The changes are aimed to simplify and clean the protocol besides addressing few main changes. Due to strategic considerations and to further focus on CB-103 development, a set of indications have been excluded at this point in time to emphasize those ones with a distinct oncogenic role of NOTCH pathway activation as well as on those which are currently included in the development plan for CB-103. Consequently, several sections of the protocol, including the exclusion/inclusion criteria, have been revised accordingly. Other inclusion/exclusion criteria have been revised for further clarity. Three more blood samples have been introduced for genotyping patients for polymorphisms of metabolizing enzymes to understand its impact on the clinical PK of CB-103. Concerning the other pre-existing specimens’ sampling, more precise time-point windows have been defined. On a case-by-case basis, intra-patient dose escalation is being considered and the circumstances under which this is allowed have been introduced. Finally, a number of other administrative or editorial changes and corrections are made throughout the protocol.

Based on incoming competitive data in the field, the solid tumour indications have been streamlined while the hematological malignancies have been excluded from the protocol at this point in time. Consequently, several sections of the protocol, including the exclusion/inclusion criteria, have been revised accordingly. Other inclusion/exclusion criteria have been modified for further clarity. Notch-dependant patient enrichment is implemented in the MTD/RP2D final cohort of the Part A of the study, hence enhancing the chances of enrolled patients to benefit from the treatment. For these patients the fresh biopsy at pre-dose and on-treatment have been made mandatory. Based on incoming clinical and pre-clinical data, this final cohort of the Part A of the study is limited to the enrolment of Adenoid Cystic Carcinoma (ACC) and Breast Cancer patients. Some blood sampling has been reduced or removed, whereas a 24-hr urine sample collection and one stool sample have been added to explore the metabolite profile of CB-103 in such matrices. In case of twice daily intake of CB-103 it has been clarified the PK sampling and ECG scheme to apply. Other exploratory biomarkers analyses have been introduced. The PK sub-study is made mandatory. In addition to the major changes above, minor edits have been made throughout the protocol to correct for typographical, formatting and other minor errors.

T-cell acute lymphoblastic leukemia (T-ALL) / T-cell lymphoblastic lymphoma (T-LBL) are being added as target disease because approximately 80% of cases have Notch pathway activation. Other Notch inhibitors have shown promising response data in this disease but could not further advance in the clinic due to toxicity issues observed with those compounds. It is believed that CB-103 has a better safety profile and can be a novel treatment for T-ALL/T-LBL patients. It will also be possible to enroll patients with any cancer (histology agnostic) that has Notch pathway activation, since these patients may benefit from treatment that targets the causal pathway. The sample size of the escalation phase has been increased because the 8 dose levels have been completed and the MTD was not reached. Optimization of the schedule (twice daily dosing of CB-103) with potential further dose escalation is being explored. Given the additional indications, and a planned expansion of the study into Asian countries, the sample size of the dose confirmation cohort was increased. The exploratory endpoints have been updated to match the clinical indications covered in the study and modified to investigate differences between indications and ethnic groups. The goal is to confirm the dose of CB-103 is safe in patients across indications and ethnicities. The MTD/RP2D cohort (previously referred to as the “final” MTD/RP2D cohort) is now referred to as the “confirmatory” cohort as it was felt that this is a better designation for this particular cohort.