disabled. Hospitalisation indicated 
though death not imminent 
30 
4 
Unable to get out of bed 
Very sick. Hospitalisation necessary. Active 
supportive treatment necessary 
20 
 
 
Moribund 
10 
 
 
Dead 
 
0 
5 
Dead 
 


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Appendix III: Common Terminology Criteria for Adverse Events (CTCAE) v5.0 
The descriptions and grading scales found in the revised National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for 
adverse event (AE) reporting. All appropriate treatment areas should have access to a copy of the 
CTCAE v5.0. A copy of the CTCAE v5.0 can be downloaded from the CTEP web site:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Quick Reference  
The NCI CTCAE is a descriptive terminology which can be utilized for Adverse Event (AE) 
reporting. A grading (severity) scale is provided for each AE term.  
Components and Organization  
System Organ Class (SOC), the highest level of the Medical Dictionary for Regulatory Activities 
(MedDRA) hierarchy, is identified by anatomical or physiological system, aetiology, or purpose 
(e.g. SOC Investigations for laboratory test results). CTCAE terms are grouped by MedDRA 
Primary SOCs. Within each SOC, AEs are listed and accompanied by descriptions of severity 
(Grade).  
CTCAE Terms  
An Adverse Event (AE) is any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medical 
treatment or procedure that may or may not be considered related to the medical treatment or 
procedure. An AE is a term that is a unique representation of a specific event used for medical 
documentation and scientific analyses. Each CTCAE v5.0 term is a MedDRA LLT (Lowest 
Level Term).  
Definitions  
A brief definition is provided to clarify the meaning of each AE term.  
Grades  
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique 
clinical descriptions of severity for each AE based on this general guideline:  
• Grade 1 Mild: asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.  
• Grade 2 Moderate:  minimal, local or non-invasive intervention indicated; limiting 
age-appropriate instrumental ADL (Activities of Daily Living).  
• Grade 3 Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL.  
• Grade 4 Life-threatening consequences: urgent intervention indicated.  
• Grade 5 Death related to AE. 


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Appendix IV: RECIST v1.1 - Tumor Evaluation Criteria 
The complete criteria are included in the published RECIST v1.1 document 80. 
https://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf  
A summary is provided below. 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorised measurable or non-measurable as 
follows: 
• Measurable: Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size 
of: 
10 mm by CT-scan (CT-scan slice thickness no greater than 5 mm). 
10 mm calliper measurement by clinical exam (lesions that cannot be accurately 
measured with callipers should be recorded as non-measurable). 
20 mm by chest X-ray.  
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be P15 mm in short axis when assessed by CT-scan (CT-scan 
slice thickness recommended to be no greater than 5 mm). At baseline and in 
follow-up, only the short axis will be measured and followed.  
• Non-measurable: Non-measurable are all other lesions, including small lesions 
(longest diameter <10 mm or pathological lymph nodes with P10 to <15 mm short 
axis) as well as truly non-measurable lesions. Lesions considered truly non-
measurable include leptomeningeal disease, ascites, pleural or pericardial effusion, 
and inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses /abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
Specifications by Methods of Measurements  
• Measurement of lesions: All measurements should be recorded in metric notation, 
using callipers if clinically assessed. All baseline evaluations should be performed as 
close as possible to the treatment start and never more than 4 weeks before the 
beginning of the treatment. 
• Method of assessment: The same method of assessment and the same technique 
should be used to characterise each identified and reported lesion at baseline and 
during follow-up. Imaging based evaluation should always be done rather than 
clinical examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam.  


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• Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and P10mm diameter as assessed using callipers (e.g. skin nodules). For 
the case of skin lesions, documentation by colour photography including a ruler to 
estimate the size of the lesion is suggested. As noted above, when lesions can be 
evaluated by both clinical exam and imaging, imaging evaluation should be 
undertaken since it is more objective and may be reviewed at the end of the trial. 
• Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression 
is an important endpoint, since CT is more sensitive than X-ray, particularly in 
identifying new lesions. However, lesions on chest X-ray may be considered 
measurable if they are clearly defined and surrounded by aerated lung.  
• CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined measurability of 
lesions on CT-scan based on the assumption that CT slice thickness is 5 mm or less. 
When CT-scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable in 
certain situations (e.g. for body scans).  
• Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. Ultrasound examinations cannot be reproduced in 
their entirety for independent review at a later date and because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next. If new lesions are identified by ultrasound in 
the course of the trial, confirmation by CT or MRI is advised. If there is concern 
about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
• Endoscopy, laparoscopy: The utilisation of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in studies 
where recurrence following complete response or surgical resection is an endpoint. 
• Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. If markers are initially above the upper normal limit, however, they must 
normalise for a patient to be considered in complete response. Because tumor markers 
are disease specific, instructions for their measurement should be incorporated into 
protocols on a disease specific basis. Specific guidelines for both CA-125 response 
(in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer), have 
been published. In addition, the Gynaecologic Cancer Intergroup has developed 
CA125 progression criteria which are to be integrated with objective tumor 
assessment for use in first-line studies in ovarian cancer.  
• Cytology, histology: These techniques can be used to differentiate between PR and 
CR in rare cases if required by protocol (for example, residual lesions in tumor types 
such as germ cell tumors, where known residual benign tumors can remain). When 
effusions are known to be a potential adverse effect of treatment (e.g. with certain 
taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be 


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considered if the measurable tumor has met criteria for response or stable disease in 
order to differentiate between response (or stable disease) and progressive disease. 
Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Only patients with 
measurable disease at baseline should be included in protocols where objective tumor response is 
the primary endpoint. Measurable disease is defined by the presence of at least one measurable 
lesion. In studies where the primary endpoint is tumor progression (either time to progression or 
proportion with progression at a fixed date), the protocol must specify if entry is restricted to 
those with measurable disease or whether patients having non-measurable disease only are also 
eligible. 
Baseline Documentation of ‘Target’ and ‘Non-Target’ Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. This means 
for instance, where patients have only one or two organ sites involved a maximum of two and 
four lesions respectively will be recorded. Target lesions should be selected based on their size 
(lesions with the longest diameter), be representative of all involved organs, but in addition 
should be those that lend themselves to reproducible repeated measurements. It may be the case 
that, on occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion, which can be measured reproducibly, should be selected.  
Lymph nodes merit special mention since they are normal anatomical structures that may be 
visible by imaging even if not involved by tumor. As noted in Section 3 above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet the 
criterion of a short axis of P15 mm by CT-scan. Only the short axis of these nodes will 
contribute to the baseline sum. The short axis of the node is the diameter normally used by 
radiologists to judge if a node is involved by solid tumor. Nodal size is normally reported as two 
dimensions in the plane in which the image is obtained (for CT-scan this is almost always the 
axial plane; for MRI the plane of acquisition may be axial, sagittal or coronal). The smaller of 
these measures is the short axis. For example, an abdominal node which is reported as being 20 
mm· 30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node. In this 
example, 20 mm should be recorded as the node measurement. All other pathological nodes 
(those with short axis P10 mm but <15 mm) should be considered non-target lesions. Nodes that 
have a short axis <10 mm are considered non-pathological and should not be recorded or 
followed. A 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. If lymph nodes 
are to be included in the sum, then as noted above, only the short axis is added into the sum. The 
baseline sum diameters will be used as reference to further characterise any objective tumor 
regression in the measurable dimension of the disease. All other lesions (or sites of disease) 
including pathological lymph nodes should be identified as non-target lesions and should be 
recorded at baseline. Measurements are not required and these lesions should be followed as 
‘present’, ‘absent’, or in rare cases ‘unequivocal progression’, (more details to follow). In 
addition, it is possible to record multiple non-target lesions involving the same organ as a single 


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item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’).  
Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on trial (this includes the baseline sum if that is the smallest 
on trial). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered 
progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on trial. 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalisation of tumor 
marker level. All lymph nodes must be non-pathological in size (<10mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-
target lesions. (Note: the appearance of one or more new lesions is also considered progression). 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the trial treatment until 
the end of treatment considering any requirement for confirmation. On occasion a response may 
not be documented until after the end of therapy so protocols should be clear if post-treatment 
assessments are to be considered in determination of best overall response. Protocols must 
specify how any new therapy introduced before progression will affect best response 
designation. The patient’s best overall response assignment will depend on the findings of both 
target and non-target disease and will also take into consideration the appearance of new lesions. 
Furthermore, depending on the nature of the trial and the protocol requirements, it may also 
require confirmatory measurement. Specifically, in non-randomized studies where response is 
the primary endpoint, confirmation of PR or CR is needed to deem either one the ‘best overall 
response’. This is described further below. 
Confirmatory Measurement/Duration of Response 
Confirmation 
In non-randomized studies where response is the primary endpoint, confirmation of PR and CR 
is required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 


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traditionally required confirmation in such studies. However, in all other circumstances, i.e. in 
randomized studies (Phase II or III) or studies where stable disease or progression are the 
primary endpoints, confirmation of response is not required since it will not add value to the 
interpretation of trial results. However, elimination of the requirement for response confirmation 
may increase the importance of central review to protect against bias, in particular in studies 
which are not blinded. In the case of SD, measurements must have met the SD criteria at least 
once after trial entry at a minimum interval (in general not less than 6–8 weeks) that is defined in 
the trial protocol. 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on trial). The duration of overall complete response is measured from the time 
measurement criteria are first met for CR until the first date that recurrent disease is objectively 
documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment (in randomized studies, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
trial (if the baseline sum is the smallest, this is the reference for calculation of PD). The clinical 
relevance of the duration of stable disease varies in different studies and diseases. If the 
proportion of patients achieving stable disease for a minimum period of time is an endpoint of 
importance in a particular trial, the protocol should specify the minimal time interval required 
between two measurements for determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of this 
guideline to define a standard follow-up frequency. The frequency should consider many 
parameters including disease types and stages, treatment periodicity and standard practice. 
However, these limitations of the precision of the measured endpoint should be considered if 
comparisons between studies are to be made. 
Progression-Free Survival/Proportion Progression-Free 
This guideline is focused primarily on the use of objective response endpoints for Phase II 
studies. In some circumstances, ‘response rate’ may not be the optimal method to assess the 
potential anticancer activity of new agents/regimens. In such cases ‘progression-free survival’ 
(PFS) or the ‘proportion progression-free’ at landmark time points, might be considered 
appropriate alternatives to provide an initial signal of biologic effect of new agents. It is clear, 
however, that in an uncontrolled trial, these measures are subject to criticism since an apparently 
promising observation may be related to biological factors such as patient selection and not the 
impact of the intervention. Thus, Phase II screening studies utilizing these endpoints are best 
designed with a randomized control. Exceptions may exist where the behaviour patterns of 
certain cancers are so consistent (and usually consistently poor), that a non-randomized trial is 
justifiable. However, in these cases it will be essential to document with care the basis for 
estimating the expected PFS or proportion progression-free in the absence of a treatment effect.


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Appendix V: PCWG3 Recommendations  
 
Reference 81: 
Scher HI, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-Resistant 
Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working 
Group 3 (PCWG3). Journal of Clinical Oncology. 2016;34:1402-1418 
 
Appended: 
 
PCWG3 Table 2: Standard Baseline Disease Assessments Recommended by PCWG3 in 
Comparison With PCWG2 Recommendations 
 
PCWG3 Table 3: Criteria for Progression at Trial Entry by Disease Manifestation 
 
PCWG3 Table 4: Suggested Frequency of Assessment for Commonly Used Measures in 
Metastatic Prostate Cancer Clinical Trials 
 
PCWG3 Table 5: Suggested Outcome Measures for Clinical Trials in Metastatic Prostate 
Cancer: Report by Disease Manifestation 
 
PCWG3 Figure 3: Swimlanes illustrating the patient experience in a trial  
 


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PCWG3 Table 2: Standard Baseline Disease Assessments Recommended by PCWG3 in 
Comparison With PCWG2 Recommendations 
 
 
 
 


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PCWG3 Table 3: Criteria for Progression at Trial Entry by Disease Manifestation 
 
 
 
 


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PCWG3 Table 4: Suggested Frequency of Assessment for Commonly Used Measures in 
Metastatic Prostate Cancer Clinical Trials 
 
 
 
 
 


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PCWG3 Table 5: Suggested Outcome Measures for Clinical Trials in Metastatic Prostate 
Cancer: Report by Disease Manifestation 
 
 
 
 


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PCWG3 Table 5: Suggested Outcome Measures for Clinical Trials in Metastatic Prostate 
Cancer: Report by Disease Manifestation (continued) 
 
 
 
 


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PCWG3 Table 5: Suggested Outcome Measures for Clinical Trials in Metastatic Prostate 
Cancer: Report by Disease Manifestation (continued) 
 
 
 
 


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PCWG3 Figure 3: Swimlanes illustrating the patient experience in a trial 
 
Fig 3. Swim lanes illustrating the patient experience on a trial. For early-phase trials, the swimmers plot is used to track individual patients on a trial, including 
time on and off therapy, adverse events, progression events, and the point at and the reason for which therapy is stopped. Progression in individual disease 
manifestations and other signiﬁcant events are recorded, including those that did not lead to trial discontinuation and those that did. Pragmatically, each line 
shows the duration on therapy. Note that this particular example depicts a trial in progress. NLCB, no longer clinically beneﬁting; PSA, prostate-speciﬁc antigen; 
rPFS, radiographic progression-free survival; SAE, serious adverse event. 
 


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Appendix VII: 
Quality of life Questionnaires 
 
FACT-global 
Please circle or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
 
GP1 
I have a lack of energy
 .......................................................................................... 
0 
1 
2 
3 
4 
GP2 
I have nausea
 .......................................................................................... 
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain
 .......................................................................................... 
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment
 .......................................................................................... 
0 
1 
2 
3 
4 
GP6 
I feel ill
 .......................................................................................... 
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed
0 
1 
2 
3 
4 
 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
 
GS1 
I feel close to my friends
 .......................................................................................... 
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family
 .......................................................................................... 
0 
1 
2 
3 
4 
GS3 
I get support from my friends
 .......................................................................................... 
0 
1 
2 
3 
4 


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Please circle or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
 
GE1 
I feel sad
 .......................................................................................... 
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness
 .......................................................................................... 
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness
 .......................................................................................... 
0 
1 
2 
3 
4 
GE4 
I feel nervous
 .......................................................................................... 
0 
1 
2 
3 
4 
GE5 
I worry about dying
 .......................................................................................... 
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse
0 
1 
2 
3 
4 
 
 
 
 
GS4 
My family has accepted my illness
 .......................................................................................... 
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my main 
support)
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life
0 
1 
2 
3 
4 


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Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home)
 .......................................................................................... 
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling
 .......................................................................................... 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life
 .......................................................................................... 
0 
1 
2 
3 
4 
GF4 
I have accepted my illness
 .......................................................................................... 
0 
1 
2 
3 
4 
GF5 
I am sleeping well
 .......................................................................................... 
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun
 .......................................................................................... 
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now
0 
1 
2 
3 
4 
 
 
 
 


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FACT-P (prostate) 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
 
ADDITIONAL CONCERNS 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
 
C2 
I am losing weight
 .......................................................................................... 
0 
1 
2 
3 
4 
C6 
I have a good appetite
 .......................................................................................... 
0 
1 
2 
3 
4 
P1 
I have aches and pains that bother me
 .......................................................................................... 
0 
1 
2 
3 
4 
P2 
I have certain parts of my body where I experience pain
 .......................................................................................... 
0 
1 
2 
3 
4 
P3 
My pain keeps me from doing things I want to do
 .......................................................................................... 
0 
1 
2 
3 
4 
P4 
I am satisfied with my present comfort level
 .......................................................................................... 
0 
1 
2 
3 
4 
P5 
I am able to feel like a man
 .......................................................................................... 
0 
1 
2 
3 
4 
P6 
I have trouble moving my bowels
 .......................................................................................... 
0 
1 
2 
3 
4 
P7 
I have difficulty urinating
 .......................................................................................... 
0 
1 
2 
3 
4 
BL2 
I urinate more frequently than usual
 .......................................................................................... 
0 
1 
2 
3 
4 
P8 
My problems with urinating limit my activities
 .......................................................................................... 
0 
1 
2 
3 
4 
BL5 
I am able to have and maintain an erection
 .......................................................................................... 
0 
1 
2 
3 
4 
 
 
 


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FACT-Taxane 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
 
ADDITIONAL CONCERNS 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
 
NTX
1 
I have numbness or tingling in my hands
 .......................................................................................... 
0 
1 
2 
3 
4 
NTX
2 
I have numbness or tingling in my feet
 .......................................................................................... 
0 
1 
2 
3 
4 
NTX
3 
I feel discomfort in my hands
 .......................................................................................... 
0 
1 
2 
3 
4 
NTX
4 
I feel discomfort in my feet
 .......................................................................................... 
0 
1 
2 
3 
4 
NTX
5 
I have joint pain or muscle cramps
 .......................................................................................... 
0 
1 
2 
3 
4 
HI12 
I feel weak all over
 .......................................................................................... 
0 
1 
2 
3 
4 
NTX
6 
I have trouble hearing
 .......................................................................................... 
0 
1 
2 
3 
4 
NTX
7 
I get a ringing or buzzing in my ears
 .......................................................................................... 
0 
1 
2 
3 
4 
NTX
8 
I have trouble buttoning buttons
 .......................................................................................... 
0 
1 
2 
3 
4 
NTX
9 
I have trouble feeling the shape of small objects when 
they are in my hand
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
An6 
I have trouble walking
 .......................................................................................... 
0 
1 
2 
3 
4 


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Tax1 
I feel bloated
 .......................................................................................... 
0 
1 
2 
3 
4 
Tax2 
My hands are swollen
 .......................................................................................... 
0 
1 
2 
3 
4 
Tax3 
My legs or feet are swollen
 .......................................................................................... 
0 
1 
2 
3 
4 
Tax4 
I have pain in my fingertips
 .......................................................................................... 
0 
1 
2 
3 
4 
Tax5 
I am bothered by the way my hands or nails look
0 
1 
2 
3 
4 
 
 
 
 
 


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TSQM76 (Version 1.4) 
Treatment Satisfaction Questionnaire for Medication  
Instructions: Please take some time to think about your level of satisfaction or dissatisfaction 
with the medication you are taking in this clinical trial. We are interested in your evaluation of 
the effectiveness, side effects, and convenience of the medication over the last two to three 
weeks, or since you last used it. For each question, please place a single check mark next to the 
response that most closely corresponds to your own experiences.  
 
1. How satisfied or dissatisfied are you with the ability of the medication to prevent or treat your 
condition?  
□1  Extremely Dissatisfied  
□2  Very Dissatisfied  
□3  Dissatisfied  
□4  Somewhat Satisfied  
□5  Satisfied  
□6  Very Satisfied  
□7  Extremely Satisfied  
 
2. How satisfied or dissatisfied are you with the way the medication relieves your symptoms?  
□1  Extremely Dissatisfied  
□2  Very Dissatisfied  
□3  Dissatisfied  
□4  Somewhat Satisfied  
□5  Satisfied  
□6  Very Satisfied  
□7  Extremely Satisfied  
 
 
 
 


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3. How satisfied or dissatisfied are you with the amount of time it takes the medication to start 
working?  
□1  Extremely Dissatisfied  
□2  Very Dissatisfied  
□3  Dissatisfied  
□4  Somewhat Satisfied  
□5  Satisfied  
□6  Very Satisfied  
□7  Extremely Satisfied  
 
4. As a result of taking this medication, do you experience any side effects at all?  
□1 Yes 
□0 No (if No, then please skip to Question 9) 
 
5. How bothersome are the side effects of the medication you take to treat your condition?  
□1  Extremely Bothersome  
□2  Very Bothersome  
□3  Somewhat Bothersome  
□4  A Little Bothersome  
□5  Not at All Bothersome  
 
6. To what extent do the side effects interfere with your physical health and ability to function 
(i.e., strength, energy levels, etc.)?  
□1  A Great Deal  
□2  Quite a Bit  
□3  Somewhat  
□4  Minimally  
□5  Not at All  
 
 
 


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7. To what extent do the side effects interfere with your mental function (i.e., ability to think 
clearly, stay awake, etc.)?  
□1  A Great Deal  
□2  Quite a Bit  
□3  Somewhat  
□4  Minimally  
□5  Not at All  
 
8. To what degree have medication side effects affected your overall satisfaction with the 
medication?  
□1  A Great Deal  
□2  Quite a Bit  
□3  Somewhat  
□4  Minimally  
□5  Not at All  
 
9. How easy or difficult is it to use the medication in its current form?  
□1  Extremely Difficult  
□2  Very Difficult  
□3  Difficult  
□4  Somewhat Easy  
□5  Easy  
□6  Very Easy  
□7  Extremely Easy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10. How easy or difficult is it to plan when you will use the medication each time?  
□1  Extremely Difficult  
□2  Very Difficult  
□3  Difficult  
□4  Somewhat Easy  
□5  Easy  
□6  Very Easy  
□7  Extremely Easy  
 
11. How convenient or inconvenient is it to take the medication as instructed?  
□1  Extremely Inconvenient  
□2  Very Inconvenient  
□3  Inconvenient  
□4  Somewhat Convenient  
□5  Convenient  
□6  Very Convenient  
□7  Extremely Convenient  
 
12. Overall, how confident are you that taking this medication is a good thing for you?  
□1  Not at All Confident  
□2  A Little Confident  
□3  Somewhat Confident  
□4  Very Confident  
□5 Extremely Confident 
 
 
 
 
 
 
 


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13. How certain are you that the good things about your medication outweigh the bad things?  
□1  Not at All Certain  
□2  A Little Certain  
□3  Somewhat Certain  
□4  Very Certain  
□5 Extremely Certain 
 
14. Taking all things into account, how satisfied or dissatisfied are you with this medication?  
□1  Extremely Dissatisfied 
□2  Very Dissatisfied  
□3  Dissatisfied  
□4  Somewhat Satisfied  
□5  Satisfied  
□6  Very Satisfied  
□7  Extremely Satisfied  
 
 
 
 


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EQ-5D-5L 
 
Under each heading, please tick the ONE box that best describes your health TODAY. 
 
MOBILITY 
I have no problems in walking about  
 
 
 
I have slight problems in walking about  
 
 
 
I have moderate problems in walking about   
 
 
I have severe problems in walking about  
 
 
 
I am unable to walk about  
 
 
 
 
 
 
SELF-CARE 
I have no problems washing or dressing myself  
 
 
I have slight problems washing or dressing myself   
 
I have moderate problems washing or dressing myself  
 
I have severe problems washing or dressing myself   
 
I am unable to wash or dress myself   
 
 
 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
I have no problems doing my usual activities  
 
 
I have slight problems doing my usual activities  
 
 
I have moderate problems doing my usual activities  
 
I have severe problems doing my usual activities  
 
 
I am unable to do my usual activities  
 
 
 
 
PAIN / DISCOMFORT 
I have no pain or discomfort   
 
 
 
 
I have slight pain or discomfort  
 
 
 
 
I have moderate pain or discomfort   
 
 
 
I have severe pain or discomfort  
 
 
 
 
I have extreme pain or discomfort  
 
 
 
 
 
ANXIETY / DEPRESSION 
I am not anxious or depressed  
 
 
 
 
I am slightly anxious or depressed  
 
 
 
 
I am moderately anxious or depressed  
 
 
 
I am severely anxious or depressed   
 
 
 
I am extremely anxious or depressed  
 
 
 


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EQ-5D-5L 
 
 
 


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Appendix VIII: 
Structured Risk Analysis 
 
Potential issues of concern 
a. Level of knowledge about mechanism of action 
As described in paragraph 1, the mechanism of action of docetaxel is well known. 
 
b. Previous exposure of human beings with the test product(s) and/or products with a similar 
biological mechanism  
As described in paragraph 1, the study drug has been tested in two prior phase I trials and one 
ongoing phase I trial. The safety of docetaxel as i.v. formulation in the patient population is well 
known. 
 
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo human cell 
material? 
The mechanism of action of docetaxel has been studied in cell material, animal and several 
human clinical studies.  
 
d. Selectivity of the mechanism to target tissue in animals and/or human beings 
As described in paragraph 1, docetaxel interferes with the cell division cycle and does not have 
selective mechanisms to specific target tissues. 
 
e. Analysis of potential effect 
As described in paragraph 7.9, the efficacy of docetaxel as oral treatment will be evaluated by 
radiological measurements, according to the international guidelines. 
 
f. Pharmacokinetic considerations 
As described in paragraph 1, the pharmacokinetic parameters of ModraDoc006/r have been 
evaluated in the prior phase I trials. Based on the observed pharmacokinetic parameters and the 
clinical experience in the prior phase I trials, the toxicity of ModraDoc006/r is expected to be 
lower and the efficacy is expected to be comparable or even superior to i.v. docetaxel treatment. 
 
g. Study population 
IV docetaxel treatment is well known. The toxicity of ModraDoc006/r is expected to be lower 
and the efficacy is expected to be non-inferior or even superior to i.v. docetaxel treatment. 
 


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h. Interaction with other products 
Besides CYP3A inducting or inhibiting products, no relevant interactions with other products are 
known for ModraDoc006/r in the study population. However, in view of potential interactions a 
list of drugs and compounds either to be given with caution or not to be given together with 
ModraDoc006/r is provided in Appendix VIIII.  
 
i. Predictability of effect 
Based on the observed pharmacokinetic parameters and the clinical experience in the prior phase 
I trials, the toxicity of ModraDoc006/r is expected to be lower and the efficacy is expected to be 
comparable or even superior to i.v. docetaxel treatment. 
 
j. Can effects be managed? 
As described in paragraph 8, all toxicities will be closely monitored and treated. 
 


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Appendix VIIII: 
Drug-Drug Interactions 
Substrates  
 
These drugs need to be used with great caution since the 
inhibition of CYP3A4 by ritonavir might result in 
elevated drug levels of these agents 
Inhibitors 
 
These inhibitors of 
CYP3A4 are not allowed 
to be used concomitantly 
with the study drug 
Inducers 
 
These inducers of 
CYP3A4 are not allowed 
to be used concomitantly 
with the study drug 
Anti-arrhythmics: 
quinidine  
alprazolam 
digoxin 
midazolam 
triazolam 
Immune Modulators: 
cyclosporine 
tacrolimus  
Antihistamines: 
astemizole 
chlorpheniramine 
terfenadine 
Calcium Channel 
Blockers: 
amlodipine 
felodipine 
lercanidipine 
nifedipine 
nisoldipine 
nitrendipine 
Other Anti-arrhythmic 
Agents: 
flecainide 
propafenone 
Antipsychotic Agent: 
lurasidone 
Lipid lowering Agents: 
simvastatin 
atorvastatin 
rosuvastatin 
Other Agents: 
alfuzosin 
aripiprazole 
astimizole 
buspirone 
cafergot 
cilostazol 
cisapride 
colchicine 
dapsone 
dextromethorphan 
dihydroergotamine 
eplerenone 
ergotamine 
finasteride 
fusidic acid 
lidocaine 
methadone 
methylergonovine 
mirabegron 
nateglinide 
pimozide 
propranolol 
quetiapine 
quinine 
risperidone 
salmeterol 
sildenafil 
sirolimus 
terfenadine 
trazodone 
zaleplon 
ziprasidone 
zolpidem 
HIV Antivirals: 
indinavir 
nelfinavir 
saquinavir 
 
Anti-microbial agents: 
clarithromycin 
itraconazole 
ketoconazole 
nefazodone 
telithromycin 
erythromycin 
fluconazole 
chloramphenicol 
ciprofloxacin 
norfloxacin 
voriconazole 
 
Cardiac agents: 
verapamil 
diltiazem 
cimetidine 
amiodarone 
 
Other agents: 
fluvoxamine 
 
Fruits 
star fruit 
grapefruit juice 
HIV Antivirals: 
efavirenz 
nevirapine 
 
Other agents: 
barbiturates 
carbamazepine 
modafinil 
nevirapine 
oxcarbazepine 
phenobarbital 
phenytoin 
pioglitazone 
rifabutin 
rifampicin 
St. John's wort 
 
 


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Substrates  
 
These drugs need to be used with 
great caution since the inhibition of 
OATP1B1 by ritonavir might result 
in elevated drug levels of these 
agents 
Inhibitors 
 
These inhibitors of OATP1B1 are 
not allowed to be used concomitantly 
with the study drug 
Inducers 
 
These inducers of OATP1B1 are not 
allowed to be used concomitantly 
with the study drug 
 
ambrisentan 
atorvastatin 
atrasentan 
bilirubin 
bosentan 
docetaxel 
empagliflozin 
enalapril 
ezetimibe 
fexofenadine 
fluvastatin 
glyburide 
glecaprevir 
grazoprevir 
irinotecan 
lovastatin 
methotrexate 
olmesartan 
paritaprevir 
phalloidin 
pitavastatin 
pravastatin 
repaglinide 
rifampicin 
rifaximin 
rosuvastatin 
simvastatin 
temocaprilat 
thyroxine 
valsartan 
velpatasvir 
voxilaprevir 
 
atazanavir 
clarithromycin 
cobicistat 
cyclosporine 
daclatasvir 
eltrombopag 
erythromycin 
gemfibrozil 
glecaprevir 
lapatinib 
lopinavir 
paritaprevir 
pibrentasvir 
ritonavir 
sacubitril 
saquinavir 
simeprevir 
telaprevir 
telithromycin 
tipranavir 
rifampicin 
roxithromycin 
velpatasvir 
voxilaprevir 
 
N/A 
 


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Substrates  
 
These drugs need to be used with 
great caution since the inhibition of 
OATP1B3 by ritonavir might result 
in elevated drug levels of these 
agents 
Inhibitors 
 
These inhibitors of OATP1B3 are 
not allowed to be used concomitantly 
with the study drug 
Inducers 
 
These inducers of OATP1B3 are not 
allowed to be used concomitantly 
with the study drug 
 
atorvastatin 
atrasentan 
bilirubin 
bosentan 
demethylphalloin 
digoxin 
docetaxel 
empagliflozin 
enalapril 
estradiol-17β-glucuronide 5–25 
estrone-3-sulfate 
fexofenadine 
fluvastatin 
irinotecan 
glecaprevir 
grazoprevir 
methotrexate 
olmesartan 
paclitaxel 
paritaprevir 
phalloidin 
pitavastatin 
rifampicin 
rifaximin 
rosuvastatin 
telmisartan 
thyroxine (T4) 
valsartan 
velpatasvir 
voxilaprevir 
 
atazanavir 
clarithromycin 
cobicistat 
cyclosporine 
daclatasvir 
erythromycin 
glecaprevir 
lopinavir/ritonavir 
paritaprevir 
pibrentasvir 
ritonavir 
sacubitril 
saquinavir 
simeprevir 
telithromycin 
rifampin 
velpatasvir 
voxilaprevir 
 
N/A 
 
 
 
 


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Substrates  
 
These drugs need to be used with 
great caution since the inhibition of 
P-glycoprotein by ritonavir might 
result in elevated drug levels of 
these agents 
Inhibitors 
 
These inhibitors of P-glycoprotein 
are not allowed to be used 
concomitantly with the study drug 
Inducers 
 
These inducers of P-glycoprotein 
are not allowed to be used 
concomitantly with the study drug 
 
abacavir 
aliskiren  
ambrisentan 
apixaban 
atazanavir 
atorvastatin 
betrixaban 
boceprevir  
bromocriptine  
carbamazepine 
carvedilol  
cimetidine 
colchicine  
cyclosporine 
dabigatran 
daclatasvir 
dapagliflozin 
dasabuvir  
dexamethasone 
digoxin 
diltiazem 
domperidone 
doxorubicin  
edoxaban 
elbasvir  
empagliflozin 
erythromycin 
estradiol 
etoposide 
everolimus 
ezetimibe 
fexofenadine 
fidaxomicin  
 
atazanavir 
amiodarone 
atorvastatin  
azithromycin  
boceprevir  
bromocriptine 
captopril 
carvedilol 
clarithromycin 
cobicistat 
conivaptan 
cyclosporine  
daclatasvir 
delavirdine  
diltiazem 
doxazosin 
dronedarone 
efavirenz 
erythromycin  
felodipine  
fluvastatin  
glecaprevir  
indinavir  
itraconazole  
ketoconazole  
ledipasvir 
linagliptin 
lopinavir and ritonavir 
lovastatin 
meperidine 
methadone 
nelfinavir  
nicardipine 
 
atazanavir 
carbamazepine 
clotrimazole  
dexamethasone 
fosamprenavir  
indinavir  
morphine  
nelfinavir 
phenobarbital 
phenothiazines  
phenytoin  
prazosin 
retinoic acid  
rifampin  
ritonavir  
saquinavir  
spironolactone 
St. John's Wort 
tipranavir 


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Substrates  
 
These drugs need to be used with 
great caution since the inhibition of 
P-glycoprotein by ritonavir might 
result in elevated drug levels of 
these agents 
Inhibitors 
 
These inhibitors of P-glycoprotein 
are not allowed to be used 
concomitantly with the study drug 
Inducers 
 
These inducers of P-glycoprotein 
are not allowed to be used 
concomitantly with the study drug 
fluvastatin  
fosamprenavir  
glecaprevir  
grazoprevir  
imatinib  
indacaterol  
indinavir  
itraconazole  
ivermectin 
lapatinib  
ledipasvir  
levomilnacipran  
linagliptin  
loperamide  
losartan  
lovastatin  
maraviroc  
methotrexate 
morphine  
nelfinavir  
nilotinib  
ombitasvir  
paclitaxel  
paliperidone  
paritaprevir  
phenytoin  
pibrentasvir  
posaconazole  
pravastatin  
prazosin  
quinidine  
ranitidine  
ranolazine  
rifaximin  
paritaprevir  
pentazocine  
pibrentasvir  
progesterone  
quercetin  
quinidine 
ranolazine 
reserpine 
ritonavir  
saquinavir 
simeprevir  
simvastatin  
suvorexant  
tacrolimus  
tamoxifen   
telaprevir  
ticagrelor  
velpatasvir 
verapamil  
vorapaxar  
voxilaprevir 


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Substrates  
 
These drugs need to be used with 
great caution since the inhibition of 
P-glycoprotein by ritonavir might 
result in elevated drug levels of 
these agents 
Inhibitors 
 
These inhibitors of P-glycoprotein 
are not allowed to be used 
concomitantly with the study drug 
Inducers 
 
These inducers of P-glycoprotein 
are not allowed to be used 
concomitantly with the study drug 
ritonavir  
rivaroxaban  
saquinavir  
saxagliptin  
silodosin 
simvastatin  
sirolimus  
sitagliptin  
sofosbuvir  
tacrolimus  
ticagrelor  
telaprevir  
tetracycline 
tipranavir  
tolvaptan  
topotecan  
umeclidinium  
vecuronium  
velpatasvir 
verapamil  
vilanterol  
vinblastine  
vincristine  
voxilaprevir 
 
 
 
 
 
 
 


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Substrates  
 
These drugs need to be used with 
great caution since the inhibition of 
MRP-2 by ritonavir might result in 
elevated drug levels of these agents 
Inhibitors 
 
These inhibitors of MRP-2 are not 
allowed to be used concomitantly 
with the study drug 
Inducers 
 
These inducers of MRP-2 are not 
allowed to be used concomitantly 
with the study drug 
 
acetaminophen 
adefovir 
ampicillin 
azithromycin 
cefodezime 
ceftriaxone 
chlorambucil 
cidofovir 
cisplatin 
cyclophosphamide 
doxorubicin 
diclofenac 
epirubicin 
etoposide  
glutathione and glucuronide 
conjugates  
grepafloxacine  
indinavir 
irinotecan 
lopinavir 
methotrexate  
mitoxantrone 
nelfinavir  
olmesartan  
phenobarbital 
ritonavir  
saquinavir 
tamoxifen 
temocaprilate 
tenofovir 
topotecan 
valsartan  
vinblastine 
vincristine 
 
abacavir 
adefovir 
benzbromarone 
cyclosporine 
cidofovir 
delavirdine 
emtricitabine 
efavirenz 
furosemide 
lamivudine 
nevirapine 
probenecid  
ritonavir 
saquinavir 
tenofovir 
 
 
 
 
  
 
 
nelfivavir 
saquinavir 
 


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Substrates  
 
These drugs need to be used with 
great caution since the inhibition of 
MRP-2 by ritonavir might result in 
elevated drug levels of these agents 
Inhibitors 
 
These inhibitors of MRP-2 are not 
allowed to be used concomitantly 
with the study drug 
Inducers 
 
These inducers of MRP-2 are not 
allowed to be used concomitantly 
with the study drug 
vinflunine 
vinorelbine  
 


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12. 
REFERENCES 
1. 
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Jamehshorani S, Salehiniya H. Incidence and mortality of prostate cancer and their 
relationship with the Human Development Index worldwide. Prostate Int. 2016;4(3):118-
124. 
2. 
Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. Part II: 
Treatment of advanced, relapsing, and castration-resistant prostate cancer. European 
urology. 2014;65(2):467-479. 
3. 
Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. part 1: 
screening, diagnosis, and local treatment with curative intent-update 2013. European 
urology. 2014;65(1):124-137. 
4. 
Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer 
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5. 
Armstrong AJ, Tannock IF, de Wit R, George DJ, Eisenberger M, Halabi S. The 
development of risk groups in men with metastatic castration-resistant prostate cancer 
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6. 
Armstrong AJ. Docetaxel for advanced prostate cancer: how early to start? Lancet 
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7. 
James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to 
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8. 
Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus 
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Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with 
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11. Kelly WK, Halabi S, Carducci M, et al. Randomized, double-blind, placebo-controlled 
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58. Baker SD, Zhao M, Lee CKK, et al. Comparative Pharmacokinetics of Weekly and every-
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61. Bruno R, Vivier N, Veyrat-Follet C, Montay G, Rhodes GR. Population pharmacokinetics 
and pharmacokinetic-pharmacodynamic relationships for docetaxel. Investigational new 
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pharmacokinetics of intravenously and orally administered docetaxel with or without co-
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66. Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response guidelines for phase II 
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SAP_001.pdf: 
Statistical Analysis Plan Amendment 2 
Sponsor Name: Modra Pharmaceuticals 
Sponsor Protocol ID: M18MDP 
 
Covance Study ID: 000000182507 
 
 
CONFIDENTIAL 
Page 1 of 62 
Document Date: 07Oct2021 
 
ST-AD-008 version 05 
 
Statistical Analysis Plan 
Amendment 2 
 
Modra Pharmaceuticals 
M18MDP 
“A multicentre Phase IIb trial to evaluate the efficacy and 
tolerability of ModraDoc006/r in subjects with metastatic   
Castration Resistant Prostate Cancer (mCRPC), suitable for 
treatment with a taxane” 
 
 
Covance Study ID: 000000182507 
Document Version: Version 3.0 Final 
Document Date: 07Oct2021 
 
 
 
 
 
 
 
Covance Inc. CDCS 
Clinical Development Commercialization Services 
 
 
 


Statistical Analysis Plan Amendment 2 
Sponsor Name: Modra Pharmaceuticals 
Sponsor Protocol ID: M18MDP 
 
Covance Study ID: 000000182507 
 
 
CONFIDENTIAL 
Page 2 of 62 
Document Date: 07Oct2021 
 
ST-AD-008 version 05 
 
Table of Contents 
1. 
Source Documents ................................................................................. 7 
2. 
Protocol Details ..................................................................................... 7 
2.1 
Study Objectives................................................................................ 7 
2.2 
Overall Study Design .......................................................................... 8 
2.3 
Sample Size and Power .................................................................... 10 
3. 
Efficacy and Safety Variables................................................................. 11 
3.1 
Primary Efficacy Endpoint(s).............................................................. 11 
3.2 
Secondary Efficacy Endpoints ............................................................ 15 
3.3 
Health Related Quality of Life (HRQoL) Variables .................................. 21 
3.4 
Safety Variables............................................................................... 23 
4. 
Pharmacokinetic/Pharmacodynamic variables .......................................... 24 
5. 
Analysis populations ............................................................................. 25 
5.1 
Screened population ......................................................................... 25 
5.2 
Randomized population..................................................................... 25 
5.3 
Safety population ............................................................................. 25 
5.4 
Full Analysis Set .............................................................................. 25 
5.5 
Per Protocol population ..................................................................... 26 
5.5.1 
Important Protocol Deviations Leading to Exclusion from the PP population Analysis ..... 26 
5.6 
Special Subpopulations ..................................................................... 27 
5.6.1 
Population evaluable for radiological response.................................................................. 27 
6. 
Data Handling ..................................................................................... 28 
6.1 
Time points and Visit Windows .......................................................... 28 
6.2 
Handling of Dropouts, Missing Data, and Outliers ................................. 29 
7. 
Statistical Methods ............................................................................... 31 
7.1 
General Principles ............................................................................ 31 
7.2 
Subject Disposition and Data Sets Analyzed ........................................ 33 
7.3 
Protocol Deviations .......................................................................... 33 
7.4 
Demographics and Other Baseline Characteristics ................................ 34 
7.4.1 
Medical History ................................................................................................................... 35 
7.4.2 
Previous and Concomitant Medications ............................................................................. 35 


Statistical Analysis Plan Amendment 2 
Sponsor Name: Modra Pharmaceuticals 
Sponsor Protocol ID: M18MDP 
 
Covance Study ID: 000000182507 
 
 
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7.5 
Measurements of Treatment Compliance ............................................. 37 
7.6 
Efficacy ........................................................................................... 39 
7.6.1 
Primary Efficacy Analysis ..................................................................................................... 39 
7.6.2 
Secondary Efficacy Analysis ................................................................................................ 39 
7.6.3 
Sensitivity Analysis .............................................................................................................. 41 
7.6.4 
Subgroup Analysis ............................................................................................................... 41 
7.6.5 
Exploratory Analysis ............................................................................................................ 42 
7.7 
Safety ............................................................................................ 43 
7.7.1 
Extent of Exposure .............................................................................................................. 43 
7.7.2 
Adverse Events .................................................................................................................... 44 
7.7.3 
Laboratory Evaluations ....................................................................................................... 47 
7.7.4 
Vital Signs ............................................................................................................................ 48 
7.7.5 
Electrocardiograms ............................................................................................................. 48 
7.7.6 
Physical Examination ........................................................................................................... 49 
7.7.7 
Other Safety Variables ........................................................................................................ 49 
7.8 
HRQol ............................................................................................. 50 
7.8.1 
FACT scales .......................................................................................................................... 50 
7.8.2 
Time to HRQoL deterioration .............................................................................................. 51 
7.8.3 
Overall Health Related Utility ............................................................................................. 51 
7.8.4 
Treatment Satisfaction ........................................................................................................ 51 
7.9 
Interim Analysis............................................................................... 52 
8. 
Changes in Planned Analysis ................................................................. 53 
9. 
Data Issues......................................................................................... 53 
10. 
References .......................................................................................... 54 
11. 
Appendices ......................................................................................... 55 
11.1 
Schedule of Assessments .................................................................. 55 
11.2 
FACT-G and FACT-P Scoring instructions ............................................. 57 
11.3 
Sample SAS® code for analyses ........................................................ 59 
11.4 
Document History ............................................................................ 62 
 
 
 


Statistical Analysis Plan Amendment 2 
Sponsor Name: Modra Pharmaceuticals 
Sponsor Protocol ID: M18MDP 
 
Covance Study ID: 000000182507 
 
 
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Reviewers 
The following reviews of the SAP were conducted: 
 
 
 
Name and Title  
 Role 
Version Last 
Reviewed 
Company/ 
Organization 
Deborah Morgan, BSc MSc 
Project Manager 
Internal Draft 
0.1 
Covance 
Pierre Gobbens 
Senior Principal Statistical 
Programmer 
Internal Draft 
0.2 
Covance 
Ronald L Nolen 
Medical Writer 
Internal Draft 
0.2 
Covance 
Markus Roters 
Associate Director, 
Biostatistics 
(Peer Review) 
Internal Draft 
1.1 
Covance 
Inga 
Jansonaite/Maksimovice 
Senior Statistical 
Programmer 
Draft 2.3 
Labcorp 
Marianne Keessen 
Project Director 
Draft 2.3 
Modra 
Pharmaceuticals 


Statistical Analysis Plan Amendment 2 
Sponsor Name: Modra Pharmaceuticals 
Sponsor Protocol ID: M18MDP 
 
Covance Study ID: 000000182507 
 
 
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Glossary of Abbreviations 
Abbreviation 
Term 
AE 
Adverse event 
ALAT 
Alanine Amino Transferase 
ASAT 
Aspartate Amino Transferase 
ATC 
Anatomical Therapeutic Chemical 
BOR 
Best Overall Response 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
COVID-19 
Coronavirus Disease of 2019 
CR 
Complete Response 
mCRPC 
Metastatic Castration Resistant Prostate Cancer 
CT 
Computed Tomography 
DCR 
Disease Control Rate 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EQ 
EuroQol 
eCRF 
Electronic Case report form 
EOT 
End of Treatment 
FACT 
Functional Assessment of Cancer Therapy 
FAS 
Full Analysis Set 
FWB 
Functional well-being 
GGT 
Gamma-Glutamyl Transferase 
HRQoL 
Health Related Quality of Life 
HR 
Hazard Ratio 
ICH 
International Council on Harmonization 
IV (or i.v.) 
intravenous 
LD 
Lactate Dehydrogenase 
MDRD 
Modification of Diet in Renal Disease  
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Magnesium 
MRI 
Magnetic Resonance Imaging 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for 
Adverse Events 
ORR 
Objective Response Rate 
PC 
Prostate Cancer 
PCS 
Prostate cancer subscale 
PCWG3 
Prostate Cancer Clinical Trials Working Group 3 
PD 
Progressive Disease  
PFS 
Progression Free Survival 
PP 
Per Protocol 
PR 
Partial Response 
PSA 
Prostate Specific Antigen 
PT 
Preferred Term 
PWB 
Physical well-being 
Q1 
First quartile 
Q3 
Third quartile 


Statistical Analysis Plan Amendment 2 
Sponsor Name: Modra Pharmaceuticals 
Sponsor Protocol ID: M18MDP 
 
Covance Study ID: 000000182507 
 
 
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RBC 
Red Blood Cell 
Q 21 days 
once every 21 days (Q3W) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
r (in PFS) 
radiographic  
/r (in ModraDoc006/r) 
ritonavir 
RR 
Response Rate 
SAE 
Serious Adverse Event 
SAF 
Safety Population 
SD 
Stable Disease (also Standard Deviation) 
SOC 
System Organ Class 
TTF 
Time to Treatment Failure 
TTP 
Time to progression 
TFLs 
Tables, Figures and Listings 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
VAS 
Visual Analogue Scale 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 
 


Statistical Analysis Plan Amendment 2 
Sponsor Name: Modra Pharmaceuticals 
Sponsor Protocol ID: M18MDP 
 
Covance Study ID: 000000182507 
 
 
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Document Date: 07Oct2021 
 
ST-AD-008 version 05 
 
1. Source Documents 
The Statistical Analysis Plan was written based on the following documentation: 
Document 
Date 
Version 
Protocol 
31Mar2020 
Version 3.0 
eCRF 
13Apr2020 
DEV 02.009 
2. Protocol Details 
2.1 Study Objectives 
The primary objective is to determine the efficacy of ModraDoc006/r, as measured 
by radiographic Progression Free Survival (rPFS), compared to standard treatment 
with intravenous (i.v.) docetaxel in subjects with metastatic Castration Resistant 
Prostate Cancer (mCRPC). 
The secondary objectives are as follows: 
 
To evaluate the efficacy of ModraDoc006/r, as measured by Prostate Cancer 
Clinical Trials Working Group 3 (PCWG3)-modified Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1 criteria of objective response rate 
(ORR), disease control rate (DCR) and duration of response (DOR) compared 
to standard treatment with i.v. docetaxel in subjects with mCRPC.  
 
To evaluate the clinical outcome in terms of rPFS at 6 months and time to 
progression (TTP) of ModraDoc006/r compared to i.v. docetaxel 
 
To evaluate the outcome in terms of PSA tumor marker evaluation for PSA 
response, PSA-PFS and time to PSA progression of ModraDoc006/r compared 
to i.v. docetaxel 
 
To compare the time to the 
first skeletal-related event between 
ModraDoc006/r and i.v. docetaxel 
 
To determine the safety and tolerability of ModraDoc006/r compared to i.v. 
docetaxel 
 
To compare subject’s Health Related Quality of Life (HRQoL) response of 
ModraDoc006/r and docetaxel i.v. 
 
 


Statistical Analysis Plan Amendment 2 
Sponsor Name: Modra Pharmaceuticals 
Sponsor Protocol ID: M18MDP 
 
Covance Study ID: 000000182507 
 
 
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Document Date: 07Oct2021 
 
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2.2 Overall Study Design 
This is a multicenter open label 1:1 randomized phase Iib trial to determine the 
efficacy and tolerability of ModraDoc006/r (i.e., ModraDoc006 in combination with 
ritonavir therapy) versus standard i.v. docetaxel in mCRPC subjects (Figure 1). 
Cohort 1 will receive docetaxel at 75 mg/m2 given i.v. as a one-hour infusion on Day 
1 every 21 days plus 5 mg oral prednisone twice daily. 
Cohort 2 will receive ModraDoc006/r 20 mg oral docetaxel in combination with 
200 mg ritonavir in the morning and 20 mg oral docetaxel in combination with 
100 mg ritonavir in the evening (7-12 hours after the morning dose), on Day 1, 8 
and 15 of a 21-day cycle, plus 5 mg oral prednisone twice daily. 
Of note, patients enrolled before and under protocol amendment 1 (Protocol V2.0) 
who are dosed with 30 mg of ModraDoc006 combined with 200 mg ritonavir in the 
morning and 20 mg of ModraDoc006 combined with 100 mg ritonavir in the evening, 
will, at the investigator’s discretion, be able to continue at this dose. 
Patients can be replaced for following reason: 
 
Patients who fail to receive any administration of docetaxel i.v./ oral 
ModraDoc006/r 
 
Patients who fail to undergo any efficacy assessment after baseline 
measurement 
As stated in protocol, patients who discontinue due to toxicity related to study drug 
will not be replaced. 
Treatment in both cohorts will continue until disease progression, unacceptable 
toxicity, or discontinuation for any other reason. The end of the trial is defined as the 
time point when all subjects have discontinued trial treatment and have been given 
follow-up for safety measurements according to the trial assessment schedule. Ten 
months after last evaluable patient enrolled, the Sponsor will terminate the study. 
Any patient still under treatment in Cohort 1 can be switched to commercially 
available i.v. docetaxel. Patients still treated in Cohort 2 and who experience clinical 
benefit, will be offered the opportunity for compassionate use ModraDoc006/r. 
For the purpose of data summarization, data analyses will be performed after the last 
patient has completed their End of Trial (EOT) visit or the last enrolled patient has 
completed six (6) months of treatment, whichever occurs first. 
 
 
 


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Figure 1: 
Schematic of study design. Metastatic Castration Resistant Prostate 
Cancer (mCRPC) patients for whom treatment with i.v. docetaxel is indicated 
according to the standard of care will be randomized 1:1 to one of the two cohorts 
depicted below. 
 
Tumor assessment will be performed (following PCWG3) by PSA every cycle and 
radiological assessment (i.e., Computed Tomography (CT)/ Magnetic Resonance 
Imaging (MRI) and bone scan) after every 8 weeks for first 24 weeks (i.e. during 
week 9, 17 and 25), thereafter every 12 weeks and at End Of Treatment (EOT), 
according to the RECIST v1.1 criteria. Both PSA response and radiological response 
(PR/CR) must be confirmed after 3-4 weeks for PSA and after 4-6 weeks for RECIST 
v1.1 in patients with measurable disease. Confirmation of changes in bone lesions by 
PCWG3 criteria will occur after a minimum of 16 weeks (i.e. scheduled assessments 
during week 17 and beyond).  
The study flowchart can be found in Appendix 1 (Section 11.1). 
 
 
Metastatic Castrate-
resistant Prostate 
Cancer
R
A
N
D
O
M
I
Z
E
ModraDoc006
30/20 mg +
ritonavir 
200/100 mg
BIDW
Docetaxel IV
75 mg/m2
Q 21 days
N=100


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2.3 Sample Size and Power 
In total, 100 patients with evaluable disease according to RECIST v1.1 and PCWG3 
criteria will be treated in this trial. Patients may be replaced (see Section 2.2), 
therefore, the total number of treated patients may be higher than the anticipated 
number of evaluable patients. This phase Iib study is being conducted to gather 
preliminary efficacy and safety information on the new ModraDoc006/r oral 
treatment. The sample size is not based on a formal hypothesis testing. However, 
sample size sensitivity assessments were performed based on precision (width of 
95% confidence interval) for the difference in the proportions of radiographic 
progression free survival (rPFS) between treatment at time of the 6 months follow-
up. The average median rPFS in patients with mCRPC with docetaxel treatment in 
previous studies (Table 1) was 8.3 months, corresponding to the proportion of 
patients with rPFS at 6 months of around 61% (assuming rPFS follows an exponential 
distribution). It is expected that ModraDoc006/r will be at least as effective as i.v. 
docetaxel. The following table provides 95% confidence intervals for the treatment 
differences in proportion of rPFS at 6 month follow-up. 
 
Docetaxel  
Response 
ModraDoc006/r 
Response 
Treatment Difference 
(ModraDoc006/r – Docetaxel) 
Median 
PFS 
% rPFS at 
6 Month 
Median 
PFS 
% rPFS at 6 
Month 
Difference 
Lower  
95% CI 
Upper 
95%CI 
8.3 
61% 
8.3 
61% 
0% 
-19.1% 
19.1% 
8.3 
61% 
9.1 
63% 
2% 
-17.0% 
21.0% 
7 
55% 
7 
55% 
0% 
-19.5% 
19.5% 
7 
55% 
7.7 
58% 
3% 
-16.4% 
22.4% 
6 
50% 
6 
50% 
0% 
-19.6% 
19.6% 
6 
50% 
6.6 
53% 
3% 
-16.6% 
22.6% 
 
 


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3. Efficacy and Safety Variables 
3.1 Primary Efficacy Endpoint(s) 
The primary efficacy endpoint for this study is rPFS according to PCWG3 criteria. 
rPFS is defined as the time from the date of randomization to the date of the first 
objective evidence of radiologic progression or death due to any cause after 
treatment discontinuation, whichever occurs first will be assessed, per PCWG3 
criteria.  
Radiographic disease progression is defined by local assessment: 
- 
Progressive disease by RECIST 1.1 for soft tissue disease (soft tissue disease 
is defined as at least 1 target lesion per RECIST 1.1 at study entry), 
- 
or the appearance of two or more new bone lesions on bone scan (PCWG3), 
that is defined as question “Is there a progression of bone metastases 
according to PCWG3?” answered “Yes” in the CRF page of Bone Scintigraphy. 
 
The documentation required for the determination of radiographic disease 
progression is listed below (Table 16 of study protocol, section 6.9.2). 
Date 
Progression 
Detected 
(Visit)a 
Criteria for Progression 
Criteria for Confirmation 
of Progression 
(requirement 
and timing) 
Criteria for 
Documentation of 
Disease 
Progression on 
Confirmatory Scan 
Week 9 
Bone lesions: 2 or more 
new lesions compared to 
baseline bone scan by 
PCWG3. 
Timing: at least 6 weeks 
after progression identified 
or at Week 17 visit.b 
Two or more new bone 
lesions on bone scan 
(compared to Week 9 
scan) 
Soft tissue lesions: 
Progressive disease* on CT 
or MRI by RECIST 1.1 
Confirmation required for 
soft tissue disease (scan of 
same modality as 
demonstrated progression)b 
Confirmation of 
progressive soft tissue 
disease by RECIST 1.1 
Week 17 
Bone lesions: Two or 
more new lesions on bone 
scan compared to Week 9 
bone scan. 
Timing: at least 6 weeks 
after progression identified 
or at Week 25 visit. 
Required for bone lesions 
observed on bone scanb 
Persistentc or increase in 
number of bone lesions 
on bone scan compared 
to Week 17 scan 
Soft tissue lesions: 
Progressive disease* on CT 
or MRI by RECIST 1.1 
No confirmatory scan 
required for soft tissue 
disease progression. 
n/a 
Week 25 and 
Later 
 
Bone lesions: Two or 
more new lesions 
compared to Week 9 bone 
scan. 
Timing: at least 6 weeks 
after progression identified. 
Required for bone lesions 
observed on bone scanb 
Persistentc or increase in 
number of lesions on 
bone scan compared to 
prior scan 
Soft tissue lesions: 
Progressive disease* on CT 
or MRI by RECIST 1.1 
No confirmatory scan 
required for soft tissue 
disease progression 
n/a 
 
 
 


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a Progression detected by bone scan at an unscheduled visit either prior to Week 9 or between 
scheduled visits will require a confirmatory scan at least 6 weeks later and should follow 
confirmation criteria outlined in the table for the next scheduled scan. Progression detected 
by CT/MRI at an unscheduled visit prior to Week 13 will require a confirmatory scan at least 
6 weeks later whereas progression on or after Week 13 does not require confirmation. 
b Confirmation must occur at the next available scan. 
c For confirmation, at least two of the lesions first identified as new must be present at that 
next available scan (confirmation scan). 
n/a, not applicable. 
* Progressive disease is defined as overall response ticked as “Progressive Disease” on CRF 
page of response according to RECIST 1.1. 
 
For computing the rPFS, the earliest documented radiologic progression will be 
selected, that fulfills above definition and confirmation requirement. For derivation 
purpose: 
 
“prior to Week 13” corresponds to an analysis day < D85 
 
“on or after Week 13” corresponds to an analysis day >=D85 
 
“confirmatory scan at least 6 weeks” corresponds to a consecutive scan >=42 
days after the considered assessment. 
 
Subjects without radiologic progression or death at time of analysis will be censored 
at the date of their last evaluable radiologic assessment as defined thereafter. 
An evaluable assessment for radiological progression as per PCWG3 is defined as two 
components: CT/MRI scan for soft tissue disease and a bone scan for bone lesions. 
The date of censoring will be the latest of date of last RECIST 1.1 assessment showing 
no progression and date of last bone scan showing no progression, i.e. the last 
evaluable radiologic assessment. Evaluable according to RECIST 1.1 means with 
response in {CR, PR, SD, PD}. Evaluable bone scan means “Is there a progression of 
bone metastases according to PCWG3?” answered “Yes” or “No”. If there is no such 
evaluable radiologic assessment, date of randomization should be used instead (e.g. 
for computing the delay of 168 days). 
Patients with several events reasons (if that may happen) will be analyzed whichever 
occurs first. Patients with several censoring reasons (if that may happen) will be 
censored whichever occurs first. 
 
Definition of date of rPFS or censoring refers to Food and Drug Administration (FDA) 
guidelines for rPFS [3] (definition including documented rPFS only), as per the table 
thereafter. 
 
 


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Situation 
Event/Censoring Date 
Outcome Description 
A] No post-baseline tumor assessments (without new anticancer treatment 
given) 
i.e. No RECIST1.1 and no bone scan at all, i.e. no assessments performed for both 
parameters post baseline. 
A1 Death <= 168 days 
after rando 
Date of death 
Event 
Death 
B] C] D] With post-baseline tumor assessments (without new anticancer 
treatment given prior to event/censor) 
 
B1 
Progression [i.e 
documented radiologic 
progression] after {0 
or 1} missing 
radiologic assessment 
or within 168 days 
after previous 
evaluable radiologic 
assessment 
Date of radiologic progression  = Min 
(Date of earliest assessment showing 
progression based on PCWG3-
modified RECIST v1.1 fulfilling 
confirmation criteria required by 
SAP/protocol ; Date of earliest bone 
scintigraphy showing progression 
based on PCWG3 fulfilling 
confirmation criteria required by 
SAP/protocol) 
Event 
Progression 
B2 
Else, Death within 168 
days after last 
evaluable radiologic 
assessment (last ( 
bone scan , RECIST)) 
Date of death 
Event 
Death 
C1 
Else, Progression after 
≥2 consecutive 
missing radiologic 
assessments  
Date of last evaluable radiologic 
assessment before missing 
assessments (either RECIST if 
considered progression was identified 
based on RECIST, either bone scan if 
considered progression was identified 
based on bone scan) 
Censored 
Progression 
after 2 or 
more 
missed 
assessments 
C2 
Else, Death > 168 
days after last 
evaluable radiologic 
assessment (last ( 
bone scan ,RECIST)) 
Date of last evaluable radiologic 
assessment = max(last recist, last 
bone scan) 
Censored 
Death after 
2 or more 
missed 
assessments 
D 
Else [i.e. No 
progression, no death] 
Date of last evaluable radiologic 
assessment = max(last recist, last 
bone scan) 
Censored 
No 
progression 
nor Death 
 
 


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E] F] New anticancer treatment started prior to observed event/censor  
E 
And No post-baseline 
tumor assessment  
Date of randomization 
Censored No 
post-
baseline 
tumor 
assessments 
F 
Else: 
Date of last evaluable radiologic 
assessment  (i.e. max(last recist, last 
bone scan)) prior to initiation of new 
anticancer treatment 
Censored Use of new 
anticancer 
treatment  
 
 
Notes: 
* New anticancer treatment is defined from medications collected in CRF form “Prior and 
Concomitant Medications” that started after first study drug administration while not allowed 
by protocol, as follows: Anatomical Therapeutic Chemical (ATC) code L02 (other than L02AE, 
L02BB and L02BX) and L01 (antineoplastic agents).  
** This 168-day interval represents 2 consecutive tumor assessments, 12 weeks apart (larger 
interval during study). 
 
 


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3.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoints are: 
 
ORR as assessed by RECIST v1.1 (local assessment) 
The best overall soft tissue response as assessed by investigators using PCWG-3-
modified RECIST 1.1 will be summarized. Only patients with measurable soft tissue 
disease at screening (i.e., at least 1 target lesion per RECIST 1.1) will be included in 
this analysis.  
To compute the ORR, Best Overall Response (BOR) of each subject will be computed, 
using investigator’s assessment of overall response at each visit, according to RECIST 
v1.1 criteria ([2]): 
- 
Use of overall response at each visit when imaging is done per protocol 
schedule:  
At each efficacy assessment (imaging), investigator is requested to assess the overall 
response according to RECIST v1.1 criteria. Overall response will be assessed from 
the evaluation of target lesions, non-target lesions, and appearance of new lesions 
at the given visit: 
 
Assessment of “Overall response” will be either Complete Response (CR), Partial 
Response (PR), Stable disease (SD), Progressive Disease (PD) or Non Evaluable (NE), 
as entered by the investigator in the eCRF. 
 
 


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- 
Computation of BOR 
The BOR is the best response recorded during study period, including follow-up visit.  
Per RECIST 1.1 guidelines: 
- 
“Confirmation of response is required for trials with response primary endpoint 
but is no longer required in randomized studies since the control arm serves 
as appropriate means of interpretation.” 
- 
“Best response in these trials is defined as the best response across all time 
points (for example, a patient who has SD at first assessment, PR at second 
assessment, and PD on last assessment has a best overall response of PR). 
When SD is believed to be best response, it must also meet the protocol 
specified minimum time from baseline. If the minimum time is not met when 
SD is otherwise the best time point response, the patient’s best response 
depends on the subsequent assessments. For example, a patient who has SD 
at first assessment, PD at second and does not meet minimum duration for 
SD, will have a best response of PD. The same patient lost to follow-up after 
the first SD assessment would be considered inevaluable.” 
 
Therefore, for this study, computation of BOR will be derived as: 
 
BOR=”CR” if there is a time point with OR (overall response)=”CR”  
 
Else BOR=”PR” if there is a time point with OR =”PR”  
 
Else BOR=”SD” if there is a time point with OR=”SD” where the date of 
assessment is >= 6 weeks after first study drug intake 
 
Else BOR=”PD” if there is a time point with OR=“PD”  
 
Else BOR=”NE”  
o That should be all remaining cases where there is no time point having 
both the [date of assessment >= Y weeks] and [OR in {CR, PR, SD, 
PD} ], i.e.: 
 
Patients without any assessment post-baseline 
 
Patients with a time point with OR=”NE” (and not previously 
considered for other BOR) 
 
Patients with a time point with OR=”SD” where the date of 
assessment is < 6 weeks after first study drug intake (and not 
previously considered for other BOR) 
Minimum duration for SD is set to 6 weeks as it corresponds to two theoretical 
cycles=42 days). 
- 
Computation of ORR 
ORR is defined as the proportion of subjects having CR or PR as BOR during the study 
treatment period, among the population evaluable for radiological response. 
 
Disease control rate (DCR) 
DCR is defined as the proportion of subjects who have a CR, PR, or stable disease 
(SD) as best overall response during study, based on RECIST v1.1 (see computation 
of BOR above). 


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 
Duration of response (DOR) based on RECIST v1.1  
DOR is defined as the time from the documentation of tumor response using RECIST 
1.1 (CR or PR, whichever is first recorded) until the first objective evidence of 
radiologic progression (i.e. according to RECIST 1.1 or bone scintigraphy as defined 
in section 3.1). 
DOR will be calculated in the subpopulation of subjects experiencing a response (CR 
or PR) among the population evaluable for radiological response. 
Subjects without documented radiologic progression at time of analysis will be 
censored at the date of their last evaluable radiologic assessment as defined in 
section 3.1. 
 
rPFS at 6 months based on RECIST v1.1  
This will be obtained using same variable as in section 3.1. 
 
 


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 
Time to progression (TTP)  
TTP is defined as the time from the date of randomization to the date of the first 
documented radiologic progression. 
The documentation required for the determination of radiographic disease 
progression is defined in section 3.1, according to PCWG3 criteria.  
For computing the TTP, the earliest documented radiologic progression will be 
selected, that fulfills above definition and confirmation requirement. 
 
Subjects without radiologic progression at time of analysis will be censored at the 
date of their last evaluable radiologic assessment as defined in section 3.1. 
Definition of date of progression or censoring referred for TTP is as follows:  
 
Situation 
Event/Censoring Date 
Outcome Description 
A] No post-baseline tumor assessments (without new anticancer treatment 
given) 
A 
All cases 
Date of randomization 
Censored 
No post-
baseline 
tumor 
assessments 
B] C] D] With post-baseline tumor assessments (without new anticancer 
treatment given prior to event/censor) 
B1 
Progression [i.e documented 
radiologic progression] after 
{0 or 1} missing radiologic 
assessment or within 168 
days after previous evaluable 
radiologic assessment 
 
Date of radiologic progression  
= Min (Date of earliest 
assessment showing 
progression based on PCWG-3-
modified RECIST v1.1 fulfilling 
confirmation criteria required 
by SAP/protocol ; Date of 
earliest bone scintigraphy 
showing progression based on 
PCWG3 fulfilling confirmation 
criteria required by 
SAP/protocol) 
Event 
Progression 
C1 
Else, Progression after ≥2 
consecutive missing 
radiologic assessments 
  
Date of last evaluable 
radiologic assessment before 
missing assessments (either 
RECIST if considered 
progression was identified 
based on RECIST, either bone 
scan if considered progression 
was identified based on bone 
scan) 
Censored 
Progression 
after 2 or 
more 
missed 
assessments 


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D 
Else [i.e. No progression] 
Date of last evaluable 
radiologic assessment = 
max(last recist, last bone scan) 
Censored 
No 
progression 
E] F] New anticancer treatment started prior to observed 
event/censor  
 
E 
And No post-baseline tumor 
assessment  
Date of randomization 
Censored No 
post-
baseline 
tumor 
assessments 
F 
Else: 
Date of last evaluable radiologic 
assessment  (i.e. max(last 
recist, last bone scan)) prior to 
initiation of new anticancer 
treatment 
Censored Use of new 
anticancer 
treatment  
 
Notes: 
* New anticancer treatment is defined from medications collected in CRF form “Prior and 
Concomitant Medications” that started after first study drug administration while not allowed 
by protocol, as follows: Anatomical Therapeutic Chemical (ATC) code L02 (other than L02AE, 
L02BB and L02BX) and L01 (antineoplastic agents).  
** This 168-day interval represents 2 consecutive tumor assessments, 12 weeks apart (larger 
interval during study). 
 
PSA response rate (PSA RR) according to PCWG3 criteria 
A PSA response is defined as PSA decline of ≥50% from baseline to lowest post-
baseline PSA result, with confirmatory read ≥3 weeks later, based on the PCWG3 
recommendations.  
A subject will be considered a responder for PSA if confirmed PSA response occurred 
at any time during study. 
Baseline PSA value to be used as reference is the last value measured prior to study 
drug administration. 
It will be computed for patients with PSA values at the baseline assessment and with 
at least 1 post baseline PSA assessment. The analysis of the tumor marker PSA will 
be performed on the efficacy population (FAS) as per PCWG3 criteria. The variables 
will be evaluated using appropriate descriptive statistics for each assessment 
point and for the changes from baseline. 
 
 


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 
PSA-PFS according to PCWG3 criteria  
PSA-PFS is defined as the time from the date of randomization to the date of the first 
PSA progression or death from any cause during study, whichever occurs first.  
PSA progression will be defined as per PCWG3 guidance: 
• 
if subject presented first a decline from baseline, progression is defined as 
the first PSA increase that is ≥ 25% and ≥ 2 ng/mL above the nadir, and 
which is confirmed by a consecutive second value ≥ 3 weeks later that 
fulfils same criteria  (ie, a confirmed rising trend); 
• 
if subject did not present a decline from baseline, progression is defined as 
the first PSA increase that is ≥ 25% and ≥ 2 ng/mL increase from baseline 
beyond 12 weeks 
The nadir is the lowest PSA value presented by the subject up to the point of PSA 
measurement, as shown by Figure 2 below. 
 
Figure 2: 
Definitions of PSA control, PSA response, time to PSA 
progression ([4]). 
 
Subjects without PSA progression or death at time of analysis will be censored at the 
date of their last PSA assessment.  
Same logic as PFS table presented in Section 3.1 should be used for analysis of 
PSA-PFS. PSA progression then replaces radiographic progression. If date of PSA 
assessment is missing (but value is available), the date of corresponding visit Will 
be used instead. 
 
 


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 
Time to PSA progression  
Time to PSA progression is defined as the time from the date of randomization to the 
PSA progression as defined by PCWG3 (see previous criteria).  
Subjects without PSA progression at time of analysis will be censored at the date of 
their last PSA assessment. 
Same logic as TTP table should be used for analysis of Time to PSA progression. 
PSA progression then replaces radiographic progression. If date of PSA assessment 
is missing (but value is available), the date of corresponding visit Will be used 
instead. 
 
Time to first skeletal-related event 
Time to first skeletal-related event is defined as the time from randomization to the 
occurrence of the first skeletal-related event (i.e., radiation therapy or surgery to 
bone, pathological bone fracture, spinal cord compression). 
If not presenting event, patient will be censored at the [date of last intake + 30 days] 
or date of death, whichever comes first. 
Skeletal-related events will be available from the following eCRF forms: 
- 
Adverse events (AEs) ticked as “Classed as a skeletal event”. Bone surgeries 
are expected to be reported there, along with pathological bone fracture, spinal 
cord compression. Date of occurrence of skeletal-related event will be 
computed as the AE start date. 
- 
Concomitant procedures: 
o Bone radiotherapies are expected to be reported there, with indication 
ticked as “Treatment of Bone Pain”. 
o Date of occurrence of skeletal-related event will be computed as the 
“concomitant procedure/therapy” start date. 
3.3 Health Related Quality of Life (HRQoL) Variables 
Several questionnaires will be employed to assess Health Related Quality of Life 
(HRQoL). 
• 
Functional Assessment of Cancer Therapy-General (FACT-G) Version 4. It 
consists of 27 items which assess patient function in four domains: Physical, 
Social/Family, Emotional, and Functional well-being [5]. Each item is rated 
on a 0 to 4 Likert type scale. Negatively stated items are reversed by 
subtracting the response from “4”. After reversing proper items, all 
subscale items are combined to produce subscale scores, as well as a global 
QoL score (range 0-108). Scoring instructions are shown in Appendix 2. 
Higher scores represent better QoL. 
 
 


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• 
FACT-Prostate (FACT-P) Version 4, a validated and frequently used 
questionnaire in metastatic prostate cancer trials which has led to HRQoL-
based approvals by the European Medicines Agency. It comprises the same 
4 domains as FACT-G questionnaire that measures general HRQoL in cancer 
patients, and a 12-items prostate cancer subscale (PCS) to assess for 
prostate related symptoms. The PCS is designed specifically to measure 
prostate cancer-specific quality of life. Each item is rated on a 0 to 4 Likert 
type scale, and then combined to produce subscale scores for each domain, 
as well as a global QoL score. Higher scores represent better QoL. Scoring 
instructions are shown in Appendix 2. From the FACT-P questionnaires, 
following score will be defined: 
o PCS (12 items, score range 0-48) 
o The FACT–P total score, computed as the sum of the FACT–G and the 
PCS (range 0-156). 
• 
FACT-taxane Version 4, for assessing the HRQoL related to toxicities. It 
comprises the same 4 domains as FACT-G questionnaire, further 
supplemented by 16 specific items of Taxane subscale. The Taxane 
subscale combines the previously validated 11-item Neurotoxicity subscale 
and 5 additional questions assessing symptoms related to arthralgia, 
myalgia, and skin discoloration [6]. Each item is rated on a 0 to 4 Likert 
type scale, and then combined to produce subscale scores for each domain 
(all 16 items of the taxane subscale are negatively stated so should be 
reverted by subtracting the response from “4”, as done for FACT-G physical 
well-being), as well as a global QoL score. Higher scores represent better 
QoL. From the FACT-taxane questionnaires, following score will be defined: 
o Taxane-specific domain score (16 items, range 0-64) 
o The FACT–taxane total score, computed as the sum of the FACT–G and 
the Taxane subscale (range 0-172). 
• 
Treatment Satisfaction according to Treatment Satisfaction Questionnaire 
for Medication (TSQM) Version 1.4. This questionnaire comprises 14 items 
across four domains focusing on effectiveness (three items), side effects 
(five items), convenience (three items), and global satisfaction (three 
items) of the medication over the previous 2–3 weeks, or since the patient's 
last use [7]. With the exception of item 4 (presence of side effects; yes or 
no), all items have five or seven responses, scored from one (least 
satisfied) to five or seven (most satisfied). Item scores are summed to give 
four domain scores, which are in turn transformed to a scale of 0–100 (no 
computed score should be lower or higher than these limits). Item 4 is not 
included for scoring. If an item score is missing, domain scores may be 
imputed as defined in the scoring algorithm [8]: 


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o EFFECTIVENESS: ([(Item 1 + Item 2 + Item 3) − 3] divided by 18) × 
100. If one item is missing: ([(Sum of Item 1? + Item 2? + Item 3?)) 
− 2] divided by (12) × 100  
o SIDE EFFECTS: ([Sum of Item 5 to Item 8) − 4] divided by 16) × 100. 
If one item is missing: ([(Sum of Item 5? to Item 8?)) − 3] divided by 
12) × 100 
o CONVENIENCE: ([Sum of Item 9 to Item 11) − 3] divided by 18) × 100. 
If one item is missing: ([(Sum of Item9? to Item11?)) − 2] divided by 
(12) × 100  
o OVERALL SATISFACTION First recode Item14_recode = (Item14 − 1) × 
5/6 Then: ([Sum of Item 12 to Item 14) − 3] divided by (12) × 100. If 
any one Item is missing: ([Sum of Item 12? to Item 14?) − 2] divided 
by (8) × 100 
• 
EQ-5D-5L, a standardized instrument developed by the EuroQol (EQ) 
Group as a measure of health-related quality of life. It consists of: 
o a descriptive system. It comprises five dimensions: mobility, self-care, 
usual activities, pain/discomfort and anxiety/depression. Mobility 
dimension asks about the person's walking ability. Self-care dimension 
asks about the ability to wash or dress by oneself, and usual activities 
dimension measures performance in "work, study, housework, family or 
leisure activities". In pain/discomfort dimension, it asks how much pain 
or discomfort they have, and in anxiety/depression dimension, it asks 
how much anxious or depressed they are. Each dimension has 5 levels: 
no problems, slight problems, moderate problems, severe problems, 
and extreme problems. It is scored as a 1-digit number expressing the 
level selected for that dimension (1 to 5). 
o a visual analogue scale (VAS). The VAS records the patient’s self-rated 
health on a vertical VAS  
The 5-level EQ-5D version (EQ-5D-5L) will be used, with 5 levels of severity 
for each of the 5 dimensions. 
3.4 Safety Variables 
The following secondary safety and tolerability endpoints will be assessed: 
• 
AEs and serious adverse events (SAEs), according to the current National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE) v5.0 
• 
Assessments of physical examinations, body weight, vital signs, World 
Health Organization (WHO) performance status, changes in hematology 
and biochemistry results, and electrocardiogram (ECG) readings. 


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4. Pharmacokinetic/Pharmacodynamic variables 
Not applicable. 
 
 


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5. Analysis populations 
5.1 Screened population 
All subjects screened will be included in the Screened population. 
5.2 Randomized population 
All subjects randomized will be included in the Randomized population. 
5.3 Safety population 
The Safety Population (SAF): all subjects receiving at least one dose of trial 
medication in either study arm. The SAF will be used for the evaluation of safety. 
Safety data will be analyzed according to the treatment actually received.  
5.4 Full Analysis Set 
The Full Analysis Set (FAS): all subjects who received at least one dose of i.v. 
docetaxel (Cohort 1) or one full cycle of ModraDoc006/r (Cohort 2) and have at least 
one post-baseline tumor assessment. To be included in FAS, there is no requirement 
to have PSA measurement. The FAS will be used for the evaluation of primary and 
secondary efficacy criteria (otherwise stated) and the HRQoL evaluation. 
Efficacy data will be analyzed according to the randomized treatment assignment and 
additionally according to the protocol version in which subject is randomized.  
 
 


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5.5 Per Protocol population 
The Per Protocol (PP) population will include all subjects in the FAS population, with 
the exclusion of subjects who are not compliant to study treatment or have at least 
one major protocol deviation that would affect the interpretation of efficacy results. 
For consistency between study protocol and terminology used by Covance and 
International Council on Harmonization (ICH E3 Q&A, June 2012), the SAP considers 
“major protocol deviation” equivalent to “important protocol deviation”.  
Section 5.5.1 details the deviations. 
5.5.1 Important Protocol Deviations Leading to Exclusion from the PP 
population Analysis 
All potential protocol deviations are defined in the study “Protocol Deviation 
Management Plan”, and classified as “important” or “non-important”. 
Only important protocol deviations considered to have a major effect on efficacy will 
lead to exclusion of the subject from the PP population. 
At time of writing this SAP and for the purposes of this study, the following criteria 
have been identified as important protocol deviations that can lead to exclusion from 
the PP population, as it is considered that the occurrences of any of these criteria 
might have an important influence on the primary efficacy endpoint. Subjects will be 
assessed purely by comparison of their eCRF data with the criteria below: 
 
Failure to complete or comply with inclusion/exclusion criteria. As far as 
possible, the determination should be made on the basis of actual data values 
rather than tick boxes on the Inclusion and Exclusion Criteria eCRF pages. In 
particular, following subjects will be excluded from PP: 
o Inclusion Criteria 2 not met: testosterone > 50 ng/dL or > 0.50 ng/mL 
or > 1.73 nmol/L, or no evidence of progressive metastatic disease) 
o Inclusion Criteria 3 not met: subjects without evaluable disease (as per 
RECIST v1.1 and/or PCWG3) 
 
Incorrect study drug dose, frequency, timing or method of drug delivery: 
o Consideration should be given to excluding subjects from the PP 
population whose compliance percentage does not fall within [70-120]. 
o Will be excluded from PP: 
 
Cohort 1 subjects not exposed to treatment  
 
Cohort 2 subjects without one full cycle of ModraDoc006/r  
 
Cases of misrandomization (allocation of an incorrect treatment 
compared to the randomization central system)  
 
Excessive number of Assessments/Visits performed outside the allowed time 
window  


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 
Non-compliance with study procedures. Subjects without any assessment of 
response as per RECIST v1.1 (for nodal or visceral lesions) nor as per PCWG3 
(for bone metastases), or without any post-baseline PSA assessment will be 
excluded from PP. 
 
Failure to receive at least 6 weekly administrations of ModraDoc006/r or 
2 standard three-weekly cycles of i.v. docetaxel 
 
Unauthorized medication: Non-compliance with study restrictions (e.g., use of 
prohibited concomitant medication or other anti-neoplastic treatment while 
receiving study therapy, refer to protocol Appendix VII) 
 
Other, e.g., consent not signed 
Regular review of deviations by Covance and the Sponsor, as defined in the Protocol 
Deviation Management Plan, will identify important protocol deviations that may lead 
to exclusion of PP population. 
Should additional important protocol deviations leading to exclusion from the PP 
population, not anticipated at the time of preparing this SAP, be identified during the 
study (or amendment of the above categories), they will be documented in a specific 
document and included in all relevant protocol deviation reviews and approvals prior 
to database lock. 
All important protocol deviations leading to exclusion from the PP population 
occurring during the study will be reviewed and approved by the Sponsor prior to 
database lock. 
5.6 Special Subpopulations 
5.6.1 Population evaluable for radiological response 
To be considered evaluable for radiological response:  
 
Subjects should have received at least 6 weekly administrations of 
ModraDoc006/r or 2 standard 3-weekly cycles of i.v. docetaxel 
 
Subjects should have measurable lesions according to RECIST v1.1. This will 
be based on question “Does the patient have target lesions” in CRF page 
“Target Lesion Measurement (Baseline)”: Yes. 
 
Response should be evaluated according to RECIST v1.1 and PCWG3. 
 
 


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6. Data Handling 
As patients may still be on trial at the time of data summarization (see study design 
section 2.2), a cut-off management macro will be used at statistical programming 
level. Based on raw data, this macro will exclude from analysis all events having its 
date posterior to the cut-off date.  
Other data handling is described below. 
6.1 Time points and Visit Windows 
Day 1 is defined as the day of first dose of treatment. 
Relative days after Day 1 are calculated as (assessment date – Day 1 date) + 1. 
Relative days prior to Day 1 are calculated as (assessment date – Day 1 date). 
The day prior to Day 1 is Day -1.  
For QOL questionnaires, due to heterogeneity of the post-baseline visits where data 
was collected in CRF, following visit windows will be applied in order to pool 
assessments performed around each visit as scheduled in protocol: 
Original visit 
Analysis visit used in summary tables 
CYCLE 03 DAY 01 
CYCLE 03 DAY 15 
CYCLE 04 DAY 01 
End of Cycle 3 
CYCLE 06 DAY 01 
CYCLE 06 DAY 15 
CYCLE 07 DAY 01 
End of Cycle 6 
CYCLE 10 DAY 01 
CYCLE 10 DAY 15 
CYCLE 11 DAY 01 
End of Cycle 10 
Visit windows do not apply to Baseline and End of Treatment visits. 
If several QOL assessments are available within the same window, the assessment 
with the worst score (indicating worst health status) will be kept for analysis, i.e.: 
Score 
Definition of Worst value  
FACT-G Physical well-being 
Lowest value 
FACT-G Social/Family well-being 
Lowest value 
FACT-G Emotional well-being 
Lowest value 
FACT-G Functional well-being 
Lowest value 


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FACT-G Total score  
Lowest value 
FACT-P PCS 
Lowest value 
FACT-P Total score 
Lowest value 
FACT-taxane Taxane-specific domain score 
Lowest value 
FACT-taxane Total score 
Lowest value 
EQ-5D-5L mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression 
Highest value 
EQ-5D-5L VAS 
Lowest value 
Treatment 
Satisfaction 
(Effectivness, 
Side 
Effects, Convenience, Overall Satisfaction) 
Lowest value 
Visit windows will be applied on subscale scores after their derivation. It will apply 
only for summary tables. Listings will show the original visits only, i.e. as collected in 
CRF. 
Except for QOL, all data will be analyzed using nominal study visits as defined in the 
Study Schedule and eCRF. No visit windows will be applied for summary and analysis. 
6.2 Handling of Dropouts, Missing Data, and Outliers 
For FACT questionnaires, missing data will be handled as following [5]: 
If there are missing items, subscale scores can be prorated. This is done by 
multiplying the sum of subscale by the number of items in the subscale, then dividing 
by the number of items actually answered, using the formula below:  
Prorated subscale score = [Sum of item scores] x [N of items in subscale]/ [N of items answered] 
Of note, prorating by subscale in this way is acceptable as long as more than 50% of 
the items are answered (e.g., a minimum of 4 of 7 items, 4 of 6 items, etc). If less 
than 50% of the items are answered for a given subscale, the subscale score remains 
empty.  
The total score is then calculated as the sum of the unweighted subscale scores.  
The FACT scale is considered to be an acceptable indicator of patient quality of life as 
long as overall item response rate is greater than 80% (e.g., at least 22 of 27 FACT-
G items completed). This is not to be confused with individual subscale item response 
rate, which allows a subscale score to be prorated for missing items if greater than 
50% of items are answered.  
Otherwise, no specific handling of missing data is planned. 
For computing the time to HRQoL deterioration, if date of QOL assessment is missing, 
corresponding visit date will be used instead. 
 
 


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Incomplete dates: 
In all listings, incomplete dates should be left as they have been recorded. 
However, for calculation / sorting / assignation based on dates, the following 
methods will be used: 
 
As general rule: 
o Incomplete start dates will be imputed as first day of the month/year 
o Incomplete end dates will be imputed as last day of the month/year 
 
The most conservative approach will be systematically considered (i.e., if the 
onset date of an AE/concomitant medication is missing / incomplete, it is 
assumed to have occurred during the study treatment phase (i.e., a TEAE for 
AEs) except if the partial onset date or other data [stop date, …] indicates 
differently). 
 
A missing/incomplete date of medical history or disease diagnosis will be 
assumed to have occurred before any study treatment. 
 
If a partial date and the associated information do not allow a statement 
about the assignment to a group / category, all the possible groups / 
categories will be considered (i.e.: an AE could be assigned to several 
possible doses at event onset according to its partial onset date and stop 
date. Particularly an AE with missing start date will be assigned to each dose 
received before its end date.). 
Where possible, the derivations based on a partial date will be presented as superior 
inequalities (i.e., for an AE started in NOV2019 after the administration performed 
on 31OCT2019, the days since last administration will be “≥2”. Similarly the duration 
of ongoing AEs or medication will be“≥xx” according to the start and last visit dates). 
No rules for outlier detection are planned.  
 
 


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7. Statistical Methods 
7.1 General Principles 
All data collected in this trial will be documented using summary tables, figures, and 
subject data listings. 
Listings will present data from all collected visits/timepoints included unscheduled 
or unplanned visits/timepoints, otherwise stated in the listing shell. Listings will be 
using Screened population, and randomization arm as treatment group per protocol 
version.  
Table and figures will display randomization arm, both per protocol version and for 
protocol versions combined, i.e. will be repeated showing treatment arms splitted by 
protocol version. 
Tables and figures will present only scheduled visits and their scheduled timepoints 
per protocol (schedule of assessment), including scheduled visits performed after 
Cycle 10 if any.  
Differences between the cohorts will be compared using parametric techniques for 
continuous variables (only in case of severe deviations of normality will the Wilcoxon-
Mann Whitney test be used) and Fisher’s exact test for categorical variables.  
Time to event data (PFS, TTP, DOR, PSA-PFS, time to PSA progression, time to HRQoL 
deterioration) will be summarized using Kaplan-Meier estimates and differences will 
be determined via the log-rank test. Univariate Cox model will provide estimates of 
hazard ratios (HR). 
Log-rank test will be performed under the hypothesis of proportional hazards. This 
hypothesis will be checked through the following means: 
 
Visually by means of plots of log(-log(survival)) versus log of survival time; 
 
And/or by the inclusion of time-dependent covariates in the Cox model. 
If the performed checks do not suggest the validity of the proportional hazards 
assumption, the Wilcoxon test will be used instead of the Log-rank test. In this case 
Cox models will not be performed and HRs will not be provided. 
All tests will be two-sided and considered significant at P<0.05.  
All data processing, summarization and analyses will be performed using Covance’s 
SAS Environment / Version 9.4 (or later) of the SAS statistical software package. 
The SAS codes are listed in Appendix 3. 
 
 


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The following principles will be applied to all TFLs unless otherwise stated: 
Principle 
Value 
Significant tests 
Two-sided and use a 5% significance level for main effects 
and 10% significance level for interaction terms. 
Treatment group labels 
and order presented 
Tables and Figures by randomization arm: 
Docetaxel i.v. 
ModraDoc006/r 
 
Tables and Figures repeated by Protocol Version: 
Docetaxel i.v. PV2.0 
ModraDoc006/r PV2.0 
Docetaxel i.v. PV3.0 
ModraDoc006/r PV3.0 
 
Listings: 
Docetaxel i.v. PV2.0 
ModraDoc006/r PV2.0 
Docetaxel i.v. PV3.0 
ModraDoc006/r PV3.0 
Screening Failures 
Tables 
Data in summary tables presented by treatment group (see 
above), assessment and visit (where applicable). 
Listings 
All data collected presented by Treatment group (see above), 
country, site, subject, visit, date/time of assessment and visit 
(where applicable), unless otherwise specified.  
Descriptive summary 
statistics for continuous 
variables 
Number of subjects/observations (N), mean, standard 
deviation (SD), first and third quartiles (Q1;Q3), median, 
minimum, and maximum. 
Descriptive summary 
statistics for categorical 
variables 
Frequency counts and percentages [n (%)] 
Denominator for 
percentages 
Number of subjects in the analysis population, unless stated 
otherwise in table shell(s) 
Include “Missing” as 
category 
Demographics and Other Baseline Characteristics only, when 
the number missing is greater than zero for at least one 
treatment group. 
Display for 0 
percentages 
0% 
Display to one more 
decimal place than 
collected value 
Mean, SD, Median, Q1, Q3 
Limit of precision for 
displays 
3 decimal places 
Date Format 
DDMMMYYYY 
 
 
 


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7.2 Subject Disposition and Data Sets Analyzed 
Subject disposition will be summarized by treatment group, both per protocol version 
and for protocol versions combined, and overall and will include the number and 
percentage of subjects for the screened population: 
 screened; 
 screened and not randomized; 
 randomized; 
 randomized and not treated; 
 included in each study population (Safety, FAS, PP, evaluable for radiological 
response). 
In addition, the number and percentage of subjects who are still ongoing, who 
complete the study and who discontinue early, including a breakdown of the primary 
reasons for discontinuation, will be presented for the randomized population.  
A corresponding listing will be provided with appropriate level of detail. 
A subject will be considered a completer if: 
- 
he discontinued the study due to radiographic disease progression (according 
to RECIST v1.1 and/or PCWG3) 
- 
he was still under study treatment when the Sponsor terminated study as 
planned by protocol. 
A summary of subject enrollment by country and site will also be provided by 
treatment group and overall for the randomized population. 
7.3 Protocol Deviations 
All protocol deviations will be listed and summarized by treatment group for the FAS 
population. It will allow to identify events related to Coronavirus Disease of 2019 
(COVID-19) and the type of COVID-19 disruption (e.g. missed visits). 
Important protocol deviations leading to exclusion from the PP population (see 
Section 5.5.1) will be listed and summarized by treatment group for the FAS 
population. 
 
 


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7.4 Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be listed and summarized by treatment 
group, both per protocol version and for protocol versions combined, and overall for 
FAS population. 
As a general rule, the baseline value of study assessment (e.g. weight) will be defined 
as last available value collected prior to the first dose of treatment. 
Standard descriptive statistics will be presented for the continuous variables of: 
 
Age (years) as captured in the eCRF  
 
Weight (kg) 
 
Height (cm) 
 
Body mass index (kg/m2) as computed in the eCRF 
 
BSA (m²)=[height (cm) x weight (kg) / 3600]^0.5 
 
Time since diagnosis of prostate cancer (PC) in months, computed from 
Baseline visit 
 
Time since diagnosis of mCRPC in months, computed from Baseline visit 
 
PSA level in ng/mL 
 
Serum testosterone level in ng/dL. If needed, the following conversion factor 
will be used: 50 ng/dL = 0.50 ng/mL = 1.73 nmol/L 
 
The total counts and percentages of subjects will be presented for the categorical 
variables of: 
 
Age group (< vs ≥ 65 years) 
 
Country 
 
Race and ethnicity 
 
Eastern Cooperative Oncology Group (ECOG) 
 
Disease Stage at diagnosis with PC (TNM staging) 
 
Type of progression at study entry: PSA only, radiological only, both 
 
Measurable disease at study entry, based on question “Does the patient have 
target lesions” in CRF page “Target Lesion Measurement (Baseline)”: Yes, 
No. 
 
Presence of bone metastases at baseline, assessed with bone scintigraphy (if 
available), otherwise as assessed at diagnosis with mCRPC. 
 
Number of bone metastases at baseline assessed with bone scintigraphy, if 
available (0, 1, 2-4, 5-9, 10-20, and > 20)  
 
 


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 
Disease site at baseline: 
o Lymph nodes only, when lymph node(s) reported as target or non-
target lesion at baseline, and does not fulfill next condition: 
o Bone/Bone+lymph 
nodes 
(no 
visceral 
involvement), 
when 
presence of bone metastases at baseline is derived as YES (see 
definition above), and does not fulfill next condition: 
o Any visceral (regardless bone or lymph nodes involvement), when 
at least one visceral lesion reported as target or non-target lesion 
at baseline 
 
Prior therapies for PC, by type of therapy: surgery, radiotherapy, hormonal 
therapy, enzalutamide, abiraterone, regular androgen deprivation therapy 
(ADT).  
 
All demographics and baseline characteristics will be presented in listings, by subject. 
Other baseline measurements, such as vital signs, hematology, biochemistry, 
urinalysis, physical examination, ECG, quality of life, will be summarized by treatment 
group and listed with the post-baseline measurements. 
7.4.1 Medical History 
Medical history will be coded by Covance using the Medical Dictionary for Regulatory 
Activities (MedDRA) Version 22.0 (or a later version if updated during the study). All 
medical history will be listed, and the number and percentage of subjects with any 
medical history will be summarized for FAS population by system organ class (SOC) 
and preferred term (PT) for each treatment group and overall. 
7.4.2 Previous and Concomitant Medications 
Medications received prior to or concomitantly with treatment will be coded by 
Covance using the WHODrug Dictionary Version March2019-Global B3 (or a later 
version if updated during the study) and Anatomical Therapeutic Chemical (ATC) 
Classification codes.  
Previous medications and concomitant medications are defined as follows: 
 
Previous medications are those with a stop date prior to the first dose date of 
treatment.  
 
Concomitant medications are those with a start date on or after the first dose 
date of treatment, or those with a start date before the first dose date of 
treatment and a stop date on or after the first dose date of treatment or 
ongoing end of study. 
If a medication cannot be classified as “previous” or “concomitant” after applying 
imputation rules for missing/incomplete dates (see Section 6.2), it will be classified 
as concomitant. 


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Previous medications and concomitant medications will be listed together using 
therapeutic class (ATC-Level 2), chemical subgroup (ATC-Level 4) and generic term, 
and sorted by medication start date. 
Concomitant medications will be summarized separately, for FAS population. The 
number and percentage of subjects using each medication will be displayed together 
with the number and percentage of subjects using at least one medication within 
each therapeutic class (ATC-Level 2) and chemical subgroup (ATC-Level 4). 
 
 


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7.5 Measurements of Treatment Compliance 
For each subject, compliance will be computed for overall study period. 
For subjects treated with ModraDoc006/R, compliance of ModraDoc006 and ritonavir 
will be computed separately, based on tablet counts. 
Percentage compliance is calculated as: 100 * actual tablets taken/expected tablets 
taken. 
Where: 
 
Actual taken is defined as number of tablets dispensed minus number of tablets 
returned. 
 
Expected taken is the sum of theoretical tablets count over all scheduled 
administrations between C1D1 and last scheduled administration of last cycle 
(inclusive), considering weekly administrations at D1, D8, D15 of each 21-days 
cycle. For subjects who have dose modifications for safety reason as defined 
in protocol (e.g., dose reduction or dose withholding), the expected number of 
capsules will be calculated according to the dose modification. 
 
 
Dosage at a scheduled visit (mg) 
Theoretical tablets count  
ModraDoc006 under 
protocol V2.0 * 
50 
5 
Reduced: 40 
4 
Reduced: 30 
3 
ModraDoc006 under 
protocol V3.0* 
40 
4 
Reduced: 30 
3 
Ritonavir 
300 
3 
* Per study protocol, patients enrolled under protocol amendment 1 (Protocol V2.0) 
who are dosed with 30 mg of ModraDoc006 combined with 200 mg ritonavir in the 
morning and 20 mg of ModraDoc006 combined with 100 mg ritonavir in the evening, 
will, at the investigator’s discretion, be able to continue at this dose. For computation 
of the compliance, if investigator chooses to reduce the dosage to comply with 
amended protocol at a given visit/timepoint, theoretical tablets count is calculated 
according to the dose modification.  
 
For subjects treated with docetaxel i.v., percentage compliance is calculated as: 
 
100 * number of injections performed/number of injections scheduled, 
where number of injections scheduled is defined as the number of 21-days theoretical 
cycles between C1D1 (included) and EOT visit. 


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Percentage compliance will be summarized descriptively by treatment group for the 
Safety population. 
The number and percentage of compliant subjects will be presented, where compliant 
is defined as percentage compliance between 70.0% and 120.0%, inclusive. The 
following percentage compliance categories will also be presented: 
 
<70.0% 
 
>120.0% 
 
 


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7.6 Efficacy 
7.6.1 Primary Efficacy Analysis 
rPFS will be summarized by treatment group, both overall and by protocol version, 
using Kaplan-Meier estimates (median and rates at 6 and 12 months, with associated 
95% CI) and illustrated graphically using a Kaplan-Meier plot. Under the condition of 
proportional hazards, differences between the cohorts will be determined using a 
non-stratified log-rank test, and univariate Cox models will provide estimation of HR 
with 95% CI. 
Analysis of rPFS will be performed on FAS and repeated on PP population as sensitivity 
analysis (see Section 7.6.3). 
7.6.2 Secondary Efficacy Analysis 
All secondary efficacy endpoints will be analyzed on the FAS, both overall and 
specified per protocol version, unless otherwise stated. 
No adjustments for multiplicity will be made as this is a phase IIb study, conducted 
to gather preliminary efficacy and safety information on the new oral treatment.  
• 
ORR based on RECIST v1.1  
ORR will be summarized by treatment group, with 95% exact Clopper-Pearson CI for 
binomial proportions. 
Population of analysis will be the subjects evaluable for radiological response as 
defined in Section 5.5.1.  
The comparison between the cohorts will be performed using Fisher’s exact test. 
In addition, the following analyses will be presented based on response assessment 
with RECIST v1.1, on the subjects evaluable for radiological response: 
- 
Response to therapy according to RECIST v1.1 will be presented as the numbers 
and proportions of the subjects evaluable for radiological response who had a 
progressive disease, stable disease, partial radiological response or complete 
radiological response as BOR.  
- 
Number and proportion of subjects per cohort who have presented response (CR 
or PR) at fixed time intervals (i.e., by assessment point) and separately at the 
“End of Trial” visit 
- 
Tumor sizes will be summarized by assessment point and for changes during the 
study: sum of diameters for target lesions will be described by assessment 
point, in raw value and in change from baseline. 
• 
DCR 
DCR will be summarized by treatment group, with 95% CI. The comparison between 
the cohorts will be performed using Fisher’s exact test. 


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• 
DOR based on RECIST v1.1  
DOR will be summarized by treatment group using Kaplan-Meier estimates (median 
and rates at 6 and 12 months, with associated 95% CI) and illustrated graphically 
using a Kaplan-Meier plot, among the population evaluable for radiological response. 
Under the condition of proportional hazards, differences between the cohorts will be 
determined using a non-stratified log-rank test, and univariate Cox models will 
provide estimation of HR with 95% CI. 
• 
rPFS at 6 months based on RECIST v1.1  
See section 7.6.1. 
• 
TTP based on RECIST v1.1, incorporating the bone metastatic variable 
according to PCWG3  
TTP will be summarized by treatment group using Kaplan-Meier estimates (median 
and rates at 6 and 12 months, with associated 95% CI) and illustrated graphically 
using a Kaplan-Meier plot. Under the condition of proportional hazards, differences 
between the cohorts will be determined using a non-stratified log-rank test, and 
univariate Cox models will provide estimation of HR with 95% CI. 
• 
PSA RR according to PCWG3 criteria 
PSA RR will be summarized by treatment group, with 95% CI. 
The comparison between the cohorts will be performed using Fisher’s exact test. 
• 
PSA-PFS according to PCWG3 criteria  
PSA-PFS will be summarized by treatment group using Kaplan-Meier estimates 
(median and rates at 6 and 12 months, with associated 95% CI) and illustrated 
graphically using a Kaplan-Meier plot. Under the condition of proportional hazards, 
differences between the cohorts will be determined using a non-stratified log-rank 
test, and univariate Cox models will provide estimation of HR with 95% CI. 
• 
Time to PSA progression  
Time to PSA progression will be summarized by treatment group using Kaplan-Meier 
estimates (median and rates at 6 and 12 months, with associated 95% CI) and 
illustrated graphically using a Kaplan-Meier plot. Under the condition of proportional 
hazards, differences between the cohorts will be determined using a non-stratified 
log-rank test, and univariate Cox models will provide estimation of HR with 95% CI. 
 
 


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• 
Time to first skeletal-related event 
Time to first skeletal-related event will be summarized by treatment group using 
Kaplan-Meier estimates (median and rates at 6 and 12 months, with associated 95% 
CI) and illustrated graphically using a Kaplan-Meier plot. Under the condition of 
proportional hazards, differences between the cohorts will be determined using a 
non-stratified log-rank test, and univariate Cox models will provide estimation of HR 
with 95% CI. 
• 
PSA values  
PSA levels will be summarized by visit and by treatment group, along with percentage 
change from baseline.  
Lowest PSA value during study will be identified as the best response. Absolute 
change in PSA from baseline to best response will be also summarized by treatment 
group.  
7.6.3 Sensitivity Analysis 
Primary efficacy analysis (rPFS) will be repeated on PP population as sensitivity 
analysis. 
As described in 7.6.1, median rPFS will be provided with 95%CI, and cohorts will be 
compared using log-rank test. 
In addition, time to treatment failure (TTF) will be analyzed on Safety Population, 
using treatment duration as defined in section 7.7.1. Subjects who haven’t 
discontinued the treatment at time of analysis will be censored. Method for time-to-
event data will be applied: median TTF will be provided with 95%CI, and cohorts will 
be compared using log-rank test. Related figure will be provided. 
Besides, the analysis of ORR will be repeated while excluding the subjects not 
belonging to the PP population, still among patients evaluable for radiological 
response. 
7.6.4 Subgroup Analysis 
Not applicable. 
 
 


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7.6.5 Exploratory Analysis 
For PSA-PFS, PFS and time to PSA progression, multivariate Cox proportional hazards 
models may be constructed to evaluate the effect of confounding variables on those 
time-to-event variables. Following prognostic factors will be tested ([9]): 
 
Age (< 65yrs versus ≥ 65yrs); 
 
Time since diagnostic of PC (in months) 
 
ECOG at baseline (0, >0); 
 
Type of progression at study entry: PSA only, radiological only, both 
 
Disease site at baseline as defined in Section 7.4 
 
PSA level at baseline (< vs ≥ median) 
 
Hemoglobin level at baseline (< vs ≥ median) 
 
Lactate dehydrogenase (LD) level at baseline (< vs ≥ median) 
 
Alkaline phosphatase at baseline (< vs ≥ median) 
 
Albumin level at baseline (< vs ≥ median) 
 
Any other covariate as discussed and approved by the Sponsor. 
These prognostic factors will be first analysed in separate univariate analyses and 
then in multivariate analysis. More specifically, each potential predictor will be tested 
in a Cox model where the considered predictor will be the only covariate included 
(treatment group will not be included in the model). 
Potential predictors with a p-value below 0.10 will be selected for the multivariate 
analysis. The selected predictors will be then all included in a multivariate Cox model 
(treatment will not be included in the model) and further selected with a backward 
selection procedure eliminating covariates showing a p-value above 0.10 in presence 
of the other covariates. Treatment group will be finally introduced as an additional 
covariate in the reduced model obtained at the end of the backward selection 
procedure. The covariate by treatment interactions will be tested by adding all 
interactions corresponding to the finally retained covariates in a separate model. 
 
 


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7.7 Safety 
7.7.1 Extent of Exposure 
Duration of exposure will be defined in months as: 
(last dose date – first dose date + 1) / (365.25/12).  
For subjects in Cohort 1, dates of docetaxel injections will be considered. 
For subjects in Cohort 2, dates of ModraDoc006 administrations will be considered. 
If date of first dose date is missing then the date of first dose dispensed will be used. 
If last dose date is missing then date of last known administration of study drug will 
be used. 
Duration of exposure will be listed and summarized using descriptive statistics for 
each treatment group for the Safety population. 
The number and percentage of subjects with duration of exposure in the following 
categories will be summarized for the Safety population:  
 
]0-3] months  
 
]3-6] months  
 
]6-12] months  
 
>12 months  
Also, number of complete cycles will be described: 
 
For Cohort 1, number of cycles = number of injections 
 
For Cohort 2, number of cycles will be estimated as the number of days 
with at least one ModraDoc006/r intake, divided by 3 (as ModraDoc006/r 
administration is planned at D1, D8 and D15 of each cycle) 
 
Data listings for dose administration and dose modifications for safety reasons 
(including dose reduction and dose withholding) will be provided. 
 
 
 


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7.7.2 Adverse Events 
All AEs recorded on the eCRF will be coded using the MedDRA dictionary Version 22.0 
(or a later version if updated during the study) and classified as either baseline signs 
and symptoms or treatment – emergent AEs (TEAEs) as follows: 
 
Baseline signs and symptoms are events that start prior to the date of first 
dose of treatment. 
 
TEAEs are events with start date and time on or after the date and time of 
first dose of treatment and up to 30 days after date of last dose of treatment, 
or events with start date and time prior to the date and time of first dose of 
treatment whose severity worsens on or after the date and time of first dose 
of treatment.  
All AE data will be listed by treatment group. Treatment-emergence status will be 
flagged in the listing. In addition, corresponding listings of SAEs, AEs leading to 
discontinuation of treatment, and AEs resulting in death will be produced. 
Summary tables of TEAEs by treatment group will be produced for the Safety 
population. 
Assessment of AE severity will be based on the NCI-CTCAE, version 5.0. The 
relationship between an AE and treatment is assessed as definite, probable, possible, 
or not related. A treatment-related AE is an AE considered by the investigator as 
definitely, possibly, or probably related to treatment or with unknown/missing 
relationship to treatment. 
An overview table will summarize the number and percentage of subjects with at 
least one of the following TEAEs, where subjects with more than one TEAE in a 
particular category are counted only once in that category:  
 
any AE;  
 
any AE by severity (NCI-CTCAE grade); 
 
treatment-related AE;  
 
treatment-related AE by severity (NCI-CTCAE grade); 
 
AE leading to treatment discontinuation;  
 
SAE;  
 
treatment-related SAE;  
 
SAE leading to death; 
 
treatment-related SAE leading to death;  
 
SAE leading to treatment discontinuation. 
 
 


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Overview table will be repeated for subset of patients being below and above median 
BSA, using the median BSA of the Safety population at baseline. 
A second overview table will also summarize the number of the following TEAEs: 
 
all AEs; 
 
AEs by severity (NCI-CTCAE grade); 
 
treatment-related AEs; 
 
treatment-related AEs by severity (NCI-CTCAE grade); 
 
SAEs; 
 
SAEs by severity (NCI-CTCAE grade); 
 
treatment-related SAEs. 
 
SAE leading to death; 
 
AE leading to treatment discontinuation;  
Specifically, the incidence of following TEAEs will be summarized and tested between 
treatment groups using Fisher’s exact test: 
 
grade 3-4 neutropenia (unique PT). 
 
febrile neutropenia (unique PT) 
 
toxicity-related hospital admissions (hospital admissions will be defined as 
an SAE with hospitalization ticked) 
 
grade 3-4 diarrhea (unique PT) 
 
grade 3-4 fatigue. Fatigue will include following PTs: Fatigue, asthenia, 
lethargy, malaise.  
 
grade 3-4 neuropathy. Acute polyneuropathy, neuropathy peripheral, 
paresthesia, peripheral sensory neuropathy, polyneuropathy, peripheral 
motor neuropathy, dysgeusia 
 
grade 3-4 treatment-related allergic reactions, that include following PTs: 
flushing, skin reactions, itching, chest tightness; difficulty in breathing, 
fever or chills, back pain, low blood pressure  
List of terms specified above may be further amended upon recommendation from 
Sponsor or medical expert. 
Otherwise, no statistical comparisons of AEs between treatment groups will be 
performed. 
 
 
 


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The number and percentage of subjects reporting each AE will be summarized by 
SOC and PT for the Safety population. Tables will be sorted alphabetically by SOC. 
PTs will be sorted by descending overall total. The following summaries will be 
produced: 
 
AEs, by SOC and PT; 
 
AEs by PT; 
 
AEs related to treatment, by SOC and PT; 
 
AEs related to treatment, by PT; 
 
AEs by maximum severity (NCI-CTCAE grade), by SOC and PT; 
 
AEs related to treatment by maximum severity (NCI-CTCAE grade), by SOC and 
PT; 
 
SAEs, by SOC and PT; 
 
SAEs related to treatment, by SOC and PT; 
 
SAEs by maximum severity (NCI-CTCAE grade), by SOC and PT; 
 
SAEs related to treatment by maximum severity (NCI-CTCAE grade), by SOC and 
PT; 
In the above summaries, subjects with more than one AE within a particular SOC are 
counted only once for that SOC. Similarly, subjects with more than one AE within a 
particular PT are counted only once for that PT. 
For summaries by maximum severity, subjects with multiple AEs within a particular 
SOC or PT will be counted under the category of their most severe AE within that 
SOC or PT. AEs with missing intensity/severity will be included (as Grade 4) in the 
overall count of subjects with AEs, but will not be included in the counts of subjects 
with AEs within a SOC or PT.  
 
 


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7.7.3 Laboratory Evaluations 
Data for the following hematology, blood chemistry, and urinalysis analytes recorded 
in the eCRF will be listed and summarized by treatment group and visit for the Safety 
population. If data for any additional analytes are also recorded then these will be 
listed only. 
Hematology 
Biochemistry 
Urinalysis (dipstick) 
Hemoglobin 
Hematocrit 
Red blood cell count 
White blood cell count 
Neutrophils count 
Lymphocyte count 
Monocyte count 
Basophil count 
Eosinophil count 
Platelet count 
 
Sodium (Na) 
Potassium (K) 
Calcium (Ca) 
 
Magnesium (Mg) 
Glucose 
Urea 
Blood Urea Nitrogen (BUN)* 
Creatinine 
Bilirubin 
Alkaline phosphatase 
Gamma-glutamyl transferase (GGT) 
Aspartate aminotransferase (ASAT) 
Alanine aminotransferase (ALAT) 
Lactate dehydrogenase (LD) 
Total protein 
Albumin 
Creatinine 
clearance 
using 
the 
Cockcroft-Gault formula or  
Modification of Diet in Renal Disease  
(MDRD). 
Protein 
Glucose 
Blood 
Ketones 
pH 
* Data recorded for BUN was allowed to be collected after first patient was included. 
All laboratory data will be reported in International System of Units (SI) units. Out-
of-reference-range values will be flagged as high (H) or low (L) in the listings.  
For analysis purposes, values preceded by a “<” or a “>” sign (i.e., those below or 
above the limits of quantification) will be considered equal to the lower or upper limit 
of quantification, respectively. 
Laboratory data will be summarized by visit using standard descriptive statistics for 
the Safety population.  
For hematology and biochemistry, changes from baseline will also be summarized.  
For the quantitative description by visit (row value and change from baseline), BUN 
results will be summarized as any other parameter. BUN will also be listed as part of 
the other collected parameters. 
 
For each laboratory analyte, the baseline value will be defined as last scheduled or 
unscheduled value collected prior to the first dose of treatment. For post-baseline, 
only data from scheduled visits will be included in the summary tables.  


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For hematology and biochemistry, shift tables presenting movement in and out of 
reference range from baseline to each scheduled post-baseline visit will be provided 
for each treatment group. For this analysis, BUN and urea will be analyzed as a 
combined parameter labelled “Urea/BUN”: per patient and per analysis, one value 
will be used (urea if available, otherwise BUN) to define abnormality criteria for the 
combined parameter (low/normal/high). 
 
7.7.4 Vital Signs 
The following vital signs will be listed and summarized by treatment group and visit 
for the Safety population. 
 
weight (kg) 
 
systolic and diastolic blood pressure (mmHg) 
 
body temperature (°C). Temperatures collected in °F will be converted to °C using 
following formula: (°F – 32) x (5/9) = °C. 
 
heart rate (bpm) 
Vital signs data and changes from baseline in vital signs will be summarized by visit 
using standard descriptive statistics for the Safety population.  
The baseline value will be defined as last scheduled or unscheduled value collected 
prior to the first dose of treatment. For post-baseline, only data from scheduled visits 
will be included in the summary tables.  
7.7.5 Electrocardiograms 
The following quantitative ECG measurements will be taken during the study: 
 
heart rate (bpm); 
 
PR interval (ms) 
 
QRS interval (ms) 
 
QT interval (ms) 
 
Bazett corrected QT (QTcB) interval (ms) 
 
Fridericia corrected QT (QTcF) interval (ms) 
 
RR interval (ms) 
An overall Investigator ECG interpretation will be provided (categories “normal”, 
“abnormal, not clinically significant” and “abnormal, clinically significant”), with 
specification if clinically significant. 
The ECG measurements and changes from baseline in ECG will be listed and 
summarized by treatment group and visit using standard descriptive statistics for the 
Safety population.  


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The Investigator assessment will be listed and the number and percentage of subjects 
within each assessment category will be tabulated by treatment group and visit for 
the Safety population.  
The baseline value will be defined as last scheduled or unscheduled value collected 
prior to the first dose of treatment. For post-baseline, only data from scheduled visits 
will be included in the summary tables.  
7.7.6 Physical Examination 
Physical examination results (normal/abnormal) and details of abnormalities will be 
listed for each subject and visits. 
7.7.7 Other Safety Variables 
WHO performance status (ECOG) will be summarized by treatment group and visit 
for the Safety population, presenting the number and percentage of subjects in each 
category. 
Listing of all ECOG assessments data will be provided. 
 
 
 


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7.8 HRQol 
HRQol analysis will be performed on the FAS population. 
7.8.1 FACT scales 
HRQoL scores and absolute changes from baseline will be summarized by visit and 
treatment group using standard descriptive statistics for the FAS population: 
• 
FACT-G: 
o Physical well-being (7 items; score range 0–28) 
o Social/Family well-being (7 items; score range 0–28) 
o Emotional well-being (6 items; score range 0–24) 
o Functional well-being (7 items; score range 0–28) 
o Total score (score range 0-108), computed only when at least 22 of 27 
FACT-G items completed 
• 
FACT-P:  
o PCS (12 items, score range 0-48) 
o Total score (FACT-G total score + PCS, score range 0-156) 
• 
FACT-taxane:  
o Taxane-specific domain score (16 items, 0 to 64) 
o Total score (0 to 172) 
For post-baseline visits, only data from scheduled visits will be included in the 
summary tables. 
Visit windows as defined in section 6.1 will be applied for analysis table of FACT (9 
scores defined above). Listing will show original visit only.Also, the following 
categorical variables will be computed and summarized by treatment group: 
• 
Overall HRQoL improvement, at least once during the study: Response is 
defined as a 10-point or greater increase in the FACT-G total score at a 
post-baseline assessment compared with baseline. 
• 
Improvements in individual HRQoL domains: 
o ≥3 for FACT-G physical well-being, at least once during the study  
o ≥3 for FACT-G social or family well-being, at least once during the study  
o ≥3 for FACT-G emotional well-being, at least once during the study  
o ≥3 for FACT-G functional well-being, at least once during the study  
o ≥3 for PCS, at least once during the study 
o ≥3 for FACT-Taxane specific items, at least once during the study  
 
 


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7.8.2 Time to HRQoL deterioration 
The time to HRQoL deterioration will be computed as the time from date of 
randomization to the date of first HRQoL deterioration, defined as: 
• 
a ≥10-point decrease in the FACT-G total score at a post-baseline 
assessment compared with baseline 
• 
or death from any cause, whichever occurs first, regardless date of death. 
Subjects without events as defined above will be censored at the date of their last 
post-baseline assessment of FACT-G total score. In the absence of post-baseline 
assessment, they will be censored at the date of randomization. 
If date of QOL assessment is missing, visit date will be used instead. 
Time to HRQoL deterioration will be summarized by treatment group using Kaplan-
Meier estimates (median and rates at 6 and 12 months, with associated 95% CI) and 
illustrated graphically using a Kaplan-Meier plot, for the FAS population. Differences 
between the cohorts will be determined using a non-stratified log-rank test. Under 
the condition of proportional hazards, Univariate Cox models will be ran and 
estimation of HR will be provided with 95% CI. 
7.8.3 Overall Health Related Utility 
The overall Health Related Utility will be assessed by the EQ-5D-5L. 
A frequency distribution of level response for each dimension (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression) and a summary of the 
visual analogue scale will be described by visit and treatment group.  
Absolute change from baseline will be summarized as well.For post-baseline visits, 
only data from scheduled visits will be included in the summary tables. 
Visit windows as defined in section 6.1 will be applied for analysis table of EQ-5D-5L. 
Listing will show original visit only. 
7.8.4 Treatment Satisfaction  
Each of the 4 domain scores computed from the TSQM will be summarized by visit 
and treatment group using standard descriptive statistics for the FAS population. 
Only data from scheduled visits will be included in the summary tables. Visit windows 
as defined in section 6.1 will be applied for analysis table of EQ-5D-5L. Listing will 
show original visit only. 
Of note, study protocol V3.0 does not require the collection at baseline visit. 
Therefore, any assessment collected at baseline visit will not be presented in the 
table by visit. 
 


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7.9 Interim Analysis 
No formal interim analysis will be performed for this study.  
 
 


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8. Changes in Planned Analysis 
The interim analysis described in protocol section 8.5 will not be performed.  
9. Data Issues 
Not applicable. 
 
 
 


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10. References 
[1] Scher et al. Trial Design and Objectives for Castration-Resistant Prostate 
Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials 
Working Group 3. J Clin Oncol. 2016; 34(12):1402-18. 
[2] Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria 
in solid tumours: revised RECIST guideline (version 1.1). European journal of 
cancer (Oxford, England: 1990). 2009;45(2):228-247. 
[3] US Food and Drug Administration, Guidance for Industry: Clinical Trial 
Endpoints for the Approval of Cancer Drugs and Biologics, December 2018. 
[4] Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response guidelines for 
phase 
II 
clinical 
trials 
in 
androgen-independent 
prostate 
cancer: 
recommendations from the Prostate-Specific Antigen Working Group. Journal of 
clinical oncology: official journal of the American Society of Clinical Oncology. 
1999;17(11):3461-3467. 
[5] Webster K, Cella D, Yost K. The Functional Assessment of Chronic Illness 
Therapy 
(FACIT) 
measurement 
system: 
properties, 
applications, 
and 
interpretation. Health Qual Life Outcomes. 2003; 1:79. 
[6] Cella D, Peterman A, Hudgens S, Webster K, Socinski MA. Measuring the side 
effects of taxane therapy in oncology: the Functional Assesment of Cancer 
therapy-Taxane (FACT-taxane). Cancer. 2003 Aug 15;98(4):822-31. 
[7] Atkinson MJ, Sinha A, Hass SL, et al. Validation of a general measure of 
treatment satisfaction, the Treatment Satisfaction Questionnaire for Medication 
(TSQM), using a national panel study of chronic disease. Health Qual Life 
Outcomes. 2004;2:12.  
[8] Atkinson MJ, Kumar R, Cappelleri JC, et al. Hierarchical construct validity of 
the treatment satisfaction questionnaire for medication (TSQM version II) among 
outpatient pharmacy consumers. Value Health, 2005; 8(S1):S9-S24. 
[9] Halabi et al. Updated Prognostic Model for Predicting Overall Survival in First-
Line Chemotherapy for Patients With Metastatic Castration-Resistant Prostate 
Cancer. J Clin Oncol. 2014; 32: 671–677. 
 
 


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Document Date: 07Oct2021 
 
ST-AD-008 version 05 
 
11. Appendices 
The list and shells of Tables, Figures and Listings will be provided in a separate 
document. 
11.1 Schedule of Assessments 
Trial procedures 
Baseline 
 
Cohort 1: 
Docetaxel 75 mg/m² iv 
Once every 3 weeks 
(cycle = 21 days with infusion on day 1) 
Premedication with oral dexamethasone 8mg, 12 hrs, 3 hrs and 1 hr before infusion, 
or according to local standard of care.  
Prednisone 2dd 5 mg continuously 
 
Cohort 2:  
ModraDoc006/r 20/20mg + 200/100mg 
Once every week twice daily  
(cycle = 21 days with ModraDoc006/r intake on day 1, 8, 15) 
Prednisone 2dd 5 mg continuously 
 
 
≤ Day 28 
Cycle 1  
Subsequent 
Cycles 
EOT*** 
FU**** 
Day 1* 
Day 3 ** 
Day 10 ** 
Day 1* 
 
 
Visit outpatient clinic 
X 
X 
 
 
X 
X 
X 
Compliance assessments 
 
 
X 
X 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Randomization 1 
X 
 
 
 
 
 
 
In-/exclusion criteria  
X 
X 
 
 
 
 
 
Demographic Data 1 
X 
 
 
 
 
 
 
Medical History2 
X 
 
 
 
 
 
 
Physical examination3 
X 
X 
 
 
X 
X 
X 
Vital Signs4 
X 
X 
 
 
X 
X 
X 
Hematology5 
X 
X 
 
 
X 
X 
X 
Clinical chemistry6 
X 
X 
 
 
X 
X 
X 
Serum testosterone 
X 
 
 
 
 
 
 
Urinalysis7 
X 
 
 
 
 
X 
 
Creatinine Clearance8 
X 
X 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
X 
 
CT-scan /MRI9 
X 
 
 
 
 
X 
X13 
Bone scintigraphy9 
X 
 
 
 
 
X 
X13 
PSA 
X 
X 
 
 
X 
X 
X 
Safety assessments10 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication11 
X 
X 
 
 
X 
X 
X 
HRQoL questionnaires 
and  
EQ-5D12 
X 
 
 
 
X12 
X 
X 
* Assessments may be performed within 3 days of day 1 
**Day 3 and 10 (+/- 1 day) safety (AEs) and compliance assessments via triage by telephone during cycle 1 only 
*** End Of Treatment (EOT) visit as soon as possible after discontinuation  
**** Follow Up visit (FU) 30 days after the last administration of ModraDoc006/r or i.v. docetaxel  
 


Statistical Analysis Plan Amendment 2 
Sponsor Name: Modra Pharmaceuticals 
Sponsor Protocol ID: M18MDP 
 
Covance Study ID: 000000182507 
 
 
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Document Date: 07Oct2021 
 
ST-AD-008 version 05 
 
1. Randomization ≤ 3 days; Demographic data: age, ethnic origin 
2. Medical History: (including details of malignancy, stage of cancer, radiotherapy and other therapies, with start and 
stop dates of therapy, number of cycles, cumulative doses, (cancer related) surgery etc., if applicable)). 
3. Physical examination: WHO Performance Status, weight in kg, height in cm (height: baseline only). 
4. Vital Signs: blood pressure, pulse rate and temperature. 
5. Hematology: hemoglobin, hematocrit, RBC, WBC with differential (differential should include: neutrophil, 
lymphocyte, monocyte, basophil and eosinophil counts), platelet count. 
6. Clinical Chemistry: ASAT, ALAT, GGT, LD, alkaline phosphatase, total and direct bilirubin, Na, K, Ca, Mg, 
glucose, urea, total protein, albumin, serum creatinine,. 
7. Urinalysis: dipstick for protein, glucose, blood, pH, and ketones. 
8. Creatinine Clearance: will be measured using Cockcroft-Gault formula or MDRD formula. 
 
For items 3) – 8): Assessments during screening less than 3 days before dosing need not to be repeated at day 1 of 
Cycle 1. 
 
9. Tumor assessment (following PCWG3) by PSA prior to every cycle and imaging/radiological assessment (i.e. 
CT/MRI + bone scan) at baseline (≤ 28 days prior to administration of study medication), every 8 weeks for first 
24 weeks (i.e. during week 9, 17 and 25), thereafter every 12 weeks and at End of Treatment (EOT), according to 
the RECIST v1.1 and PCWG3 criteria. Both PSA response and radiological response must be confirmed either 
after at least 3 weeks for PSA and after 4-6 weeks for RECIST v1.1. Of note: In this randomized comparative 
trial, the scheduled assessments should not be affected by delays in therapy, drug holidays or any other events that 
might lead to imbalance in a treatment arm in the timing of disease assessment (see Table 15 in study protocol 
section 6.9.1 for further details).  
10. Toxicity assessments: baseline signs and symptoms and all related and unrelated adverse events will be assessed 
using the NCI-CTCAE criteria Version 5.0, including start and stop dates, severity, relationship to study drug, 
outcome and action taken. 
11. Concomitant medication: including start and stop dates, dose, frequency, route of administration and indication. 
12. Baseline, at the end of cycle 3, 6 and 10 or at EOT (if this would occur earlier): FACT global, FACT-P and 
FACT-taxane, Treatment Satisfaction (excluding baseline) and EQ-5D-5L questionnaire. 
13. Imaging to be performed in the Follow Up visit, in case of unconfirmed PR or CR. 
 


Statistical Analysis Plan Amendment 2 
Sponsor Name: Modra Pharmaceuticals 
Sponsor Protocol ID: M18MDP 
 
Covance Study ID: 000000182507 
 
 
CONFIDENTIAL 
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Document Date: 07Oct2021 
 
ST-AD-008 version 05 
 
11.2 FACT-G and FACT-P Scoring instructions 
 


Statistical Analysis Plan Amendment 2 
Sponsor Name: Modra Pharmaceuticals 
Sponsor Protocol ID: M18MDP 
 
Covance Study ID: 000000182507 
 
 
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Document Date: 07Oct2021 
 
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FACT-P Scoring Guidelines (Version 4) 
 
 
 
 


Statistical Analysis Plan Amendment 2 
Sponsor Name: Modra Pharmaceuticals 
Sponsor Protocol ID: M18MDP 
 
Covance Study ID: 000000182507 
 
 
CONFIDENTIAL 
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Document Date: 07Oct2021 
 
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11.3 Sample SAS® code for analyses  
 
Tables that need descriptive statistics – continuous variables: 
PROC UNIVARIATE DATA=dset NOPRINT; 
    VAR var1 var2 var3 …varn; 
   BY byvar; (optional) 
   OUTPUT OUT=outname; 
   N=n MEAN=mean MIN=min MAX=max MEDIAN=median STD=std; 
RUN; 
 
Tables that need frequency counts: 
PROC FREQ DATA=dset NOPRINT; 
  
BY byvar; (optional) 
   TABLES var1*var2; 
  
OUTPUT OUT=outname; 
RUN; 
 
Tables that need exact (Clopper-Pearson)95% CIs between groups for 
proportions: 
PROC FREQ DATA=dset; 
  
BY byvar; (optional) 
   TABLES var1 * var2 / binomial(exact) MEASURES ALPHA=0.05; 
RUN; 
Notes: 1 Estimates are computed for 2x2 tables only 
      2 This code also gives exact 95% CIs within group for binomial proportions 
 
Tables that need 95% CIs within group for binomial proportions: 
PROC FREQ DATA=dset; 
  
BY byvar; (optional) 
   TABLES var1; 
  
EXACT BINOMIAL; 
RUN; 
 
Tables that require analysis of (co)variance and 95/90% CIs between 
arms for continuous variables: 
PROC GLM DATA= dset  OUTSTAT=outset; 
 
CLASS class variables; 
 
MODEL response = <effect> <treatment> / SOLUTION; 
 
LSMEANS treatment / STDERR PDIFF CL; <ADD: ALPHA=0.1 for 90% CIs> 
 
ESTIMATE 'T1 - T2' treatment 1  -1 0; or 'T2 – T1' treatment -1 1 0 if applic. 
   ESTIMATE 'T1 - T3' treatment 1 0  -1; 
   ESTIMATE 'T2 – T3' treatment 0 1  -1; 
 
BY byvar; (optional) 
 
WHERE wherever; (optional) 
RUN; 
QUIT; 
Note: (Treatment order: 1=drug 1,2= drug 2,3= drug 3, etc… 5= placebo) 
 
 


Statistical Analysis Plan Amendment 2 
Sponsor Name: Modra Pharmaceuticals 
Sponsor Protocol ID: M18MDP 
 
Covance Study ID: 000000182507 
 
 
CONFIDENTIAL 
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Document Date: 07Oct2021 
 
ST-AD-008 version 05 
 
 
Tables that present Fisher’s Exact or CMH: 
PROC FREQ DATA=dset NOPRINT; 
   BY byvar; (optional) 
   TABLES var1*var2/CMH score=MODRIDIT  EXACT; 
   OUTPUT OUT=outname CMH EXACT; 
RUN; 
 
Tables that need to use WILCOXON: 
PROC NPAR1WAY DATA=dset WILCOXON; 
 
CLASS class variables; 
 
VAR  variable; 
RUN; 
 
Tables that need number of events/censored and probabilities of 
failure/survival at cut off times: 
PROC LIFETEST DATA=dset OUTSURV=LIFE METHOD=LT INTERVALS=12, 24,; 
 
TIME duration*censor (0 or 1); 
 
ID subject; 
 
STRATA treatment; 
RUN; 
 
Tables that need life table with estimates of survival, with CIs and log 
rank test:  
PROC LIFETEST DATA=dset OUTSURV=LIFE METHOD=KM; 
 
 TIME duration*censor (0 or 1); 
 
ID subject; 
 
STRATA treatment; 
RUN; 
 
 Kaplan-Meier curves for treatment: 
PROC LIFETEST data=dataset plots=survival(strata=individual); 
 
TIME time*event(0); 
 
STRATA treatment; 
RUN; 
 
Tables that need Cox Proportional Hazards models: 
PROC PHREG data=dataset; 
CLASS treatment; 
MODEL time*event(0) = treatment / ties=exact; 
CONTRAST 'a vs b' treatment 1 / estimate=exp; 
RUN; 
 


Statistical Analysis Plan Amendment 2 
Sponsor Name: Modra Pharmaceuticals 
Sponsor Protocol ID: M18MDP 
 
Covance Study ID: 000000182507 
 
 
CONFIDENTIAL 
Page 61 of 62 
Document Date: 07Oct2021 
 
ST-AD-008 version 05 
 
Testing PH assumptions: 
 
PROC PHREG data=dataset; 
CLASS treatment; 
MODEL time*event(0) = treatment / ties=exact; 
Treatment_t = treatment*log(time); 
Proportionality_test: test treatment_t ; 
RUN; 
 
Model for time dependent covariate:PROC PHREG data=dataset; 
CLASS treatment; 
MODEL time*event(0) = treatment vartimedependant / ties=exact; 
CONTRAST 'a vs b' treatment 1 / estimate=exp; 
Vartimedependant=var*(time>x); 
RUN; 
 
 
Vartimedependant=var*(time>x) will be defined after review the results of model 
with interaction and HR curves 
 
 
 


Statistical Analysis Plan Amendment 2 
Sponsor Name: Modra Pharmaceuticals 
Sponsor Protocol ID: M18MDP 
 
Covance Study ID: 000000182507 
 
 
CONFIDENTIAL 
Page 62 of 62 
Document Date: 07Oct2021 
 
ST-AD-008 version 05 
 
11.4 Document History  
Document Version, Status, 
Date 
Summary/Reason for Changes 
Version 1, Final, 
18 October 2019 
Not applicable; the first version 
Version 2, Final, 
23 November 2020 
Major updates: 
- 
Use of protocol Final Version 3.0 (Amendment 
2) dated 31Mar2020, including change from 
Objective Response Rate to radiographic 
Progression Free Survival as primary endpoint 
- 
BOR/ORR/DCR/DOR: confirmation of response 
is not required 
- 
Section 7.1: Tables and Listings will be split by 
protocol version  
- 
Section 7.7.2: Additional AE summaries 
according to baseline BSA level 
- 
Clarification of some planned statistical analysis 
mainly for programming purpose  
- 
Use of Covance template ST-AD-008 version 05 
instead of version 4 (Removed approvals page 
as this is now a separate associated document, 
Document history moved to the Appendix) 
Version 3, Final, 
07 October 2021 
Main updates: 
- 
Disposition of patients: Add number of ongoing 
subjects 
- 
Efficacy:  
o 
Clarification of event/censoring rules for 
time-to-event data 
o 
Analysis of TTF as sensitivity analysis, 
with additional Table 14.2.1.5 and Figure 
14.2.1.6. 
o 
Analysis of ORR repeated on the PP 
population, among the patients 
evaluable for radiological response 
- 
Use of visit windows for analysis of Quality of 
Life questionnaires 
- 
Safety: Consideration of BUN parameter 
 
Of note, template ST-AD-008 version 06 is not used 
because changes motivating this SAP amendment are 
not critical and do not justify its use. Same template as 
SAP Version 2.0 is used  i.e. ST-AD-008 Version 05.