1. Changes: Add prescreening procedures for NGS evaluation, and clarify biopsy requirements for archival and fresh tumor tissue. Clarify the procedure for confirmation of response. Shorten recruitment duration to 18 months. Rationale: Requested by sites to ensure only patients with activating Notch mutation will proceed into screening. 2. Changes: Safety laboratories to be done locally Rationale: Requested by sites, to allow faster review of data by investigator 3. Changes: Add and modify laboratory tests to be done during the study. Rationale: To enhance safety monitoring and align with the AL101 investigator’s brochure. 4. Changes: Align dose modifications for hematological Grade 4 toxicities with AL101 Investigator’s Brochure. Correct dose reduction instruction Rationale: To enhance safety monitoring, and alignment with the AL101 investigator’s brochure and to ensure accuracy. 5. Changes: Update tissue archival collection to within 3 years and specify the number of unstained slides required (25). Rationale: To ensure tissue is viable for study purposes.

1. Changes: Change primary endpoint to be Investigator assessed. Rationale: Investigator-assessed is appropriate for this study phase. Radiological images are being collected for central review should this become required. 2. Add objective/endpoint for patient reported outcome measure (EORTC QLQ-C30) to Cohort 2. Rationale: To evaluate the effect of AL101 6 mg QW on patients’ quality of life. 3. Add sequential Cohort 2 (6 mg once weekly; QW) and clarify enrollment process. Rationale: Study expansion and higher dose (while adhering to set safety toxicity management guidelines), may improve efficacy and maintain patient’s safety. The current results in patients with ACC suggest that a higher dose of AL101 may be well tolerated in this patient population particularly with the use of steroids and other toxicity management guidelines. Prior studies suggest that the increase to 6 mg will result in a higher exposure and more substantial inhibition of the Notch pathway and this may result in improved efficacy in this difficult to treat patient population. 4. Add dose reduction guidelines and toxicity management for Cohort 2 (6 mg QW). Rationale: To ensure safety.

1. Delete exclusion criterion 9 - Patients treated with a nucleoside analogue within 6 months prior to administration of investigational product. Rationale: Based on data reanalysis, excluding nucleoside analogues is not supported with clinical or nonclinical data 2. Update exclusion criterion 12f - creatinine clearance <60 mL/min (Calculation of CrCl will be based on acceptable institution standard) Rationale: Allow inclusion based on normal creatinine values, as well as sufficient GFR, as AL101 is not expected to impact renal function 3. Introduce change in regimen (2 weeks on / 1 week off) for first episode of Grade 2 or 3 diarrhea and Grade 2 Colitis before dose reduction on subsequent episodes. Rationale: To allow investigators to use a 2 weeks on / 1 week off regimen at 6 mg QW, before implementing dose reduction. The aim is to introduce a scheduled dose interruption to prevent recurrence of toxicity