Conditions: NUT Midline Carcinoma Triple Negative Breast Cancer Non-small Cell Lung Cancer With Rearranged ALK Gene/Fusion Protein or KRAS Mutation Castrate-resistant Prostate Cancer CRPC Pancreatic Ductal Adenocarcinoma
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 47
Healthy volunteers: no

Brief summary:
Open-label, phase I, non-randomized, multicentric study of single-agent birabresib (MK-8628) (formerly known as OTX015) administered according to two distinct regimens to participants with selected advanced tumors.

The study will be performed in two parts.

Dose Escalation Part:

This step is designed to determine the maximum tolerated dose (MTD) in each of the two regimens, which will be evaluated in parallel. Participants will receive oral birabresib according to:

Continuous Dosing Regimen: continuous, once daily for 21 consecutive days (21-day cycles).

OR Days 1-7 Dosing Regimen: once daily on Days 1 to 7, repeated every 3 weeks (21-day cycles; 1 week ON/2 weeks OFF).

Participants will be sequentially assigned to Continuous Dosing Regimen or Days 1-7 Dosing Regimen according to the next available place and receive birabresib at escalating doses levels (DL). Cohorts of 3 participants will be treated, and an additional 3 participants will be treated at the first indication of dose-limiting toxicity (DLT). MTD assessment will be based on the tolerability observed during the first 21 days of treatment.

Expansion Part:

The efficacy of birabresib in each of the five indications (i.e., Bromodomain-Nuclear Protein in Testis \[BRD-NUT\] midline carcinoma, triple negative breast cancer \[TNBC\], non-small cell lung cancer \[NSCLC\] harboring a rearrangement Anaplastic Lymphoma Kinase \[ALK\] gene/fusion protein or Kirsten Ras \[KRAS\] mutation, castrate-resistant prostate cancer, and pancreatic ductal carcinoma) will be assessed in terms of response (Response Evaluation Criteria in Solid Tumors v1.1 \[RECIST v1.1\] or Prostate Cancer Clinical Trials Working Group 2 \[PCWG2\]) using a selected regimen.

Detailed description:

Arms:
arm 1: Participants receive birabresib capsules once daily in a fasted state in the morning on Days 1-21 of each 21-day cycle. Starting dose for dose escalation is 80 mg. arm 2: Participants receive birabresib capsules once daily in a fasted state in the morning on Days 1-7 of each 21-day cycle. Starting dose for dose escalation is 100 mg.

Interventions: intervention 1: Birabresib
Intervention descriptions: intervention 1: Birabresib 10, 20 and/or 40 mg oral capsules

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Official Protocol Title: A Phase IB Trial with OTX015/MK-8628, a Small Molecule 
Inhibitor of the Bromodomain and Extra-Terminal (BET) Proteins, 
in Patients with Selected Advanced Solid Tumors 
 
NCT number: 
NCT02259114
Document Date: 
19-November-2015


 
 
The information in this document is the property of OncoEthix and is confidential. Neither the document nor the information  
contained therein may be reproduced or disclosed outside OncoEthix without their written consent.  
Page 1 
 
Sponsor: ONCOETHIX, Oncoethix GmbH, a wholly owned subsidiary of Merck, Sharp & Dohme 
Corp., a subsidiary of Merck & Co., Inc. 
CLINICAL STUDY PROTOCOL 
OTX015_108/MK-8628-003 
EUDRACT NUMBER: 2014-002680-15 
A Phase IB Trial with OTX015/MK-8628, a Small Molecule Inhibitor of the Bromodomain and 
Extra-Terminal (BET) Proteins, in Patients with Selected Advanced Solid Tumors 
Coordinating Investigator: 
 
 
 
 
 
Canada 
 
Tel: 
  
Fax: 
  
E-mail: 
  
 
 
 
 
Sponsor Medical Expert 
 
Merck Research Laboratories, Oncology Product 
Development 
126 E. Lincoln Avenue, RY34-B184, Rahway, NJ 
07065, US 
Tel: 
 / Fax: 
 
E-mail: 
 
 
CRO Medical Monitor 
 
OTD (Oncology Therapeutic Development) SARL 
100 rue Martre, 92110 Clichy, France  
Tel : 
 / Fax: 
 
E-mail: 
 
 
CRO Project Manager 
  
OTD (Oncology Therapeutic Development) SARL  
100 rue Martre, 92110 Clichy, France  
Tel: 
 / Mobile: 
  
Fax: 
 
E-mail: 
 
 
 
Date of issue: 
19 November, 2015 
Version N°: F5.00 
 
 
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Protocol OTX015_108/MK-8628-003 
 
Version F5.00; 19 November, 2015 
 
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contained therein may be reproduced or disclosed outside OncoEthix without their written consent.  
Page 2 
STUDY PROTOCOL AGREEMENT FORM 
 
I, __________________________________________, have reviewed this Study Protocol OTX015_108/ 
MK-8628-003, Final Version F5.00, dated 19 November, 2015, entitled:  
 
A Phase IB Trial with OTX015/MK-8628, a Small Molecule Inhibitor of the Bromodomain and 
Extra-Terminal (BET) Proteins, in Patients with Selected Advanced Solid Tumors 
I confirm that I have read the above protocol. The information it contains is consistent with the current 
risk-benefit evaluation of the investigational product. 
I understand it, and I agree to conduct the study according to this protocol and to comply with its 
requirements, subject to scientific, ethical and safety considerations. Specifically, I will work according to 
the principles of GCP as described in CPMP/ICH/135/95 and 21 CFR parts 50, 54, 56, and 312, and 
according to applicable local requirements. 
I understand that I must keep confidential the information contained in the study documents that I have 
been or will be provided with. 
I understand that, should the decision be made by the Sponsor to terminate prematurely or suspend the 
study at any time for whatever reason, such a decision will be communicated to me in writing. Should I 
decide to withdraw from participating in the study I will communicate immediately such a decision in 
writing to the Sponsor. 
Furthermore, by the present, I am committed to enroll the first patient in this study within a month. 
 
 
SPONSOR: ONCOETHIX 
INVESTIGATOR 
 
 
 
Dr. _______________________________ 
CRO Representative, Medical Monitor 
Principal Investigator 
Oncology Therapeutic Development 
Institution 
100 rue Martre, 92110 Clichy, France 
Address 
 
Date: 
 
d 
m 
y 
 
 
 d 
m 
     y 
 
 
 
Signature 
 
 
 
_____________________________ 
 
Signature 
 
 
_______________________________ 
 
 
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Protocol OTX015_108/MK-8628-003 
 
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TABLE OF CONTENTS 
SYNOPSIS ................................................................................................................................................................. 7 
STUDY SCHEDULE .............................................................................................................................................. 15 
ABBREVIATIONS AND DEFINITIONS ............................................................................................................ 16 
1 
BACKGROUND .......................................................................................................................................... 18 
1.1 
BROMODOMAIN AND EXTRATERMINAL (BET) PROTEIN INHIBITION ........................................ 18 
1.2 
OVERVIEW OF SOLID TUMOR INDICATIONS ..................................................................................... 19 
1.2.1 BRD-NUT Midline Carcinoma ............................................................................................................... 19 
1.2.2 Non-Small Cell Lung Cancer: KRAS Mutated and ALK Positive .......................................................... 20 
1.2.3 Triple Negative Breast Cancer ................................................................................................................. 21 
1.2.4 Castrate-Resistant Prostate Adenocarcinoma .......................................................................................... 22 
1.2.5 Pancreatic Ductal Carcinoma ................................................................................................................... 23 
1.3 
DEVELOPMENT OF OTX015 .................................................................................................................... 23 
1.3.1 Description of OTX015 ........................................................................................................................... 23 
1.3.2 Preclinical Data ........................................................................................................................................ 24 
1.3.3 Clinical Data ............................................................................................................................................ 26 
1.4 
RATIONALE FOR THE CURRENT STUDY ............................................................................................. 40 
1.4.1 Rationale for the Trial Design ................................................................................................................. 41 
1.4.2 Justification for the Regimens and Starting Dose .................................................................................... 42 
2 
STUDY OBJECTIVES ............................................................................................................................... 43 
2.1 
PRIMARY OBJECTIVE............................................................................................................................... 43 
2.2 
SECONDARY OBJECTIVES ...................................................................................................................... 43 
3 
STUDY DESIGN, DURATION AND DATES .......................................................................................... 43 
3.1 
STUDY DESIGN .......................................................................................................................................... 43 
3.2 
INDEPENDENT SAFETY AND DATA MONITORING COMMITTEE .................................................. 44 
3.3 
STUDY DURATION AND DATES ............................................................................................................ 44 
4 
SELECTION OF PATIENTS .................................................................................................................... 45 
4.1 
NUMBER OF PATIENTS ............................................................................................................................ 45 
4.2 
INCLUSION CRITERIA .............................................................................................................................. 45 
4.3 
EXCLUSION CRITERIA ............................................................................................................................. 46 
4.4 
PATIENTS OF REPRODUCTIVE POTENTIAL ........................................................................................ 46 
5 
STUDY TREATMENT ............................................................................................................................... 47 
5.1 
FORMULATION AND MANUFACTURER .............................................................................................. 47 
5.2 
DOSAGE SCHEDULE ................................................................................................................................. 47 
5.2.1 Prophylactic Medication Regimen ........................................................................................................... 47 
5.2.2 Schedule ................................................................................................................................................... 47 


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5.2.3 Dose Escalation ....................................................................................................................................... 48 
5.2.4 Dose Limiting Toxicity ............................................................................................................................ 49 
5.2.5 Maximum Tolerated Dose ....................................................................................................................... 49 
5.2.6 Expansion Cohort .................................................................................................................................... 49 
5.2.7 Dose Adaptation ...................................................................................................................................... 49 
5.2.8 Supportive Care Guidelines for Study Treatment Toxicity ..................................................................... 50 
5.2.9 Potential Phototoxicity ............................................................................................................................. 51 
5.3 
TREATMENT DURATION ......................................................................................................................... 51 
5.4 
TREATMENT ASSIGNMENT .................................................................................................................... 52 
5.5 
PACKAGING AND LABELING ................................................................................................................. 53 
5.6 
SUPPLIES AND ACCOUNTABILITY ....................................................................................................... 53 
5.7 
COMPLIANCE ............................................................................................................................................. 53 
6 
PRIOR AND CONCOMITANT ILLNESSES AND TREATMENTS ................................................... 54 
6.1 
MEDICAL CONDITIONS ........................................................................................................................... 54 
6.2 
MEDICATIONS ........................................................................................................................................... 54 
7 
STUDY PROCEDURES AND SCHEDULE............................................................................................. 55 
7.1 
PRE-STUDY SCREENING VISIT............................................................................................................... 55 
7.2 
EVALUATIONS DURING STUDY TREATMENT ................................................................................... 56 
7.3 
END OF TREATMENT VISIT AND FOLLOW-UP ................................................................................... 56 
8 
ASSESSMENT OF SAFETY ..................................................................................................................... 57 
8.1 
CLINICAL SAFETY .................................................................................................................................... 57 
8.2 
LABORATORY MEASUREMENTS .......................................................................................................... 57 
8.3 
DEFINITIONS (21 CFR§312.32) ................................................................................................................. 57 
8.4 
DOCUMENTATION .................................................................................................................................... 59 
8.5 
GRADE AND SEVERITY ........................................................................................................................... 59 
8.6 
RELATIONSHIP TO STUDY TREATMENT ............................................................................................. 60 
8.7 
SAE REPORTING ........................................................................................................................................ 60 
8.8 
PERIOD OF OBSERVATION ..................................................................................................................... 61 
8.9 
EVENTS OF CLINICAL INTEREST .......................................................................................................... 61 
9 
EFFICACY ASSESSMENTS ..................................................................................................................... 62 
9.1 
RECIST ......................................................................................................................................................... 62 
9.1.1 Imaging Technique .................................................................................................................................. 62 
9.1.2 Evaluation of Lesions .............................................................................................................................. 62 
9.1.3 Definition of Best Overall Tumor Response............................................................................................ 63 
9.2 
PCWG2 ......................................................................................................................................................... 64 
9.2.1 PSA .......................................................................................................................................................... 64 
9.2.2 Measurable Soft-Tissue Lesions .............................................................................................................. 64 
9.2.3 Bone ......................................................................................................................................................... 65 


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10 
PHARMACOKINETICS ASSESSMENTS .............................................................................................. 67 
10.1 
SAMPLE COLLECTION ............................................................................................................................. 67 
10.2 
ASSAY METHOD AND PARAMETERS ANALYZED ............................................................................ 67 
11 
STATISTICAL CONSIDERATIONS ....................................................................................................... 68 
11.1 
STATISTICAL DESIGN AND SAMPLE SIZE .......................................................................................... 68 
11.2 
STUDY ENDPOINTS .................................................................................................................................. 68 
11.3 
ANALYSIS POPULATIONS ....................................................................................................................... 69 
11.4 
STATISTICAL METHODS ......................................................................................................................... 69 
11.5 
INTERIM ANALYSIS .................................................................................................................................. 69 
12 
ETHICAL AND LEGAL ASPECTS ......................................................................................................... 69 
12.1 
GOOD CLINICAL PRACTICE .................................................................................................................... 69 
12.2 
DELEGATION OF INVESTIGATOR DUTIES .......................................................................................... 69 
12.3 
PATIENT INFORMATION AND INFORMED CONSENT ....................................................................... 70 
12.4 
CONFIDENTIALITY ................................................................................................................................... 70 
12.5 
APPROVAL OF THE CLINICAL STUDY PROTOCOL AND AMENDMENTS ..................................... 70 
12.6 
ONGOING INFORMATION FOR IEC/ IRB AND HEALTH AUTHORITIES ......................................... 71 
12.7 
STUDY CLOSURE ...................................................................................................................................... 71 
12.8 
RECORD RETENTION ............................................................................................................................... 71 
12.9 
LIABILITY AND INSURANCE .................................................................................................................. 71 
12.10 FINANCIAL DISCLOSURE ........................................................................................................................ 72 
13 
STUDY MONITORING AND AUDITING .............................................................................................. 72 
13.1 
MONITORING AND SOURCE DATA VERIFICATION .......................................................................... 72 
13.2 
ON-SITE AUDITS/INSPECTIONS ............................................................................................................. 72 
14 
DOCUMENTATION AND USE OF STUDY FINDINGS....................................................................... 72 
14.1 
DOCUMENTATION OF STUDY FINDINGS ............................................................................................ 72 
14.2 
CONFIDENTIALITY/USE OF STUDY FINDINGS ................................................................................... 73 
15 
REFERENCES ............................................................................................................................................ 74 
16 
APPENDICES ............................................................................................................................................. 82 
16.1 
APPENDIX 1: ECOG PERFORMANCE STATUS ..................................................................................... 82 
16.2 
APPENDIX 2: CALCULATION OF RENAL CLEARANCE ..................................................................... 83 
16.3 
APPENDIX 3: NON-EXHAUSTIVE LIST OF DRUGS AND SUBSTANCES WITH THE 
POTENTIAL TO INTERFERE WITH CYP3A4 AND CYP2A6 ................................................................ 84 
16.4 
APPENDIX 4: SAFETY MONITORING COMMITTEE COMPOSITION AND CHARTER ................... 85 
16.5 
APPENDIX 5: GUIDANCE FOR POTENTIAL DRUG-INDUCED LIVER INJURY (DILI) ................... 87 
16.5.1 Purpose .................................................................................................................................................... 87 
16.5.2 Introduction ............................................................................................................................................. 87 
16.5.3 Close Observation Recommendations ..................................................................................................... 88 
16.5.4 Hepatic Assessment Flow Chart .............................................................................................................. 89 


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16.5.5 Factors to Consider in Assessing Potential DILI ..................................................................................... 89 
16.5.6 Contacts ................................................................................................................................................... 93 
16.5.7 References ............................................................................................................................................... 93 


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SYNOPSIS 
STUDY TITLE  
A Phase IB Trial with OTX015/MK-8628, a Small Molecule Inhibitor of the Bromodomain and 
Extra-Terminal (BET) Proteins, in Patients with Selected Advanced Solid Tumors 
INVESTIGATORS / LOCATIONS  
At least 7 centers in Belgium, Canada, France, Spain and Switzerland.  
Coordinating investigator: 
 (Canada) 
Principal investigators: 
 (Belgium), 
 (France), 
 
 (Switzerland), 
 (France), 
 (Switzerland), 
 
 (Spain). 
STUDY OBJECTIVES 
Primary 
• To determine the Maximal Tolerated Dose (MTD) defined as the recommended phase II dose for two 
distinct regimens of OTX015/MK-8628 administered orally to patients with selected advanced solid 
tumors 
Secondary 
• To assess the safety profile of single-agent OTX015/MK-8628 
• To characterize pharmacokinetics parameters of OTX015/MK-8628 
• To determine the antitumor activity of OTX015/MK-8628 in selected solid tumors 
 
STUDY DESIGN  
Open-label, phase I, non-randomized, multicentric study of single-agent OTX015/MK-8628 administered 
according to two distinct regimens to patients with selected advanced tumors. 
The study will be performed in two parts. 
Dose Escalation Part 
This step is designed to determine the maximum tolerated dose (MTD) in each of the two regimens, which 
will be evaluated in parallel. Patients will receive oral OTX015/MK-8628 according to: 
Regimen 1: continuous, once daily for 21 consecutive days (21-day cycles).  
Or 
Regimen 2: once daily on days 1 to 7, repeated every three weeks (21-day cycles; 1 week ON/2 weeks OFF).
Patients will be sequentially assigned to Regimen 1 or Regimen 2 according to the next available place and 
receive OTX015/MK-8628 at escalating doses levels (DL). Cohorts of 3 patients will be treated, and an 
additional 3 patients will be treated at the first indication of dose-limiting toxicity (DLT). MTD assessment 
will be based on the tolerability observed during the first 21 days of treatment. 
Expansion Part 
The efficacy of OTX015/MK-8628 in each of the five indications (i.e., BRD-NUT midline carcinoma, triple 
negative breast cancer, non-small cell lung cancer harboring a rearrangement ALK gene/fusion protein or 
KRAS mutation, castrate-resistant prostate cancer, and pancreatic ductal carcinoma) will be assessed in 
terms of response (RECIST v1.1 or PCWG2) using a selected regimen. 
STUDY POPULATION 
Inclusion Criteria 
Patients must fulfill all of the following requirements to enter the study: 
1. Signed informed consent obtained prior to initiation of any study-specific procedures and treatment; 
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2. Histologically or cytologically confirmed diagnosis of one of the following advanced or metastatic solid 
tumors for which standard therapy either does not exist or has proven ineffective, intolerable or 
inacceptable for the patient: 
- 
NUT midline carcinoma (ectopic expression of NUT protein as determined by IHC and/or detection 
of BRD-NUT gene translocation as determined by FISH); 
- 
Triple negative breast cancer defined according to ASCO recommendations (Hammond et al., 2010; 
Wolff et al., 2007); 
- 
Non-small cell lung cancer harboring a rearranged ALK gene/fusion protein (FISH or IHC) or 
KRAS mutation (as defined by any molecular analysis); 
- 
Castrate-resistant prostate cancer (CRPC); 
- 
Pancreatic ductal adenocarcinoma; 
3. At least one measurable lesion as per RECIST version 1.1., except for CRPC patients who may be 
enrolled with objective evidence of disease as per Prostate Cancer Clinical Trials Working Group 
(PCWG2) criteria; 
4. Age ≥ 18 years at the time of informed consent; 
5. Life expectancy ≥ 3 months; 
6. ECOG Performance Status (PS) ≤ 1; 
7. Adequate bone marrow reserve, renal and liver function:  
- 
Absolute neutrophil count ≥ 1.5 x109/L, 
- 
Platelet count ≥ 150 x109/L, 
- 
Hemoglobin ≥ 9 g/dL (blood transfusion ≤ 7 days of screening not permitted), 
- 
Creatinine clearance ≥ 30 mL/min calculated according to the Cockroft and Gault formula or 
MDRD formula for patients aged > 65 years, 
- 
Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤3 x ULN, if alkaline 
phosphatase (ALP) > 2.5 X ULN, then liver fraction should be ≤ 2.5 X ULN, and total bilirubin ≤ 
1.25 x ULN (in case of liver involvement, total bilirubin ≤ 2 x ULN will be allowed), 
- 
Serum albumin ≥ 2.0 g/dL for NMC, ≥ 3.0 g/dL for NSCLC, CRPC, TNBC and pancreatic cancer 
- 
INR ≤ 1.5 or INR < 3 for patients treated with antivitamin K; 
8. An interval of ≥ 3 weeks since chemotherapy (≥ 6 weeks for nitrosoureas or mitomycin C), 
immunotherapy, hormone therapy or any other anticancer therapy or surgical intervention resection, or 
≥ 3 half-lives for monoclonal antibodies, or ≥ 5 half-lives for other non-cytotoxic agents (whichever is 
longer); 
9. CRPC patients must maintain ongoing androgen deprivation therapy with a gonadotropin releasing 
hormone (GnRH) analogue, antagonist or orchiectomy providing serum testosterone is < 50 ng/dL 
(<1.7 nmol/L); 
10. Patients receiving bisphosphonate or denosumab therapy must be on stable doses for at least 4 weeks 
before initiating study treatment. 
 
Exclusion Criteria 
The presence of any of the following criteria excludes a patient from participating in the study: 
1. Inability to swallow oral medications or presence of a gastrointestinal disorder (e.g. malabsorption) 
deemed to jeopardize intestinal absorption of OTX015/MK-8628; 
2. Persistent grade >1 clinically significant toxicities related to prior antineoplastic therapies (except for 
alopecia); stable sensory neuropathy ≤ grade 2 NCI-CTCAE v. 4.0 is accepted. 


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3. Known primary CNS malignancy or CNS involvement;  
4. History of prior or concomitant malignancies (other than excised non-melanoma skin cancer or cured in 
situ cervical carcinoma) within 3 years of study entry; 
5. Other serious illness or medical conditions, such as active infection, unresolved bowel obstruction, or 
psychiatric disorders; 
6. Known HIV positivity; 
7. Participation in another clinical trial or treatment with any investigational drug within 30 days prior to 
study entry; 
8. Other concomitant anticancer treatment; 
9. Concomitant therapy with strong CYP3A4 interfering drugs; 
10. Current use of anticoagulants (e.g. warfarin, heparin) at therapeutic levels within 7 days prior to the first 
dose of OTX015/MK-8628. Low-dose (prophylactic) low molecular weight heparin (LMWH) is 
permitted; 
11. Pregnant or breast-feeding patients, and men and women with childbearing potential not using effective 
contraception while on study treatment. 
STUDY DRUG 
Study Drug and Formulation  
OTX015/MK-8628 is administered orally. It is provided as size 3 gelatin capsules containing 10 or 20 mg 
OTX015/MK-8628 (free base) and size 0 gelatin capsules containing 40 mg OTX015/MK-8628 (free base) 
as a solid molecular dispersion with hypromellose acetate succinate (HPMCAS), mixed with lactose 
monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium 
stearate excipients. Capsules should be stored at 2°C to 8°C. 
Study Drug Administration  
• 
OTX015/MK-8628 is to be administered per os once daily in a fasted state just before breakfast (around 
8 a.m. [±2h]), either continuously (Regimen 1) or for 7 consecutive days every 3 weeks (Regimen 2), as 
a flat dose without adaptation for body weight or surface area. 
• 
A treatment cycle is 3 weeks (21 days). 
• 
Patients participating in pharmacokinetics will be observed for ≥ 8 hours after the first study drug 
administration to collect PK blood samples and check vital signs, when appropriate. 
• 
Patients should receive the study treatment within 7 days following registration. 
• 
Dosing not performed at the same time (±2h) as on other days will be omitted. Patients are to be 
instructed that if they vomit or omit their dose in that time frame, it is not to be replaced. 
 
 
Dose Escalation Scheme 
• 
Up to four OTX015/MK-8628 dose levels (DLs) are planned for each regimen. Patients will be 
sequentially assigned to Regimen 1 or Regimen 2, according to the next available place. 
• 
The starting dose will be 80 mg per os given once daily for Regimen 1, and 100 mg given once daily for 
7 days every 3 weeks for Regimen 2. 
• 
DLT assessment in each regimen will be independent and based on tolerability observed during the first 
21 days of study treatment. 
• 
The first patient enrolled in a higher DL cohort will not start the study treatment until the last treated 
patient in the DL immediately below has completed 3 weeks of study treatment. 
• 
If 1/3 patients of a cohort has DLT during cycle 1 (i.e. the first 21 days following study treatment 


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initiation), up to 3 additional patients will be entered at this DL. If no more than 1/6 evaluable patients 
has DLT, dose escalation will proceed to the DL immediately above. If more than 1/6 patients (or more 
than 1/3) has DLT, the DL will be considered to exceed the MTD (see table below). 
• 
Patients not evaluable for DLT (i.e. receiving less than 85% of the intended cumulative dose of the first 
21-day cycle period for any reason other than toxicity; <18 days of treatment for Regimen 1, or <6 days 
of treatment for Regimen 2) and who do not experience DLT will be replaced. 
 
Dose 
Level  
OTX015 Dose (mg/day) 
Outcome (#DLT/#Patients)* / Actions to be taken 
Regimen 1 
(continuous) 
Regimen 2  
(D1-7, q3w) 
DL 1 
80 
100 
At each DL for each regimen: 
- If 0 of 3 patients has DLT, escalate dose in next cohort of 3 patients 
- If 1 of 3 patients has DLT, treat next 3 patients at the same dose level 
(6 patients total) 
- If ≥ 2 of 3 patients has DLT, halt dose escalation (MTD exceeded) 
- If 1 of 6 patients has DLT, escalate dose for next cohort of 3 patients 
- If ≥ 2 of 6 patients has DLT, halt dose escalation (MTD exceeded) 
DL 2 
100 
120 
DL 3 
120 
160 
DL 4 
160 
200 
* Evaluated during the first 21 days of treatment 
 
DLT Definition 
A DLT is defined as any of the following toxicities occurring during the first 21 days of treatment and 
considered by the investigator to be related to OTX015/MK-8628. 
Hematologic toxicity 
• 
Any grade 4 hematologic toxicity or febrile neutropenia 
• 
Grade 3 neutropenia with infection 
• 
Grade 3 thrombocytopenia with bleeding or lasting > 7 days 
Non-hematologic toxicity 
• 
Any grade 3 or 4 non-hematologic toxicity (regardless of duration) unless it was not optimally managed 
with supportive care (e.g. grade 3 vomiting not adequately treated according to antiemetic standard of 
care). 
• 
Any grade 3 or 4 laboratory abnormality, with or without symptoms, lasting > 48 hours.  
• 
Any intolerable grade 2 non-hematologic toxicity resulting in study drug discontinuation or delay > 7 
days with or without dose reduction. 
• 
Any of the following liver test abnormalities** (see Appendix 5) 
- 
ALT or AST > 8 x ULN  
- 
ALT or AST > 5 x ULN for > 2 weeks 
- 
ALT or AST > 3 x ULN AND (total bilirubin > 2 x ULN OR INR > 1.5) 
- 
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash and/or eosinophilia (> 5%) 
Other 
• 
Treatment delay > 2 weeks or dose reduction requirement for initiating cycle 2. 
**Note: All patients with these liver test abnormalities should be monitored weekly until all abnormalities 
return to normal or to the baseline state. For patients with isolated total bilirubin increases >2 x ULN or 2 x 
baseline (if elevated at baseline), monitoring should be every 2 weeks until bilirubin returns to normal or to 
the baseline state. Drug induced liver injury (DILI) may develop or progress even after the causative drug 


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has been stopped. Results should be recorded on the CRF and in the database. See guidelines on the 
handling of these events (potential Hy’s law cases) 
MTD (recommended phase II dose) Definition 
The MTD is defined as the dose immediately preceding the DL at which DLTs are observed in ≥ 2 out of 3 
to 6 patients; i.e., the DL at which 0 of 3 patients or ≤ 1 of 6 patients experience DLT. The MTD will be 
determined in each of the two regimens evaluated. 
Expansion Part  
Once the MTD is established for each regimen with at least 3 patients having received at least 2 evaluable 
cycles of study drug, the study will be extended with the inclusion of 10 evaluable patients per indication at 
the MTD. The regimen used in each expansion cohort (i.e., each indication) will be decided by the SMC. 
Prophylactic and Concomitant Medications  
• 
No premedication is planned. 
• 
During the study, patients must not receive other investigational drugs, agents or devices, or any other 
therapy for cancer treatment.  
• 
Drugs given with prophylactic intent are not permitted during cycle 1. 
• 
Patients requiring biphosphonates or denosumab therapy must have been on stable doses for at least 4 
weeks prior to study entry. Bisphosphonates or denosumab are permitted from cycle 3. 
• 
Use of anticoagulants (e.g. warfarin, heparin) at curative therapeutic levels within 7 days prior to the 
study treatment start is not allowed. Preventive low-dose LMWH or antivitamin K (INR < 3) are 
permitted. INR must be monitored in accordance with local institutional practices. 
• 
For prostate cancer patients, concomitant androgen deprivation therapy with GnRH analogue or 
antagonist is mandatory unless the patient had previous bilateral orchiectomy as part of his hormone 
therapy.  
• 
All other medication necessary for the well-being of the patient and which is not expected to interfere 
with evaluation of the study drug may be given at the investigator’s discretion. 
• 
Use of strong CYP3A4 interfering drugs/substances is not permitted. The concomitant use of other 
CYP3A4 interfering drugs or any CYP2A6 interfering drug is allowed provided a careful follow-up of 
laboratory results that may be influenced by the concomitant agent is performed (e.g. INR if the 
concomitant agent is an anticoagulant, blood cell counts if the concomitant drug is hematotoxic must be 
followed up more frequently than required by the protocol)(Appendix 3).  
Treatment Adaptation  
OTX015/MK-8628 will be interrupted until recovery to ≤ grade 1 or baseline value and the dose reduced or 
the schedule modified in the event of: 
Hematologic toxicity 
• 
Any grade 4 hematologic toxicity or febrile neutropenia 
• 
Grade 3 neutropenia with infection 
• 
Grade 3 thrombocytopenia with bleeding or lasting > 7 days 
Non-hematologic toxicity 
• 
Any grade 3 or 4 non-hematologic toxicity (regardless of duration) unless it was not optimally managed 
with supportive care (e.g. grade 3 vomiting not adequately treated according to antiemetic standard of 
care). 
• 
Any grade 3 or 4 laboratory abnormality, with or without symptoms, lasting > 48 hours. 
• 
Any intolerable grade 2 non-hematologic toxicity resulting in study drug discontinuation or delay > 7 
days with or without dose reduction. 
 
 


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No more than two dose reductions (or schedule modifications) should be implemented, unless the 
investigator thinks it in the patient’s best interests to pursue study treatment with a further dose reduction 
(an additional dose level), with the Sponsor’s agreement. 
 
Dose / Schedule Modifications: Regimen 1 
Initial OTX015 Dose  
1st Modification 
2nd Modification 
80 mg QD continuously 
80 mg QD,  
2 weeks ON/ 1 week OFF, q3w 
60 mg QD,  
2 weeks ON/1 week OFF, q3w 
100 mg QD continuously 
100 mg QD,  
2 weeks ON/1 week OFF, q3w 
80 mg QD,  
2 weeks ON/1 week OFF, q3w 
120 mg QD continuously 
120 mg QD,  
2 weeks ON/1 week OFF, q3w 
100 mg QD,  
2 weeks ON/1 week OFF, q3w 
160 mg QD continuously 
160 mg QD,  
2 weeks ON/1 week OFF, q3w 
120 mg QD,  
2 weeks ON/1 week OFF, q3w 
 
 
Dose / Schedule Modifications: Regimen 2 
Initial OTX015 Dose  
1st Modification 
2nd Modification 
100 mg QD, Days 1-7, q3w 
80 QD, Days 1-7, q3w 
60 QD, Days 1-7, q3w 
120 mg QD, Days 1-7, q3w  
100 mg QD, Days 1-7, q3w 
80 QD, Days 1-7, q3w 
160 mg QD, Days 1-7, q3w  
120 mg QD, Days 1-7, q3w 
100 mg QD, Days 1-7, q3w 
200 mg QD, Days 1-7, q3w  
160 QD, Days 1-7 q3w 
120 mg QD, Days 1-7, q3w 
Dosing interruption for > 2 weeks due to toxicity or liver toxicity (see treatment duration for details) will 
lead to definitive study treatment discontinuation unless the investigator thinks it is in the patient’s best 
interests to pursue study treatment, with the Sponsor’s agreement. 
Safety Monitoring Committee 
An SMC is responsible for making final decisions on stopping dose escalation, further dose escalation, 
determining the RD and starting cohort expansion enrollment. According to the nature, suspected 
relationship to study drug, or other clinical considerations, the SMC will make ad-hoc decisions, such as 
replacing non-evaluable patients, adding more patients at the same DL, adding intermediate DLs, exploring 
additional doses and/or regimens (e.g., if the MTD is not reached at the highest dose), not considering a 
given DLT as clinically relevant for the determination of the RD, progressing with the dose expansion part, 
and the regimen to be followed in each indication in the expansion part of the study. Serial assessments of 
PK results may be taken into account for the determination of the MTD. 
The SMC will be composed of the principal investigators of each participating center, the pharmacokinetics 
specialist, the medical and safety representatives of the Sponsor, and an independent medical expert in 
oncology drug development. All decisions made by the SMC and their rationale will be recorded in meeting 
minutes. 
Duration of Treatment (per patient) 
Treatment will be continued until: 
• Disease progression 
• Unacceptable toxicity 
• Patient withdrawal of consent 
• Patient non-compliance 
• Treatment interruption > 2 weeks for any reason (except in the event of perceived benefit, with Sponsor 
agreement) 


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• Recurrence of DLT despite dose reduction (except in the event of perceived benefit, with Sponsor 
agreement) 
• 
Any of the following liver test abnormalities** (see Appendix 5) 
- 
ALT or AST > 8 x ULN  
- 
ALT or AST > 5 x ULN for > 2 weeks 
- 
ALT or AST > 3 x ULN AND (total bilirubin > 2 x ULN OR INR > 1.5)  
- 
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash and/or eosinophilia (> 5%) 
 
Duration of Observation  
Patients are to be followed up for safety for at least 30 days following the last OTX015/MK-8628 dosing 
and until recovery or stabilization of all related toxicities. Tumor measurements are to be made every 6 
weeks and bone scans will be performed every 12 weeks until progressive disease is observed.  
Treatment Compliance 
Patients will record daily in a diary, the number of OTX015/MK-8628 capsules swallowed, time of intake, 
as well as any eventual reactions, including vomiting, and their time of occurrence. At each study visit the 
hospital pharmacist of the study center will provide the patient with the necessary number of OTX015/MK-
8628 capsules until the next visit and retrieve any unused capsules/vials that will be kept until study end for 
accountability. 
ASSESSMENTS 
Activity 
Disease assessments (RECIST version 1.1 or PCWG2) will be made at baseline (within 4 weeks prior to 
treatment start). Tumor measurements (using the same method as at baseline) will be made every 2 cycles 
(q6w) and bone scans every 4 cycles (q12w) until progression. Objective responses must be confirmed at 
least 4 weeks after first documentation. PCWG2 criteria will be used for CRPC patients.  
Safety  
Adverse events will be evaluated throughout the study and graded according to the NCI-CTCAE v4.03. A 
physical examination will be performed and vital signs evaluated before each cycle. Hematology laboratory 
values will be assessed twice weekly for the first 2 cycles and weekly thereafter, and biochemistry 
laboratory values will be assessed weekly for the first 2 cycles and every cycle thereafter.  
Pharmacokinetics  
Pharmacokinetic variables reflecting serum OTX015/MK-8628 exposure will be evaluated in the dose 
escalation part of the study and in selected patients from the expansion cohort. Six blood samples will be 
drawn over the first 7 hours of day 1 of cycle 1, T0 (immediately before OTX015/MK-8628 intake), 
T15min (±5 min), T1h (±15min), T2h (±15min), T3h (±15min), T7h (±15min) post-dose. 
EVALUATION CRITERIA 
Evaluation Populations  
Evaluable for DLT: patients who receive at least 85% of the planned dose of study drug (18 days for 
Regimen 1, or 6 days for Regimen 2) or experience DLT during the first 21-day cycle. 
Treated population: patients who receive at least one dose of study drug. 
Evaluable for efficacy: patients who receive at least 2 complete cycles (6 weeks) of treatment and have 
undergone baseline assessment and one on-study tumor assessment, or who discontinue early due to disease 
progression. 
 


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Endpoints  
Primary: The number of patients experiencing at least one DLT in cycle 1 (day 1 to 21) for each of the two 
regimens independently. 
Secondary: 
Safety: Incidence, severity and relationship of AEs, laboratory abnormalities, SAEs, discontinuations due to 
AEs, dose adaptations due to AEs, and DLT. 
Efficacy: The number of patients with clinical benefit (defined as complete response, partial response or 
stable disease) and progressive disease based on the best overall response from tumor evaluations performed 
every 2 cycles, according to RECIST v1.1 or PCWG2, and tumor marker assessment. 
Pharmacokinetics: Plasma parameters of OTX015/MK-8628 including Cmax, Cmin, Tmax, AUC [0-∞], Vdss, t1/2, 
CL. 
Statistical Methods  
The dose escalation part of the study is designed to assess the safety of OTX015/MK-8628 in this patient 
population. The small numbers per cohort are not intended for statistical hypotheses. Treatment decisions 
will be made by the SMC.  
The expansion cohort part will start once the MTD and a regimen are determined. Ten patients will be 
enrolled per indication to give a total of 50 evaluable patients for efficacy.  
Quantitative variables will be summarized using descriptive statistics. Continuous variables will be 
presented as N, mean and/or median, standard deviation, range. Categorical variables will be presented 
using frequencies and percentage. 
Patient disposition and demographics will be analyzed in all included patients, response will be analyzed in 
patients evaluable for efficacy, and safety will be analyzed in the treated population with an additional 
analysis in patients evaluable for DLT for the dose escalation part. 
Data will be analyzed according to dose level and regimen for the dose escalation part of the study, and 
according to indication and/or regimen for the dose expansion part of the study. 
Total Number of Patients  
Dose escalation part: 
Up to 48 patients evaluable for DLT (i.e. up to 24 patients per regimen) will be accrued depending on the 
number of DLTs encountered. The final sample size will depend on the number of DLTs encountered at 
each DL, and may be increased if within the two proposed regimens and four planned DLs, MTD is not 
reached and additional DLs are required. 
Expansion cohort part: 
Once the MTD is established with at least 3 patients having received at least 2 cycles of study drug, an 
expansion cohort of up to 50 additional evaluable patients (10 patients per indication) will be enrolled. The 
regimen used in the expansion cohort will be decided for each indication by the SMC. 
 


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STUDY SCHEDULE 
Parameter 
Pre-study 
visit 
(≤2 weeks 
before 
treatment) 
Day 1    visit 
every 
cycle 
Twice a 
week 
cycles 1+ 2,
then 
weekly 
Weekly  
cycles 
1+ 2 
Day 1 
visit of 
C3, C5,   
C7 etc. 
Treatment  
discontinuation 
visit (35±5 days) 
after last 
treatment intake 
Informed consent 
X 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
Demographics, medical history 
X 
 
 
 
 
 
Diagnosis, prior treatment for malignancy 
X 
 
 
 
 
 
Physical examination, PS, vital signs1  
X1 
X 
 
 
 
X 
Pregnancy test if child-bearing potential 
(urine test) 
X 
 
 
 
 
 
Baseline symptoms and complaints 
X 
 
 
 
 
 
Concomitant medication  
X 
X 
 
 
 
X 
Complete blood count (CBC)2  
X 
X 
X 
 
 
X 
INR and Factor VII 
X 
X 
 
X 
 
X 
Serum chemistries3 
X 
X3 
 
X3 
 
X 
Drug dispensation 
 
 
 
 
 
 
 
Regimen 1 
 
QD 
continuous 
 
 
 
 
 
Regimen 2 
 
Days 1-7  
q3w 
 
 
 
 
Adverse events 
 
X 
 
 
 
X 
CT, MRI, chest X-ray (PA and lateral),  
bone scan 
X4 
 
 
 
X4 
X 
Tumor markers5 
X 
X 
 
 
 
X 
PK blood sampling 
 
X6 
 
 
 
 
Other investigations as indicated  
X 
X 
 
X 
 
X 
1) Vital signs include temperature, blood pressure, and pulse; Body weight at each visit and height at baseline only; 
2) Hemoglobin, RBC counts, WBC and differential, platelet counts; 
3) Minimum: Na, K, Ca, Mg, P, Cl, HCO3, creatinine, total protein, albumin, glucose, alkaline phosphatase, total bilirubin, AST, 
ALT, LDH; from cycle 3 on, in the absence of ≥ grade 2 abnormalities, these tests will be performed every cycle, otherwise they 
are to be done weekly until resolution to baseline levels or < grade 2. All patients with specific liver test abnormalities (see DLT 
definition) should be monitored weekly until all abnormalities return to normal or to the baseline state. For patients with isolated 
total bilirubin increases >2 x ULN or 2 x baseline (if elevated at baseline), monitoring should be every 2 weeks until bilirubin 
returns to normal or to the baseline state; 
4) Radiologic exams (CT, MRI, chest X-ray) performed as part of the patient’s standard follow-up within 4 weeks prior to the first 
treatment cycle, are acceptable. Radiologic assessment will be performed every 2 cycles (6 weeks) as per RECIST 1.1 or PCWG2 
until progression; Bone scans are mandatory in CRPC patients and will be performed every 4 cycles (12 weeks) until progression; 
5) As appropriate for tumor type;  
6) Pharmacokinetics will be performed in cycle 1 only, during the dose escalation part of the study and in selected patients from the 
expansion cohorts: T0 (just before OTX015/MK-8628 intake), then T15min (±5 min), T1h (±15min), T2h (±15min), T3h 
(±15min), and T7h (±15min) post-dose.  
 


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ABBREVIATIONS AND DEFINITIONS 
AE 
Adverse Event 
AL 
Acute Leukemia 
ALK 
Anaplastic Lymphoma Kinase 
ALT 
Alanine Aminotransferase 
ALL 
Acute Lymphoblastic Leukemia 
AML 
Acute Myeloid Leukemia 
ALP 
Alkaline Phosphatase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under The Plasma Concentration Versus Time Curve 
BC 
Breast Cancer 
BET 
Bromodomain and Extraterminal 
BID 
Twice Daily 
BRD 
Bromodomain 
BRDT 
BRD Testis-Specific Protein 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CL 
Total Plasma Clearance 
Cmax  
Peak Concentration  
Cmin 
Residual Concentration 
CNS 
Central Nervous System 
CT-scan 
Computerized Tomography scan 
CR 
Complete Response 
CRPC 
Castrate-Resistant Prostate Cancer 
DCF 
Data Correction Form 
DILI 
Drug Induced Liver Injury 
DL 
Dose Level 
DLT 
Dose Limiting Toxicity 
ECI 
Events of Clinical Interest 
eCRF 
Electronic Case Report Form 
EML4 
Echinoderm Microtubule-Associated Protein-Like 4 
ER 
Estrogen Receptor 
FISH 
Fluorescence In Situ Hybridization 
GnRH 
Gonadotropin Releasing Hormone 
Hb 
Hemoglobin 
HER2 
Human Epidermal Growth Factor Receptor 2 
IEC 
Independent Ethics Committee 
ICF 
Informed Consent Form 
IHC 
Immunohistochemistry 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 


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KRAS 
Kirsten Ras 
LDH 
Lactate Dehydrogenase 
LMWH 
Low Molecular Weight Heparin 
MRI 
Magnetic Resonance Imaging  
MTD 
Maximum Tolerated Dose 
NCI-CTCAE 
National Cancer Institute -Common Toxicity Criteria for Adverse Events 
NMC 
NUT Midline Carcinoma 
NSCLC 
Non-Small Cell Lung Cancer 
NUT 
Nuclear Protein in Testis 
OHM 
Other Hematologic Malignancies 
OS 
Overall Survival 
PCWG2 
Prostate Cancer Clinical Trials Working Group 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PgR 
Progesterone Receptor 
PIL 
Patient Information Leaflet 
PK 
Pharmacokinetics 
PR 
Partial Response 
PS 
Performance Status 
P-TEFb 
Positive Transcription Elongation Factor b 
QD 
Once Daily 
RBC 
Red Blood Cells 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious Adverse Event 
SAERF 
Serious Adverse Event Report Form 
SAR 
Suspected Adverse Reaction 
SCC 
Squamous Cell Carcinoma 
SD 
Stable Disease 
SMC 
Safety Monitoring Committee 
SUSAR 
Serious, Unexpected Suspected Adverse Reaction 
t1/2 
Terminal Half-Life 
TEAE 
Treatment Emergent Adverse Event 
Tmax 
Time to Peak Concentration 
TNBC 
Triple-Negative Breast Cancer 
ULN 
Upper Limit of Normal 
UPN 
Unique Patient Number 
UPLC-MS/MS 
Ultra Performance Liquid Chromatography, with tandem Mass Spectrometry  
Vdss 
Volume of Distribution At Steady State 
WBC 
White Blood Cell 
 


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Page 18 
1 
BACKGROUND 
1.1 
Bromodomain and Extraterminal (BET) Protein Inhibition 
In cancer, pathologic activation of c-MYC plays a central role in disease pathogenesis, by the coordinated 
upregulation of a transcriptional program influencing cell division, metastatic adaptation and survival 
(Dang et al., 2009)(Kim et al., 2008). Amplification of MYC is one of the most common genetic 
alterations observed in cancer genomes (Beroukhim et al., 2010), and the validation of c-MYC as 
therapeutic target is supported by numerous lines of experimental evidence (Stewart et al., 1984)(Leder et 
al., 1986)(Harris et al., 1988)(Soucek et al., 2002)(Jain et al., 2002)(Fukazawa et al., 2010). Nevertheless, 
despite the central importance of MYC in cancer pathogenesis, conventional approaches toward its direct 
inhibition have not proven successful. The absence of a clear ligand-binding domain is a formidable 
obstacle to direct inhibition, a challenging feature shared by many compelling transcriptional targets in 
cancer (Darnell, 2002). Considering chromatin as a platform for signal transduction (Schreiber and 
Bernstein, 2002), the inhibition of MYC transcription and function has been achieved through 
displacement of chromatin-binding, co-activator proteins, the bromodomains (BRD), using competitive 
small molecules (Delmore et al., 2011). 
BRDs are protein interaction modules that specifically recognize Ɛ-N-acetylated lysine residues (Mujtaba 
et al., 2002)(Filippakopoulos et al., 2012). BRDs are common in nuclear proteins that regulate gene 
transcription and chromatin organization and play a key function of recruiting these protein complexes to 
acetylated chromatin. Dysfunction of BRD-containing proteins has been linked to the development of 
diverse diseases, and in particular to the development of cancer (Muller et al., 2011). BRDs are highly 
sequence diverse but share a conserved fold comprised of a left-handed bundle of four alpha helices (αZ, 
αA, αB, αC) (Dhalluin et al., 1999). The acetyl-lysine side chain is typically anchored by a hydrogen bond 
to a conserved asparagine residue and has water-mediated interactions with a conserved tyrosine 
(Filippakopoulos et al., 2012)(Owen et al., 2000). Crystal structures of BET complexes with di-acetylated 
histone 4-tail peptides showed that the first BRDs of BRD4 and BRDT may accommodate two acetyl-
lysines in a single site (Filippakopoulos et al., 2012)(Morinière et al., 2009).  
The BET family of BRD proteins, which includes BRD2, BRD3, BRD4, and BRD testis-specific protein 
(BRDT), are epigenetic reader proteins that bind acetylated lysine residues on histones playing critical 
roles in cellular proliferation and cell-cycle progression (Dey et al., 2009). BRD4 binds to the positive 
transcription elongation factor b (P-TEFb), a cyclin-dependent kinase, and stimulates RNA polymerase II-
dependent elongation (Yang et al., 2005)(Jang et al., 2005). BRD4 is critical for survival of several diverse 
tumors due to its function promoting transcription of growth-promoting and anti-apoptotic genes 
(Filippakopoulos et al., 2010), which has prompted the development of potent and selective protein 
interaction inhibitors targeting BET BRDs. 
The biological action of BET proteins occurs through a protein-protein interaction (BET protein binding to 
an acetylated histone protein) and, as such, this biochemical activity has historically possessed poor 
tractability for small molecule drug discovery identification. The identification by Chung and colleagues 
(Chung et al., 2011) of potent, selective BET inhibitors was not the result an oncology drug discovery 
effort to “drug” the BRD4 protein to target NMC, but rather was fortuitous, being the result a high-
throughput screen to identify molecules for potential use in atherosclerosis (apolipoprotein A1 
upregulation). In independent studies during the same time period, Mitsubishi Tanabe scientists reported 
the discovery and development of thienotriazolodiazepine as a BET inhibitor (including OTX015) 
[Mitsubishi Tanabe Pharma Corporation. Antitumor agent. WO 2009084693; 2009]. Building on these 
findings, Bradner and colleagues synthesized a thienotriazolodiazepine, JQ1(Filippakopoulos et al., 2010). 
The initial presumption of low tractability of the BET proteins has proven not to be the case, as multiple 


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researchers have identified other potent, selective BET inhibitors with substantially different chemical 
structures (Filippakopoulos et al., 2010)(Nicodeme et al., 2010)(Dawson et al., 2011)(Picaud et al., 2013). 
The crystal structures of these small molecule inhibitors bound to BRD4 illustrate that the binding pocket, 
which also binds acetyl-lysine, is small, deep, and hydrophobic. 
1.2 
Overview of Solid Tumor Indications 
1.2.1 
BRD-NUT Midline Carcinoma 
NUT midline carcinoma (NMC) is an aggressive subtype of squamous cell carcinoma (SCC) defined by 
chromosomal rearrangement of the gene nuclear protein in testis (NUT). In the most cases, NUT (nuclear 
protein in testis) on chromosome 15 is fused to BRD4 on chromosome 19 (French et al., 2008), providing 
the first indication of a link between BRDs and cancer. Human BRD4 was first identified as a result of its 
involvement in NMC. A minor NMC subset has alternative rearrangements that create BRD3-NUT fusion 
genes. These genetic rearrangements of the BRD3 and BRD4 loci in which in-frame chimeric proteins of 
the N-terminal BRDs of BRD3 or BRD4 with NUT, give rise to a uniformly fatal SCC subtype, (French, 
2012). The somatic alteration defining NMC is a t(15;19)(q14;p13.1) chromosomal translocation that 
results in a fusion protein between the BET proteins BRD3 or BRD4 and the nuclear protein NUT (French, 
2010a). 
With a median survival time of 6.7 months (Bauer et al., 2012), NMC is far more aggressive than typical 
non-cutaneous SCC. The lack of effective treatments means a diagnosis of NMC comes with substantial 
clinical challenges. NMC has no organ or tissue of origin and can occur anywhere but most commonly 
along the midline, with typical sites being the head, neck and mediastinum. However, cases arising in the 
bladder, pancreas, adrenal gland, kidney and salivary gland have been described (French, 2010b), 
challenging the notion that this is strictly a midline neoplasm. Although rare, the true incidence of NMC is 
still unknown because it is frequently confused with common forms of SCC that arise most often in the 
aero-digestive tract; NMC is still undoubtedly underdiagnosed.  
The key to the diagnosis of NMC is a high index of suspicion coupled with molecular testing. Given that 
NUT expression is restricted to the testes, the tumor can be diagnosed with virtually 100% specificity by 
immunohistochemistry (IHC) for NUT protein expression (Haack et al., 2009). Because NMC cannot be 
diagnosed by morphology alone, and occurs in many organs and across a wide range of ages (from 
neonates to the elderly), it is recommended that testing for NUT expression by IHC be performed in all 
poorly differentiated non-cutaneous carcinomas that lack glandular differentiation (French, 2014).  
The optimal treatment for patients with NMC is unclear. Although a number of therapeutic regimens have 
been used, the overall effectiveness of chemotherapy is questionable. In the series by Bauer et al., gross 
total resection was associated with improved survival, both progression-free survival (PFS) and overall 
survival (OS) (Bauer et al., 2012). Intriguingly, these tumors seem to respond well to early administration 
of radiotherapy.  
Given that the disruption of complexes containing BRD proteins is a critical facet of NMC pathogenesis 
and that that these proteins are key oncogenic drivers for this cancer (French et al., 2008), it was 
hypothesized that an agent that would block the biological activity of BRD4-NUT and/or BRD3-NUT may 
be an effective therapy for NMC. Recent laboratory studies have suggested that the NUT fusion protein 
results in aberrant histone acetylation and blockade of differentiation. Efforts have been made to develop 
targeted therapeutic approaches such as direct acting inhibitors of the BRD3 and BRD4 bromodomains. 
OTX015, an orally bioavailable small molecule inhibitor of BRD2, BRD3 and BRD4 has been shown to 
inhibit the growth of Ty82 BRD-NUT carcinoma in nude mice by 79% (Noel et al., 2013). 


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1.2.2 
Non-Small Cell Lung Cancer: KRAS Mutated and ALK Positive 
Approximately 50%-60% of NSCLC patients have at least one identifiable driver mutation, with the most 
common mutations being the Kirsten ras (KRAS) gene (24%-27%) and the epidermal growth factor 
receptor (EGFR) gene (13%-22%), with translocations involving anaplastic lymphoma kinase (ALK) in 
another 5%-6% (Sequist et al., 2011)(Gainor et al., 2013)(Kris et al., 2011). Several additional mutations 
have been identified. 
KRAS, like other RAS family of oncogenes, encodes a guanine triphosphate-binding protein involved in 
cellular growth, differentiation, and apoptosis by interacting with multiple effectors. Among NSCLC 
patients, KRAS mutations have been identified more commonly among Caucasians, smokers (26% versus 
6% of never smokers), and patients with adenocarcinoma histology (30% versus 5% with squamous cell 
carcinoma histology) (Riely et al., 2009)(Riely et al., 2008)(Mao et al., 2010)(Graziano et al., 1999). 
KRAS mutations are typically mutually exclusive of EGFR mutations, occurring in different patient 
populations (Riely et al., 2009)(Roberts et al., 2010)(Gainor et al., 2013). The presence of a KRAS 
mutation appears to have at most a limited effect on OS in patients with early stage NSCLC (Shepherd et 
al., 2013), although some older data suggested that it was with a worse prognosis (Mascaux et al., 2005). 
However, in stage IV NSCLC patients, the presence of a KRAS mutation appears to be associated with a 
worse prognosis. In a controlled phase III trial of maintenance erlotinib, KRAS mutation conferred a 
shorter time to progression than wild-type patients (HR 1.50, 95%CI: 1.06-2.12) among the 239 patients on 
the placebo arm. However, the difference in OS was not statistically significant (HR 1.30, 95% CI: 0.90-
1.90) (Brugger et al., 2011). In a retrospective series of 1036 patients, multivariate analysis demonstrated 
that the presence of a KRAS mutation was associated with a shorter OS (HR 1.21, p = 0.048), while EGFR 
mutations were associated with longer survival (HR 0.6, p <0.001) (Johnson et al., 2013). Mutant KRAS is 
a strong activator of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) 
pathways (Malumbres and Barbacid, 2003), and the inhibition of KRAS-dependent MAPK and PI3K 
pathways results in MYC dephosphorylation (Sears et al., 2000)(Pelengaris et al., 2002), which contributes 
to its degradation. Recent studies in NSCLC preclinical models report that the BET bromodomain 
inhibitor, JQ1, exerts remarkable antitumor activity in NSCLC harboring KRAS mutation but this 
sensitivity is highly influenced by LKB1 mutation status, as Kras/Lkb1 mutant models are comparatively 
more resistant. Furthermore, in vivo experiments using genetically engineered mouse lung cancer models 
confirmed that JQ1 prompts tumor regression in mutant Kras mouse lung cancers (Shimamura et al., 
2013). In the same report, sensitivity both in vitro and in vivo was found to be mediated by MYC 
downregulation.  
A subgroup of NSCLC patients have tumors containing an inversion in chromosome 2 that juxtaposes the 
5' end of the echinoderm microtubule-associated protein-like 4 (EML4) gene with the 3' end of the ALK 
gene, resulting in the novel fusion oncogene EML4-ALK (Shaw and Solomon, 2011). This fusion 
oncogene rearrangement is transforming both in vitro and in vivo and defines a distinct clinicopathologic 
subset of NSCLC. 
Tumors that contain the EML4-ALK fusion oncogene or its variants are associated with specific clinical 
features, including never or light (<10 packet years) smoking history, younger age, and adenocarcinoma 
with signet ring or acinar histology. ALK gene arrangements are largely mutually exclusive with EGFR or 
KRAS mutations (Takahashi et al., 2010). Screening for this fusion gene in NSCLC is important, as "ALK-
positive" tumors (tumors harboring a rearranged ALK gene/fusion protein) are highly sensitive to therapy 
with ALK-targeted inhibitors. The oncogenic role of the ALK fusion oncogene provides a potential avenue 
for therapeutic intervention. Cancer cell lines harboring the EML4-ALK translocation are effectively 
inhibited by small molecule inhibitors that target the ALK tyrosine kinase (Koivunen et al., 2008). In vivo, 
treatment of EML4-ALK transgenic mice with ALK inhibitors results in tumor regression (Soda et al., 


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2008), supporting the notion that ALK-driven lung cancers are "addicted" to the fusion oncogene. ALK 
gene rearrangements or the resulting fusion proteins may be detected in tumor specimens using 
fluorescence in situ hybridization (FISH), IHC, and reverse transcription polymerase chain reaction of 
cDNA (Weickhardt et al., 2013). Nevertheless, the gold standard assay for diagnosing ALK-positive 
NSCLC is FISH, the only approved test to diagnose ALK positive tumors (Martelli et al., 2009)(Boland et 
al., 2009)(Shaw et al., 2009)(Perner et al., 2008) while IHC is widely used in Europe to detect ALK 
rearrangement. 
ALK-rearranged tumors depend on ALK for growth and survival and show marked sensitivity to ALK 
inhibitors such as crizotinib. Among patients with advanced ALK-rearranged NSCLC, crizotinib has been 
associated with response rates of approximately 60% across multiple studies and a median PFS of 8 to 10 
months (Camidge et al., 2012)(Shaw et al., 2013). Despite initial response to crizotinib, the majority of 
patients relapse within 12 months, with the development of resistance (Katayama et al., 2012)(Doebele et 
al., 2012). Approximately one-third of patients with ALK-rearranged NSCLC relapse due to an acquired 
mutation within the ALK tyrosine kinase domain or amplification of the ALK fusion gene. In the remaining 
resistant cases, the ALK fusion gene is unchanged, and a variety of resistance mechanisms have been 
reported (Katayama et al., 2012)(Doebele et al., 2012)(Shaw et al., 2013).Treatment options after the 
failure of crizotinib are limited and include cytotoxic chemotherapy, palliative radiotherapy, and 
supportive care. 
A recent preclinical report indicates that OTX015 is broadly active in both EMLA4-ALK positive and 
negative NSCLC cell lines, and its sensitivity is not correlated to basal levels of BRDs, c-MYC, N-MYC, 
BCL2 or p21 (Vazquez et al., 2014). In sensitive NSCLC cell lines, OTX015 results in a rapid and 
sustained downregulation of c-MYC or N-MYC. In addition, OTX015 exhibits in vitro additive activity 
when combined with crizotinib in ALK positive NSCLC cell lines. 
1.2.3 
Triple Negative Breast Cancer 
Triple negative breast cancer (TNBC) is a distinct subset of breast cancer defined by the lack of IHC 
expression of the estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor 
receptor 2 (HER2), accounting for approximately 15%-20% of breast cancer patients. According to the 
ASCO guideline recommendations, breast cancer is considered negative for ER or PgR if less than 1% of 
tumor cell nuclei are immunoreactive (Hammond et al., 2010), and negative for HER2 if either the IHC 
score is 0 or 1+, or FISH average gene copy < 4 signals per cell nucleus (Wolff et al., 2007). 
TNBC terminology is confusing since it reflects a heterogeneous population (Lehmann et al., 2011) with a 
more complex molecular transcriptome than is suggested by the triple-negative IHC expression. 
Classification of breast tumors by their gene expression signature revealed distinct subtypes with important 
implications for outcome (Sørlie et al., 2001)(Hu et al., 2006). Of these subtypes, which include HER2-
enriched, luminal A, luminal B, and basal-like breast cancer, the latter has the poorest prognosis (Perou, 
2011). Gene expression analysis demonstrates that the molecular signature of TNBC generally overlaps 
with basal-like breast cancer, with concordance rates of 70%-90% (Nielsen et al., 2004)(Kreike et al., 
2007). However, not all TNBC can be defined as basal-like breast cancer (Perou, 2011)(Prat and Perou, 
2011), as a small minority of BLBC patients do in fact, have some ER and HER2 expression. TNBC is also 
associated with BRCA-related breast cancer, although the incidence of BRCA mutations in TNBC varies 
from 16% to 42% (Atchley et al., 2008)(Gonzalez-Angulo et al., 2011). Other mechanisms resulting in 
downregulation of BRCA1/2, including epigenetic alterations and overexpression of BRCA1 inhibitors 
(Turner et al., 2004)(Miyoshi et al., 2008)(Abd El-Rehim et al., 2005)(Turner et al., 2007), are also 
associated with TNBC and likely contribute to aneuploidy and genomic instability characteristics of this 
subgroup.  


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Chemotherapy remains the core option for TNBC patients. However, treatment with cytotoxic 
chemotherapy produces mixed results and has a variable impact on long-term prognosis (Haffty et al., 
2006)(Kassam et al., 2009)(Onitilo et al., 2009)(Foulkes et al., 2010). In the neoadjuvant setting, TNBC 
exhibits a better response to chemotherapy compared with non-TNBC (Liedtke et al., 2008). Patients who 
do not respond well to preoperative chemotherapy have a high risk of relapse within the first 2 years and 
worse OS (3-year survival, 68% versus 94% pathological complete response non-responders versus 
responders) (Haffty et al., 2006)(Dent et al., 2007)(Carey et al., 2006)(Bauer et al., 2007)(Millikan et al., 
2008)(Liedtke et al., 2008).  
Metastatic TNBC is an aggressive disease that is associated with a high proliferation index (Hugh et al., 
2009), visceral and CNS metastases (Liedtke et al., 2008)(Smid et al., 2008)(Heitz et al., 2009), and poor 
outcome despite treatment. Median survival of advanced TNBC is at best 12 months (Gelmon et al., 2012), 
much shorter than the duration of survival seen in other subtypes of advanced breast cancer. The most 
dramatic improvements in survival are associated with targeted therapy. However, TNBC trials of targeted 
therapy as single agents or in combination with chemotherapy, despite a strong biological rationale in 
many cases, have been less promising, resulting in modest gains in PFS and no gains in OS (Gelmon et al., 
2012). Retrospective evaluations of anti-angiogenic agents have demonstrated encouraging efficacy signals 
in TNBC, with a doubling of PFS in select trials (O’Shaughnessy et al., 2009)(Brufsky et al., 
2012)(O’Shaughnessy et al., 2010)(Miller et al., 2007). However, PFS gains remain modest (∼3 months) 
(Brufsky et al., 2012)(O’Shaughnessy et al., 2010). Therefore, identification of more active therapies for 
TNBC patients remains an important clinical challenge. 
MYC expression was found to be disproportionally elevated in TNBC, and in primary tumors, MYC 
signaling did not predict response to neoadjuvant conventional chemotherapy but was associated with 
shortened disease-free survival (Horiuchi et al., 2012). Furthermore, a recent report on TNBC indicates 
that the interaction with BRD4 is critical for the oncogenic function of Twist, a key activator of epithelial-
mesenchymal transition. In addition, pharmacologic inhibition of the Twist-BRD4 association reduces 
invasion, cancer stem cell-like properties, and tumorigenicity of TNBC cells (Shi et al., 2014). 
1.2.4 
Castrate-Resistant Prostate Adenocarcinoma 
Patients who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the 
disease. Progression to CRPC after androgen deprivation therapy is predominantly driven by deregulated 
androgen receptor (AR) signaling (Taylor et al., 2010)(Chen et al., 2004)(Visakorpi et al., 1995). 
Maintenance of AR signaling is the most common resistance mechanism that patients with advanced 
prostate cancer develop after conventional hormone treatments (Harris et al., 2009). AR amplification, 
mutation and alternative splicing have all been suggested as potential resistance mechanisms to anti-
androgen treatments (Chen et al., 2004)(Taplin et al., 1999)(Sun et al., 2010). Over one half of CRPC 
patients have at least one of these aberrations in the AR pathway (Grasso et al., 2012). 
Despite the success of recently approved therapies targeting AR signaling, such as abiraterone (Stein et al., 
2012)(Reid et al., 2010)(de Bono et al., 2011) and second-generation anti-androgen therapy including 
enzalutamide (Mukherji et al., 2012)(Scher et al., 2012), durable responses are limited, presumably owing 
to acquired resistance.  
Recent preclinical studies showed that AR-signaling-competent human CRPC cell lines are preferentially 
sensitive to BET bromodomain inhibition (Asangani et al., 2014). BRD4 physically interacts with the N-
terminal domain of the AR and can be disrupted by the BET inhibitor JQ1 (Delmore et al., 
2011)(Filippakopoulos et al., 2010). Like the direct AR antagonist enzalutamide, JQ1 disrupted AR 
recruitment to target gene loci. By contrast with enzalutamide, JQ1 functions downstream of AR, and more 
potently abrogated BRD4 localization to AR target loci and AR-mediated gene transcription, including 


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induction of the TMPRSS2-ERG gene fusion and its oncogenic activity (Asangani et al., 2014). 
Furthermore, in vivo, BET bromodomain inhibition was found to be more efficacious than direct AR 
antagonism in CRPC xenograft mouse models. As BET inhibitors function downstream of AR, these 
compounds may be effective in the context of AR-mediated resistance, including compensatory 
mechanisms involving related steroid hormone receptors that are also likely to require BET bromodomain 
functioning. 
1.2.5 
Pancreatic Ductal Carcinoma 
Pancreatic ductal adenocarcinoma (PDAC) continues to be the leading cause of cancer-related death, in 
part due to limited efficacy of conventional chemotherapy and few therapeutic options. As such, there is a 
strong interest in developing inhibitors targeting epigenetic changes, such as targeting BET proteins that 
bind acetylated histones to regulate gene transcription. Treatment with BET inhibitors decreases PDAC 
cell growth in collagen (Sahai et al., 2014). Transfection with siRNA against BRD4, which is increased in 
human PDAC tumors, also decreased PDAC cell growth. Interestingly, BET inhibitors additionally 
decreased growth in collagen of PDAC cells that have undergone epithelial-to-mesenchymal transition or 
have become resistant to chemotherapy. 
1.3 
Development of OTX015 
1.3.1 
Description of OTX015  
OTX015 is a synthetic small molecule targeted to bromodomains (BRD) 2, 3 and 4 of the tandem-BRD-
containing family of transcriptional regulators known as the BET (bromodomain and extraterminal) 
proteins. The structure is summarized below: 
Chemical name: 
2-[(6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a] 
[1,4]diazepin-6-yl]-N-(4-hydroxyphenyl)acetamide dihydrate 
I.N.N.:  
Not yet issued 
Molecular mass: 
528.02 
Molecular formula: 
C25H22ClN5O2S • 2H2O 
Structural formula: 
 
OTX015 is provided as size 3 gelatin capsules containing 10 or 20 mg OTX015 (free base) or size 0 gelatin 
capsules containing 40 mg OTX015 (free base) as a solid molecular dispersion with hypromellose acetate 
succinate (HPMCAS), mixed with lactose monohydrate, microcrystalline cellulose, croscarmellose 
sodium, colloidal silicone dioxide, and magnesium stearate excipients. 


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1.3.2 
Preclinical Data  
1.3.2.1 
Pharmacology 
In vitro pharmacodynamic studies showed that OTX015 interacts directly with the BET bromodomain 
proteins BRD2, 3, and 4 with EC50 values ranging from 10 to 19 nM. Competitive inhibition by OTX015 
inhibited binding of BRD 2, 3, and 4 to acetylated histone A4 with IC50 values ranging from 92 to 112 
nM. 
Given the IC50 ~100 nM for OTX015 inhibition of BRD2/3/4 binding to acetylated histone A4, human 
tumor cell lines were considered to be sensitive to OTX015 if the GI50 was ≤500 nM, as assessed by MTT 
assays after 72 hours exposure. By these criteria, a wide variety of hematologic malignancy cell lines were 
sensitive to OTX015, including 4/4 acute lymphoblastic leukemia (ALL) lines, 2/5 acute myeloid leukemia 
(AML) lines, 15/23 diffuse large B-cell lymphoma (DLBCL) lines, 3/3 splenic marginal zone lymphoma 
lines, 7/8 anaplastic large T-cell lymphoma (ALCL) lines, and 7/8 multiple myeloma lines; only mantle 
cell lines were resistant to OTX015 (0/3). Most solid tumor lines were not sensitive to OTX015, though 
hepatocellular carcinoma (4/5 lines), medulloblastoma (4/4 lines), neuroblastoma (3/4 lines), and ovarian 
cancer (3/3 lines) were, and the Ty82 midline carcinoma cell line with a BRD-NUT fusion was highly 
sensitive (GI50 = 40 nM). 
Treatment with 500 nM OTX015 induced G1 arrest and apoptosis in leukemia and multiple myeloma cells 
lines as well as patient-derived primary leukemia and multiple myeloma cells and in a subgroup of ABC-
DLBCL lines with mutated MYD88 gene and wild type p53. In other lymphoma lines, OTX015 treatment 
resulted in G1 arrest and induction of senescence. 
Most sensitive cell lines showed downregulation of MYC mRNA as well as putative MYC target genes 
(CAD, NUC, NPM-ALK). Downregulation was observed after only 1 hour exposure, but recovered within 
2 hours after washout. 
In selected DLBCL and leukemia cell lines, synergistic or additive effects on cell proliferation were 
observed when OTX015 was combined with both targeted agents (mTOR inhibitor, BTK inhibitor, HDAC 
inhibitor, hypomethylating agent, immunomodulator, anti-CD20 monoclonal antibody) and standard 
chemotherapy agents (bendamustine, cytarabine, daunorubicin, doxorubicin). 
In vivo, OTX015 treatment significantly inhibited tumor growth in the Ty82 midline carcinoma model with 
a BRD4-NUT fusion (79% tumor growth inhibition at 100 mg/kg/day). In the same model, the 
combination of OTX015 and docetaxel was curative. OTX015 treatment significantly prolonged OS 
compared with vehicle controls in mice bearing established IMR5/75 MYCN-amplified neuroblastoma or 
orthotopic U87MG glioblastoma xenografts. 
Safety pharmacology studies showed that OTX015 had no effects on general safety assessments at doses 
up to 10 mg/kg per os. OTX015 had no effect on hERG current at concentrations up to 580 nM and no 
effects on respiration rate, blood pressure, heart rate, and electrocardiogram in anesthetized dogs at doses 
up to 3 mg/kg intravenously. 
1.3.2.2 
Pharmacokinetics 
Pharmacokinetic measurements following administration of single intravenous doses (in 20% ethanol/20% 
PEG400) and various solid dispersion oral formulations showed that bioavailability differed with species 
(lower in rats than in dogs) and with formulation (higher for PVP and HPMCAS solid dispersions than for 
Eudragit solid dispersions). Toxicokinetic assessments following 28-day and chronic dosing of the PVP 
solid dispersion formulation to rats and dogs showed no significant difference between genders in either 
species. Although toxicokinetic analyses showed dose-proportional increases in the 4-week and 52-week 


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dog studies, more than dose-proportional increases in exposure were observed in the 4-week and 26-week 
rat studies. Likewise, while no dose accumulation was observed in the 4-week and 52-week dog studies, 
1.5- to 2-fold accumulation was observed in the 4-week and 26-week rat studies. 
Following a single oral administration of radiolabeled PVP solid dispersion formulation to rats, the highest 
levels of radioactivity were found in the stomach (and contents), small intestine (and contents), and liver. 
Excretion was predominantly via feces. 
OTX015 was ~95% bound to plasma proteins in rats, dogs, and humans. Over the concentration range 
from 30 to 300 ng/mL, the distribution ratios into blood cells ranged from 43% to 46% in rats, 29% to 33% 
in dogs, and 13% to 20% in humans. 
From consideration of the chemical structure of OTX015, the primary metabolites expected were an 
oxidized metabolite and a glucuronic acid conjugate. LC-MS/MS analysis of liver microsomes incubated 
with OTX015 in the presence of a NADPH regeneration system detected the two expected metabolites in 
all species, as well as a unique (unidentified) metabolite in humans. Following a single oral administration 
of radiolabeled OTX015:PVP solid dispersion formulation to rats, both oxidation products and the 
glucuronide conjugate were observed. Results from incubations with cytochrome P450 isoenzymes 
suggested that OTX015 is metabolized mainly by CYP3A4 and, to lesser extent, by CYP2C9. Results from 
incubations with pooled human liver microsomes suggested that OTX015 has a tendency to inhibit CYPs 
2A6 and 3A4. 
1.3.2.3 
Toxicology 
The adverse effects of OTX015 were evaluated in 4-week repeated oral dose toxicity studies in rats (dosed 
at 0, 3, 10, 30 and 60 mg/kg) and dogs (dosed at 0, 1, 3, 10, and 20 mg/kg); 26-week repeated oral dose 
toxicity studies in rats (dosed at 0, 3, 10, and 30 mg/kg); 13-week repeated oral dose toxicity studies in 
dogs (dosed at 0, 1, 3, and 10 mg/kg); and 52-week repeated oral dose toxicity studies in dogs (dosed at 0, 
0.6, 2, and 6 mg/kg). Studies were conducted using a solid dispersion of 10% or 25% OTX015:PVP, either 
suspended in water for administration to rats or combined with lactose, corn starch, crystalline cellulose, 
and calcium carmelose excipient and filled into gelatin capsules for administration to dogs. 
Considering results from the 28-day repeated dose and chronic toxicity studies, the main target organ in 
terms of toxicity is the digestive system, particularly the liver. Other organs which should be monitored are 
lymphoid tissues, hematopoietic organs, lungs, and the male reproductive organs. Briefly: 
• 
Digestive system: In both rats and dogs, clinical signs of loose stools and diarrhea were accompanied by 
histopathologic findings of mononuclear cell infiltration of the lamina propria mucosa and degeneration of 
the epithelium of the small and large intestine. In chronic toxicity studies, abnormal liver function tests 
were observed in both rats (decreased total protein and albumin) and dogs (increased ALT and AST), 
accompanied by histologic findings of pigment deposition in perilobular Kupffer cells in the livers of both 
species and cholestasis and vacuolization of the centrilobular hepatocytes in livers of dogs. Prolonged 
activated partial prothrombin time (APTT) in both species was observed after 28-day dosing in rats and 
after both 28-day and chronic dosing in dogs. 
• 
Hematopoietic system: Both rats and dogs showed decreased lymphocytes after 28-day dosing, 
accompanied by histopathologic findings of depletion of lymphocytes in the spleen and mesenteric and 
submandibular lymph nodes and myeloid hypoplasia in the bone marrow of femur and sternum. Rats 
showed decreased red blood cells after both 28-day and chronic dosing, accompanied by histopathologic 
findings of extramedullary hematopoiesis in the spleen after chronic dosing; however, the decrease in red 
blood cells (RBC) was of small magnitude and the incidence of extramedullary hematopoiesis in the spleen 
was consistent with background. 


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• 
Lungs: In rats, histopathologic exams showed intra-alveolar foamy macrophages in lungs and bronchus in 
both sexes after 28-day and chronic dosing; these resolved after 1 month in the 28-day study. 
• 
Reproductive organs in males: In male dogs, histopathologic exams showed tubular degeneration of the 
testes after both 28-day and chronic dosing and a bilateral decrease in sperm in the epididymides after 
chronic dosing. 
OTX015 showed no genotoxic effects in the standard panel of in vitro and in vivo tests. 
1.3.3 
Clinical Data 
1.3.3.1 
Healthy Volunteer Studies 
Three studies in healthy volunteers have been performed: 
• 
Study Y-803-E01 (E01 study) was a double-blind, randomized study to evaluate the safety, tolerability, 
and pharmacokinetics of single ascending oral doses of 2.5, 5, 10, 20, 40, 80, 120, and 180 mg OTX015 
compared with placebo in healthy adults; 
• 
Study Y-803-E02 (E02 study) was an open label, randomized, three-way crossover study to assess the 
bioavailability of a single oral dose of 20 mg OTX015 in healthy male subjects in a fasted state and before 
and after food, with at least a 10-day wash-out between doses; and 
• 
Study Y-803-E-04 (E04 study) was a double-blind, placebo-controlled repeat dose study to assess the 
safety, tolerability, and pharmacokinetics of OTX015 following a single oral dose and once daily oral 
doses of 10, 20, and 40 mg OTX015 for 10 days in healthy male subjects. 
For all three studies, OTX015 was supplied in capsules containing microcrystalline cellulose spheres 
coated with an ethanolic solution of OTX015, triethyl citrate, aminoalkyl methacrylate copolymer RS, and 
methacrylic acid copolymer, then spray dried and mixed with talc, magnesium aluminometasilicate, and 
light anhydrous silicic acid (Eudragit formulation). This formulation was designed to deliver OTX015 to 
the lower intestine for treatment of inflammatory bowel disease. Bioavailability studies in dogs showed 
that systemic drug levels following administration of the Eudragit formulation were about 50% of those 
obtained following administration of the solid dispersion OTX015:PVP formulation used for toxicology 
studies and the solid dispersion OTX015:HPMCAS formulation planned for use in clinical studies in 
cancer patients. 
All three healthy volunteer studies assessed safety, tolerability, and plasma and urinary pharmacokinetics 
of OTX015 and its two main metabolites, the glucuronide conjugate and an oxidation product termed M1. 
Additionally, the single dose studies assessed fecal excretion of OTX015 and the M1 metabolite. 
Following administration of single oral doses of OTX015 to fasted subjects, plasma concentrations of 
OTX015 increased slowly, reaching Cmax at a median of 4 to 6 hours; thereafter, plasma levels declined 
slowly for all dose levels, maintaining levels about 50%-60% of Cmax at 12 hours post-dose and 25% to 
30% of Cmax at 24 hours post-dose. Semi-logarithmic plasma concentration-time curves gave an apparent 
monophasic decline, with mean t1/2 ranging from 12.0 to 16.3 hours for all dose levels. The mean t1/2 and 
median Tmax were statistically constant. Exposure (Cmax, AUC0-24h, and AUC0-∞) increased in a dose 
proportional manner over the range from 2.5 to 80 mg. The mean residence time, Cl, Cl/F, and Vz/F 
ranged from 17.8 to 21.4 h, from 0.11 to 0.20 L/h, from 28.2 to 54.0 L/h, and from 477.6 to 1159.6 L, 
respectively. 
Mean plasma concentrations of the OTX015 glucuronide conjugate and the M1 metabolite were parallel to 
those of OTX015 for all dose levels. In Cmax and AUC, the OTX015 glucuronide conjugate ranged from 


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50%-73% and from 40%-64% of the OTX015 level, respectively, while the M1 metabolite ranged from 
3%-5% and from 3%-6% of the OTX015 level, respectively. 
Pharmacokinetic assessments during 10-day repeated dosing showed that steady-state was achieved after 
24 hours of dosing at each dose level. Geometric mean pre-dose (trough) plasma concentrations at steady 
state ranged from 3.9 to 4.9 ng/mL for the 10 mg dose, from 5.9 to 8.5 ng/mL for the 20 mg dose, and from 
13.6 to 22.4 ng/mL for the 40 mg dose; for each dose level the pre-dose plasma concentrations were 
constant. Statistical analysis of the first and last dose across all dose levels showed t1/2, MRT, CL/F, and 
Vz/F to be independent of dose, with no differences between the first and last dose. Interestingly, the mean 
Cmax of 52-66 ng/mL achieved with 40 mg repeated dosing was equivalent to approximately 100 nM, an 
active concentration against hematologic malignancies in in vitro experiments. 
Pharmacokinetic assessments from the food effect study showed that intake of a high-fat breakfast after 
and before administration decreased plasma OTX015 concentration: Cmax by 45% and 47%, AUC0-24h by 
35% and 38%, and AUC0-∞ by 20% and 27%, respectively, compared to the fasted state. The Tmax of 
OTX015 was prolonged by food intake after and before administration, from 6h (fasted state) to 9h and 
10h, respectively, while the MRT was constant for all dosing conditions. 
Overall, OTX015 was well tolerated. No severe or serious adverse events (AEs) were reported. The most 
frequent AEs, occurring in ≥3% of subjects receiving OTX015, were headache (17% of subjects), 
abdominal pain/discomfort (15%), diarrhea/loose stools (8%), constipation (4%), myalgia (4%), back pain 
(3%), and paresthesia (3%). With the exception of one transient moderate headache, all of these events 
were both transient and mild. The most frequent AEs among subjects receiving OTX015 also occurred 
with similar frequency among subjects receiving placebo, i.e., headache (17% of subjects), diarrhea/loose 
stools (17%), and abdominal pain/discomfort (13%), suggesting the involvement of formulation excipients 
rather than the active pharmaceutical ingredient. 
1.3.3.2 
Patients with Advanced Hematologic Malignancies 
Study OTX015_104, an open label phase I dose-finding and pharmacokinetic study in patients with 
advanced hematologic malignancies was initiated in January 2013 and is ongoing at the time of preparation 
of the current protocol. Dose escalation is being performed using a conventional 3+3 design. Cohorts of 
patients with acute leukemias (AL) and patients with other hematologic malignancies (OHM) are being 
evaluated independently for the determination of the maximum tolerated dose (MTD). Once the MTD has 
been determined, cohort expansion will be performed. 
OTX015 is supplied in size 3 gelatin capsules containing 10 or 20 mg OTX015 as a solid molecular 
dispersion of OTX015 and hypromellose acetate succinate (HPMCAS) mixed with lactose 
monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and 
magnesium stearate excipients. Bioavailability studies in dogs showed 4 to 5-fold increased 
bioavailability for this formulation compared with the Eudragit formulation used in the healthy 
volunteer studies. OTX015 is administered daily, once daily (QD) or twice daily (BID). AL patients 
receive a discontinuous schedule (14 days on, 7 days off), and OHM patients receive a continuous 
schedule. Alternative schedules are currently being evaluated. A cycle is 3-weeks.  
Dose escalation, DLT determination, cohort expansion and patient safety are assessed by a Safety 
Monitoring Committee (SMC). 
 
 


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Patient Disposition 
As of June 9, 2014, 64 patients (31 with AL and 33 with OHM) were enrolled. Amongst them 49 (26 with 
AL and 23 with OHM) were evaluable for DLT assessment at the time of the current protocol (10 non-
evaluable patients, 4 too early, and one not yet treated were not assessable for DLTs). 
Table 1: Patient disposition (N=64) in the hematologic malignancy trial 
 
Subset 
(schedule) 
Dose 
level 1 
10 mg  
QD 
Dose 
level 2 
20 mg  
QD 
Dose 
level 3 
40 mg  
QD 
Dose 
level 4 
80 mg 
 QD 
Dose 
level 4 
BID 
40 mg x2 
Dose 
level 5 
120 mg 
QD 
Dose 
level 6  
160 mg 
QD 
Total 
 
 
Patients 
enrolled 
AL (2 weeks, 
q3w) 
3 
3 
4 
3 
8 
3 
4 
 
31 
AL 
(continuously) 
0 
0 
0 
0 
0 
3 
0 
OHM 
(continuously) 
5 
3 
4 
4 
6 
7 
0 
 
 
33 
OHM (2 weeks, 
q3w) 
0 
0 
0 
0 
0 
2 
0 
OHM (5 days a 
week) 
0 
0 
0 
 
0 
2 
0 
Patients  
AL 
3 
3 
4 
3 
8 
6 
3 
30 
Treated 
OHM 
5 
3 
4 
4 
6 
11 
 
33 
Patients 
evaluable 
for DLT* 
AL 
3 
3 
3 
3 
6 
6 
2 
26 
OHM 
3 
3 
3 
3 
5 
6 
- 
23 
Patients 
with DLT 
AL 
0 
0 
0 
0 
0 
0 
2 
2 
OHM 
0 
0 
0 
0 
3 
3 
- 
6 
AL: acute leukemia; OHM: other hematologic malignancies 
*Patients receiving at least 19 of the first 21 days treatment 
Key demographic and clinical characteristics of treated patients are summarized below by dose level and 
patient subset (AL vs OHM). 
Table 2: Patient characteristics by dose level (N=64) 
Dose  
10 mg 
QD 
N=8 
20 mg 
QD 
N=6 
40 mg 
QD 
N=8 
80 mg 
QD 
N=7 
40 mg 
BID 
N=14 
120 mg 
QD 
N=17 
160 mg 
QD 
N=4 
Total 
N=64 
Median Age in years 
(range) 
67.5  
(40-79) 
68  
(32-83) 
72.5  
(62-80) 
68  
(49-73) 
64.5  
(33-85) 
65  
(19-80) 
65  
(62-75) 
68  
(19-85) 
Gender M/F 
7/1 
2/4 
4/4 
4/3 
8/6 
13/4 
4/0 
42/22 
PS 0-1/2 
6/2 
5/1 
7/1 
6/1 
12/2 
16/1 
4/0 
56/8 
Treated conditions 
AML 
3 
2 
4 
2 
8 
6 
3 
28 
ALL 
- 
1 
- 
1 
- 
- 
 
2 
HR-MDS 
- 
- 
- 
- 
- 
- 
1 
1 
DLBCL 
3 
1 
- 
2 
2 
8 
- 
16 
Lymphoma other* 
1 
- 
2 
1 
1 
3 
- 
8 
MM 
1 
2 
2 
1 
3 
- 
- 
9 
Previous systemic therapies 
Median N lines 
(range) 
3.5 (1-7) 
2.5 (1-5) 
2.5 (1-8) 
3.0 (2-5) 
3.0 (2-8) 
3.0 (1-7) 
2.5 (2-3) 
3.0 (1-8) 
ASCT/aSCT 
2/1 
0/1 
2/0 
2/0 
3/0 
1/2 
0/0 
10/4 


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ALL: acute lymphoblastic lymphoma; AML: acute myeloid leukemia; aSCT: allogeneic stem cell transplantation; ASCT: 
autologous stem cell transplantation; DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; HR-MDS: high-risk 
myelodysplastic syndrome; MM: multiple myeloma; MCL: mantle cell lymphoma; PTCL: peripheral T-cell lymphoma; PS: 
ECOG performance status 
*FL: 2; MCL: 1; PTCL (NOS): 2; lymphoplasmacytic lymphoma: 1; Burkitt’s lymphoma: 1 
 
Table 3: Patient characteristics by hematologic subset (N=64) 
Dose  
AL (N=31) 
OHM (N=33) 
Age in years, median (range) 
70 (19-85) 
67 (27-83) 
Male/female, N 
20/11 
22/11 
ECOG PS (0-1 / 2), N 
29/2 
27/6 
Treated Conditions 
AML 
28 
- 
De novo/secondary + post-therapy 
15/13 
- 
NPM1 mut/MLL 
rearrangement/EVI1+/ JAK2 mut 
6/1/0/1* 
- 
ALL 
2 
- 
HR-MDS 
1 
- 
DLBCL 
- 
16 
Other lymphomas 
- 
8 
Multiple myeloma 
- 
9 
Previous Systemic Therapies 
 
 
 
Number of lines, median (range) 
2 (1-4) 
4 (2-8) 
Auto SCT/allo SCT 
0/4 
10/0 
ALL: acute lymphoblastic lymphoma; AML: acute myeloid leukemia; HR-MDS: high-risk myelodysplastic syndrome; 
NPM1, nucleophosmin-positive,  
* Presence of JAK2 mut in AML cells unknown 
 
Dose Escalation and Schedule Adaptation 
Acute leukemia cohort 
No DLT was observed from a dose of 10 mg QD through 80 mg QD. Based on preclinical data with 
OTX015 (and published results for the OTX015 analog JQ1) suggesting a higher efficacy with a BID 
schedule and residual plasma concentrations at 24 hours, below the in vitro active concentrations in 
patients treated at 80 mg QD, it was decided to proceed to DL4 of 40 mg BID, and to allow AL patients 
who had tolerated at least one cycle of treatment with an intermittent schedule (14 days ON/7 days OFF) to 
switch to a continuous treatment schedule.  
No DLT was reported in the 6 evaluable patients enrolled and treated at DL4 of 40 mg BID. The SMC 
decided to proceed with dose escalation. Due to the potential risk of severe liver injury by doubling the 
dose, the decision was to escalated cautiously using a Fibonacci-like dose escalation model with a smaller 
dose increment using a once daily schedule rather than the BID schedule, as had already been implemented 
in the OHM patient cohort (see below). 
Three patients have been enrolled so far at DL5 120 mg QD 14/21, none of whom experienced DLT in 
Cycle 1. The SMC therefore decided to proceed to DL6 (160 mg QD 14/21). In addition the SMC decided 
to evaluate a continuous administration schedule (21/21) at 120 mg QD (DL5) from the first cycle.  
Amongst four patients enrolled at DL6 (160 mg QD 14/21), two experienced DLT (grade 3 diarrhea and 
grade 3 asthenia with anorexia, respectively). Thus DL6 could be considered exceeding the MTD.  


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Three patients have been enrolled at DL5 (120 mg QD 21/21). None have presented DLT to date. 
 
 
Other hematologic malignancies cohort 
No DLT was observed from a dose of 10 mg QD through 80 mg QD. it was decided to proceed to DL4 of 
40 mg BID based on preclinical data with OTX015 (and published results for the OTX015 analog JQ1) 
suggesting a higher efficacy with a BID schedule and residual plasma concentrations at 24 hours, below 
the in vitro active concentrations in patients treated at 80 mg QD. 
Three of five evaluable patients treated at DL4 of 40 mg BID, experienced DLTs (grade 3-4 
thrombocytopenia), and this DL was considered exceeding the MTD. A schedule dependency was 
suspected and it was decided to continue dose escalation with the QD schedule only. Nevertheless a 
Fibonacci-like escalation model was chosen out of caution, with a 1.5-fold dose increment. 
Three patients were initially treated at DL5 of 120 mg QD. The first patient (with bone marrow 
involvement and baseline grade 1 thrombocytopenia) experienced a DLT (grade 3 thrombocytopenia on 
Day 8 with gastrointestinal bleeding). Four additional patients have been enrolled, one of whom 
experienced DLT (grade 4 thrombocytopenia on Day 15). Finally, another initially deemed not evaluable 
had repeated dose interruptions and dose reduction due to grade 3 hyponatremia, associated with grade 3 
thrombocytopenia and was retrospectively considered as having DLT. Thus, three patients out of seven 
experienced DLT with this dose and schedule which exceeds the MTD. 
The SMC of April 24th therefore decided to add 3 patients at DL4 (80 mg QD) to confirm its tolerability, 
since only three OHM patients had been treated without DLT at this DL. Furthermore, it was decided to 
explore alternative discontinuous schedules at DL5 (120 mg QD): 14 days ON/7 days OFF (14/21) and 5 
days ON/2 days OFF every week (5/7). 
 
Safety Findings 
Extent of Exposure 
The number of treatment cycles, dose reductions, dose interruptions, and reasons for treatment 
discontinuation for the 63 treated patients is summarized in Table 3 and Table 4 below.  
The majority of patients (63%) discontinued OTX015 treatment due to disease progression, and among the 
52 patients who could have received at least 3 cycles (i.e., more than 9 weeks elapsed between study 
treatment initiation and the cut-off date of the present report), 17 (33%) had received more than 3 cycles 
(median 5.0; range 4-14+). 
Study treatment was interrupted for more than one day in 15 patients due to related AEs, 9 with grade 3-4 
thrombocytopenia, two with grade 4 neutropenia, and one each with aminotransferase elevation, 
coagulation factor VII decrease and fever of unknown origin, aggravation of diabetes mellitus, and grade 3 
hyponatremia. 
 
 


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Table 4: Patient exposure in treated acute leukemia patients (N=30) 
Dose 
10 mg QD 
14/21 
N=3 
20 mg QD 
14/21 
N=3 
40 mg QD 
14/21 
N=4 
80 mg QD 
14/21 
N=3 
40 mg BID 
14/21 
N=8 
120 mg QD 
14/21 
N= 3 
120 mg QD 
21/21 
N=3 
160 mg QD 
14/21 
N=3* 
Total  
 
N=30* 
Median (range) 
# cycles 
6 (1-7) 
3 (2-4) 
3 (1-14+) 
5 (1-5) 
2 (<1-8) 
2 (2-3) 
2+ (2-3+) 
2+ (1+-3+) 
2 (<1-14+) 
Dose reduction 
0 
0 
0 
0 
0 
0 
0 
2 
2 
Intrapatient dose escalation 
1 (20 mg) 
0 
1 (120 mg) 
0 
0 
0 
0 
0 
2 
Dose interruption > 1 day 
2 
(unrelated) 
1 
(unrelated) 
2  
(1 unrelated)
0 
1 
0 
0 
0 
6 
Reason for study treatment discontinuation 
Tumor progression 
2 
3 
1 
3 
5 
3 
0 
0 
17 
Consent withdrawal 
1 
0 
1 
 
1 
0 
0 
0 
3 
Deterioration general 
condition 
0 
0 
1 
0 
0 
0 
0 
0 
1 
No further benefit 
0 
0 
0 
0 
1 
0 
0 
0 
1 
Early death (unrel) 
0 
0 
0 
0 
1 
0 
1 
0 
2 
Treatment ongoing 
0 
0 
1 
0 
0 
0 
2 
3 
6 
*One additional patient (AL cohort, DL6, 160 mg QD 14 / 21) was enrolled but not yet treated due to leukemia-related sepsis 
 
 


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Table 5: Patient exposure in treated OHM patients (N=33) 
Dose 
10 mg QD 
21/21 
N=5 
20 mg QD 
21/21 
N=3 
40 mg QD 
21/21 
N=4 
80 mg QD 
21/21 
N=4 
40 mg BID 
21/21 
N=6 
120 mg QD 
21/21 
N= 7 
120 mg QD 
14/21 
N=2 
120 mg QD  
5/7 
N=2 
Total  
 
N=33 
Median (range) 
N cycles 
3 (<1-8) 
2 (2-2) 
3 (2-10) 
3 (1-10+) 
1.5 (1-2) 
3+ (1-5+) 
Too early 
Too early 
2 (<1-10+) 
Dose reduction 
0 
0 
1 
(unrelated) 
0 
0 
3 
Too early 
Too early 
4 
Intrapatient dose escalation 
1 (20 mg) 
0 
1 (80 mg) 
1  
(120 mg 5/7)
0 
0 
Too early 
Too early 
3 
Dose interruption > 1 day 
2 
(1 unrelated) 
0 
2  
(1 unrelated) 
2 
4 
5 
Too early 
1  
(unrelated) 
16 
Reason for study treatment discontinuation 
Tumor progression 
5 
3 
3 
3 
3 
6 
0 
0 
23 
Unrelated AE 
0 
0 
1 
0 
0 
0 
0 
0 
1 
ASCT in PR 
0 
0 
0 
0 
0 
1 
0 
0 
1 
Treatment ongoing 
0 
0 
0 
1 
0 
3 
2 
2 
8 


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Page 33 
Six AML patients, initially treated with a discontinuous (14/21) schedule, switched to a continuous 
schedule, which is being explored in AL patients from Cycle 1 at 120 mg. 
Adverse Events (AEs)  
Treatment emergent AEs at least possibly related to study medication are summarized in Table 4. Of 62 
patients treated and evaluable for safety to date, 48 (21 AL, 27 OHM) experienced a total of 145 treatment-
emergent AEs. Among them, 39 patients (13 AL, 26 OHM) experienced 101 AEs considered to be at least 
possibly related to OTX015. 
In OHM patients, for whom hematologic toxicity is evaluable (AL patients have baseline pancytopenia), 
thrombocytopenia appears the most common toxicity and is dose limiting (Table 4). It occurred in 69% 
(22/32) of evaluable patients regardless of severity or dose.  
Thrombocytopenia incidence and severity increased with dose and is possibly schedule dependent: Only 2 
out of 8 OHM patients treated at DL 40 or 80 mg QD experienced grade 4 thrombocytopenia versus 10/13 
treated at DL 40 mg BID or 120 mg QD. Moreover, despite the same total daily dose, one of four evaluable 
patients treated at 80 mg QD experienced grade 4 thrombocytopenia, versus five of six patients treated at 
40 mg BID.  


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Page 34 
Table 6: AL patients with TEAEs possibly/probably related to OTX015 (N=30 evaluable patients) 
 
Any Grade 
Grade 3-4 AE 
Dose (mg) 
Schedule 14/21 
unless otherwise 
specified 
10 
 
N=3 
20 
 
N=3 
40 
 
N=4 
80 
 
N=3 
40x2 
 
N=8 
120 
 
N=3 
120 
21/21 
N=3 
160 
 
N=3 
10 
 
N=3 
20 
 
N=3 
40 
 
N=4 
80 
 
N=3 
40x2 
 
 
N=8 
120 
 
N=3 
120 
21/21 
N=3 
160 
 
N=3 
N pt with AE 
0 
0 
1 
0 
4 
2 
3 
3 
0 
0 
0 
0 
1 
0 
1 
2 
Non-blastic aplasia 
0 
0 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
1 
0 
Hyperglycemia 
0 
0 
1§ 
0 
1 
1§ 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Diarrhea 
0 
0 
0 
0 
2 
1 
2 
2 
0 
0 
0 
0 
0 
0 
0 
1 
Dysgueusia 
0 
0 
0 
0 
2 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Nausea 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Anorexia 
0 
0 
0 
0 
0 
1 
0 
1 
0 
0 
0 
0 
0 
0 
0 
1 
Abdominal pain 
0 
0 
0 
0 
1 
0 
1 
1 
0 
0 
0 
0 
0 
0 
0 
0 
FUO 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Fatigue 
0 
0 
0 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
1 
Factor VII ↓ 
0 
0 
1 
0 
1 
1 
2 
1 
0 
0 
0 
0 
0 
0 
0 
0 
Direct bilirubin ↑ 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Aminotransferases ↑ 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
1 
0 
0 
0 
Thrombocytopenia and neutropenia are not assessable in AL patients  
FUO: fever of unknown origin 
§ patient with preexisting diabetes 
 


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Page 35 
Table 7: OHM patients with TEAEs possibly/probably related to OTX015 (N=32 evaluable patients*) 
 
Any Grade 
Grade 3-4 AE 
Dose (mg) 
Schedule 21/21 
unless otherwise 
specified 
10 
 
N=5 
20 
 
N=3 
40 
 
N=4 
80 
 
N=4 
40x2 
 
N=6 
120 
 
N=7 
120 
14/21 
N=1 
120 
5/7 
N=2 
10 
 
N=5 
20 
 
N=3 
40 
 
N=4 
80 
 
N=4 
40x2 
 
N=6 
120 
 
N=7 
120 
14/21 
N=1 
120 
5/7 
N=2 
N pt with AE 
2 
2 
4 
4 
6 
7 
0 
1 
1 
0 
3 
3 
6 
6 
0 
0 
Thrombocytopenia 
0 
2 
2 
4 
6 
7 
0 
1 
0 
0 
2 
3 
6 
5 
0 
0 
Neutropenia 
1 
0 
0 
0 
0 
2 
0 
0 
1 
0 
0 
0 
0 
2 
0 
0 
Hyperglycemia 
0 
0 
2§ 
2 (1§) 
1 
3 (1§) 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
Diarrhea 
0 
0 
2 
0 
2 
4 
0 
10 
0 
0 
1 
0 
0 
0 
0 
0 
Vomiting 
0 
0 
2 
0 
1 
 
0 
0 
0 
0 
0 
0 
1 
0 
0 
0 
Dysgueusia 
0 
1 
0 
1 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Nausea 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
 
Bowel movements 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Anorexia 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Abdominal pain 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Skin rash 
1 
0 
1 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Factor VII ↓ 
0 
0 
0 
0 
0 
2 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Direct bilirubin ↑ 
0 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Hypomagnesemia 
0 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Hyponatremia 
0 
0 
1 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
1 
0 
0 
Weight loss 
0 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Dizziness 
0 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Headache 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Thrombocytopenia and neutropenia are assessable only in patients with OHM.  
§ patient with preexisting diabetes 
* One patient had just started treatment on the cut-off date and was not included in the AE analysis 
 


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Grade 3-4 thrombocytopenia occurred in 16 (50%) evaluable patients, including 9 with grade 4 (28%). 
Characteristics of grade 3-4 thrombocytopenia are shown in Figure 1.  
Two of these 16 patients only had “anecdotal” grade 3; one patient experienced grade 3 toxicity for the 
first time during the 7th cycle, whereas this patient had been treated continuously at 80 mg QD. A second 
patient experienced one day of grade 3 thrombocytopenia, which resolved without treatment interruption.  
Among the 14 remaining patients with clinically significant grade 3-4 thrombocytopenia, ten had nadir 
occurring around 3 weeks after study treatment initiation, while 4 patients had earlier nadir. 
Recovery to grade < 3 was usually rapid after treatment interruption/discontinuation (i.e., within 10 days), 
with the exception of 4 patients. 
Figure 1: Platelets counts versus time in patients with grade 3-4 thrombocytopenia 
 
Six of the 10 OHM patients with grade 4 thrombocytopenia had previous high dose chemotherapy with 
autologous stem cell transplantation (ASCT) and/or known bone marrow involvement. Furthermore, 
platelet counts at baseline, even in the normal range, could predict severe thrombocytopenia. Prior ASCT, 
bone marrow involvement and baseline platelet count are probably non-independent factors that all reflect 
bone marrow reserves. Their potential predictive role will be further evaluated and should be clarified. 
The mechanism of action of OTX015-induced thrombocytopenia may be complex and will be explored 
systematically. 
Of note, most clinically relevant and treatment-limiting thrombocytopenia in the OHM cohort has been 
observed at DLs and schedules considered as exceeding the MTD.  
 
 
 


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contained therein may be reproduced or disclosed outside OncoEthix without their written consent.  
Page 38 
Clinical Activity 
Among 20 AML patients and 19 lymphoma patients evaluable for efficacy, evidence of clinical activity 
has been observed in 11 patients (5 with AML and 6 with lymphoma) (Table 6).  
While clinical activity does not clearly appear to be dose-dependent for leukemia patients, there may be a 
trend for a dose response in DLBCL patients. 
Table 9: Patients with evidence of clinical activity 
Dose (mg) 
AL 
OHM 
10 QD 
AML secondary to JAK2 mut PV 
 
- 
20 QD 
- 
- 
40 QD 
AML post chemotherapy 
 CR 
FL 
 
80 QD 
AML (NPM1+) secondary to MDS 
 CRi 
AML secondary to MDS 
 
LPL 
 
DLBCL 
 PR 
40 BID 
AML (NPM1+/flt3 mut) de novo 
 
 
120 QD 
- 
DLBCL 
 PR 
DLBCL 
 PR 
DLBCL 
 
AML: acute myelogenous leukemia; JAK2: Janus Kinase 2; PV: polycthemia Vera; MDS: myelodysplastic syndrome; NPM1: 
nucleophosmine; FL: follicular lymphoma; LPL: lymphoplasmacytic lymphoma; DLBCL: diffuse large B-cell lymphoma; CR: 
complete remission; CRi: complete remission with incomplete recovery; PR: partial response. 
 
Five of these patients met standard response criteria: 
• 
One patient 
 with post-treatment AML (fludarabine, cyclophosphamide and rituximab) given for 
previous Waldenström disease in remission, with normal karyotype, no MLL translocation, and over-
expression of WT1 as the sole molecular abnormality, who was treated at 40 mg QD had decreased bone 
marrow blasts (from 94% at baseline to 59%) at the end of Cycle 1, then disappearance of peripheral blood 
blasts (from 0.84 x 109/L at baseline to complete clearance) at the end of Cycle 2,  followed by clinically 
significant hematologic improvement during Cycles 2 to 4, with absolute neutrophil counts rising from 
0.05 x 109/L at baseline to 3.1 x 109/L at Cycle 4 and platelet counts rising from grade 4 with transfusion 
dependence at baseline to 112 x 109/L at the end of Cycle 4 without further transfusion need from mid-
Cycle 2. This patient refused to undergo the Day 43 myelogram, but accepted at the end of Cycle 4, which 
showed 2% blasts in a normal rich bone marrow. This case meets the criteria for complete remission (CR). 
The patient remained in CR until Cycle 12, then relapsed (CR duration 5 months). 
 is now being 
rechallenged with substantial dose increase (120 mg) in Cycles 13 and 14 (ongoing). The results of this 
dose escalation rechallenge are pending. 
• 
One patient 
 with AML secondary to myelodysplastic, syndrome, NMP1+ without flt3-ITD or 
mutation, who was treated at 80 mg QD had disappearance of bone marrow blasts on Day 22 (from 85% in 
a rich marrow at baseline to 0 in a poor marrow), confirmed on Day 43 (<1% of blasts ). The ratio NPM1 
mutated gene/abl in bone marrow shifted from 1.937% at baseline to 0.039% on Day 22. This patient had a 
slow increase in neutrophil counts from Cycle 2 Day 8, up to complete recovery > 1.5 x 109/L around 
Cycle 3 Day 15, without platelet count improvement, but decreased platelet transfusion needs, while red 
blood cell transfusions were no longer required. These findings meet the criteria for CR with incomplete 
recovery (CRi). This patient relapsed at the end of Cycle 5. 
• 
One patient 
 with DLBCL secondary to Hodgkin’s lymphoma who was treated at 80 mg QD 
experienced rapid improvement at Cycle 1 Day 8 with decrease (and almost complete radiologic clearance) 
of pleural effusion and improvement of dyspnea without new pleural paracenthesis at the beginning of 
Cycle 2. This patient also showed a 50% decrease of supraclavicular, mediastinal and iliac lymph node. 
Both CT-scan and PET-scan at the end of Cycle 2 confirmed a PR. PR was further confirmed in successive 
tumor assessment until 
 9th cycle, with major clinical benefit (autonomous and oxygen independent). 
Tumor progression was seen at Cycle 9, and the patient is currently being rechallenged at 120 mg QD 
(5/7). 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Page 39 
• 
One patients 
 with DLBCL treated at 120 mg (21/21), experienced a minor response (-41% tumor 
shrinkage) of mediastinal target lymph nodes and partial metabolic response (SUV 8.5→3.3) at the end of 
Cy 2 which reached PR criteria (-70% tumor shrinkage) at the end of Cy 4. This young patient was 
withdrawn from study at the end of Cycle 5 in preparation of intensification with ASCT followed by aSCT, 
because the magnitude of tumor shrinkage achieved with OTX015 is the highest ever observed during 
previous therapies. 
• 
One patient 
 with DLBCL treated at 120 mg (21/21), experienced PR at CT-scan with complete 
metabolic response (these criteria meet complete remission criteria) of abdominal lymph nodes. In 
addition, B-symptoms (night sweats) were completely cleared on therapy. This patient is ongoing at Cycle 
5. 
An additional six patients, although not fulfilling standard response criteria, had significant clinical 
evidence of activity, with clinical benefit in two of them. 
• 
One patient 
 with AML secondary to JAK2 mutated polycythemia vera who was treated at 10 mg 
QD had a regular decrease of high baseline peripheral blasts counts (from 11 x 109/L to complete 
clearance) and late decrease in bone marrow blasts (from 82% to 21%) without improvement of 
cytopenias, before disease progression after 6 cycles.  
• 
One patient 
 with cutaneous follicular lymphoma being treated at 40 mg QD experienced complete 
relief of a severe disease-related pruritus, previously refractory to symptomatic therapies. Tumor 
assessment with CT-scan at Cycle 5 showed minor tumor shrinkage of 32% not meeting criteria of PR. 
Treatment was discontinued after 
 10th cycle, due to severe unrelated corneal ulcer (patient with 
previous cornea graft). 
• 
One patient 
 with AML secondary to myelodysplastic syndrome who was treated at 80 mg QD had 
hyperleukocytosis (19.7 x 109/L at study entry), rapidly increasing to 27.8 x 109/L on Day 12, necessitating 
two courses of hydroxyurea during Cycles 1 and 2. At the end of Cycle 2 white blood cells were 2.0 x 
109/L with 51% blasts and bone marrow showed 87% blasts. However, OTX015 treatment was pursued 
without need for hydroxyurea from Cycle 3. At the end of Cycle 3, peripheral blood blasts were cleared 
and bone marrow blasts were 8%. During Cycle 4, neutrophil count slowly increased up to 1.2 x 109/L 
(starting from 0.4 x 109/L at baseline) and bone marrow blast infiltration was 12%. The patient remained 
dependent on platelet transfusion. At Cycle 5, disease progressed with recurrence of neutropenia, 
peripheral blasts and bone marrow infiltration with 89% blasts and the patient went off study. 
• 
One patient 
 with lymphoplasmacytic lymphoma and Waldenström magroglobulinemia who was 
treated at 80 mg QD experienced a 50% decrease in size and SUV at PET-scan at the end of Cycle 2 and a 
decrease of size of target lymph nodes on a CT-scan, which did not meet the criteria for PR. This patient 
had disappearance of B-symptoms, but progressed at the end of 
 5th cycle. The IgM M-component was 
not measured at the time of response. 
• 
One patient 
 with AML (NMP1+/flt3 mutated) treated at 40 mg BID (14/21) experienced resolution 
of painful gum hypertrophy from Cycle 1. 
 remained stable over 8 cycles, but without hydroxyurea that 
was needed prior to study entry. During 
 7th cycle, 
 ANC increased to normal values, while blasts 
increased concomitantly. The patient needed hydroxyurea again, experienced aplasia again and 
 
 The meaning of this ANC increase without blast decrease remains elusive. 
• 
One patient 
 with DLBCL was treated at 120 mg (21/21) and experienced minor response (-18% 
tumor shrinkage) of a large retroperitoneal mass compressing the vena cava inferior with lumbar pain and 
lower limb edema. As a result, tumor-related symptoms resolved. This patient is ongoing in Cycle 5 and 
will have a second tumor assessment. 
Finally, two AML patients 
 treated at 10 mg QD subsequently increased to 20 mg QD and 
 
treated at 40 mg QD) had stable disease for 7 and 5 cycles, respectively, which was quite unusual after 
relapse. 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Page 40 
1.4 
Rationale for the Current Study 
In the present study, adult patients with selected advanced solid tumors with the potential to respond to 
BET inhibition including NMC, NSCLC with RAS mutations or ALK rearrangement, TNBC, CRPC, and 
PDAC, will receive OTX015 orally using a 3+3 dose escalation scheme to determine the RD for phase II 
studies for two different administration regimens. 
OTX015, a pan-BET bromodomain inhibitor, shows activity in several preclinical hematologic and 
somatic cancer models. Meaningful antitumor activity has also been reported in patients with heavily 
pretreated hematological malignancies in the ongoing phase I clinical study treated with OTX015. 
Accumulating studies reveal the critical roles of BET bromodomains in cancer development. The first clue 
linking BRD4 with cancer was identification of the BRD4-NUT fusion oncogene which was recognized as 
an important mechanism in NMC. Besides the chromosomal rearrangement-induced NMC, other studies 
have also indicated that BRDs may contribute to cancer development through different mechanisms. 
Knockdown of BRD4 exhibited a robust antileukemic activity against AML in vitro and in vivo. Other 
recent studies with small molecule inhibitors of the BET proteins revealed the critical role of BRD4 in the 
development of several hematopoietic and somatic cancers. Accordingly, small molecule inhibitors 
targeting BET, such as OTX015, have been proven to be a promising drug for cancer therapy. 
Mutant KRAS is a strong activator of the MAPK and PI3K pathways, and the inhibition of KRAS-
dependent MAPK and PI3K pathways results in the dephosphorylation of MYC which contributes to its 
degradation. Recent studies in NSCLC preclinical models reported that the BET bromodomain inhibitors, 
OTX015 and its analog JQ1, exert remarkable antitumor activity in NSCLC harboring KRAS mutation. 
However, the concurrent mutation in KRAS and LKB1 genes abrogates effects of these BET inhibitors. 
Furthermore, in vivo experiments using genetically engineered mouse lung cancer models confirmed that 
JQ1 prompts tumor regression in mutant Kras mouse lung cancers, and sensitivity both in vitro and in vivo 
was found to be mediated by MYC downregulation. OTX015 is also broadly active in several NSCLC cell 
lines harboring EML4-ALK gene fusion supporting its further clinical development in patients with either 
KRAS mutated or ALK positive NSCLC. 
Myc expression was found to be disproportionally elevated in TNBC, and in primary tumors, Myc 
signaling was associated with shortened disease-free survival. A recent report on TNBC indicates that the 
interaction with BRD4 is critical for the oncogenic function of Twist, a key activator of epithelial-
mesenchymal transition. In addition pharmacologic inhibition of the Twist-BRD4 association reduces 
invasion, cancer stem cell-like properties, and tumorigenicity of TNBC cells highlighting the use of 
OTX015 in this poor prognosis tumor. 
In CRPC, the BET inhibitor JQ1 disrupts AR recruitment to target gene loci and functions downstream of 
AR, and abrogated BRD4 localization to AR target loci and AR-mediated gene transcription. In addition, 
in vivo, BET bromodomain inhibition was found to be more efficient than direct AR antagonism in CRPC 
xenograft mouse models. As BET inhibition functions downstream of AR, OTX015 may be effective in the 
context of AR-mediated resistance, including compensatory mechanisms involving related steroid hormone 
receptors that are also likely to require BET bromodomain function. 
PDAC continues to be the leading cause of cancer-related death in part due to limited efficacy of 
conventional chemotherapy. PDAC cell proliferation in collagen decreased in the presence of BET 
inhibitors and with transfection with siRNA against BRD4, which is increased in human PDAC tumors, 
including in cells that had undergone epithelial-to-mesenchymal transition or were resistant to 
chemotherapy, making OTX015 a potential drug in this pathology. 
Preliminary data, from an ongoing phase I clinical trial in advanced hematologic malignancies, show that 
OTX015 is well tolerated from 10 mg to 120 mg QD (days 1-14, q3w) in AL patients, with no DLT 


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observed. The dose of 160 mg QD (days 1-14, q3w) may exceed the MTD with 2 out of 3 patients 
experiencing non-hematologic DLTs (grade 3 diarrhea and grade 3 asthenia, respectively) and will soon be 
assessed by the SMC. A 120 mg QD (continuous) has been explored concurrently and one patient may 
have experienced non-blastic aplasia, needing further assessment in three more patients. 
For OHM patients, thrombocytopenia emerged as a DLT at 40 mg BID and 120 mg QD (continuous), with 
11/13 patients experiencing grade 3-4 thrombocytopenia, including 9 with grade 4 thrombocytopenia 
leading to treatment interruption. Both of these dose levels/schedules exceed the MTD. Higher trough 
concentrations achieved with both dose/ schedule may be at least partly responsible for the higher 
frequency and severity of thrombocytopenia. Other parameters may influence the occurrence and severity 
of thrombocytopenia, such as bone marrow reserve, estimated by previous ASCT, baseline platelet counts 
and/or bone marrow involvement. 
Evidence of clinically significant antitumor activity has been observed at non-toxic doses in AL patients 
(including one sustained CR at 40 mg QD and one CRi at 80 mg QD) and also in lymphoma patients 
(including 3 sustained PRs at 80 mg and 120 mg QD), as well as at the toxic dose of 120 mg QD 
(continuously). 
Optimization of dose and schedule are ongoing before initiating expansion cohorts. In AL, additional 
patients are being enrolled at 120 mg QD (continuously) and 120 mg QD (days 1-14, q3w), while shorter 
administration with 160 mg (e.g. Days 1-7, q3w) may be decided by the SMC. In OHM patients, three 
schedules are being explored simultaneously with additional patients at 80 mg QD (continuously), 120 mg 
QD (Days 1-14, q3w) and 120 mg QD (5days a week every week). A discontinuous schedule may be 
necessary to allow prolonged treatment. 
1.4.1 
Rationale for the Trial Design 
The purpose of this trial is to determine the MTD of OTX015 for further phase II trials in patients with 
selected solid tumors that might benefit from BET inhibition, in order to optimize the dose and schedule in 
this patient population with non-compromised bone marrow (i.e., without high-dose chemotherapy and 
autologous stem cell transplantation or bone marrow involvement), which is expected to be higher than the 
MTD of patients with hematologic malignancies, as well as to generate safety and pharmacokinetic data in 
this population. Antitumor effects over single and multiple cycles of two different administration regimens 
will be explored using a 3+3 dose escalation scheme based on DLT assessment, and a cohort expansion. 


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1.4.2 
Justification for the Regimens and Starting Dose  
Regimen 1: Daily continuous 
A starting dose of 80 mg OTX015 administered orally once daily on a continuous basis will be used based 
on the following considerations:  
1) The 80 mg dose was given safely in the ongoing phase I trial in patients with advanced hematologic 
malignancies (Study OTX015_104).  
2) Patients with solid tumors (without compromised bone marrow) are expected to tolerate higher 
OTX015 doses better than those with hematologic malignancies; thus their MTD is predicted to be 
higher. 
3) A single daily dose of 80 mg was chosen instead of a 40 mg BID schedule in light of preliminary 
results from the phase I study in hematologic malignancies suggesting a degree of schedule-
dependency, with higher rates of grade 3-4 thrombocytopenia with the BID schedule, which was dose-
limiting in patients with hematologic malignancies other than leukemia. 
Regimen 2: Days 1-7, every 21 days 
A starting dose of 100 mg OTX015 administered orally once daily for 7 consecutive days, repeated every 3 
weeks will be explored in an attempt to determine if discontinuous drug administration can reduce: 
1) The incidence and severity of thrombocytopenia which appears to be the most common toxicity of 
OTX015 in patients with hematologic malignancies, emerging at ≥ 80 mg daily continuous dose after 
nearly 2 weeks of treatment exposure (grade 3-4 thrombocytopenia occurred in 50% of patients with 
28% having a grade 4), with an incidence/severity appearing to increase with dose suggesting a 
possible schedule-dependency.  
2) Given that in the ongoing phase I study in patients with advanced hematologic malignancies, severe 
thrombocytopenia tends to occur after approximately 2 weeks of continuous treatment, and that 
furthermore a recovery interval of approximately 10 days is required for severe thrombocytopenia to 
return to lower grades, a discontinuous regimen may be required to allow re-treatment every 3 weeks. 
This is important to take into account for future combination clinical studies. 
These two regimens (with or without recovery period) will be tested in parallel, i.e., Regimen 1 (daily 
continuous dosing) and Regimen 2 (7 days every 21 days). This will allow selection of the optimal regimen 
for further studies in terms of balance between tolerability, pharmacokinetics and antitumor activity. 


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Page 43 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
• 
To determine the Maximal Tolerated Dose (MTD) defined as the recommended phase II dose for two 
distinct regimens of OTX015/MK-8628 administered orally to patients with selected advanced solid 
tumors. 
2.2 
Secondary Objectives 
• 
To assess the safety profile of single-agent OTX015/MK-8628 
• 
To characterize pharmacokinetics parameters of OTX015/MK-8628 
• 
To determine the antitumor activity of OTX015/MK-8628 in selected solid tumors 
 
3 
STUDY DESIGN, DURATION AND DATES 
3.1 
Study Design 
This is an open-label, multicentric, international, non-randomized phase I trial with dose optimization of 
single-agent OTX015/MK-8628 administered per os in patients with selected advanced tumors (NMC, 
TNBC, NSCLC, CRPC and PDAC). 
The study will be performed in two parts. In the first part a dose escalation study will be performed 
evaluating two regimens in parallel to establish the MTD in each of the selected indications. In the second 
part, the efficacy of OTX015/MK-8628 will be evaluated in expansion cohorts of each of the five 
indications using a selected regimen. Patients will be included in at least seven centers worldwide. 
The two regimens evaluated in parallel in the dose escalation part are: 
Regimen 1: continuous, once daily for 21 consecutive days (21-day cycles), at a starting dose of 80 
mg/day. 
Regimen 2: once daily on days 1 to 7, repeated every 3 weeks (21-day cycles; 1 week ON/2 weeks OFF), 
at a starting dose of 100 mg/day. 
A sequential accrual design with standard dose escalation is used. Patients will be included in the next 
available regimen.  
Up to four dose levels will be evaluated for each regimen.  
Regimen 1: 80, 100, 120 and 160 mg/day, continuous, 21-day cycles 
Regimen 2: 100, 120, 160 and 200 mg/day, 1 week ON/2 weeks OFF, 21-day cycles 
Patients will undergo a dose and/or schedule modification in the event of toxicity. 
Three patients will be enrolled per dose level, and up to three additional patients at the first occurrence of a 
DLT (see Section 5.2.4) during the first 21 days of treatment. Up to 48 patients evaluable for DLT will be 
enrolled in the dose escalation part (24 for each regimen). 
The MTD will be the dose level at which fewer than one-third of the patients experience DLT during the 
first 21 days, and is defined as the DL at which 0 out of 3 patients or 1 out of 6 patients experiences DLT, 
with the next higher DL having at least 2 out of 3 to 6 patients having DLT. 
Once the MTD is established for each regimen and at least 3 patients have received at least two evaluable 
cycles of study drug at the MTD, an expansion step will be initiated to assess the efficacy of OTX015/MK-


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8628 in these populations, as measured by clinical benefit (CR, PR or SD, according to RECIST v1.1 or 
PCWG2). Up to 50 evaluable patients (10 per indication) will be accrued in the expansion phase.  
3.2 
Independent Safety and Data Monitoring Committee 
The SMC will be composed of the principal investigators of each participating center, the 
pharmacokinetics (PK) specialist, medical and safety representatives of the Sponsor and an independent 
expert in the field of oncology early drug development (see Appendix 4). All decisions made by the SMC 
and their rationale will be recorded. 
The SMC will be responsible for the following decisions: 
• 
Proceeding to the next higher DL or stopping dose escalation 
• 
Adding patients at a given DL 
• 
Determining the MTD and closing patient enrollment in that dose level and regimen 
• 
Progressing with the dose expansion part 
• 
Selecting the regimen to be followed in each indication in the expansion part of the study 
• 
Performing optional study parts 
• 
Making decisions aimed at improving participating patients’ safety. 
In addition, according to the nature, suspected relationship to study drug, or other clinical considerations, 
the SMC will make ad-hoc decisions, such as replacing non-evaluable patients, adding more patients at the 
same DL, adding intermediate DLs, exploring additional doses and/or regimens (e.g., if the MTD is not 
reached at the highest dose), or not considering a given DLT as clinically relevant for the determination of 
the MTD. PK results will be forwarded to the SMC as they become available and will be taken into 
account for the determination of the MTD, notably if no DLT occurs. 
3.3 
Study Duration and Dates 
Patients will begin treatment within a week after registration, followed by the treatment period (3-week 
cycles), and a follow-up period of at least 2 treatment cycles after the last patient has started treatment. 
Study period: patients are on the study from the time of Informed Consent Form (ICF) signature until the 
last visit or death, whichever comes first. 
Treatment period: the time from the initiation of study therapy until the last study drug intake, plus a 30 
day safety observation period during which OTX015/MK-8628-related TEAEs are reported. 
End of study: the study is considered completed after the last patient has been evaluated for efficacy with 
a follow-up of at least 2 cycles. 
The duration of this study will depend on the number of DLTs encountered in each regimen, the number of 
dose levels explored in each regimen and the rate of accrual in each of the five expansion cohorts. 
The study will be closed after the last visit of the last patient still on study. 
 
 


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4 
SELECTION OF PATIENTS 
4.1 
Number of Patients 
The study will be carried out in two steps.  
The dose escalation step will explore up to four OTX015/MK-8628 DLs using two regimens to determine 
the MTD in each regimen. Up to 48 patients evaluable for DLT (i.e. up to 24 patients per regimen) will be 
accrued depending on the number of DLTs encountered.  
Up to 50 additional patients will be included in five expansion cohorts (10 patients per indication). 
Overall, the total number of patients expected to be accrued in this study is up to 98 evaluable patients. The 
final sample size will depend on the number of DLTs encountered at each DL in each regimen, and may be 
increased if the MTD is not reached for either of the two proposed regimens with the four planned DLs, 
and additional DLs are required. 
4.2 
Inclusion Criteria 
Patients must fulfill all of the following requirements to enter the study: 
1. Signed informed consent obtained prior to initiation of any study-specific procedures and treatment; 
2. Histologically or cytologically confirmed diagnosis of one of the following advanced or metastatic solid 
tumors for which standard therapy either does not exist or has proven ineffective, intolerable or 
inacceptable for the patient:  
- 
NUT midline carcinoma (ectopic expression of NUT protein as determined by IHC and/or detection of 
BRD-NUT gene translocation as determined by FISH); 
- 
Triple negative breast cancer defined according to ASCO recommendations (Hammond et al., 2010; 
Wolff et al., 2007); 
- 
Non-small cell lung cancer harboring a rearranged ALK gene/fusion protein (FISH or IHC) or KRAS 
mutation (as defined by any molecular analysis); 
- 
Castrate-resistant prostate cancer (CRPC); 
- 
Pancreatic ductal adenocarcinoma; 
3. At least one measurable lesion as per RECIST version 1.1., except for CRPC patients who may be enrolled 
with objective evidence of disease as per Prostate Cancer Clinical Trials Working Group (PCWG2) 
criteria; 
4. Age ≥ 18 years at the time of informed consent; 
5. Life expectancy ≥ 3 months; 
6. ECOG Performance Status (PS) ≤ 1; 
7. Adequate bone marrow reserve, renal and liver function:  
- 
Absolute neutrophil count ≥ 1.5 x109/L, 
- 
Platelet count ≥ 150 x109/L, 
- 
Hemoglobin ≥ 9 g/dL (blood transfusion ≤ 7 days of screening not permitted), 
- 
Creatinine clearance ≥ 30 mL/min calculated according to the Cockroft and Gault formula or MDRD 
formula for patients aged > 65 years, 
- 
Alanine aminotransferase (ALT), aspartate aminotransferase (AST) < 3 x ULN, if alkaline phosphatase 
(ALP) > 2.5 X ULN, then liver fraction should be ≤ 2.5 X ULN, and total bilirubin ≤ 1.25 x ULN (in 
case of liver involvement, total bilirubin ≤ 2 x ULN will be allowed), 
- 
Serum albumin ≥ 2.0 g/dL for NMC , ≥ 3.0 g/dL for NSCLC, CRPC, TNBC and pancreatic cancer 
- 
INR ≤ 1.5 or INR < 3 for patients treated with antivitamin K; 


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8. An interval of ≥ 3 weeks since chemotherapy (≥ 6 weeks for nitrosoureas or mitomycin C), 
immunotherapy, hormone therapy or any other anticancer therapy or surgical intervention resection, or ≥ 3 
half-lives for monoclonal antibodies, or ≥ 5 half-lives for other non-cytotoxic agents (whichever is longer); 
9. CRPC patients must maintain ongoing androgen deprivation therapy with a gonadotropin releasing 
hormone (GnRH) analogue, antagonist or orchiectomy providing serum testosterone is < 50 ng/dL (<1.7 
nmol/L); 
10. Patients receiving bisphosphonate or denosumab therapy must be on stable doses for at least 4 weeks 
before initiating study treatment. 
4.3 
Exclusion Criteria 
The presence of any of the following criteria excludes a patient from participating in the study: 
1. Inability to swallow oral medications or presence of a gastrointestinal disorder (e.g. malabsorption) 
deemed to jeopardize intestinal absorption of OTX015/MK-8628; 
2. Persistent grade >1 clinically significant toxicities related to prior antineoplastic therapies (except for 
alopecia); stable sensory neuropathy ≤ grade 2 NCI-CTCAE v. 4.0 is accepted. 
3. Known primary CNS malignancy or CNS involvement;  
4. History of prior or concomitant malignancies (other than excised non-melanoma skin cancer or cured in 
situ cervical carcinoma) within 3 years of study entry; 
5. Other serious illness or medical conditions, such as active infection, unresolved bowel obstruction, or 
psychiatric disorders; 
6. Known HIV positivity; 
7. Participation in another clinical trial or treatment with any investigational drug within 30 days prior to 
study entry; 
8. Other concomitant anticancer treatment; 
9. Concomitant therapy with strong CYP3A4 interfering drugs; 
10. Current use of anticoagulants (e.g. warfarin, heparin) at therapeutic levels within 7 days prior to the first 
dose of OTX015/MK-8628. Low-dose (prophylactic) low molecular weight heparin (LMWH) is permitted; 
11. Pregnant or breast-feeding patients, and men and women with childbearing potential not using effective 
contraception while on study treatment. 
Any waiver of these inclusion and exclusion criteria should be exceptional and justified and must be 
approved by the investigator and the Sponsor on a case-by-case basis prior to enrolling the patient. This 
must be documented by both the Sponsor and the investigator. 
4.4 
Patients of Reproductive Potential 
The patient must not be pregnant or breast-feeding at inclusion in the study. Absence of pregnancy must be 
demonstrated by urine testing unless there is proven menopause (age ≥ 50 years and last menarche ≥ 3 
years, or documented menopausal sex hormone profile, or surgical castration) prior to exposure to the 
investigational product or any study procedure with potential risk to the fetus. 
Female patients must not become pregnant or start breast-feeding during the study, and women of 
childbearing potential (i.e. without proven menopause, see above) must use a medically effective 
contraception during the study and within 6 months after the last study medication intake, as must male 
patients with a sexual partner of childbearing potential. 


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5 
STUDY TREATMENT 
5.1 
Formulation and Manufacturer 
 
Drug code  
OTX015/MK-8628 (investigational agent) 
INN 
Not yet issued 
Formulation 
OTX015/MK-8628 is provided in gelatin capsules as a solid molecular dispersion as 
follows: 
10 mg capsules (white, size 3): OTX015/MK-8628 free base (10 mg), hypromellose 
acetate succinate (HPMCAS; 10 mg), lactose monohydrate (85 mg), microcrystalline 
cellulose (70 mg), croscarmellose sodium (10 mg), colloidal silicon dioxide (2.5 mg), 
and magnesium stearate excipients (2.5 mg). 
20 mg capsules (green, size 3): OTX015/MK-8628 free base (20 mg), HPMCAS (20 
mg), lactose monohydrate (74 mg), microcrystalline cellulose (61 mg), croscarmellose 
sodium (10 mg), colloidal silicon dioxide (2.5 mg), and magnesium stearate excipients 
(2.5 mg). 
40 mg capsules (white, size 0): OTX015/MK-8628 free base (40 mg), HPMCAS (40 
mg), lactose monohydrate (196 mg), microcrystalline cellulose (162 mg), croscarmellose 
sodium (25 mg), colloidal silicon dioxide (6 mg), and magnesium stearate excipients (6 
mg). 
Storage 
Capsules should be stored at +2 to +8°C (refrigerated) 
Manufacturers Agere Pharmaceuticals Inc.  
62925 NE 18th Street, Bend, Oregon 97701, USA 
Merck Sharp & Dohme Limited 
Hertford Road, Hoddesdon, Hertfordshire, EN11 9BU , United Kingdom 
5.2 
Dosage Schedule 
5.2.1 
Prophylactic Medication Regimen 
No systematic premedication will be given at least during the first cycle, however low dose prophylactic 
low molecular weight heparin (LMWH) is permitted throughout the study, including cycle 1. 
5.2.2 
Schedule 
OTX015/MK-8628 is to be administered per os once daily in a fasted state with a little water just before 
breakfast (around 8 a.m. [±2h]). Flat doses will be used with no adjustment for BSA or weight. 
Two regimens will be evaluated; OTX015/MK-8628 will be administered either continuously (Regimen 1) 
or for 1 week ON/2 weeks OFF (Regimen 2). Capsules must not be opened or chewed. 
A treatment cycle is 21 days (3 weeks). The subsequent cycle will begin on day 22 or after recovery from 
any AEs associated with the previous cycle. 
Patients should receive study treatment within 7 days following registration. 
Dosing not performed at the same time (±2h) as on other days will be omitted. Patients are to be instructed 
that if they vomit or omit their dose in that time frame, it is not to be replaced.  
Details of the exact dose and time of administration will be documented in a patient diary and reported in 
the electronic case report form (eCRF). 


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5.2.3 
Dose Escalation 
Two regimens will be evaluated with four planned OTX015/MK-8628 dose levels for each. Patients will 
be sequentially assigned to Regimen 1 or Regimen 2, according to the next available place. 
The starting dose will be 80 mg per os given once daily for Regimen 1, and 100 mg per os given once 
daily for 7 days every 3 weeks for Regimen 2 (1 week ON/2 weeks OFF). 
Dose escalation will be performed independently in each regimen, according to 3+3 cohort design with 3 
or 6 patients per cohort. The criteria for dose escalation are based on the occurrence of DLT. DLT 
assessment will be performed during the first 21 days of study treatment for each patient during the dose 
escalation phase of the study. 
If none of the first 3 evaluable patients treated at a given DL experience DLT during cycle 1 (i.e., the first 
21 days following study treatment initiation), dose escalation will proceed to the next highest DL. 
If 1 out of 3 patients of a cohort has DLT during cycle 1, up to 3 additional patients will be entered at this 
DL. If no more than 1 of 6 evaluable patients has DLT, dose escalation will proceed to the DL immediately 
above. If more than 1 of 6 patients (or more than 1 of 3) has DLT, the DL will be considered to exceed the 
MTD (see table below). 
The first patient enrolled in a higher DL cohort will not start the study treatment until the last treated 
patient in the DL immediately below has completed one cycle of study treatment (21 days following study 
treatment initiation). 
Patients not evaluable for DLT (i.e. receiving less than 85% of the intended cumulative dose in cycle 1 for 
any reason other than toxicity; <18 days of treatment for Regimen 1, or <6 days of treatment for Regimen 
2) and who do not experience DLT will be replaced. 
Table 10: OTX015/MK-8628 Dose Escalation Scheme 
Dose 
Level  
OTX015 Dose (mg/day) 
Outcome (#DLT/#Patients)* / Actions to be taken 
Regimen 1 
(continuous) 
Regimen 2  
(D1-7, q3w) 
DL 1 
80 
100 
At each DL for each regimen: 
- If 0 of 3 patients has DLT, escalate dose in next cohort of 3 patients 
- If 1 of 3 patients has DLT, treat next 3 patients at the same dose level 
(6 patients total) 
- If ≥ 2 of 3 patients has DLT, halt dose escalation (MTD exceeded) 
- If 1 of 6 patients has DLT, escalate dose for next cohort of 3 patients 
- If ≥ 2 of 6 patients has DLT, halt dose escalation (MTD exceeded) 
DL 2 
100 
120 
DL 3 
120 
160 
DL 4 
160 
200 
* Evaluated during the first 21 days of treatment 
 
Patients will receive OTX015/MK-8628 at the DL they were assigned at entry throughout the study, or at a 
reduced dose according to toxicity encountered. 


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5.2.4 
Dose Limiting Toxicity 
DLT is defined as any of the following toxicities occurring during the first 21 days of treatment and 
considered by the investigator to be related to OTX015/MK-8628. 
Hematologic toxicity 
• 
Any grade 4 hematologic toxicity or febrile neutropenia 
• 
Grade 3 neutropenia with infection 
• 
Grade 3 thrombocytopenia with bleeding or lasting > 7 days 
Non-hematologic toxicity 
• 
Any grade 3 or 4 non-hematologic toxicity (regardless of duration) unless it was not optimally 
managed with supportive care (e.g. grade 3 vomiting not adequately treated according to antiemetic 
standard of care). 
• 
Any grade 3 or 4 laboratory abnormality, with or without symptoms, lasting > 48 hours. 
• 
Any intolerable grade 2 non-hematologic toxicity resulting in study drug discontinuation or delay > 7 
days with or without dose reduction. 
• 
Any of the following liver test abnormalities** (see Appendix 5) 
- 
ALT or AST > 8 x ULN  
- 
ALT or AST > 5 x ULN for > 2 weeks 
- 
ALT or AST > 3 x ULN and (total bilirubin > 2 x ULN OR INR > 1.5) 
- 
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash and/or eosinophilia (> 5%) 
Other 
• 
Treatment delay > 2 weeks or dose reduction requirement for initiating cycle 2. 
**Note: All patients with these liver test abnormalities should be monitored weekly until all abnormalities 
return to normal or to the baseline state. For patients with isolated total bilirubin increases >2 x ULN or 2 x 
baseline (if elevated at baseline), monitoring should be every 2 weeks until bilirubin returns to normal or to 
the baseline state. Drug induced liver injury (DILI) may develop or progress even after the causative drug 
has been stopped. Results should be recorded in the CRF and in the database. See guidelines on the 
handling of these events (potential Hy’s law cases)(Appendix 5). 
DLTs must be reported immediately to the Sponsor using a Serious Adverse Event Report Form (SAERF) 
with the reason for seriousness “other important medical event” if there is no other reason for seriousness. 
5.2.5 
Maximum Tolerated Dose  
The MTD (recommended phase II dose) is defined as the dose immediately preceding the DL at which 
DLTs are observed in ≥ 2 out of 3 to 6 patients, i.e., the DL at which 0 of 3 patients or ≤ 1 of 6 patients 
experience DLT.  
The MTD will be determined in each of the two regimens evaluated. 
5.2.6 
Expansion Cohort 
Once the MTD is established for each regimen with at least 3 patients having received at least 2 evaluable 
cycles of study drug, the study will be extended with the inclusion of 10 evaluable patients per indication at 
the MTD. The regimen used in each expansion cohort (i.e., each indication) will be decided by the SMC. 
5.2.7 
Dose Adaptation 
OTX015/MK-8628 will be interrupted until recovery to ≤ grade 1 or baseline value in the event of any of 
the following toxicities: 


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Hematologic toxicity 
• 
Any grade 4 hematologic toxicity or febrile neutropenia 
• 
Grade 3 neutropenia with infection 
• 
Grade 3 thrombocytopenia with bleeding or lasting > 7 days 
Non-hematologic toxicity 
• 
Any grade 3 or 4 non-hematologic toxicity (regardless of duration) unless it was not optimally managed 
with supportive care (e.g. grade 3 vomiting not adequately treated according to antiemetic standard of 
care). 
• 
Any grade 3 or 4 laboratory abnormality, with or without symptoms, lasting > 48 hours. 
• 
Any intolerable grade 2 non-hematologic toxicity resulting in study drug discontinuation or delay > 7 days 
with or without dose reduction. 
After recovery from toxicity, the dose will be resumed as follows and detailed in Table 11: 
• 
For Regimen 1, the continuous schedule will be initially modified to a discontinuous schedule, then with a 
dose reduction for the second modification.  
• 
For Regimen 2, two consecutive dose reductions may be implemented. 
Table 11: OTX015/MK-8628 Dose / Schedule Modifications 
Dose / Schedule Modifications: Regimen 1 
Initial OTX015 Dose  
1st Modification 
2nd Modification 
80 mg QD continuously 
80 mg QD,  
2 weeks ON/ 1 week OFF, q3w 
60 mg QD,  
2 weeks ON/1 week OFF, q3w 
100 mg QD continuously 
100 mg QD,  
2 weeks ON/1 week OFF, q3w 
80 mg QD,  
2 weeks ON/1 week OFF, q3w 
120 mg QD continuously 
120 mg QD,  
2 weeks ON/1 week OFF, q3w 
100 mg QD,  
2 weeks ON/1 week OFF, q3w 
160 mg QD continuously 
160 mg QD,  
2 weeks ON/1 week OFF, q3w 
120 mg QD,  
2 weeks ON/1 week OFF, q3w 
 
Dose / Schedule Modifications: Regimen 2 
Initial OTX015 Dose  
1st Modification 
2nd Modification 
100 mg QD, Days 1-7, q3w 
80 QD, Days 1-7, q3w 
60 QD, Days 1-7, q3w 
120 mg QD, Days 1-7, q3w  
100 mg QD, Days 1-7, q3w 
80 QD, Days 1-7, q3w 
160 mg QD, Days 1-7, q3w  
120 mg QD, Days 1-7, q3w 
100 mg QD, Days 1-7, q3w 
200 mg QD, Days 1-7, q3w  
160 QD, Days 1-7 q3w 
120 mg QD, Days 1-7, q3w 
No more than two dose reductions (or schedule modifications) should be implemented unless the 
investigator thinks it in the patient’s best interests to pursue study treatment with further dose reduction 
(additional dose reduction by one dose level), with the Sponsor’s agreement.  
Dosing interruption for > 2 weeks due to toxicity or liver toxicity (see Section 5.3 for details) will lead to 
definitive study treatment discontinuation, unless the investigator thinks it in the patient’s best interests to 
pursue study treatment, with the Sponsor’s agreement. 
5.2.8 
Supportive Care Guidelines for Study Treatment Toxicity 
Toxicity will be managed by the investigator according to the local standard of care. Supportive treatment 
must be reported in the concomitant medication section of the eCRF. 


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Handling of hepatotoxicity for potential DILI will be managed according to the treatment guidelines 
outlined in Appendix 5. 
5.2.9 
Potential Phototoxicity 
No phototoxicity studies have been performed in humans to date. However as OTX015/MK-8628 absorbs 
light in the range of 290 and 400 nm with a molar extinction coefficient (MEC) of >1000 L/mol.cm, it is 
recommended that patients avoid sun and UV exposure until results of phototoxicity studies are available. 
 
5.3 
Treatment Duration 
Patients will continue study treatment until any of the following events at which point it will be definitively 
discontinued:  
• 
Disease progression 
• 
Unacceptable toxicity 
• 
Patient withdrawal of consent 
• 
Patient non-compliance 
• 
Treatment interruption for > 2 weeks for any reason (except in the event of perceived benefit, with Sponsor 
agreement) 
• 
Recurrence of DLT despite dose reduction (except in the event of perceived benefit, with Sponsor 
agreement) 
• 
Any of the following liver test abnormalities** (see Appendix 5) 
- 
ALT or AST > 8 x ULN  
- 
ALT or AST > 5 x ULN for > 2 weeks 
- 
ALT or AST > 3 x ULN and (total bilirubin > 2 x ULN OR INR > 1.5) 
- 
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash and/or eosinophilia (> 5%) 
However, in case of investigator’s perceived benefit for the patient, treatment continuation can be 
considered with dose reduction despite delay/interruption > 2 weeks or reoccurrence of a DLT with the 
same intensity after one dose reduction. The perceived benefit of the investigator is defined by 1) any 
objective tumor response, or 2) any tumor shrinkage not meeting standard response criteria, but which 
could improve with additional treatment, or 3) any symptomatic improvement, which, in the investigator’s 
opinion, could not be achieved by other means. If, in the cases described above, DLT recurs with the same 
intensity despite one dose reduction, a second dose reduction may be considered. The decision should be 
discussed with the Sponsor, but the final decision must be made by the investigator. 
In all cases, the reason for and date of study treatment discontinuation must be recorded in the eCRF and 
source documented in the patient's medical records. As far as possible, there should be only one reason for 
treatment discontinuation. If there are several (e.g. concomitant progressive disease and toxicity), the 
primary one must be reported. The patient must be followed up to establish whether the reason was a 
TEAE, and if so, this must be reported as such. 
As far as possible, all examinations scheduled for the final study day must be performed for all patients 
who receive the investigational product but who do not complete the study according to protocol. 


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The investigator must make every effort to contact patients lost to follow-up, especially when a patient is 
treated in another non-study center. 
5.4 
Treatment Assignment 
All patients must be registered prior to treatment start. After verifying that the patient meets eligibility 
criteria and has signed the Informed Consent Form, the investigator will request a patient number by 
faxing/e-mailing the Patient’s Registration Form to: 
 
Medical Monitor, Oncology Therapeutic Development (OTD) 
Fax: 
 
Phone: 
 
Mobile: 
 
E-mail: 
 
 
The Patient’s Registration Form (provided separately) contains the following information necessary to 
determine eligibility: 
1. Institution name 
2. Sender’s name 
3. Principal investigator’s name 
4. Patient’s identification (first letter of first, middle and last name) 
5. Patient’s age and gender 
6. ECOG performance status 
7. Planned date of treatment 
8. Date when informed consent was obtained 
9. Verification of selected inclusion and exclusion criteria including hematologic and biochemistry results 
and dates examinations were performed 
10. Prior anticancer therapies and dates of last therapies 
11. Comorbidities and tumor-related symptoms present at screening 
 
After validation and signature by the CRO’s Medical Monitor, the registration form will be returned to the 
investigator, with or without inclusion agreement.  
For patients not included, the reason for inclusion refusal will be specified. 
For included patients, the dose level and regimen allocated will be specified on the form, along with a 
unique patient number (UPN). Included patients will receive a UPN only when treatment is about to be 
started, which must be within 7 days after registration. 
PPD
PPD
PPD
PPD
PPD


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The UPN will consist of 5 digits (2 for the center and 3 for the patient, by increasing order of inclusion) 
and will be recorded on the eCRF. The next consecutive number will be assigned. Once a number has been 
assigned, it must not be used again. 
5.5 
Packaging and Labeling 
The investigational product OTX015/MK-8628 is manufactured by Agere Pharmaceuticals, Inc. or Merck 
Sharp & Dohme Limited and packaged by Packaging Coordinators, Inc. It will be supplied as size 3 gelatin 
capsules containing 10 or 20 mg of OTX015/MK-8628 or size 0 gelatin capsules containing 40 mg 
OTX015/MK-8628, in bottles of 21 capsules. Clinical supplies will be affixed with a clinical label in 
accordance with regulatory requirements. 
 
5.6 
Supplies and Accountability 
The pharmacist of the investigational center will inventory and acknowledge receipt of all shipments of the 
investigational medicinal product which must be kept in a locked area with restricted access. It must be 
stored and handled in accordance with the manufacturer’s instructions and temperature traceability is 
required.  
At each study visit, the hospital pharmacist will provide patients with the adequate number of 
OTX015/MK-8628 capsules to ensure continuous study treatment until the next visit. The study drug must 
be used only as directed in the protocol and must be dispensed only to patients enrolled in this study. 
The pharmacist will also keep accurate records of the quantities of the investigational product dispensed, 
used, and returned by each patient. The Sponsor’s study monitor will periodically check the supplies of 
investigational product held by the pharmacist to verify accountability of all investigational product used. 
The Sponsor will verify that a final report of drug accountability to the unit dose level is prepared and 
maintained in the Pharmacy Study File. At the conclusion of the study, all unused investigational product 
and all medication containers will be destroyed by the pharmacist after final accountability by the study 
monitor and drug accountability has been reviewed and reconciled by the Sponsor and the Sponsor has 
authorized destruction or return. A certificate of destruction will be provided by the pharmacist to the 
Sponsor. Alternatively, study medication may be returned to the clinical supply distributor after 
notification to OTD and OncoEthix. All delivery records must be reconciled with usage records and 
destroyed or returned. It is essential that all study drugs be accounted for by the site’s pharmacist, and that 
discrepancies are explained and documented. 
Complete instructions and contact information for ordering clinical supplies will be supplied in the 
Investigator File. 
5.7 
Compliance 
Administration of the investigational product will be supervised by the investigator. Any delegation of this 
responsibility must follow Section 12.2.  
In practice, on study visit days study nurses will supervise the intake of the appropriate OTX01/MK-86285 
dose, explaining to patients the exact number of capsules they should take. Nurses will document in the 
eCRF the administration, the dose, the time of administration, as well as any immediate reactions at the 
time of intake. 
For non-visit days, OTX015/MK-8628 will be taken at home. The patient will note the number of capsules 
taken, the time of administration, as well as any reactions including the date/time in a specific patient’s 
diary. 


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When a patient attends a study visit, he/she will bring any unused capsules and their diary. According to 
the center procedures, the diary will be used to complete the eCRF treatment administration section, either 
directly as a Source Document or as an aid for completing the nurse’s notes which will be used as a Source 
Document. 
 
6 
PRIOR AND CONCOMITANT ILLNESSES AND TREATMENTS 
6.1 
Medical Conditions 
Additional illnesses, independent of the treated condition, present at the time informed consent is given or 
within 4 weeks prior to first study treatment administration must be documented in the eCRF. Relevant 
past illnesses (including other cancers) must also be documented in the section “Prior and Concomitant 
Conditions” of the eCRF. 
Medical conditions first occurring or detected during the study or worsening of a concomitant illness 
during the study, are to be considered TEAEs and must be documented in the “Adverse Events” section of 
the eCRF.  
6.2 
Medications 
All treatments taken by patients at study entry or within 4 weeks or 5 half-lives prior to initiating treatment 
(whichever is longer) or at any time during the study, in addition to the investigational product are 
considered concomitant medications and must be documented in the eCRF. 
No premedication is planned. 
Allowed 
• 
Supportive treatment of symptoms/AEs or standard treatment of concomitant conditions, including 
corticosteroids, aspirin, transfusion support, and antibiotics,  
• 
Growth factors (G-CSF, EPO etc.) after cycle 1. 
• 
For CRPC patients, maintenance treatment with ongoing androgen deprivation therapy with a 
gonadotropin releasing hormone (GnRH) analogue or antagonist is mandatory providing serum 
testosterone is < 50 ng/dL (<1.7 nmol/L), unless the patient had previous bilateral orchiectomy as part of 
his hormone therapy. 
• 
Chemotherapy, hormone therapy or any other anticancer therapy or surgical intervention resection 
performed ≥ 3 weeks prior to study start (≥ 6 weeks for nitrosoureas or mitomycin C) or ≥ 3 half-lives for 
monoclonal antibodies or ≥ 5 half-lives for other non-cytotoxic agents (whichever is longer). Palliative 
radiation therapy (for analgesia) is authorized only if the irradiated field does not include target lesions. 
• 
Bisphosphonates or denosumab given at stable doses for ≥ 4 weeks prior to study start. Bisphosphonates 
or denosumab are permitted from cycle 3. 
• 
Prophylactic low-dose LMWH or antivitamin K (INR < 3); INR must be monitored in accordance with 
local institutional practices. Patients who develop venous thromboembolic events during study requiring 
therapeutic levels of LMWH must be closely monitored for their platelet counts. 
Not allowed 
• 
Other concurrent investigational drugs, agents or devices or any other therapy for cancer treatment. 
• 
Any drugs given with a prophylactic intent during the first cycle. 


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• 
Concurrent treatment with strong CYP3A4 interfering drugs/substances is not permitted. The concomitant 
use of other CYP3A4 interfering drugs or any CYP2A6 interfering drug is allowed provided a careful 
follow-up of laboratory results that may be influenced by the concomitant agent is performed (e.g. INR if 
the concomitant agent is an anticoagulant, blood cell counts if the concomitant drug is hematotoxic must 
be followed up more frequently than required by the protocol). A list is provided in Appendix 3, however 
since this list is not comprehensive, the investigator should use his/her medical judgment when a patient 
presents with a medication not on the list or call the Sponsor Medical Expert for clarification. 
• 
Current use of anticoagulants (e.g. warfarin, heparin) at curative therapeutic levels within 7 days prior to 
the first dose of OTX015/MK-8628, with the exception of prophylactic low-dose LMWH or antivitamin K 
(INR < 3).  
 
7 
STUDY PROCEDURES AND SCHEDULE 
7.1 
Pre-Study Screening Visit 
Each candidate patient will be examined before starting the study to determine eligibility for participation. 
This must be done within 2 weeks prior to the first study treatment administration, except for radiologic 
assessment which can have been performed up to 4 weeks prior to study start. The following investigations 
will be performed: 
• 
Informed consent: obtain written patient informed consent prior to any specific study procedure 
• 
Verification of eligibility criteria 
• 
Demographics, medical history, including non-cancer medical history, and concurrent illnesses 
• 
Diagnosis and prior treatment for malignancy (a confirmatory diagnosis of NUT midline carcinoma or 
NSCLC at screening is not required) 
• 
Physical examination, PS (Appendix 1), vital signs (temperature, blood pressure, pulse), body weight, 
height 
• 
Pregnancy test if child-bearing potential (urine test) 
• 
Baseline symptoms and complaints 
• 
Complete blood count (CBC), including hemoglobin, RBC counts, WBC and differential, platelet counts 
• 
INR, Factor VII 
• 
Serum chemistries: Na, K, Ca, Mg, P, Cl, HCO3, creatinine, total protein, albumin, glucose, alkaline 
phosphatase, total bilirubin, AST, ALT, LDH 
• 
Tumor evaluation: physical examination, CT, MRI, and/or chest X-ray (PA and lateral), as indicated by the 
patient’s diagnosis. A bone scan is mandatory for CRPC patients. 
• 
Serum tumor markers, according to indication (PSA, CA19-9, CA15-3, CEA, etc.); as far as possible, 
subsequent measures must be made in the same laboratory 
• 
Concomitant medications  
 
 
 


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7.2 
Evaluations During Study Treatment 
Visit: Day 1 of each cycle 
For cycle 1, patients participating in pharmacokinetics will be observed for ≥ 8 hours after the first study 
drug administration to collect PK blood samples and check vital signs, when appropriate. 
• 
Physical examination, PS, vital signs, body weight 
• 
CBC 
• 
INR, Factor VII 
• 
Serum chemistries: all patients with specific liver test abnormalities (see Section 5.2.4) should be 
monitored weekly until all abnormalities return to normal or to the baseline state. For patients with isolated 
total bilirubin increases >2 x ULN or 2 x baseline (if elevated at baseline), monitoring should be every 2 
weeks until bilirubin returns to normal or to the baseline state. DILI may develop or progress even after the 
causative drug has been stopped. 
• 
Concomitant medications 
• 
Adverse events 
• 
Tumor markers, as appropriate for tumor type; as far as possible, measures must be made in the same 
laboratory 
• 
Dispensing of study drug (adequate quantity until day 1 visit of next cycle) 
• 
Day 1 of cycle 1 only: PK blood sampling in patients included in the dose escalation part of the study and 
selected patients from the expansion cohort (see Section 10 for full PK details): T0 (just before 
OTX015/MK-8628 intake), T15min (±5 min) post-dose, T1h (±15 min) post-dose, T2h (±15min) post-
dose, T3h (±15min) post-dose, and T7h (±15min) post-dose, post-dose 
• 
Day 1 of every 2nd cycle (C3, C5, C7, etc.; i.e., every 6 weeks): Tumor imaging (CT, MRI, and/or chest 
X-ray, as indicated) and response assessment 
• 
Day 1 every 4th cycle (C5, C9, C13 etc.; i.e., every 3 months): Bone scan for CRPC patients 
Twice a week for cycles 1 and 2 then weekly thereafter 
• 
CBC 
Weekly for cycles 1 and 2  
• 
Serum chemistries; from cycle 3 on, in the absence of ≥ grade 2 abnormalities these tests will be performed 
every cycle; otherwise they are to be done weekly until resolution to baseline levels or < grade 2. 
• 
INR, Factor VII 
7.3 
End of Treatment Visit and Follow-Up  
After the last treatment administration, patients will be followed up for safety for 30 days and then until 
resolution of any TEAEs for which a relationship to OTX015/MK-8628 cannot definitely be excluded (or 
categorized as sequelae). 
A visit will be performed 35 days (±5 days) after the last OTX015/MK-8628 intake, including the 
following: 
• 
Physical examination, PS, vital signs, body weight  


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• 
CBC 
• 
INR, Factor VII 
• 
Serum chemistries 
• 
Concomitant medications 
• 
Adverse events 
• 
Tumor imaging 
• 
Tumor markers 
The last patient will be followed-up for at least two cycles after treatment initiation to allow for evaluation 
of efficacy. 
 
8 
ASSESSMENT OF SAFETY 
In emergency situations, the investigator should immediately contact a Sponsor representative at the 
telephone number or email address given on the title page of this protocol. 
Patients will be monitored for signs and symptoms of AEs throughout the study by a qualified oncologist, 
with experience in clinical research. All AEs will be reported in the eCRF, including seriousness, NCI-
CTCAE v4.03 grade severity, causal relationship to the study medication, and action taken. The first 
concern will be the safety of the study participant.  
Incidence, severity and relationship of AEs and laboratory abnormalities, SAEs, discontinuations and dose 
adaptations due to AEs will be recorded. 
8.1 
Clinical Safety 
Clinical and physical examinations, as well as vital signs evaluation, will be performed. Patient data will be 
analyzed for evidence of cumulative toxicity with repeated cycles of therapy. 
TEAEs and signs and symptoms of disease observed by the investigator (preferably by the same physician 
for a same patient) or reported by patients to the study nurses will be recorded and graded according to 
NCI-CTCAE version 4.03, accessible via internet [http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-
06-14_QuickReference_8.5x11.pdf]. It is crucial that all events, including those considered not related to 
the study drug are reported in the eCRF. 
8.2 
Laboratory Measurements 
Any laboratory abnormality assessed as related, probably related, or possibly related must be reported as a 
TEAE in the eCRF. Clinically significant laboratory values must be reported as TEAEs in the eCRF. 
Clinically significant laboratory results are those which have clinical consequences (i.e. need treatment or 
corrective measures, result in study drug dose reduction, delay or discontinuation, hospitalization, 
prolongation of hospitalization, or death, are life-threatening, are reported as an SAE whatever the reason, 
or are considered a toxicity of the treatment). The seriousness, the action taken regarding study medication 
and patient participation in the study, relation to study medication and the most likely cause, must be 
recorded. 
8.3 
Definitions (21 CFR§312.32) 
• 
Adverse event (AE) means any untoward medical occurrence associated with use of a drug in humans, 
whether or not considered drug related. The term treatment emergent adverse event [TEAE] covers any 


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unfavorable and unintended sign, symptom, syndrome, or illness that develops or worsens during the 
period of observation in the clinical study. Surgical or other procedures themselves are not TEAEs. The 
condition for which the surgery/other procedure is required, is a TEAE, if it occurs or is detected during 
the study period. Planned surgical or other procedures planned/permitted by the study protocol and the 
condition(s) leading to these measures are not TEAEs, if the condition(s) was (were) known before the 
start of study treatment. In the latter case the condition should be reported as medical history. 
• 
Adverse drug reaction (ADR) means an AE caused by the drug. 
• 
Suspected adverse reaction (SAR) means any AE for which there is a reasonable possibility that the drug 
caused the AE. A “reasonable possibility” means there is evidence to suggest a causal relationship between 
the drug and the AE. SAR implies a lesser degree of certainty about causality than an ADR, and include: 
-  A single occurrence of an event that is uncommon and known to be strongly associated with drug 
exposure; 
- One or more occurrences of an event that is not commonly associated with drug exposure, but is 
otherwise uncommon in the population exposed to the drug (e.g., tendon rupture); 
- An aggregate analysis of specific events observed in a clinical trial (such as known consequences of the 
underlying disease or condition under investigation or other events that commonly occur in the study 
population independent of drug therapy) that indicates those events occur more frequently in the drug 
treatment group than in a concurrent or historical control group. 
 
• 
Serious adverse event (SAE) or serious suspected adverse reaction (SSAR) is an event that, in the view 
of either the investigator or Sponsor, results in any of the following outcomes: 
- 
Death occurring on study or within 30 days after the last administration of study drug (regardless of 
relationship to study treatment) or within any interval if related to the study drug. Although death may 
occur as a result of the disease, all deaths occurring within 30 days of the last administration of study 
drug must be managed as SAEs and reported as such; 
- 
A life-threatening AE; 
- 
Inpatient hospitalization or prolongation of existing hospitalization; 
- 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions;  
- 
A congenital anomaly/birth defect. 
In addition, medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in situations where none of the outcomes listed above occurred. Important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient’s safety or may require intervention to prevent one of the outcomes listed in the definition above 
should also usually be considered serious. Examples of such events include overdose even without 
complications, or an AE requiring intensive treatment without hospitalization. A diagnosis of a new cancer 
type during the course of a treatment should be considered as medically important. In addition, any 
pregnancy diagnosed in a female patient on treatment with the investigational product or in the partner of a 
male patient on treatment with the investigational product must be reported to the Sponsor immediately. 
The List of Critical Terms (1998 adaptation of WHO Adverse Reaction Terminology Critical Terms List, 
provided in the “Instructions for completing the ‘Serious Adverse Event/Expedited Report from a Clinical 
Trial’ form”) should be used as guidance for AEs that may be considered serious because they are 
medically important. 
For the purpose of the dose-finding part of this study, any suspected DLT occurring during the dose 
escalation part will be considered as medically important and reported as an SAE even if it does not meet 
other criteria for seriousness. In the latter case, the reason for seriousness will be “other important medical 
event”. 


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● Life-threatening AE or life-threatening SAR is an AE that, in the view of either the investigator or 
Sponsor, places the patient at immediate risk of death. It does not include an AE or SAR that, had it 
occurred in a more severe form, might have caused death. 
● Unexpected AE or unexpected SAR is an AE or SAR that is not listed in the investigator brochure or is 
not listed at the specificity or severity that has been observed. For example, under this definition, hepatic 
necrosis would be unexpected (by virtue of greater severity) if the investigator brochure referred only to 
elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would 
be unexpected (by virtue of greater specificity) if the investigator brochure listed only cerebral vascular 
accidents. “Unexpected”, as used in this definition, also refers to AEs or SARs that are mentioned in the 
investigator brochure as occurring with a class of drugs or as anticipated from the pharmacologic 
properties of the drug, but are not specifically mentioned as occurring with the particular drug under 
investigation. 
8.4 
Documentation  
All TEAEs occurring during the course of the study, whether or not considered related to the study drug or 
to underlying disease, must be individually recorded in the eCRF, including the nature of the event, date 
and time of onset (where appropriate), duration of effect, action taken, seriousness, severity, and 
relationship to study medication. Any consequent change to the dosage schedule or corrective therapy 
should be recorded.  
Every attempt should be made to describe the TEAE in terms of a diagnosis. If a clear diagnosis has been 
made, individual signs and symptoms will not be recorded. If a clear diagnosis cannot be established, each 
sign and symptom must be recorded individually. 
All patients who experience a TEAE, regardless of the relationship to study treatment, must be monitored 
to determine the outcome. The clinical course of the AE will be followed up even after the end of the 
period of observation for related TEAEs, until a satisfactory explanation is found or the investigator 
considers it medically justifiable to terminate follow-up. Should the AE result in death, a post-mortem 
examination should be considered as far as possible. 
After last study treatment administration, patients will be observed for at least 30 days to document any 
late side effects and until resolution in cases of TEAEs for which a relationship to OTX015/MK-8628 
cannot definitely be excluded. 
AEs already recorded and designated as “continuing” should be reviewed at each subsequent assessment. If 
resolved, details are to be recorded in the eCRF. If an AE worsens in frequency of attacks/symptoms or in 
severity, a new record of the event must be started (i.e., distinct AE reports are required for differing 
frequencies and/or severity of the same event to enable comprehensive safety reports and later analysis).  
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, must be reported under 
“concomitant procedures” in the eCRF and not as an AE. The medical condition for which the procedure 
was performed must be reported. 
8.5 
Grade and Severity 
All AEs, whether or not they are considered related to the study drug, must be graded using the NCI 
Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03, which can be found at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. 
The 
worst 
grade is to be documented. 
AE grades usually reflect their severity, with grade 1 meaning “mild”, grade 2 meaning “moderate”, grade 
3 meaning “severe”, grade 4 meaning “life-threatening” and grade 5 meaning “fatal”. 


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The term “severity” is used to describe the intensity of an AE; the event itself, however, may be of 
relatively minor clinical significance (e.g., ‘severe’ headache). This is not the same as “serious”. 
Seriousness of AEs is based on the outcome/action of an AE and usually is associated with events that pose 
a threat to a patient’s life or functioning. 
Intensity of the AE will be evaluated using the following criteria: 
● Mild: The patient is aware of the sign or symptom, but finds it easily tolerated. The event is of little 
concern to the patient and of little clinical significance. The event is not expected to have any effects on the 
patient’s overall health or wellbeing. 
● Moderate: The patient has discomfort enough to cause interference with or change in usual activities. The 
event is of some concern to the patient’s health or wellbeing and may require medical intervention and/or 
close follow-up. 
● Severe: The AE interferes considerably with the patient’s usual activities. The event is of definite concern 
to the patient and/or poses substantial risk to the patient’s health or wellbeing. The event is likely to require 
medical intervention and/or close follow-up and may be incapacitating or life-threatening. Hospitalization 
and treatment may be required. 
8.6 
Relationship to Study Treatment 
All TEAEs occurring during treatment with an investigational agent may be related to the investigational 
agent. All TEAEs, regardless of the supposed relationship to study treatment, must therefore be collected. 
However, the investigator often has arguments to think that a TEAE is or is not related to the study 
treatment. Albeit subjective, and susceptible to be challenged, the assessment of relationship to study 
treatment is an important role of the investigator. Thus, the investigators should decide, based on their 
knowledge and medical expertise, whether, in their opinion, an AE is “reasonably related” or “unlikely 
related” to the study treatment (or to study specific procedures).  
8.7 
SAE Reporting  
SAEs and other AEs that fulfill a reason for expedited reporting to Pharmacovigilance (overdose and 
pregnancy) must be documented on a Serious Adverse Event Report Form (SAERF) at the time the SAE is 
detected. This form must be completed and sent within 24 hours or at the latest on the following working 
day to the Sponsor’s Pharmacovigilance representative: 
 
Oncology Therapeutic Development (OTD) 
Tel: 
  
Fax: 
  
E-mail: 
  
The SAERF and guidelines for completing it are provided in the Investigator Study File. The Sponsor is 
responsible for ensuring that all legal reporting requirements are met. 
The initial report must be as complete as possible, including details of the current illness and AE(s), and an 
assessment of the causal relationship between the event(s) and the investigational product. 
Information not available at the time of the initial report (e.g., an AE end date or laboratory values received 
after the report) must be documented on a follow-up SAERF. 
PPD
PPD
PPD


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8.8 
Period of Observation 
For the purposes of this study, the period of observation for collection of AEs extends from the start of 
treatment with the investigational product until the end of study treatment period, 30 days after the last 
study drug administration, except for TEAEs for which a relationship to OTX015/MK-8628 cannot 
definitely be excluded, which must be reported during follow-up until resolution or change of causality 
from related to non-related or initiation of further antitumor therapy. 
If the investigator detects an SAE after the end of the period of observation, and considers the event 
possibly related to prior study treatment, he/she should contact the Sponsor to determine how the AE 
should be documented and reported. 
8.9 
Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) and 
must be reported to the Sponsor. 
For the time period beginning when the consent form is signed until patient registration, any ECI, or follow 
up to an ECI, that occurs to any patient must be reported within 24 hours to the Sponsor if it causes the 
patient to be excluded from the trial, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, or a procedure. 
For the time period beginning at patient registration through 30 days following cessation of treatment, any 
ECI, or follow up to an ECI, whether or not related to the Sponsor’s product, must be reported within 24 
hours to the Sponsor, either by electronic media or paper.  Electronic reporting procedures can be found in 
the data entry guidelines.   
1. An elevated AST or ALT lab value that is ≥3X ULN and an elevated total bilirubin lab value that is ≥2X 
ULN and, at the same time, an alkaline phosphatase lab value that is < 2X ULN, as determined by 
protocol-specified laboratory testing or unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose of the criteria 
is to specify a threshold of abnormal hepatic tests that may require an additional evaluation for an 
underlying etiology. The trial site guidance for assessment and follow up of these criteria can be found in 
Appendix 5 and the Investigator Brochure section on discussion and guidance for investigator. 
2. An elevated total bilirubin lab value that is ≥ 2X ULN. 
3. Any of the following liver test abnormalities are observed (see also Appendix 5): 
- 
ALT or AST > 8X ULN  
- 
ALT or AST > 5X ULN for more than 2 weeks 
- 
ALT or AST > 3X ULN AND (total bilirubin > 2X ULN OR INR > 1.5) 
- 
ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash and/or eosinophilia (> 5%) 
**All patients with these liver test abnormalities should be followed weekly until all abnormalities return 
to normal or to the baseline state. DILI may develop or progress even after the causative drug has been 
stopped. Results should be recorded on the case report form and in the database. See Appendix 5 for 
guidelines on the handling of events of ALT or AST >3 x ULN AND total bilirubin >2 x ULN or INR>1.5 
(potential Hy’s law cases). 
 


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9 
EFFICACY ASSESSMENTS 
Efficacy will be measured in terms of tumor response, according to either RECIST, or PCWG2 for CRPC 
patients. Tumor markers will also be assessed; CEA (for NSCLC), CA19-9 and CEA (for PDAC), PSA 
(for CRPC), CA15-3 (TNBC), and other nonspecific tumor markers as appropriate. Tumor measurements 
are to be made every 6 weeks and bone scans will be performed every 12 weeks until progressive disease is 
observed. 
9.1 
RECIST  
Tumor lesions will be assessed throughout the study according to RECIST criteria (version 1.1) 
(Eisenhauer et al., 2009). Any tumor shrinkage, in terms of percentage of tumor regression, will be 
reported even if it does not meet RECIST criteria for response. While RECIST criteria (version 1.1) do not 
require confirmation of objective response in clinical studies where response rate is not the study primary 
endpoint, as a convincing proof-of-concept of antitumor activity, efforts should be made to confirm 
objective response at least 4 weeks apart. 
9.1.1 
Imaging Technique  
To ensure comparability, the baseline and subsequent tumor measurements to assess response should be 
performed using identical imaging techniques (i.e., preferably the same machine, contrast agent and 
standard volume of contrast agent, etc.). 
9.1.2 
Evaluation of Lesions 
Table 12: Evaluation of response in 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. 
Progression (PD) 
At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is 
the smallest on study).  
In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.  
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 study
Table 13: Evaluation of non-target lesions 
Complete Response (CR) 
Disappearance of all non-target lesions. All lymph nodes must be non-
pathological in size (<10 mm 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. 
Progression (PD) 
Unequivocal progression of existing non-target lesions; see Section 4.3.4 of 
Eisenhauer et al., 2009 for further details.  
Note: the appearance of one or more new lesions is also considered 
progression. Unequivocal progression of existing non-target lesions, other 
than pleural effusions without cytological proof of neoplastic origin, in the 
opinion of the treating investigator (in this circumstance an explanation 
must be provided)1.  
1Although clear progression of non-target lesions only is exceptional, in such circumstances, the opinion of the 
treating physician should prevail and the progression status should be confirmed later by the Medical Monitor. 


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9.1.3 
Definition of Best Overall Tumor Response  
The best overall response is the best response recorded between the start and the end of treatment, as 
described below. Overall response is calculated for each assessment time point according to Table 14. 
Table 14: Overall response in patients with target (+/– non-target) disease 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable 
 
The best overall response is determined once all data for a given patient are available. Table 15 below 
summarizes the best overall tumor response. 
Table 15: Best overall response 
Overall response 
First time point 
Overall response 
Subsequent time 
points 
Best overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR1 
CR 
SD 
SD provided minimum criteria for SD duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, otherwise NE 
NE 
NE 
NE 
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable 
1. If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes CR may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the first time 
point. Under these circumstances, the original CR should be changed to PR and the best response is PR. 
 


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Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration”. Every 
effort should be made to document the objective progression even after discontinuation of treatment.  
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the next 
scheduled assessment, progression is confirmed, the date of progression should be the earlier date when 
progression was suspected. 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of complete response depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/ biopsy) before confirming the complete response status. 
9.2 
PCWG2  
For CRPC patients, PSA response rates will be measured according to the PCWG2 criteria (Scher et al., 
2008). RECIST v1.1 is used to assess soft tissue disease (Eisenhauer et al., 2009). Progression of bone 
disease is defined using PCWG2 criteria, namely a confirmed increase of at least two new lesions on a 
bone scan. 
9.2.1 
PSA 
For control/relief/eliminate end points 
The PCWG2 advises against reporting PSA response rates because they are of little value given the 
uncertain significance of a defined degree of decline from baseline, be it 50% or 30%, and no criterion has 
been shown prospectively to be a surrogate of clinical benefit (Fleming et al., 2006). 
To report PSA-based outcomes, PCWG2 recommends that the percentage of change in PSA from baseline 
to 12 weeks (or earlier for those who discontinue therapy), as well as the maximum decline in PSA that 
occurs at any point after treatment be reported for each patient using a waterfall plot (Seidman et al., 1992). 
Waterfall plots provide a broader and more sensitive display of data, and are more informative until a 
validated surrogate of clinical benefit becomes available. PCWG2 recommends that the same waterfall plot 
be used to illustrate outcomes for noncytotoxic agents. It discourages the use of changes in PSA-doubling 
time or PSA slope as a primary end point, given that their clinical significance is uncertain, and also 
recommends avoiding reporting duration of PSA control, as described in PCWG1 guidelines, because its 
interpretation varies between investigators. 
For delay/prevent end points 
PCWG2 defines PSA progression as the date that a 25% or greater increase and an absolute increase of ≥2 
ng/mL from the nadir is documented, which is confirmed by a second value obtained 3 or more weeks 
later. This will be used to determine both PSA progression and response duration. This recommendation 
recognizes that variations in progression times might occur simply on the basis of the rate of PSA rise. 
Where no decline from baseline is documented, PCWG2 defines PSA progression as a 25% increase from 
the baseline value along with an increase in absolute value of 2 ng/mL or more (rather than 5 ng/mL) after 
12 weeks of treatment. 
9.2.2 
Measurable Soft-Tissue Lesions 
For control/relieve/eliminate end points 
PCWG2 accepts with modifications RECIST criteria for evaluating drugs or approaches anticipated to 
produce tumor regression. The modifications are that changes in nodal and visceral sites be recorded and 
reported separately, and lymph nodes in the pelvis must measure at least 2 cm in their greatest diameter to 


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be considered target lesions. PCWG2 also recommends that the complete elimination of disease at a 
particular site be recorded separately. PCWG2 reinforces the recommendation in RECIST that any 
favorable change should be confirmed using a second follow-up scan. As with changes in PSA, PCWG2 
suggests that changes in the size of the target lesions be reported as a waterfall plot to facilitate comparison 
between studies.  
For prevent/delay end points 
Progression in a nodal or visceral site should also be defined using RECIST, with the recognition that, for 
some therapies, early unfavorable changes may not accurately reflect disease status. As noted, a 
lymphocytic infiltration of a tumor mass after successful immunization may result in an enlarged soft-
tissue lesion that could be an early indication that the treatment is working. Further, because the effects of 
some agents (non-cytotoxic) may be delayed, the degree of increase in tumor size at the first 12-week 
assessment should also be confirmed before it is considered a treatment failure.  
9.2.3 
Bone 
Given the frequency of bone involvement in patients with progressive, castration-resistant disease, the 
decreased emphasis of early changes in PSA, and the increased availability of cytostatic agents, reliable 
methods to assess changes in bone are of increasing importance. PCWG2 recognizes that standards for 
using MRI and PET to assess bone metastases are under active investigation, so only radionuclide bone 
scans are considered here. PCWG2 also recognizes that there are no validated criteria for response on 
radionuclide bone scan.  
For control/relieve/eliminate end points 
PCWG2 recommends that post-treatment changes be recorded simply as either “no new lesions” or “new 
lesions.” However, progression at the first scheduled assessment should be confirmed on a second scan 
performed 6 or more weeks later, in the absence of clearly worsening soft-tissue (nodal and visceral) 
disease or disease-related symptoms. In the rare case where visible lesions disappear, this too should be 
confirmed at the next scheduled assessment.  
For prevent/delay end points 
Progressing disease on bone scan is considered when a minimum of two new lesions is observed. PCWG1 
made the provision that a worsening bone scan on the first follow-up manifests tumor “flare”; PCWG2 
does not recommend performing a follow-up bone scan before 12 weeks of treatment unless clinically 
indicated. At the first 12-week reassessment, defining disease progression requires a confirmatory scan 
(which shows additional new lesions compared with the first follow-up scan) performed 6 or more weeks 
later, because lesions visible at the 12-week assessment may represent disease that was not detected on the 
pretreatment scan. When further progression is documented on the confirmatory scan, the date of 
progression recorded for the trial, is the date of the first scan that shows the change. 
Note that symptoms will not be evaluated in this phase Ib study.  


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Table 16: The Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria 
Variable 
PCWG2 Criteria (Scher et al., 2008) 
PSA 
For control/relieve/eliminate end points: 
 
Record the percent change from baseline (rise or fall) at 12 weeks, and separately, the 
maximal change (rise or fall) at any time using a waterfall plot 
 
Progression: 
 
Decline from baseline: record time from start of therapy to first PSA increase that is ≥ 
25% and ≥ 2 ng/mL above the nadir, and which is confirmed by a second value 3 or 
more weeks later (i.e., a confirmed rising trend) 
 
The requirement of an increase of 5 ng/mL is decreased to 2 ng/mL, and the 
requirement for a 50% increase is reduced to 25% 
 
Recording the duration of PSA decline of little value 
 
No decline from baseline: 
 
PSA progression ≥ 25% and ≥ 2 ng/mL after 12 weeks 
Soft-tissue 
lesions 
For control/relieve/eliminate end points: 
 
Use RECIST with caveats 
 
 
Only report changes in lymph nodes that were ≥ 2 cm in diameter at baseline 
 
 
Record changes in nodal and visceral soft tissue sites separately 
 
 
Record complete elimination of disease at any site separately 
 
 
Confirm favorable change with second scan 
 
 
Record changes using waterfall plot 
 
For delay/prevent end points: 
 
Use RECIST criteria for progression, with additional requirement that progression at 
first assessment be confirmed by a second scan 6 or more weeks later 
 
Note that for some treatments, a lesion may increase in size before it decreases 
Bone 
For control/relieve eliminate end points: 
 
Record outcome as new lesions or no new lesions 
 
First scheduled reassessment: 
 
No new lesions: continue therapy 
 
New lesions: perform a confirmatory scan 6 or more weeks later 
 
Confirmatory scan: 
 
No new lesions: continue therapy 
 
Additional new lesions: progression 
 
Subsequent scheduled reassessments: 
 
No new lesions: continue 
 
New lesions: progression 
 
For prevent/delay end points (progression): 
 
The appearance of ≥ 2 new lesions, and, for the first reassessment only, a confirmatory 
scan performed 6 or more weeks later that shows a minimum of 2 or more additional 
new lesions 
 
The date of progression is the date of the first scan that shows the change 
PSA, prostate-specific antigen 


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10 PHARMACOKINETICS ASSESSMENTS 
10.1 Sample collection 
PK sampling will be performed in all patients enrolled in the dose escalation phase and selected patients 
from the expansion cohort.  
A plasma sampling schedule including a total of 6 time-points over the first 7 hours of day 1 of cycle 1 
will be performed to characterize the PK profile of OTX015 (Cmax, Cmin, Tmax, AUC [0-∞], Vdss, t1/2, and CL), 
as follows: T0 (immediately before OTX015/MK-8628 intake), T15min (±5 min), T1h (±15min), T2h 
(±15min), T3h (±15min), T7h (±15min) post-dose. 
Blood samples of 3.0 mL will be collected in EDTA tubes, inverted a few times to mix the anticoagulant 
and then processed as soon as possible (within 15 min). Samples will be centrifuged at 1500 g (4,000 rpm 
for a 14-15 cm centrifuge) at +4°C for 10 minutes. Plasma will be immediately aliquoted and stored in 
airtight stoppered polypropylene tubes at -20°C.  
In total, six blood samples of 3.0 mL each will be collected, i.e. approximately 18 mL of blood will be 
drawn per patient from a peripheral venous access for PK analysis. 
Blood samples must be sent as soon as possible to the laboratory for analysis, to allow for availability of 
results at the SMC meeting. If two patients in the same center are treated at the same time or a few days 
apart, samples of these two patients should be sent together.  
All samples will be labeled with: 
• 
Sponsor and Protocol Number 
• 
UPN and patient initials 
• 
Sample number with actual date and time of collection 
All samples must be shipped at -20°C to: 
  
Laboratoire de Pharmacologie  
Institut Curie (Hôpital René Huguenin) 
35, rue Dailly 
92210 Saint-Cloud, France 
Phone: 
 
Fax: 
 
 
 
10.2 Assay Method and Parameters Analyzed 
Plasma concentrations of OTX015/MK-8628 will be measured using Ultra Performance Liquid 
Chromatography with tandem Mass Spectrometry detection (UPLC-MS/MS). 
The following parameters will be determined: Trough (Cmin) and peak (Cmax) concentrations, Tmax, AUC[0-
∞], Vdss, t1/2, steady state, total clearance (CL). 
Descriptive statistics will be used to summarize PK parameters with mean, standard deviation (SD), 
coefficient of variation (CV) and ranges. Analyses will be carried out using the nonlinear mixed effect 
modeling software program Monolix version 3.2s (http://wfn.software.monolix.org). 
PPD
PPD
PPD
PPD


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PK data for OTX015/MK-8628 will be interpreted in terms of safety findings and compared with historical 
data. 
11 STATISTICAL CONSIDERATIONS 
11.1 Statistical Design and Sample Size 
The exploratory part of the study is designed to assess the safety of OTX015/MK-8628 in patients with 
advanced or metastatic solid tumors. The small numbers per cohort are not intended for statistical 
hypotheses. Treatment decisions will be made by the SMC. The expansion cohort part will start once the 
MTD and a regimen are determined. 
In the dose escalation part, up to 48 patients evaluable for DLT (i.e. up to 24 patients per regimen) will be 
accrued depending on the number of DLTs encountered. Once the MTD is established with at least 3 
patients having received at least 2 cycles of study drug, an expansion cohort of up to 50 additional 
evaluable patients (10 patients per indication) will be enrolled. The regimens used in the expansion cohort 
will be decided for each indication by the SMC. 
The final sample size will depend on the number of DLTs encountered at each DL and in each regimen, 
and may be increased if within the two proposed regimens and four planned DLs, the MTD is not reached 
and additional DLs are required. 
11.2 Study Endpoints 
Primary: The number of patients experiencing at least one DLT in cycle 1 (day 1 to 21) for each of the two 
regimens independently. 
Secondary: 
Safety: Incidence, severity and relationship of AEs, laboratory abnormalities, SAEs, discontinuations due 
to AEs, dose adaptations due to AEs, and DLT. 
Efficacy: The number of patients with clinical benefit (defined as complete response, partial response or 
stable disease) and progressive disease based on the best overall response from tumor evaluations 
performed every 2 cycles, according to RECIST v1.1 or PCWG2, and tumor marker assessment. 
Pharmacokinetics: Plasma parameters of OTX015/MK-8628 including Cmax, Cmin, Tmax, AUC [0-∞], Vdss, 
t1/2, CL. 


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11.3 Analysis Populations 
• 
Evaluable for DLT: patients who receive at least 85% of the planned dose of study drug (18 days for 
Regimen 1, or 6 days for Regimen 2) or experience DLT during the first 21-day cycle.  
• 
Treated population: patients who receive at least one dose of study drug. 
• 
Evaluable for efficacy: patients who receive at least 2 complete cycles (6 weeks) of treatment and have 
undergone baseline assessment and one on-study tumor assessment, or who discontinue early due to 
disease progression. 
11.4 Statistical Methods  
Quantitative variables will be summarized using descriptive statistics; continuous variables will be 
presented as N, mean and/or median, standard deviation, range, and categorical variables will be presented 
using frequencies and percentage. For CRPC patients, waterfall plots for percent change from baseline at 
12 weeks, as well as maximal change at any time will be prepared. 
Patient disposition and demographics will be analyzed in all included patients, safety will be analyzed in 
the treated population with an additional analysis in patients evaluable for DLT for the dose escalation part, 
and response will be analyzed in patients evaluable for efficacy. 
AEs will be coded according to the most recent version of the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be tabulated by System Organ Class and Preferred Term. Laboratory values outside 
normal limits will be summarized using the NCI-CTCAE version 4.03. Concomitant medications will be 
coded according to the WHO Drug Dictionary. 
Data will be presented by dose level and regimen for the dose escalation part, by indication and/or regimen 
for the dose expansion part of the study. No imputations for missing data will be made. 
A Statistical Analytical Plan (SAP) will be finalized prior to analysis. Any deviations from the statistical 
methods in the study protocol will be described and justified in the SAP and in the statistical report. 
Pharmacokinetics will be analyzed and reported separately, as described in Section 10. 
11.5 Interim Analysis 
No formal interim analysis is planned.  
During the dose escalation phase, regular assessment of data from the most recent cohort of three patients 
of each regimen evaluable for DLT will be performed by the SMC. 
 
12 ETHICAL AND LEGAL ASPECTS 
12.1 Good Clinical Practice 
This clinical study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), as 
defined in ICH Guidance E6: Good Clinical Practice: Consolidated Guidance, in agreement with the 
Declaration of Helsinki and applicable federal and local regulatory requirements. 
12.2 Delegation of Investigator Duties 
The investigator should ensure that all persons assisting with the trial are adequately qualified, informed 
about the protocol, any amendments to the protocol, the study treatments, and their trial-related duties and 
functions. 


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The investigator should maintain a list of sub-investigators and other appropriately qualified persons to 
whom he/she has delegated significant trial-related duties. 
12.3 Patient Information and Informed Consent 
Before being enrolled in the clinical study, patients must give written informed consent to participate in the 
study.  
A Patient Information Leaflet (PIL), including an Informed Consent Form (ICF) (provided separately) will 
be given to each patient screened in the study. This document contains all the information required by the 
ICH E6 Guideline for Good Clinical Practice and any additional elements required by local regulations. 
The master document (in English) is also translated into the national language(s) and in terms that are 
understandable to any patient. In addition to the document, the investigator should provide oral information 
and answer to patient’s questions. Patients should have an adequate time for thought and to ask questions 
and should not sign the ICF when it is first given to them.  
The patient's consent must be confirmed by their dated signature and the name and dated signature of the 
principal investigator or sub-investigator conducting the informed consent discussions. 
A copy of the signed consent document must be given to the patient. The original signed consent document 
will be retained in the Investigator Study File. 
The investigator will not undertake any measure specifically required for the clinical study until valid 
consent has been obtained. 
12.4 Confidentiality 
Patient names will not be supplied to the Sponsor. Only the UPN and initials will be recorded in the eCRF. 
If the patient name appears on any document (e.g., laboratory report), it must be eliminated on the copy of 
the document supplied to the Sponsor. Study findings stored on a computer will be kept in accordance with 
local data protection laws. Patients will be informed that representatives of the Sponsor, independent ethics 
committee (IEC)/ institutional review board (IRB), or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for inspection 
will be handled in strictest confidence and in accordance with local data protection laws. 
The investigator will maintain a patient identification list (UPN with the corresponding patient name) to 
enable records to be identified. 
12.5 Approval of the Clinical Study Protocol and Amendments 
Before the start of the study, the clinical study protocol, PIL/ICF, and any other appropriate documents will 
be submitted to the IEC/IRB and to the national Health Authorities, in accordance with local legal 
requirements. 
Before the first patient is enrolled in the study, all ethical and legal requirements must be met. 
The IEC/IRB and the authorities must be informed of all administrative changes and any important finding 
that could modify the risk of exposed patients. They also must be informed or their authorization obtained 
for all subsequent amended protocols, in accordance with local legal requirements.  
The investigator must keep a record of all communication with the IEC/IRB and the Health Authorities. 


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12.6 Ongoing Information for IEC/ IRB and Health Authorities 
The Sponsor must submit the following to all investigators, the IEC/IRB and Health Authorities: 
• Information on serious or unexpected AEs from any investigational site, as soon as possible. 
• Expedited safety reports according to regulations. 
• Periodic reports on the study progress. 
12.7 Study Closure  
The study must be closed at the site on completion. Furthermore, the Sponsor or the investigator has the 
right to close a study site at any time.  
Study materials must be returned, disposed of or retained as directed by the Sponsor. 
12.8 Record Retention 
Study documents should be retained by the investigator for at least 15 years. Beyond this period, the 
investigator still must obtain approval in writing from the Sponsor before destruction of any records. 
The documents to be retained include: 
• Original signed ICFs for all patients 
• Patient identification code list, screening log and enrollment log 
• Record of all communications between the investigator and the IEC/IRB 
• Composition of the IEC/IRB  
• Record of all communications between the investigator and Sponsor (or CRO) 
• List of sub-investigators and other appropriately qualified persons to whom the investigator has 
delegated significant trial-related duties, together with their roles in the study and their signatures 
• Copies of CRFs and of documentation of corrections on data correction forms (DCF) for all patients 
• Investigational product accountability records 
• Record of any body fluids or tissue samples retained 
• All other source documents (patient medical records, hospital records, laboratory records, etc.) 
• All other documents as listed in Section 8 of the ICH E6 Guideline for Good Clinical Practice (Essential 
Documents for the Conduct of a Clinical Trial) 
12.9 Liability and Insurance 
Liability and insurance provisions for this study are given in separate agreements. 
The Sponsor has taken out an insurance covering their civil responsibility. 
The Sponsor, OncoEthix, is a company established outside the European Union. As such, they have 
empowered the Contract Research Organization (CRO) OTD (Oncology Therapeutic Development) 
SARL, 100 rue Martre, 92110 Clichy, France, to represent them in the European Union. 


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12.10 Financial Disclosure 
Before the start of the study, the investigator will disclose to the Sponsor any proprietary or financial 
interests he or she might hold in the investigational products or the Sponsor company as outlined in the 
financial disclosure form provided by the Sponsor. The investigator agrees to update this information in 
case of significant changes during the study or within one year of its completion. The investigator also 
agrees that, where required by law or regulation, the Sponsor may submit this financial information to 
domestic or foreign regulatory authorities in applications for marketing authorizations. 
Similar information will be provided by each sub-investigator to whom the investigator delegates 
significant study related responsibilities. 
 
13  STUDY MONITORING AND AUDITING 
Monitoring and auditing procedures developed or endorsed by the Sponsor will be followed, in order to 
comply with GCP guidelines. Direct access to the on-site study documentation and medical records must 
be ensured. 
13.1 Monitoring and Source Data Verification 
Monitoring will be done by personal visits from representatives of the Sponsor (study clinical research 
assistant and medical monitor) who will check the eCRFs for completeness and clarity, and crosscheck 
them with source documents. In addition to the monitoring visits, frequent communications (letter, 
telephone, e-mail and fax), by the study monitors will ensure that the investigation is conducted according 
to protocol design and regulatory requirements. 
Study close-out will be performed by the study monitor upon closure of the study. 
13.2 On-Site Audits/Inspections 
An external auditor, appointed by the Sponsor, or the EC/IRBs, as well as inspectors, appointed by 
domestic and foreign regulatory authorities, may request access to all source documents, case report forms, 
and other study documentation for on-site audit or inspection. Direct access to these documents must be 
guaranteed by the investigator, who must provide support at all times for these activities. Medical records 
and other study documents may be copied during audit or inspection provided that patient names are 
obliterated on the copies to ensure confidentiality. 
 
14  DOCUMENTATION AND USE OF STUDY FINDINGS 
14.1 Documentation of Study Findings 
An eCRF will be used. 
All protocol-required information collected during the study must be entered by the investigator, or 
designated representative, in the eCRF. Details of eCRF completion and correction will be explained to the 
investigator. If the investigator authorizes other persons to make entries in the eCRFs, the names, positions, 
signatures, and initials of these persons must be supplied to the Sponsor. 
The investigator, or designated representative, should complete the eCRF pages as soon as possible after 
data are collected, preferably on the same day that a study patient is seen for an examination, treatment, or 


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any other study procedure and at the latest before the next monitoring visit. An explanation should be 
given for all missing data. 
A source data location list will be prepared prior to study start. This list will be filed in both the Trial 
Master File and the Investigator Study File and updated as necessary. 
The completed eCRFs must be reviewed and signed by the investigator named in the clinical study 
protocol or by a designated co-investigator. 
All errors detected after the monitoring visit will be queried using DCFs. The Sponsor will answer the 
question and/or correct errors in the DCF duly signed and dated. Original DCFs will be collected by the 
Sponsor’s study monitor, while a copy will be kept by the investigator and recorded in the Investigator 
Study File with the corresponding eCRFs. 
A copy of the eCRF will be printed and filed in the Trial Master File. The Sponsor will retain the originals 
of all eCRFs. The investigator will retain a copy of all completed eCRF pages and DCFs. 
14.2 Confidentiality/Use of Study Findings 
All information concerning the product as well as any matter concerning the operation of the Sponsor, such 
as clinical indications for the drug, its formula, methods of manufacture and other scientific data relating to 
it, that have been provided by the Sponsor and are unpublished, are confidential and must remain the sole 
property of the Sponsor. The investigator will agree to use the information only for the purposes of 
carrying out this study and for no other purpose unless prior written permission from the Sponsor is 
obtained. 
The Sponsor has full ownership of the original eCRFs completed as part of the study. 
By signing the clinical study protocol, the investigator agrees that the results of the study may be used for 
the purposes of national and international registration, publication, and information for medical and 
pharmaceutical professionals. The authorities will be notified of the investigator's name, address, 
qualifications, and extent of involvement. 
The Sponsor will ensure that a clinical study report on the study is prepared. 
All materials, documents and information supplied by the Sponsor to the investigator, and all materials, 
documents and information prepared or developed in the course of the study to be performed under this 
protocol, shall be the sole and exclusive property of the Sponsor. Subject to obligations of confidentiality, 
the investigator reserves the right to publish only the results of the work performed pursuant to this 
protocol, provided, however, that the investigator provides an authorized representative of the Sponsor 
with a copy of any proposed publication for review and comment at least 45 days in advance of its 
submission for publication. In addition, if requested, the investigator will withhold publication an 
additional 90 days to allow for filing a patent application or taking such other measures as Sponsor deems 
appropriate to establish and preserve its proprietary rights. 
It is agreed that, consistent with scientific standards, publication of the results of the study shall be made 
only as part of a publication of the results obtained by all sites performing the protocol. 


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Takahashi, T., Sonobe, M., Kobayashi, M., Yoshizawa, A., Menju, T., Nakayama, E., Mino, N., Iwakiri, 
S., Sato, K., Miyahara, R., et al. (2010). Clinicopathologic features of non-small-cell lung cancer with 
EML4-ALK fusion gene. Ann. Surg. Oncol. 17, 889–897. 
Taplin, M.E., Bubley, G.J., Ko, Y.J., Small, E.J., Upton, M., Rajeshkumar, B., and Balk, S.P. (1999). 
Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer 
Res. 59, 2511–2515. 
Taylor, B.S., Schultz, N., Hieronymus, H., Gopalan, A., Xiao, Y., Carver, B.S., Arora, V.K., Kaushik, P., 
Cerami, E., Reva, B., et al. (2010). Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 
11–22. 
Turner, N., Tutt, A., and Ashworth, A. (2004). Hallmarks of “BRCAness” in sporadic cancers. Nat. Rev. 
Cancer 4, 814–819. 
Turner, N.C., Reis-Filho, J.S., Russell, A.M., Springall, R.J., Ryder, K., Steele, D., Savage, K., Gillett, 
C.E., Schmitt, F.C., Ashworth, A., et al. (2007). BRCA1 dysfunction in sporadic basal-like breast cancer. 
Oncogene 26, 2126–2132. 
Vazquez, R., Astorgues-Xerri, L., Bekradda, et al (2014). OTX015, a novel pan BET-BRD inhibitor is 
active in non-small-cell lung cancer (NSCLC) cell lines bearing the fusion protein EML4-ALK. Proc 105th 
Annual Meeting AACR Apr 5-9, San Diego, USA Abstr. #5530. 
Visakorpi, T., Hyytinen, E., Koivisto, P., Tanner, M., Keinänen, R., Palmberg, C., Palotie, A., Tammela, 
T., Isola, J., and Kallioniemi, O.P. (1995). In vivo amplification of the androgen receptor gene and 
progression of human prostate cancer. Nat. Genet. 9, 401–406. 
Weickhardt, A.J., Aisner, D.L., Franklin, W.A., Varella-Garcia, M., Doebele, R.C., and Camidge, D.R. 
(2013). Diagnostic assays for identification of anaplastic lymphoma kinase-positive non-small cell lung 
cancer. Cancer 119, 1467–1477. 
Wolff, A.C., Hammond, M.E.H., Schwartz, J.N., Hagerty, K.L., Allred, D.C., Cote, R.J., Dowsett, M., 
Fitzgibbons, P.L., Hanna, W.M., Langer, A., et al. (2007). American Society of Clinical Oncology/College 
of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing 
in breast cancer. J. Clin. Oncol.  25, 118–145. 
Yang, Z., Yik, J.H.N., Chen, R., He, N., Jang, M.K., Ozato, K., and Zhou, Q. (2005). Recruitment of P-
TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol. Cell 19, 535–
545. 
 


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16 APPENDICES 
16.1 Appendix 1: ECOG Performance Status 
 
 
ECOG 
Characteristics 
0 
Normal activity 
1 
Symptoms of disease, but ambulatory and able to carry out activities of daily living 
2 
Out of bed more than 50% of the time, occasionally needs assistance 
3 
In bed more than 50% of the time, needs nursing care 
4 
Bed ridden, may need hospitalization  
 
 


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16.2 Appendix 2: Calculation of renal clearance 
 
Patients aged < 65 years: Cockroft &Gault formula 
 
Male = 1.25 x weight (kg) x (140-age) / serum creatinine (µmol/L)  
Female = 1.04 x weight (kg) x (140-age) / serum creatinine (µmol/L) 
 
Patients aged > 65 years: MDRD (Modification of Diet in Renal Disease) formula 
 
Male = 186 x (serum creatinine (µmol/L) x 0,0113)-1,154 x age- 0,203 
        x 1,21 in subjects with black skin  
        x 0.742 in female 
 
Clearance can be calculated using tools available via the internet, e.g.  
http://filfola.fr/medecine/cockroft_MDRD.html 
or http://mdrd.com/ 
 


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16.3 Appendix 3: Non-Exhaustive List of Drugs and Substances with the Potential to Interfere with 
CYP3A4 and CYP2A6 
Strong CYP3A4 interfering agents are prohibited (in bold and underlined). A strong inhibitor 
increases the AUC of a substrate for a given CYP by ≥5-fold or > 80% decrease in clearance. A strong 
inducer decreases the AUC of a substrate for a given CYP by ≥ 80%. 
CYP3A4 inducers 
CYP3A4 inhibitors 
avasimibe 
carbamazepine 
phenytoin 
rifampicin 
St John’s wort1 
amobarbital 
dexamethasone 
efavirenz 
felbamate 
nevirapine 
omeprazole 
phenobarbital 
pioglitazone 
primidone 
rifabutin 
tamoxifen 
troglitazone 
boceprevir 
clarithromycin 
conivaptan 
grapefruit juice1 
indinavir 
itraconazole 
ketoconazole 
lopinavir 
mibefradil  
nefazodone 
nelfinavir 
posaconazole 
ritonavir  
saquinavir 
telaprevir 
telithromycin 
tipranavir 
voriconazole 
atazanavir  
amiodarone 
amprenavir 
aprepitant 
cimetidine 
cyclosporine 
darunavir 
delavirdine 
diltiazem  
erythromycin 
fluconazole 
fosamprenavir 
imatinib 
miconazole  
suboxone  
verapamil 
 
 
CYP2A6 inducers 
CYP2A6 inhibitors 
Other CYP2A6 substrates 
phenobarbital  
rifampicin  
 
grapefruit juice  
ketoconazole  
methoxsalen  
pilocarpine  
tranylcypromine  
coumarin 
halothane  
losigamone  
methoxyflurane  
nicotine  
quinoline 
SM-12502  
valproic acid 
1. Preparation-dependent 
 


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16.4 Appendix 4: Safety Monitoring Committee Composition and Charter  
The study will be reviewed on an ongoing basis by an SMC composed of the principal clinical 
investigators (or a sub-investigator delegated by the principal investigator), the study PK specialist, 
Sponsor representatives and an independent medical expert in oncology drug development. 
 
Name 
Institution/Company 
Position 
Sponsor 
Representative
Coordinating Investigator 
NO 
Principal Investigator 
NO 
Principal Investigator 
NO 
Principal Investigator 
NO 
Principal Investigator 
NO 
Principal Investigator 
NO 
Principal Investigator 
NO 
Pharmacokineticist 
NO 
OTD, Clichy, France 
Medical Monitor 
YES (CRO) 
Merck, USA 
Medical Monitor 
YES 
Merck, USA 
Drug Safety 
YES 
Independent Expert 
NO 
Curriculum vitae are provided in the Trial Master File. 
 
PPD
PPD
PPD


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Safety Monitoring Committee Charter 
• 
The SMC will meet on a regular basis (physically or through teleconference), every 8 weeks, as soon as 
possible after the full clinical data sets of a cohort of 3 patients over their first 21 days of treatment (cycle 
1) have been collected. PK data from at least day 1 of these 3 patients must be available for the meeting. 
• 
After examination of the clinical and PK data and discussion, the SMC will make any necessary decisions 
to ensure/improve patients’ safety, and in particular the following: 
1. Validate DLTs 
2. Replace non-evaluable patients 
3. Proceed to the DL immediately above 
4. Add more patients at the same DL 
5. Stop dose escalation and expand a DL 
6. Decide on the regimen to be used for each tumor indication expansion cohort 
7. Add intermediate unplanned DLs 
8. Exploring additional doses and/or regimens (e.g., if the MTD is not reached at the highest dose) 
9. Recommend systematic premedication/supportive care for common toxicities 
10. Establish the MTD 
11. Discuss the relevance of the MTD for further studies taking into account on PK and PD results 
12. Recommend initiation of optional study parts (schedule optimization, cohort expansion, etc.) 
• 
The minutes of the meetings will be written by the designed secretary (the Sponsor’s safety officer by 
default) within a week, approved and signed by all attendees. The minutes of all meetings will be archived 
in the Trial Master File. 
• 
In addition, the SMC could be met in case of exceptional circumstance, justifying immediate decision to 
ensure patients’ safety. If it is not possible to hold a meeting or teleconference of the whole SMC, at least 
the Independent Expert will meet with the Sponsor’s representatives. 
• 
In addition, the Independent Expert will review all CIOMs forms released by the Safety Officer before they 
are sent to the Health Authorities, EC/IRB and investigators. 
 
 
 


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16.5 Appendix 5: Guidance for Potential Drug-Induced Liver Injury (DILI)  
16.5.1 Purpose 
The purpose of this document is to provide guidance to enable the investigator/study coordinator to provide 
clinical follow-up and systematically gather and report data on potential DILI.  The data collected will be 
used by the Sponsor to create narratives for regulatory agency reporting. 
16.5.2 Introduction 
Hepatotoxicity is injury or damage to the liver that may be associated with impaired liver function 
(Navarro and Senior 2006). Drug-induced hepatotoxicity is one of the most common causes of termination 
of drug development, a major reason for refusal of market authorization and for restricted use, and the 
single most important cause of the withdrawal of market authorization for products (Björnsson and Olsson 
2005).  Thus, drug-induced hepatotoxicity is a major concern during the discovery, development to post-
authorization phases of the product life cycle (excerpted from Draft Guidance Document, Hepatotoxicity 
of Health Products, Ministry of Public Health, Canada, December 2010). 
As stated in the United States Food and Drug Administration (FDA) “Guidance for Industry - Drug-
Induced Liver Injury: Premarketing Clinical Evaluation”; hepatocellular injury (usually detected by serum 
aminotransferase elevations [AT]) can be caused by drugs that rarely, if ever, cause severe DILI (e.g., 
aspirin, tacrine, statins, and heparin), as well as by drugs that do cause such injury. The frequency of serum 
AT elevations also is not a good indicator of a potential for severe DILI because drugs such as tacrine (not 
a cause of severe DILI) can cause AT elevations in as many as 50 percent of patients. Very high levels of 
observed ATs may be a somewhat better indicator of potential for severe DILI, but the most specific 
indicator is evidence of altered liver function accompanying or promptly following evidence of 
hepatocellular injury. 
The single clearest (most specific) predictor found to date of a drug’s potential for severe hepatotoxicity, is 
the occurrence of hepatocellular injury (AT elevation) accompanied by increased serum total bilirubin 
(TBL) not explained by any other cause, such as viral hepatitis or exposure to other hepatotoxins, and 
without evidence of cholestasis, together with an increased incidence of AT elevations in the overall trial 
population compared to control.  Increased plasma prothrombin time, or its international normalized ratio 
(INR), a consequence of reduced hepatic production of Vitamin K-dependent clotting factors, is another 
potentially useful measure of liver function that might suggest the potential for severe liver injury. 
Recognition of the importance of altered liver function, in addition to liver injury, began with Hyman 
Zimmerman’s observation that drug-induced hepatocellular injury (i.e., AT elevation) accompanied by 
jaundice (i.e., TBL elevation) had a poor prognosis, with a 10 to 50 percent mortality from acute liver 
failure (in pretransplantation days) (Zimmerman 1978, 1999).  This became known as "Hy's Law".  This 
document describes the recommended process for monitoring and evaluation of patients meeting the 
laboratory criteria for potential DILI defined as: 
• 
an elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab value that is greater than or 
equal to three times (3X) the upper limit of normal (ULN) and  
• 
an elevated TBL lab value that is greater than or equal to two times (2X) ULN and 
• 
at the same time, an alkaline phosphatase (ALP) lab value that is less than 2X ULN,  
as a result of within-protocol-specific testing or unscheduled testing.  


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The protocol identifies these laboratory criteria for potential DILI as ECIs.  ECIs are selected adverse 
experiences that must be reported to the Sponsor within 24 hours. The Principal Investigator should record 
these ECIs on the Adverse Experience CRFs and complete pertinent adverse experience fields as outlined 
in the Data Entry Guidelines (DEGs). 
16.5.3 Close Observation Recommendations 
The following steps should be taken when a patient is observed to have an elevated AST or ALT lab value 
that is greater than or equal to 3X ULN and an elevated TBL lab value that is greater than or equal to 2X 
ULN and, at the same time, an ALP lab value that is less than 2X ULN, as a result of within-protocol-
specific testing or unscheduled testing. In addition, close monitoring of isolated bilirubin increases greater 
than 2X ULN will be required. 
Initiate close observation, defined below, and continue performing follow-up to resolution.  
Close observation is defined as follows:  
• 
Repeat liver enzyme and serum bilirubin tests two (2) or three (3) times weekly.  Frequency of retesting 
can decrease to once a week or less if abnormalities stabilize or study drug has been discontinued and the 
patient is asymptomatic. 
o For patients with isolated bilirubin elevations greater than 2X ULN, repeat serum bilirubin tests 
every 2 weeks until the bilirubin returns to normal or baseline. 
• 
Obtain a more detailed history of symptoms and prior or concurrent diseases. (See Section 16.5). 
• 
Obtain a history of concomitant medication use (including prescription and nonprescription medications, 
herbal and other dietary supplements), alcohol use, recreational drug use and special diets. (See Section 
16.5 for details.) 
• 
Obtain a history of exposure to chemical agents or other environmental toxins.  
• 
Obtain additional history and complete Stage 1 work-up to attempt to rule out other potential causes of the 
transaminase elevation, including but not limited to the following:  acute viral hepatitis types A, B, C, D, 
and E; autoimmune or alcoholic hepatitis; non-alcoholic steatohepatitis (NASH); hypoxic/ischemic 
hepatopathy; and biliary tract disease. (See Section 16.5.5 for details.) 
• 
Consider gastroenterology or hepatology consultation.   
In general, treatment with study therapy should be stopped if the laboratory criteria for potential 
DILI are met.  Please refer to the specific discontinuation criteria in the protocol as appropriate. 
 


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16.5.4 Hepatic Assessment Flow Chart 
Hepatic Assessment Flow Chart 
 
16.5.5 Factors to Consider in Assessing Potential DILI 
When there is a potential DILI, it is important to thoroughly assess the patient’s history, hepatic risk 
factors, clinical condition and hepatic function until resolution (normal or baseline levels).  
Answers to the following questions should be recorded in source documents and in appropriate CRFs as 
outlined in the DEGs. 
16.5.5.1 Study Medication 
Considerations should include the following: What was the time interval between administration of study 
medication and the laboratory abnormality(ies)? What is the status of study medication use: Continuing? 
Interrupted? Discontinued?  Was the patient re-challenged with study medication? 
16.5.5.2 Treatment 
Record any concomitant treatments. 
16.5.5.3 Signs and Symptoms (associated with the potential DILI event) 
Does the patient have a concomitant illness?  Does the patient currently exhibit signs or symptoms of 
hepatitis/DILI?  What are the patient’s signs and symptoms (see examples below)?  What are the pertinent 
findings from medical history, physical/laboratory examination (e.g., fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia > 5%, hepatomegaly, splenomegaly, etc.) that 
could suggest DILI? 
Category 
Examples of Signs and Symptoms 
Triggering Event 
ALT or AST > 
3X ULN with 
TBL>2x ULN 
and ALP <2X 
ULN 
Within 48-72 hours, 
perform stage 1 testing. 
Initiate Close 
Observation (as defined 
in Section 3) and follow-
up to resolution. 
Investigator: investigate 
potential etiology, gather 
history, more 
information  
Follow-up 
Enter/update in CRF 
Dialogue with Sponsor staff 
Sponsor staff, if appropriate, will prepare 
narrative for report 
Enter data into CRF 
and report within 24 
hours of learning the 
event to the sponsor 
If results of Stage 
1 evaluation are 
negative, perform 
Stage 2 work-up 
within one (1) 
week of receiving 
Stage 1 result)  
(see Section 5.5) 


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Blood/lymphatic 
Eosinophilia, coagulopathy, susceptibility to 
bleeding/bruising 
Circulatory 
Varicose veins, edema 
Constitutional 
Fever, fatigue, malaise, weight gain, other (identify). 
Digestive/hepatic 
Anorexia, diarrhea, bloody or black stool, light-colored 
stools, nausea, vomiting, hematemesis, upper quadrant 
abdominal pain, upper quadrant tenderness, hepatomegaly, 
jaundice, splenomegaly, ascites, cholestasis 
Endocrine/reproductive 
Loss of libido 
Integumentary 
Rash, pruritus 
Muscular 
Myalgia 
Nervous 
Changes in mental status or level of consciousness 
Urinary 
Dark urine 
 
16.5.5.4 Confounding Variables 
What are the relevant medical history and findings?  What is the differential diagnosis? What risk factors 
does the patient have for hepatic injury? (See examples below.) Provide onset of risk factor and duration. 
Category 
Examples of Confounding Variables 
Subject medical history 
Autoimmune disorder, cancer, Gilbert’s syndrome, obesity, Wilson’s 
disease 
Substance use/abuse 
Alcohol, illegal drugs, illegal intravenous (IV) drugs  
Prior & Concomitant Medications:  
Review all non-study medications 
and therapies, including: over-the-
counter (OTC), as well as 
prescription. Ask the patient to bring 
products/packaging to site and 
review contents. 
History of recent concomitant acetaminophen (APAP)/paracetamol 
use, excessive nonsteroidal anti-inflammatory drug (NSAID) intake, 
use of non-study drug or therapy that can cause liver damage or 
idiosyncratic adverse drug reactions 
Herbal and nutritional supplements 
Herbal, complementary therapies, and nutritional supplements 
Adulteration of products 
History of previous exposure to the product or a similar product, and 
information on potential contamination or adulteration of products 
Chemical exposure 
Occupational or in other situations 
Potential exposure to infectious 
agents  
Infectious hepatitis, transfusion, travel, tattoos, sexually transmitted 
diseases, new sexual partner, shared needles 
Special Diet 
Special diet started since randomization 
Other 
Recent physical trauma, excessive exercise, or other prolonged 
physical exertion 
Family history  
Autoimmune disorder, cancer, Gilbert’s syndrome, Wilson’s disease 
 
 
 


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16.5.5.5 Evaluation algorithm for potential DILI if there are no other clinical reasons 
Note: If clear etiology for the laboratory abnormalities has been confirmed, Stage 1 and 2 testing may not 
be required.  In this case, consultation with the Sponsor is recommended. 
Stage 1 work-up should be performed within 48-72 hours:  
• 
ALT 
• 
AST 
• 
Bilirubin: total, direct, indirect 
• 
Alkaline phosphatase (ALP)  
• 
Prothrombin Time (PT)/international normalized ratio (INR)  
• 
Creatine phosphokinase (CPK) 
• 
Manual eosinophil count (if automated count was elevated)  
• 
Toxicology screen for drugs of abuse (including ethanol) and for acetaminophen/paracetamol level 
should also be sent.  Investigators may order additional toxicology tests as clinically indicated. 
• 
Evaluate patient for the following signs and symptoms: fatigue, nausea, vomiting, right upper quadrant 
abdominal pain or tenderness, fever, rash. 
• 
Obtain the following additional history and assessment for associated risk/confounding factors: 
- 
More detailed history of symptoms and prior or concurrent illness 
- 
Aminotransferase values obtained prior to the study or administration of study medication 
- 
Alcohol consumption (recent and historical) 
- 
Acetaminophen (APAP)/paracetamol use  
- 
New prescription, concomitant, or non-prescription (including herbal and other dietary 
supplements) medications 
- 
Unusual foods (e.g. mushrooms) or special diets. Consumption of seasonal foods. 
- 
Recreational drug use 
- 
Prior history of liver injury or disease, including but not limited to Gilbert's syndrome, 
autoimmune disorders, cancer, Wilson's disease, NASH, alcoholic or infectious hepatitis, biliary 
tract disease, hypoxic/ischemic hepatopathy 
- 
Obesity/abdominal adiposity (record weight, height, and waist circumference) 
- 
Occupational history and history of exposure to chemical agents or other environmental toxins 
- 
Recent travel (last three [3] years) 
- 
Transfusion history 
• 
Perform the following required laboratory tests:  
- 
Albumin 
- 
Eosinophils (percentage and absolute; obtain manual count if automated count is elevated) 
- 
Viral hepatitis serologies (obtain appropriate consent prior to testing, if required locally) 
 
A (IgG, IgM) 
 
B (HepBs Ag, Hep Bs Ab, Hep Bc Ab, Hep Be Ag) 
 
C (RNA) 
 
D (requires concomitant hepatitis B infection) 
- 
Human Immunodeficiency Virus (HIV) testing (obtain appropriate consent prior to testing, if 
required locally) 
- 
Evaluation for autoimmune hepatitis:  
 
Serum gamma globulin levels/ serum protein electrophoresis   
 
Antinuclear antibody (ANA)  
 
Anti-mitochondrial antibody (if ALP or TBL >ULN) 
- 
If AST/ALT ratio is greater than one (1) with suspicions of increased alcohol intake, perform the 
following: 
 
Gamma-glutamyl transferase (GGT) 
• 
Obtain a right upper quadrant ultrasound 


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Stage 2 work-up tests should be drawn within one (1) week of receiving the Stage 1 work-up results 
and the results of Stage 1 evaluation are negative. 
Note: A specific test may be performed earlier if the investigator determines that the clinical 
presentation leads to a certain diagnosis. 
Stage 2 work-up: 
• 
Perform the following laboratory tests: 
- 
Genetic test for Gilbert's disease if there is a suspicious history. Ensure appropriate patient consent 
is obtained for this test. 
- 
Viral hepatitis E (IgG and IgM, obtain appropriate consent prior to testing, if required locally)  
- 
Anti-smooth muscle antibody  
- 
Anti-liver-kidney microsomal antibody  
- 
Anti-soluble liver antigen 
- 
Serologies for the following: 
 
Cytomegalovirus (CMV) (IgG, IgM) 
 
Epstein-Barr Virus (EBV) (IgG, IgM) 
 
Herpes simplex 
 
Toxoplasmosis 
 
Varicella 
 
Parvovirus 
- 
Ceruloplasmin 
- 
Serum alpha-1 anti-trypsin 
- 
Genetic test for hemochromatosis. Ensure appropriate patient consent is obtained for this test  
- 
Iron Studies:  
 
serum ferritin,  
 
serum iron,   
 
total iron binding capacity 
• 
Consider referral to hepatologist/gastroenterologist 
• 
Consider screen for celiac disease and cystic fibrosis if clinically indicated  
• 
If laboratory tests or ultrasound evidence of biliary tract obstruction, consider obtaining Endoscopic 
Retrograde Cholangiopancreatography (ERCP) or Magnetic Resonance Cholangiopancreatography 
(MRCP) 
If applicable, request copies of hospital discharge summaries, consultation reports, pathology reports, 
special studies (e.g. imaging or biopsy), etc. 
16.5.5.6 Potential diagnosis 
What diagnosis do the history, clinical course, and laboratory tests suggest? 
16.5.5.7 Overall clinical impression 
What are the investigator’s overall clinical impressions (e.g., differential diagnosis, potential alternative 
causes)? 
16.5.5.8 Treatment plan 
What is the plan for treatment and follow-up? 


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16.5.6 Contacts 
If you have any questions, please refer to your Sponsor contact list for the following personnel: 
- 
 (OTD)  
- 
 (Merck) 
 
16.5.7 References 
• 
Navarro, VJ and JR Senior, 2006, Drug-Related Hepatotoxicity, N Eng J Med, 354(7):731-9. 
• 
Björnsson, E and R Olsson, 2005, Outcome and Prognostic Markers in Severe Drug-Induced Liver 
Disease, Hepatology, 42(2):481-9. 
• 
Zimmerman, HJ, 1978, Drug-Induced Liver Disease, in: Hepatotoxicity, The Adverse Effects of Drugs 
and Other Chemicals on the Liver, 1st ed., pp. 351-3, Appleton-Century-Crofts, New York. 
• 
Zimmerman, HJ, 1999, Drug-Induced Liver Disease, in: Hepatotoxicity, The Adverse Effects of Drugs 
and Other Chemicals on the Liver, 2nd ed., pp. 428-33, Lippincott Williams & Wilkins, Philadelphia. 
• 
Draft Guidance Document, Hepatotoxicity of Health Products, Ministry of Public Health, Canada, 
December 2010 
http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/consultation/drug-
medic/draft_ebauche_hepatotox_guide_ld-eng.pdf  
• 
FDA Guidance for Industry - Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009 
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf 
 
PPD
PPD

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Official Protocol Title: A Phase IB Trial with OTX015/MK-8628, a Small Molecule 
Inhibitor of the Bromodomain and Extra-Terminal (BET) Proteins, 
in Patients with Selected Advanced Solid Tumors 
 
NCT number: 
NCT02259114
Document Date: 
09-February-2017


MK-8628
PAGE 1
PROTOCOL NO. 003
SAP
                   February 09 2017
Statistical Analysis Plan (SAP)
1. INTRODUCTION
This SAP is a companion document to the protocol OTX015_108/MK-8628-003, A Phase IB 
Trial with OTX015/MK-8628, a Small Molecule Inhibitor of the Bromodomain and Extra-
Terminal (BET) Proteins, in Patients with Selected Advanced Solid Tumors. In addition to the 
information presented in the protocol statistical considerations section which provides the 
principal features of analyses for this trial, this SAP provides additional statistical analysis
details/data derivations and documents modifications or additions to the analysis plan that are not 
“principal” in nature and result from information that was not available at the time of protocol 
finalization.
2. ANALYTICAL AND METHODOLOGICAL DETAILS
2.1
Responsibility for Analyses/In-House Blinding
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The trial is open-label, i.e., subjects, Investigators, and Sponsor personnel will be aware of 
subject treatment assignment after each subject is enrolled and treatment is assigned.  Allocation 
to treatment will not be randomized.
2.2
Statistical Design and Sample Size
The study is designed to assess the safety of OTX015/MK-8628 in patients with advanced or 
metastatic solid tumors. The small numbers per cohort are not intended for statistical hypotheses. 
Treatment decisions will be made by the SMC.
In study part 1, up to 48 patients evaluable for DLT were expected in QD Regimens 1 and 2 (i.e. 
up to 24 patients per regimen, 6 patients per four dose levels) depending on the number of 
patients experiencing DLTs.
In study part 2, up to 42 evaluable patients (6-14 per three dose levels) will be included in the 
BID regimen.
Overall, a total of up to 90 evaluable patients are expected to be accrued in this study. The final 
sample size will depend on the number of patients experiencing DLTs at each DL and in each 
regimen, and may be increased if the MTD is not reached and additional DLs are required.
 
 
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2.3
Study Objectives
Primary Objective

To determine the Maximal Tolerated Dose (MTD) defined as the recommended phase II 
dose for three distinct regimens of OTX015/MK-8628 administered orally to patients 
with selected advanced solid tumors.
Secondary Objectives

To assess the safety profile of single-agent OTX015/MK-8628

To characterize pharmacokinetics parameters and pharmacodynamics of OTX015/MK-
8628

To determine the antitumor activity of OTX015/MK-8628 in selected solid tumors
2.4
Study Endpoints
Primary Endpoint

The number of patients experiencing at least one DLT in cycle 1 (day 1 to 21) for each of 
the regimens independently
Secondary Endpoints

Safety: Incidence, severity and relationship of AEs, laboratory abnormalities, SAEs, 
discontinuations due to AEs, dose adaptations due to AEs, and DLT

Efficacy: The number of patients with clinical benefit (defined as complete response, 
partial response or stable disease) and progressive disease based on the best overall 
response from tumor evaluations performed every 2 cycles, according to RECIST v1.1 or 
PCWG2, and tumor marker assessment

Pharmacokinetics: Plasma parameters of OTX015/MK-8628
as appropriate and 
according to analyses performed (non-compartmental or nonlinear mixed effect 
modelling)

Pharmacodynamics: Efficacy signal or incidence and severity of AEs along with PK 
parameters, analyzed in relation to the most pertinent biomarker(s), if any
2.5
Analysis Populations
Evaluable for DLT: Patients who receive at least 85% of the planned dose of study drug (18 
days for QD Regimen 1 and the BID regimen, or 6 days for QD Regimen 2) or experience DLT 
during the first 21-day cycle
Treated population: Patients who receive at least one dose of study drug
 
 
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Evaluable for efficacy: Patients who receive at least 2 complete cycles (6 weeks) of treatment 
and have undergone baseline assessment and one on-study tumor assessment, or who discontinue 
early due to disease progression
2.6
Statistical Methods 
The study is designed to assess the safety of OTX015/MK-8628 in patients with solid tumors. 
The small numbers per cohort are not intended for statistical hypotheses.
Quantitative variables will be summarized using descriptive statistics; continuous variables will 
be presented as N, mean and/or median, standard deviation, range, and categorical variables will 
be presented using frequencies and percentage. For CRPC patients, since no response was 
observed, waterfall plots will not be prepared.
Patient disposition and demographics will be analyzed in all included patients, response will be 
analyzed in patients evaluable for efficacy, and safety will be analyzed in the treated population 
with an additional analysis in patients evaluable for DLT.
AEs will be coded according to the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be tabulated by System Organ Class and Preferred Term. 
Laboratory values outside normal limits will be summarized using the NCI-CTCAE version 4.03. 
Concomitant medications will be coded according to the WHO Drug Dictionary.
Data will be presented by dose level, regimen, and where appropriate by indication. No 
imputations for missing data will be made.
Pharmacokinetics and pharmacodynamics will be analyzed and reported separately.
2.7
Interim Analysis
No formal interim analysis is planned.
During the dose escalation phase, regular assessment of data from the most recent cohort of three 
patients of each regimen evaluable for DLT will be performed by the SMC.
 
 
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