clinical protocol
any subject with ocular symptoms

Subjects that have ocular symptoms at any time should be managed as per the guidelines in Table 10 and as outlined in the current version of the Investigator's Brochure. Additional modification to the type and or frequency of these exams could be made based on emerging data and/or in consultation with regulatory agencies. If and when such changes are made they will be communicated and incorporated into existing protocols.  
Protocol Number: Pending FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib PI: Michael T. Schweizer Protocol Version: 6.0 Protocol Number: Pending FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib  
| Table 10:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Guidelines for Management of Eye Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                    |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Definition                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Study Drug Management                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | SymptomManagement                                                                                                                                                                                                                                                                  |
| Asymptomatic or mild symptoms; clinical or diagnostic observations only                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Refer for an ophthalmologic examination. If an ophthalmologic exam cannot be performed within 7 days, withhold treatment of erdafitinib until an examination can be performed. If there is no evidence of eye toxicity on ophthalmologic examination, continue erdafitinib therapy at the same dose level. If diagnosis from ophthalmologic examination is keratitis or retinal abnormality such as central serous retinopathy (CSR)/ retinal pigment epithelial detachments (RPED), withhold erdafitinib until signs and symptoms have resolved. If toxicity is reversible (complete resolution or stabilization and asymptomatic) in 4 weeks according to ophthalmologic examination, resume erdafitinib therapy at the next lower dose level after consultation with the medical monitor.a Monitor for recurrence every 1 to 2 weeks for a month and as clinically appropriate thereafter. If there is no recurrence then re-escalation can be considered in consultation with the medical monitor.a | Refer the subject for an ophthalmologic examination. For retinal pathology perform OCT as appropriate and consider referral to a retinal specialist for further evaluation. Follow specific treatment per the ophthalmologist's recommendation.                                    |
| Or abnormal Amsler grid test Moderate; minimal, local symptoms Or noninvasive intervention indicated; limiting age appropriate instrumental ADL                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Immediately withhold erdafitinib therapy.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Refer subject to an ophthalmologist for evaluation with an ophthalmologic examination. For retinal pathology, perform OCT as appropriate and consider referral to a retinal specialist for further evaluation. Follow specific treatment per the ophthalmologist's recommendation. |
| If there is no evidence of drug-related corneal or retinal pathology on ophthalmologic examination, withhold erdafitinib until signs and symptoms have resolved. Resume erdafitinib therapy at the next lower dose level. If diagnosis from ophthalmologic examination is keratitis or retinal abnormality such as CSR/RPED, withhold erdafitinib until signs and symptoms have resolved, stabilized, or subject is lost to follow-up or withdraws consent (which ever happens first). If toxicity is reversible (complete resolution or stabilization and asymptomatic) within 4 weeks according to ophthalmologic examination, resume erdafitinib therapy at the next lower dose level after consultation with the medical monitor. Retinal pigment epithelial detachment, if observed, should  be monitored at approximately 2-3-week intervals until  resolution.  Monitor for recurrence every 1 to 2 weeks for a month and  as clinically appropriate thereafter. If there is no recurrence,  then re-escalation can be considered in consultation with  the medical monitor. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                                                    |
| Severe or medically significant but not immediate sight-threatening symptoms; hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self-care ADL                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Report as a serious adverse event and immediately withhold erdafitinib therapy. If toxicity is not reversible, permanently discontinue erdafitinib. If however the toxicity is reversible (complete resolution or stabilization and asymptomatic) within 4 weeks and the subject is having clinical benefit, and the investigator and the Sponsor-Investigator agree that restarting drug is in the best interest of the subject, then erdafitinib therapy may be resumed at 2 dose levels lower if appropriate. Monitor for recurrence using appropriate investigations every 1 to 2 weeks for a month and as clinically appropriate thereafter. For cases of recurrence consider permanent discontinuation.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Refer subject to an ophthalmologist for evaluation with an ophthalmologic examination. For retinal pathology, perform OCT as appropriate and consider referral to a retinal specialist for further evaluation. Follow specific treatment per the ophthalmologist's recommendation  |  
| JNJ-42756493 Erdafitinib Table 10: Guidelines for Management of Eye Toxicity Definition Study Drug Management                                                                                                                                                                                                                                                                      | SymptomManagement                                                                                                                                                   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Symptoms with sightthreatening consequences; urgent intervention indicated; blindness (20/200 or worse) in the affected eye                                                                                                                                                                                                                                                                                                                                                                                    | Promptly refer subject to an ophthalmologist for evaluation with an ophthalmologic examination. Follow specific treatment per the ophthalmologist's recommendation. |
| Eye toxicities should be graded according to NCI-CTCAE. ADL=Activities of Daily Living, OCT= Optical Coherence Tomography Permanently discontinue treatment with erdafitinib . Report as a serious adverse event and monitor resolution of the event until complete resolution, stabilization or the subject is lost to follow-up or withdraws consent (which ever happens first). |                                                                                                                                                                     |
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6.1.2.7 guidelines for the management

- General **considerations:** Avoid unnecessary exposure to sunlight, use sunglasses in bright light.  
- **Prophylactic management:** Frequent use of artificial tear substitutes is strongly recommended.  
- Reactive **management**:  
− Withhold erdafitinib for Grade 3 toxicity − Artificial tear substitutes if not started, every 4 to 6 hours
− Hydrating /lubricating eye gels and ointments − Severe treatment-related dry eye should be evaluated by an ophthalmologist
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6.2. enzalutamide

Enzalutamide is administered in capsules containing 40 mg of enzalutamide. It will be administered at the FDA approved dose of 160 mg (4 capsules) by mouth daily. Enzalutamide doses should be taken as close as possible to the same time each day. Subjects will take 4 capsules of enzalutamide once daily.
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6.2.1. dose modifications

Patients who experience a Grade 3 or greater toxicity deemed at least possibly related to enzalutamide that cannot be ameliorated by the use of adequate medical intervention should have their treatment interrupted until the toxicity improves to a Grade 2 or lower severity. The exception will be non-clinically significant AEs such as hot flashes. Patients may subsequently be re-started on study drug, including at a reduced dose of 120 mg (3 tablets) by mouth daily will be allowed with approval by the sponsor-investigator.
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6.3. abiraterone acetate

Abiraterone acetate is administered in 250 mg tablets. It will be administered at the FDA approved dose of 1000 mg (4 tablets) by mouth daily. Systemic exposure of abiraterone acetate is increased when administered with food, with an approximate 7- and 5-fold increase in the Cmax and AUC respectively when given with a low-fat meal. When given with a fatty meal, the Cmax and AUC increased 17- and 10-fold respectively. Given this variation, no food should be consumed at least 2 hours before and one hour after taking abiraterone acetate. Abiraterone acetate is associated with symptoms of mineralocorticoid excess, and should be taken concurrently with prednisone 5 mg by mouth twice daily to blunt these side effects. Abiraterone Protocol Number: Pending FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib PI: Michael T. Schweizer Protocol Version: 6.0 acetate doses should be taken as close as possible to the same time each day. Subjects will take 4 tablets of abiraterone acetate once daily.
clinical protocol
6.3.1. dose modifications for lft

Dose modifications are provided as guidance and should not replace the investigator's own clinical judgment.  
| clinical judgment. Toxicity Dose of abiraterone acetate                                      | Dose of prednisone   |           |
|----------------------------------------------------------------------------------------------|----------------------|-----------|
| Grade 1                                                                                      | No change            | No change |
| Hold until return to Grade 1 or baseline, resume after discussion                            | No change            |           |
| and agreement with the SponsorInvestigator *                                                                                              |                      |           |
| Grade 2                                                                                      |                      |           |
| ≥Grade 3                                                                                     | Discontinue          | Taper off |
| *Note: Treatment will be permanently discontinued for Grade 3 toxicity lasting longer than 5 |                      |           |  
*Note: Treatment will be permanently discontinued for Grade 3 toxicity lasting longer than 5 days, or any grade toxicity that has not resolved to Grade 1 or less within 2 weeks
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6.3.2. dose modifications for hypokalemia

Dose modifications are provided as guidance and should not replace the investigator's own clinical judgment.  
| Toxicity                                                                                     | Dose of abiraterone acetate                                                                         | Dose of prednisone   |
|----------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------|----------------------|
| Initiate oral potassium                                                                      |                                                                                                     |                      |
| supplementation, titrate to                                                                  |                                                                                                     |                      |
| ≥3.5 to ≤5.0 mmol/L, maintenance at ≥4.0 mmol/L recommended*                                 | No change                                                                                           |                      |
| Grade 1 or 2                                                                                 | Hold and initiate IV potassium and cardiac monitoring, resume only after discussion and approval by | No change            |
| the Sponsor-Investigator *                                                                   |                                                                                                     |                      |
| ≥Grade 3  Recurrence ≥Grade 3, or Grade 4                                                    | Discontinue                                                                                         | Taper off            |
| *Note: Treatment will be permanently discontinued for Grade 3 toxicity lasting longer than 5 |                                                                                                     |                      |  
*Note: Treatment will be permanently discontinued for Grade 3 toxicity lasting longer than 5 days, or any grade toxicity that has not resolved to Grade 1 or less within 2 weeks. Subjects will  
PI: Michael T. Schweizer Protocol Version: 6.0 Protocol Number: CC10288 FGFR Inhibition in DNPC JNJ-42756493 Erdafitinib be allowed to resume/continue treatment if serum potassium level is maintained ≥3.5 to ≤5.0 mmol/L with oral potassium supplementation.
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6.3.3. dose modifications for hypertension

| clinical judgment. Toxicity Dose of abiraterone acetate                                      | Dose of prednisone                                             |           |
|----------------------------------------------------------------------------------------------|----------------------------------------------------------------|-----------|
| Grade 1                                                                                      | No change                                                      | No change |
| Grade 2                                                                                      | Hold until return to Grade 1 or baseline, resume at full dose* | No change |
| Hold until Grade 1 or baseline,                                                              |                                                                |           |
| ≥Grade 3                                                                                     | resume at full dose*                                           | No change |
| Recurrence ≥Grade 3, or                                                                      | Discontinue                                                    | Taper off |
| Grade 4                                                                                      |                                                                |           |
| *Note: Treatment will be permanently discontinued for Grade 3 toxicity lasting longer than 5 |                                                                |           |  
*Note: Treatment will be permanently discontinued for Grade 3 toxicity lasting longer than 5 days, or any grade toxicity that has not resolved to Grade 1 or less within 2 weeks.
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7 treatment compliance

The investigator or designated study personnel will maintain a log of the amount of study drug dispensed and returned. Drug supplies will be inventoried and accounted for throughout the study. Subjects will receive instructions on compliance with study treatment at the screening visit. A drug diary (Appendix 3) will be given to the subject to record date and time of drug intake at home. During the course of the study, the investigator or designated study research staff will be responsible for providing additional instruction to reeducate any subject who is not compliant with the study drug schedule.
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8 concomitant therapy

Concomitant therapies are to be recorded at the time of screening (within 30 days prior to the first dose of study drug), throughout the study, and up to 30 days after the last dose of study drug in the appropriate section of the CRF. All therapies (prescriptions or over the counter medications) continued at the start of the study or started during the study and different from the study drug must be documented in the concomitant therapy section of the CRF. Caution should be exerted for subjects taking anti-coagulant therapies. Frequent monitoring for international normalized ratio (INR) is allowed at the treating physician's discretion. The Sponsor Investigator must be notified in advance, or as soon as possible thereafter, of any instances where prohibited medications are administered.
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8.1 permitted medications

Throughout the study, investigators may prescribe concomitant medications or treatments (including nutritional support, correction of metabolic disorders, optimal symptom control, and pain management) deemed necessary to provide adequate supportive care. Concurrent use of hormones for non-cancer related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable. Permitted medications are to be recorded at the time of screening (within 30 days prior to the first dose of study drug), throughout the study, and up to 30 days after the last dose of study drug in the appropriate section of the eCRF. In addition, the following medications may be administered during the study:  
- Standard supportive care therapies (antiemetics, antidiarrheals, anticholinergics, antispasmodics, antipyretics, antihistamines, analgesics, antibiotics and other antimicrobials, histamine receptor [H2] antagonists or proton pump inhibitors, and other medications intended to treat symptoms or signs of disease) as clinically indicated, according to institutional standards and as deemed necessary by the investigator.  
- Documented infectious complication should be treated with oral or IV antibiotics or other anti-infective agents as considered appropriate by the treating investigator for a given infectious condition, according to standard institutional practice.  
- Growth factor support for the management of treatment-emergent hematological toxicity as recommended according to National Comprehensive Cancer Network/European Organization for Research and Treatment of Cancer (NCCN/EORTC) guidelines.  
- Palliative radiotherapy: Localized radiotherapy for symptomatic control is permitted, but should not include definitive radiation to target lesions.  
- Chronic supportive therapies: Ongoing bisphosphonates and denosumab or other supportive therapies are permitted..
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8.2 prohibited medications

The following concomitant medications are prohibited during the study. The Sponsor-Investigator must be notified in advance, or as soon as possible thereafter, of any instances in which prohibited therapies were administered.  
- Concurrent investigational agents - Medications known to increase serum levels of calcium (thiazide diuretics, vitamin A
supplements, vitamin D supplements, calcium dietary supplements, calcium antacids, lithium, estrogens, anti-estrogens). Vitamin D and calcium supplements may be given if clinically indicated (in the setting of low serum vitamin D and calcium levels). Medications known to have calcium as an excipient should be avoided unless no alternatives exist.  
- Medications known to increase serum levels of phosphate, such as potassium phosphate supplements (oral or IV), vitamin D supplements, antacids, and phosphate-containing enemas and laxatives (oral/rectal) thought to increase serum phosphate levels. Medications known to have phosphate as an excipient should be avoided unless no alternatives exist.
The following precautions are advised for subjects receiving erdafitinib:
- Based on in vitro data, erdafitinib is metabolized by cytochrome CYP2C9 and CYP3A4. A
clinical drug-drug interaction study showed that on average, erdafitinib exposure (Cmax and AUC) was increased 5-34% when co-administered with itraconazole (a strong inhibitor of CYP3A4) and 21-49% when co-administered with fluconazole (a moderate inhibitor of CYP2C9). For this reason, strong CYP3A4 and moderate CYP2C9 inhibitors should be used with caution (see Attachment 5). Consider alternative therapies that are not strong inhibitors of CYP3A4 or moderate inhibitors of CYP2C9 during treatment with erdafitinib. If co administration of these drugs is unavoidable, monitor the subject closely for adverse reactions and consider dose modifications accordingly. If the strong inhibitor of CYP3A or moderate inhibitor of CYP2C9 is discontinued, the erdafitinib dose may be increased in the absence of drug-related toxicity
- The impact of moderate to strong inducers of CYP3A4 and CYP2C9 (such as rifampin) on erdafitinib was not clinically studied. Caution should be exercised for concomitant administration of erdafitinib and CYP inducers (see Attachment 5)
- Erdafitinib was shown to inhibit, in in vitro experiments, human P-glycoprotein (P-gp) at concentrations achieved at therapeutic doses in humans. If the compound is administered with drugs that are substrates of P-gp, there is the potential for observing increased concentrations of the substrate drug. Therefore, caution should be exercised for co administered drugs that are P-gp substrates, such as digoxin, dabigatran, and fexofenadine (https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf); in addition, drugs with a narrow therapeutic index should only be used where the benefit outweighs the potential risk
- For subjects taking erdafitinib: medications known to increase serum levels of phosphate, such as potassium phosphate supplements (oral or IV), vitamin D supplements, antacids, and phosphate-containing enemas and laxatives (oral/rectal) thought to increase serum phosphate levels. Caution should be exercised considering the risk benefit ratio, and more frequent monitoring of phosphate levels during treatment with medications known to increase the serum level of phosphate put in place
- Concomitant use of medications that are known strong inducers of CYP3A4 is to be avoided with erdafitinib
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9 study evaluations 9.1 study

The Time and Events Schedule summarizes the frequency and timing of safety, efficacy, biomarker, and other measurements applicable to this study. The number of blood samples and volume of blood that will be required from each subject for the various study procedures is outlined in the Laboratory Manual. The number of samples and the blood volume will vary depending on the number of cycles of the study drug that the subject receives. Unscheduled blood samples may be required for safety issues of individual subjects The maximum research blood volume to be collected from each subject will be approximately 40 mL at any given timepoint.
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9.1.2 screening phase

The Study Screening Period is 30 days before the first dose of study medication. Subjects must meet all of the inclusion and none of the exclusion criteria in Section 4. All information required for determining eligibility must be available prior to C1D1. Retesting of abnormal laboratory values that may lead to exclusion will be allowed once. Retesting will take place during an unscheduled visit in the screening phase. The following procedures will occur during the Study Screening Period:  
1. Comprehensive medical history and physical exam, including height and weight, medications, blood pressure and heart rate 2. ECOG performance status assessment 3. Ophthalmic examination 4. PSA (Prostate-specific antigen) 5. CBC (Complete blood count) with differential 6. CMP (Comprehensive Metabolic Panel - Sodium, Potassium, Chloride, BUN, Serum Creatinine, Calcium, Total Protein, Albumin, Total Bilirubin, AST, ALT, Alkaline Phosphatase, CO2)
7. Serum testosterone 8. Phosphate level 9. PT/INR and PTT
10. Radiographic assessments: CT chest/abdomen/pelvis and Bone scan 11. Electrocardiogram (EKG)  
12. Pathologic evaluation of tumor tissue acquired at any time to assess for DNPC phenotype in patients who have only progressed on one AR-directed therapy and not previously treated with taxane chemotherapy (see Section 9.2.1.1). Note: metastatic biopsy obtained within 8 weeks of enrollment is preferred.
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9.1.3 treatment phase

Assessments must be done within ±7 days of the specified time point unless indicated otherwise. All procedures are to be completed on Day 1 of each cycle unless otherwise noted.  
1. Comprehensive medical history and physical exam, including weight, medications, blood pressure and heart rate 2. ECOG performance status assessment
Version Date: 17 September 2020 Protocol Number: CC10288 FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib  
3. PSA (Prostate-specific antigen) [to be completed after every 3 cycles (e.g. C4D1, C7D1, C10D1, etc)].  
4. CBC (Complete blood count) with differential 5. CMP (Comprehensive Metabolic Panel - Sodium, Potassium, Chloride, BUN, Serum Creatinine, Calcium, Total Protein, Albumin, Total Bilirubin, AST, ALT, Alkaline Phosphatase, CO2)
6. Phosphate level [Day 1 of each cycle AND on C1D14 ±2 days] 7. Radiographic assessments: CT chest/abdomen/pelvis and Bone scan [to be completed after every 3 cycles (e.g. C4D1, C7D1, C10D1, etc)].  
8. Correlative blood draw [C1D1 and C4D1]
clinical protocol
9.1.4 end of treatment

Assessments must be done within ±14 days of the specified time point unless indicated otherwise. All procedures are to be completed on Day 1 of each cycle unless otherwise noted. Procedures need not be repeated if done within the past 14 days.  
1. Comprehensive medical history and physical exam, including weight, medications, blood pressure and heart rate 2. ECOG performance status assessment 3. PSA (Prostate-specific antigen) 4. CBC (Complete blood count) with differential 5. CMP (Comprehensive Metabolic Panel - Sodium, Potassium, Chloride, BUN, Serum Creatinine, Calcium, Total Protein, Albumin, Total Bilirubin, AST, ALT, Alkaline Phosphatase, CO2)
6. Phosphate level 7. Radiographic assessments: CT chest/abdomen/pelvis and Bone scan 8. Correlative blood draw 9. Metastatic research biopsy. Will only be obtained if feasible (i.e. safe and amenable metastatic lesion).
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9.2 efficacy evaluations

Disease assessments will be performed according to the Time and Events Schedule. Assessment of responses for solid tumors will be performed according to RECIST (version 1.1) by Protocol Number: CC10288 FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib PI: Michael T. Schweizer Protocol Version: 6.0 investigators. For subjects who discontinue study drug before disease progression, tumor assessments should continue as described in Section 9.1.3. More frequent radiological assessments are allowed, if clinically indicated/desirable. Identical methodology should be used for disease assessment at baseline, and throughout the course of the study, to characterize each identified and reported lesion to document disease status. Patients will ideally undergo CT and bone scans to assess for radiographic progression; however, MRI may substitute the CT scan with approval of the sponsor-investigator. Ultrasound, fluorine 18fluorodeoxyglucose positron emission tomography (FDG-PET), and plain x-rays are not acceptable methods of evaluating disease response in the absence of CT or MRI scans. If symptomatic deterioration (on the basis of global deterioration of health status) occurs without documentation of radiographic progression, the clinical findings used to make this determination must be specified in the eCRF and documented in the source documents. Every effort should be made to document the objective progression even after discontinuation of treatment for symptomatic deterioration. Tumor response will be reported by the investigator in the eCRF.
clinical protocol
9.2.1. evaluations 9.2.1.1 pathologic assessment

It is well recognized that in the late stages of prostate cancer, dependency on AR-signaling is often lost, with ~10% tumors trans-differentiating into small cell/NE variants36,37. Recognizing the presence of small cell prostate cancer is imperative, as standard of care for these cases involves platinum-doublet chemotherapy akin to the regimens used to treatsmall cell lung cancer37,38.Clinical criteria to identify these cases, include: visceral metastases only, predominately lytic bone lesions, bulky lymphadenopathy, bulky high-grade prostatic or pelvic mass, low PSA level, neuroendocrine markers in serum and short interval to developing CRPC36,37. Given that many of these clinical features are expected to overlap with those of DNPC, it is recommended that the treating physician obtain a standard of care metastatic biopsy prior to enrollment to rule out predominate small cell/NE prostate cancer. Pathologic assessment during screening will involve IHC for AR or proteins that are regulated by AR-signaling (e.g. PSA, NKX3.1, etc.) and a NE marker (e.g. synaptophysin, INSM1, chromogranin, etc.). We will utilize a composite score for AR/AR regulated proteins and NE marker expression to define DNPC. This composite score will be calculated as follows: AR/AR regulated protein or NE marker composite expression score = (Percentage of *nuclear* AR/AR regulated protein or NE marker positive cells) x (Intensity of staining, where *1=low* intensity, 2=moderate intensity and 3=high *intensity)* We will define AR/AR regulated protein negative as a score <40 and NE marker negative as a score <10. These cutoffs were selected based on prior experience from our rapid autopsy program. Of 73 AR+ cases, only 3 had AR composite expression scores <40. Similarly, 0 of 5 NE/small cell cases had synaptophysin scores <10. These cut offs were selected to avoid being overly stringent in defining the study population given that we have observed heterogeneity acrosstumors from rapid autopsy patients, with at least one case demonstrating a NE tumor in one location and a DNPC in the other24. Patients with evidence of small cell morphology on biopsy will be excluded.  
Protocol Number: CC10288 FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib PI: Michael T. Schweizer Protocol Version: 6.0 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 DNPC5,39.  
Given that intra/inter-tumoral phenotypic heterogeneity is increasingly recognized in late stage prostate cancer, and that FGFR inhibition plays an important role in mediating lineage plasticity in this clinical context, we will not require histologic confirmation of DNPC in late stage prostate cancer19-22. Patients who have previously progressed on two next-generation AR-directed therapies
(e.g. abiraterone, enzalutamide) AND at least one prior taxane will not be required to undergo histologic assessment to determine eligibility. However, metastatic biopsy should be performed if there is clinical suspicion for a small cell/NE variant as outlined above.
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9.2.1.2. recist assessment of disease

RECIST 1.1 is an accepted methodology by regulatory authorities. RECIST 1.1 will be applied by the investigator as the primary measure for assessment of tumor response, date of disease progression, and as a basis for all protocol guidelines related to disease status (e.g., discontinuation of study therapy). After screening, imaging will be repeated during the study as indicated in the Time and Events Schedule.
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9.2.1.3. radiographic images assessment

Bone scan and Computed tomography (CT) scans of the chest, abdomen, pelvis, and any other location where disease is present will be performed at Screening. During the study, disease response will be assessed using bone scan and CT scans of the locations of known disease. Magnetic resonance imaging may be used to evaluate sites of disease that cannot be adequately imaged using CT (in cases where MRI is desirable, the MRI must be obtained at baseline and at all subsequent response evaluations or in cases where use of CT scan is clinically contraindicated). For all other sites of disease, MRI studies do not replace the required chest, abdomen, and pelvic CT scans. Brain MRI and lumbar puncture are required, only if clinically indicated. Imaging should not be delayed due to delays in cycle starts or extension of cycle intervals. After disease progression is documented, subjects will be monitored as outlined in Section 9.1.4.  
If the site study team makes an initial assessment of disease progression, and if the subject is clinically stable, treatment may be continued if the investigator and sponsor-investigator agree that continuation of treatment is in the best interest of the subject considering the terminal nature of the underlying disease, he/she may receive study treatments until such time as the treating physician and the sponsor-investigator agree that further continuation of treatment is no longer beneficial to the subject or he has completed two years of treatment total, whichever comes first.
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9.3. correlative research

This study will also include a number of correlative studies aimed at identifying candidate biomarkers for response/resistance to FGFR inhibitor therapy. We will evaluate pre- and posttreatment tissue as well as serial blood samples in order to develop blood-based biomarkers for response/resistance to erdafitinib. 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 Version Date: 17 September 2020 blood samples. Biospecimen samples (e.g., blood, tumor tissue) will be stored for up to five years following the completion of this study and any unused samples will be destroyed at the end of this time period.  
Samples will be stored at University of Washington and/or Fred Hutchinson Cancer Research Center, and the Sponsor-Investigator will oversee access to biospecimens. In order to protect the identity of study subjects, all biospecimen samples will be labeled with a subject-specific study ID code. Samples will be analyzed at University of Washington and/or Fred Hutchinson Cancer Research Institute. Biospecimens will used for research pertaining to this clinical study only.
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next-generation sequencing

Patients will undergo next-generation sequencing (NGS) using UW-OncoPlex, a comprehensive whole gene NGS panel that has been validated for use on tumor tissue and cell-free circulating tumor DNA (ctDNA)40. A research-based sequencing assay may also be utilized in order to evaluate for mutations in genes not covered by UW-OncoPlex. Sequencing studies will be prioritized for patients that have demonstrated a clinical response to treatment.
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transcript profiling studies

Transcript profiling studies (e.g. RNA-seq, NanoString) will be performed 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 treatment41,42. We may also perform circulating tumor cell (CTC)-based transcript profiling studies using AdnaTest and multiplex qPCR or another blood-based transcript profiling assay..
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protein expression studies

Protein expression studies at baseline and at the time of progression, including IHC for AR, PSA, phospho-FRS2 (a downstream target of the FGF8 cognate receptors: FGFR1IIIc and FGFR2IIIc) and phosphor-FGFR. Additional protein expression studies may be added depending on the results of NGS and transcript profiling studies.
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9.4. safety evaluations

Safety assessments will be based on medical review of adverse event reports and the results of vital sign measurements, physical examinations, clinical laboratory tests, ECOG performance status, ophthalmic examinations, and other safety evaluations at specified time points as described in the Time and Events Schedule. Any clinically significant abnormalities or toxicities persisting at the end of the study will be followed by the investigator until resolution or until reaching a clinically stable endpoint. For adverse events such as skin/nail and mucosal toxicity, upon subject consent, photographs may be taken for assessment and monitoring of the toxicity.
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9.4.1. adverse events

Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the subject's legally acceptable representative) for the duration of the study. The incidence of adverse events will be tabulated and reviewed for potential significance and clinical importance. Adverse events will be graded according the NCI-CTCAE, Version 4.0. Adverse events will be Protocol Number: CC10288 FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib followed by the investigator as specified in Section 11, Adverse Event Reporting.
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9.4.2. clinical laboratory tests

Blood samples for serum chemistry and hematology will be collected according to the Time and Events Schedule. More frequent clinical laboratory tests may be performed, as indicated by the overall clinical condition of the subject and for abnormalities that warrant more frequent monitoring. The investigator must review the laboratory report, document this review, and record any clinically relevant changes occurring during the study in the adverse event section of the eCRF. Laboratory test results completed on Cycle 1 Day 1 should be reviewed prior to dosing and subjects should continue to meet eligibility requirements per the Inclusion/Exclusion criteria. The following tests will be performed:
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serum chemistry panel

-sodium -chloride -blood urea nitrogen -glucose  
-potassium -bicarbonate (CO2)  
-creatinine -phosphate -albumin -total protein -alanine aminotransferase (ALT) -direct bilirubin -aspartate aminotransferase (AST) -total bilirubin -alkaline phosphatase
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9.4.4. electrocardiogram

Screening electrocardiograms, to be used to determine subject eligibility, will be performed at the study site. The subject should rest in a supine position for at least 5 minutes before ECG recording, and should refrain from talking or moving arms or legs. Triplicate ECGs should be performed with 5 minute intervals between each assessment. At least 1 printout should be produced and stored in the subject's source documents. The 12-lead ECG recorder device used should have been recently serviced and calibrated. The following variables should be measured: heart rate, RR, QT, PR, QRS, QTc (Fridericia) intervals. QTcF (Fridericia) will be used for assessment of QTc interval. The investigator will comment on the clinical relevance and document this in the eCRF (along with details of clinically significant findings).
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9.4.5. ophthalmic examination

All subjects should have an ophthalmological examination performed at Screening by an Version Date: 17 September 2020 Protocol Number: CC10288 FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib PI: Michael T. Schweizer Protocol Version: 6.0 ophthalmologist, which should include assessment of visual acuity, tonometry, fundoscopy (examination of both central and peripheral zones should be performed) and an Amsler Grid test; where available, an Optical Coherence Tomography (OCT) should be performed. A follow-up examination should be performed as clinically necessary based on the findings of the Amsler grid tests and clinical assessment.  
When Central Serous Retinopathy (CSR)/Retinal Pigment Epithelial Detachments (RPED) is suspected, an OCT should be performed. Fluorescein angiography could be considered appropriate in conditions such as suspected Retinal Vein Occlusion (RVO). It is also recommended that color Protocol Number: CC10288 FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib PI: Michael T. Schweizer Protocol Version: 6.0 fundus photos or OCT images be obtained and stored in the subject's records for future reference.  
In subjects with suspected retinal pathology such as CSR or RVO, a consultation with a retina specialist should be considered. Amsler grid testing will be administered by the treating physician or nurse at timepoints according to the Time and Events Schedule. Observation of wavy, broken or distorted lines, or a blurred/missing area of vision is equivalent to a positive Amsler grid test. For any positive Amsler grid test, subject should be referred for full ophthalmologic exam within 7 days. However, if the subject has an abnormal Amsler grid test at baseline (during Screening), then a repeat ophthalmic examination would be recommended only if, in the opinion of the investigator, there is a likelihood of significant change from the subject's baseline Amsler Grid test at Screening, or the subject has developed new clinical symptoms.
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9.4.6. vital signs

Blood pressure (systolic and diastolic), heart rate, and oral or tympanic temperature will be assessed. Abnormalities will be recorded as AEs
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9.4.7. physical examination

A full physical examination, including height, and weight will be performed at screening. Targeted physical examinations of involved organs, and including weight, will be performed at subsequent visits as listed in the Time and Events Schedule. New abnormalities will be recorded as AEs.
clinical protocol
9.4.8. ecog performance status

Eastern Cooperative Oncology Group performance status score will be determined at pre-specified time points listed in the Time and Events Schedule. Eastern Cooperative Oncology Group scoring information is provided in Appendix 1.
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9.5. sample collection and handling

The actual dates and times of sample collection must be recorded in the laboratory requisition form/source documentation. Refer to the Time and Events Schedules for the timing and frequency of all sample collections. Instructions for the collection, handling, and shipment of samples are found in the Laboratory Manual.
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10 subject completion/discontinuation of study

A subject will be considered as having completed the study if he or she has died during the study or has not been withdrawn from the study by the end of the study.
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discontinuation of study treatment

A subject who discontinues study treatment will continue to participate in the study for follow-up of survival status, resolution of any ongoing AEs, and disease assessments if treatment discontinuation occurs before disease progression. A subject's study treatment must be discontinued if:
- The investigator believes that for safety reasons or tolerability reasons (e.g., adverse event) it is in the best interest of the subject to discontinue study treatment  
- Disease progression
− Exception: if the investigator and sponsor-investigator agree that continuation of treatment is in the best interest of the subject considering the terminal nature of the underlying disease, he may receive erdafitinib until such time as the treating physician and the sponsor-investigator agree that further continuation of treatment is no longer beneficial to the subject.  
- The subject refuses further treatment with the study drug - The Sponsor-Investigator terminates the study - Investigator decision approved by the sponsor
If a subject discontinues treatment, an End-of-Treatment visit should be conducted within 30 days of the subject's last dose of study drug. The primary reason for treatment discontinuation will be clearly documented in the subject's medical record and recorded in the eCRF. Once a subject discontinues treatment with the study drug, the subject will not be permitted to be retreated.  
If a subject discontinues study treatment for any reason before the end of the treatment phase, posttreatment assessments should be obtained and scheduled assessments should be continued.
clinical protocol
withdrawal from the study

A subject will be withdrawn from the study for any of the following reasons:  
- Lost to follow-up
- Withdrawal of consent
If a subject discontinues study drug and withdraws from the study before the end of the treatment period, all post-treatment assessments should be obtained. If a subject is lost to follow-up, every reasonable effort must be made by the study-site personnel to contact the subject and determine the reason for discontinuation/withdrawal. The measures taken to follow up must be documented. When a subject withdraws consent before completing the study, the reason for withdrawal is to be documented in the CRF and in the source document. In addition, subjects who withdraw consent must complete and sign a withdrawal of consent form to specify if they agree to have survival data collected or not. Study drug assigned to the withdrawn subject may not be assigned to another Protocol Number: CC10288 FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib PI: Michael T. Schweizer Protocol Version: 6.0 subject. Subjects may be replaced only if the subject withdrew prior to the study drug administration.
clinical protocol
10.3. withdrawal from the use

The subject may withdraw consent for use of samples for research. In such a case, samples will be destroyed after they are no longer needed for the clinical study. Details of the sample retention for research are presented in the main ICF.
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11 data monitoring and adverse

Institutional support of trial monitoring will be in accordance with the FHCRC/University of Washington Cancer Consortium Institutional Data and Safety Monitoring Plan. Under the provisions of this plan, FHCRC Clinical Research Support coordinates data and compliance monitoring conducted by consultants, contract research organizations, or FHCRC employees unaffiliated with the conduct of the study. Independent monitoring visits occur at specified intervals determined by the assessed risk level of the study and the findings of previous visits per the institutional DSMP. In addition, protocols are reviewed at least annually and as needed by the Consortium Data and Safety Monitoring Committee (DSMC), FHCRC Scientific Review Committee (SRC) and the FHCRC/University of Washington Cancer Consortium Institutional Review Board (IRB). The review committees evaluate accrual, adverse events, stopping rules, and adherence to the applicable data and safety monitoring plan for studies actively enrolling or treating patients. The IRB reviews the study progress and safety information to assess continued acceptability of the risk-benefit ratio for human subjects. Approval of committees as applicable is necessary to continue the study. The trial will comply with the standard guidelines set forth by these regulatory committees and other institutional, state and federal guidelines. Additionally, scheduled meetings will take place weekly and will include the Sponsor Investigator (Michael Schweizer, MD), research nurse, data manager, and, when appropriate, the collaborators, sub-investigators, and biostatistician involved with the conduct of the protocol. During these meetings the investigators will discuss matters related to: safety of protocol participants, validity and integrity of the data, enrollment rate relative to expectation, characteristics of participants, retention of participants, adherence to protocol (potential or real protocol violations), data completeness, and progress of data for secondary objectives. If ≥3 out of the first 10 subjects enrolled are removed from the study due to a safety issue, the trial will terminate prematurely. Depending on the number of patients removed from the study due to safety issues, study accrual may have to be put on hold until the 10th subject has completed at least one treatment cycle. For example, if 2 subjects were removed for safety reasons prior to accruing the 10th subject, accrual would not continue until the 10th subject completes the first cycle. Safety issues will be continually monitored and safety oversight will be provided through the weekly meetings between the PI and relevant staff.
clinical protocol
11.1 management of safety data

As the Sponsor-Investigator of the Study, Dr. Michael T. Schweizer shall be solely responsible for complying with required timelines, any safety-reporting obligation to competent Health Authorities, IRB/ECs and any participating (co or sub) investigators, as defined in applicable laws and regulations. This Study has been designated as an interventional study. As such, all adverse events, special situations including pregnancies and product quality complaints will be reported from the time a subject has signed and dated an Informed Consent Form (ICF) until 30 days after the last documented use of the product under study within the study. All subsequent AEs and SAEs will be collected after this period if the Principal Investigator considers the AE/SAE to be causallyrelated to the use of the study drug. For the purposes of this study, the J&J medicinal product(s) are: Balversa (erdafitinib (JNJ42756493) and Zytiga (abiraterone acetate).
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11.2 definitions adverse event (ae)

An adverse event is any untoward medical occurrence in a clinical study subject administered a medicinal (investigational or non-investigational) product. An adverse event does not necessarily have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non- investigational) product, whether or not related to that medicinal (investigational or non-investigational) product. (Definition per International Conference on Harmonisation [ICH]) This includes any occurrence that is new in onset or aggravated in severity or frequency from the baseline condition, or abnormal results of diagnostic procedures, including laboratory test abnormalities.
clinical protocol
adverse events of special interest

Adverse events of special interest are events that Janssen Research & Development is actively monitoring as a result of a previously identified signal (even if non-serious). For erdafitinib, the adverse events of special interest are:  
- Central Serous Retinopathy: including PTs of retinal detachment, chorioretinopathy, detachment of retinal pigment epithelium, retinopathy, vitreous detachment, retinal edema, detachment of macular retinal pigment epithelium
There are no adverse events of special interest for abiraterone acetate.
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individual case safety report (icsr)

A valid ICSR must contain the four minimum criteria required to meet regulatory reporting Version Date: 17 September 2020  
requirements.  
- an identifiable subject (but not disclosing personal information such as the subject's name, initials or address)
- an identifiable reporter (investigational site)
- The name of the investigational product (i.e. erdafitinib, abiraterone acetate and/or enzalutamide)
- an adverse event, outcome, or certain special situations
The minimum information required is:
- date of therapy (start and end date, if available)  
- batch or lot number, if available
- Suspected J&J medicinal product (doses, indication) - subject details (subject ID and country) - age at AE onset
- reporter ID - adverse event detail (AE verbatim in English), onset date, relatedness, causality, action taken, outcome, (if available)
- J&J protocol ID
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adverse drug reaction (adr)

A noxious and unintended response to any dose of the drug (or biological) product for which there is a reasonable possibility that the product cause the response. ''Reasonable possibility'' means there is evidence to suggest a causal relationship between the drug and the adverse event. Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug.
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product quality complaint (pqc)

A product quality compliant is defined as any suspicion of a product defect related to a potential quality issue during manufacturing, packaging, release testing, stability monitoring, dose preparation, storage or distribution of the product, or delivery system. Not all PQCs involve a subject. Lot and batch numbers are of high significance and need to be collected whenever available. Examples of PQC include but not limited to:  
- Functional Problem: e.g., altered delivery rate in a controlled release product
PI: Michael T. Schweizer Protocol Version: 6.0  
- Physical Defect: e.g. abnormal odor, broken or crushed tablets
- Potential Dosing Device Malfunction: e.g., auto-injector button not working, needle detaching from syringe
- Suspected Contamination
- Suspected Counterfeit
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serious adverse event (sae)

A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for Human Use is any untoward medical occurrence that at any dose:  
- Results in death
- Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that hypothetically might have caused death if it were more severe.)  
- Requires inpatient hospitalization or prolongation of existing hospitalization
- Results in persistent or significant disability/incapacity
- Is a congenital anomaly/birth defect
- Is a suspected transmission of any infectious agent via a medicinal product
- Is medically important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is also appropriate in other situations, such as important medical events that may not be immediately life threatening or result in death or hospitalization but may jeopardize the subject or may require intervention to prevent one of the other outcomes listed in the definition above. These should usually be considered serious.
clinical protocol
note death for any reason

For reports of hospitalization, it is the sign, symptom or diagnosis which led to the hospitalization that is the serious event for which details must be provided. Any event requiring hospitalization or prolongation of hospitalization that occurs during the study must be reported as a serious adverse event, except hospitalizations for the following:
PI: Michael T. Schweizer Protocol Version: 6.0 Protocol Number: CC10288 FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib  
- Hospitalizations not intended to treat an acute illness or adverse event (e.g., social reasons such as pending placement in long-term care facility)
- Surgery or procedure planned before entry into the study. [Note: Hospitalizations that were planned before the start of data collection and where the underlying condition for which the hospitalization was planned has not worsened will not be considered serious adverse events. Any adverse event that results in a prolongation of the originally planned hospitalization is to be reported as a new serious adverse event.]
clinical protocol
life-threatening conditions

The cause of death of a subject in a study within 30-days of the last dose of one or more of the Study Drugs, whether or not the event is expected or associated with the study drug, is considered a serious adverse event. Disease progression should not be recorded as an adverse event or serious adverse event term; instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of efficacy will be reported if they fulfill the serious adverse event definition.
clinical protocol
unlisted (unexpected) adverse event/reference safety

An adverse event is considered unlisted if the nature or severity is not consistent with the applicable product reference safety information. For a medicinal product(s) with a marketing authorization, the expectedness of an adverse event will be determined by whether or not it is listed in the applicable product information. For erdafitinib, the expectedness of an adverse event will be determined by whether or not it is listed in Section 6 of the Investigator's Brochure (reference safety information for assessment of expectedness of serious adverse reactions). For abiraterone acetate, the expectedness of an adverse event will be determined by whether or not it is listed in the FDA prescribing information.  
https://www.zytiga.com/
https://www.balversa.com/ For Balversa™ (erdafitinib) and Zytiga™ (abiraterone acetate), the expectedness of an adverse event will be determined by whether or not it is listed in the Investigator's Brochure
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special reporting situations

Safety events of interest for a J&J medicinal product that require expediting reporting and/or safety evaluation include, but are not limited to:
- Drug exposure during pregnancy (maternal and paternal)
- Overdose of a J&J medicinal product
- Exposure to a J&J medicinal product from breastfeeding
- Suspected abuse/misuse of a J&J medicinal product
PI: Michael T. Schweizer Protocol Version: 6.0 Protocol Number: CC10288 FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib  
- Inadvertent or accidental exposure to a J&J medicinal product
- Any failure of expected pharmacological action (i.e., lack of effect) of a J&J medicinal product
- Medication error (includes potential, intercepted or actual) involving a J&J
medicinal product (with or without patient exposure to the J&J medicinal product(s) under study, e.g., name confusion)
- Suspected transmission of any infectious agent via administration of a medicinal product
- Unexpected therapeutic or clinical benefit from use of a J&J medicinal product These safety events may not meet the definition of an adverse event; however, from a Janssen Research & Development perspective, they are treated in the same manner as adverse events. Special situations should be recorded on the Adverse Event page of the CRF. Any special situation that meets the criteria of a serious adverse event should be recorded on a Serious Adverse Event Report Form and be reported to Janssen Research & Development **within 24 hours of becoming aware of the event.**
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11.3 pregnancy

Erdafitinib is developed as an anticancer agent. There are no reproductive or developmental toxicology data available for erdafitinib. There may be unforeseeable risks to the embryo or fetus. Subjects (with a partner of child-bearing potential) must use medically acceptable methods of birth control prior to study entry and for the duration of the study, and for at least 3 months after the last intake of study drug. Subjects must use a condom with spermicide when sexually active and must not donate sperm from the first dose of study drug until 3 months after the last dose of study drug. Medically acceptable methods of contraception that may be used by the subject and/or his partner include hormonal prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, true sexual abstinence, and surgical sterilization (e.g., confirmed successful vasectomy or tubal ligation). True sexual abstinence is an acceptable method of contraception and is defined as refraining from heterosexual intercourse during the entire period of the study, including up to 3 months after the last dose of study drug is given. Periodic abstinence (calendar, symptothermal, postovulation methods) is not considered an acceptable contraceptive method. Because the study drug may have an effect on sperm, pregnancies in partners of male subjects included in the study must be reported by the Sponsor-Investigator within 24 hours to of their knowledge of the event using the Serious Adverse Event Form. All pregnancies must be reported from the time of informed consent and 90 days following last dose. Depending on local legislation this may require prior consent of the partner. Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the infant will be required.
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11.4. adverse event monitoring and

The Sponsor Investigator, Sub-Investigators, and/or the research nurse will monitor each patient closely for the development of adverse events and toxicities and record all such events. Patients Protocol Number: CC10288 FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib PI: Michael T. Schweizer Protocol Version: 6.0 will be evaluated for toxicity if they have received one dose of any of the Study Drugs. The timely reporting of adverse events (including toxic deaths) is required by the Food and Drug Administration (FDA). In general, the Sponsor-Investigator must immediately report (i.e. within 24 hours) to Janssen Research & Development any serious adverse event and Special Reporting Situations, whether or not considered drug related. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be reported in accordance with the protocol unless there is evidence suggesting a causal relationship between the drug and the event (e.g., death as a result of anaphylactic reaction or fatal hepatic necrosis). In that case, the investigator must immediately report the event to Janssen Research & Development. The sponsor must record non-serious adverse events and report them to Janssen Research & Development according to the timetable outlined in the Research Funding Agreement section entitled Reporting of Data and to fulfill regulatory reporting requirements. For each subject, AEs, SAEs, Adverse Events of Special Interest and Special Reporting Situations should be recorded after informed consent is obtained until the subject has completed participation in the study as follows: A Serious Adverse event must be reported if it occurs during a subject's participation in the Study (whether receiving Study Product or not) and within 30 days of receiving the last dose of Study Product. Any serious adverse event that is ongoing when a subject completes his/her participation in the Study must be followed until any of the following occurs:
- the event resolves or stabilizes;  
- the event returns to baseline condition or value (if a baseline value is available); - the event can be attributed to agents(s) other than the Study Product, or to factors unrelated to Study conduct.
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11.5. procedures for reporting safety

All adverse events, whether serious or non-serious, related or not related, following exposure to study drugs are to be documented by the investigator and recorded in the CRF and in the subject's source records. Investigators must record in the CRF their opinion concerning the relationship of the adverse event to the study drugs.  
All (serious and non-serious) adverse events reported for the study drugs should be followed up- in accordance with clinical practice.
clinical protocol
11.5.1. serious adverse events (sae)

All serious adverse events that have not resolved by the end of the study, or that have not resolved upon discontinuation of the subject's participation in the study, Version Date: 17 September 2020  
- The event resolves
- The event stabilizes - The event returns to baseline, if a baseline value/status is available - The event can be attributed to agents other than the study drug or to factors unrelated to study conduct
- It becomes unlikely that any additional information can be obtained
(subject or health care practitioner refusal to provide additional information, lost to follow-up after demonstration of due diligence with follow-up efforts)
The Sponsor Investigator will transmit all SAEs, Adverse Events of Special Interest and special situations following exposure to the Study Drugs in a form provided by the Janssen Research & Development within 24-hours of **becoming** aware of the event(s). All follow-up information for serious adverse events that are not resolved at the end of the study or by the time of patient withdrawal must be reported directly by the Sponsor Investigator, within 24 hours **becoming aware**, to Janssen Research & Development using their Serious Adverse Event Report All available clinical information relevant to the evaluation of a related SAE, Adverse Events of Special Interest, serious ADR or special situation is required.  
- The Sponsor Investigator is responsible for ensuring that these cases are complete and if not are promptly followed-up. A safety report is not considered complete until all clinical details needed to interpret the case are received. Reporting of follow-up information should follow the same timeline as initial reports.  
- Copies of any and all relevant correspondences with regulatory authorities and ethics committees regarding any and all serious adverse events, irrespective of association with the Study Drugs, are to be provided to the Janssen Research & Development within 24 hours of such **report or** correspondence being sent to applicable health authorities.
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11.5.2. product quality complaints reporting

A PQC may have an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and analysis of PQC information from studies are crucial for the protection of patients, investigators, and Janssen Research & Development, and are mandated by regulatory agencies worldwide. Janssen Research & Development has established procedures in conformity with regulatory requirements worldwide to ensure appropriate reporting of PQC information. Lot and/or Batch \#s shall be collected or any reports failure of expected pharmacological action (i.e., lack of effect). The product should be quarantined immediately and if possible, take a picture. All initial PQCs involving J&J medicinal product(s) under study must be reported to Janssen Research & Development by the Sponsor Investigator **within** 24
clinical protocol
hours after being made aware

If the defect for the Lot and/or Batch of the J&J medicinal product(s) under study is combined with either a serious adverse event or non-serious adverse event, the Sponsor Investigator must report the PQC to Janssen Research & Development according to the serious adverse event reporting timelines. A sample of the suspected product should be maintained for further investigation if requested by Janssen Research & Development.  
For SAEs, special reporting situations and PQCs following exposure to a nonJ&J medicinal product under study, the Sponsor Investigator should notify the appropriate regulatory/competent authority or the manufacturer of that medicinal product (in the absence of appropriate local legislation) as soon as possible.
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11.6. evaluating adverse events

The grade and severity of the event will be determined using the DCT/NCI Common Terminology Criteria, CTCAE v.5.0 (Appendix 2). All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. Study staff must use one of the CTCAE criteria to define the event. Adverse events not included in the CTCAE v.5.0 should be reported and graded under the "Other" adverse event within the appropriate category and grade 1 to 5 according to the general grade definitions, mild, moderate, severe, life-threatening, fatal or disabling, as provided in the CTCAE.  
The event will be determined to be expected or unexpected. The determination of whether an AE is expected is based on agent-specific adverse event information provided in the Investigators Brochure (erdafitinib) or the FDA Prescribing Information (abiraterone acetate and enzalutamide). Unexpected AEs are those not listed in the agent-specific adverse event information. The event will be evaluated for relationship to the medical treatment or procedure. The Investigator should document his/her opinion of the relationship of the event to study medication as follows:  
- *Unrelated*- The adverse event is clearly not related to the investigational agent(s).  
- *Unlikely*- The adverse event is doubtfully related to the investigational agent(s).  
- *Possible*-The adverse event may be related to the investigational agent(s).
- *Probable*-The adverse event is most likely related to the investigational agent(s).  
- *Definite*- The adverse event is clearly related to the investigational agent(s).
Based on this information, a decision will be made whether an adverse event should be reported as an expedited report (Serious Adverse Event) in addition to the routinely reported clinical data. All expedited adverse event reports that meet reporting criteria per institutional requirements should be submitted to the Institutional Review Board (IRB) and to the FDA. Additionally, all SAEs should be submitted to Janssen Research & Development within 24 hours of becoming aware of event and via secure e-mail.
clinical protocol
11.6.1. documenting adverse events

Each individual sign or symptom must be documented separately. Worksheets must be signed and dated by person conducting evaluation to be used as source documentation. The attribution of all adverse events must be verified by an investigator. Evaluation of laboratory toxicities may be documented directly on a printed laboratory report or CRF provided it is signed by the investigator. However, if an action was conducted due to this abnormality (e.g. RBC transfusion due to low Hgb) this would be recorded on the AE form also. Recording should be done in a concise manner using standard, acceptable medical terms. The adverse event recorded should not be a procedure or a clinical measurement (i.e. a laboratory value or vital sign) but should reflect the reason for the procedure or the diagnosis based on the abnormal measurement. Preexisting conditions that worsen in severity or frequency during the Study should also be recorded (a preexisting condition that does not worsen is not an adverse event). Further, a procedure or surgery is not an adverse event; rather, the event leading to the procedure or surgery is considered an adverse event. Any event requiring in-patient hospitalization that occurs during the course of a subject's participation in a trial must be reported as an SAE. Hospitalizations that do not meet the criteria for SAE reporting are:
A. Reasons described in the Protocol, e.g. drug administration, Protocolrequired testing B. Surgery or procedure planned prior to entry into the Study.  
If, in the Sponsor Investigator's judgment, a clinical significant worsening from baseline is observed in any laboratory or other test parameter (e.g. electrocardiogram (ECG), angiogram), physical exam finding, or vital sign, a corresponding clinical adverse event should be recorded. If a specific medical diagnosis has been made, that diagnosis or syndrome should be recorded as the adverse event, whenever possible. However, a complete description of the signs, symptoms and investigations which led to the diagnosis Protocol Number: CC10288 FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib PI: Michael T. Schweizer Protocol Version: 6.0 should be provided. For example, if clinically significant elevations of liver function tests are known to be secondary to hepatitis, "hepatitis" and not "elevated liver function tests" should be recorded. If the cause is not known, the abnormal test or finding should be recorded as an adverse event, using appropriate medical terminology (e/g/ thrombocytopenia, peripheral edema, QT prolongation).
clinical protocol
11.6.2. maintenance of safety information

All safety data should be maintained in a clinical database in a retrievable format.  
The Sponsor Investigator shall provide all adverse events, both serious and nonserious, in report format. However, in certain circumstances more frequent provision of safety data may be necessary, e.g. to fulfill a regulatory request, and as such the data shall be made available within a reasonable timeframe at Janssen Scientific Affairs' request.
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11.6.3. saes listing

At a minimum, on a semi-annual basis and at the end of the Study, Janssen Research & Development will provide to the Sponsor Investigator a listing of all SAEs reported to the Janssen Research & Development. The Sponsor Investigator will review this listing and will resolve any discrepancies with the data provided by Janssen Research & Development.
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11.7. irb reporting

The Sponsor Investigator is responsible to report serious adverse events and protocol problems (e.g. protocol deviations, non-adherence) to the FHCRC/University of Washington Cancer Consortium Institutional Review Board (IRB). Adverse events (AEs) that are unexpected, possibly related to the study drug, and serious or suggest a risk of greater harm from the research than previously known will be reported to the IRB per institutional policy. In addition, all safety data must be submitted to Janssen Research & Development. The following methods are acceptable for transmission of safety information to Janssen Research & Development.:
- Electronically via J&J SECURE Email service (preferred)  
- For business purposes, if SECURE Email is non-functional:
o Facsimile (fax), receipt of which is evidences in a successful fax transmission report o Telephone (if fax is non-functional)
Contact information for Janssen Research & Development is below:
SAE email: IIS-BIO-VIRO-GCO@its.jnj.com SAE fax: 1-866-651-0219 PI: Michael T. Schweizer Protocol Version: 6.0 Protocol Number: CC10288 FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib Follow-up reports must be submitted in a timely fashion as additional information becomes available. The initial SAE report should be updated with the pertinent follow up information.
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11.8. protocol amendments

Any changes to the protocol will be made in the form of an amendment and must be approved by the IRB before implementation. Changes to the protocol or informed consent will be reviewed and approved by Janssen Research & Development prior to submitting to the IRB for approval.
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11.9. informed consent

Written informed consent will be obtained by a study investigator working on this study. An explanation of the nature of study, its purpose, procedures involved, expected duration, potential risks and benefits will be provided to each participant by the investigator or the research nurse. Each participant will be informed that participation in the study is voluntary and that he may withdraw from the study at any time, and that withdrawal of consent will not affect his subsequent medical treatment. Participants will be allowed time needed to make an informed decision. Participants will be encouraged to ask questions about the study and the consent before signing the consent form. Original signed consent forms will be filed in each patient's research chart, while each patient will receive a copy of the consent document. No patient will enter the study before his informed consent has been obtained.
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12 statistical methods

Statistical analysis will be done by the sponsor investigator or under the authority of the Sponsor- Investigator. A general description of the statistical methods to be used to analyze the efficacy and safety data is outlined below. The primary objective will be to determine the objective tumor response rate in subjects with measurable lesions as defined by RECIST v1.1 criteria in mCRPC patients with DNPC receiving either enzalutamide or abiraterone acetate. 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.
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12.1. subject information 12.2. sample

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 post-docetaxel setting:
Protocol Number: CC10288 FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib PI: Michael T. Schweizer Protocol Version: 6.0 with ORRs ranging from 3-8%.5,6 Therefore, if we assume a historical-control 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
12.3. efficacy analyses

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. If a patient drops out of the study prior to first on-study 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. We will also present ORR, with 95% confidence intervals, for the patients receiving erdafitinib in combination with abiraterone acetate or enzalutamide separately. 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.
clinical protocol
12.4. correlative research analyses

Exploratory correlative work will be conducted with the goal to determine if there are biomarkers predictive of response/resistance to erdafitinib in combination with a next-generation AR-signaling inhibitor. Studies to be conducted include 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 and blood 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 the primary and secondary endpoints using chi-square tests and logistic regression, or (for PFS and OS) using proportional hazards models, Kaplan-Meier methods and log-rank tests.
clinical protocol
references

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3. Scher HI, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. *J Clin Oncol.* 2016;34(12):1402-1418.  
4. Labrecque MP, Coleman IM, Brown LG, et al. Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer. *The Journal of clinical investigation.*
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6. Loriot Y, Bianchini D, Ileana E, et al. Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100). Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2013;24(7):1807-1812.  
7. Schrader AJ, Boegemann M, Ohlmann CH, et al. Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. *Eur Urol.* 2014;65(1):30-36.  
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11. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial.  
Lancet. 2010;376(9747):1147-1154.  
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15. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. *The New England journal of medicine.* 2013;368(2):138-148.  
16. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. *The New England journal of medicine.* 2012;367(13):1187-1197.  
17. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. *N Engl J Med.* 2004;351(15):1502-1512.  
18. Graham L, Schweizer MT. Targeting persistent androgen receptor signaling in castration-resistant prostate cancer. *Medical oncology (Northwood, London, England).* 2016;33(5):44.  
19. Chan JM, Zaidi S, Love JR, et al. Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling. *Science (New York, NY).* 2022:eabn0478.  
20. Beltran H, Hruszkewycz A, Scher HI, et al. The Role of Lineage Plasticity in Prostate Cancer Therapy Resistance. *Clinical cancer research : an official journal of the American Association for Cancer Research.*
2019;25(23):6916-6924.  
21. Ku SY, Rosario S, Wang Y, et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. *Science (New York, NY).* 2017;355(6320):78-83.  
22. Brady L, Kriner M, Coleman I, et al. Inter- and intra-tumor heterogeneity of metastatic prostate cancer Protocol Number: CC10288 FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib PI: Michael T. Schweizer Protocol Version: 6.0 determined by digital spatial gene expression profiling. *Nature communications.* 2021;12(1):1426.  
23. Schweizer MT, Antonarakis ES. Abiraterone and other novel androgen-directed strategies for the treatment of prostate cancer: a new era of hormonal therapies is born. *Ther Adv Urol.* 2012;4(4):167-178.  
24. Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. *Lancet.* 2010;375(9724):1437-1446.  
25. Haidar S, Ehmer PB, Barassin S, Batzl-Hartmann C, Hartmann RW. Effects of novel 17alphahydroxylase/C17, 20-lyase (P450 17, CYP 17) inhibitors on androgen biosynthesis in vitro and in vivo. J
Steroid Biochem Mol Biol. 2003;84(5):555-562.  
26. Ryan CJ, Tindall DJ. Androgen receptor rediscovered: the new biology and targeting the androgen receptor therapeutically. *J Clin Oncol.* 2011;29(27):3651-3658.  
27. Vasaitis TS, Bruno RD, Njar VC. CYP17 inhibitors for prostate cancer therapy. *J Steroid Biochem Mol Biol.*
2011;125(1-2):23-31.  
28. Attard G, Reid AH, Yap TA, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. *J Clin Oncol.*
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29. O'Donnell A, Judson I, Dowsett M, et al. Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. British journal *of cancer.* 2004;90(12):2317-2325.  
30. Bryce A, Ryan CJ. Development and clinical utility of abiraterone acetate as an androgen synthesis inhibitor. *Clin Pharmacol Ther.* 2012;91(1):101-108.  
31. Attard G, Reid AH, Auchus RJ, et al. Clinical and biochemical consequences of CYP17A1 inhibition with abiraterone given with and without exogenous glucocorticoids in castrate men with advanced prostate cancer. *J Clin Endocrinol Metab.* 2012;97(2):507-516.  
32. Ryan CJ, Smith MR, Fong L, et al. Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. *J Clin Oncol.* 2010;28(9):1481-1488.  
33. Danila DC, Morris MJ, de Bono JS, et al. Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. *J Clin Oncol.* 2010;28(9):1496-1501.  
34. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. *N Engl J Med.* 2013;368(2):138-148.  
35. Taplin ME, Montgomery B, Logothetis CJ, et al. Intense androgen-deprivation therapy with abiraterone acetate plus leuprolide acetate in patients with localized high-risk prostate cancer: results of a randomized phase II neoadjuvant study. *Journal of clinical oncology : official journal of the American Society of Clinical* Oncology. 2014;32(33):3705-3715.  
36. Beltran H, Tomlins S, Aparicio A, et al. Aggressive variants of castration-resistant prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2014;20(11):28462850.  
37. Nadal R, Schweizer M, Kryvenko ON, Epstein JI, Eisenberger MA. Small cell carcinoma of the prostate.  
Nature reviews Urology. 2014;11(4):213-219.  
38. Aparicio AM, Harzstark AL, Corn PG, et al. Platinum-based chemotherapy for variant castrate-resistant prostate cancer. *Clinical cancer research : an official journal of the American Association for Cancer* Research. 2013;19(13):3621-3630.  
39. Labrecque MP, Coleman IM, Brown LG, et al. Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer. *The Journal of clinical investigation.*
2019;130.  
40. Pritchard CC, Salipante SJ, Koehler K, et al. Validation and implementation of targeted capture and sequencing for the detection of actionable mutation, copy number variation, and gene rearrangement in clinical cancer specimens. *The Journal of molecular diagnostics : JMD.* 2014;16(1):56-67.  
Protocol Number: CC10288 FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib PI: Michael T. Schweizer Protocol Version: 6.0 41. Delpuech O, Rooney C, Mooney L, et al. Identification of Pharmacodynamic Transcript Biomarkers in Response to FGFR Inhibition by AZD4547. *Molecular cancer therapeutics.* 2016;15(11):2802-2813.  
42. Veldman-Jones MH, Brant R, Rooney C, et al. Evaluating Robustness and Sensitivity of the NanoString Technologies nCounter Platform to Enable Multiplexed Gene Expression Analysis of Clinical Samples.  
Cancer research. 2015;75(13):2587-2593.  
| Grade                                                                                                                                                                                                    | Description                                                                                                                                                                                    |            |               |      |                 |             |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------|---------------|------|-----------------|-------------|
| 0                                                                                                                                                                                                        | Normal                                                                                                                                                                                         | activity.  | Fully active, | able | to carry on all | pre-disease |
| performance without restriction. Symptoms, but ambulatory. Restricted                                                                                                                                    | in                                                                                                                                                                                             | physically | strenuous     |      |                 |             |
| 1                                                                                                                                                                                                        | activity, but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work). In bed <50% of the time. Ambulatory and capable of all self-care, but |            |               |      |                 |             |
| 2                                                                                                                                                                                                        | unable to carry out any work activities. Up and about more than 50% of waking hours.                                                                                                           |            |               |      |                 |             |
| 3                                                                                                                                                                                                        | In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.                                                                            |            |               |      |                 |             |
| 4                                                                                                                                                                                                        | 100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.                                                                                          |            |               |      |                 |             |
| 5                                                                                                                                                                                                        | Dead.                                                                                                                                                                                          |            |               |      |                 |             |
| *As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology |                                                                                                                                                                                                |            |               |      |                 |             |
clinical protocol
appendix 1 ecog performance status

*As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E.,
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, *1982.* The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.  
Protocol Number: CC10288 FGFR Inhibition in DNPC
JNJ-42756493 Erdafitinib PI: Michael T. Schweizer Protocol Version: 6.0
appendix 2 common terminology criteria
appendix 1 ecog performance status

The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R eference_5x7.pdf
appendix 3 pill diary templates
participant pill diary

STUDY \#
Participant Study ID: _  
| Erdafitinib           |                                           |                         |       |
|-----------------------|-------------------------------------------|-------------------------|-------|
| Dose (mg) per tablet: | Number of Tablets or Capsules/Time of Day |                         |       |
| Time                  |                                           |                         |       |
| Date                  | Day                                       | Erdafitinib tablets/day | AM/PM |
| l                     |                                           |                         |       |
| 2                     |                                           |                         |       |
| 3                     |                                           |                         |       |
| 4                     |                                           |                         |       |
| S                     |                                           |                         |       |
| 6                     |                                           |                         |       |
| 7                     |                                           |                         |       |
| 8                     |                                           |                         |       |
| 9                     |                                           |                         |       |
| 10                    |                                           |                         |       |
| 11                    |                                           |                         |       |
| 12                    |                                           |                         |       |
| 13                    |                                           |                         |       |
| 14                    |                                           |                         |       |
| 15                    |                                           |                         |       |
| 16                    |                                           |                         |       |
| 17                    |                                           |                         |       |
| 18                    |                                           |                         |       |
| 19                    |                                           |                         |       |
| 20                    |                                           |                         |       |
| 21                    |                                           |                         |       |  
l l JNJ-42756493  Erdafitinib  
STUDY \#
Participant Study ID:
Enzalutamide  
| Number of Tablets or Capsules/Time of Day   |                         |       |
|---------------------------------------------|-------------------------|-------|
| Time                                        |                         |       |
| Date                                        | Enzalutamide 160 mg/day | AM/PM |
| Day                                         |                         |       |
| 1                                           |                         |       |
| 2                                           |                         |       |
| 3                                           |                         |       |
| 4                                           |                         |       |
| s                                           |                         |       |
| 6                                           |                         |       |
| 7                                           |                         |       |
| 8                                           |                         |       |
| 9                                           |                         |       |
| 10                                          |                         |       |
| 11                                          |                         |       |
| 12                                          |                         |       |
| 13                                          |                         |       |
| 14                                          |                         |       |
| 15                                          |                         |       |
| 16                                          |                         |       |
| 17                                          |                         |       |
| 18                                          |                         |       |
| 19                                          |                         |       |
| 20                                          |                         |       |
| 21                                          |                         |       |  
STUDY \#
Participant Study ID:
Abiraterone  
| Number of Tablets or Capsules/Time of Day   |     |                         |       |
|---------------------------------------------|-----|-------------------------|-------|
| Time                                        |     |                         |       |
| Date                                        | Day | Abiraterone 1000 mg/day | AM/PM |
| l                                           |     |                         |       |
| 2                                           |     |                         |       |
| 3                                           |     |                         |       |
| 4                                           |     |                         |       |
| S                                           |     |                         |       |
| 6                                           |     |                         |       |
| 7                                           |     |                         |       |
| 8                                           |     |                         |       |
| 9                                           |     |                         |       |
| 10                                          |     |                         |       |
| 11                                          |     |                         |       |
| 12                                          |     |                         |       |
| 13                                          |     |                         |       |
| 14                                          |     |                         |       |
| 15                                          |     |                         |       |
| 16                                          |     |                         |       |
| 17                                          |     |                         |       |
| 18                                          |     |                         |       |
| 19                                          |     |                         |       |
| 20                                          |     |                         |       |
| 21                                          |     |                         |       |  
l Protocol Number: CC10288 FGFR Inhibition in DNPC
JNJ-42756493  Erdafitinib