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a phase 1b study of

Receptor-Positive, HER2-Negative, FGFR-Altered **Advanced Breast Cancer**
Coordinating Center Stanford Cancer Institute 875 Blake Wilbur Drive Stanford, CA 94305 Protocol Director Jennifer L Caswell-Jin, MD
Assistant Professor of Medicine (Oncology)
269 Campus Dr, CCSR 1145C
Stanford Medicine at Stanford University; M/C 5769 Stanford, CA 94305-5769 Telephone: 650-724-3250 e-mail: caswell@stanford.edu  
| Sub-Investigators                                                                                                                                         |                                                                                                                                         |            |             |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------|------------|-------------|
| George W Sledge, Jr, MD Professor of Medicine                                                                                                             |                                                                                                                                         |            |             |
| Stanford Medicine at Stanford Univ M/C 5151 269 Campus Drive West; CCSR 1115  Stanford, CA 94305-5151 Phone 650-724-4397 e-mail: gsledge@stanford.edu     | Christina Curtis, PhD, MSc                                                                                                              |            |             |
| Assistant Prof of Medicine (Oncology) & Genetics                                                                                                          |                                                                                                                                         |            |             |
| Lorry Lokey Building/SIM1 Campus Dr, Suite G2120C  Stanford Medicine at Stanford Univ  Stanford, CA 94305 Tel: 650-498-9943 e-mail: cncurtis@stanford.edu |                                                                                                                                         |            |             |
| Biostatisticians                                                                                                                                          |                                                                                                                                         |            |             |
| Kristen Cunanan, PhD 1701 Page Mill Road Palo Alto, CA 94304 Tel: 650-723-7356                                                                            |                                                                                                                                         |            |             |
| e-mail: cunanank@stanford.edu                                                                                                                             | Manisha Desai, PhD                                                                                                                      |            |             |
| 1070 Arastradero Road, Room 305 Palo Alto, CA 94304 Tel: 650-725-1946 e-mail: manisha.desai@stanford.edu                                                  |                                                                                                                                         |            |             |
| Vandana Sundaram, MPH 1701 Page Mill Road Stanford, CA 94305 Telephone: 650-736-4367 e-mail: sund@stanford.edu                                            | Clinical Research Coordinator Allison Zhang, MPH 780 Welch Road Palo Alto, CA 94305 Telephone: 650-736-5790 e-mail: axkong@stanford.edu |            |             |
| IRB-53650                                                                                                                                                 | BRS0113                                                                                                                                 | IND-149509 | NCT04504331 |  
Version 11 / Version Date: 11 November 2021 Initial SRC Approval Date: 06 April 2020 (for version 27 March 2020)  
| TABLE OF CONTENTS                                                                                                                                           |                                                                                                                                                           |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------|
| PROTOCOL SYNOPSIS ...................................................................................................................................6      |                                                                                                                                                           |
| SCHEMA .                                                                                                                                                    |                                                                                                                                                           |
| LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................................9                                             |                                                                                                                                                           |
| 1.                                                                                                                                                          | OBJECTIVES                                                                                                                                                |
| 1.1.                                                                                                                                                        | PRIMARY OBJECTIVE .....................................................................................................................................10 |
| SECONDARY OBJECTIVES .................................................................................................................................10    |                                                                                                                                                           |
| 1.2.                                                                                                                                                        |                                                                                                                                                           |
| 1.3.                                                                                                                                                        | E XPLORATORY OBJECTIVES                                                                                                                                   |
| BACKGROUND ..............................................................................................................................................10 |                                                                                                                                                           |
| 2.                                                                                                                                                          |                                                                                                                                                           |
| 2.1                                                                                                                                                         | S TUDY D ISEASE                                                                                                                                           |
| 2.2                                                                                                                                                         | STUDY AGENT                                                                                                                                               |
| 2.3                                                                                                                                                         | R R ATIONALE .                                                                                                                                            |
| 2.4                                                                                                                                                         | SCREENING T UMOR S EQUENCING A SSAYS .                                                                                                                    |
| 2.5                                                                                                                                                         | S S TUDY D ESIGN                                                                                                                                          |
| 2.6                                                                                                                                                         | CORRELATIVE STUDIES BACKGROUND .                                                                                                                          |
| 3.                                                                                                                                                          | PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES .................................23                                                                       |
| 3.1                                                                                                                                                         | INCLUSION CRITERIA .                                                                                                                                      |
| 3.2                                                                                                                                                         | E E CLUSION C RITERIA                                                                                                                                     |
| 3.3                                                                                                                                                         | I NFORMED C ONSENT P ROCESS                                                                                                                               |
| 3.4                                                                                                                                                         | S TUDY T IMELINE .                                                                                                                                        |
| 4.                                                                                                                                                          | TREATMENT PLAN....................................................................................................................................31      |
| 4.1                                                                                                                                                         | GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES                                                                                             |
| 4.2                                                                                                                                                         | CRITERIA FOR REMOVAL FROM STUDY ........................................................................................36                                |
| 4.3                                                                                                                                                         | A A TERNATIVES .                                                                                                                                          |
| 5.                                                                                                                                                          | INVESTIGATIONAL AGENT INFORMATION                                                                                                                         |
| 5.1                                                                                                                                                         | I NVESTIGATIONAL A GENT ......................................................................................................................37          |
| 5.2                                                                                                                                                         | AVAILABILITY                                                                                                                                              |
| 5.3                                                                                                                                                         | AGENT ORDERING                                                                                                                                            |
| 5.4                                                                                                                                                         | AGENT ACCOUNTABILITY .............................................................................................................39                      |
| 6.                                                                                                                                                          | DOSE MODIFICATIONS                                                                                                                                        |
| 7.                                                                                                                                                          | ADVERSE EVENTS AND REPORTING PROCEDURES ..................................................47                                                              |  
IRB-53650 Version 11 A Phase 1B Study of Infigratinib in Combination with Tamoxifen in  
| Hormone Receptor-positive, HER2-negative, FGFR-altered Advanced Breast Cancer                                    |                                                                                                                                                                 |
|------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 7.1                                                                                                              | P P OTENTIAL A DVERSE E VENTS ..........................................................................................................47                      |
| 7.2                                                                                                              | A A DVERSE E VENTS D EFINITIONS  ..........................................................................................................48                   |
| 7.3                                                                                                              | A DVERSE EVENTS R EPORTING                                                                                                                                      |
| 7.4                                                                                                              | REPORTING SERIOUS ADVERSE EVENTS ...................................................................................49                                          |
| 7.5                                                                                                              | P P REGNANCY                                                                                                                                                    |
| CORRELATIVE/SPECIAL STUDIES                                                                                      |                                                                                                                                                                 |
| 8.                                                                                                               | LABORATORY CORRELATIVE STUDIES                                                                                                                                  |
| 8.1                                                                                                              |                                                                                                                                                                 |
| 9.                                                                                                               | STUDY CALENDAR .                                                                                                                                                |
| MEASUREMENTS                                                                                                     |                                                                                                                                                                 |
| 10.                                                                                                              |                                                                                                                                                                 |
| 10.1                                                                                                             | PRIMARY ENDPOINT                                                                                                                                                |
| 10.2                                                                                                             | SECONDARY ENDPOINTS                                                                                                                                             |
| 10.3                                                                                                             | O O UTCOMES FOR C LINICAL T RIALS . GOV .                                                                                                                       |
| 1.                                                                                                               | REGULATORY CONSIDERATIONS ............................................................................................62                                        |
| 1.1                                                                                                              | INSTITUTIONAL REVIEW OF PROTOCOL ......................................................................................62                                       |
| 11.2                                                                                                             | DATA SHARING WITH COLLABORATORS  ............................................................................................62                                 |
| 1.3                                                                                                              | DATA AND SAFETY MONITORING PLAN                                                                                                                                 |
| 1.4                                                                                                              | DATA MANAGEMENT PLAN ......................................................................................................................63                   |
| 12.                                                                                                              | STATISTICAL CONSIDERATIONS ................................................................................................63                                   |
| 12.1                                                                                                             | S TATISTICAL D ESIGN AND S AMPLE S IZE D ETERMINATION  ...........................................................................63                            |
| 12.2                                                                                                             | I NTERIM A NALYSES                                                                                                                                              |
| 12.3                                                                                                             | DESCRIPTIVE STATISTICS AND EXPLORATORY DATA ANALYSIS ..................................................63                                                       |
| 12.4                                                                                                             | PRIMARY SAFETY ANALYSIS                                                                                                                                         |
| 12.5                                                                                                             | SECONDARY SAFETY ANALYSIS .................................................................................................................64                   |
| 12.6                                                                                                             | EFFICACY ANALYSIS                                                                                                                                               |
| 12.7                                                                                                             | ANALYSIS P OPULATION                                                                                                                                            |
| 12.8                                                                                                             | A C C R U L C O N S I D E R A T I O N S                                                                                                                         |
| 12.9                                                                                                             | CRITERIA FOR F UTURE S TUDIES  ..............................................................................................................................65 |
| 13.                                                                                                              | REFERENCES                                                                                                                                                      |
| APPENDICES                                                                                                       |                                                                                                                                                                 |
| APPENDIX A:  L IST OF P ROHIBITED M EDICATIONS AND S UBSTANCES  ..............................................69 |                                                                                                                                                                 |
| APPENDIX B:  L IST OF D RUGS TO BE U SED WITH C AUTION W HILE ON S TUDY                                          |                                                                                                                                                                 |  
IRB-53650 Version 11 1 November 2021 APPENDIX C: RECIST V1.1.....................................................................................................71  
| Document History   |                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                   |
|--------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------|
| Date               | Summary                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                   |
| 27 March 2020      | Initial version to SRC (approved 6 April 2020)                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                   |
| 29 April 2020      |                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Document History table added                                                                                                      |
|                   | Number of subjects corrected (up to 36 total)                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                   |
|                   | Cohort 1 dose levels clarified                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                   |
|                   | ClinicalTrials.gov outcomes adjusted                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                   |
|                   | Minor typography and syntax                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                   |
| 30 July 2020       |                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Cohort 1 infigratinib dose levels increased from 2 dose levels (100 mg and 125 mg) to  3 dose levels (75 mg, 100 mg, and 125 mg). |
|                   | Cohort 1 recommended infigratinib dose when 0 of 3 or 1 of 6 subjects experience a DLT  in their first 2 cycles at that dose.                                                                                                                                                                                                                                                                                                                     |                                                                                                                                   |
|                   | Intra-subject dose escalation allowed in Cohort 1 only, such that if a subject starts at  infigratinib 100 mg and remains on-study after 2 cycles with no DLTs seen, they will  begin receiving infigratinib 125 mg, and the number of DLTs in Cycles 3 and 4 will count  toward the primary endpoint in Cohort 1 at this dose.                                                                                                                   |                                                                                                                                   |
|                   | Number of subjects adjusted for Cohort 1 (minimum 3 total instead of 6 total) and for both  Cohorts together (maximum 33 instead of 36).                                                                                                                                                                                                                                                                                                          |                                                                                                                                   |
|                   | Clarification for Cohort 2 that expansion to 12 subjects at recommended dose should  include N = 6 IC2, and N = 6 IC6.                                                                                                                                                                                                                                                                                                                            |                                                                                                                                   |
|                   | Multiplexed ion beam imaging (MIBI) mentioned as another possible in situ proteomic  method for exploratory analysis, in addition to Digital Spatial Profiling (DSP)                                                                                                                                                                                                                                                                              |                                                                                                                                   |
|                   | Research tissue biopsies to be sent to the Curtis lab for processing                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                   |
| 21 August 2020     |                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Administrative changes, updates, and corrections                                                                                  |
| 31 August 2020     |                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Moved ondansetron from Appendix A to Appendix B.                                                                                  |
|                   | Corrections to the following: o Cohort 2 treatment group numbering as 4 to 6, not 3 to 5 (in Section 2.5). o Table 4 was mislabeled as Figure 1 (in section 2.5).  o AE drug relationship are to be determined for infigratinib, tamoxifen (Cohort 1);  fulvestrant (Cohort 2); or palbociclib (Cohort 2), removing gemcitabine plus cisplatin  (in Section 7.3). o REDCap will be used as data management, rather than OnCore (in Section 11.3). |                                                                                                                                   |
|                   | Administrative changes, updates, and corrections, including the addition of hyperlinks  (not highlighted)                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                   |  
| 23 Sept 2020   |                                                                                                                                                                                                                                                                                                                                                                                                                                              | QED Therapeutics will be notified within 24 hours of learning of occurrence of an SAE,  Suspected Unexpected Serious Adverse Reactions or pregnancy event (Sections 7.4 and  7.5), instead of within 7 days.   |
|----------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
|               | QED Therapeutics will supply the Case Report Forms for SAE and Pregnancy events to  be reported to QED. QED may be notified via by email (SAEintake@covance.com) using  their provided CRFs or upload to electronic SAE portal (Sections 7.4 and 7.5).                                                                                                                                                                                        |                                                                                                                                                                                                                |
|               | Instead of within 7 days, Suspected Unexpected Serious Adverse Reactions will be  submitted to the FDA via an IND amendment within 15 days, and within 7 days for  life-threatening conditions and death (Section 7.4), to match with the defined FDA  guidance document on reporting.                                                                                                                                                        |                                                                                                                                                                                                                |
|               | Eliminating pharmacokinetics assessments per QED Therapeutics, as the data collection  is no longer required                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                |
| 1 Oct 2020     | Removes Cohort 2 throughout                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                |
| 9 Oct 2020     | The frequency of echocardiogram (ECHO) monitoring has been adjusted to Baseline,  Cycle 2 Day 1, and End of Treatment.                                                                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                |
| 5 Apr 2021     |                                                                                                                                                                                                                                                                                                                                                                                                                                              | Dr. Jennifer Caswell-Jin is assuming the role of IND-holder, Principal Investigator, and  Protocol Director.                                                                                                   |
|               | In Section 5.1.2, the allowed dosing time interval for infigratinib was revised to be  24 ± 4 hour for consistency with the Pharmacy Manual (Section 7.0). Clarified that  infigratinib should be dosed in the morning when possible, with the understanding that  there may be scheduling limitations at times (eg, delay in drug dispense on days with  clinic visit).                                                                      |                                                                                                                                                                                                                |
|               | Updated Study Calendar (Section 9).  o Added Complete Metabolic Panel as an optional assessment in the "Other  Follow-up" timepoint. o Clarified in footnote 25 that only clinical indicated assessments need to be performed  beyond 30 days.  o Clarified that "End of Treatment/Withdrawal" should be 0 to 14 days from the  decision made to discontinue study treatment (previously 0 to 14 days from  final dose) to match footnote 23. |                                                                                                                                                                                                                |
|               | Administrative changes, updates, and corrections                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                |
| 28 Oct 2021    |                                                                                                                                                                                                                                                                                                                                                                                                                                              | Updates regulatory status information for infigratinib (Section 2.2)                                                                                                                                           |
|               | Updates Participant Selection and Enrollment Procedures (Section 3) to identify the 3rd reviewer of eligibility to be a member of the study team (eg, investigator or back-up study  coordinator)                                                                                                                                                                                                                                             |                                                                                                                                                                                                                |
|               | Specifies / elaborates that the tamoxifen dosing window is 4 to 8 hours after infigratinib  administration.                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                |
|               | Identifies QED Therapeutic's partner, the Helsinn Group, throughout the protocol,  including for data sharing / access (Section 11.2).                                                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                |
|               | Administrative changes, updates, and corrections.                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                |
| 11 Nov 2021    |                                                                                                                                                                                                                                                                                                                                                                                                                                              | Updates safety reporting in sections 7.4 and 7.5, per manufacturer's request                                                                                                                                   |  
| PROTOCOL SYNOPSIS   |                                                                                                                                                                                                                                                                                                      |                                                                    |
|---------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------|
| TITLE               | A Phase 1B Study of Infigratinib in Combination with  Tamoxifen in Hormone Receptor-Positive, HER2-Negative FGFR-Altered Advanced Breast Cancer                                                                                                                                                      |                                                                    |
| STUDY PHASE         | 1B                                                                                                                                                                                                                                                                                                   |                                                                    |
| INDICATION          | Advanced breast cancer, ER and/or PR+ , HER2- . Additional  inclusion and exclusion criteria outlined in n Section 3.1 and  Section 3.2.                                                                                                                                                             |                                                                    |
| INVESTIGATIONAL     | Cohort 1: Infigratinib + Tamoxifen                                                                                                                                                                                                                                                                   |                                                                    |
| PRODUCT  PRIMARY    | Identify the recommended dose of infigratinib to be used in                                                                                                                                                                                                                                          |                                                                    |
| OBJECTIVE           | combination with the FDA-approved dose and schedule of tamoxifen.                                                                                                                                                                                                                                    |                                                                    |
| SECONDARY           | 1.                                                                                                                                                                                                                                                                                                   | Estimate the incidence of treatment-emergent adverse events.       |
| OBJECTIVES          | 2.                                                                                                                                                                                                                                                                                                   | Estimate the objective tumor response rate.                        |
| 3.                  | Estimate progression-free survival.                                                                                                                                                                                                                                                                  |                                                                    |
| 4.                  | Estimate the clinical benefit rate.                                                                                                                                                                                                                                                                  |                                                                    |
| EXPLORATORY         | 1.                                                                                                                                                                                                                                                                                                   | Establish viable tumor-derived organoid cultures to study in vitro |
| OBJECTIVES          | tumor response to combination targeted therapy.                                                                                                                                                                                                                                                      |                                                                    |
| 2.                  | Examine cell-free DNA from plasma across therapy to identify  markers of therapeutic resistance.                                                                                                                                                                                                     |                                                                    |
| 3.                  | Examine tumor and microenvironmental changes across therapy  using in situ proteomics.                                                                                                                                                                                                               |                                                                    |
| STUDY               | Eligible subjects will be adults with ER-positive and/or PR-positive,                                                                                                                                                                                                                                |                                                                    |
| POPULATION          | HER2-negative breast cancer and radiographic evidence of  metastatic disease, or locally recurrent unresectable disease.  Women must be postmenopausal. Due to length, the Eligibility  Criteria are only presented in one instance. See Section 3  Participant Selection and Enrollment Procedures. |                                                                    |
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protocol synopsis

| PROTOCOL SYNOPSIS   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
|---------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| TREATMENT           | Infigratinib is an oral selective FGFR1-3 inhibitor that has been tested                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| SUMMARY             | in phase 1 and 2 clinical trials as a single agent. This phase 1B  study will assess the safety and tolerability of infigratinib in  combination with the FDA-approved dose and schedule of tamoxifen (Cohort 1). In Cohort 1, up to 3 dose levels of infigratinib will be  evaluated: 125 mg; 100 mg; and 75 mg, starting with the middle  dose level (100 mg). Infigratinib will be administered orally daily,  3 weeks on, 1 week off. Subjects will also be given tamoxifen 20 mg orally continuously. If toxicity presents, individual subjects may  dose-reduce by 25 mg infigratinib per reduction, to a lower limit of  75 mg infigratinib (See Sections 2.5 and 6). Treatment with study drug will continue for 18 months or confirmed  disease progression, unacceptable toxicity deemed probably-related  to study drug, whichever occurs first, or other reasons outlined in  Section 4.3. |
| SAMPLE SIZE         | Up to 12 subjects evaluable (minimum 3), not including subject replacement.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
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list of abbreviations and definition

| LIST OF ABBREVIATIONS AND DEFINITION OF TERMS AE Adverse event ASCO-CAP American Society of Clinical Oncology-College of American Pathologists CBC Complete blood count CLIA Clinical Laboratory Improvement Amendments CNS Central nervous system CR Complete Response CRF Case report/record form CTCAE Common Terminology Criteria for Adverse Events ctDNA Circulating tumor deoxyribonucleic acid CYP3A Cytochrome P450 3A DLT Dose-limiting Toxicity DSMB Data Safety Monitoring Board ECG Electrocardiogram ECHO Echocardiogram  ER Estrogen receptor FDA Food and Drug Administration FFPE Formalin-fixed paraffin-embedded FGF Fibroblast growth factor FGFR Fibroblast growth factor receptor FISH Fluorescence in situ hybridization HR Hormone receptor IC Integrative Cluster IHC Immunohistochemistry IRB Institutional Review Board LLN Lower limit of normal MAD Maximum administered dose METABRIC Molecular Taxonomy of Breast Cancer International Consortium MTD Maximum tolerated dose OCT Optical coherence tomography ORR Objective response rate  PFS Progression-free survival  PD Progressive Disease PR Progesterone receptor RECIST Response evaluation criteria in solid tumors RR Response rate SAE Serious adverse event SD Stable disease TCGA The Cancer Genome Atlas TEAE Treatment-emergent adverse event   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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1. objectives 1.1. primary objective

Determine the maximum (no greater than 125 mg) dose of infigratinib used in combination with the FDA-approved dose and schedule of tamoxifen (Cohort 1), in terms of the number of dose-limiting toxicities observed in the first 2 cycles of therapy in subjects with hormone receptor-positive, HER2-negative advanced breast cancer.
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1.2. secondary objectives

Estimate the incidence of treatment-emergent adverse events (serious and non-serious). Estimate the objective tumor response rate (ORR) in subjects with measurable disease.  
Estimate the progression-free survival (PFS).  
Estimate the durable clinical benefit rate.
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1.3. exploratory objectives

Establish viable tumor-derived organoid cultures to study *in vitro* tumor response to combination targeted therapy  
Examine cell-free DNA from plasma across therapy to identify markers of therapeutic resistance Examine tumor and microenvironmental changes across therapy using in situ proteomics.
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2. background 2.1 study disease

Advanced-stage, or metastatic, breast cancer remains incurable in the vast majority of cases, with an estimated median survival of approximately 3 years.  
1 Hormone receptor-positive (HR+)
disease is generally viewed as less aggressive than triple-negative or HER2+breast cancer, but recent data from our group suggest that a subset of HR
+breast cancers are highly aggressive, exhibiting recurrence rates higher than triple-negative breast cancers or HER2+breast cancers in the era prior to trastuzumab.  
2 These high-risk HR
+breast cancer subtypes classify as one of four integrative clusters (ICs or "IntClusts"), each defined by a characteristic gene amplification as follows. 2,3 IC1, defined by *RPS6KB1* (17q23) IC2, defined by *FGF3/4/19* and *CCND1* (11q13). IC2 is associated with a poor prognosis amongst ER-positive tumors, with a 10-year disease-specific survival rate of only about 50%.  
IC6, defined by *FGFR1* (8p12). IC6 is associated an intermediate prognosis and a 10-year disease-specific survival of around 60%.  
IC9, defined by MYC (8q24)
1B
Notably for IC2, *FGF3/4/19* and *CCND1* are tightly located within the 11q13 genomic region and are almost universally amplified together as a cassette in breast cancer; 2,3 thus amplification of either is generally consistent with amplification of both. *FGFR1* amplifications occur in approximately 10% and *CCND1/FGF3/4/19* amplifications in approximately 6% of early-stage ER+/HER2-breast cancers; 2,3 proportions are likely higher in advanced-stage breast cancer given the higher rates of recurrence. While these characteristic amplifications are almost universally present within tumors classifying as the relevant integrative subtype, the converse is not true: in the METABRIC cohort, approximately one quarter of HR
+/HER2-tumors that carry the *CCND1* amplification classify as integrative subtype 2, and approximately half of those that carry the *FGFR1* amplification classify as integrative subtype 6. It is plausible that these amplifications may be passenger events rather than driver events in the tumors that do not classify as the relevant integrative subtypes.  
The current treatment paradigm for these tumors does not include testing for integrative subtype or targeting the subtype-defining gene amplifications. Metastatic HR
+/HER2-breast cancer is typically treated in the first line with endocrine therapy (most commonly an aromatase inhibitor),
often in combination with a CDK4/6 inhibitor 4-6; in the second line, endocrine therapy is typically used again, either alone, in combination with a CDK4/6 inhibitor if not used in the first-line 7-9, or in combination with an mTOR inhibitor.  
10 After progression on two lines of endocrine therapy, the disease is often considered endocrine-resistant and treated with sequential single-agent chemotherapies until progression.  
11 There is an urgent need to find more effective therapies for HR
+/HER2- metastatic breast cancer, and we hypothesize that targeting the FGFR axis in tumors that may be driven by FGFR signaling, as defined either by amplification or integrative subtype, may improve outcomes for patients with these tumor types. This study evaluates the safety and efficacy of infigratinib, an FGFR 1 to 3 inhibitor, in combination treatment for eligible HR+/HER2-breast cancer patients whose tumors classify as the IC2 or IC6 subtypes (see criterion 2 in Section 3.1). As noted above, IC2 and IC6 are associated with alternations in FGF and/or FGFR.
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2.2 study agent - infigratinib

2.2.1 Regulatory status: Infigratinib (BGJ398) was approved by FDA as Truseltiq pursuant the Accelerated Approval regulations on 28 May 2021 for the indication of previously-treated, unresectable, locally-advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement, in adults.  
2.2.2 Mechanism of action: Infigratinib (BGJ398) is an orally-bioavailable, potent, selective inhibitor of the fibroblast growth factor receptors (FGFR 1-3, but 60-fold less active on FGFR4). The FGFR family of receptor tyrosine kinases consists of four members (FGFR1-4), which serve as the high affinity receptors for 22 FGF ligands. These growth factors control cell proliferation, migration, angiogenesis, apoptosis, and differentiation. A subfamily of FGF ligands including FGF19 additionally act as endocrine hormones.  
12 2.2.3 Pharmacokinetics: The pharmacokinetics of infigratinib was investigated in mouse, rat, and dog after oral and intravenous administration. In all 3 species, the clearance and the volume of distribution at steady state was high. The terminal elimination half-life in plasma was 9.3 hours in mouse, 4.5 hours in rat, and 3.1 hours in dog. The absolute bioavailability was 2.4% in dog and approximately 30% in mouse and rat. In oncology patients, the mean terminal elimination half-life on Day 1 was 3 to 7 hours; accumulation was observed with daily dosing at doses ≥ 60 mg, with mean accumulation ratio ranging from 3 to 8 on Day 15 and Day 28.  
2.2.4 Metabolism: The in *vitro* metabolism of [14C]-infigratinib was studied in hepatocytes from rat, dog, and human. Two main biotransformation pathways were observed in all species investigated: N-oxidation to BQR917 (predominant pathway in dog) and D-deethylation to BHS697 (predominant pathway in human) (in rat, the two pathways were of similar importance). Additional biotransformation pathways included glutathione conjugation, O-demethylation, hydrolysis, C-hydroxylation, and others. The in *vivo* metabolism of [14C]-infigratinib was studied in rats and dogs, and of unlabeled infigratinib in dogs and humans. 13 metabolites were identified and semi-quantified in human plasma with the cleavage product CQM157 the most abundant one; all except 1 minor metabolite were also detected in rat and/or dog plasma after oral dosing. 2.2.5 Major route of elimination: The major route of elimination in rats and dogs dosed orally or intravenously with [14C]-infigratinib was the feces. Urinary excretion amounted to ≤ 6.5% of dose. In rats, 2.6% of the dose was recovered in bile and 0.16% in urine. In dogs, 1.5% of the dose was recovered in urine. 2.2.6 Potential for drug interactions: Infigratinib is likely subject to a major intestinal metabolic first-pass effect via cytochrome P450 3A (CYP3A), and consequently, concomitant use with CYP3A inhibitors or inducers is expected to have clinical implications. Accordingly, strong inhibitors or inducers or CYP3A4, as well as narrow therapeutic index substrates of CYP3A4, are prohibited on this study (Appendix A); moderate inhibitors or inducers of CYP3A4, as well as sensitive CYP3A substrates, are to be used with caution on this study (Appendix B). 2.2.7 Safety in animal studies: Repeated-dose toxicity studies were performed in rat and dog and are summarized below:
Infigratinib increased serum fibroblast growth factor 23 (FGF23) and serum calcium and/or phosphorus, associated with ectopic mineralization (mostly lungs and kidneys) and bone growth plate thickening and increased trabecular bone. Generally these changes were either reversible or showed a trend toward reversibility. FGF23 is secreted by osteocytes and acts on the kidney to decrease reabsorption and increase excretion of phosphorus; it is hypothesized that inhibition of the FGF23/FGFR pathway leads to the observed phosphorus elevation with infigratinib.  
Vasculopathy was observed in rat studies at higher dose levels; in dog studies, this was observed only in the gallbladder.  
In rats and dogs increases in alanine aminotransferase, aspartate aminotransferase, and/or decreases in glucose were noted. These changes were either without correlative histopathological findings or (in dogs at high doses) with minimal liver cell necrosis as well as bile ducts hypertrophy/hyperplasia.  
There was an accumulation of foam cell aggregates in the lung. Decreases in reticulocyte, platelet, total white blood cells, neutrophils, and lymphocytes as well as bone marrow hypocellularity were noted at higher doses.  
Cornea opacity (trend towards reversibility) as well as epithelial thinning for the tongue and nasal cavity (reversible) as well as incisors (not reversible) were observed.  
Longer hair/fur was noted starting at approximately week 8 and continuing through recovery. In dogs, reversible atrophy of the sebaceous gland was seen.  
2.2.8 Efficacy in animal studies: In *vivo* studies in mice and rats have shown that significant tumor growth inhibition and tumor regression can be achieved with infigratinib in a variety of FGFR-dependent tumor xenograft models, at well tolerated doses when given orally once per day. 2.2.9 Safety in humans: Infigratinib has been evaluated in cancer patients in two phase 1 studies in patients with advanced solid malignancies (NCT01697605 and NCT01004224) and three phase 2 studies (NCT01975701 in glioblastoma; NCT02150967 in cholangiocarcinoma, and NCT02160041 in solid tumors and/or hematologic malignancies). It has also been evaluated in combination with the PI3K alpha specific inhibitor BYL719 in a phase 1b study (NCT01928459), a combination no longer being pursued. Approximately 650 subjects (healthy adult volunteers and adult patients with malignancies) have received infigratinib. Dose-limiting toxicities: There were no DLTs reported in NCT01697605. In NCT01004224, where infigratinib was given as a single agent, there was one DLT in the 100 mg cohort (out of 6 subjects) (Grade 3 AST/ALT elevation), one DLT in the 125 mg cohort (out of 8 subjects) (hyperphosphatemia greater than 14 days despite adequate therapy), and 2 DLTs in the 150 mg cohort (out of 6 subjects) (one Grade 3 AST/ALT elevation and one Grade 1 corneal toxicity). The maximum tolerated dose was determined to be 125 mg daily. The 3 weeks on / 1 week off schedule was implemented based on observations of the timing and duration of drug interruptions during Cycle 1 necessitated by episodes of hyperphosphatemia: median time to drug interruption during continuous dosing was 22 days and median duration of the interruption was 7 days. Treatment-emergent adverse events: Table 1 summarizes adverse events, regardless of relationship, to infigratinib as a single agent at the maximum tolerated dose of 125 mg, 3 weeks on, 1 week off (N = 433 subjects), and Table 2 summarizes Grade 3 to 4 adverse events. The on-target effects on calcium-phosphorus homeostasis result in the observed increases in calcium (13.4% any grade, 3.2% Grade 3-4), phosphorus (61.2% any grade, 6.7% Grade 3 to 4), and creatinine (23.8% any grade). These are not associated with clinical symptoms and in general have been mild to moderate in severity, manageable, and reversible. Guidelines for management of on-target hyperphosphatemia have been implemented. Ocular adverse events (corneal or retinal) occur in about 50% of subjects, but in general are mild to moderate in severity and reversible: for example, Grade 1 to 2 dry eye was reported in 21.5% and Grade 1 to 2 blurry vision in 9.9%. Grade 3 ocular events occurred in 3% of subjects; no Grade 4 ocular events have been reported. Grade 3 adverse events of cataract (N = 3, 0.7%), visual impairment (N = 2, 0.5%), and keratitis (N = 2, 0.5%) were the events that 1B
occurred in more than one subject; others were reported once. Adverse events of blurred vision, visual impairment, and keratitis led to study drug discontinuation for N = 2, 0.5% subjects each. Since the cornea and retina were identified from preclinical safety studies as a potential target organ of interest, protocol-mandated ophthalmologic examinations have been performed routinely and frequently throughout studies. Subjects have been monitored for potential QT prolongation: N = 3 (0.7%) of subjects have had a new QTc value > 500 msec, N = 4 (1.0%) have had a QTcF change of > 60 msec, and N = 63 (15.0%) have had a QTcF change > 30 and ≤ 60 msec. None of these events was considered serious nor led to treatment withdrawal or dose reduction/interruption. Subjects have also been monitored for potential decrease in ventricular ejection fraction by echocardiogram or multi-gated acquisition. N = 6 (1.4%) of subjects had a Grade 2 abnormality (no Grade 3-4 events), which did not lead to study drug discontinuation. Other notable adverse events include stomatitis (34.9%) and alopecia (26.8%).  
| treated with infigratinib monotherapy                                                               |           |                   |            |            |
|-----------------------------------------------------------------------------------------------------|-----------|-------------------|------------|------------|
| Urothelial                                                                                          | All Other |                   |            |            |
| Cholangiocarcinoma                                                                                  | Carcinoma | Monotherapy       |            |            |
| Subjects                                                                                            | Subjects  | Oncology Subjects | Total      |            |
| n(%)                                                                                                | n (%)     | n (%)             | n (%)      |            |
| Preferred Term                                                                                      | (N = 118) | (N = 82)          | (N = 233)  | (N = 433)  |
| Total no. of subjects                                                                               | 15 (97.5) | 81 (98.8)         | 21 (99.1)  | 427 (98.6) |
| Hyperphosphataemia                                                                                  | 87 (73.7) | 3 (40.2)          | 145 (62.2) | 256 (61.2) |
| Fatigue                                                                                             | 53 (44.9) | 35 (42.7)         | 87 (37.3)  | 175 (40.4) |
| Constipation                                                                                        | 48 (40.7) | 31 (37.8)         | 80 (34.3)  | 159 (36.7) |
| Stomatitis                                                                                          | 59 (50.0) | 2 (26.8)          | 70 (30.0)  | 151 (34.9) |
| Decreased appetite                                                                                  | 28 (23.7) | 31 (37.8)         | 70 (30.0)  | 129 (29.8) |
| Nausea                                                                                              | 32 (27.1) | 24 (29.3)         | 69 (29.6)  | 125 (28.9) |
| Diarrhoea                                                                                           | 30 (25.4) | 17 (20.7)         | 70 (30.0)  | 17 (27.0)  |
| Alopecia                                                                                            | 45 (38.1) | 25 (30.5)         | 46 (19.7)  | 16 (26.8)  |
| Blood creatinine increased                                                                          | 26 (22.0) | 35 (42.7)         | 42 (18.0)  | 103 (23.8) |
| Dry mouth                                                                                           | 31 (26.3) | 27 (32.9)         | 43 (18.5)  | 101 (23.3) |
| Dry eye                                                                                             | 41 (34.7) | 16 (19.5)         | 36 (15.5)  | 93 (21.5)  |
| Dysgeusia                                                                                           | 39 (33.1) | 18 (22.0)         | 34 (14.6)  | 91 (21.0)  |
| Vomiting                                                                                            | 28 (23.7) | 17 (20.7)         | 43 (18.5)  | 88 (20.3)  |
| 17 (14.4)                                                                                           |           |                   |            |            |
| Anaemia                                                                                             | 28 (34.1) | 30 (12.9)         | 75 (17.3)  |            |
| Arthralgia                                                                                          | 34 (28.8) | 14 (17.1)         | 20 (8.6)   | 68 (15.7)  |
| Dyspepsia                                                                                           | 21 (17.8) | 6 (7.3)           | 39 (16.7)  | 66 (15.2)  |
| Aspartate aminotransferase increased                                                                | 21 (17.8) | 6 (7.3)           | 36 (15.5)  | 63 (14.5)  |
| 14 (11.9)                                                                                           | 14 (17.1) | 34 (14.6)         | 62 (14.3)  |            |
| Abdominal pain                                                                                      |           |                   |            |            |
| Dyspnoea                                                                                            | 1 (9.3)   | 14 (17.1)         | 36 (15.5)  | 61 (14.1)  |
| Hypercalcaemia                                                                                      | 27 (22.9) | 12 (14.6)         | 19 (8.2)   | 58 (13.4)  |
| Weight decreased                                                                                    | 20 (16.9) | 29 (12.4)         | 58 (13.4)  |            |
| 9 (11.0)                                                                                            |           |                   |            |            |
| Alanine aminotransferase increased                                                                  | 17 (14.4) | 5 (6.1)           | 34 (14.6)  | 56 (12.9)  |
| Dry skin                                                                                            | 25 (21.2) | 10 (12.2)         | 21 (9.0)   | 56 (12.9)  |
| Hypophosphataemia                                                                                   | 2 (18.6)  | 10 (12.2)         | 21 (9.0)   | 53 (12.2)  |
| Palmar-plantar erythrodysaesthesia syndrome                                                         | 32 (27.1) | 9 (11.0)          | 10 (4.3)   | 51 (11.8)  |
| 7 (8.5)                                                                                             | 26 (11.2) | 51 (11.8)         |            |            |
| Pyrexia                                                                                             | 18 (15.3) |                   |            |            |
| Back pain                                                                                           | 17 (14.4) | 9 (11.0)          | 24 (10.3)  | 50 (11.5)  |
| 20 (16.9)                                                                                           | 50 (11.5) |                   |            |            |
| Pain in extremity                                                                                   | 7 (8.5)   | 23 (9.9)          |            |            |
| 15 (12.7)                                                                                           | 9 (11.0)  | 25 (10.7)         | 49 (11.3)  |            |
| Cough                                                                                               | 14 (11.9) | 12 (14.6)         | 2 (9.4)    | 48 (11.1)  |
| Lipase increased                                                                                    | 10 (8.5)  | 21 (25.6)         | 17 (7.3)   | 48 (11.1)  |
| Nail disorder                                                                                       |           |                   |            |            |
| Headache                                                                                            | 20 (16.9) | 2 (2.4)           | 24 (10.3)  | 46 (10.6)  |
| Hyponatraemia                                                                                       | 13 (11.0) | 12 (14.6)         | 21 (9.0)   | 46 (10.6)  |
| Asthenia                                                                                            | 6 (5.1)   | 7 (8.5)           | 32 (13.7)  | 45 (10.4)  |
| Blood phosphorus increased                                                                          | 4 (3.4)   | 9 (11.0)          | 32 (13.7)  | 45 (10.4)  |
| Blood alkaline phosphatase increased                                                                | 14 (11.9) | 7 (8.5)           | 23 (9.9)   | 4 (10.2)   |
| Epistaxis                                                                                           | 17 (14.4) | 8 (9.8)           | 19 (8.2)   | 4 (10.2)   |
| Vision blurred                                                                                      | 23 (19.5) | 10 (12.2)         | 10 (4.3)   | 43 (9.9)   |
| Urinary tract infection                                                                             | 13 (11.0) | 14 (17.1)         | 14 (6.0)   | 41 (9.5)   |
| Includes Studies NCT01697605 (CSR in preparation; data cutoff 18Mar2019), NCT01004224, NCT01975701, |           |                   |            |            |
| NCT02150967 (ongoing; data cutoff 31May2019), NCT02160041.                                          |           |                   |            |            |  
Table 1: Adverse events occurring in ≥ 10% of adult oncology subjects treated with infigratinib monotherapy  
| adult oncology subjects treated with infigratinib monotherapy                                       |           |             |            |            |
|-----------------------------------------------------------------------------------------------------|-----------|-------------|------------|------------|
| Urothelial                                                                                          | All Other |             |            |            |
| Cholangiocarcinoma                                                                                  | Carcinoma | Monotherapy |            |            |
| Oncology Subjects                                                                                   |           |             |            |            |
| Subjects                                                                                            | Subjects  | Total       |            |            |
| n (%)                                                                                               | n (%)     | n (%)       | n (%)      |            |
| Preferred Term                                                                                      | (N = 118) | (N = 82)    | (N = 233)  | (N = 433)  |
| Total no. of subjects                                                                               | 79 (66.9) | 55 (67.1)   | 131 (56.2) | 256 (61.2) |
| 14 (11.9)                                                                                           |           |             |            |            |
| Hypophosphataemia                                                                                   | 7 (8.5)   | 12 (5.2)    | 3 (7.6)    |            |
| Hyponatraemia                                                                                       | 12 (10.2) | 5 (6.1)     | 13 (5.6)   | 30 (6.9)   |
| Hyperphosphataemia                                                                                  | 14 (11.9) | 1 (1.2)     | 14 (6.0)   | 29 (6.7)   |
| Lipase increased                                                                                    | 9 (7.6)   | 8 (9.8)     | 10 (4.3)   | 27 (6.2)   |
| Fatigue                                                                                             | 6 (5.1)   | 6 (7.3)     | 12 (5.2)   | 24 (5.5)   |
| 2 (2.4)                                                                                             | 21 (4.8)  |             |            |            |
| Stomatitis                                                                                          | 13 (11.0) | 6 (2.6)     |            |            |
| Alanine aminotransferase increased                                                                  | 4 (3.4)   | 2 (2.4)     | 10 (4.3)   | 16 (3.7)   |
| Palmar-plantar erythrodysaesthesia syndrome                                                         | 7 (5.9)   | 5 (6.1)     | 3 (1.3)    | 15 (3.5)   |
| Anaemia                                                                                             | 5 (4.2)   | 5 (6.1)     | 4 (1.7)    | 14 (3.2)   |
| Hypercalcaemia                                                                                      | 7 (5.9)   | 2 (2.4)     | 5 (2.1)    | 14 (3.2)   |
| Dyspnoea                                                                                            | 0         | 2 (2.4)     | 1 (4.7)    | 13 (3.0)   |
| Abdominal pain                                                                                      | 6 (5.1)   | 2 (2.4)     | 4 (1.7)    | 12 (2.8)   |
| Aspartate aminotransferase increased                                                                | 4 (3.4)   | 0           | 8 (3.4)    | 12 (2.8)   |
| Decreased appetites                                                                                 | 1 (0.8)   | 5 (6.1)     | 6 (2.6)    | 12 (2.8)   |
| 3 (2.5)                                                                                             | 3 (3.7)   | 6 (2.6)     | 12 (2.8)   |            |
| Nausea                                                                                              |           |             |            |            |
| Vomiting                                                                                            | 1 (0.8)   | 3 (3.7)     | 7 (3.0)    | 1 (2.5)    |
| Dehydration                                                                                         | 2 (1.7)   | 1 (1.2)     | 7 (3.0)    | 10 (2.3)   |
| Diarrhoea                                                                                           | 3 (2.5)   | 3 (3.7)     | 3 (1.3)    | 9 (2.1)    |
| Gamma-glutamyltransferase increased                                                                 | 2 (1.7)   | 1 (1.2)     | 6 (2.6)    | 9 (2.1)    |
| 3 (2.5)                                                                                             | 1 (1.2)   | 5 (2.1)     | 9 (2.1)    |            |
| Pain in extremity                                                                                   | 9 (2.1)   |             |            |            |
| Sepsis                                                                                              | 2 (1.7)   | 1 (1.2)     | 6 (2.6)    |            |
| Blood alkaline phosphatase increased                                                                | 5 (4.2)   | 0           | 3 (1.3)    | 8 (1.8)    |
| General physical health deterioration                                                               | 2 (1.7)   | 1 (1.2)     | 5 (2.1)    | 8 (1.8)    |
| Urinary tract infection                                                                             | 2 (1.7)   | 3 (3.7)     | 3 (1.3)    | 8 (1.8)    |
| Back pain                                                                                           | 6 (2.6)   | 6 (1.4)     |            |            |
| 0                                                                                                   | 0         |             |            |            |
| Blood bilirubin increased                                                                           | 3 (2.5)   | 0           | 3 (1.3)    | 6 (1.4)    |
| Pyrexia                                                                                             | 2 (1.7)   | 1 (1.2)     | 3 (1.3)    | 6 (1.4)    |
| Arthralgia                                                                                          | 2 (1.7)   | 3 (3.7)     | 0          | 5 (1.2)    |
| Asthenia                                                                                            | 2 (2.4)   | 3 (1.3)     | 5 (1.2)    |            |
| 0                                                                                                   |           |             |            |            |
| Dysphagia                                                                                           | 1 (1.2)   | 4 (1.7)     | 5 (1.2)    |            |
| 0                                                                                                   |           |             |            |            |
| Hypertension                                                                                        | 1 (0.8)   | 0           | 4 (1.7)    | 5 (1.2)    |
| Mucosal inflammation                                                                                | 0         | 1 (1.2)     | 4 (1.7)    | 5 (1.2)    |
| Pneumonia                                                                                           | 5 (2.1)   | 5 (1.2)     |            |            |
| 0                                                                                                   | 0         |             |            |            |
| Includes Studies NCT01697605 (CSR in preparation; data cutoff 18Mar2019), NCT01004224, NCT01975701, |           |             |            |            |
| NCT02150967 (ongoing; data cutoff 31May2019), NCT02160041.                                          |           |             |            |            |  
Table 2:  Grade 3 or 4 adverse events occurring in ≥ 1.0% of Serious adverse events:  Serious adverse events (SAEs) to single-agent infigratinib are summarized in Table 3.  The most common SAEs reported (approximately 2%) were pyrexia, dyspnea, general physical health deterioration, sepsis, vomiting, abdominal pain, anemia, hypercalcemia, and pneumonia.  Most of the SAEs would be expected for oncology subjects and for the indications under study.  
| All Other                                                                                           |           |                   |            |          |
|-----------------------------------------------------------------------------------------------------|-----------|-------------------|------------|----------|
| Urothelial                                                                                          |           |                   |            |          |
| Cholangiocarcinoma                                                                                  | Carcinoma | Monotherapy       |            |          |
| Subjects                                                                                            | Subjects  | Oncology Subjects | Total      |          |
| n(%)                                                                                                | n (%)     | n (%)             | n (%)      |          |
| Preferred Term                                                                                      | (N = 233) |                   |            |          |
| (N = 118)                                                                                           | (N = 82)  | (N = 433)         |            |          |
| 4 (37.3)                                                                                            | 29 (35.4) | 91 (39.1)         | 164 (37.9) |          |
| Total no. of subjects                                                                               |           |                   |            |          |
| Pyrexia                                                                                             | 6 (5.1)   | 3 (3.7)           | 3 (1.3)    | 12 (2.8) |
| Dyspnoea                                                                                            | 0         | 1 (1.2)           | 9 (3.9)    | 10 (2.3) |
| General physical health deterioration                                                               | 2 (1.7)   | 1 (1.2)           | 6 (2.6)    | 9 (2.1)  |
| Sepsis                                                                                              | 2 (1.7)   | 1 (1.2)           | 6 (2.6)    | 9 (2.1)  |
| Vomiting                                                                                            | 1 (0.8)   | 2 (2.4)           | 6 (2.6)    | 9 (2.1)  |
| Abdominal pain                                                                                      | 2 (2.4)   | 8 (1.8)           |            |          |
| 5 (4.2)                                                                                             | 1 (0.4)   |                   |            |          |
| 3 (2.5)                                                                                             | 2 (2.4)   | 8 (1.8)           |            |          |
| Anaemia                                                                                             | 3 (1.3)   |                   |            |          |
| 4 (3.4)                                                                                             | 2 (2.4)   | 2 (0.9)           | 8 (1.8)    |          |
| Hypercalcaemia                                                                                      |           |                   |            |          |
| Pneumonia                                                                                           | 0         | 8 (3.4)           | 8 (1.8)    |          |
| 0                                                                                                   |           |                   |            |          |
| Acute kidney injury                                                                                 | 2 (1.7)   | 2 (2.4)           | 2 (0.9)    | 6 (1.4)  |
| Constipation                                                                                        | 3 (2.5)   | 3 (1.3)           | 6 (1.4)    |          |
| 0                                                                                                   |           |                   |            |          |
| Dehydration                                                                                         | 0         | 1 (1.2)           | 5 (2.1)    | 6 (1.4)  |
| Nausea                                                                                              | 0         | 2 (2.4)           | 4 (1.7)    | 6 (1.4)  |
| Urinary tract infection                                                                             | 2 (1.7)   | 2 (2.4)           | 2 (0.9)    | 6 (1.4)  |
| Dysphagia                                                                                           | 1 (1.2)   | 3 (1.3)           | 4 (0.9)    |          |
| 0                                                                                                   |           |                   |            |          |
| Hyponatraemia                                                                                       | 2 (1.7)   | 1 (1.2)           | 1 (0.4)    | 4 (0.9)  |
| Pleural effusion                                                                                    | 2 (1.7)   | 0                 | 2 (0.9)    | 4 (0.9)  |
| Arthralgia                                                                                          | 2 (1.7)   | 1 (1.2)           | 0          | 3 (0.7)  |
| Asthenia                                                                                            | 0         | 1 (1.2)           | 2 (0.9)    | 3 (0.7)  |
| Back pain                                                                                           | 0         | 0                 | 3 (1.3)    | 3 (0.7)  |
| Bile duct obstruction                                                                               | 1 (0.8)   | 0                 | 2 (0.9)    | 3 (0.7)  |
| Bone pain                                                                                           | 1 (0.8)   | 1 (1.2)           | 1 (0.4)    | 3 (0.7)  |
| Cellulitis                                                                                          | 2 (1.7)   | 1 (1.2)           | 0          | 3 (0.7)  |
| Chest pain                                                                                          | 1 (0.8)   | 1 (1.2)           | 1 (0.4)    | 3 (0.7)  |
| Cholangitis                                                                                         | 2 (1.7)   | 0                 | 1 (0.4)    | 3 (0.7)  |
| Decreased appetite                                                                                  | 0         | 1 (1.2)           | 2 (0.9)    | 3 (0.7)  |
| Diarrhoea                                                                                           | 1 (0.8)   | 1 (1.2)           | 1 (0.4)    | 3 (0.7)  |
| Fatigue                                                                                             | 0         | 0                 | 3 (1.3)    | 3 (0.7)  |
| 2 (1.7)                                                                                             | 1 (1.2)   | 3 (0.7)           |            |          |
| Hypophosphataemia                                                                                   | 0         |                   |            |          |
| 1 (0.8)                                                                                             | 2 (0.9)   | 3 (0.7)           |            |          |
| Infection                                                                                           | 0         |                   |            |          |
| Muscular weakness                                                                                   | 1 (0.8)   | 1 (1.2)           | 1 (0.4)    | 3 (0.7)  |
| 1 (0.8)                                                                                             | 2 (0.9)   | 3 (0.7)           |            |          |
| Pain in extremity                                                                                   | 0         |                   |            |          |
| Pulmonary embolism                                                                                  | 3 (1.3)   | 3 (0.7)           |            |          |
| 0                                                                                                   | 0         |                   |            |          |
| Respiratory failure                                                                                 | 1 (1.2)   | 2 (0.9)           | 3 (0.7)    |          |
| 0                                                                                                   |           |                   |            |          |
| Septic shock                                                                                        | 0         | 1 (1.2)           | 3 (0.7)    |          |
| 2 (0.9)                                                                                             |           |                   |            |          |
| Small intestinal obstruction                                                                        | 1 (0.8)   | 2 (2.4)           | 3 (0.7)    |          |
| 0                                                                                                   |           |                   |            |          |
| Stomatitis                                                                                          | 1 (0.8)   | 1 (1.2)           | 1 (0.4)    | 3 (0.7)  |
| Includes Studies NCT01697605 (CSR in preparation; data cutoff 18Mar2019), NCT01004224, NCT01975701, |           |                   |            |          |  
Table 3:  SAEs occurring in 0.5% of adult oncology subjects treated with infigratinib monotherapy
Includes Studies NCT01697605 (CSR in preparation; data cutoff 18Mar2019), NCT01004224, NCT01975701, NCT02150967 (ongoing; data cutoff 31May2019), NCT02160041.  
Deaths:  Of the 433 subjects treated with infigratinib monotherapy, N = 45 (10.4%) have died on-treatment.  Most deaths were deemed related to study indication / disease progression. One death due to cardiac arrest and 1 death due to intestinal ischemia were considered to be related to study drug.  
1B
2.2.10 Efficacy in humans: In NCT01004224, a phase 1 dose-escalation study, 4 of 36 subjects  
 with non-small cell lung cancer and 3 of 8 subjects with urothelial carcinoma achieved partial response (Figure 1).  
13 Of the 26 subjects with metastatic breast cancer (21 with *FGFR1* amplification), 4 had reduced tumor burden but did not achieve partial response (3 with *FGFR1* amplification).  
13 In addition, of the 37 additional subjects with urothelial carcinoma, 12 achieved partial response and 1 achieved complete response (CR).  
14 In NCT02150967, 15 of 59 subjects achieved partial response.  
least 100 mg infigratinib. From Nogova et al (2016) *JCO.*
Subsequently, in a phase 2 study of infigratinib 125 mg orally daily 3 weeks on / 1 week off in N = 67 subjects with metastatic urothelial carcinoma with *FGFR3* alterations, an overall response rate of 25.4% and a disease control rate of 64.2% was observed.  
14 In another phase 2 study of infigratinib 125 mg orally daily 3 weeks on / 1 week off in N = 61 subjects with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR alterations, an overall response rate of 14.8% and a disease control rate of 75.4% was observed.  
15 2.2.11 Additional information: Further details are available in the Investigator's Brochure, which is included with the IRB submission. This study will be conducted under IND 147595 (pre-assigned). Infigratinib was approved by FDA as Truseltiq pursuant the Accelerated Approval regulations on 28 May 2021 for the indication of previously-treated, unresectable, locally-advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement, in adults.
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2.3 rationale

2.3.1 Rationale for combination of infigratinib with endocrine therapy: An analysis of 1,980 subjects with molecular data and 20 years of follow-up was recently performed. In this work, it was found that tumors classifying as integrative subtype 2 (characterized by the 11q13/14 amplification including *FGF3/4/19* and accounting for approximately 5% of all HR+/HER2-breast tumors) or integrative subtype 6 (characterized by the 8p12 amplification including *FGFR1* and account for approximately 5% of all HR+/HER2-tumors) exhibit an exceedingly high risk of distant relapse up to 20 years post-diagnosis (median 42 to 55%).  
2 Substantial improvement in progression-free survival has been seen in HR
+/HER2- metastatic breast cancer with the addition of CDK4/6 inhibition to endocrine therapy, 4-9 but virtually all tumors will eventually progress, leading to breast cancer-related death. The current treatment paradigm of metastatic HR
+/HER2- FGF(R)-altered breast cancer does not include inhibition of the FGFR pathway. As a single agent in humans, infigratinib has shown some antitumor activity in pre-treated metastatic breast cancers with *FGFR1* amplification, but not achieving the level of a partial response (Figure 1).  
13 Breast tumors with FGF(R) pathway alterations are in urgent need of more effective therapies, and we propose that combining infigratinib with endocrine therapy could achieve this goal.  
Accumulating preclinical and clinical data suggests that *FGFR1* amplification may drive endocrine therapy resistance in breast cancer.  
16,17 For example, *FGFR1*-amplified cell lines showed resistance to 4-hydroxytamoxifen, which was reversed by RNA silencing of FGFR1.  
18 ER+/*FGFR1*-amplified tumors treated with letrozole prior to surgery did not show decreases in proliferation as measured by Ki67 as is typically seen in sensitive tumors, and this primary resistance to aromatase inhibition appeared to be mediated by an upregulation of FGFR1 and FGF ligand expression allowing persistent activation of estrogen response.  
17 Similarly, another study found that time to progression on first-line endocrine therapy was shorter in FGFR1-amplified ER+ metastatic breast cancers than in ER+ metastatic breast cancers that were not *FGFR1*-amplified, a difference not seen for first-line chemotherapy.  
19 Combining lucitanib (a non-selective FGFR inhibitor) with fulvestrant improved growth inhibition of ER+/*FGFR1*-amplified cell lines and patient-derived xenografts.  
17 Another study validated the finding of intrinsic endocrine therapy resistance in ER+/*FGFR1*-amplified primary tumors, and also reported a similar phenomenon for tumors with *CCND1/FGF3/4/19* amplification.  
20 In sum, these data provide a rationale for combining infigratinib with endocrine therapy may overcome the intrinsic endocrine therapy resistance of ER+/*FGFR1*-amplified or ER+/*CCND1/FGF3/4/19*-amplified tumors. For those subjects whose tumors have demonstrated primary or secondary resistance to endocrine therapy (ie, by progression on an aromatase inhibitor or fulvestrant), adding FGFR inhibition may allow these tumors to sensitize to endocrine therapy. Notably, FGFR inhibition in combination with fulvestrant has been attempted previously in breast cancer, in a phase 2, randomized, placebo-controlled study of dovitinib in combination with fulvestrant in postmenopausal subjects with hormone receptor-positive, HER2-negative breast cancer that progressed during or after prior endocrine therapy.  
21 This study of N = 97 subjects showed median progression-free survival of 5.5 months in the dovitinib arm and 5.5 months in the placebo arm (HR 0.68) in the overall cohort. Findings were not significantly different in the FGF pathway-amplified subgroup (N = 31): median PFS 10.9 months in the dovitinib arm and 5.5 months in the placebo arm (HR 0.64). However, dovitinib is one of several non-selective multi-kinase inhibitors with greater impact on VEGFR than FGFR (another example is lucitinib), and subsequent studies have strongly suggested that these multi-kinase inhibitors may not effectively inhibit the FGFR pathway in subjects.  
22,23 The efficacy of FGFR
inhibition is most established thus far in *FGFR*-altered (most commonly *FGFR3*-mutated) advanced urothelial carcinoma, the setting for which the selective FGFR inhibitor erdafitinib received FDA approval as Balversa on 12 April 2019 (Accelerated Approval). Dovitinib was studied in this setting as well in a phase 2 study that treated N = 12 *FGFR3*-mutated and N = 31 FGFR3-wild-type advanced urothelial cancer subjects.  
24 In this study, the ORR in the FGFR3-mutated subgroup was 0% (3.2% in the wild-type subgroup). Also, and importantly, no hyperphosphatemia was observed in these subjects, nor in other subjects who have been treated with dovitinib. Hyperphosphatemia is a key on-target effect of FGFR inhibition and its absence with dovitinib and other multi-kinase inhibitors suggests poor FGFR inhibition.  
22,23 Conversely, in the phase 2 study of FGFR-altered advanced urothelial cancer that led to erdafitinib's approval, the ORR was 32% (28 of 87 subjects) with 69% experiencing hyperphosphatemia, 25 and in a similar phase 2 study of infigratinib, the ORR was 25%
(16 of 67 subjects) with 50% experiencing hyperphosphatemia.  
14 Dovitinib is no longer widely considered an effective FGFR inhibitor, 22,23 while the new generation of selective FGFR
inhibitors are rapidly gaining ground in establishing their efficacy in FGFR-altered cancers.  
14,15,25 We therefore believe it is time to assess the hypothesis that selective FGFR
inhibition in combination with endocrine therapy may have a benefit for FGFR-altered hormone receptor-positive advanced breast cancer patients.  
2.3.2 Comparison to other active trials: To our knowledge, there are 2 active clinical trials examining FGFR inhibition in combination with endocrine therapy in metastatic breast cancer, one of which also adds CDK4/6 inhibition. NCT04024436 opened October 2019 and is a nonrandomized phase 2 study will administer TAS-120 (Taiho) in combination with fulvestrant to 4 cohorts, 3 of which will have an *FGFR2* amplification and 1 of which will have a high-level (ratio to centromere ≥ 5) *FGFR1* amplification. Neither of these studies will examine the efficacy of FGFR inhibition in combination with endocrine therapy in tumors harboring amplification of the ligand (*FGF3*; integrative subtype 2). The hypothesis driving the present trial is that the unique drivers identified via integrative subtyping (a subset of tumors with *FGFR1* amplification classifying as integrative subtype 6; and a subset of tumors with *FGF3* amplification classifying as integrative subtype 2) will be uniquely sensitive to FGFR inhibition.  
2.3.3 Rationale for dose of tamoxifen: The dose and schedule selected for tamoxifen
(20 mg/day by mouth continuously) is FDA-approved for the treatment of ER+ metastatic breast cancer.
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2.4 screening tumor sequencing assays

Potential subjects will be eligible if their tumor classifies as integrative cluster 2 (IC2) or 6 (IC6) based on the results of the FoundationOne (F1CDx) FDA-approved assay. There are 11 validated integrative subtypes or clusters of breast cancer, defined initially from the METABRIC cohort based on the integration of genomic copy number alterations and transcriptional profiles.  
3 Our recent study examining 20 years of clinical follow-up from 1,980 subjects in the initial METABRIC cohort revealed substantial variability in the risk of relapse amongst HR+/HER2-subjects.  
2 In particular, integrative subtypes 1, 2, 6, and 9 exhibited exceedingly high (median 42 to 55%) risk of distant relapse up to 20 years post-diagnosis. Each of these integrative subtypes is characterized by distinct copy number amplification events and concomitant over-expression of candidate driver genes: integrative subtype 2 has the *FGF3/FGF4/FGF19, CCND1* (11q13/14) amplification and integrative subtype 6 has the *FGFR1* (8p12) amplification. While these characteristic amplifications are almost universally present within tumors classifying as the relevant integrative subtype, the converse is not true: only approximately one-quarter of ER+/HER2-tumors that carry the CCND1/FGF3/4/19 amplification classify as integrative subtype 2, and approximately one-half of ER+/HER2-tumors that carry the *FGFR1* amplification classify as integrative subtype 6. It is plausible that these amplifications may be passenger events rather than driver events in the tumors that do not classify as the relevant integrative subtypes. Using additional information from targeted sequencing panels can improve the accuracy of integrative cluster classification, and we hypothesize better delineate in which tumors the FGFR pathway is the oncogenic driver than the simple presence of the amplification.  
2,3 Thus, subjects will be eligible if their tumor's F1CDx results are consistent with integrative cluster 2 or 6, per the classifier. The classifier was developed to predict integrative cluster classification from the copy number values and mutational status of the genes on the F1CDx panel in two large cohorts of breast tumors, METABRIC 3 and The Cancer Genome Atlas 28. This classifier will be applied to the integer copy number values and gene mutation calls generated by the F1CDx assay and analysis.
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2.5 study design

The primary purpose for this study is treatment. The protocol is designed to evaluate one or more interventions for treating a disease, syndrome, or condition.  
The interventional model is Sequential.  
The number of intervention arms is up to 3.  
The study will be not be masked (not blinded).  
The study will be not be randomized.  
This is a phase 1b study evaluating the safety and tolerability of infigratinib. Cohort 1 will utilize the combination of tamoxifen and infigratinib. We anticipate that this combination may play a role in the future development of infigratinib for hormone receptor-positive breast cancer, necessitating the establishment of their safety. For example, tamoxifen and infigratinib might be used in the early-stage, (neo)adjuvant setting as well as the late-stage, metastatic setting.  
1B
In Cohort 1, up to 3 dose levels of infigratinib may be evaluated (125 mg; 100 mg; and 75 mg) in combination with tamoxifen. This pilot study is a necessary step for the future development of infigratinib in combination with tamoxifen and will serve as a safety run-in evaluation for a follow-up study. For this cohort, a 3 + 3 design will be employed starting at 100 mg, and allowing subjects who start at 100 mg to escalate to 125 mg (see Section 12.4).
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2.6 correlative studies background

2.6.1 Organoid cultures: Three-dimensional organoid cultures established from viable tumor cells have the potential to re-capitulate *in vitro* subject- and tumor-specific phenotypes, enabling the study of drug response and tumor evolution in the lab.  
32-34 Tumor organoid cultures can be established as a renewable source of tissue for *in vitro* and i*n vivo* experimentation; they are amenable to high-throughput drug screens and complementing xenograft-based approaches. Organoid culture can be used to evaluate the efficacy of novel therapeutic agents in specific genetic contexts. It is planned to establish organoids from tumors in this study, classifying as integrative subtypes 2 and 6, allowing testing of novel drug combinations to improve response and overcome resistance to FGFR inhibition in these high-risk subgroups. Furthermore, as these organoids will be treated *in vitro* with the same agents that the study subjects from whose tumors they were derived will be, we will be able to compare response between the *in vitro* and subjects. We will also be able to compare the genomic alterations that arise with treatment in subjects (Section 2.6.2) with those that arise with treatment in the organoids. These experiments may inform our understanding of genomic determinants of sensitivity and resistance to FGFR inhibition, as well as the optimal combinations of therapies to produce response in FGFR-altered breast tumors. 2.6.2 Cell-free DNA analyses: Cell-free DNA is believed to be representative of the heterogeneity present even in micro-metastatic lesions.  
35 Thus, it may better capture the spectrum of subclonal populations with the potential to grow in response to therapy than serial tumor biopsies. Furthermore, it has been shown that cell-free DNA sequencing can detect and characterize clonal dynamics in metastatic breast cancer.  
36-38 It is planned to collect blood from subjects prior to initiation of study drug, after the first 2 weeks of therapy, and at time of confirmed progression. The blood samples will be separated into plasma and buffy coat and banked. Sequencing (eg, whole-exome or whole-genome) of the cell-free DNA extracted from these banked plasma samples will allow us to identify novel mutations or copy number changes that appear at time of progression in subjects who initially responded, as well as to compare baseline genomic changes between responders and non-responders. The banked buffy coat samples will allow us to identify somatic variants that act as driver mutations and compare them to a matched normal sample through tumor-normal whole-genome sequencing. Furthermore, we can cross-reference these findings with genomic findings in the organoid models (Section 2.6.1). These analyses may allow us to identify genetic mechanisms of resistance to the study drug and/or endocrine therapy. 2.6.3 Proteomic profiling: Proteomic changes may be examined in tumor cells and the surrounding microenvironment *in situ* to delineate compensatory signaling pathways and mechanisms of response/resistance to the evaluated targeted agents. Paired pre- and 1B
post-treatment tissue samples from the trial may be profiled on the Nanostring GEOMx Digital Spatial Profiling (DSP) platform (Research Use Only) 39,40 or with mutiplexed ion beam imaging (MIBI). 41-43 There is growing evidence that functional heterogeneity in the tumor and microenvironment contribute to treatment response, highlighting the importance of spatially resolved approaches such as DSP. DSP enables geographic and phenotypic selection of tissue regions - for example, those that are enriched for pancytokeratin-positive tumor cells. Molecular changes observed with treatment may inform intelligent combinations of therapy in the future to overcome primary resistance or enhance treatment response.
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3. participant selection and enrollment

Inclusion and Exclusion Criteria are provided on Participant Eligibility Checklist following. This document may be extracted from this document for use in screening potential subjects. The Participant Eligibility Checklist in the following subsection must be completed in its entirety for each subject prior to registration. The Participant Eligibility Checklist may be extracted from this document for use in screening potential subjects. The completed, signed, and dated checklist must be retained in the subject's study file, and the study's Regulatory Binder. Screening results will be collectively documented on the Study Participant Log. Pursuant to Stanford Medicine SOP "Confirmation of Participant Eligibility in Clinical Trials," the treating Physician (investigator); the Study Coordinator; and a third reviewer from the study team (eg, investigator or back-up study coordinator) will verify that the subject's eligibility is accurate; complete; and legible in source records. A description of the eligibility verification process should be included in the EPIC or other Electronic Medical Record progress note.
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participant eligibility checklist i. protocol

| A Phase 1B Study of Infigratinib in Combination with Tamoxifen in   |                                                                                |
|---------------------------------------------------------------------|--------------------------------------------------------------------------------|
| Protocol Title:                                                     | Hormone Receptor-Positive, HER2-Negative, FGFR-Altered Advanced  Breast Cancer |
| eProtocol number:                                                   | IRB-53650                                                                      |
| OnCore number:                                                      | BRS0113                                                                        |
| Principal Investigator [per 21CFR§312.3(b)]:                        | Jennifer L Caswell-Jin, MD                                                     |
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3.1 inclusion criteria

| Prospective Participant Must MATCH          | Supporting                                                                                                                                                                                                                                                                                                                                                           |    |                 |
|---------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|-----------------|
| ALL these Inclusion Criteria to be Eligible | Yes                                                                                                                                                                                                                                                                                                                                                                  | No | Documentation * |
| 1.                                          | History of biopsy-proven ER-positive and/or  PR-positive, HER2-negative breast cancer and  radiographic evidence of metastatic disease, or  locally recurrent unresectable disease. ER-positivity  and PR-positivity are defined as ≥ 1% cells staining  positive by immunohistochemistry. HER2-negativity  is defined by IHC or FISH, per ASCO-CAP 2018  guidelines |    |                 |
| 2.                                          | Cancer subtype indicative of alterations to the  fibroblast growth factor ligand or receptor  (FGF/FGFR alteration): Predicted integrative  (IntClust) subtype classification of IC2 or IC6  according classifier on targeted sequencing data  from FoundationOne.                                                                                                   |    |                 |  
| Supporting                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                           |    |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|
| Prospective Participant Must MATCH                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Documentation *                                                                                                                                                                                                                                                                                                                                                                           |    |
| ALL these Inclusion Criteria to be Eligible                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Yes                                                                                                                                                                                                                                                                                                                                                                                       | No |
| 3.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Evaluable or measurable disease. Cohort 1 only: Evaluable or measurable disease,  as defined by RECIST v1.1. Bone-only disease is  acceptable.                                                                                                                                                                                                                                            |    |
| 4.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | ≥ 18 years old                                                                                                                                                                                                                                                                                                                                                                            |    |
| 5.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Eastern Cooperative Oncology Group (ECOG)  performance status 0 to 2                                                                                                                                                                                                                                                                                                                      |    |
| 6.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Prior cancer therapy (except for endocrine therapy,  denosumab, or bisphosphonates) must be  discontinued for 2 weeks prior to initiation of study  drugs. Recovery from adverse events of previous  cancer therapies to baseline or Grade 1 except for  alopecia or stable Grade 2 neuropathy.  Radiotherapy must also be completed at least  2 weeks prior to initiation of study drugs |    |
| 7.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Absolute neutrophil count (ANC) ≥ 1,000/mm3                                                                                                                                                                                                                                                                                                                                               |    |
| 8.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Platelets ≥ 75,000/mm3                                                                                                                                                                                                                                                                                                                                                                    |    |
| 9.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Hemoglobin ≥ 9.0 g/dL                                                                                                                                                                                                                                                                                                                                                                     |    |
| 10. Total bilirubin ≤ 1.8 mg/dL (unless documented  Gilbert's disease) 11. Aspartate aminotransferase (AST) and alanine  aminotransferase (ALT) < 90 U/L  12. Estimated glomerular filtration rate (GFR)  ≥ 45 mL/min  13. Phosphorus between 2.5 and 4.5 mg/dL, inclusive  14. Total corrected (for albumin) serum calcium  between 8.5 and 10.5 mg/dL, inclusive 15. Amylase < 200 U/L 16. Lipase < 120 U/L 17. Ability to understand and the willingness to sign a  written informed consent document |                                                                                                                                                                                                                                                                                                                                                                                           |    |  
| Supporting                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                 |    |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------|----|
| Prospective Participant Must MATCH                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Documentation * |    |
| ALL these Inclusion Criteria to be Eligible                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Yes             | No |
| 18. Agrees to take sevelamer, if indicated, and has no  contraindications to use of this medication (that is:  known hypersensitivity to sevelamer or component  of the formulation; bowel obstruction; active bowel  mucosal injury such as ulcerative colitis or  gastrointestinal bleeding). 19. Agrees to follow low-phosphate diet, if indicated  20. Able to swallow and retain oral medication 21. Women must be postmenopausal, defined as  (at least one of):  - ≥ 60 years of age; - amenorrhea for at least 24 months; - amenorrhea for at least 12 months with   serum estradiol < 20 pg/mL; - prior bilateral oophorectomy;   OR - treatment with a luteinizing hormone (LH)-  releasing hormone agonist (such as   goserelin acetate or leuprolide acetate) initiated   at least 28 days prior to study enrollment.  22. Women being treated with a LH-releasing agonist  but who are otherwise of childbearing potential (did  not undergo total hysterectomy or bilateral tubal  ligation at least 6 weeks before first dose of study  drug) must have a negative pregnancy test within  7 days of the first dose of study drug. 23. Women who are being treated with an LH-releasing  agonist but are otherwise of childbearing potential  must agree to use barrier contraception or an  intrauterine device while taking study drug and for  3 months following their last dose of study drug.  Alternatively, total abstinence is acceptable if  preferred by the subject. |                 |    |  
| Supporting                                                                                                                                                                                                                                                                                                                                                            |                 |    |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------|----|
| Prospective Participant Must MATCH                                                                                                                                                                                                                                                                                                                                    | Documentation * |    |
| ALL these Inclusion Criteria to be Eligible                                                                                                                                                                                                                                                                                                                           | Yes             | No |
| 24. Sexually-active men must agree to use a condom  during intercourse while taking drug and for  3 months after the last dose of the study drug and  should not father a child during this period.  A condom is required to be used also by  vasectomized men as well as during intercourse  with a male partner to prevent delivery of the drug  via seminal fluid. |                 |    |  
| 3.2                                     | Exclusion Criteria                                                                                                                                                                                                                                                                                                                                                                                 |    |                 |
|-----------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|-----------------|
| Prospective Participants Must NOT Match | Supporting                                                                                                                                                                                                                                                                                                                                                                                         |    |                 |
| ANY of These Exclusion Criteria         | Yes                                                                                                                                                                                                                                                                                                                                                                                                | No | Documentation * |
| 1.                                      | History of another primary malignancy within 3 years  except adequately treated in situ carcinoma of the  cervix or non-melanoma carcinoma of the skin or  any other curatively treated malignancy that is not  expected to require treatment for recurrence during  the course of the study.                                                                                                      |    |                 |
| 2.                                      | Neurologic symptoms related to central nervous  system metastases requiring increasing doses of  corticosteroids. Note that subjects with central  nervous system metastases ARE eligible if they are  on a stable corticosteroid dose for at least 2 weeks  preceding study entry.                                                                                                                |    |                 |
| 3.                                      | Current evidence of corneal or retinal  disorder/keratopathy including, but not limited to,  bullous/band keratopathy, corneal abrasion,  inflammation/ulceration, keratoconjunctivitis,  confirmed by ophthalmologic examination. Subjects  with asymptomatic ophthalmologic conditions  assessed by the investigator to pose minimal risk for  study participation may be enrolled in the study. |    |                 |  
| Supporting                                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |    |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|
| Prospective Participants Must NOT Match                                                                                                                                                                                                                  | Documentation *                                                                                                                                                                                                                                                                                                                                                                                                                                                          |    |
| ANY of These Exclusion Criteria                                                                                                                                                                                                                          | Yes                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | No |
| 4.                                                                                                                                                                                                                                                       | Current evidence of extensive tissue calcification  including, but not limited to, the soft tissue, kidneys,  intestine, myocardium, and lung with the exception  of calcified lymph nodes, minor pulmonary  parenchymal calcifications, and asymptomatic  coronary calcification.                                                                                                                                                                                       |    |
| 5.                                                                                                                                                                                                                                                       | Impairment of gastrointestinal (GI) function or GI  disease that may significantly alter the absorption of  oral infigratinib (eg, ulcerative diseases,  uncontrolled nausea, vomiting, diarrhea,  malabsorption syndrome, small bowel resection).                                                                                                                                                                                                                       |    |
| 6.                                                                                                                                                                                                                                                       | Current evidence of endocrine alterations of  calcium/phosphate homeostasis, eg, parathyroid  disorders, history of parathyroidectomy, tumor lysis,  or tumoral calcinosis.                                                                                                                                                                                                                                                                                              |    |
| 7.                                                                                                                                                                                                                                                       | Currently receiving or planning during study  participation to receive treatment with agents that  are known strong inducers or inhibitors of CYP3A4  and medications which increase serum phosphorus  and/or calcium concentration. Subjects are not  permitted to receive enzyme-inducing anti-epileptic  drugs, including carbamazepine, phenytoin,  phenobarbital, and primidone. See Appendix A for  a list of prohibited concomitant medications and  supplements. |    |
| 8.                                                                                                                                                                                                                                                       | Has consumed grapefruit, grapefruit juice, grapefruit  hybrids, pomegranates, star fruits, pomelos, Seville  oranges, or products containing juice of these fruits  within 7 days prior to first dose of study drug.                                                                                                                                                                                                                                                     |    |
| 9.                                                                                                                                                                                                                                                       | Have used amiodarone within 90 days prior to first  dose of study drug.                                                                                                                                                                                                                                                                                                                                                                                                  |    |
| 10. Has used medications known to prolong the  QT interval and/or are associated with a risk of  Torsades de Pointes (TdP) 7 days prior to first dose  of study drug. See Appendix A for a list of  prohibited concomitant medications and  supplements. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |    |  
| Supporting                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                 |    |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------|----|
| Prospective Participants Must NOT Match                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Documentation * |    |
| ANY of These Exclusion Criteria                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Yes             | No |
| 11. Has used calcium or vitamin D within 3 days prior to  first dose of study drug. Calcium supplementation  may subsequently be used as clinically indicated  (for hypocalcemia) on study. 12. Have clinically significant cardiac disease including  any of the following: a. Congestive heart failure requiring treatment  (New York Heart Association Grade ≥ 2), left  ventricular ejection fraction (LVEF) < 50% or  local lower limit of normal as determined by  multiple gated acquisition (MUGA) scan or  echocardiogram (ECHO), or uncontrolled  hypertension (refer to the European Society of  Cardiology and European Society of  Hypertension guidelines [Williams et al., 2018]) b. Presence of Common Terminology Criteria for  Adverse Events (CTCAE) v5.0 Grade ≥ 2  ventricular arrhythmias, atrial fibrillation,  bradycardia, or conduction abnormality c. Unstable angina pectoris or acute myocardial  infarction ≤ 3 months prior to first dose of study  drug d. Corrected QT interval-Fredericia (QTcF) > 470  msec (males and females). Note: If the QTcF is  > 470 msec in the first electrocardiogram (ECG),  a total of 3 ECGs separated by at least 5  minutes should be performed. If the average of  these 3 consecutive results for QTcF is ≤ 470  msec, the subject meets eligibility in this regard.  e. Known history of congenital long QT syndrome 13. Have had a recent (≤ 3 months) transient ischemic  attack or stroke.  14. Pregnant or nursing  * All subject files must include supporting documentation to confirm subject eligibility. The |                 |    |  
* All subject files must include supporting documentation to confirm subject eligibility. The method of confirmation can include, but is not limited to, laboratory test results, radiology test results, subject self-report, and medical record review.
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v. statement of eligibility

By signing this form of this trial I verify that this subject is: eligible / ineligible for participation in the study. This study is approved by the Stanford Cancer Institute Scientific Review Committee, the IRB of record, and has finalized financial and contractual agreements as required by Stanford School of Medicine's Research Management Group.  
| Study Coordinator printed name:                | Date:   |
|------------------------------------------------|---------|
| Signature: Investigator printed name:          | Date:   |
| Signature: Triple-check reviewer printed name: | Date:   |
| Signature:                                     |         |
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3.3 informed consent process

All subjects must be provided a consent form describing the study with sufficient information for subjects to make an informed decision regarding their participation. Subjects must sign the IRB
approved informed consent prior to participation in any study specific procedure. The subject must receive a copy of the signed and dated consent document. The original signed copy of the consent document must be retained in the medical record or research file.
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3.4 study timeline primary completion

It is anticipated that the study will reach primary completion (30 days after final subject completes treatment with study agents) 24 months from the time the study opens to accrual.
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study completion

It is anticipated that the study will reach study completion (final date on which data are collected) 36 months from the time the study opens to accrual.
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4. treatment plan

Potential subjects who preliminarily meet inclusion criteria and exclusion criteria as determined by study staff (for example, the investigator or clinical research coordinator) will meet with study staff to review the study and informed consent in detail. At this time, inclusion and exclusion criteria will be confirmed with the subjects and treating clinicians as necessary. All eligible subjects (meeting criteria described in Section 3) will receive the drug combination of infigratinib with tamoxifen. Once a dose level for infigratinib is determined, Cohort 1 will close. All subjects in whom a research biopsy of a disease site is deemed feasible and safe by the investigator will be required to undergo a biopsy to donate 4 to 8 cores of tumor tissue before and on-treatment to be used for research purposes, including genomic/transcriptomic/proteomic analysis and organoid culture derivation as described in Section 2.6. The on-treatment biopsy is recommended to occur on Day 15 of treatment, but any time on treatment is acceptable.  
Tissue will be transported to the Curtis lab for processing and analysis. Subjects who require a tumor biopsy for eligibility assessment will undergo the collection of tissue cores for research simultaneously, whenever possible. Archival tumor tissue, including stored at Stanford University and at other institutions, may be obtained for use for tissue correlative studies as well. Only tissue not needed for diagnostic purposes will be used for research.  
Subjects in Cohort 1 will receive tamoxifen 20 mg orally continuously starting on Day 1 and will additionally receive infigratinib orally daily 3 weeks on, 1 week off (28-day cycle) at the dose level dictated by study protocol (125 mg, 100 mg, or 75 mg). Subjects will continue receiving cycles as above until 18 months on treatment, progression, or unacceptable toxicity (or other reasons outlined in Section 4.3). If toxicity is deemed per the investigator to be related to endocrine therapy (tamoxifen) and not infigratinib, subjects will be given the option of continuing infigratinib only (without endocrine therapy) until progression.  
1B
Details on study procedures during Screening, Treatment, and Post-Treatment are provided in the Study Calendar and footnotes (Section 9).
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4.1 general concomitant medication and

Administration of other anticancer therapies within 2 weeks of enrollment, except ongoing administration of a bisphosphonate drug or denosumab as treatment for bone metastasis or ongoing administration of a luteinizing hormone-releasing hormone agonist (such as goserelin acetate or leuprolide acetate) or other endocrine therapy, is prohibited. Palliative radiotherapy on study is permitted for the treatment of painful bony lesions providing the lesions were known at the time of study entry and the investigator clearly indicates that the need for palliative radiotherapy is not indicative of disease progression. In view of the current lack of data about the interaction of infigratinib with radiotherapy, infigratinib treatment should be interrupted during palliative radiotherapy, resuming infigratinib treatment after recovery to ≤ Grade 1 radiotherapy-related toxicity.  
Details for specific medications prohibited while on study are provided in Appendix A. The rationale for the restricted medications is provided below. Strong inhibitors of CYP3A4 such as the ones listed in Appendix A are prohibited because infigratinib is a likely substrate of this isoenzyme.  
Strong inducers of CYP3A4 are prohibited because their usage may decrease the exposure of infigratinib. Therefore, agents such as those listed in Appendix A are prohibited. Please note that the list may not be exhaustive.  
Subjects must also avoid the consumption of grapefruits; grapefruit juice; grapefruit hybrids; pomegranates; star fruits; pomelos; Seville oranges; or juice within 7 days prior to the first dose of infigratinib and throughout the treatment period due to a potential CYP3A4 interaction with study drug. Medications that increase the serum levels of phosphorus and/or calcium are prohibited. Preliminary clinical data have shown that infigratinib has no effect on cardiac conduction or ECG intervals (See current version of the infigratinib Investigator's Brochure). However, medications that are known to prolong the QT/QTc interval or induce TdP (risk of TdP/QT prolongation) are prohibited. List of these medications is given in Appendix A. Please note that the list might not be comprehensive.  
Medications that are allowed but should be administered with caution are provided in Appendix B. The rationale for these medications is provided below. Infigratinib is characterized by pH-dependent solubility, and therefore, medicinal products that alter the pH of the upper GI tract may alter the solubility of infigratinib, and limit bioavailability. These agents include, but are not limited to, proton pump inhibitors (eg, omeprazole), H2-antagonists (eg, ranitidine) and antacids. If possible, proton pump inhibitors should be avoided due to their long PD effect and replaced with H2-antagonists or antacids. Study drug should be taken ≥ 2 hours before or 10 hours after dosing with a gastric protection agent.  
1B
Infigratinib is a substrate of CYP3A4. Therefore, moderate inhibitors and inducers should be used with caution if an alternative is not available. If anticoagulation is required, heparin and/or low-molecular-weight heparins or direct thrombin inhibitors and/or Factor Xa inhibitors that are not metabolized by CYP3A4 (eg, dabigatran, edoxaban) are preferred. If unavoidable, anticoagulants that are CYP3A4 substrates and have a narrow therapeutic index [eg, warfarin sodium or any other coumadin-derivative anticoagulants or certain direct thrombin inhibitors (eg, argatroban or Factor Xa inhibitors, eg, rivaroxaban)] should be used with caution. Infigratinib was shown in vitro to inhibit the drug transporter breast cancer resistance protein
(BCRP), with an IC50 of 210 nM. While the clinical relevance of this inhibition is unknown, drugs transported by BCRP should be used with caution. Anti-emetics are recommended as clinically appropriate at the first sign of nausea and vomiting or as prophylaxis to prevent emesis, along with supportive care according to clinical practice guidelines. It is recommended to avoid using drugs that are known to cause QT prolongation. Note that some anti-emetics have a known risk for Torsade de Pointes, and therefore need to be used with caution. See Appendix B for list of drugs that need to be used with caution. Aprepitant (brand name: Emend) is both a sensitive substrate and a moderate CYP3A4 inhibitor and should be used with caution if an alternative is not available. Preliminary clinical data have shown that infigratinib has no effect on cardiac conduction or ECG intervals (see current version of the infigratinib Investigator's Brochure). However, medications that have the potential to prolong the QT/QTc interval or induce Torsade de Pointes (possible and conditional risk of TdP/QT prolongation) are allowed with caution. Investigators at their discretion may co-administer such medications, but subjects should be carefully monitored. See Appendix B for list of drugs that need to be used with caution. Please note that the list might not be comprehensive. Otherwise, concomitant treatment considered necessary for the subject's well-being may be given at discretion of the treating physician. All concomitant medications (including herbal supplements and vitamins), blood products, as well as interventions (eg, paracentesis, etc.)
received by subjects from screening until the end of study visit will be recorded in the CRF.
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4.1.2 supportive care guidelines

Any palliative and supportive care for disease related symptoms, including any medication or therapy for a concurrent medical condition are permitted, except if specifically prohibited below.
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hematopoietic growth factors

Hematopoietic growth factors [eg, erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF)] and blood transfusions are not to be administered prophylactically or to be used to meet eligibility criteria. However, these drugs may be administered as per the label of these agents or as dictated by local practice or guidelines established by the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), or other appropriate regional societies.
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management of hyperphosphatemia

Hyperphosphatemia is a recognized on-target effect of potent and selective inhibitors of the FGFR pathway. The goal of a low-phosphate diet, when one is recommended per management strategy below, is to restrict dietary phosphate to 600 to 800 mg/day by avoiding high-phosphate foods.  
High-phosphate foods include dairy products; meats, nuts, and other high-protein foods; processed foods; and dark colas. In general, subjects will be instructed to liberalize their diet on days they are not taking infigratinib (including Days 22 to 28, and during interruption of infigratinib for indications other than hyperphosphatemia), unless their serum phosphorus is currently > 5.5 mg/dL. Similarly, subjects who are taking sevelamer (phosphate-lowering medication) will be instructed to hold it on days they are not taking infigratinib (including Days 22 to 28, and during interruption of infigratinib for indications other than hyperphosphatemia), unless their serum phosphorus is currently > 5.5 mg/dL.  
Below is the recommended management strategy for hyperphosphatemia. Section 6 also outlines instructions for when to interrupt and/or dose-reduce infigratinib in addition to these recommendations for management. Notably, these instructions for increased monitoring of serum phosphorus, interruption, and dose reduction begin if serum phosphorus > 7.0 mg/dL. All subjects will have a serum phosphorus checked on C1D4:  
If serum phosphorus > 5.5 and ≤ 7.0 mg/dL, subjects will be instructed to follow a low-phosphate diet and to take sevelamer 800 mg orally 3 times daily with meals.  
If serum phosphorus > 7.0 mg/dL, subjects will be instructed to follow a low-phosphate diet and to take sevelamer 1200 mg orally 3 times daily with meals.  
All subjects will have a serum phosphorus checked on Cycle 1 Day 15:
For subjects who are not currently following a low-phosphate diet or taking sevelamer:  
o If serum phosphorus > 5.5 and ≤ 7.0 mg/dL, subjects will be instructed to follow a low-phosphate diet and to take sevelamer 800 mg orally 3 times daily with meals.  
o If serum phosphorus > 7.0 mg/dL, subjects will be instructed to follow a low-phosphate diet and to take sevelamer 1200 mg orally 3 times daily with meals.  
For subjects who are currently following a low-phosphate diet and taking sevelamer:
o If serum phosphorus < 5.0 mg/dL, subjects will be given the option of liberalizing their diet or stopping the sevelamer (not both).  
o If serum phosphorus > 5.5 and ≤ 7.0 mg/dL, subjects will be instructed to increase the dose of sevelamer to 1200 mg orally 3 times daily with meals.  
o If serum phosphorus > 7.0 mg/dL, subjects will be instructed to increase the dose of sevelamer to 1600 mg orally 3 times daily with meals.
Subsequent (after Cycle 1) management of hyperphosphatemia is as follows:
For subjects who are not currently following a low-phosphate diet or taking sevelamer:  
o If serum phosphorus > 5.5 and ≤ 7.0 mg/dL, subjects will be instructed to follow a low-phosphate diet and to take sevelamer 800 mg orally 3 times daily with meals.
1B  
o If serum phosphorus > 7.0 mg/dL, subjects will be instructed to follow a low-phosphate diet and to take sevelamer 1200 mg orally 3 times daily with meals.  
For subjects who are currently either following a low-phosphate diet or taking sevelamer, but not both:
o If serum phosphorus > 5.5 and ≤ 7.0 mg/dL, subjects will be instructed to follow a low-phosphate diet and to take sevelamer 800 mg orally 3 times daily with meals.  
o If serum phosphorus > 7.0 mg/dL, subjects will be instructed to follow a low-phosphate diet and to take sevelamer 1200 mg orally 3 times daily with meals.  
For subjects who are currently following a low-phosphate diet and taking sevelamer 800 mg orally 3 times daily:
o If serum phosphorus > 5.5 and ≤ 7.0 mg/dL, subjects will be instructed to increase sevelamer to 1200 mg orally 3 times daily with meals.  
o If serum phosphorus > 7.0 mg/dL, subjects will be instructed to increase sevelamer to 1600 mg orally 3 times daily with meals.  
For subjects who are currently following a low-phosphate diet and taking sevelamer 1200 mg orally 3 times daily:
o If serum phosphorus > 5.5 mg/dL, subjects will be instructed to increase sevelamer to 1600 mg orally 3 times daily with meals.
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management of diarrhea

Subjects should be instructed to notify their physician immediately at the first signs of poorly formed or loose stool or an increased frequency of bowel movements. Administration of antidiarrheal/anti-motility agents is recommended at the first sign of diarrhea as initial management. Some subjects may require concomitant treatment with more than one antidiarrheal agent. When therapy with antidiarrheal agents does not control the diarrhea to tolerable levels, study drug should be temporarily interrupted or dose reduced (see Section 6).
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management of skin toxicity

| Grade 1   | Consider minoxidil 5% (OTC) solution or foam once daily to scalp.                                                        |
|-----------|--------------------------------------------------------------------------------------------------------------------------|
| Grade 2   | Consider minoxidil 5% (OTC) solution or foam twice daily to scalp. Consider  fluocinonide 0.05% solution daily to scalp. |  
Palmar-plantar erythrodysesthesia syndrome: See also Section 6 for when to interrupt or dose-reduce infigratinib (Grade 3).  
| Grade 1      | Consider urea 20% or ammonium lactate 12% lotions twice daily to hands and feet.                                                                      |
|--------------|-------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 2 or 3 | Consider urea 20% or ammonium lactate 12% lotions twice daily to hands and feet.  Consider fluocinonide 0.05% solution twice daily to hands and feet. |  
| Grade 1 to 3   | Consider cefadroxil 500 mg orally twice daily or TMP/SMX orally twice daily for 14 days.  Soak for 15 minutes daily in white vinegar in tap water 1:1. Obtain bacterial cultures to  confirm sensitivity to antimicrobial. Consult dermatology.   |
|----------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Stomatitis: Subjects should be instructed to follow good oral hygiene during therapy. Prophylactic dexamethasone 10 mg/5 mL swish/spit 4 times a day for the first 8 weeks can be considered for prevention of stomatitis, 44 for example, for subjects who have had significant stomatitis from previous cancer therapies. Also see Section 6 for when to interrupt or dose-reduce infigratinib (Grade 3).  
| Grade 1   | Consider dexamethasone elixir 0.5 mg/mL swish and spit 1 teaspoon (5 mL) 3 times  daily.                                                                                                                                                       |
|-----------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 2   | Consider dexamethasone elixir 0.5 mg/mL swish and spit 1 teaspoon (5 mL) 3 times  daily AND doxepin 10 mg/mL swish and spit 1 teaspoon 5 mL every 6 hours as needed  for pain.                                                                 |
| Grade 3   | Consider dexamethasone elixir 0.5 mg/mL swish and spit 1 teaspoon (5 mL) 3 times  daily AND doxepin 10 mg/mL solution swish and spit 1 teaspoon 5 mL every 6 hours as  needed for pain. Consider clotrimazole 10 mg lozenges four times daily. |
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4.2 criteria for removal from

Subjects may withdraw from treatment at any time at their own request, or they may be withdrawn at the discretion of the investigator for safety, behavioral, or administrative reasons. Reasons for subject discontinuation of study treatment may include:  
Objective disease progression according to RECIST criteria v1.1; 18 months of study drug therapy has been completed; Global deterioration of health status requiring discontinuation; Unacceptable toxicity deemed per investigator to be related to study drug, which may also be an adverse event; Significant protocol violation; Lost to follow-up; Subject refused further treatment; Study terminated by the investigator or sponsor; Death; Pregnancy.
Reasons for subject withdrawal from study follow-up may include:
Completed study follow-up;  
Study terminated by the PI or infigratinib distributor QED Therapeutics;
Lost to follow-up; Refusal for further follow-up for survival;  
Start of an alternative treatment regimen; Death.
If a subject does not return for a scheduled visit, every effort should be made to contact the subject. In any circumstance, every effort should be made to document subject outcome, if possible. The investigator should inquire about the reason for withdrawal, request the subject to return for a final visit, and follow-up with the subject regarding any unresolved adverse events. The early termination final visit should include all assessments listed for the End of Treatment visit. If the subject withdraws consent for disclosure of future information, no further study specific evaluations should be performed, and no additional data should be collected. The investigators may retain and continue to use any data collected before such refusal for further follow-up.
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4.3 alternatives

Standard treatment options for HR
+/HER2- metastatic breast cancer after progression on endocrine therapy in combination with a CDK4/6 inhibitor include alternative endocrine therapy, sometimes in combination with an mTOR inhibitor (everolimus), or one of numerous chemotherapy options (eg, taxanes, anthracyclines, capecitabine, gemcitabine, and vinorelbine). For the potential subset of subjects who not yet received a CDK4/6 inhibitor, standard treatment for HR
+/HER2- metastatic breast cancer that has not progressed on endocrine therapy in combination with a CDK4/6 inhibitor is endocrine therapy in combination with a CDK4/6 inhibitor or, in select subjects with lower-risk disease, endocrine therapy alone.
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5. investigational agent information 5.1

For a summary, see Section 2.2. For complete details, see Investigator's Brochure, provided as a separate document.
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5.1.1 infigratinib dosage form

Hard gelatin capsules in dosage strengths from 25 mg and 100 mg (expressed as mg of infigratinib free-base). Excipients will include microcrystalline cellulose, lactose monohydrate, HPMC2910, crospovidone, colloidal silicon dioxide, magnesium stearate, and hard gelatin capsule. Infigratinib will be manufactured under Good Manufacturing Practice for investigational use.
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5.1.2 subject instructions for infigratinib

Subjects should be instructed to take the daily dose of infigratinib in the morning as much as their schedule and appointment allow, at approximately the same time each day (24 ± 4 hour interval).  
Infigratinib should be taken in the fasted state at least 1 hour before or 2 hours after a meal. It should be taken with a large glass of water (~250 mL) and consumed over as short a time as possible. Subjects should be instructed to swallow the capsules whole and not chew them. Subjects in Cohort 1 should take their daily dose of tamoxifen 4 to 8 hours after their dose of infigratinib.  
If the subject forgets to take the scheduled dose of infigratinib in the morning, he/she should not take the dose more than 4 hours after the usual time and should continue treatment the next day. Any doses that are missed should be skipped altogether and should not be replaced or made up at the next scheduled dosing.  
If vomiting occurs following dosing with infigratinib, re-dosing is not permitted the same day.  
Dosing should resume the next day. Infigratinib is characterized by pH-dependent solubility; therefore, medicinal products that alter the pH of the upper GI tract may alter the solubility of infigratinib and limit bioavailability. These agents include, but are not limited to, proton pump inhibitors (eg, omeprazole), H2-antagonists
(eg, ranitidine) and antacids. If possible, proton pump inhibitors should be avoided due to their long pharmacodynamic effect and replaced with H2-antagonists or antacids. Infigratinib should be taken at least 2 hours before or 10 hours after dosing with a gastric protection agent. Subjects must avoid the consumption of grapefruits, grapefruit juice, grapefruit hybrids, pomegranates, star fruits, pomelos, Seville oranges or juice within 7 days prior to the first dose of infigratinib and throughout the treatment period. This is due to a potential CYP3A4 interaction with study drug. Normal oranges and orange juice are allowed.
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5.1.3 packaging and labeling

Infigratinib capsules will be packaged in high-density polyethylene bottles with child-resistant closures. Labels will include storage conditions for the drug.
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5.3 agent ordering

Infigratinib will be shipped by QED Therapeutics to the Investigational Drug Service at Stanford University Medical Center, shipping address:
Stanford Health Care Stanford University Investigational Drug Service 300 Pasteur Dr, Room H0302 Stanford, CA, USA 94305
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5.4 agent accountability

Infigratinib capsules will be received by designated personnel at the study site, handled and stored safely and properly, and kept in a secured location to which only the investigator and designated site personnel have access. Upon receipt, infigratinib should be stored according to the instructions specified on the drug label and in the Investigator's Brochure. Refer to the Pharmacy Manual for further details.  
The investigator or designee must maintain an accurate record of the shipment and dispensing of infigratinib in a drug accountability log. Subjects in the infigratinib group will be asked to return all used and unused bottles of infigratinib and packaging on a regular basis, at the end of the study, or at the time of study drug discontinuation. Drug accountability will be assessed by the investigator and/or study personnel, and captured in a subject drug accountability log. This information must be captured in the source document at each subject visit.  
At study close-out, infigratinib can be destroyed at the site if permitted by local regulations.  
Alternatively, the study drug can be destroyed at a third-party depot.