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| Official Title:        | Erdafitinib plus Abiraterone Acetate or Enzalutamide in  Double Negative Prostate Cancer   |
|------------------------|--------------------------------------------------------------------------------------------|
| NCT Number:            | NCT03999515                                                                                |
| Document Type:         | Study Protocol and Statistical Analysis Plan                                               |
| Date of the  Document: | 10/17/2022                                                                                 |
clinical protocol
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Erdafitinib plus **Abiraterone Acetate or Enzalutamide in Double Negative Prostate Cancer**
Protocol Version 6.0 Protocol: RG1005038 (CC10288)
Date: August 26, 2022 Sponsor-Investigator / PI: **Michael T. Schweizer**
University of Washington / Fred Hutchinson Cancer Center Email: schweize@uw.edu
clinical protocol
jnj-42756493 erdafitinib

Drug and Funding Support: Janssen Research **& Development ***
*Janssen Research & Development is a global organization that operates through different legal entities in various countries. Therefore, the legal entity providing drug and funding support for Janssen Research & Development studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP;
Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Sciences Ireland UC; or Janssen Research & Development, LLC.  
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR Part 312).  
Status: Approved Date: 26 August 2022 Prepared by: Michael T. Schweizer GCP **Compliance:** This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory requirements.  
Confidentiality **Statement**
The information in this document contains trade secrets and commercial information that are privileged or confidential and may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or confidential.
clinical protocol
table of contents

| TABLE OF CONTENTS                                                                                                         |                                                                                                                                              |
|---------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------|
| TIME AND EVENTS SCHEDULE                                                                                                  |                                                                                                                                              |
| ABBREVIATIONS                                                                                                             |                                                                                                                                              |
| 1.                                                                                                                        | INTRODUCTION                                                                                                                                 |
| 1.1.                                                                                                                      | Background .                                                                                                                                 |
| 1.2.                                                                                                                      | Double Negative Prostate Cancer                                                                                                              |
| 1.3.                                                                                                                      | Fibroblast Growth Factor Receptors and Erdafitinib ...................................................................................... 19 |
| 1.3.1.                                                                                                                    | Fibroblast Growth Factor Receptors                                                                                                           |
| 1.3.2.                                                                                                                    | Erdafitinib                                                                                                                                  |
| 1.3.2.1.                                                                                                                  | Erdafitinib Efficacy .                                                                                                                       |
| 1.3.2.2.                                                                                                                  | Erdafitinib Safety                                                                                                                           |
| Enzalutamide .                                                                                                            |                                                                                                                                              |
| 1.4.                                                                                                                      |                                                                                                                                              |
| Refer to Enzalutamide's FDA label for additional pharmacology and clinical data. .                                        |                                                                                                                                              |
| Abiraterone Acetate                                                                                                       |                                                                                                                                              |
| 1.5.                                                                                                                      |                                                                                                                                              |
| 1.6.                                                                                                                      | Overall Rationale for the Study                                                                                                              |
| 2.                                                                                                                        | OBJECTIVE AND ENDPOINTS                                                                                                                      |
| 2.1.                                                                                                                      | Primary Objective                                                                                                                            |
| 2.2.                                                                                                                      | Secondary Objectives .                                                                                                                       |
| 2.3.                                                                                                                      | Planned Exploratory Objectives .                                                                                                             |
| 3.                                                                                                                        | STUDY DESIGN AND RATIONALE .                                                                                                                 |
| 4.                                                                                                                        | SUBJECT POPULATION                                                                                                                           |
| 4.1.                                                                                                                      | Inclusion Criteria .                                                                                                                         |
| 4.2.                                                                                                                      | Exclusion Criteria .                                                                                                                         |
| 5.                                                                                                                        | TREATMENT ALLOCATION AND BLINDING                                                                                                            |
| DOSAGE AND ADMINISTRATION                                                                                                 |                                                                                                                                              |
| 6.                                                                                                                        | E                                                                                                                                            |
| 6.1.                                                                                                                      |                                                                                                                                              |
| 6.1.1.                                                                                                                    | Dose Modifications and Dose Delays for Erdafitinib                                                                                           |
| 6.1.2.                                                                                                                    | Guidance for Specific Erdafitinib Toxicities .                                                                                               |
| Grading of Hyperphosphatemia and Nail Disorders                                                                           |                                                                                                                                              |
| 6.1.2.1.                                                                                                                  |                                                                                                                                              |
| 6.1.2.2.                                                                                                                  | Guidelines for the Management of Elevated Phosphate Levels .                                                                                 |
| 6.1.2.3.                                                                                                                  | Guidelines for the Management of Dry Mouth and Stomatitis                                                                                    |
| 6.1.2.4.                                                                                                                  | Guidelines for the Management of Dry Skin and Skin Toxicity                                                                                  |
| 6.1.2.5.                                                                                                                  | Guidelines for Management of Nail Toxicity (Onycholysis, Onychodystrophy, and                                                                |
| Paronychia)                                                                                                               |                                                                                                                                              |
| 6.1.2.6.                                                                                                                  | Guidelines for Eye Toxicity Associated With Vision Changes ...................................................................42             |
| 6.1.2.7.                                                                                                                  | Guidelines for the Management of Dry Eye .                                                                                                   |
| 6.2.                                                                                                                      | Enzalutamide                                                                                                                                 |
| 6.2.1.                                                                                                                    | Dose Modifications                                                                                                                           |
| 6.3.                                                                                                                      | Abiraterone Acetate                                                                                                                          |
| Dose Modifications for LFT Abnormalities Attributed to Abiraterone Acetate ........................................... 45 |                                                                                                                                              |
| 6.3.1.                                                                                                                    |                                                                                                                                              |
| 6.3.2.                                                                                                                    | Dose Modifications for Hypokalemia Attributed to Abiraterone Acetate                                                                         |
| Dose Modifications for Hypertension and Edema/Fluid Retention Attributed to Abiraterone                                   |                                                                                                                                              |
| 6.3.3.                                                                                                                    | A ACETATE                                                                                                                                    |
| 7.                                                                                                                        | TREATMENT COMPLIANCE                                                                                                                         |
| 8.                                                                                                                        | CONCOMITANT THERAPY                                                                                                                          |
| 8.1.                                                                                                                      | Permitted Medications                                                                                                                        |
| 2                                                                                                                         |                                                                                                                                              |
| Version Date: 17 September 2020                                                                                           |                                                                                                                                              |  
l  
| Protocol Number: CC10288                                                                | PI: Michael T. Schweizer                                                           |
|-----------------------------------------------------------------------------------------|------------------------------------------------------------------------------------|
| FGFR Inhibition in DNPC                                                                 | Protocol Version: 6.0                                                              |
| JNJ-42756493  Erdafitinib                                                               |                                                                                    |
| 8.2.                                                                                    | Prohibited Medications .                                                           |
| 8.3.                                                                                    | Precautions for Concomitant Medications                                            |
| 9.                                                                                      | STUDY EVALUATIONS                                                                  |
| 9.1.                                                                                    | Study Procedures                                                                   |
| 9.1.1.                                                                                  | OVERVIEW                                                                           |
| 9.1.2.                                                                                  | Screening Phase                                                                    |
| 9.1.3.                                                                                  | T Treatment Phase                                                                  |
| 9.1.4.                                                                                  | End of Treatment .                                                                 |
| 9.2.                                                                                    | Efficacy Evaluations .                                                             |
| 9.2.1.                                                                                  | Evaluations                                                                        |
| Pathologic Assessment                                                                   |                                                                                    |
| 9.2.1.1.                                                                                |                                                                                    |
| 9.2.1.2.                                                                                | RECIST Assessment of Disease .                                                     |
| 9.2.1.3.                                                                                | Radiographic Images Assessment .                                                   |
| 9.3.                                                                                    | Correlative research .                                                             |
| 9.4.                                                                                    | Safety Evaluations .                                                               |
| 9.4.1.                                                                                  | Adverse Events .                                                                   |
| 9.4.2.                                                                                  | Clinical Laboratory Tests                                                          |
| 9.4.3.                                                                                  | Renal Toxicity Evaluation                                                          |
| 9.4.4.                                                                                  | EE                                                                                 |
| 9.4.5.                                                                                  | Ophthalmic Examination                                                             |
| 9.4.6.                                                                                  | Vital Signs                                                                        |
| 9.4.7.                                                                                  | Physical Examination                                                               |
| 9.4.8.                                                                                  | ECOG Performance Status                                                            |
| 9.5.                                                                                    | Sample Collection and Handling .                                                   |
| 10.                                                                                     | SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL                  |
| FROM THE STUDY .                                                                        |                                                                                    |
| 10.1.                                                                                   | COMPLETION .                                                                       |
| 10.2.                                                                                   | Discontinuation of Study Treatment/Withdrawal from the Study                       |
| 10.3.                                                                                   | WING AND IN THE PROPERTIES IN THE PROPERTIES IN THE PROPERTIES OF                  |
| 1.                                                                                      | DATA MONITORING AND ADVERSE EVENT REPORTING                                        |
| 1.1.                                                                                    | Management of Safety Data                                                          |
| 1.2.                                                                                    | DEFINITIONS                                                                        |
| 1.3.                                                                                    | Pregnancy                                                                          |
| 1.4.                                                                                    | Adverse Event Monitoring and Reporting .                                           |
| 1.5.                                                                                    | Procedures for Reporting Safety and Data and Product Quality Complaints (PQCs) for |
| J&J Medicinal Products to the Company                                                   |                                                                                    |
| Serious Adverse Events (SAE), Adverse Events of Special Interest, and Special Reporting |                                                                                    |
| 1.5.1.                                                                                  | Situations                                                                         |
| Product Quality Complaints Reporting                                                    |                                                                                    |
| 11.5.2.                                                                                 |                                                                                    |
| 1.6.                                                                                    | Evaluating Adverse Events                                                          |
| 11.6.2.                                                                                 | Maintenance of Safety Information                                                  |
| 1.6.3.                                                                                  | SES Listing                                                                        |
| 1.7.                                                                                    | IRB Reporting                                                                      |
| 1.8.                                                                                    | Protocol Amendments                                                                |
| 1.9.                                                                                    | Informed Consent                                                                   |
| 12.                                                                                     | STATISTICAL METHODS                                                                |
| 12.1.                                                                                   | Subject Information                                                                |
| 12.2.                                                                                   | Sample Size Determination                                                          |
| 12.3.                                                                                   | Efficacy Analyses                                                                  |
| 12.4.                                                                                   | Correlative Research Analyses                                                      |
| REFERENCES                                                                              |                                                                                    |
| Appendix 2: Common Terminology Criteria for Adverse Events V5.0 (CTCAE)                 |                                                                                    |  
3
clinical protocol
erdafitinib plus abiraterone acetate or

Many of the treatments for metastatic castration-resistant prostate cancer (mCRPC) are directed at suppressing the androgen receptor (AR)-signaling axis. While AR-directed therapies are initially effective, resistance inevitability occurs. The continued lethality of this disease underscores the importance of testing therapeutics aimed at alternate pathways. Mechanistic studies have revealed that MAPK-signaling, which is activated by FGF/FGFR signaling, is an important AR bypass mechanism in men with late stage, double negative prostate cancer (DNPC). Importantly, targeting FGF/FGFR-signaling with pan-FGFR
inhibitors results in significant tumor growth inhibition in both engineered LNCaPAPIPC cells and DNPC LuCaP 173.2 PDX models1. It is important to note that unlike other malignancies
(e.g. bladder and lung cancer), patients with a DNPC phenotype usually do not harbor genomic alterations in FGFR, and over-activation of FGF/FGFR-signaling is primarily driven by autocrine/paracrine activation of this pathway. In total, this data demonstrates that FGF/FGFR-signaling is a critical driver of late stage CRPC, and supports testing FGFR inhibitors in DNPC patients. On this basis, we are launching a phase II trial testing the pan-FGFR inhibitor erdafitinib in men with metastatic CRPC who have previously progressed on either abiraterone acetate or enzalutamide and who have exhibited a DNPC phenotype on biopsy. Patients will continue on the most recent next- generation AR-directed therapy they progressed on (i.e. either abiraterone acetate or enzalutamide) in order to maintain suppression of AR-signaling, and erdafitinib will be added to their regimen. Erdafitinib will be dosed at the recommended Phase II dose, and abiraterone acetate or enzalutamide will be administered at their respective FDA approved dose. Study subjects will continue on erdafitinib plus either abiraterone acetate or enzalutamide until radiographic progression or intolerable toxicity. *We hypothesize that erdafitinib in combination* with a next-generation AR-directed therapy will show clinical efficacy in men with mCRPC with a DNPC phenotype who have progressed on abiraterone acetate *or enzalutamide*
clinical protocol
objectives

Primary Objective: To determine the objective tumor response rate in subjects with measurable lesions as defined by RECIST v1.1 criteria in mCRPC patients with a DNPC molecular phenotype receiving either enzalutamide or abiraterone acetate in combination with erdafitinib.
clinical protocol
secondary objectives

1. Determine the radiographic PFS in patients using RECIST 1.1 criteria for soft tissue metastases and Prostate Cancer Working Group 3 (PCWG3) criteria for bone metastases2,3 2. Determine the time to response using RECIST 1.1 criteria2 3. Determine the overall survival defined as the time interval from C1D1 to the date of death
4 4. PSA response, defined as >50% reduction in PSA compared with baseline at any point during treatment 5. Assess the incidence and severity of adverse events according to National Cancer Institute- Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
clinical protocol
planned exploratory objectives

Correlative work will be performed in order to determine biomarkers predictive of response to combination therapy. Examples of correlative work may include, but will not be limited to:
1. Immunohistochemistry (IHC) for phosphorylated FGFR and FGFR substrate 2 (FRS2)
in tumor tissue 2. IHC for PSA and AR expression in tumor tissue 3. Tumor tissue transcript profiling studies to assess candidate biomarkers for response/resistance to FGFR inhibitor therapy and to evaluate core signaling program for FGF/FGFR, MAPK, and AR.  
4. Next-generation sequencing of pre-treatment tumor biopsies and cell-free circulating tumor DNA (ctDNA) to identify genomic alterations correlating with response or resistance to treatment, and confirm FGFR alteration status 5. Serial blood (baseline, 12-weeks, progression) will be obtained in order to develop a blood-based gene expression response signature 6. Serum FGF ligand levels (FGF8, FGF9, FGF19) will be drawn at baseline, 12-weeks and at progression
clinical protocol
study design

This will be a phase II trial testing the pan-FGFR inhibitor, erdafitinib, in men with metastatic CRPC who have progressed on either abiraterone acetate or enzalutamide (Fig 6). Eligible patients must have CRPC (defined as disease progression in spite of a castrate serum testosterone [≤50 ng/dl]), and evidence of RECIST evaluable disease to enroll2. Given that the patient population of interest will be heavily pre-treated, and likely enriched for both small cell/NE and double negative prostate cancer, it is recommended that patients undergo a baseline metastatic biopsy prior to enrolling to rule out predominate small cell/NE variant prostate cancer. Patients with DNPC defined by IHC criteria will be eligible to enroll (see Section 9.2.1.1). Transcript profiling methods for identifying DNPC may also be accepted for determining trial eligibility at the PI's discretion. This is based on data showing that transcriptional signatures can accurately define the various prostate cancer subtypes, including DNPC4,5. Eligible patients must have demonstrated evidence of active progression per Prostate Cancer Working Group 3 (PCWG3)
criteria while on enzalutamide or abiraterone acetate at any time prior to enrollment3. If not surgically castrated, participants must be maintained on an LHRH analogue (e.g. leuprolide, goserelin) Eligible patients will continue on the next-generation AR-directed therapy they most recently progressed on (i.e. either abiraterone acetate or enzalutamide) in order to maintain suppression of AR-signaling, and erdafitinib will be added to their regimen. If a trial subject is not currently on abiraterone or enzalutamide at the time of screening, they must restart the AR-
5 directed therapy most recently received and demonstrate two successive PSA rises or other evidence of progression prior to starting treatment per protocol. Erdafitinib will be administered at 8 mg once daily orally, with pharmacodynamic uptitration to 9 mg if serum phosphate was below 5.5mg/dL in absence of significant toxicity on cycle 1 day 14 (see Section 6.1). Abiraterone acetate or enzalutamide will be administered at their respective FDA approved dose (i.e. abiraterone acetate 1000 mg PO daily; enzalutamide 160 mg PO daily). Subjects continuing on abiraterone acetate will also be required to receive prednisone 5 mg PO twice daily in order to blunt mineralocorticoid symptoms associated with abiraterone acetate. Study subjects will continue on erdafitinib plus either abiraterone acetate or enzalutamide until radiographic progression, intolerable toxicity or two-years of treatment, whichever comes first.
clinical protocol
study schema

Eligibility Inclusion Criteria:  
1. Patients must be > 18 years of age prior to signing informed consent 2. History of histologically diagnosed prostatic adenocarcinoma  
3. Participants must have evidence of castration resistant prostate cancer as evidenced by a confirmed rising PSA or radiographic progression (per Prostate Cancer Working Group 3
[PCWG3] criteria) and a castrate serum testosterone level (i.e. < 50 ng/dL)3 4. Participants must have previously progressed on abiraterone acetate and/or enzalutamide, with PSA or radiographic progression on the most recent agent per PCWG3 criteria. If the most recent agent received was abiraterone or enzalutamide, there should be no washout prior to initiating erdafitinib per protocol3 5. Measurable disease as defined per RECIST v1.1 criteria2
6 6. Subjects who have progressed on only one next-generation AR-directed therapy (e.g.  
abiraterone, enzalutamide) and who have not received taxane chemotherapy will be required to have evidence of double-negative prostate cancer as defined by immunohistochemistry (see Section 9.2.1.1) on biopsy. A fresh metastatic biopsy within 8 weeks is preferred; however, any archival tissue showing a DNPC phenotype will be acceptable for determining eligibility. Patients who have received two prior lines of ARdirected therapy and at least one prior taxane do not require histologic confirmation of DNPC. Note: transcript profiling methods for defining DNPC may be accepted per the PI's discretion 7. ECOG performance status score <2 8. Clinical and laboratory values and cardiovascular measurements at screening:  
| Hematology > 8 g/dL (>5 mmol/L) (must be without                                                                                                                                                                                                                                                                                                      |                                                                                                                        |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------|
| Hemoglobin                                                                                                                                                                                                                                                                                                                                            | red blood cell [RBC] transfusion within 7  days prior to the laboratory test)                                          |
| Platelets                                                                                                                                                                                                                                                                                                                                             | > 75 x 109 /L > 1.5 x 109 /L (prior growth factor support                                                              |
| Absolute Neutrophil Count (ANC)                                                                                                                                                                                                                                                                                                                       | is permitted but must be without support in  the 7 days prior to the laboratory test)                                  |
| Chemistry                                                                                                                                                                                                                                                                                                                                             |                                                                                                                        |
| AST and ALT                                                                                                                                                                                                                                                                                                                                           | < 2.5 x upper limit of normal (ULN) or < 5  x ULN for subjects with liver metastases                                   |
| Creatinine clearance                                                                                                                                                                                                                                                                                                                                  | >40 mL/min/1.73 m2 based upon Modified  Diet in Renal Disease formula calculation < 1.5 x ULN; except in subjects with |
| Total bilirubin                                                                                                                                                                                                                                                                                                                                       | congenital bilirubinemia, such as Gilbert's  syndrome                                                                  |
| Cardiovascular <480 msec based on the average of                                                                                                                                                                                                                                                                                                      |                                                                                                                        |
| Corrected QT interal (QTcF or QTcB)                                                                                                                                                                                                                                                                                                                   | triplicate assessments performed  approximately 5 minutes apart                                                        |
| ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate  aminotransferase; GFR = glomerular filtration rate; QTcB = QT corrected interval by the  Bazett's formula; QTcF = QT corrected interval by the Fridericia's formula; ULN =  upper limit of normal IF Glibert's disease is present, direct bilirubin can be measured |                                                                                                                        |  
9. Subjects must agree to use acceptable contraception (see Section 11.3 for requirements)  
10. Must sign an informed consent form (ICF) indicated that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study
7
clinical protocol
exclusion criteria

1. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 14 days prior to enrollment 2. Active malignancies (i.e. requiring treatment change in the last 24 months) other than malignancy under study (except skin cancers within the last 24 months that are considered completely cured)
3. Evidence of predominant small cell or neuroendocrine variant prostate cancer (see section 9.2.1.1) on most recent standard of care metastatic biopsy 4. Symptomatic central nervous system (CNS) metastases. Treated CNS metastases will be allowed if these are stable for at least 8 weeks prior to enrollment 5. Received prior FGFR inhibitor treatment or if the subject as known allergies, hypersensitivity, or intolerance to erdafitinib or its excipients 6. Current central serous retinopathy (CSR) or retinal pigment epithelial detachment of any grade 7. Has persistent phosphate level >ULN during screening (on 2 consecutive assessments at least 1 week apart, within 14 days of treatment and prior to Cycle 1 Day 1) and despite medical management 8. Has a history of current uncontrolled cardiovascular disease including:
a. Unstable angina, myocardial infarction, ventricular fibrillation, Torsades de Pointes, cardiac arrest, or known congestive heart failure Class III-V within the preceding 3 months; cerebrovascular accident or transient ischemic attack within the preceding 3 months b. Pulmonary embolism or other VTE (venous thromboembolism) within the preceding 2 months 9. Has known active AIDS (human immunodeficiency virus (HIV) infection) 10. Hepatitis B infection as defined according to the American Society of Clinical Oncology guidelines. In the event the infection status is unclear, quantitative levels are necessary to determine the infection status. Hepatitis C (anti-hepatitis C virus [HCV] antibody positive or HCV-RNA quantitation positive) or known to have a history of hepatitis C. If positive, further testing of quantitative levels to rule out positivity is required 11. Has not recovered from reversible toxicity of prior anticancer therapy (except toxicities which are not clinically significant such as alopecia, skin discoloration, hot flashes, Grade 1 neuropathy, Grade 1-2 hearing loss)
8 12. Has impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions 13. Major surgery within 2 weeks of the first dose, or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study or within 2 weeks after the last dose of study drug administration (Note: subjects with planned surgical procedures to be conducted under local anesthesia may participate)
14. Any serious underlying medical conditions, such as:
a. Evidence of serious active viral, bacterial, or uncontrolled systemic fungal infection b. Active autoimmune or a documented history of autoimmune disease
clinical protocol
statistical considerations sample size justification

Although there are no published data on ORR among patients with progressive disease on both abiraterone acetate and enzalutamide, several small studies have explored the objective response rates of abiraterone acetate following enzalutamide and vice *versa* in the postdocetaxel setting: with ORRs ranging from 3-8%6,7. Therefore, if we assume a historicalcontrol ORR (H0) of 5% and an alternative hypothesis of a 25% ORR (H1), a sample size of 23 patients gives 86% power to detect a difference in ORR of the hypothesized magnitudes with a type-1 error of 3% based on an exact binomial test. We will therefore plan to enroll up to 25 patients to account for 10% dropout.
clinical protocol
analysis plan

The primary objective will be to determine the ORR, which will be calculated as the percentage of patients, with 95% confidence intervals, achieving a complete response (CR) or partial response (PR) across the entire study population at any time. On the basis of an exact binomial test, 4 responses are needed to reject the null hypothesized 5% historical control ORR in favor of the alternative at a significance level of p=0.026. Secondary objectives will include determining: radiographic progression free survival (PFS) in patients using RECIST 1.1 criteria for soft tissue metastases and Prostate Cancer Working Group 3 (PCWG3) criteria for bone metastases; time to response using RECIST 1.1 criteria; overall survival (OS) defined as the time interval from C1D1 to the date of death; PSA response, defined as >50% reduction in PSA compared with baseline at any point during treatment; and the incidence and severity of adverse events according to National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE) version 5.02,3. Survival endpoints (e.g. PFS, OS) will be presented with Kaplan-Meier curves, and the median survival with 95% CI will be calculated. Rates will be reported as percentages with 95% CI. We will characterize AEs by type and grade. Safety will be summarized as the severity and frequency of a given AE.  
9 Protocol Number: CC10288 FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib
clinical protocol
time and events schedule

| TIME AND EVENTS SCHEDULE PreScreeninge                                            | Screening    | Treatment Cycles   | End of           |                 |                 |               |                              |
|--------------------------------------------|--------------|--------------------|------------------|-----------------|-----------------|---------------|------------------------------|
| Treatment                                  |              |                    |                  |                 |                 |               |                              |
| Treatment Cycle                            | Pre              |                    |                  |                 |                 |               |                              |
| Screeninge                                 | Screening    | Cycle 1            | Cycle 2          | Cycle 3         | Cycle 4         | After Cycle 4 | Discontinue Within 14  daysg |
| Administrative Procedures                  |              |                    |                  |                 |                 |               |                              |
| Informed Consent                           | X            |                    |                  |                 |                 |               |                              |
| Inclusion/Exclusion Criteria Cycle Day     | Day -56 to 0 | Day -30 to 0       | Day 1 ± 7  daysf | Day 14 ± 2 days | Day 1 ± 7  days |               |                              |
| X                                          |              |                    |                  |                 |                 |               |                              |
| Demographics and Medical History           | X            |                    |                  |                 |                 |               |                              |
| Prior and Concomitant Medication Review    | X            | X                  | X                | X               | X               | Q1C           | X                            |
| Erdafitinib Dispensation                   | X            | X                  | X                | X               | Q1C             |               |                              |
| Clinical Assessments Review Adverse Events | X            | X                  | X                | X               | Q1C             | X             |                              |
| ECOG Performance Status                    | X            | X                  | X                | X               | X               | Q1C           | X                            |
| Vital Signs and Weight                     | X            | X                  | X                | X               | X               | Q1C           | X                            |
| Ophthalmic exam                            | X            |                    |                  |                 |                 |               |                              |
| Physical Examinationa                      | X            | X                  | X                | X               | X               | Q1C           | X                            |
| EKG                                        | X            |                    |                  |                 |                 |               |                              |
| Laboratory  Assessments PSA                | X            | X                  | Q3C              | X               |                 |               |                              |
| Testosterone Level                         | X            |                    |                  |                 |                 |               |                              |  
| Pre                                               |                                                                                         |                  |                  |                 |                 |               |                              |    |
|-----------------------------------------------|-----------------------------------------------------------------------------------------|------------------|------------------|-----------------|-----------------|---------------|------------------------------|----|
| Screeninge                                    | Screening                                                                               | Treatment Cycles | End of           |                 |                 |               |                              |    |
| Treatment                                     |                                                                                         |                  |                  |                 |                 |               |                              |    |
| Treatment Cycle                               | Pre                                                                                         |                  |                  |                 |                 |               |                              |    |
| Screeninge                                    | Screening                                                                               | Cycle 1          | Cycle 2          | Cycle 3         | Cycle 4         | After Cycle 4 | Discontinue Within 14  daysg |    |
| Phosphate Level                               | X                                                                                       | X                | X                | X               | X               | X             | Q1C                          | X  |
| CBC with Differential                         | X                                                                                       | X                | X                | X               | X               | X             | Q1C                          | X  |
| Comprehensive Serum Chemistry Panel Cycle Day | Day -56 to 0                                                                            | Day -30 to 0     | Day 1 ± 7  daysf | Day 14 ± 2 days | Day 1 ± 7  days |               |                              |    |
| X                                             | X                                                                                       | X                | X                | X               | Q1C             | X             |                              |    |
| PT/INR and PTT                                | X                                                                                       | X                |                  |                 |                 |               |                              |    |
| Correlative Studies Blood Collectionb         | X                                                                                       | X                | X                |                 |                 |               |                              |    |
| Research biopsy                               | X                                                                                       | Xh               |                  |                 |                 |               |                              |    |
| Pathologic evaluationc                        | X                                                                                       | X                |                  |                 |                 |               |                              |    |
| Radiographic assessmentsd                     | X                                                                                       | X                | Q3C              | Xi              |                 |               |                              |    |
| a.                                            | Full physical exam is required at screening. Subsequent physical exams may be targeted. |                  |                  |                 |                 |               |                              |    |  
a. Full physical exam is required at screening. Subsequent physical exams may be targeted. b. Refer to Laboratory Manual for details on correlative blood sample processing. c. Pathologic assessment of a biopsy demonstrating DNPC at any point in the patient's treatment history is a pre-screening requirement.  
However, a fresh biopsy within 8 weeks of enrollment is recommended to rule out predominate small cell/NE variant prostate cancer. Research biopsy will only occur if considered safe by the treatment team.  
d. Radiographic assessments should include a CT chest/abdomen/pelvis and bone scan. e. If archival metastatic tissue previously obtained is already available and suitable for pathologic evaluation, another metastatic biopsy will not be mandated. CBC with Differential, PT/INR and PTT will only be obtained if metastatic biopsy is planned.  
f. Assessments done during the screening period do not need to be repeated if within 7 days. g. Assessments do not need to be repeated if within 7 days. h. Research biopsy will be performed only if feasible (i.e. safe and metastatic lesion amenable to biopsy is present). i. Radiographic assessments do not need to be repeated if within 8 weeks.  
| ABBREVIATIONS ADT   | Androgen Deprivation Therapy                    |
|---------------------|-------------------------------------------------|
| AE                  | Adverse Event                                   |
| ANC                 | Absolute Neutrophil Count                       |
| aPTT                | Activated Partial Thromboplastin Time           |
| AR                  | Androgen Receptor                               |
| AR-V                | Androgen Receptor Splice Variant                |
| ARFL                | Full Length Androgen Receptor                   |
| ARV7                | Androgen Receptor Splice Variant 7              |
| BID                 | Twice Daily                                     |
| CR                  | Complete Response                               |
| CRPC                | Castration-Resistant Prostate Cancer            |
| CTC                 | Circulating Tumor Cell                          |
| CTCAE               | Common Terminology Criteria for Adverse Events  |
| ctDNA               | Cell-Free Circulating Tumor DNA                 |
| ECOG                | Eastern Cooperative Oncology Group              |
| eCRF                | Electronic Case Report Form                     |
| FFPE                | Formalin-Fixed Paraffin Embedded                |
| FHCRC               | Fred Hutchinson Cancer Research Center          |
| HSPC                | Hormone-sensitive Prostate Cancer               |
| IF                  | Immunofluorescence                              |
| IHC                 | Immunohistochemistry                            |
| INR                 | International Normalized Ratio                  |
| IV                  | Intravenous                                     |
| LHRH                | Luteinizing Hormone-Releasing Hormone           |
| mCRPC               | Metastatic Castration-Resistant Prostate Cancer |
| NCI                 | National Cancer Institute                       |
| OTC                 | Over-The-Counter                                |
| PC                  | Prostate Cancer                                 |
| PCWG                | Prostate Cancer Working Group                   |
| PD                  | Progressive Disease                             |
| PD                  | Pharmacodynamic                                 |
| PDX                 | Patient Derived Xenograft                       |
| PK                  | Pharmacokinetic                                 |
| PO                  | By Mouth                                        |
| PR                  | Partial Response                                |
| PSA                 | Prostate Specific Antigen                       |
| PSA50               | 50% Decline in PSA from Baseline                |
| PT                  | Prothrombin Time                                |
| Q1C                 | Every 1 Cycle                                   |  
PI: Michael T. Schweizer  
Protocol Version: 6.0  
Protocol Number: CC10288  
FGFR Inhibition in DNPC  
JNJ-42756493 Erdafitinib  
Q3C Every 3 Cycles Q3W Every 3 weeks qPCR Quantitative Real-Time PCR RNA-Seq RNA Sequencing SD Stable Disease T Testosterone ULN Upper Limit of Normal UW University of Washington
clinical protocol
1. introduction 1.1. background

Prostate cancer is the second leading cause of cancer death among American men8. It is primarily an androgen driven malignancy, with treatment of metastatic disease aimed at removing androgen stimulus. Since the 1940s, the backbone of treatment for men with newly diagnosed advanced prostate cancer has entailed either surgical or medical castration (i.e. androgen deprivation therapy; ADT). While ADT is initially highly effective in men with metastatic prostate cancer, resistance invariably develops, with disease progression despite castrate levels of serum testosterone (i.e. ≤50 ng/dL) signifying the emergence of a disease state known as castration resistant prostate cancer (CRPC). Metastatic CRPC (mCRPC) remains a fatal disease despite six treatments approved by the FDA
since 2004, which have been shown to extend survival9-17. The first of these agents to be approved was docetaxel, a semisynthetic taxane which inhibits microtubule synthesis. The landmark TAK-327 and SWOG-9916 trials reported that docetaxel had an overall survival benefit in mCRPC when compared to mitoxantrone14,17. Since then, a second taxane, cabazitaxel has been shown to have a survival benefit in men with mCRPC who had progressed after docetaxel treatment and was approved for use in this setting11. There has also been a radiopharmaceutical and an immunotherapeutic agent which have gained approval for mCRPC. Radium-223 is an alpha emitting calcium mimetic which prolongs survival in men with mCRPC
that is predominately metastatic to the bones13. Sipuleucel-T is an immunotherapy in which autologous peripheral blood monocytes (PBMCs) are activated by a recombinant fusion protein consisting of the prostate antigen prostatic acid phosphatase fused to granulocyte-macrophage colony-stimulating factor12.  
The observation that AR regulated genes (e.g. PSA) remain expressed in a castrate state led to the further exploration of the AR-signaling axis as a therapeutic target in men with mCRPC and have resulted in the development of effective new AR-directed agents like abiraterone acetate and enzalutamide. Both of these drugs inhibit AR-signaling in men with mCRPC through disrupting the ligand-AR interaction (abiraterone acetate through ligand depletion and enzalutamide through receptor antagonism)9,10,15 These agents are unfortunately not curative, however, and resistance typically occurs within 1-2 years. In addition, given the considerable mechanistic overlap between abiraterone acetate and enzalutamide, it is not surprising that clinical evidence of cross-resistance between these agents has begun to emerge6,7 Recent work by our group has shown that in the face of chronic AR-signaling inhibition, a subset of these patients will develop androgen pathway-independent prostate cancer (APIPC) - a molecular prostate cancer subset defined by no AR-signaling activity and the absence of neuroendocrine features (i.e. double negative prostate cancer; DNPC)1.  
Mechanistic studies have revealed that MAPK-signaling, which is activated by the fibroblast growth factor (FGF)/FGF receptor (FGFR) pathway, is an important AR bypass mechanism in men with DNPC. Importantly, targeting FGF/FGFR-signaling with pan-FGFR inhibitors results in significant tumor growth inhibition in both engineered APIPC cells and DNPC patient derived xenograft (PDX) models1. In contrast to other malignancies (e.g. bladder and lung cancer),
patients with DNPC usually do not harbor genomic alterations in FGFR, and over-activation of FGF/FGFR-signaling is primarily driven by autocrine/paracrine activation of this pathway. In total, this data demonstrates that FGF/FGFR-signaling is a critical driver of late stage mCRPC and supports our hypothesis that the pan-FGFR inhibitor erdafitinib in combination with abiraterone acetate or enzalutamide will be effective in men with multi-drug resistance mCRPC.
clinical protocol
1.2. double negative prostate cancer

Despite multiple effective therapies, mCRPC remains an invariably fatal disease with resistance  
 to currently available therapies occurring in 1-2 years in most cases. Various pathways to resistance have been described, many of which still rely on the androgen axis18. Recent work, however, has demonstrated that a subset of these cancers become completely independent of ARsignaling, without expressing classic neuroendocrine (NE) or small cell markers (e.g.  
synaptophysin) - a disease state herein referred to as double negative prostate cancer (DNPC) or androgen pathway independent prostate cancer (APIPC). Additional work has shown that DNPC, as well as other prostate cancer subtypes (e.g. AR+/NE-, AR-/NE+ and AR+/NE+) are associated with reproducible transcriptional profiles, which accurately define these molecular subtypes4,5. The emergence of DNPCs has become more prevalent with the widespread use of the next-generation AR-signaling inhibitors abiraterone acetate and enzalutamide. As an example, there has been a shift toward more tumors demonstrating a DNPC phenotype following the approval of abiraterone acetate in 2011 compared to the pre-abiraterone acetate era, and data from our rapid autopsy program has shown that 23.3% of mCRPC patients will die with DNPC
compared to only 5% prior to 20111.  
Given that nearly 1/4 mCRPC patients will die of DNPC - a clinical state with no proven therapies - new therapeutic approaches for these men are sorely needed. In order to study the molecular drivers of DNPC, our group created an AR-null/NE-null engineered cell-line model from parental LNCaP cells (Fig 2)1. LNCaP prostate cancer cells were transduced with an PI: Michael T. Schweizer Protocol Version: 6.0 Protocol Number: CC10288 FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib inducible anti-AR short hairpin RNA (shRNA) as well as an androgen response element-driven  
  
suicide gene (LNCaPshAR/pATK). LNCaPshAR/pATK cells were then subjected to increasingly severe AR pathway suppression. After 2 weeks of androgen deprivation in charcoal stripped serum(CSS), medium was supplemented with 1 mg/mL doxycycline (Dox) to induce the anti-AR shRNA, which produced >99% cell death. After 5 months, a residual population of viable cells remained. This colony was treated with a 2-week course of ganciclovir to eliminate cells expressing functional AR. Surviving cells were designated LNCaP-AR Program-Independent Prostate Cancer (LNCaPAPIPC).  
AR and PSA were nearly undetectable in LNCaPAPIPC and transcripts comprising an AR activity signature were substantially decreased compared to the parental cell line (Fig 3A). Likewise, there was no AR or PSA protein expression in LNCaPAPIPC grown *in vivo* as subcutaneous xenografts24. Importantly, NE-associated genes were not upregulated in LNCaPAPIPC cells grown with or without androgen supplementation (Fig 3B). Furthermore, LNCaPshAR/pATK and LNCaPAPIPC grown as murine xenografts do not express the NE markers chromogranin or synaptophysin. Studies examining the drivers of LNCaPAPIPC cell growth found that an autocrine FGF signaling program is likely activated in LNCaPAPIPC in the absence of AR to maintain cell survival and growth via MAPK (Fig 3C and D). Importantly, RNA-seq data from our rapid autopsy program demonstrates that DNPC patients have a similar transcriptional program to our LNCaPAPIPC model, with overexpression of FGF ligands, FGF receptors and genes comprising the MEK/ERK activity signature1.  
FGFR Inhibition in DNPC  
JNJ-42756493  Erdafitinib  
  
  
To demonstrate that FGF8 was sufficient to promote the growth of cells cultured under total AR
pathway suppression, we treated parental LNCapshAR/pATK grown in androgen-deprived conditions with Dox to suppress AR expression, and added FGF8b 1 . FGF8b maintained cell proliferation during AR pathway ablation (Fig 5A). Of note, the addition of the FGFR
antagonist, PD173074, to cells treated with Dox and FGF8 was growth inhibitory. LNCaPAPIPC
murine xenografts were also inhibited by PD173074 (Fig 5B). We also tested whether FGFR inhibition was an effective strategy in a patient derived xenograft (PDX) model of DNPC, the LuCaP 173.2 model, and found that treatment with the FGFR antagonist CH-5183284 did indeed result in significant growth inhibition (Fig 5C). Finally, we compared the growth inhibitory effects of erdafitinib (a potent pan-FGFR inhibitor) vs. CH-5183284 in LNCaPAPIPC cells grown in androgen-deprived culture conditions and found that erdafitinib was a more potent inhibitor of LNCaPAPIPC growth. These data indicate that pharmacologic inhibition of FGFR activity is likely to be effective in men with DNPC.  
PI: Michael T. Schweizer Protocol Version: 6.0 Protocol Number: CC10288 FGFR Inhibition in DNPC  
  
More recent data has broadly implicated a FGFR signaling as a key mediator of lineage plasticity, which typically accompanies resistance to AR-signaling inhibitors and occurs increasingly in late stage prostate cancer19,20. This work has shown that erdafitinib may also be able to reprogram CRPC toward a more differentiated phenotype. Indeed, additional unpublished work from our group has demonstrated that FGFR inhibition may exert an anti-tumor effect across a variety of prostate cancer phenotypes (Figure 6). These data support using erdafitinib more broadly iin the treatment of late stage prostate cancer. In addition, we have observed marked phenotypic heterogeneity in men with late stage prostate cancer, indicating that metastatic biopsies targeting a single lesion may fail to appreciate lineage plasticity at other sites of disease and/or emergence of DNPC phenotypes20-22.
clinical protocol
1.3. fibroblast growth factor receptors

The family of fibroblast growth factor receptors (FGFRs) consists of four highly conserved transmembrane receptors tyrosine kinases, namely FGFR1 to 4 and a 5th receptor, which lacks the intracellular kinase domain (FGFR5, also known as FGFRL1). Together, these receptors are able to bind to over 20 different fibroblast growth factor (FGF) ligands. FGFR signaling has been shown to be enhanced by genetic alterations such as gene amplification, mutation or chromosomal translocation, thereby affecting various cellular mechanisms such as angiogenesis, anti-apoptosis, cell migration and proliferation in a variety of cancer entities.
clinical protocol
1.3.2. erdafitinib

Erdafitinib is a highly selective and potent oral pan-FGFR tyrosine kinase inhibitor with high affinity and low nanomolar inhibitory activity for all FGFR family members, FGFR 1, 2, 3 and 4. In FGFR pathway activated cancer cell lines, the concentration required for 50% inhibition
(IC50) is in the low nanomolar range 0.1 to 129.2 nM. It has demonstrated activity in FGFR
pathway-activated cancer cell lines including squamous non-small cell lung cancer (NSCLC), gastric, breast, hepatocellular cancer (HCC), endometrial, bladder, multiple myeloma, and acute myeloid leukemia. Non-FGFR driven cell lines require significantly higher drug concentration for inhibition of cell proliferation to be observed. Target inhibition and pathway modulation have been demonstrated in cellular models at active cellular concentrations. Brief exposure to erdafitinib has been demonstrated to result in long-term target inhibition. Erdafitinib has been shown to have in vivo antitumor activity in mouse xenograft models of FGFR-driven gastric, bladder, and squamous NSCLC tumor models, and in patient-derived xenografts from squamous NSCLC, gastric, breast, and hepatocellular tumors. In humans, absorption of erdafitinib was estimated to be near complete. Following single and multiple once-daily administration, erdafitinib exposure (Cmax and AUC) increased in a doseproportional manner across the dose range of 0.5 to 12 mg. Multiple dose erdafitinib PK was time independent and steady state was achieved after 2 weeks of daily administration. With a once daily dose regimen, mean (coefficient of variation [CV%]) steady state accumulation ratio for AUC from time 0 to 24 hours after daily dosing (AUCτ) was 4.07 (32.0%), corresponding to a mean effective half-life (t1/2) of 58.9 hours. For the most comprehensive nonclinical and clinical information regarding erdafitinib, refer to the latest version of the Investigator's Brochure and Addenda for erdafitinib (Erdafitinib IB).
clinical protocol
1.3.2.1. erdafitinib efficacy study blc2001

This is an ongoing Phase 2, multicenter, open-label study to evaluate the efficacy and safety of single- agent erdafitinib in subjects with advanced ie, metastatic or surgically unresectable urothelial carcinoma and whose tumors had certain FGFR genetic alterations. Key efficacy results are based on response for the 87 chemo-relapsed/refractory subjects in the 8mg daily regimen. Responses were assessed using Response Evaluation Criteria in Solid Tumors (RECIST), (version 1.1). Investigator assessed response indicated that the primary objective had been met (objective response rate [ORR] of 40% and the lower bound of the 95% CI exceeding 25%). IRRC assessment of response for subjects treated in the 8-mg daily regimen was comparable to that reported by investigator. Responses were rapid and durable, with a median time to first response of 1.41 months and median duration of response (DOR) of 5.98 months. An estimated 30% of responders had response for more than 1 year. Median progression-free survival (PFS) was 5.52 months, with a median follow up of 11.2 months. Median overall survival (OS) was 13.8 months and the 12-month survival rate was 53%.
clinical protocol
study edi1001

This was a Phase 1, first-in-human, open label, multicenter, 4-part, dose escalation study to explore the safety, PK, and pharmacodynamics (PD) of erdafitinib administered orally to adult subjects with advanced or refractory solid malignancies or lymphoma. Of the 187 subjects treated in this study, 30 subjects had urothelial carcinoma. The 10 subjects treated with erdafitinib 9 mg once daily who responded to treatment with erdafitinib all carried mutations or translocations in FGFR. The ORR for response-evaluable urothelial subjects with FGFR mutations or translocations was 70.0% which included 7 subjects with PR. All 9 subjects with cholangiocarcinoma carried mutations or translocations of FGFR. The ORR for response-evaluable subjects with cholangiocarcinoma was 27.3%; 3 subjects achieved PR.
clinical protocol
study hcc1001

Study HCC1001 is an open-label, multicenter, 2-part, Phase 1/2a study to evaluate the safety, PK, PD, and clinical responses of erdafitinib administered orally to Asian subjects ≥18 years of age and with advanced HCC. Of the 53 subjects treated, 52 subjects with advanced HCC were evaluable for response. The best response to treatment was PR, for 2 subjects in the 10-mg intermittent group. The ORR was 3.8% for all response-evaluable subjects, and 4.8% for 42 response-evaluable subjects with FGF19 amplification. This low response rate led to the discontinuation of recruitment to the study.
clinical protocol
study luc1001

Study LUC2001 is an open-label, multicenter, phase 2a clinical study to evaluate the clinical efficacy, safety, and PK of erdafitinib in Asian subjects with selected FGFR translocations or mutations, RET activating mutations or translocations, or other evidence of FGFR pathway activation. Of the 24 subjects treated, 23 subjects were evaluable for response. The ORR was 26.1%; 6 subjects had a PR. For the 11 subjects with cholangiocarcinoma, all of whom were treated with 8mg daily and who had an FGFR2 mutation of translocation, 5 subjects had a confirmed PR, for an ORR of 45.5% and 9 subjects had at least SD, for a disease control rate (DCR) of 81.8%.
clinical protocol
1.3.2.2. erdafitinib safety

In pooled analyses for subjects who received erdafitinib doses of 8 or 9 mg once daily in Studies EDI1001, BLC2001, and GAC1001, all 164 subjects experienced at least 1 adverse event (AE). The most frequently reported adverse events were hyperphosphatemia (81.7%), stomatitis (56.1%), dry mouth (45.7%), diarrhea (41.5%), decreased appetite (37.8%), constipation (35.4%), dysgeusia (35.4%), and dry skin (31.7%). Grade 3 or higher treatment-emergent adverse events (TEAEs) were reported for 66.5% of subjects. The most frequently reported Grade 3 or worse AEs were stomatitis (10.4%), hyponatremia (9.8%), asthenia (6.1%), anemia (5.5%), fatigue (4.3%), and dyspnea (3.7%). Serious adverse events (SAE) were reported for 40.9% of subjects. Thirty subjects (18.3%) had TEAEs that resulted in discontinuation of treatment. A total of 11 subjects (6.7%) had AEs that were fatal and included general physical health deterioration (2.4%) and asthenia (1.2%) in the context of disease progression. None of the fatal AEs were considered drugrelated.  
Central serous retinopathy (CSR; inclusive of chorioretinopathy, detachment of macular retinal pigment epithelium, detachment of retinal pigment epithelium, retinal detachment, retinal edema, retinopathy, and vitreous detachment) is an adverse event of special interest. Adverse events of clinical importance include other eye disorders (excluding CSR), skin and nail changes, hyperphosphatemia, and arrhythmias. Adverse drug reactions include hyperphosphatemia, nail disorders, skin disorders, palmar-plantar erythrodysesthesia syndrome (PPES), and central serous retinopathy.
clinical protocol
1.4. enzalutamide

Enzalutamide works through competitive AR inhibition and, unlike the older anti-androgens (e.g.  
bicalutamide, nilutamide), is a pure AR antagonist. It additionally has the ability to prevent AR
nuclear translocation and DNA binding to nuclear response elements23. It was approved in 2012 for men with mCRPC post-docetaxel16 It has also gained approval for men who are docetaxel-naïve given that a recently completed Phase III study showed OS improvements in a pre-chemotherapy population as well9 In that patient population enzalutamide was shown to result in a 37% reduced risk of death compared to placebo (HR 0.63, 95% CI, 0.53-0.75; P<0.001)9. Enzalutamide was initially tested in a Phase I/II dose escalation trial24. In that study enzalutamide was tested at doses ranging from 30 mg to 600 mg by mouth daily. It was found to exert an antitumor effect at all doses tested, with a PSA response rate (i.e. ≥50% PSA declines) in 78 out of 140 enrolled subjects (56%). Fatigue was the most common adverse event (AE) and generally occurred following 30-days of treatment. At doses ≥240 mg daily, an increasing proportion of patients required dose reductions secondary to fatigue. Overall grade 3-4 AEs included: fatigue (11%), anemia (3%), arthralgia (2%), asthenia (2%) and seizures (2%). Overall mild (i.e. grade 2) AEs included: fatigue (27.1%), nausea (8.6%), dyspnea (7.9%), anorexia (5.7%) and back pain (5.7%). Two witnessed seizures and one questionable seizure occurred in patients receiving doses of 600 mg, 360 mg and 480 mg, respectively. Only 1/87 patients treated at a daily dose of ≤240 mg discontinued treatment for an AE, compared to 7/53 at doses ≥360 mg. While 240 mg daily was deemed the maximum tolerated dose, it was noted that extent and proportion of patients achieving PSA decreases plateaued somewhere between 150 mg and 240 mg daily. As such, enzalutamide 160 mg by mouth daily was ultimately selected for further investigation. On the basis of the aforementioned Phase I/II results, the AFFIRM trial, a large randomized Phase III study powered to detect differences in survival, was launched16 This enrolled men with CRPC who had already progressed on docetaxel. Subjects were randomized 2:1 between enzalutamide 160 mg daily (N=800) and placebo (N=399). This study met its primary endpoint, demonstrating a median OS of 18.4 months with enzalutamide compared to 13.6 months with placebo (HR for death, 0.63; 95% CI, 0.53 to 0.75; P<0.001). The rate of AEs between enzalutamide and placebo were similar. Enzalutamide had a lower rate of grade 3 or higher AEs compared to placebo (45.3% vs 53.1%, respectively). Rates of fatigue, diarrhea and hot flashes were higher with enzalutamide (Table 1). There were notably 5 patients (0.6%) that experienced a seizure in the enzalutamide arm compared to zero in the placebo arm. One of these seizure required medical intervention, the others were self-limited. Predisposing factors were present in several patients, and included: two subjects with brain metastases, one subject inadvertently received IV lidocaine prior to the seizure and one subject had brain atrophy and a history of heavy alcohol use. The results from this study ultimately lead to the approval of enzalutamide in men with CRPC who had already received prior docetaxel. More recently, the results of another randomized Phase III study, the PREVAIL trial, were released9 This study randomized men with CRPC who were docetaxel naïve between enzalutamide 160 mg daily (N=871) and placebo (N=844). As was the case with AFFIRM, the PREVAIL trial demonstrated an OS advantage with enzalutamide. The median OS improved from 30.2 months to 32.4 months with enzalutamide treatment (HR for death, 0.706; 95% CI, 0.60 to 0.84; P<0.0001). While improvement in survival is modest, it should be noted that those in the placebo group received other proven prostate cancer therapies at a higher rate than those on the enzalutamide arm (e.g. 32.8% vs 56.7% received docetaxel and 20.5% vs 45.6% received abiraterone acetate). AEs occurred at comparable rates between the enzalutamide and placebo arms. Refer to Enzalutamide's FDA label for additional pharmacology and clinical data.  
| PREVAIL                                                                                           | AFFIRM          |                      |                 |     |     |     |    |     |
|---------------------------------------------------------------------------------------------------|-----------------|----------------------|-----------------|-----|-----|-----|----|-----|
| Enzalutamide (N=871)                                                                              | Placebo (N=844) |                      |                 |     |     |     |    |     |
| All  Grad es                                                                                      | Grade           |                      |                 |     |     |     |    |     |
| (%)                                                                                               | 3-4 (%)         | Enzalutamide (N=800) | Placebo (N=399) |     |     |     |    |     |
| All                                                                                               | All             |                      |                 |     |     |     |    |     |
| Grad                                                                                              | Grade           |                      |                 |     |     |     |    |     |
| Grad es                                                                                           | 3-4             |                      |                 |     |     |     |    |     |
| es                                                                                                |                 |                      |                 |     |     |     |    |     |
| Adverse Event                                                                                     | All             | Grade                |                 |     |     |     |    |     |
| Grades                                                                                            | 3-4             |                      |                 |     |     |     |    |     |
| (%)                                                                                               | (%)             |                      |                 |     |     |     |    |     |
| Fatigue                                                                                           | 35.6            | 1.8                  | 25.8            | 1.9 | 34  | 6   | 29 | 7   |
| Back pain                                                                                         | 27              | 2.5                  | 22.2            | 3   |     |     |    |     |
| Constipation                                                                                      | 22.2            | 0.5                  | 17.2            | 0.4 |     |     |    |     |
| Diarrhea                                                                                          | 21              | 1                    | 18              | 0.3 |     |     |    |     |
| Hot flashes                                                                                       | 20              | 0                    | 10              | 0   |     |     |    |     |
| Arthralgias / musculoskel etal pain                                                               | 20.3            | 1.4                  | 16              | 1.1 | 14  | 1   | 10 | 0.3 |
| Headache                                                                                          | 12              | 0.8                  | 6               | 0   |     |     |    |     |
| Cardiac event/disord er                                                                           | 10.1            | 2.8                  | 7.8             | 2.1 | 6.3 | 1.1 | 8  | 2.5 |
| Hypertensio n                                                                                     | 13.4            | 6.8                  | 4.1             | 2.3 | 6.6 | 3.3 |    |     |
| Abnormal liver function testing                                                                   | 0.9             | 0.2                  | 0.6             | 0.1 | 1   | 0.4 | 2  | 0.8 |
| Seizure                                                                                           | 0               | 0                    | 0.1             | 0   | 0.6 | 0.6 | 0  | 0   |
| Table 1: Adverse events associated with enzalutamide. Data from the AFFIRM and PREVAIL trials9,16 |                 |                      |                 |     |     |     |    |     |
clinical protocol
1.5. abiraterone acetate

Developed through rational design based on a parent pregnenolone structure, abiraterone acetate functions through inhibition of cytochrome P450-17 (CYP-17), a key family of enzymes involved in gonadal, adrenal and intratumoral androgen synthesis25-27 When given in conjunction with a GnRH analogue, it has the ability to rapidly drive castrate level testosterone (i.e. <20-50 ng/dL) to undetectable28,29 Unlike ketoconazole, another CYP-17 inhibitor used in the CRPC setting, abiraterone acetate is highly specific for the CYP-17 family of enzymes, making it generally better tolerated than ketoconazole27,29,30. It can lead to mineralocorticoid excess, however, through a compensatory elevation in adrenocorticotropic hormone (ACTH) that occurs in response to depressed cortisol levels. When prednisone is co-administered with abiraterone acetate, mineralocorticoid associated side effects (e.g. fluid retention, hypokalemia and hypertension) are mostly prevented, although these are observed more frequently in those receiving abiraterone acetate compared to placebo10,15,31 Abiraterone acetate is currently FDA approved for the treatment of CRPC in patients who are either preor post-docetaxel.  
Two dose escalation Phase I studies were completed utilizing abiraterone acetate28,32. Neither study documented dose-limiting toxicities, however, side effects of note included: hypertension (12-29%), hypokalemia (24-48%) and peripheral edema (5-24%). This side effect profile was felt most likely to be a result of mineralocorticoid excess secondary to a compensatory elevation in ACTH occurring in the context of partially blocking adrenal steroid synthesis. These side effects were managed with eplerenone, beta-blockers, diuretics and/or corticosteroids. Furthermore, these studies provided preliminary evidence for abiraterone acetate's efficacy in men with chemotherapy naïve CRPC. A subsequent Phase II study evaluated abiraterone acetate in men with CRPC post-docetaxel treatment33. This study incorporated prednisone 5 mg twice daily into the treatment regimen in an effort to mitigate the aforementioned mineralocorticoid associated side effects. At a dose of 1000 mg daily, abiraterone acetate was found to produce PSA declines of at least 50% in 22/58 (36%) men. Partial responses by Response Evaluation Criteria in Solid Tumors (RECIST) criteria were seen in 4/22 (18%) patients with evaluable tumors. Importantly, no significant hypertension or hypokalemia was noted - likely due to the co-administration of prednisone. Proof of principle that further androgen suppression is effective in controlling CRPC was provided for in the landmark Phase III COU-AA-301 trial. In that study it was demonstrated that abiraterone acetate, when given to men with CRPC previously treated with docetaxel, resulted in a significant reduction in the risk of death compared to placebo (HR 0.65, 95% CI, 0.54-0.77; P<0.001)10. Subsequently the COU-AA-302 trial demonstrated similar efficacy in men with CRPC pre-docetaxel (HR 0.79, 95% CI, 0.66-0.96; P < .0151)15. These two trials demonstrated a higher incidence of mineralocorticoid associated side effects in spite of the co-administration of prednisone. Hypokalemia, peripheral edema and hypertension occurred at approximate rates of 17%, 28-31% and 10-22% in the abiraterone acetate cohorts respectively. Other adverse events observed were generally low grade. Of note there did appear to be higher rates of fatigue, arthralgias, aminotransferase abnormalities and non-fatal cardiac events with abiraterone acetate. Overall, abiraterone acetate was felt to be generally well tolerated, however. A summary of the adverse events observed in these two Phase III trials are listed in Table 1. Ultimately, on the basis of the COU-AA-301 and COU-AA-302 trials abiraterone acetate was approved in the postand pre-docetaxel setting respectively.  
Protocol Number: CC10288 FGFR Inhibition in DNPC JNJ-42756493 Erdafitinib PI: Michael T. Schweizer Protocol Version: 6.0  
| COU-AA-301                                                                | COU-AA-302                    |                                           |                               |                |                 |     |     |    |
|---------------------------------------------------------------------------|-------------------------------|-------------------------------------------|-------------------------------|----------------|-----------------|-----|-----|----|
| Version Date: 17 September 2020 Abiraterone acetate +  Prednisone (n=791) | Placebo + Prednisone  (n=394) | Abiraterone acetate +  Prednisone (n=542) | Placebo + Prednisone  (n=540) |                |                 |     |     |    |
| Adverse Event                                                             | Grade 3-4  (%)                |                                           |                               |                |                 |     |     |    |
| Anemia                                                                    | 23                            | 7.5                                       | 26                            | 7.4            | -               | -   | -   | -  |
| Grade 3-4  (%)                                                            | All Grades  (%)               | Grade 3-4  (%)                            | All Grades  (%)               | Grade 3-4  (%) | All Grades  (%) |     |     |    |
| All Grades (%)                                                            |                               |                                           |                               |                |                 |     |     |    |
| Thrombocytopenia                                                          | 4                             | 1.4                                       | 3                             | 0.5            | -               | -   | -   | -  |
| Neutropenia                                                               | 1                             | 0.1                                       | 0.3                           | 0.3            | -               | -   | -   | -  |
| Febrile neutropenia                                                       | 0                             | 0                                         | 0                             | 0              | -               | -   | -   | -  |
| Diarrhea                                                                  | 18                            | 0.6                                       | 53                            | 1.3            | 22              | 18  |     |    |
| Fatigue                                                                   | 44                            | 8.3                                       | 169                           | 9.9            | 39              | 34  |     |    |
| Asthenia                                                                  | 13                            | 2.3                                       | 52                            | 2              | -               | -   | -   | -  |
| Back pain                                                                 | 30                            | 5.9                                       | 129                           | 9.6            | 32              | 32  |     |    |
| Nausea                                                                    | 30                            | 1.6                                       | 124                           | 2.5            | -               | -   | -   | -  |
| Vomiting                                                                  | 21                            | 1.8                                       | 97                            | 2.8            | -               | -   | -   | -  |
| Hematuria                                                                 | 8                             | 1.4                                       | 31                            | 2.3            | -               | -   | -   | -  |
| Abdominal pain                                                            | 12                            | 2                                         | 44                            | 1.5            | -               | -   | -   | -  |
| Pain in arm or leg                                                        | 17                            | 2.4                                       | 79                            | 5              | 17              | 16  |     |    |
| Dyspnea                                                                   | 13                            | 1.3                                       | 46                            | 2.3            | -               | -   | -   | -  |
| Constipation                                                              | 26                            | 1                                         | 120                           | 1              | 23              | 19  |     |    |
| Pyrexia                                                                   | 9                             | 0.4                                       | 35                            | 1.3            | -               | -   | -   | -  |
| Arthralgia                                                                | 27                            | 4.2                                       | 89                            | 4.1            | 28              | 24  |     |    |
| Urinary tract infection                                                   | 12                            | 2.1                                       | 28                            | 0.5            | -               | -   | -   | -  |
| Pain                                                                      | 2                             | 0.6                                       | 19                            | 1.8            | -               | -   | -   | -  |
| Bone pain                                                                 | 25                            | 5.6                                       | 110                           | 7.4            | 20              | 19  |     |    |
| Fluid retention or edema                                                  | 31                            | 2.3                                       | 88                            | 1              | 28              | 0.7 | 24  | 2  |
| Hypokalemia                                                               | 17                            | 3.8                                       | 33                            | 0.8            | 17              | 2   | 13  | 2  |
| Cardiac disorder*                                                         | 13                            | 4.1                                       | 42                            | 2.3            | 19              | 6   | 16  | 3  |
| Liver-function test  abnormalities or  Hepatotoxicity                     | 10                            | 3.4                                       | 32                            | 3              | 4.2             | 8   | 9.8 | 3  |
| 27                                                                        |                               |                                           |                               |                |                 |     |     |    |  
Protocol Number: CC10288 FGFR Inhibition in DNPC JNJ-42756493 Erdafitinib PI: Michael T. Schweizer Protocol Version: 6.0  
Hypertension 10 1.3 31 0.3 - - - - Hot flush - - - - 22 18 Muscle spasm - - - - 14 20  
Cough - - - - 17 14  
Table 2: Adverse events observed on the COU-AA-30110 and COU-AA-30234 trials.  
*Cardiac disorders included: ischemic heart disease, myocardial infarction, supraventricular tachyarrhythmias, ventricular tachyarrhythmias, cardiac failure and possible arrhythmia-related tests, signs and symptoms  
Abiraterone acetate plus the GnRH agonist leuprolide have also been tested in the neoadjuvant setting. Taplin and colleagues recently reported on the results of a randomized Phase II study35 In that trial men were randomized between 24 weeks of neoadjuvant GnRH agonist plus 12 weeks of abiraterone acetate (N=28) and 24 weeks of both neoadjuvant GnRH plue abiraterone acetate (N=30). That trial demonstrated a negative margin rate of 90% and pCR rate of 10% in the cohort receiving 24 weeks of both leuprolide and abiraterone acetate, with an additional 14% of patients achieving a near pCR (defined as ≤5 mm residual tumor). The cohort receiving 24 weeks of GnRH agonist and 12 weeks of abiraterone acetate achieved a negative margin rate of 81%, a pCR rate of 4% and a near pCR rate of 0%. Differences in pathologic outcomes between cohorts were not statistically significant; although, the trial was not powered to detect these differences.
clinical protocol
1.6. overall rationale for the

Many of the treatments for mCRPC are directed at suppressing the AR-signaling axis. While AR-directed therapies are initially effective, resistance inevitability occurs. The continued lethality of this disease underscores the importance of testing therapeutics aimed at alternate pathways. As outlined above, mechanistic studies have revealed that MAPK-signaling, which is activated by FGF/FGFR signaling, is an important AR bypass mechanism in men with late stage, DNPC. Importantly, targeting FGF/FGFR-signaling with pan-FGFR inhibitors results in significant tumor growth inhibition in both engineered LNCaPAPIPC cells and DNPC LuCaP 173.2 PDX models1. It is important to note that unlike other malignancies (e.g. bladder and lung cancer), patients with a DNPC phenotype usually do not harbor genomic alterations in FGFR, and over-activation of FGF/FGFR-signaling is primarily driven by autocrine/paracrine activation of this pathway. In total, this data demonstrates that FGF/FGFR-signaling is a critical driver of late stage CRPC, and supports testing FGFR inhibitors in DNPC patients. On this basis, we are launching a phase II trial testing the pan-FGFR inhibitor erdafitinib in men with metastatic CRPC who have previously progressed on abiraterone acetate and/or enzalutamide and exhibit a DNPC phenotype on biopsy. Patients will continue on the most recent next-generation AR-directed therapy they progressed on (i.e. either abiraterone acetate or enzalutamide) in order to maintain suppression of AR-signaling, and erdafitinib will be added to their regimen. Erdafitinib will be dosed at the recommended Phase II dose, and abiraterone acetate or enzalutamide will be administered at their respective FDA approved dose. Study subjects will continue on erdafitinib plus either abiraterone acetate or enzalutamide until radiographic progression or intolerable toxicity. We hypothesize that erdafitinib *in combination* with a next-generation AR-directed therapy will show clinical efficacy in men with *mCRPC with* a DNPC phenotype who have progressed *on abiraterone* acetate *or enzalutamide*
clinical protocol
2. objective and endpoints 2.1.

To determine the objective tumor response rate in subjects with measurable lesions as defined by RECIST v1.1 criteria in mCRPC patients with a DNPC molecular phenotype receiving either enzalutamide or abiraterone acetate in combination with erdafitinib.
clinical protocol
2.2. secondary objectives

1. Determine the radiographic PFS in patients using RECIST 1.1 criteria for soft tissue metastases and Prostate Cancer Working Group 3 (PCWG3) criteria for bone metastases2,3 2. Determine the time to response using RECIST 1.1 criteria2 3. Determine the overall survival defined as the time interval from C1D1 to the date of death 4. PSA response, defined as >50% reduction in PSA compared with baseline at any point during treatment 5. Assess the incidence and severity of adverse events according to National Cancer Institute- Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
clinical protocol
2.3. planned exploratory objectives

Correlative work will be performed in order to determine biomarkers predictive of response to combination therapy. Examples of correlative work may include, but will not be limited to:
1. Immunohistochemistry (IHC) for phosphorylated FGFR and FGFR substrate 2 (FRS2) in tumor tissue 2. IHC for PSA and AR expression in tumor tissue 3. Tumor tissue transcript profiling studies to assess candidate biomarkers for response/resistance to FGFR inhibitor therapy and to evaluate core signaling program for FGF/FGFR, MAPK, and AR.  
4. Next-generation sequencing of pre-treatment tumor biopsies and cell-free circulating tumor DNA (ctDNA) to identify genomic alterations correlating with response or resistance to treatment, and confirm FGFR alteration status 5. Serial blood (baseline, 12-weeks, progression) will be obtained in order to develop a blood-based gene expression response signature 6. Serum FGF ligand levels (FGF8, FGF9, FGF19) will be drawn at baseline,12-weeks and at progression
clinical protocol
3. study design and rationale

This will be a phase II trial testing the pan-FGFR inhibitor, erdafitinib, in men with metastatic CRPC who have previously progressed on abiraterone acetate and/or enzalutamide (Fig 7). Eligible patients must have CRPC (defined as disease progression in spite of a castrate serum testosterone
[≤50 ng/dl]), and evidence of RECIST evaluable disease to enroll2. Given that the patient population of interest will be heavily pre-treated, and likely enriched for both small cell/NE and double negative prostate cancer, it is recommended that patients undergo a baseline biopsy prior to enrollment to rule out predominate NE/small cell variant prostate cancer. Patients with DNPC as defined by IHC criteria will be eligible to enroll (see Section 9.2.1.1). Transcript profiling methods for identifying DNPC may also be accepted for determining trial eligibility at the PI's discretion. This is based on data showing that transcriptional signatures can accurately define the various prostate cancer subtypes, including DNPC4,5. Eligible patients must have demonstrated evidence of progression per Prostate Cancer Working Group 3 (PCWG3) criteria while on enzalutamide or Version Date: 17 September 2020 PI: Michael T. Schweizer Protocol Version: 6.0 Protocol Number: CC10288 FGFR Inhibition in DNPC JNJ-42756493 Erdafitinib abiraterone acetate at any time prior to enrollment3. If not surgically castrated, participants must be maintained on an LHRH analogue (e.g. leuprolide, goserelin). Eligible patients will continue on the most recent next-generation AR-directed therapy they progressed on (i.e. either abiraterone acetate or enzalutamide) in order to maintain suppression of AR-signaling and erdafitinib will be added to their regimen. If a trial subject is not currently on abiraterone or enzalutamide at the time of screening, they must restart the AR-directed therapy most recently received and demonstrate two successive PSA rises or other evidence of progression prior to starting treatment per protocol. Erdafitinib will be administered at 8 mg once daily orally, with pharmacodynamic uptitration to 9 mg if serum phosphate was below 5.5mg/dL in absence of significant toxicity on cycle 1 day 14 (see Section 6.1). Abiraterone acetate or enzalutamide will be administered at their respective FDA approved dose (i.e. abiraterone acetate 1000 mg PO daily; enzalutamide 160 mg PO daily). Subjects continuing on abiraterone acetate will also be required to receive prednisone 5 mg PO twice daily in order to blunt mineralocorticoid symptoms associated with abiraterone acetate. Study subjects will continue on erdafitinib plus either abiraterone acetate or enzalutamide until radiographic progression, intolerable toxicity or two-years of treatment, whichever comes first. The primary objective will be to determine the objective tumor response rate in measurable lesions as defined by RECIST v1.1 criteria. For the purpose of defining objective response rate, confirmation of response will not be required. If a patient drops out of the study prior to first onstudy radiographic assessment, they will be considered a non-responder for the purpose of the primary analysis; however, an additional subject will be accrued to account for early dropouts. Key secondary objectives will include determining: radiographic progression free survival (PFS) in patients using RECIST 1.1 criteria for soft tissue metastases and Prostate Cancer Working Group 3 (PCWG3) criteria for bone metastases; time to response using RECIST 1.1 criteria; overall survival (OS) defined as the time interval from C1D1 to the date of death; PSA response, defined as >50% reduction in PSA compared with baseline at any point during treatment; and the incidence and severity of adverse events according to National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE) version 5.02,3.  
This study will also include a number of correlative studies aimed at identifying candidate biomarkers for response/resistance to FGFR inhibitor therapy. We will plan to obtain pre- and post-treatment biopsies as well as serial blood samples in order to develop blood-based biomarkers for response/resistance to erdafitinib. Given our rapidly evolving understanding of prostate cancer biology, it is impossible to prospectively define all the relevant biomarkers for the patient population enrolled on this study. Examples of the studies to be conducted may include, but will not be limited to the following. Protein expression studies at baseline and at the time of progression, including IHC for AR, PSA, phospho-FRS2 and phosphor-FGFR. Transcript profiling studies (RNA-seq) on metastatic biopsies to assess activation of the core AR-, MAPK- and FGF/FGFR-signaling programs, and to identify unknown pathways involved in mediating response/resistance to treatment. Next-generation sequencing to assess for FGFR mutations. Baseline protein and transcript expression, as well as changes in these parameters with treatment will be correlated with clinical outcomes. This information will be used to develop a gene expression *response-signature*, which we will be assessed in blood samples.  
PI: Michael T. Schweizer Protocol Version: 6.0 Protocol Number: CC10288 FGFR Inhibition in DNPC
clinical protocol
4.1inclusion criteria 4. subject population

Full study screening for eligible subjects will be performed within 30 days before administration of the study drug. The inclusion and exclusion criteria for enrolling subjects in this study are described in the following 2 subsections.  
Each potential subject must satisfy all of the following criteria to be enrolled in the study:  
1. Patients must be > 18 years of age prior to signing informed consent 2. History of histologically diagnosed prostatic adenocarcinoma 3. Participants must have evidence of castration resistant prostate cancer as evidenced by a confirmed rising PSA or radiographic progression (per Prostate Cancer Working Group 3 [PCWG3] criteria) and a castrate serum testosterone level (i.e. < 50 ng/dL)
4. Participants must have previously progressed on abiraterone acetate and/or enzalutamide, with PSA
or radiographic progression on the most recent agent per PCWG3 criteria. If the most recent agent received was abiraterone or enzalutamide there should be no washout prior to initiating erdafitinib per protocol 5. Measurable disease as defined per RECIST v1.1 criteria 6. Subjects who have progressed on only one next-generation AR-directed therapy (e.g. abiraterone, enzalutamide) and who have not received taxane chemotherapy will be required to have evidence of double-negative prostate cancer as defined by immunohistochemistry (see Section 9.2.1.1) on biopsy. A fresh metastatic biopsy within 8 weeks is preferred; however, any archival tissue showing a DNPC phenotype will be acceptable for determining eligibility. Patients who have received two Version Date: 17 September 2020 31 Fig 7. Study schema.  
PI: Michael T. Schweizer Protocol Version: 6.0 Protocol Number: CC10288 FGFR Inhibition in DNPC JNJ-42756493 Erdafitinib prior lines of AR-directed therapy and at least one prior taxane do not require histologic confirmation of DNPC. Note: transcript profiling methods for defining DNPC may be accepted per the PI's discretion 7. ECOG performance status score <2 8. Clinical and laboratory values and cardiovascular measurements at screening:  
| Hematology                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                    |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------|
| Hemoglobin                                                                                                                                                                                                                                                                                                                                            | > 8 g/dL (>5 mmol/L) (must be without  red blood cell [RBC] transfusion within 7  days prior to the laboratory test)               |
| Platelets                                                                                                                                                                                                                                                                                                                                             | > 75 x 109 /L                                                                                                                      |
| Absolute Neutrophil Count (ANC)                                                                                                                                                                                                                                                                                                                       | > 1.5 x 109 /L (prior growth factor support  is permitted but must be without support in  the 7 days prior to the laboratory test) |
| Chemistry                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                    |
| AST and ALT                                                                                                                                                                                                                                                                                                                                           | < 2.5 x upper limit of normal (ULN) or < 5  x ULN for subjects with liver metastases                                               |
| Creatinine clearance                                                                                                                                                                                                                                                                                                                                  | >40 mL/min/1.73 m2 based upon Modified  Diet in Renal Disease formula calculation                                                  |
| Total bilirubin                                                                                                                                                                                                                                                                                                                                       | < 1.5 x ULN; except in subjects with  congenital bilirubinemia, such as Gilbert's  syndrome                                        |
| Cardiovascular                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                    |
| Corrected QT interal (QTcF or QTcB)                                                                                                                                                                                                                                                                                                                   | <480 msec based on the average of  triplicate assessments performed  approximately 5 minutes apart                                 |
| ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate  aminotransferase; GFR = glomerular filtration rate; QTcB = QT corrected interval by the  Bazett's formula; QTcF = QT corrected interval by the Fridericia's formula; ULN =  upper limit of normal IF Glibert's disease is present, direct bilirubin can be measured |                                                                                                                                    |  
9. Subjects must agree to use acceptable contraception (see Section 11.3 for requirements) 10. Must sign an informed consent form (ICF) indicated that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study
clinical protocol
exclusion criteria

1. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 14 days prior to enrollment  
2. Active malignancies (i.e. requiring treatment change in the last 24 months) other than malignancy under study (except skin cancers within the last 24 months that are considered completely cured)
PI: Michael T. Schweizer Protocol Version: 6.0 Protocol Number: CC10288 FGFR Inhibition in DNPC JNJ-42756493 Erdafitinib 3. Evidence of predominant small cell or neuroendocrine variant prostate cancer (see section 9.2.1.1)
on most recent standard of care metastatic biopsy 4. Symptomatic central nervous system (CNS) metastases. Treated CNS metastases will be allowed if these are stable for at least 8 weeks prior to enrollment 5. Received prior FGFR inhibitor treatment or if the subject as known allergies, hypersensitivity, or intolerance to erdafitinib or its excipients 6. Current central serous retinopathy (CSR) or retinal pigment epithelial detachment of any grade 7. Has persistent phosphate level >ULN during screening (on 2 consecutive assessments at least 1 week apart, within 14 days of treatment and prior to Cycle 1 Day 1) and despite medical management 8. Has a history of current uncontrolled cardiovascular disease including:
a. Unstable angina, myocardial infarction, ventricular fibrillation, Torsades de Pointes, cardiac arrest, or known congestive heart failure Class III-V within the preceding 3 months; cerebrovascular accident or transient ischemic attack within the preceding 3 months b. Pulmonary embolism or other VTE (venous thromboembolism) within the preceding 2 months 9. Has known active AIDS (human immunodeficiency virus (HIV) infection) 10. Hepatitis B infection as defined according to the American Society of Clinical Oncology guidelines.  
In the event the infection status is unclear, quantitative levels are necessary to determine the infection status. Hepatitis C (anti-hepatitis C virus [HCV] antibody positive or HCV-RNA quantitation positive) or known to have a history of hepatitis C. If positive, further testing of quantitative levels to rule out positivity is required 11. Has not recovered from reversible toxicity of prior anticancer therapy (except toxicities which are not clinically significant such as alopecia, skin discoloration, hot flashes, Grade 1 neuropathy, Grade 1-2 hearing loss)
12. Has impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions 13. Major surgery within 2 weeks of the first dose, or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study or within 2 weeks after the last dose of study drug administration (Note: subjects with planned surgical procedures to be conducted under local anesthesia may participate)
14. Any serious underlying medical conditions, such as:
a. Evidence of serious active viral, bacterial, or uncontrolled systemic fungal infection b. Active autoimmune or a documented history of autoimmune disease c. Psychiatric conditions (e.g., alcohol or drug abuse), dementia, or altered mental status 15. Any other issue that would impair the ability of the subject to receive or tolerate the planned treatment at the investigational site, to understand informed consent or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments 16. Patient, who, in the opinion of their treating physician, requires immediate treatment (e.g. those with extensive liver metastases)
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. If a subject's clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study drug is given such that he or she no longer meets all eligibility criteria, then the subject should be excluded from participation in the study. Section 9.1.2, Screening Phase, describes options for retesting. Section 17.4, Source Documentation, describes the required documentation to support meeting the enrollment criteria.
clinical protocol
5 treatment allocation and blinding

Erdafitinib will be provided as a tablet for oral administration. Subjects will be instructed to take erdafitinib orally once daily for 21 days on a 21-day cycle. Treatment will be up-titrated to 9 mg, maintained at 8 mg, or withheld, based on phosphate level measured on Cycle 1 Day 14, and taking into account observed toxicity to that day. Erdafitinib is to be taken with approximately 240 mL (8 ounces) of water. The tablets should be swallowed intact and subjects should not attempt to PI: Michael T. Schweizer Protocol Version: 6.0 Protocol Number: CC10288 FGFR Inhibition in DNPC JNJ-42756493 Erdafitinib dissolve them in water. Each dose should be taken at approximately the same time each day.  
Subjects should avoid consuming grapefruit or Seville orange, due to CYP450 3A4/5 inhibition by such fruits.
clinical protocol
up-titration guidelines

All subjects will start erdafitinib 8 mg once daily from Day 1 to Day 14. On Day 14, a blood sample will be drawn to determine serum phosphate concentration.  
- Subjects with serum phosphate levels higher than 9 mg/dL will withhold erdafitinib treatment, with at least weekly assessment of serum phosphate until it returns to less than 7.0 mg/dL (see Table 4 for detailed guidelines regarding further treatment).  
- Subjects with serum phosphate levels between 7.0 to 9.0 mg/dL should increase the erdafitinib dose to 9 mg once daily, while concurrently initiating treatment with a phosphate binder such as sevelamer (see Table 4 for details).  
- Subjects with serum phosphate level less than 7.0 mg/dL will increase the erdafitinib dose to 9 mg once daily without concomitant phosphate binder such as sevelamer.
The study drug will be dispensed at the first visit of each cycle. All study drug doses dispensed must be captured in the source documents, including the subject's diary card, and the electronic case report form (eCRF). Unused study drug in the issued bottles and empty bottles must be returned to the site at each study visit. Study drug must be returned to the site when a subject discontinues study treatment. Returned tablets cannot be re-issued in this study or outside the study (follow study drug accountability guidelines per institutional guidelines). If a dose is missed, it can be taken up to 6 hours after the scheduled time; the subject may return to the normal schedule the following day. If it has been more than 6 hours since the missed dose, then that dose should be skipped and the subject should continue treatment at the scheduled time the next day. Missed doses will not be replaced and the next dose will remain unchanged. If vomiting occurred with drug administration, no replacement dose will be taken and any such event that occurs up to 4 hours following dose administration must be recorded on the subject's diary card and the eCRF.
clinical protocol
6.1.1 dose modifications and dose

Treatment with erdafitinib should be discontinued or modified based on toxicity as described in Table 1. For eye, skin/nail, dry mouth/mucositis, liver, and phosphate toxicity, specific recommendations in the management guidelines are provided in Sections 6.1.2.2 through 6.1.2.7.  
| Table 1.                                                                                                                                      | Erdafitinib Dose Modification Rules Based on Toxicity   |                                                                                                                                                                          |
|-----------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Toxicity                                                                                                                                      | Action                                                  | Dose modification after resolution of AE                                                                                                                                 |
| Grade 1                                                                                                                                       | None                                                    | Continue same dose                                                                                                                                                       |
| 2                                                                                                                                             | None or consider interruption                           | If interrupted, restart at same dose or 1 dose lower, if necessary.                                                                                                      |
| 3                                                                                                                                             | Interrupt drug                                          | Restart at 1 or 2 doses lower if recovery (to ≤Grade 1 or back to baseline for non-hematologic toxicity) is within 28 days. Discontinue drug if unresolved for >28 days. |
| 4                                                                                                                                             | Interrupt drug                                          | Discontinue*                                                                                                                                                             |
| a For eye, skin/nail, dry mouth/mucositis, liver, and phosphate toxicity please follow specific recommendations in the management guidelines. |                                                         |                                                                                                                                                                          |  
- Subjects with any grade of toxicity (Grade 1 to 4) should be provided symptomatic treatment where applicable.  
- If erdafitinib is interrupted consecutively for 1 week or longer due to drug-related toxicity, erdafitinib may be reintroduced at either the same dose level or the first reduced dose level following recovery from the toxicity (see dose reduction levels in Table 2). A second dose reduction may be implemented following a second occurrence of drug-related toxicity.  
- If erdafitinib must be withheld for more than 28 days for a drug-related adverse event that fails to resolve to acceptable level (e.g., ≤Grade 1 non-hematologic toxicity or back to baseline), treatment with erdafitinib should be discontinued except when the subject has been deriving benefit from treatment, and the investigator can demonstrate that continued treatment with erdafitinib is in the best interest of the subject. Erdafitinib may be re-started at the same or a lower dose (Table 2) if the Sponsor-Investigator (Dr. Schweizer) concurs with the assessment.  
- If erdafitinib was dose-reduced and the adverse event that was the reason for this dosereduction has completely resolved, the dose may be re-escalated to the next higher dose if the subject was deriving benefit from treatment, and the investigator can demonstrate that dose re-escalation of erdafitinib is in the best interest of the subject and the Sponsor-Investigator concurs with the assessment.  
- In all cases of clinically significant impaired wound healing or imminent surgery or potential bleeding complications, it is recommended that dose administration be interrupted, appropriate clinical laboratory data (e.g., coagulation) be carefully monitored, and supportive therapy administered, where applicable. Dose administration may be restarted when it is considered safe and at an appropriate dose, according to the investigator's assessment.  
| Table 2.           | Erdafitinib Dose Reduction Levels   |                   |      |
|--------------------|-------------------------------------|-------------------|------|
| Category           | No up-titration                     | With up-titration |      |
| Dose               | Dose                                |                   |      |
| Starting dose      | 6 mg                                | 8 mg              | 8 mg |
| Up-titration       | None                                | None              | 9 mg |
| 1st dose reduction | 5mg                                 | 6 mg              | 8 mg |
| 2nd dose reduction | 4mg                                 | 5 mg              | 6 mg |
| 3rd dose reduction | stop                                | 4 mg              | 5 mg |
| 4th dose reduction | stop                                | 4 mg              |      |
| 5th dose reduction | stop                                |                   |      |
clinical protocol
6.1.2 guidance for specific erdafitinib

Hyperphosphatemia and adverse events related to nails will be graded as outlined in Table 3.  
| Table 3:          | Grading of Hyperphosphatemia and Nails Adverse Events                    |                                                                                                                          |                                                                                                                                               |                                                                                            |
|-------------------|--------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------|
| Adverse Event     | Grade 1                                                                  | Grade 2                                                                                                                  | Grade 3                                                                                                                                       | Grade 4                                                                                    |
| Nail Changes      | Nail discoloration,                                                      |                                                                                                                          |                                                                                                                                               |                                                                                            |
| (onychodystrophy) | asymptomatic separation of the nail bed from the nail plate or nail loss | Nail/finger tips pain,symptomatic separation of the nail bed from the nail plate or nail loss; limiting instrumental ADL | Severe nail finger tips pain, symptomatic separation of the nail bed from the nail plate or nail loss;significantly limiting instrumental ADL | Life-threatening consequences, urgent intervention indicated                               |
| Hyperphosphatemia | 5.5-6.9 mg/dl                                                            | 7.0-8.9 mg/dl                                                                                                            | 9.0-10.0 mg/dl (2.9- 3.2 mmol/L), or asymptomatic soft tissue calcification with any phosphate level                                          | >10 mg/dl (>3.2 mmol/L), or symptomatic soft tissue calcification with any phosphate level |
| 1.8-2.2 mmol/L    | 2.3-2.9 mmol/L                                                           |                                                                                                                          |                                                                                                                                               |                                                                                            |
clinical protocol
6.1.2.2 guidelines for the management

Guidelines for the clinical management of elevated serum phosphate levels are presented in Table 4. Hyperphosphatemia should be graded according to Table 3.  
| Table 4:                                                                                                                                                                                                                                                                     | Guidelines for Management of Serum Phosphate Elevation                             |                                                                                                                                                |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------|
| Serum Phosphate Level                                                                                                                                                                                                                                                        | Study Drug Management                                                              | SymptomManagement                                                                                                                              |
| <5.5 mg/dL                                                                                                                                                                                                                                                                   | Continue erdafitinib treatment.                                                    | None.                                                                                                                                          |
| (<1.8 mmol/L) 5.5-6.9 mg/dL                                                                                                                                                                                                                                                  | Continue erdafitinib treatment.                                                    | Restriction of phosphate intake to                                                                                                             |
| (1.8-2.2 mmol/L)                                                                                                                                                                                                                                                             | 600 - 800 mg/day.                                                                  |                                                                                                                                                |
| 7.0-9.0 mg/dL                                                                                                                                                                                                                                                                | Continue erdafitinib treatment.                                                    |                                                                                                                                                |
| (2.3-2.9 mmol/L)                                                                                                                                                                                                                                                             | Restriction of phosphate intake to 600 - 800 mg/day.                               |                                                                                                                                                |
| A dose reduction will be implemented for persistenta hyperphosphatemia defined as serum phosphate ≥7 mg/dL for a period of 2 months) or if clinically necessary (e.g., in the presence of additional adverse events linked to hyperphosphatemia or electrolyte disturbances) | Start sevelamer 800 to 1,600 mg TID with food until phosphate level is <7.0 mg/dL. |                                                                                                                                                |
| >9.0-10 mg/dL                                                                                                                                                                                                                                                                | Withholdb erdafitinib treatment until serum phosphate                              |                                                                                                                                                |
| (>2.9-3.2 mmol/L)                                                                                                                                                                                                                                                            | level returns to <7.0 mg/dL (weekly testing recommended).                          | Restriction of phosphate intake to 600 - 800 mg/day. Sevelamer up to 1,600 mg TID with food until serum phosphate level returns to <7.0 mg/dL. |
| Re-start treatment at the same dose level. A dose reduction will be implemented for persistenta hyperphosphatemia (defined as serum phosphate                                                                                                                                |                                                                                    |                                                                                                                                                |  
| Table 4:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Guidelines for Management of Serum Phosphate Elevation                                                                                                                                                                                                                                                                                                      |                                               |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------|
| Serum Phosphate Level                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Study Drug Management                                                                                                                                                                                                                                                                                                                                       | SymptomManagement                             |
| ≥9 mg/dL for a period of 1 month) or if clinically necessary (e.g., in the presence of additional adverse events linked to hyperphosphatemia or electrolyte disturbances)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                             |                                               |
| >10.0 mg/dL                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Withholdb erdafitinib treatment until serum phosphate                                                                                                                                                                                                                                                                                                       |                                               |
| (>3.2 mmol/L)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | level returns to <7.0 mg/dL (weekly testing recommended).                                                                                                                                                                                                                                                                                                   | Medical management as clinically appropriate. |
| Re-start treatment at the first reduced dose level. If persistenta hyperphosphatemia (≥10 mg/dL) for >2 weeks, erdafitinib should be discontinued permanently.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                             |                                               |
| Significant alteration in baseline renal function or Grade 3 hypocalcemia                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Erdafitinib should be discontinued permanently. (In situations where the subject is having clinical benefit and the investigator and the Sponsor-Investigator agree that continuation of treatment is in the best interest of the subject, the drug may be re-started at 2 dose levels lower if appropriate. Follow other recommendations described above.) | Medical management as clinically appropriate. |
| Note: These are general guidelines that are based on emerging data and consensus experience of participating investigators or the experts in the field. The treating physicians must use clinical judgment and local standard of care to decide the best way to manage phosphate elevation. If sevelamer hydrochloride (Renagel®) is not available, use of other phosphate binders (non- calcium containing) based on the local standard is recommended, including sevelamer carbonate (Renvela) or lanthanum carbonate (Fosrenol®). These guidelines will be updated based on emerging data. Additional information on phosphorous in foods by class of food can also be found at www.permanente.net/homepage/kaiser/pdf/42025.pdf. Additional information for phosphate management and diet can be found at the National Kidney Foundation website (http://www.kidney.org/atoz/content/phosphorus.cfm) a. Persistent hyperphosphatemia is considered to be more than 1 sequential phosphate value above the cut-off. b. Study drug interruptions for hyperphosphatemia suggested to be 7 days duration. |                                                                                                                                                                                                                                                                                                                                                             |                                               |
clinical protocol
6.1.2.3 guidelines for the management

Guidelines for the clinical management of dry mouth (xerostomia) and stomatitis are provided in Table 5 and Table 6, respectively.
clinical protocol
- general prophylaxis

− Good oral hygiene
− Use a soft toothbrush − Avoidance of spicy, acidic, hard, and hot food and beverages
− Use of mild-flavored toothpastes
− Use of saline-peroxide or salt and baking soda mouthwashes 3 or 4 times per day
− Water soluble lubrication agents like artificial saliva (for xerostomia or dry mouth)  
| Table 5:                                                                                                                                                                          | Guidelines for the Management of Dry Mouth (Xerostomia)                                                                                                                                                    |                                                                        |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|
| Grade and Definition                                                                                                                                                              | Study Drug Management                                                                                                                                                                                      | SymptomManagement                                                      |
| Grade 1: symptomatic (e.g., dry or thick saliva) withoutsignificant dietary alteration; unstimulated saliva flow >0.2 mL/min                                                      | Continue erdafitinib at                                                                                                                                                                                    | Sorbitol lozenges PRN                                                  |
| current dose.                                                                                                                                                                     |                                                                                                                                                                                                            |                                                                        |
| Grade 2: moderate symptoms; oral intake alterations(e.g., copious water, other lubricants, diet limited to purees and/orsoft, moist foods); unstimulated saliva 0.1 to 0.2 mL/min | Continue erdafitinib at                                                                                                                                                                                    | Sorbitol lozenges PRN and                                              |
| current dose.                                                                                                                                                                     | Cevimiline 30 mg TID or Pilocarpine 5 mg TID                                                                                                                                                               |                                                                        |
| Grade 3: inability to adequately aliment orally; tube feeding or TPN indicated; unstimulated saliva less than 0.1 ml/min                                                          | Hold erdafitinib (for up to 28 days), with weekly reassessments of clinical condition. When resolved to ≤Grade 1 or baseline, restart at 1 dose level below in consultation with the Sponsor-Investigator. | Sorbitol lozenges PRN and Cevimiline 30 mg TID or Pilocarpine 5 mg TID |
| Grade 4: life-threatening consequences,                                                                                                                                           | Discontinue erdafitinib.                                                                                                                                                                                   | Evaluation and therapy as                                              |
| urgent intervention indicated                                                                                                                                                     | clinically indicated                                                                                                                                                                                       |                                                                        |  
| Table 6:                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Guidelines for the Management of Oral Mucositis                                                                                                                                                                                                                                                       |                                                 |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------|
| Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Study Drug Management                                                                                                                                                                                                                                                                                 | SymptomManagement                               |
| Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Continue study drug at current dose.                                                                                                                                                                                                                                                                  | - Continue general prophylaxis                  |
| 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | recommendations.                                                                                                                                                                                                                                                                                      |                                                 |
| - Dexamethasone solution (0.5 mg/5mL  solution) swish and spit QID or similar solution that is available in your  country and lidocaine 2-5% jelly or solution. - Consider clotrimazole/nystatin if subjects are  at risk of developing oral candidiasis.                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                       |                                                 |
| Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | - Consider holding study drug if the                                                                                                                                                                                                                                                                  |                                                 |
| 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | subject has other study-drug related  concomitant Grade 2 AEs.                                                                                                                                                                                                                                        |                                                 |
| - Hold study drug if the subject was  already on symptom management  (dexamethasone solution swish and  spit and lidocaine 2-5% jelly or  solution) for more than a week. - If the study drug is withheld, reassess  in 1-2 weeks. - If this is the first occurrence of  toxicity and resolves to ≤Grade 1 or  baseline within 2 weeks, restart at  same dose. - If recurrent event or takes >2 weeks  to resolve to ≤Grade 1 or baseline,  then restart at 1 dose level below. | - Dexamethasone solution (0.5 mg/5mL  solution) swish and spit QID or similar solution that is available in your  country and lidocaine 2-5% jelly or solution. - Consider concomitant etiologies such as oral  candidiasis, oral herpes and recommend  appropriate anti-fungal or anti-viral agents. |                                                 |
| Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | - Hold study drug, with reassessments                                                                                                                                                                                                                                                                 |                                                 |
| 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | of clinical condition in 1-2 weeks.                                                                                                                                                                                                                                                                   |                                                 |
| - When resolves to ≤Grade 1 or baseline, restart at 1 dose level below in consultation with the medical monitor.                                                                                                                                                                                                                                                                                                                                                                | - Dexamethasone solution (0.5 mg/5mL  solution) swish and spit QID or similar solution that is available in your  country  and lidocaine 2-5% jelly or solution. - Consider pain management strategies. - Consider IV hydration.                                                                      |                                                 |
| Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Discontinue study drug.                                                                                                                                                                                                                                                                               | Evaluation and therapy as clinically indicated. |
| 4 AE=adverse event; QID=quater in die (four times each day).                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                                                                       |                                                 |
clinical protocol
6.1.2.4 guidelines for the management

Guidelines for the management of dry skin are provided in Table 7.
clinical protocol
- general prophylaxis

− Avoid unnecessary exposure to sunlight and excessive use of soap.  
− Avoid bathing in excess; use tepid rather than hot water.  
− Use moisturizers regularly; apply thick, alcohol-free and oil-in-water based emollient cream on exposed and dry areas of the body.  
− Avoid perfumed products, bubble bath, perfumed soaps, and take breaks from shaving.  
− Use broad spectrum sunscreen with a skin protection factor (SPF) ≥15.  
− Wear cotton clothes next to skin rather than wool, synthetic fibers, or rough clothing. − Use occlusive alcohol-free emollient creams (jar or tub) for treatment of mild/moderate xerosis.  
− For scaly areas, use exfoliants (ammonium lactate 12% or lactic acid cream 12%).  
| Table 7:                                                                                                                                      | Guidelines for Management of Dry Skin                                                                                                                                                                      |                                                                                                                                                                                                                                                            |
|-----------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade and Definition                                                                                                                          | Study Drug Management                                                                                                                                                                                      | SymptomManagement                                                                                                                                                                                                                                          |
| Grade 1: Dry skin covering less than 10% body surface area (BSA) and no associated erythema or pruritus                                       | Continue erdafitinib at current dose.                                                                                                                                                                      | Use fragrance free moisturizing cream or ointment BID over entire body. Use ammonium lactate 12% cream or salicylic acid 6% cream BID over dry/scaly/hyperkeratotic areas such as palms and soles.                                                         |
| Grade 2: Dry skin covering 10 to 30% BSA and associated with erythema or pruritis with limited instrumental activities of daily living (IADL) | Continue erdafitinib at current dose.                                                                                                                                                                      | Use fragrance free moisturizing cream or ointment BID over entire body. Use ammonium lactate 12% cream or salicylic acid 6% cream BID over dry/scaly/hyperkeratotic areas such as palms and soles. Use zinc oxide 13-40% at night for areas with fissures. |
| Grade 3: Dry skin covering >30% BSA and associated with pruritis; limiting self-care activities of daily living (ADL)                         | Hold erdafitinib (for up to 28 days), with weekly reassessments of clinical condition. When resolves to ≤Grade 1 or baseline, restart at 1 dose level below in consultation with the Sponsor-Investigator. | Use topical steroid ointment or cream* BID and zinc oxide 13-40% at night for areas with fissures.                                                                                                                                                         |
| Grade 4: Dry skin with lifethreatening consequences, urgent intervention indicated                                                                                                                                               | Discontinue erdafitinib.                                                                                                                                                                                   | Evaluation and therapy as clinically indicated                                                                                                                                                                                                             |
| *Topical Steroid Ointments: Clobetasol 0.05%, Betamethasone 0.05%, Fluocinonide 0.05%                                                         |                                                                                                                                                                                                            |                                                                                                                                                                                                                                                            |
clinical protocol
6.1.2.5 guidelines for management of

Guidelines for management of nail discoloration/loss/ridging (onycholysis/onychodystrophy) are provided in Table 8. Guidelines for the management of paronychia are provided in Table 9.  
PI: Michael T. Schweizer Protocol Version: 6.0 Protocol Number: Pending FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib
clinical protocol
- general prophylaxis

− Good hygienic practices, keep fingers and toes clean.  
− Keep nails trimmed
− Use gloves for housecleaning and gardening to minimize damage and prevent infection
− Nail polish and imitation fingernails should not be worn until the nails have grown out and returned to normal
− Wearing comfortable shoes (wide sized shoes with room for the toes)
− Trimming nails but avoiding aggressive manicuring Protocol Number: Pending FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib PI: Michael T. Schweizer Protocol Version: 6.0  
| Table 8:                             | Guidelines for Management of Nail Discoloration/Loss/Ridging (Onycholysis/  Onychodystrophy)                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
|--------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade                                | Study Drug Management                                                                                                                                                                                                                                                                                                     | SymptomManagement                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| Grade 1                              | Continue study drug at current dose.                                                                                                                                                                                                                                                                                      | - Continue general prophylaxis  recommendations - Over-the-counter nail strengthener OR polyurea urethane nail lacquer (Nuvail) OR  diethylene glycol monoethylether nail  lacquer (Genadur) daily. - Use non-alcohol-containing moisturizing  creams.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| Grade 2                              | Consider holding study drug with  reassessment in 1-2 weeks. If first occurrence and it resolves to  ≤Grade 1 or baseline within 2 weeks,  restart at same dose. If recurrent event or takes >2 weeks to  resolve to ≤Grade 1 or baseline, then  restart at 1 dose level below in  consultation with the medical monitor. | - Manage as per Grade 1 - For signs of infection (periungal edema/erythema/ tenderness or discharge), obtain bacterial cultures, and then start the following: o treatment with oral antibiotic for 2 weeks (cefadroxil 500 mg BID, ciprofloxacin 500 mg BID, or sulfamethoxazole/ trimethoprim BID) AND o topical antifungal lacquer daily for 6+ weeks (ciclopirox olamine 8% OR efinaconazole 10% OR amorolfine 5% weekly OR bifonazole/urea ointment daily) - Silver nitrate application weekly AND  topical antibiotics AND vinegar soaksa |
| Grade 3                              | Hold study drug, with reassessment in 1-2  weeks. When resolves to ≤Grade 1 or baseline, restart at 1 dose level below in consultation with the medical monitor.                                                                                                                                                          | Silver nitrate application weekly AND topical antibiotics AND vinegar soaks.a For signs of infection (periungal edema/erythema/ tenderness or discharge), obtain bacterial cultures, and then start the following: treatment with oral antibiotic for 2 weeks (cefadroxil 500 mg BID, ciprofloxacin 500 mg BID, or sulfamethoxazole/trimethoprim BID). For cases of severe/refractory infection consider intravenous antibiotics. Consider dermatological or surgical evaluation.                                                               |
| Grade 4                              | Discontinue study drug.                                                                                                                                                                                                                                                                                                   | Evaluation and therapy as clinically indicated.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| a                                    | Vinegar soaks consist of soaking fingers or toes in a solution of white vinegar in water 1:1 for 15 minutes every day. Examples of topical antibiotic ointments: Mupirocin 2%, gentamycin, bacitracin zinc/polymixin B.                                                                                                   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| BID=bis in die (two times each day). |                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |  
| Table 9:                                                                                                                                                                                                                 | Guidelines for Management of Paronychia                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade and Definition                                                                                                                                                                                                     | Study Drug Management                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | SymptomManagement                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| Grade 1: Nail fold edema or                                                                                                                                                                                              | Continue erdafitinib at current                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Topical antibiotics AND vinegar                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| erythema; disruption of the cuticle                                                                                                                                                                                      | dose.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | soaksa                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| Grade 2: Nail fold edema or erythema with pain; associated with discharge or nail plate separation; limiting instrumental ADL                                                                                            | Topical antibiotics AND vinegar soaksa AND topical antifungal lacquer daily for 6+ weeks (ciclopirox olamine 8% OR efinaconazole 10% OR amorolfine 5% weekly OR bifonazole/urea ointment daily) For signs of infection (periungal edema/erythema/tendernessand/or discharge), obtain bacterial cultures, and then start the following: treatment with oral antibiotic for 2 weeks (cefadroxil 500 mg BID, ciprofloxacin 500 mg BID, or sulfamethoxazole/ trimethoprim (Bactrim) DS BID). |                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| Grade 3: Limiting self-care ADLs, surgical intervention, or intravenous antibioticsindicated                                                                                                                             | Continue erdafitinib at current dose. Consider erdafitinib holding if no improvement in 1 to 2 weeks. When resolves to ≤Grade 1 or baseline, restart at same or 1 dose level below in consultation with the Sponsor-Investigator.                                                                                                                                                                                                                                                        | Vinegar soaksa AND consider nail avulsion For signs of infection (periungal edema/erythema/tendernessand/or discharge), obtain bacterial cultures, and then start the following: treatment with oral antibiotic for 2 weeks (cefadroxil 500 mg BID, ciprofloxacin 500 mg BID, or sulfamethoxazole/ trimethoprim (Bactrim) DS BID). For cases of severe/refractory infection consider intravenous antibiotics. Consider dermatological and/or surgical evaluation. |
| Grade 4: life-threatening consequences, urgent intervention indicated                                                                                                                                                    | Hold erdafitinib (for up to 28 days), with weekly reassessments of clinical condition. When resolves to ≤ grade 1 or base line, restart at one dose level below in consultation with the Sponsor-Investigator. Discontinue erdafitinib.                                                                                                                                                                                                                                                  | Evaluation and therapy as clinically indicated                                                                                                                                                                                                                                                                                                                                                                                                                    |
| a Vinegar soaks consist of soaking fingers or toes in a solution of white vinegar in water 1:1 for 15 minutes every day. Examples of topical antibiotic ointments: Mupirocin 2%, gentamycin, bacitracin zinc/polymixin B |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
clinical protocol
6.1.2.6 guidelines for eye exam

The baseline ophthalmological examinations must be performed by an ophthalmologist and should include assessment of visual acuity, slit lamp examination, fundoscopy (examination of both central and peripheral zones should be performed) and slit lamp biomicroscopy. An Optical Coherence Tomography (OCT) will also be performed at Screening. The ophthalmological test should be performed once during screening. The Amsler Grid test will also be administered by the treating physician or nurse as screening visit. Additional exams should be performed as clinically necessary based on the findings of the Amsler grid test and clinical assessment at regular intervals as deemed necessary by the screening ophthalmologist. When CSR/ retinal pigment epithelial detachments (RPED) is suspected then an OCT should be performed. Fluorescein angiography could be considered appropriate in conditions such as suspected Version Date: 17 September 2020 Protocol Number: Pending FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib retinal vein occlusion (RVO). It is also recommended that color fundus photos or OCT images be obtained and stored in the patient's file for future reference. In patients with suspected retinal pathology such as CSR or RVO a consultation with a retina specialist should be considered.
clinical protocol
assessment and evaluation plan for

- Patients that are yet to be consented should have a baseline ophthalmological exam including fundoscopy as described, prior to the first dose of study medication.  
- Additionally, an Amsler grid test should be performed at the beginning of every new cycle, end of treatment, and at follow up visits to identify any new abnormalities (observation of wavy, broken or distorted lines or a blurred or missing area of vision).  
- If the subject is asymptomatic and the Amsler grid test is negative, then continue study medication at current dose and schedule.  
- If the subject is asymptomatic and the Amsler grid test is positive (observation of wavy, broken or distorted lines or a blurred or missing area of vision) then the subject should have a full ophthalmological exam as described, within 7 days. If this is not possible then the study drug should be withheld until a full ophthalmological exam is performed.  
- If the subject has ocular abnormalities, manage as outlined below.
clinical protocol
subjects currently enrolled with no

- An Amsler grid test should be performed at the beginning of every new cycle, end of treatment and at follow up visits to identify any new abnormalities (observation of wavy, broken or distorted lines or a blurred or missing area of vision).  
- If the subject is asymptomatic and the Amsler grid test is negative, then continue study medication at the current dose and schedule.  
- If the subject is asymptomatic and the Amsler grid test is positive
(observation of wavy, broken or distorted lines or a blurred or missing area of vision) then the subject should have a full ophthalmological exam as described, within 7 days. If this is not possible then the study drug should be withheld until a full ophthalmological exam is performed.