Protocol version 3 date 16 October 2013 was amended to update the times of collection PK/PD samples.

Protocol version 7 date 26 September 2014 was amended - to include nucleic acid sequencing on study samples - to modify or to extend dose escalation - to shorten the accrual interval between patients enrolled in a given dose cohort. Patients were included consecutively in each dose level with a minimum time interval of one week to allow for detection of serious and/or unexpected AEs before further patients were treated. -to assess ORY1001 PK parameters in whole blood

Protocol version 7.1 date 28 January 2015 .At the request of the Medicines and Healthcare Products Regulatory Authority, UK, a maximum dose of ORY-1001 was included in the protocol. A maximum dose of 580 μg/m2/day was chosen (unless DLT are identified at a lower dose) based on the initial maximal dose (141 μg/m2) corrected by the factor for pre-clinical (dog) to human exposure (< 4.5 X 141 μg/m2=630 μg/m2) and 2 new cohorts, with

Protocol version 8.0 date 06 March 2015 The change in maximum dose of ORY-1001 requested by the Medicines and Healthcare Products Regulatory Authority, UK, and included in Protocol version 7.1 date 28 January 2015 was included in the global protocol. -The planned number of sites was increased to include 3 sites in France, and 1 more site in the UK. -The time frame of the study was prolonged; study end was planned for the 2nd quarter 2016. -An interim analysis was planned when the MTD was reached. After the Interim Report the Safety Monitoring Committee decided the priority subtypes of AML to be included in the extension arm, dosing regimen and total number of patients in the extension. For clarification of the definition of the analysis population to be used for the safety analysis the following statement of the protocol was ignored: “Patients who are treated with ORY-1001, but have no follow up for safety, will not be included in safety analyses, because their inclusion would dilute percentages of patients with AEs or laboratory toxicities.“ (see protocol section. 10.6. Procedures for handling missing, unused and spurious data). This was contradictory to the definition of the safety set given in the former sections of the protocol. Instead all patients who received any amount of ORY-1001 were included in data summaries for safety

Protocol version 9.0 date 12 October 2015 -PD-LSD1 target engagement analysis was added to the PD assessments to assess the pharmacokinetic/pharmacodynamic (PK/PD) relationship and dose response to LSD1 inhibitors in clinical samples. -To improve recruitment, the number of sites was increased to 5 hospitals in Spain, 2 in UK and 3 in France. -Changes to the planned analyses Transfusions can interfere with PK/PD measurements, it was therefore planned that if the patient required a transfusion during the 5 day treatment block, the PK/PD readouts following the transfusion would be recorded but omitted from analysis. This was not done because the PD responses measured over 24 hours on Days 1, 5 and 26 were expected to be relatively independent of these factors. Additional analyses -The Medical Statistics Core Facility at IDIBAPS (Institute d'investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain performed an additional analysis of the peripheral blasts. - A population pharmacokinetic/ pharmacodynamic model was developed to identify and quantify the impact of intrinsic and extrinsic factors on the pharmacokinetics of ORY1001 and to evaluate the relationship between exposure and effect (changes on blasts counts). Marta Valle, PharmD, PhD was responsible for the PKPD modeling and simulation at the Institut de Recerca de l'HSCSP, Hospital de la Santa Creu i Sant Pau, Spain. The complete report is included in Section 16.1.14.