• Change the in vitro companion diagnostic device (IVD) designated for use in the trial • As an addition to Section 3.1, blood samples for tumor markers were to be collected for all enrolled subjects. Blood samples for biomarkers and ctDNA were to be collected only if the study passed the interim analysis and collected from newly enrolled subjects.

• Clarified that medication could be administered with or without food • Clarifications added concerning exploratory objective and efficacy endpoints • ‘Creatinine clearance of ≥ 60 mL/min as estimated by the Cockcroft-Gault equation’ was added to the inclusion criteria • It was clarified in Section 6.7 Tumor Biopsy, that ‘archived tissue specimens may be submitted if they meet the requirements outlined in the Laboratory Manual.’ • Section 10.6.3 Exploratory Efficacy Analyses was augmented to include that ‘Other analyses such as correlation between tumor and biomarkers, toxicity, responses, and PK parameters to be conducted and to be further described in the Statistical Analysis Plan.’

• Made minor change to title page to clarify the designation of the study as phase 2 rather than phase 3. This change was also reflected in the synopsis and elsewhere if noted. • Added the name of the medical monitor to title page.

• The change in sponsorship from ArQule Inc. to Basilea Pharmaceutica International Ltd. was implemented in the protocol. • The exploratory evaluation of ORR using modified RECIST criteria was removed from the protocol. • The exploratory objectives were amended so that time to progression by blinded independent central review for derazantinib was to be evaluated overall, and not only by line of prior systemic therapy. The associated exploratory endpoints were updated for consistency. • Inclusion criterion 4 was changed to clarify the approach to the assessment of FGFR2 gene fusion status for the purposes of enrollment. Similar clarification was added to other related sections of the protocol. • Additional ECG assessments were scheduled to coincide with each collection of a plasma sample for pharmacokinetic assessment. • The protocol and Informed Consent Form were changed to specify that metabolites of derazantinib could be assessed from the same samples already planned to determine the population PK parameters of derazantinib. • Change of the safety vendor. • Text restricting the 30-day safety follow-up to adverse events thought to be related to study drug was deleted. • The definition of a related adverse event was clarified to include any adverse event considered definitely, probably, or possibly related to derazantinib, or when the relationship is unknown. • The reference to treatment groups was removed from Section 10.3 (Safety Analyses), along with consistency corrections in the same section. • A change was made to permit an earlier interim analysis if 5 or more objective responses were observed and confirmed based on blinded independent central review before the the previously-required enrollment of 40 evaluable patients

• Study expanded by adding a separate group of patients with FGFR2 gene mutations or amplifications to assess the potential expanded utility of derazantinib in the treatment of iCCA. • The original primary objective of the study was adjusted to allow both the original patients (now termed Substudy 1 and Substudy 2) to be included in the primary objectives. The primary objective of Substudy 2 was to evaluate the anti-tumor activity of derazantinib by progression-free survival at 3 months (PFS3). • Addressed requests by Health Authorities among others considering Clinical Trial Applications in additional countries, including: Revision of sections related to pregnancy and contraception; revision of sections related to QT/QTc; revision of sections related to UV-light protection. • Implemented central ECG assessments. • Defined subgroups of patients who underwent a more intensive biomarker and/or PK assessment schedule. • Clarifications added concerning screening procedures for genomic aberrations. • The secondary objectives of the study were amended to include for Substudy 2 an objective to evaluate the anti-cancer activity by ORR by central radiology. • Exploratory endpoints were added. • For patient-reported outcomes, an additional outcome for HRQOL (the EuroQoL-5D visual analog scale) was included. • Various inclusion and exclusion criteria were updated • A complete eye examination was added to the list of assessments to be conducted at the 30-day Safety Follow-up Visit. • Relevant examinations and laboratory tests were updated • Provision for informed consent to participate in the study to be provided by the patient’s legal representative was removed.

• Section 3.4 was amended to clarify that for patients who demonstrate continued benefit from derazantinib at the time of study closure, the Sponsor aims to provide continued access to derazantinib. • Clarified that patients considered eligible for enrollment in Substudy 2 should have exhausted all satisfactory treatment alternatives. • Exclusion criterion 9 was amended to require patients enrolled in the study to have serum potassium levels within normal ranges. • Section 7.3.3 was clarified that in the event of a prolonged QTc interval ≥ 501 ms being observed on at least two separate ECGs (CTCAE v4.03 Grade 3 event), derazantinib was to be withheld until the QTc has returned to ≤ 470 msec, and a decision made whether to continue treatment with derazantinib. • Clarified the position for patients who were enrolled and dosed on the basis of a positive local test result for FGFR2 gene fusion (Substudy 1). • For the management of patients whose FGFR2 gene fusion status was not centrally confirmed after treatment has commenced, the a case by case assessment was required for these patients. • Inclusion criterion 9 was amended to ensure that ‘highly effective’ contraceptive measures were required during the study; ‘acceptable’ birth control methods were not sufficient. • Clarifications to tumor assessment methods were added. • Clarification in Appendix 8 (List of FGFR2 mutations eligible for enrollment in Substudy 2) that newly detected mutations could be added to the list

• CYP2C8 ligands were added to the list of CYP enzymes in Appendix 4, substrates of which should be avoided or used with caution. • A requirement was added to Section 6.8 for patients who discontinue study drug treatment to have a tumor assessment as soon as possible after discontinuation. • It was clarified that the Substudy 2 sample size refers to mITT-evaluable patients. • Section 10.7 was amended to clarify that in Substudy 2, a decision to proceed with Stage 2 or stop for futility was to be made as soon as the number of events allows it, and that enrollment in Stage 2 was to be suspended if the required number of patients was not reached at the time of full enrollment to Stage 1. • Time windows were introduced for PK sample collection and the collection of the 10 and 12 hours samples was made optional. • The list of FGFR2 mutations eligible for enrollment in Substudy 2 was updated in Appendix 8.

• Details were added throughout the protocol update and clarify details of alternative NGS testing options for prospective patient enrollment in Substudy 2. • The FGFR2 genetic aberration status required for eligibility for Substudy 2 was clarified, along with the testing requirements. • The definition of adequate renal function for eligibility for enrollment into the study, was updated to a creatinine clearance of ≥ 30 mL/min as estimated by the Cockcroft-Gault equation. • Details regarding prohibited prior anti-cancer treatments were updated. • Further clarification was made regarding previous treatments with an FGFR inhibitor, which exclude the patient from eligibility for the study. • Further details were added regarding ophthalmological exclusion criteria. • Patients with any severe infections were added to exclusions from study . • References to a biomarker study were changed to pharmacodynamic assessments, and the processes for collecting archival tumor and blood and urine samples, and for conducting pharmacodynamic analyses, were clarified accordingly. • Administration of derazantinib with a light meal was permitted in the event of nausea or vomiting which is assessed as moderate (CTCAE Grade ≥ 2). • Advice relating to dose delays/reductions in the event of a CTCAE Grade 4 adverse event was revised. • The CSP was updated to include a new requirement to perform complete ophthalmological examination. • Transaminase elevations (AST and ALT increased) were removed from the list of potential risks, and upgraded to an identified risk. Phototoxicity was removed from the list of potential risks. The list of important potential risks was updated to include hyponatremia, and redefined ‘creatinine increase’ as ‘blood creatinine increased / renal disorders’. • Removed the list of FGFR2 genetic aberrations (GAs) eligible for enrollment in Substudy 2 from Appendix 8, in favor of a description of the categories of applicable GAs