Clinical trial NCT03238196
Conditions: Metastatic Breast Cancer
Keywords: FGFR inhibitor ER+ metastatic breast cancer CDK4/6 inhibitor Endocrine therapy
Sponsor: Vanderbilt-Ingram Cancer Center
Start date: 2017-08-18; Completion date: 2024-03-20
Enrollment: 35 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is an open-label, multi-institution, phase Ib trial that evaluates the safety and tolerability and preliminary anti-tumor activity of fulvestrant, palbociclib and erdafitinib in patients with ER+/HER2-/FGFR-amplified metastatic breast cancer.

Detailed description:
Primary Objectives

To determine the safety and tolerability of fulvestrant, palbociclib and erdafitinib in patients with ER+/HER2-/FGFR-amplified MBC.

Secondary Objectives

* To determine the anti-tumor effect of fulvestrant, palbociclib and erdafitinib in patients with ER+/HER2-/FGFR-amplified MBC.
* Pharmacokinetic assessments of erdafitinib

Correlative Objectives

* To determine the therapeutic predictive role of FGFR1-4, CCND1-2, CDK4 and CDK6 amplifications, and RB1 and ESR1 mutations on clinical outcome
* To determine if the FGFR1 amplification levels is an early surrogate of response
* To determine if the cfDNA results at disease progression show new genomic alterations potentially associated with resistance to CDK4/6 and FGFR inhibition
* To determine pharmacodynamic biomarkers of FGFR inhibition

Arms: arm 1: Fulvestrant - injection into muscle 1 time per month

Palbociclib capsule taken by mouth 1 time per day every 21 days followed by 1 week of rest (no drug taken)

Erdafitinib tablet taken by mouth 1 time per day arm 2: Fulvestrant - injection into muscle 1 time per month

Palbociclib capsule taken by mouth 1 time per day every 21 days followed by 1 week of rest (no drug taken)

Erdafitinib tablet taken by mouth 1 time per day
Interventions: intervention 1: Erdafitinib intervention 2: Palbociclib intervention 3: Fulvestrant
Intervention descriptions: intervention 1: 4mg - 8mg intervention 2: 125 mg intervention 3: 500 mg

Protocol documents:
Prot_SAP_000.pdf: 
Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 Protocol Version:11/4/21 
CONFIDENTIAL 
Page 1 of 97 
This document is confidential 
Do not disclose or use except as authorized 
PROTOCOL TITLE: 
A phase Ib trial of fulvestrant, palbociclib (CDK4/6 inhibitor) and erdafitinib (JNJ-
42756493, pan-FGFR tyrosine kinase inhibitor) in ER+/HER2–/FGFR-amplified metastatic 
breast cancer (MBC) 
Protocol Number 
VICCBRE16126 (NCT03238196) 
Protocol Chair 
PI Name: Vandana Abramson, MD 
Institution: Vanderbilt-Ingram Cancer Center (VICC) 
Address: 2200 Pierce Ave. 777 PRB, Nashville, TN 37232 
Phone:  615-936-8422 
Fax: 615-343-7602 
Email: vandana.abramson@vumc.org 
Co-Investigators 
Medical Oncology 
Komal Jhaveri, MD – Memorial Sloan Kettering Cancer Center 
(MSKCC) 
Hope Rugo, MD – University of California San Francisco (UCSF) 
Erica Stringer Reasor, MD – University of Birmingham Alabama 
(UAB) 
Adam Brufsky, MD – University of Pittsburgh Medical Center 
(UPMC) 
Pathology 
Melinda Sanders, MD 
Melinda.sanders@vumc.org  
Vanderbilt-Ingram Cancer Center (VICC) 
Laboratory Correlatives  
Komal Jhaveri, MD – Memorial Sloan Kettering Cancer Center 
(MSKCC) 
jhaverik@mskcc.org 
Carlos L. Arteaga, MD - UT Southwestern (UTSW) 
Carlos.arteaga@utsouthwestern.edu  
Statistician 
Fei Ye, PhD 
Fei.ye@vumc.org 
Vanderbilt-Ingram Cancer Center (VICC) 
Supporters 
Pfizer  
Janssen Research and Development 
Funding Mechanism 
ASPIRE Breast Cancer Research Awards Program 
Coordinating Center/ 
Sponsor 
Vanderbilt-Ingram Cancer Center (VICC) 
Multi-Institutional Coordinating Office 
Fax: (615) 875-0040 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
 Protocol Version:11/4/21 
CONFIDENTIAL 
Page 2 of 97 
 
This document is confidential 
 
Do not disclose or use except as authorized 
 
 
 
 
 
 
Email: Coordinating.center@vumc.org 
 
Study Liaison:  
Jannine Hewitt, RN 
Jannine.hewitt@vumc.org  
 
Investigational New Drug (IND) Number   
134219 
 
 
 
 
 
- Protocol Revision Record - 
 
 
Original Protocol: 
 
10/13/16 
 
 
Amendment #1: 
 
07/17/2017 
Amendment #2:   
08/15/2017 
Amendment #3: 
 
01/09/2018  
Amendment #4: 
 
11/26/2019 
Amendment #5: 
 
04/08/2020 
Amendment #6: 
 
11/04/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
 Protocol Version:11/4/21 
CONFIDENTIAL 
Page 3 of 97 
 
This document is confidential 
 
Do not disclose or use except as authorized 
 
Table of Contents 
 
 
SCHEMA ...................................................................................................................................................................... 5 
PROTOCOL SYNOPSIS ........................................................................................................................................... 6 
1. 
STUDY DESIGN/SUMMARY ......................................................................................................................... 12 
2. 
OBJECTIVES AND ENDPOINTS ................................................................................................................. 13 
3. 
BACKGROUND ............................................................................................................................................... 14 
3.1 
ESTROGEN RECEPTOR-POSITIVE (ER+) BREAST CANCER ...................................................................... 14 
3.2 
ENDOCRINE THERAPY AND CDK4/6 INHIBITION ....................................................................................... 15 
3.3 
FIBROBLAST GROWTH FACTOR RECEPTOR-1 (FGFR1) IN ER+ BREAST CANCER ................................ 17 
3.4 
FGFR AND CDK4/6 INHIBITION IN ER+ BREAST CANCER - PRELIMINARY DATA ................................... 19 
3.5 
RATIONALE ................................................................................................................................................. 22 
3.6 
CORRELATIVE SCIENCE BACKGROUND ..................................................................................................... 22 
4. 
PARTICIPANT SELECTION .......................................................................................................................... 23 
4.1 
INCLUSION CRITERIA .................................................................................................................................. 24 
4.2 
EXCLUSION CRITERIA ................................................................................................................................ 26 
4.3 
INCLUSION OF UNDERREPRESENTED POPULATIONS ................................................................................ 27 
5. 
REGISTRATION PROCEDURES ................................................................................................................. 28 
5.1 
GUIDELINES FOR VICC AND TBCRC INSTITUTIONS ................................................................................ 28 
6. 
STUDY CALENDAR ....................................................................................................................................... 30 
7. 
TREATMENT PLAN ........................................................................................................................................ 33 
7.1 
OVERVIEW .................................................................................................................................................. 33 
7.2 
SCREENING PHASE .................................................................................................................................... 33 
7.3 
AGENT ADMINISTRATION ........................................................................................................................... 33 
7.4 
DEFINITION OF DOSE-LIMITING TOXICITY (DLT) ....................................................................................... 35 
7.5 
DEFINITION OF MAXIMUM TOLERATED DOSE (MTD) ................................................................................ 38 
7.6 
CONCOMITANT TREATMENT AND SUPPORTIVE CARE GUIDELINES .......................................................... 39 
7.7 
DURATION OF THERAPY ............................................................................................................................. 40 
7.8 
DURATION OF FOLLOW-UP ........................................................................................................................ 40 
7.9 
CRITERIA FOR REMOVAL FROM STUDY ..................................................................................................... 40 
7.10 
DISCONTINUATION OF TREATMENT ........................................................................................................... 40 
7.11 
REPLACEMENT OF PATIENTS WHO DISCONTINUE EARLY ........................................................................ 41 
7.12 
WITHDRAWAL FROM STUDY ....................................................................................................................... 41 
8. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS ....................................... 41 
8.1 
ERDAFITINIB ............................................................................................................................................... 41 
8.2 
FULVESTRANT ............................................................................................................................................ 45 
8.3 
PALBOCICLIB .............................................................................................................................................. 45 
8.4 
PALBOCICLIB AND ERDAFITINIB DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITIES .................... 46 
8.5 
SPECIAL CONSIDERATIONS........................................................................................................................ 52 
9. 
DRUG FORMULATION/STORAGE/SUPPLY ............................................................................................ 53 
9.1 
ERDAFITINIB ............................................................................................................................................... 53 
9.2 
FULVESTRANT ............................................................................................................................................ 54 
9.3 
PALBOCICLIB .............................................................................................................................................. 55 
9.4 
DRUG ACCOUNTABILITY ............................................................................................................................. 57 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
 Protocol Version:11/4/21 
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10. 
CORRELATIVE/SPECIAL STUDIES ....................................................................................................... 58 
10.1 
OVERVIEW .................................................................................................................................................. 58 
10.2 
BLOOD SAMPLES FOR PHARMACODYNAMIC ASSESSMENTS .................................................................... 60 
10.3 
BLOOD SAMPLES FOR CFDNA .................................................................................................................. 60 
10.4 
BLOOD SAMPLES FOR NGS CONTROL ...................................................................................................... 61 
10.5 
TISSUE SAMPLES ....................................................................................................................................... 61 
10.6 
PHARMACOKINETICS .................................................................................................................................. 65 
10.7 
GENETIC TESTING ...................................................................................................................................... 67 
11. 
SPECIMEN BANKING ............................................................................................................................... 68 
12. 
MEASUREMENT OF EFFECT .................................................................................................................. 69 
12.1 
DEFINITIONS ............................................................................................................................................... 69 
12.2 
DISEASE PARAMETERS .............................................................................................................................. 69 
12.3 
RESPONSE CRITERIA ................................................................................................................................. 71 
12.4 
DURATION OF RESPONSE .......................................................................................................................... 73 
13. 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................. 73 
13.1 
GENERAL .................................................................................................................................................... 73 
13.2 
DEFINITIONS ............................................................................................................................................... 73 
13.3 
REPORTING PROCEDURES ........................................................................................................................ 75 
14. 
DATA AND SAFETY MONITORING ....................................................................................................... 80 
14.1 
DATA MANAGEMENT AND REPORTING ...................................................................................................... 80 
14.2 
DATA HANDLING AND RECORD KEEPING .................................................................................................. 81 
14.3 
MEETINGS .................................................................................................................................................. 82 
14.4 
MONITORING .............................................................................................................................................. 82 
15. 
REGULATORY CONSIDERATIONS ....................................................................................................... 84 
15.1 
PRE-STUDY DOCUMENTATION .................................................................................................................. 84 
15.2 
PROTOCOL REVIEW AND AMENDMENTS .................................................................................................... 84 
15.3 
INFORMED CONSENT ................................................................................................................................. 85 
15.4 
CONFIDENTIALITY AND DISCLOSURE ......................................................................................................... 85 
15.5 
RECORDS RETENTION ............................................................................................................................... 86 
15.6 
STUDY TERMINATION ................................................................................................................................. 86 
15.7 
ETHICS AND GCP ...................................................................................................................................... 87 
15.8 
COMPLIANCE WITH TRIAL REGISTRATION AND RESULTS POSTING REQUIREMENTS ............................... 87 
16. 
MULTI-CENTER GUIDELINES ................................................................................................................. 87 
16.1 
STUDY DOCUMENTATION ........................................................................................................................... 87 
16.2 
RECORDS RETENTION ............................................................................................................................... 88 
16.3 
PUBLICATION .............................................................................................................................................. 88 
17. 
STATISTICAL CONSIDERATIONS ......................................................................................................... 88 
17.1 
STUDY DESIGN/ ENDPOINTS ...................................................................................................................... 88 
17.2 
SAMPLE SIZE AND STATISTICAL ANALYSIS ................................................................................................ 88 
17.3 
REPORTING AND EXCLUSIONS ................................................................................................................... 92 
18. 
REFERENCES ............................................................................................................................................. 93 
19. 
MEDICATIONS TO BE USED WITH CAUTION .................................................................................... 96 
 
 
 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
Protocol Version:11/4/21 
CONFIDENTIAL 
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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
 Protocol Version:11/4/21 
CONFIDENTIAL 
Page 6 of 97 
 
This document is confidential 
 
Do not disclose or use except as authorized 
 
PROTOCOL SYNOPSIS 
Sponsor 
Vanderbilt-Ingram Cancer Center 
Protocol Title 
A phase Ib trial of fulvestrant, palbociclib (a CDK4/6 inhibitor) and erdafitinib 
(JNJ-42756493, a pan-FGFR tyrosine kinase inhibitor) in ER+/HER2–
/FGFR-amplified metastatic breast cancer (MBC) 
Protocol Number 
VICCBRE16126 (NCT03238196) 
Phase of 
Development 
Phase Ib 
Investigational 
Product and 
Mechanism 
• 
Erdafitinib, an oral pan-FGFR inhibitor (please note that the 
combination of erdafitinib, palbociclib and fulvestrant is also 
investigational) 
Non-Investigational 
Products and 
Mechanism 
• 
Palbociclib, a CDK4/6 inhibitor 
• 
Fulvestrant, a selective estrogen-receptor downregulator (SERD) 
Treatment Schedule 
Dose/Route 
• 
Erdafitinib (4 – 8 mg) mg PO daily  
• 
Palbociclib 125 mg PO daily from day 1 – 21, every 28 days 
• 
Fulvestrant 500 mg IM once every 28 days 
Objectives 
Primary Objectives 
• 
To determine the safety and tolerability of fulvestrant, palbociclib and 
erdafitinib in patients with ER+/HER2-/FGFR-amplified MBC. 
 
Secondary Objectives 
• 
To determine the anti-tumor effect of fulvestrant, palbociclib and 
erdafitinib in patients with ER+/HER2-/FGFR-amplified MBC. 
• 
Pharmacokinetic assessments of erdafitinib 
 
Correlative Objectives 
• 
To determine the therapeutic predictive role of FGFR1-4, CCND1-2, 
CDK4 and CDK6 amplifications, and RB1 and ESR1 mutations on 
clinical outcome 
• 
To determine if the FGFR1 amplification levels by FISH and cfDNA is 
an early surrogate of response  
• 
To determine if the cfDNA results at disease progression show new 
genomic alterations potentially associated with resistance to CDK4/6 
and FGFR inhibition 
• 
To determine pharmacodynamic biomarkers of FGFR inhibition 
Endpoints 
Primary Endpoint 
• 
Assessment of DLT during the first 4 weeks of treatment (cycle 1) 
• 
Determination of MTD 
 
Secondary Endpoints 
• 
Progression Free-Survival (PFS) 
• 
Overall response rate (ORR) 
• 
Clinical benefit rate (CBR; complete response + partial response + 
stable disease without disease progression at 6 months) 
• 
Pharmacokinetic assessments of erdafitinib 
 
Correlative Endpoints 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
 Protocol Version:11/4/21 
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• 
FGFR1 fluorescence in situ hybridization (FISH) 
• 
Next Generation Sequencing (NGS) of baseline or archival tumor 
specimen 
• 
Plasma tumor cell free [cf] DNA at baseline, at 4 weeks and at disease 
progression 
• 
Serial measurements of serum phosphate, calcium, vitamin D, 
parathyroid hormone (PTH), FGF23, sFGFR2, sFGFR3 and sFGFR4 
Trial Design 
This is an open-label, multi-institution, phase Ib trial that evaluates the safety, 
tolerability, and anti-tumor activity of fulvestrant, palbociclib with erdafitinib 
in patients with ER+/HER2-/FGFR-amplified metastatic breast cancer 
(MBC). 
Number of Patients 
• 
Minimum: 26 patients  
• 
Maximum: 35 patients  
Participating 
Institutions 
• 
Vanderbilt-Ingram Cancer Center (Coordinating Center) 
• 
TBCRC (4 centers) 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment will 
continue until: 
• 
Disease progression 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patients decides to withdraw from the study 
• 
Significant patient non-compliance with protocol 
Duration of Follow-
up 
• 
Patients will be followed every three months until disease progression, 
or until death from any cause (whichever occurs first) 
• 
Patients removed from study for unacceptable treatment related adverse 
event(s) will be followed until resolution or stabilization of all treatment 
related adverse events to Grade 2 or lower  
• 
Patients continuing fulvestrant who have discontinued erdafitinib or 
palbociclib for any reason other than disease progression will be followed 
until disease progression 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
 Protocol Version:11/4/21 
CONFIDENTIAL 
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Patient Selection 
Inclusion Criteria (abbreviated) 
• 
Patients (female or male) must provide informed written consent and 
must complete all screening assessments as outlined in the protocol  
• 
Patients must be able to swallow and retain oral medication 
• 
Patients must be ≥ 18 years of age 
• 
Female patients of no childbearing potential.   
Patients must be post-menopausal by at least one of the following criteria 
prior to enrollment:  
o Subjects at least 60 years of age; OR 
o Subjects under 60 years of age and naturally (spontaneous, no 
alternative pathologic or physiological cause) amenorrhea for at least 
12 months; OR  
o Medical ovarian failure confirmed by follicle-stimulating hormone 
(FSH) and estradiol levels in the post menopausal range per local 
institutional normal range; OR 
o Prior bilateral oophorectomy; OR  
o Prior radiation castration with amenorrhea for at least 6 months; OR  
o Treatment with a luteinizing hormone-releasing hormone (LH-RH) 
agonist (such as goserelin acetate or leuprolide acetate) is permitted 
for induction of ovarian suppression as long as it has been initiated 
at least 28 days prior to study enrollment 
• 
ECOG performance status 0 - 1 
• 
Clinical stage IV or inoperable locoregional recurrent invasive mammary 
carcinoma that is: 
o ER+ 
and/or 
PgR+ 
(≥ 
1% 
positive 
stained 
cells) 
by 
immunohistochemistry (IHC)  
o HER2-negative (by IHC or FISH, per ASCO guidelines)  
o FGFR1 - 4amplified (may be determined by local assessment 
through either targeted capture next generation sequencing (NGS), 
plasma tumor cell free [cf] DNA or FISH) in 50% of the patients 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
 Protocol Version:11/4/21 
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participating in the expansion cohort of the trial (not necessary in the 
escalation cohort) 
o Evaluable (may have either measurable or non-measurable disease) 
• 
Patients must have available tissue (archival formalin-fixed paraffin 
embedded (FFPE) blocks or fresh frozen biopsy from primary tumor or 
metastatic tumor biopsy) for correlative studies. Tissue source needs to 
be located and available at the time of registration (tissue needs to be 
submitted within 3 weeks of study initiation). Patients will not be able to 
start study drugs without tissue availability.  Submission of tissue can be 
waived, if approved by the Study Chair in case of extraordinary/ 
catastrophic circumstances.  
• 
Current use of any of the drugs listed on the Cautionary Concomitant 
Medications list has to be approved by the Study Chair 
• 
Patient must have had at least one line of therapy in the metastatic 
setting 
• 
Patients must have adequate hematologic, hepatic, and renal function. 
All laboratory tests must be obtained within 2 weeks from study entry.  
These include: 
o ANC ≥ 1,500/mm3 
 
o Platelet count ≥ 100,000/mm3 
 
o HgB ≥ 9.0 g/dL 
 
o Creatinine clearance ≥ 40 mL/min/1.73 m2  
 
o SGOT, SGPT ≤ 2.5 x ULN if no liver metastasis present  
 
o SGOT, SGPT ≤ 4 x ULN if liver metastasis present 
 
o Albumin ≥ 2.0 g/dL 
 
o Total serum bilirubin ≤ 1.5 x ULN (≤ 3 x ULN or direct bilirubin ≤ 1.5 
x ULN if known Gilbert’s syndrome) 
 
o Potassium within institutional normal limits 
 
o Phosphorus ≤ institutional upper limit of normal  
  
Exclusion Criteria (abbreviated) 
• 
Prior use of an FGFR inhibitor  
• 
More than 2 lines of chemotherapy in the metastatic setting. There is no 
limit on endocrine therapy lines  


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
 Protocol Version:11/4/21 
CONFIDENTIAL 
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Do not disclose or use except as authorized 
 
• 
Radiation therapy ≤ 2 weeks prior to study entry.  Patients who have 
received prior radiotherapy must have recovered from toxicity (≤ grade 
1) induced by this treatment (except for alopecia) 
• 
Prior cancer therapy (except for endocrine therapy) must have been 
discontinued for 1 week prior to initiation of study drugs  
• 
Concurrent anti-cancer therapy other than the ones specified in the 
protocol is not permitted during study participation. Bisphosphonates or 
denosumab are allowed  
• 
Major surgery within 4 weeks of enrollment 
• 
Herbal preparations are not allowed throughout the study, and must be 
discontinued at least 14 days prior to initiation of study treatment 
• 
Any corneal or retinal abnormality likely to increase the risk of eye 
toxicity, such as: 
o Current corneal pathology such as keratitis, keratoconjunctivitis, 
keratopathy, corneal abrasion, inflammation or ulceration 
o Uncontrolled glaucoma despite standard of care therapy 
o Diabetic retinopathy with macular edema 
o Known active wet, age-related macular degeneration (AMD) 
o Known central serous retinopathy (CSR) or retinal vascular occlusion 
(RVO) 
• 
Uncontrolled intercurrent illness including, but not limited to: 
o Malabsorption syndrome significantly affecting gastrointestinal 
function 
o Ongoing or active infection requiring antibiotics/ antivirals 
o Impairment of lung function (COPD > grade 2, lung conditions 
requiring oxygen therapy) 
o Symptomatic congestive heart failure (class III or IV of the New York 
Heart Association classification for heart disease)  
o Unstable angina pectoris, angioplasty, stenting, or myocardial 
infarction within 6 months 
o Clinically significant cardiac arrhythmia (multifocal premature 
ventricular contractions, bigeminy, trigeminy, ventricular tachycardia 
that is symptomatic or requires treatment [National Cancer Institute -


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
 Protocol Version:11/4/21 
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Common Terminology Criteria for Adverse Events, Version 4.03, 
grade 3]  
o QTcF ≥ 480 msec on screening EKG  
o Known history of QT/QTc prolongation or Torsades de Pointes (TdP) 
o ST depression or elevation of ≥ 1.5 mm in 2 or more leads 
o Diarrhea of any cause ≥ CTCAE grade 2 that does not resolve within 
a few days under adequate treatment 
o Psychiatric illness/social situations that would compromise patient 
safety or limit compliance with study requirements including 
maintenance of a compliance/pill diary 
o Symptomatic brain metastases (patients with a history of brain 
metastases must be clinically stable for more than 4 weeks from 
completion of radiation treatment and off steroids) 
o Known history of chronic liver or renal failure 
o Poor wound healing capacity 
Study Assessments 
Safety Assessment:  
• 
History, physical exam, and routine blood work such as blood counts and 
comprehensive metabolic panel will be performed on day 1 of each 
treatment cycle. 
• 
Analyses will be performed for all patients having received at least one 
dose of study drugs. The study will use the NCI CTCAE v4.03. 
 
Anti-tumor Assessments: 
• 
CT scans of the chest, abdomen, and pelvis and bone scan (when 
applicable) are to be performed approximately every 8 weeks 
 
Exploratory Assessments: 
• 
Tumor tissue collection: baseline 
• 
Plasma collection: every other month. cfDNA will be performed at 
baseline , at 4 weeks after treatment initiation (Cycle 2 Day 1), and at 
disease progression (end-of-treatment) 
• 
Pharmacodynamic studies: Day 1 and 15 of cycles 1 and 2 (for 
escalation portion only) 
• 
Pharmacokinetic studies: Day 1 and 15 of cycles 1 and 2 (for escalation 
portion only) 
 
 
 
 
 
 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
 Protocol Version:11/4/21 
CONFIDENTIAL 
Page 12 of 97 
 
This document is confidential 
 
Do not disclose or use except as authorized 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 
STUDY DESIGN/SUMMARY 
This is an open-label, multi-institution, phase Ib trial that evaluates the safety and tolerability and 
preliminary anti-tumor activity of fulvestrant, palbociclib and erdafitinib in patients with ER+/HER2-
/FGFR-amplified metastatic breast cancer (MBC). Briefly, patient’s eligibility criteria will include: 
post-menopausal women with metastatic ER+/HER2-/FGFR-amplified breast cancer without prior 
use of a CDK4/6 inhibitor or an FGFR inhibitor; ECOG performance status ≤1, normal baseline 
blood counts and chemistry laboratory profile; and no intercurrent uncontrolled illness. Treatment 
will be given until disease progression or unacceptable toxicity. To assess the anti-tumor effect of 
therapy, we will estimate the overall tumor burden at baseline to which subsequent measurements 
(performed every 8 weeks using the Solid Tumor Response Criteria [RECIST] v1.1) will be 
compared. Samples for pharmacokinetic and pharmacodynamic assessments will be obtained 
throughout the escalation portion of the study. A baseline biopsy of a metastatic site or archival 
tissue will be obtained in all patients for Next Generation Sequencing, to determine the therapeutic 
predictive role of FGFR1-4, CCND1-2, CDK4 and CDK6 amplifications, and RB1 and ESR1 
mutations on clinical outcome. Plasma will also be serially obtained, initially for measurement of 
plasma cell-free tumor DNA (cfDNA) at baseline, at 4 weeks after treatment initiation and at 
disease progression). This would allow us to determine if the FGFR1 amplification levels detected 
by cfDNA at 4 weeks is an early surrogate of response to the triple-combination proposed, and if 
the cfDNA results at disease progression show new genomic alterations potentially associated 
with resistance to CDK4/6 and FGFR inhibition. 
 
 
 
 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
 Protocol Version:11/4/21 
CONFIDENTIAL 
Page 13 of 97 
 
This document is confidential 
 
Do not disclose or use except as authorized 
 
2. 
OBJECTIVES AND ENDPOINTS 
 
 
Objectives 
Endpoints 
Primary 
 
To determine the safety and tolerability 
of fulvestrant, palbociclib and erdafitinib 
in patients with ER+/HER2-/FGFR-
amplified MBC 
 
• 
Assessment of DLT during the 
first 4 weeks of treatment (cycle 
1) 
• 
Determination of MTD 
 
Secondary 
 
• 
To determine the anti-tumor effect of 
fulvestrant, palbociclib and erdafitinib 
in patients with ER+/HER2-/FGFR-
amplified MBC 
• 
Pharmacokinetic assessments of 
erdafitinib 
• 
Progression-free survival (PFS) 
• 
Overall response rate (ORR) 
• 
Clinical benefit rate (CBR; 
complete response + partial 
response + stable disease 
without disease progression at 6 
months) 
• 
Pharmacokinetic (PK) 
assessments of erdafitinib 
Correlative 
 
• 
To determine pharmacodynamic 
biomarkers of FGFR inhibition 
• 
To determine the therapeutic 
predictive role of FGFR1-4, CCND1-
2, CDK4 and CDK6 amplifications, 
and RB1 and ESR1 mutations on 
clinical outcome 
• 
To determine if the FGFR1 
amplification levels by FISH and 
cfDNA is an early surrogate of 
response  
• 
To determine if the cfDNA results at 
disease progression show new 
genomic alterations potentially 
associated with resistance to 
CDK4/6 and FGFR inhibition. 
• 
Serial measurements of serum 
phosphate, calcium, vitamin D, 
parathyroid hormone (PTH), 
FGF23, sFGFR2, sFGFR3 and 
sFGFR4 
• 
FGFR1 FISH 
• 
Next Generation Sequencing 
(NGS) of baseline or archival 
tumor specimen 
• 
Plasma cfDNA at baseline, at 4 
weeks and at disease 
progression 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3. 
BACKGROUND 
3.1 
Estrogen receptor-positive (ER+) Breast Cancer 
Despite advances in early detection and therapeutic options, unresectable or metastatic breast 
cancer remains incurable and is one of the leading causes of cancer-related mortality1.  Breast 
cancer is a molecularly heterogeneous disease with three distinct molecular subtypes2.  The first 
group is characterized by estrogen receptor (ER) expression positivity and/or progesterone 
receptor (PgR) positivity with the absence of over-expression or amplification of HER2. The 
second group is characterized by over-expression or amplification of HER2, with more than half 
of these tumors being positive (+) for expression of ER/PgR. The third group lacks detectable ER 
and PgR, and overexpression of HER2, and is thus referred to as triple-negative breast cancer. 
Approximately 65% of newly diagnosed breast cancers are ER/PgR+ and HER2-negative (also 
referred to as luminal tumors), while an additional 20% of newly diagnosed cases are HER2+. 
ER-targeted drugs, specifically drugs that antagonize estrogen binding to the ER (tamoxifen), 
drugs that block estrogen biosynthesis (non-steroidal and steroidal aromatase inhibitors [AI] - only 
effective in postmenopausal patients), and drugs that antagonize and downregulate the ER 
(fulvestrant), have been the mainstay of systemic treatment for patients with both localized and 
metastatic ER/PgR+ breast cancers3.   
Fulvestrant is the most recent addition to the armamentarium of hormonal therapies available to 
treat these patients. However, acquired resistance (and occasionally primary resistance) to anti-
estrogen therapy universally develops in patients with ER+ MBC4. Interestingly, even after 
acquired resistance develops, breast cancer cells appear to still depend on low-level ER activity 
in addition to signaling through sometimes acquired oncogenic signaling pathways5. In addition, 
in patients initially diagnosed with ER/PgR+ localized breast cancer who later recur, tumors 
usually demonstrate some degree of resistance to antiestrogen therapy at the time of recurrence6. 
Therefore, improving the efficacy of endocrine therapy would be of great benefit to patients with 
breast cancer and represents a large unmet medical need. 
3.1.1 Fulvestrant 
Fulvestrant (a selective estrogen receptor downregulator or SERD) is currently a standard of care 
hormonal therapy option in patients with ER+ MBC7. Fulvestrant has an affinity for ER comparable 
to estradiol. It blocks the trophic actions of estrogens without any partial agonist (estrogen-like) 
activity, and is currently indicated for the treatment of ER+ MBC in postmenopausal women with 
disease progression following primary antiestrogen therapy. Clinical trials in postmenopausal 
women with primary breast cancer have shown that fulvestrant significantly downregulates tumor 
ER protein levels compared with placebo. There was also a significant decrease in PgR 
expression consistent with inhibition of ERα transcription. Further, treatment with fulvestrant 
inhibits tumor cell proliferation as measured by Ki67 immunohistochemistry8. 
Two phase III clinical trials were completed in a total of 851 postmenopausal women with breast 
cancer who had disease recurrence on or after adjuvant endocrine therapy or progression 
following endocrine therapy for advanced disease9. These trials compared the safety and efficacy 
of monthly administration of fulvestrant 250 mg vs. the non-steroidal AI anastrozole at 1 mg/daily. 
Monthly 250 mg fulvestrant was at least as effective as anastrozole in terms of PFS, OR, and time 
to death. The combined data showed an objective response rate for fulvestrant of 19.2% 
compared with 16.5% for anastrozole. The median time to death was 27.4 months for patients 
treated with fulvestrant and 27.6 months for patients treated with anastrozole. The hazard ratio of 
fulvestrant 250 mg to anastrozole for time to death was 1.01 (95% CI 0.86 to 1.19). 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
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Doses of fulvestrant higher than 250 mg have greater pharmacodynamic activity against the ER 
pathway. Thus, a 500 mg monthly dose after an initial load is now the FDA-approved standard of 
care. A phase III clinical trial (CONFIRM)10 was completed in 736 postmenopausal women with 
breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression 
following endocrine therapy for advanced disease. The study included 423 patients whose 
disease had recurred or progressed during antiestrogen therapy and 313 patients whose disease 
had recurred or progressed during AI therapy. This trial compared the efficacy and safety of 
fulvestrant 500 mg (n=362) vs. 250 mg (n=374). PFS for fulvestrant 500 mg was 6.5 months 
compared to 5.5 months for fulvestrant 250 mg. Overall survival data from the time of final analysis 
showed a median time to death of 26.4 months for fulvestrant 500 mg vs. 22.3 months for 
fulvestrant 250 mg [HR (95%CI) 0.81 (0.69, 0.96), p=0.016].  
The routes of elimination for fulvestrant include combinations of a number of possible 
biotransformation pathways analogous to those of endogenous steroids, including oxidation, 
aromatic hydroxylation, and conjugation with glucuronic acid and/or sulphate. There are no known 
drug-drug interactions. Fulvestrant does not significantly inhibit any of the major CYP isoenzymes, 
including CYP 1A2, 2C9, 2C19, 2D6, and 3A4 in vitro, and studies of co-administration of 
fulvestrant with midazolam indicate that therapeutic doses of fulvestrant have no inhibitory effects 
on CYP 3A4 or alter blood levels of drugs metabolized by that enzyme. Although fulvestrant is 
partly metabolized by CYP 3A4, a clinical study with rifampin, an inducer of CYP 3A4, showed no 
effect on the pharmacokinetics (PK) of fulvestrant. Also results from a healthy volunteer study 
with ketoconazole, a potent inhibitor of CYP3A4, indicated that ketoconazole had no effect on the 
PK of fulvestrant, and therefore, dosage adjustment is not necessary in patients with co-
prescribed CYP 3A4 inhibitors or inducers. 
3.2 
Endocrine Therapy and CDK4/6 Inhibition 
Identifying well-tolerated targeted therapies that obviate the need for systemic chemotherapy, 
delay disease progression, and, ideally, prolong survival, as well as characterizing their optimal 
usage, remain a main objective in breast cancer research. Traditionally, chemotherapy with 
minimal activity and significant toxicity has been the only option to treat patients with anti-estrogen 
resistance. This changed in 2012 with the approval of the molecularly targeted mTOR inhibitor 
everolimus to be used in combination with the steroidal AI exemestane in patients with metastatic 
ER+/HER2-negative breast cancer who have progressed on a non-steroidal AI. Everolimus 
appears to at least temporarily restore sensitivity to antiestrogen therapy and results in a PFS 
benefit11.  
More recently, inhibitors of the cyclin-dependent kinases 4 and 6 (CDK4/6) have demonstrated 
impressive activity in patients with ER+/HER2-negative MBC with marked improvements in PFS12.  
3.2.1 Palbociclib 
Palbociclib is an orally active pyridopyrimidine, first-in-class compound that is a potent and highly 
selective reversible inhibitor of CDK4/613. Estrogen-activated ER transcription activates cyclin D1 
leading to the formation of the cyclin D1-CDK4/6-Rb complex where CDK4/6 phosphorylates and 
inactivates Rb. Phosphorylated Rb uncouples from E2F transcription factors, which in turn, 
mediate progression from G1 into S phase of the cell cycle. Thus, by inhibiting CDK4/6, palbociclib 
prevents tumor cell entry into S phase14. Consistent with its CDK4/6 specificity, treatment with 
palbociclib reduces expression of the proliferation marker Ki67 and is completely inactive in Rb-
deficient tumor cells15. Preclinical data have shown that endocrine-resistant ER+ breast cancer 
cells are highly sensitive to the combination of palbociclib with anti-hormonal therapy or 
palbociclib alone16. 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
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Blockade of the ER signaling pathway is synergistic with cell cycle arrest induction, as 
demonstrated by the more than doubling in median PFS observed in the PALOMA-3 clinical trial17. 
The combination of palbociclib with tamoxifen has also shown synergy in vitro against ER+ human 
breast cancer cell lines18. Also, recent data in endocrine resistant models (MCF7-CYP19) indicate 
a significant benefit of the combination of palbociclib and letrozole as well as palbociclib and 
fulvestrant over letrozole and fulvestrant alone (Pfizer, Investigational Brochure, Version Dec 
2013). 
Laboratory studies have shown that human breast cancer cell lines that are more sensitive to 
palbociclib (IC50 <150 nM) have low levels of CDKN2A (p16) and high levels of Rb1, while 
resistant cells show the opposite characteristics. Sensitive cell lines were mostly of the luminal 
ER+ subtype16. A phase I trial tested 3 dose levels of palbociclib in patients with solid tumors, 
enrolling 41 patients at three dose levels, with drug given for 21 days out of every 28 days19. The 
dose limiting toxicity was neutropenia, and the recommended phase II dose was 125 mg. Clinical 
benefit with objective response was seen in 10/41 (27%) patients for at least 4 cycles, and in 6 
patients for at least 10 cycles, one of whom had breast cancer. Other than neutropenia, which 
was proportionate to drug exposure, palbociclib was well tolerated. 
A phase II study was conducted with single agent palbociclib in 37 women with advanced breast 
cancer, of whom 89% had ER+ disease20. Palbociclib was given at 125 mg orally, days 1- 21 of 
a 28-day cycle. Over 90% had prior chemotherapy for metastatic disease and 84% had prior 
endocrine therapy. Clinical benefit was seen in 7 out of the 37 patients, and only in those with 
ER+ disease for a rate in that subpopulation of 21%. The overall response rate was just 6% in 
ER+ disease. Grade 3/4 toxicity included neutropenia in 54%, thrombocytopenia in 19%, and 
grade 1/2 fatigue in 70%.  
Encouraging phase II data in patients with ER+/HER2-negative postmenopausal patients with 
newly diagnosed MBC indicated that the addition of palbociclib to letrozole extends PFS with a 
tolerable safety profile17. The multicenter randomized phase I/II PALOMA-1 study evaluated the 
combination of palbociclib with the AI letrozole vs. letrozole alone in patients with previously 
untreated metastatic ER+/HER2-negative MBC17. The phase I component of the study 
established the safety of this combination. The phase II component of the study accrued 165 
patients and was divided into two parts, with the first part open to all participants in the study and 
a second part open only to patients selected for CCND1 amplification or p16 loss (N=99). After 
exploratory analysis failed to demonstrate that CCND1 amplification or p16 loss predicted 
response to palbociclib, the two parts were combined for a final efficacy analysis. Compared to 
letrozole alone, the combination of palbociclib and letrozole provided a very impressive increase 
in PFS, the predefined primary outcome, from 10.2 months to 20.2 months [Hazard Ratio 
(HR)=0.37; p=0.0004]. Based on these results, in February 2015 the FDA granted accelerated 
approval for the use of palbociclib and letrozole as first line treatment of patients with ER+/HER2-
negative MBC. The confirmatory phase III randomized PALOMA-2 study completed accrual and 
its preliminary results have been presented at the 2016 American Society of Clinical Oncology 
(ASCO) meeting21. A total of 666 post-menopausal patients with no prior systemic therapy for 
ER+ MBC were randomized 2:1 to receive letrozole with palbociclib or letrozole with placebo. 
Median PFS (primary endpoint) was 24.8 months vs. 14.5 months in favor of the palbociclib arm 
(HR=0.58 [0.46–0.72], p < 0.000001). Response rate was also improved in the palbociclib arm 
(42.1% vs. 34.7%, p=0.031; 55.3% vs. 44.4% in patients with measurable disease [p=0.013]), 
and clinical benefit rate was 84.9% vs. 70.3% (p < 0.0001).  
The double blind phase III PALOMA-3 trial22 investigated the combination of fulvestrant and 
palbociclib in 521 pre- and post-menopausal patients with ER+/HER2-negative MBC, with 
disease relapse or progression after at least one line of hormonal therapy and at most one line of 


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chemotherapy, but naïve to CDK4/6 inhibitors23. Patients received fulvestrant with placebo or with 
palbociclib. The PFS at time of interim analysis was 9.2 months in the investigational arm vs. 3.8 
months for fulvestrant plus placebo arm (HR=0.42; p<0.000001). The most common grade 3 or 4 
adverse events in the palbociclib-fulvestrant group were neutropenia (62.0%, vs. 0.6% in the 
placebo-fulvestrant group), leukopenia (25.2% vs. 0.6%), anemia (2.6% vs. 1.7%), 
thrombocytopenia (2.3% vs. 0%), and fatigue (2.0% vs. 1.2%). Thirty-three percent of patients 
had received one line of prior chemotherapy for metastatic disease. Based on these results, in 
February 2016 palbociclib was FDA-approved in combination with fulvestrant for second line 
treatment of patients with ER+/HER2-negative MBC.  
Of note, the potential for a clinically significant drug-drug interaction between the CDK4/6 inhibitor 
palbociclib and fulvestrant is very low. A phase III trial has completed accrual, with an initial safety 
assessment with trough plasma concentrations demonstrating no pharmacokinetic interactions 
between fulvestrant and palbociclib24. In vitro data indicate that CYP3A and SULT enzyme 
SULT2A1 are mainly involved in the metabolism of palbociclib. The strong CYP3A inhibitor 
itraconazole increased palbociclib AUCinf  by approximately 87%, relative to palbociclib given 
alone. As expected, coadministration of rifampin, a strong CYP3A inducer, decreased palbociclib 
AUCinf by 85% relative to palbociclib given alone. Palbociclib is a weak time-dependent inhibitor 
of CYP3A following administration of the clinical 125 mg dose: palbociclib increased the 
midazolam AUCinf values by 61%, as compared with midazolam alone. In vitro, palbociclib is not 
an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, and 2D6, and is not an inducer of CYP1A2, 
2B6, 2C8, and 3A4 at clinically relevant concentrations.  In vitro evaluations indicated that 
palbociclib has a low potential to inhibit the activities of drug transporters at clinically relevant 
concentrations. 
3.3 
Fibroblast Growth Factor Receptor-1 (FGFR1) in ER+ Breast Cancer 
Somatic mutations in the FGFR pathway result in its aberrant activation, leading to cellular 
transformation, tumorigenesis and cancer progression25. Several lines of evidence support a role 
for FGFRs in breast cancer26. 
FGFR1 amplification is present in 
about 
15% 
of 
ER+ 
breast 
cancers27, and is an independent 
predictor of overall survival in 
patients with ER+ breast cancer 
treated with tamoxifen28. FGFR 
overexpression has been shown 
experimentally 
to 
mediate 
resistance to endocrine therapy 
through activation of the MAPK 
and PI3K pathways26. About 30-
40% of breast tumors with 
FGFR1 amplification also exhibit 
amplification 
of 
CCND1, 
FGF3/4/19 in chromosome 11q29. 
This 
co-amplification 
is 
also 
associated with a reduction of 
patients’ survival30. Based on 
these 
data, 
several 
pharmaceutical companies have developed drugs targeting FGFR (Table 1), focusing their 


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clinical development on tumor subtypes with a high likelihood of dependence on FGFR pathway 
signaling. These include tumor types with FGFR amplifications, activating mutations and fusions.  
3.3.1 Erdafitinib 
Erdafitinib (JNJ-42756493), a potent, oral pan-FGFR tyrosine kinase inhibitor with IC50 values in 
the low nanomolar range for FGFR 1-4, was recently tested in a phase I trial in solid tumors31. It 
has demonstrated potent inhibition of cell proliferation with IC50 values ranging from <1 to <1000 
nM in FGFR pathway-activated cancer cell lines including squamous non-small cell lung cancer 
(NSCLC), gastric, breast, hepatocellular cancer (HCC), endometrial, bladder, multiple myeloma, 
and acute myeloid leukemia. Non-FGFR driven cell lines require significantly higher drug 
concentration for inhibition of cell proliferation to be observed. Target inhibition and pathway 
modulation have been demonstrated in cellular models at the active cellular concentrations. Brief 
exposure (1 h) to erdafitinib has been demonstrated to result in long-term (>8 h) target inhibition. 
Erdafitinib inhibits the growth of pre-established subcutaneous (s.c.) and orthotopically injected 
xenografts tumors in both immunodeficient mice and rats. Tumor regression was observed in rats 
bearing human FGFR2-overexpressing SNU-16 gastric cancer xenografts after oral 
administration at 20 and 50 mg/kg daily doses of JNJ-42756493. Similar findings were observed 
in mice with SNU-16 tumors and patient-derived gastric, breast, hepatocellular, and NSCLC 
xenografts. 
Erdafitinib exhibited a dose-related increase in Cmax and area under the analyte concentration-
time curve (AUC) and time-independent PK within the dose range of 0.5 to 12 mg, both after 
single and multiple daily dosing. The actual sampling time to reach maximum concentration (tmax) 
ranged between 2-4 hours (erdafitinib as tablet), independent of the studied formulations. PK was 
characterized by moderate intersubject variability (CV% 31-39%) and low intra-subject variability 
(9-10%). Erdafitinib is primarily excreted in feces either as unchanged drug or as metabolites. In 
vitro data indicated that CYP3A and 2C9 are involved in erdafitinib metabolism. 70% and 20% of 
the radioactivity was recovered in feces and urine, respectively, with approximately 11% of 
unchanged drug recovered in urine. Erdafitinib is highly bound to plasma proteins, especially to 
α1-AGP (fraction unbound in oplsma being 0.36% and 0.50% in patients and healthy subjects, 
respectively. Apparent volume of distribution (Vd/F) of the terminal phase based on total plasma 
erdafitinib in healthy subjects is small (approximately 31 L), suggesting it is limited by the binding 
to plasma protein. Erdafitinib has low total plasma oral clearance (mean CL/F in subjects with 
cancer averaged 0.29 L/h; the corresponding value for healthy subjects was 0.43 L/h), likely 
restricted by protein binding. As a consequence, the apparent elimination half-life (t1/2) of 
erdafitinib is long (approximately 50 hours in healthy subjects) resulting an approximately 3- to 4-
fold accumulation in Cmax and AUC following multiple daily dosing. 
Erdafitinib is being investigated as an anti-cancer agent in several clinical studies (refer to most 
updated version of erdafitinib IB). As of June 2016, 305 subjects have been treated with 
erdafitinib. The median extent of drug exposure as of June 2016 was 7 weeks (range: 0 – 102 
weeks). There does not appear to be any dose-related trends in mean or median drug exposure, 
suggestive of tolerability of the drug. As for clinical efficacy, responses were observed at doses 
of 9 mg once daily or higher (range of responses: ~12 – 40%), particularly in patients with FGFR 
mutations.  
The most common adverse events included hyperphosphatemia (63%), asthenia (55%), dry 
mouth (45%), skin toxicities (38%), nail toxicity (30%), constipation (34%), decreased appetite 
(32%), and dysgeusia (31%), and eye toxicities (25%)31. Of note, QT prolongation was not 
reported. Adverse events of special interest include events that are class effects of FGFR 
inhibitors that have been experienced by patients treated with other FGFR inhibitors. These 
events include skin (xerosis, skin fissures, palmar-plantar erythrodysesthesia), mucosal (dryness, 


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mucositis, ulceration), nail changes (onycholysis, nail dystrophy), hyperphosphatemia, and eye 
toxicities (dry eyes, keratitis, and reversible retinal pigment epithelial detachment - RPED or 
central serous retinopathy [CSR]). 
3.4 
FGFR and CDK4/6 Inhibition in ER+ Breast Cancer - Preliminary Data 
A. In a pre-surgical study with the aromatase inhibitor letrozole in post-menopausal patients with 
ER+/HER2-negative operable breast cancer (NCT00651976), we discovered that amplification of 
FGFR1 (in 8p) and CCND1, FGF3/4/19 (in 11q), previously associated with tamoxifen 
resistance28, was statistically more frequent in tumors that retain high proliferation, as measured 
by Ki67 immunohistochemistry (IHC), upon treatment. FGFR1 IHC of primary tumors showed an 
increase in FGFR1 expression in tumor cell cytoplasm and nucleus after treatment with letrozole 
only in FGFR1-amplified cancers, suggesting that FGFR1 amplification is a mechanism of 
resistance to letrozole-induced estrogen deprivation. We performed Proximity Ligation Assays 
(PLA) and confocal microscopy in sections from 
primary tumors and found an increase in a nuclear 
ERD/FGFR1 
complex 
following 
letrozole 
treatment. Chromatin immunoprecipitation (ChIP) 
with FGFR or ERD antibodies of crosslinked DNA-
proteins from estrogen-deprived ER+/FGFR1 
amplified cells showed recovery of PCR amplified 
gene promoters containing estrogen-response 
elements 
(EREs), 
suggesting 
an 
estrogen-
independent FGFR1-ERD interaction driving ER 
transcription 
and 
potentially 
explaining 
the 
antiestrogen resistance seen in FGFR-amplified 
tumors treated in the trial. The observed FGFR1-
ERD association was abrogated by treatment of 
cells with the FGFR TKI lucitanib or by transfection 
of a tyrosine kinase dead (K514M) mutant of 
FGFR1, suggesting it is dependent on the FGFR1 
tyrosine kinase activity. Finally, co-treatment of 
ER+/FGFR1-amplified CAMA-1 breast cancer 
cells with lucitanib and fulvestrant was markedly 
more effective than either lucitanib or fulvestrant 
alone, while simultaneously inhibiting p-FRS2 and 
p-ERK and downregulating ER levels (Figure 1).  
B. To identify potential mechanisms of resistance 
to fulvestrant alone and in combination with a 
CDK4/6 inhibitor, we conducted a gain-of-function 
discovery screen using a library containing 559 
human kinases open reading frames (ORFs)32 in 
MCF7 ER+ breast cancer cells treated with 
fulvestrant ± LEE011 (ribociclib, Novartis), a small 
molecule CDK4/6 inhibitor with an IC50 against 
CDK4 and CDK6 of 10 and 39 nM, respectively. In 
both screens, FGFR1 was the top ORF rescuing 
from the antitumor effect of fulvestrant ± ribociclib. 
This result was confirmed in a secondary screen 
using fulvestrant ± the FDA-approved CDK4/6 inhibitor palbociclib.  


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ER+/FGFR1-amplified CAMA-1, MDA-134 and HCC1500 breast cancer cells were relatively 
resistant to the combination of fulvestrant and palbociclib compared to ER+/FGFR-low MCF7 
cells. In CAMA-1 cells, addition of lucitanib to fulvestrant and palbociclib completely eliminated 
CAMA-1 cell viability. Consistent with the potent growth inhibition observed, the triple therapy was 
most effective at simultaneously reducing p-Rb, ERD and p-ERK levels after only 6 h of treatment 
(Figure 2).  
Finally, in nude mice bearing either MCF7-wild type cells (MCF7wt) transduced with a lentivirus 
control vector or MCF7 cells overexpressing a stably transduced FGFR1 expression vector 
(MCF7FGFR1) xenografts, the combination of lucitanib, fulvestrant and palbociclib was markedly 
more effective in reducing or eliminating established tumors than either lucitanib alone or the 
combination of fulvestrant and palbociclib. This difference was particularly strong in mice with 
MCF7FGFR1 xenografts (Figure 3).  


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Similarly, in an ER+/FGFR1-amplified TM00368 patient-derived xenograft (PDX) model the 
combination of fulvestrant, palbociclib and erdafitinib was also markedly more effective in 
reducing or eliminating established tumors than either palbociclib or fulvestrant alone or the 
combination of fulvestrant and palbociclib (Figure 4). 
 


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3.5 
Rationale 
Preliminary evidence demonstrates that specific FGFR blockade with compounds such as 
erdafitinib has a manageable tolerability profile with promising clinical activity. The optimal 
strategies for combining FGFR inhibition with other anticancer agents requires further research. 
Ongoing clinical trials with FGFR inhibitors are being enriched for tumors harboring specific FGFR 
mutations and amplifications presumed to be highly addicted to this pathway. To date, preliminary 
clinical data suggest that FGFR and/or FGF3/4/19 ligand amplification is associated with clinical 
benefit from FGFR inhibitors33,34, suggesting these are biomarkers of tumor dependence on the 
FGF/FGFR pathway. Other data in support of this hypothesis are: 
• 
In ER+ breast cancers, most FGFR1 amplifications coexist with 11q amplification (CCND1, 
FGF3/4/19) and are associated with endocrine resistance30  
• 
Activation of FGFR1 increases transcription and expression of cyclin D1 (not shown) 
• 
In ER+/FGFR1-amplified breast cancer cells, an FGFR inhibitor does not inhibit pRb and a 
CDK4/6 inhibitor does not inhibit ERK or AKT (Figure 2) 
• 
The combination of FGFR and CDK4 inhibitors has a synergistic effect against FGFR1-
amplified breast cancer cells (Figure 3 and 4) 
We hypothesize that FGFR amplification attenuates the response of ER+ breast cancers to the 
combination of ER and CDK4/6 antagonists. Thus, the triple combination of an antiestrogen plus 
a CDK4/6 and an FGFR inhibitor would have synergistic activity in ER+/FGFR-amplified MBC. In 
this application, we propose a clinical trial of fulvestrant, palbociclib with the FGFR tyrosine kinase 
inhibitor (TKI) erdafitinib in patients with ER+/ HER2–/FGFR1-4-amplified MBC. Within this 
proposal, we will perform a dose escalation phase Ib study to determine the safety and tolerability 
and preliminary anti-tumoral activity of the triple combination. Once the recommended dose for 
phase II trials (RDP2) is defined, a future open-label randomized phase II trial of fulvestrant and 
palbociclib with or without erdafitinib will be conducted. 
3.6 
Correlative Science Background 
3.6.1 Blood Samples for Pharmacodynamic Assessments 
As previously shown31,35, FGFR inhibition is expected to produce blockade of FGF23 release from 
the bone and, therefore, hyperphosphatemia and changes on vitamin D and PTH are considered 
on-target effects. Blood collection for pharmacodynamic assessments (serum phosphate, 
calcium, vitamin D, parathyroid hormone [PTH], FGF23, sFGFR2, sFGFR3 and sFGFR4) will be 
performed on Days 1 (pre-treatment) and 15 of Cycle 1 and 2 in all patients participating in the 
phase Ib escalation portion of the study, to confirm drug target engagement by erdafitinib. 
3.6.2 Blood Samples for cfDNA 
Circulating DNA fragments carrying tumor-specific sequence alterations (circulating tumor DNA) 
are found in the cell-free fraction of plasma, representing a variable and generally small fraction 
of the total circulating DNA36,37. Circulating tumor DNA is an informative, inherently specific, and 
highly sensitive biomarker of metastatic breast cancer, as it has shown good correlation with 
changes in tumor burden and early tumor response38. Therefore, to determine if the level of 
FGFR1 amplification in plasma is an early surrogate of response, and to determine if the cfDNA 
results at disease progression show new genomic alterations associated with resistance to 
CDK4/6 and FGFR inhibition, blood collection for cfDNA will be performed every other month in 
all patients, but cfDNA analysis, initially, will be performed at the following time-points: baseline 
(Cycle 1 Day 1), at 4 weeks after treatment initiation (Cycle 2 Day 1), and at disease progression 
(end-of-treatment).  


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3.6.3 FGFR1 Fluorescence In Situ Hybridization (FISH) 
In situ hybridization scoring techniques for characterizing FGFR1-2 amplification have varied in 
trials reported to date39. Although amplification of FGF3/4/19 ligands may also predict those 
patients more likely to benefit from FGFR blockade33, the heterogeneity in published definitions 
makes it difficult to assess the true significance of these biomarkers given the lack of standardized 
measurement. Nevertheless, it is a reproducible test that can be done in a CLIA certified 
laboratory and has a quick turn-around. We propose to utilize FGFR1 FISH analysis in all patients 
enrolled in this study as a screening method for eligibility, and to determine the therapeutic 
predictive role of FGFR1 amplification by FISH on FFPE blocks on clinical outcome. 
In view of the higher prevalence of FGFR1 amplification compared to FGFR2-4 amplifications, 
patients with known FGFR1 amplification (by targeted capture next gene sequencing, cfDNA or 
FISH) will require central confirmation of FGFR amplification by FISH, but will not be required to 
wait for that result to initiate study treatment. Patients without known FGFR1 amplification will be 
screened by FISH analysis at the Vanderbilt-Ingram Cancer Center (VICC). From the time tissue 
arrives at the Coordinating Center Breast Cancer Tissue Core (Dr. Melinda Sanders), a turn-
around time of no longer than 7 days should be expected for the FISH results to become available.  
Tumors are considered as FGFR1 positive (‘amplified’) under one of the following conditions: 
(1) The FGFR1/CEN8 ratio is ≥2.0; 
(2) The average number of FGFR1 signals per tumor cell nucleus is ≥640. 
3.6.4 Targeted capture next generation sequencing (NGS) 
• 
Amplification of FGF3/4/19 ligand genes on chromosome 11q12-14 has been observed in 
15% of human breast cancers41,42. Notably, one-third of FGFR1-amplified tumors also harbor 
amplification of CCND1, FGF3, FGF4 and FGF1930. This co-amplification has been 
associated with resistance to estrogen deprivation in ER+ breast cancer and poor patient 
outcome30, thus suggesting the possibility of ligand-receptor cooperativity. 
• 
Recent studies suggest that acquired resistance to CDK4/6 inhibition in ER+ breast cancer 
results from bypass of cyclin D1–CDK4/6 dependence as a result of CCNE1 amplification or 
RB1 loss43.  
• 
ESR1 mutations, which occur in ~25% of metastatic breast cancer progressing on aromatase 
inhibitors, are an emerging mechanism of endocrine resistance44,45. The combination of 
fulvestrant and palbociclib has been shown to be effective against ESR1-mutant cell line-
derived and patient-derived xenografts18. This combination was also effective among patients 
harboring ESR1 mutant cancers in the PALOMA-3 trial22. Our preliminary data in Figure 2 
would suggest aberrant FGFR signaling limits the effect of fulvestrant/palbociclib and, 
therefore, in these patients the addition of an FGFR inhibitor may be beneficial.  
Therefore, we will determine the therapeutic predictive role of FGFR1-4, FGF3/4/19, CCND1-2, 
CDK4 and CDK6 amplifications, and RB1 and ESR1 mutations on clinical outcome, FFPE tissue 
from primary tumor or from a metastatic tumor biopsy will be collected for NGS in all patients 
enrolled in the study at the time of registration.  
 
4. 
PARTICIPANT SELECTION 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
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4.1 
Inclusion Criteria 
4.1.1 Patients (female or male) must provide informed written consent and must complete all 
screening assessments as outlined in the protocol 
4.1.2 Patients must be able to swallow and retain oral medication 
4.1.3 Patients must be ≥ 18 years of age 
4.1.4 Female patients of no childbearing potential.  
Patient must be post-menopausal by at least one of the following criteria prior to 
enrollment: 
a. Subjects at least 60 years of age; OR 
b. Subjects under 60 years of age and naturally (spontaneous, no alternative pathologic 
or physiological cause) amenorrhea for at least 12 months; OR  
c. Medical ovarian failure confirmed by follicle-stimulating hormone (FSH) and estradiol 
levels in the post menopausal range per local institutional normal range; OR 
d. Prior bilateral oophorectomy; OR  
e. Prior radiation castration with amenorrhea for at least 6 months; OR  
f. 
Treatment with a luteinizing hormone-releasing hormone (LH-RH) agonist (such as 
goserelin acetate or leuprolide acetate) is permitted for induction of ovarian 
suppression as long as it has been initiated at least 28 days prior to study enrollment 
4.1.5 ECOG performance status 0 - 1 
4.1.6 Clinical stage IV or inoperable locoregional recurrent invasive mammary carcinoma that 
is: 
a. ER+ and/or PgR+ (≥ 1% positive stained cells) by immunohistochemistry (IHC)  
b. HER2-negative (by IHC or FISH, per ASCO guidelines)  
c. FGFR1 – 4 amplified* (may be determined by local assessment through either 
targeted capture next generation sequencing (NGS), plasma cell-free tumor [cf] DNA 
or FISH [in the case of FGFR1 amplifications]*) in 50% of the patients participating in 
the expansion cohort of the trial (not necessary in the escalation cohort) 
*Cases will be considered as FGFR1-positive (‘amplified’) under one of the following 
conditions: 
(1) The FGFR1/CEN8 ratio is ≥2.0; 
(2) The average number of FGFR1 signals per tumor cell nucleus is ≥ 640 


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d. Evaluable (may have either measurable or non-measurable disease) 
4.1.7 Patients must have available tissue [archived formalin-fixed paraffin embedded (FFPE) 
blocks or fresh frozen biopsy from primary tumor or metastatic tumor biopsy] for correlative 
studies. Tissue source needs to be located and available at the time of registration (tissue 
needs to be submitted within 3 weeks of study initiation). Patients will not be able to start 
study drugs without tissue availability. Submission of tissue can be waived, if approved by 
the Study Chair in case of extraordinary/ catastrophic circumstances 
4.1.8 Patients must have had at least one line of systemic therapy in the metastatic setting 
4.1.9 Current use of any of the drugs listed on the Cautionary Concomitant Med list has to be 
approved by the Study Chair 
4.1.10 Patients must have adequate hematologic, hepatic and renal function. All laboratory tests 
must be obtained within 2 weeks from study drug initiation.  These include: 
a. ANC ≥ 1,500/mm3 
b. Platelet count ≥ 100,000/mm3 
c. HgB ≥ 9.0 g/dL 
d. Creatinine clearance ≥ 40 mL/min/1.73 m2  
e. SGOT, SGPT ≤ 2.5 x ULN if no liver metastasis present; SGOT, SGPT ≤ 4 x ULN if 
liver metastasis present 
f. 
Albumin ≥ 2.0 g/dL 
g. Total serum bilirubin ≤ 1.5 x ULN (≤ 3 x ULN or direct bilirubin ≤ 1.5 x ULN if known 
Gilbert’s syndrome) 
h. Potassium within institutional normal limits 
i. 
Phosphorus ≤ institutional upper limit of normal   


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4.2 
Exclusion Criteria 
4.2.1 Prior use of an FGFR inhibitor 
4.2.2 More than 2 lines of chemotherapy in the metastatic setting. No limit on endocrine therapy 
lines. Prior exposure to CDK4/6 inhibitor acceptable. 
4.2.3 Radiation therapy ≤ 2 weeks prior to study entry.  Patients who have received prior 
radiotherapy must have recovered from toxicity (≤ grade 1) induced by this treatment 
(except for alopecia) 
4.2.4 Prior cancer therapy (except for endocrine therapy) must have been discontinued for 1 
week prior to initiation of study drugs 
4.2.5 Concurrent anti-cancer therapy other than the ones specified in the protocol is not 
permitted during study participation. Bisphosphonates or denosumab are allowed 
4.2.6 Major surgery within 4 weeks of enrollment 
4.2.7 Herbal preparations are not allowed throughout the study, and should be discontinued 14 
days prior to initiation of study treatment 
4.2.8 Any corneal or retinal abnormality likely to increase the risk of eye toxicity, such as: 
a. 
Current corneal pathology such as keratitis, keratoconjunctivitis, keratopathy, 
corneal abrasion, inflammation or ulceration 
b. 
Uncontrolled glaucoma despite standard of care therapy 
c. 
Diabetic retinopathy with macular edema 
d. 
Known active wet, age-related macular degeneration (AMD) 
e. 
Known central serous retinopathy (CSR) or retinal vascular occlusion (RVO) 
4.2.9 Uncontrolled intercurrent illness including, but not limited to: 
a. Malabsorption syndrome significantly affecting gastrointestinal function 
b. Ongoing or active infection requiring antibiotics/ antivirals 
c. Impairment of lung function (COPD > grade 2, lung conditions requiring oxygen 
therapy) 
d. Symptomatic congestive heart failure (class III or IV of the New York Heart Association 
classification for heart disease)  
e. Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 
6 months 


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f. 
Clinically significant cardiac arrhythmia (multifocal premature ventricular contractions, 
bigeminy, trigeminy, ventricular tachycardia that is symptomatic or requires treatment 
[National Cancer Institute -Common Terminology Criteria for Adverse Events, Version 
4.03, grade 3]  
g. QTcF ≥ 480 msec on screening EKG  
h. Known history of clinically significant QT/QTc prolongation or Torsades de Pointes 
(TdP) 
i. 
ST depression or elevation of ≥ 1.5 mm in 2 or more leads 
j. 
Diarrhea of any cause ≥ CTCAE grade 2 that does not resolve within a few days when 
adequately treated with anti-diarrhea medications 
k. Psychiatric illness/social situations that would compromise patient safety or limit 
compliance with study requirements including maintenance of a compliance/pill diary 
l. 
Symptomatic brain metastases (patients with a history of brain metastases must be 
clinically stable for more than 4 weeks from completion of radiation treatment and be 
off steroids) 
m. Known history of chronic liver or chronic renal failure 
n. Poor wound healing capacity 
4.3 
Inclusion of Underrepresented Populations 
Individuals of all races and ethnic groups are eligible for this trial. There is no bias towards 
age or race in the clinical trial outlined. This trial is open to the accrual of women and men. 
 
 
 
 


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5. 
REGISTRATION PROCEDURES 
5.1 
Guidelines for VICC and TBCRC Institutions 
Prior to registration, a copy of the IRB approval at the site will be requested and on file at VICC. 
Eligible participants will be entered on study centrally at the VICC Coordinating Center by the 
Project Manager or designee. All sites should email the Project Manager or designee at 
coordinating.center@vumc.org to verify treatment availability.  
All patients MUST be registered with the Vanderbilt-Ingram Cancer Center (VICC) prior to 
the start of protocol treatment. Registration can only be conducted during the business 
hours of 8AM – 5PM Monday through Friday.  
Note: VICC Coordinating Center requests 24-48 hours to review all documents and confirm 
eligibility. Same day treatment registrations will only be accepted with prior notice and 
discussion with the Lead Institution. Please email the CTO if enrollment is needed sooner at 
coordinating.center@vumc.org. 
The registration procedures are as follows: 
1) All sites should email the Coordinating Center at coordinating.center@vumc.org: to notify 
of upcoming registration and slot availability. 
2) Copy of the patient’s signed and dated Informed Consent including documentation of the 
consent process  
3) Patient Enrollment Form  
4) Complete provided protocol-specific eligibility checklist (using the eligibility assessment 
documented in the participant’s medical/research record. To be eligible for registration to the 
study, the participant must meet each inclusion and exclusion criterion listed in the 
eligibility checklist.  
5) Tissue Block Registration  
6) Email the following documents to the Coordinating Center 
coordinating.center@vvumc.org: 
• 
Completed Eligibility Checklist 
• 
Copies of laboratory, imaging and pathology reports 
• 
Patient signed complete Consent Form 
• 
HIPAA authorization form (if separate from the main consent form) 
• 
Tissue Block Registration 
• 
Copy of the IRB approval at the site (if not previously sent) 
7) Once registration confirmation from Coordinating Center is received, proceed with protocol 
procedures. 
Please contact the Clinical Research Specialist or designee at coordinating.center@vumc.org 
with any questions regarding this process. 
The VICC Coordinating Center will assign sequence numbers to all patients in screening.  Only 
patients deemed eligible will be registered to investigational treatment. Sequence numbers will 
not be re-used if a patient screen fails. Following registration, eligible participants should begin 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
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study treatment consistent with the protocol no later than 28 days after registration by the VICC 
Coordinating Center. If a participant does not receive protocol therapy following registration within 
the allowed time period, the participant’s registration on the study may be canceled.  The Project 
Manager should be notified of cancellations as soon as possible. 
Issues that would cause treatment delays should be discussed with the Protocol Chair. If a 
participant does not receive protocol therapy following enrollment within allowed time period, the 
participant will become ineligible and will be removed from the study. Such patients will have to 
undergo re-screening in order to participate in the study. Any requests for eligibility exceptions 
and/or deviations must be approved in writing by the Protocol Chair, the VICC DSMC and the 
IRB.  
As is generally accepted, standard of care procedures performed prior to consent, but within the 
protocol defined screening window for each assessment, can be used for study purposes.  All 
research-only procedures must be performed after the consent date. 
 
 


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6. 
STUDY CALENDAR 
Parameter 
Pre-
Study1 
Month/Week/Cycle 
End of 
Treatment6 
 
 
 
28 Day  
Follow-
up17 
 
 
Long 
Term 
Follow-
up18 
D1, 8, 
15 and 
22 
Cycle 
1 
D1 
and 15 
Cycle2 
D1 of 
every 
Cycle9 
Every 
8 
weeks 
Demographics 
X 
 
 
 
 
 
 
 
CLINICAL EVALUATIONS: 
History and 
Physical 
X 
X 
X 
X 
 
X 
 
 
Toxicity 
Assessments 
X 
X 
X 
X 
 
X 
X 
 
 Concomitant 
Medications 
Assessments 
X 
X 
X 
X 
 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
Vital Signs and 
Weight 
X 
X 
X 
X 
 
X 
 
 
Performance 
Status 
X 
X 
X 
X 
 
X 
 
 
Ophthalmologic 
Exam 
X12, 13, 
14 
 
 
 
 
 
 
 
Amsler Grid 
Test12, 14 
 
 
 
X 
 
X 
 
 
LABORATORY/RADIOLOGIC EVALUATIONS: 
Hematology 
(CBC/diff, PLT) 
X 
X 
X 
X 
 
X 
 
 
Comprehensive 
Metabolic Panel2 
X 
X 
X 
X 
 
X 
 
 
Magnesium 
X 
X 
X 
X 
 
X 
 
 
Phosphorus 
X 
X 
X 
X 
 
X 
 
 
Parathyroid 
Hormone (PTH) 
 
X8 
X 
 
 
 
 
 
Total vitamin D 
 
X8 
X 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
Tumor Evaluation3 
X 
 
 
 
X 
 
 
 
TREATMENT ADMINISTRATION: 
Erdafitinib 
 
Daily 
 
 
 
Palbociclib 
 
Days 1 - 21 of every 28-days cycle 
 
 
 
Fulvestrant 
 
X10 
 
X 
 
 
 
 
Pill Diary5 
 
 
 
X 
 
 
 
 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
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Meal Record 
 
X16 
X 
 
 
 
 
 
CORRELATIVE STUDIES: 
Tumor Tissue 
Collection4 
X 
 
 
 
 
 
 
 
Blood Collection 
needed to 
accompany tissue 
for NGS analysis15 
X 
 
 
 
 
 
 
 
FGFR1 FISH 
Analysis 
X 
 
 
 
 
 
 
 
Blood Collection 
for cfDNA11 
X 
 
 
 
X 
X 
 
 
Blood Collection 
for 
Pharmacokinetic 
Assessments 
 
X7 
X 
 
 
 
 
 
Blood Collection 
for 
Pharmacodynamic 
Assessments 
 
X8 
X 
 
 
 
 
 
FOLLOW-UP: 
Chart review for 
progression 
status18 
 
 
 
 
 
 
 
X 
 
Notes:   
• 
Additional tests may be performed at the discretion of the treating investigator as clinically indicated.  The sample 
collection schedules outlined above are based on an ideal subject.  
• 
All appointment/procedures may be performed ± 3 days to accommodate unexpected scheduling issues, 
weekends and holidays. The sample schedule should be followed as closely as is realistically possible; however, 
the schedule may be modified due to problems such as scheduling delays or conflicts (e.g., clinic closure, poor 
weather conditions, vacations, etc.). 
• 
Shaded cells (gray) represent RESEARCH procedures; white cells represent STANDARD OF CARE procedures 
 
1. 
Pre-study assessments should be performed within 28 days prior to starting treatment, unless otherwise noted. 
Please note that the labs obtained on Cycle 1, Day 1 also need to meet eligibility criteria. Screening procedures 
(i.e. history and physical exam, etc.), excluding labs, which are conducted within 1 week of C1D1 do not need to 
be repeated. Labs performed on C1D1 for screening are permitted given that they are submitted to the 
Coordinating Center and approved prior to study treatment initiation. 
2. 
Chemistry includes measurement of sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, total 
bilirubin, calcium, total protein, albumin, AST, ALT, and alkaline phosphatase. 
3. 
CT scans (chest/abdomen/pelvis) are acceptable for tumor evaluations. MRI of the brain is to be performed only 
at the discretion of treating physician. Baseline scans should be performed up to 4 weeks prior to study drugs 
initiation. The scans may be performed ± 5 days of patient’s scheduled appointment, to accommodate weekends 
and holidays      
4. 
FFPE blocks may be from the primary tumor (time of original diagnosis) or a metastatic biopsy site. If available, a 
previously stored fresh-frozen tissue will also be collected. Tissue collected should be submitted at the time of 
registration. If patients are agreeable, at any time prior, during, or after study drug exposure, an optional (but 
encouraged) fresh-frozen tissue research biopsy of a metastatic site of disease will be performed and collected 
(see Section 10.3 for more details). It is assumed that about 20% patients will agree to a fresh biopsy. 
5. 
Pill Diary dispensed with study drug for all patients in the study. 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
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6. 
End of treatment procedures will be carried out  after patients are off study drugs at either their current visit or 
within 7 days of coming off the study drug.  
7. 
Blood for PK (see Section 10): Plasma for pharmacokinetic assessments will be collected on Days 1 and 15 of 
Cycles 1 and 2 only in  patients participating in the escalation portion of the trial. Of note, PK samples could be 
obtained from additional patients if there are concerns about the PK profiling and/or clinical safety based on the 
available results.  For further details (including sampling schedule if an alternative dosing schedule is adopted) 
please see the Lab Manual. A meal record should be completed on days of PK assessment. 
8. 
Blood for pharmacodynamic assessments [serum Calcium, Phosphate, PTH, vit D, FGF23, sFGFR2, sFGFR3 
and sFGFR4; Section 10] will be performed on Days 1 and 15 of Cycles 1 and 2 in all patients in the escalation 
part of the trial. 
9. 
C1D1 procedures are not required; the baseline procedure will be the one done within 28 days of trial treatment 
initiation (pre-study). 
10. Fulvestrant loading dose should be administered on Cycle 1 Day 15 
11. cfDNA will be collected at: baseline (Cycle 1, Day 1), Day 1 of every even cycle after treatment initiation, and 
at the time of disease progression if the patient was still receiving study treatment at the time of disease 
progression. (end-of-treatment) 
12. All subjects should have monthly Amsler grid tests and an initial ophthalmological examination performed at 
Screening by an ophthalmologist, which should include assessment of visual acuity, tonometry, fundoscopy 
(examination of both central and peripheral zones should be performed); where available, an Optical Coherence 
Tomography (OCT) should be performed. A follow-up ophthalmological examination should be performed as 
clinically necessary based on the findings of the monthly Amsler grid tests and clinical assessment. It is assumed 
that about 30% patients will require follow-up ophthalmological examinations. 
13. 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 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. 
14. Amsler grid testing will be administered by the treating physician or nurse on Day 1 of each 28-day cycle. 
Observation of wavy, broken or distorted lines, or reporting of 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. 
15. This tube of whole blood is necessary to be used as germline control once the Next Generation Sequencing is 
performed in the tissue collected. See Lab Manual for details. 
16. Meal Record should be completed only on days of long PK assessments.  
17. The 28 day follow-up visit will also be considered the off study visit for all patients removed for disease 
progression.  
18. Patients removed from study drugs for reasons other than disease progression will be followed by chart review 
every three months until progression of disease occurs. 
 
 
 
 
 
 
 


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7. 
TREATMENT PLAN 
7.1 
Overview 
This is an open-label, multi-institution, phase Ib (3+3 dose escalation design) that evaluates the 
safety profile (assessment of DLTs and MTD of the combination), tolerability and anti-tumor 
activity (progression-free survival [PFS] and lack of disease progression for ≥ 6 months [clinical 
benefit rate; CBR]) of fulvestrant, palbociclib and erdafitinib in patients with metastatic ER+/HER2-
/FGFR-amplified breast cancer.  
When feasible, a baseline biopsy of a metastatic site will be obtained for NGS and/or FGFR FISH 
prior to therapy initiation. Plasma will also be obtained at baseline, 4 weeks after treatment 
initiation and at disease progression for measurement of cfDNA. Treatment will be given until 
disease progression or unacceptable toxicity. To assess for anti-tumor effects, we will estimate 
the overall tumor burden at baseline to which subsequent measurements (performed every 8 
weeks using the Solid Tumor Response Criteria [RECIST] v1.1) will be compared. 
Pharmacokinetic and pharmacodynamic studies will be obtained throughout the study.  
7.2 
Screening Phase 
At screening, the patient will provide a signed informed consent form prior to any study related 
activities. Patients with known FGFR1 amplification (by NGS, cfDNA or FISH) will require central 
confirmation of FGFR1 amplification by FISH, but will not be required to wait for that result to 
initiate study treatment. Patients with known FGFR2-4 amplification (by NGS, cfDNA or FISH) will 
not require central confirmation of FGFR amplification by FISH. Patients without known FGFR 
amplification will be screened for FGFR1 amplification (as this is the most prevalent one) by FISH 
analysis at the Vanderbilt-Ingram Cancer Center (VICC). See Section 10 for details on tissue 
submission requirements and testing procedures. Once patients are deemed eligible, participants 
should begin study treatment consistent with the protocol as soon as possible but no later than 
28 days after registration by the VICC Coordinating Center. 
7.3 
Agent Administration 
The investigator will instruct the patient to take the study drugs as follows: 
• 
Palbociclib: taken orally once daily, with food, for 21 days out of a 28-day cycle 
• 
Erdafitinib: taken orally once daily, with ot without food, at approximately the same time every 
day, in a 28-day cycle  
• 
Fulvestrant: IM once every 28 days (except on cycle 1, when fulvestrant will also be 
administered on day 15). On the days that patients come in for clinic visit/ fulvestrant 
administration on even cycles (i.e. when tumor measurements or PKs are done), 
administration of palbociclib and erdafitinib should wait to be done in clinic. 
A pill diary will be given to all patients enrolled in the study.  
 
1 cycle = 28 days 
N of 
pts. 
Dose 
Level 
Fulvestrant  
(IM q28 
days)§ 
Palbociclib*  
(PO daily x 21 out of  
28 days) 
Erdafitinib  
(PO daily) 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
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3-6 
3 
500 mg 
125 mg 
8 mg 
3-6 
2 
500 mg 
125 mg 
6 mg 
3-6 
1 
500 mg 
125 mg 
5 mg 
3-6 
–1 
500 mg 
125 mg 
4 mg 
* Palbociclib dose may be adjusted per standard of care clinical guidelines based on blood cell 
counts 
§ On cycle 1, fulvestrant will also be administered on day 15 (loading dose) 
7.3.1 Fulvestrant 
Fulvestrant is FDA-approved for the treatment of ER+ MBC. It does not require specific 
prophylactic or supportive regimens. It is an intramuscular therapy that should be prepared 
according to manufacturer’s recommendations.  
Fulvestrant (500 mg) will be given on Day 1 and 15 in cycle 1 and then only Day 1 of each 
subsequent cycle during the treatment phase (± 3 days), in a 28-day cycle. Fulvestrant is 
administered intramuscularly, slowly, as two 5mL injections, one in each buttock. It can be 
administered with or without food. 
On days when fulvestrant is administered, pharmacokinetic (PK) sampling should follow these 
additional guidelines:  
• 
The pre-dose sample should be drawn just before fulvestrant dosing.  
• 
The sampling time of the pre-dose PK sample and the dosing time of fulvestrant must be 
precisely recorded. 
7.3.2 Palbociclib 
Palbociclib is FDA-approved in combination with fulvestrant for the treatment of ER+ MBC. 
Administration is performed on an outpatient, self-administration basis, at a starting dose of 125 
mg orally once daily, with food, on Days 1-21 followed by 7 days off treatment, in a 28-day cycle. 
Capsules of 75, 100 and 125 mg are available in case dose reductions are necessary (see Dose 
Modification guidelines, Section 8). 
On days when patient is scheduled for a clinic visit, the patient should take scheduled palbociclib 
dose once all visit assessments have been performed and are within acceptable range) unless 
otherwise indicated. Patients should be instructed to record daily administration of the study drugs 
in the pill diary. 
Missed doses of palbociclib should not be made up. For example, if a dose is vomited any time 
after taking palbociclib, a replacement dose should NOT be taken. If a dose is entirely missed for 
one day, dose should be skipped and NOT made up the next day; patients should resume regular 
dosing as prescribed the following day. Patients who inadvertently take one extra dose during a 
day must skip the next day’s dose. If patient takes more than two doses of palbociclib in a day, 
the patient should bring this to the attention of his or her treating physician.  
On days with PK sampling, the following additional guidelines should be followed: 
• 
The pre-dose sample should be drawn before palbociclib dosing 
• 
On days and time points when PK, biochemistry, hematology or other blood samples are to 
be performed, the PK sample must be drawn first  
• 
The sampling time of the pre-dose PK sample and the dosing time of palbociclib must be 
precisely recorded  


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• 
If vomiting occurs, the exact time of the first vomiting episode within the first 4 hours post-
dosing on that day must be noted 
• 
Time of administration of gastric protection agents on days of PK sampling should be precisely 
recorded 
7.3.3 Erdafitinib 
Erdafitinib is an investigational product manufactured and provided by Janssen Research & 
Development, as film-coated tablets of 3, 4 and 5 mg. Administration is performed on an 
outpatient, self-administration basis, at a stipulated starting dose based on the escalation cohort 
level. Tablets should be swallowed intact, once daily, with 240 mL of water (8 ounces), with or 
without food, at approximately the same time every day, in a 28-day cycle. For dose adjustments, 
see Dose Modification guidelines, Section 8.  
If a dose is missed, it can be taken up to 6 hours after the scheduled time. Otherwise, that dose 
should be skipped and subject should continue treatment at the scheduled time the next day. 
Missed doses of erdafitinib should not be made up. For example, if a dose is vomited any time 
after taking erdafitinib, a replacement dose should NOT be taken. If a dose is entirely missed for 
one day, dose should be skipped and NOT made up the next day; patients should resume regular 
dosing as prescribed the following day. Patients who inadvertently take one extra dose during a 
day must skip the next day’s dose. If patient takes more than two doses of erdafitinib in a day, the 
patient should bring this to the attention of his or her treating physician.  
On days when patient is scheduled for a clinic visit, the patient should take scheduled erdafitinib 
dose once all visit assessments have been performed and are within acceptable range unless 
otherwise indicated. Patients should be instructed to record daily administration of the study drugs 
in the pill diary. 
On days with PK sampling, additional guidelines should be followed: 
• 
The pre-dose sample should be drawn before erdafitinib dosing  
• 
On days and time points when PK, biochemistry, hematology or other blood samples are to 
be performed, the PK sample must be drawn first 
• 
The sampling time of the pre-dose PK sample and the dosing time of erdafitinib from the day 
before and current day must be precisely recorded  
• 
If vomiting occurs, the exact time of the first vomiting episode within the first 4 hours post-
dosing on that day must be noted  
• 
Time of administration of gastric protection agents on days of PK sampling should be precisely 
recorded 
7.4 
Definition of Dose-Limiting Toxicity (DLT) 
Any of the following events that occur during cycle 1 (first 4 weeks) will be considered a DLT when 
classified as possibly, probably or definitively related to investigational study treatment (according 
to NCI CTEP Adverse Event Reporting Requirements). Apart from the criteria listed below, if a 
lower grade AE leads to a dose interruption of more than 21 consecutive days of erdafitinib for 
the first 4 weeks of Cycle 1, this AE will be considered a DLT; patients must receive at least 75% 
of study drug during cycle 1 in order to be evaluable for the DLT observation period. Whenever a 
patient experiences toxicity that fulfills the criteria for a DLT, treatment with the study drug 
responsible for the toxicity will be interrupted (patient may continue the remainder study drugs) 
and the toxicity will be followed up. The Protocol Chair must be notified immediately of any DLT: 
 


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TOXICITY 
DLT CRITERIA 
Blood and lymphatic 
system disorders 
Anemia CTCAE Grade ≥ 3 will not be considered DLT unless 
judged to be a hemolytic process secondary to erdafitinib.   
Febrile neutropenia CTCAE Grade ≥ 3 
ANC CTCAE Grade 3 for > 14 consecutive days 
ANC CTCAE Grade 4 
Platelet count CTCAE Grade 3 for > 7 consecutive days and/or 
with signs of bleeding 
Platelet count CTCAE Grade 4 
 
Ocular disorders 
CTCAE Grade ≥ 2 for > 21 days 
CTCAE Grade ≥ 3 
 
General disorders and 
administration site 
conditions  
Fatigue CTCAE Grade 3 for > 7 consecutive days 
 
Skin and subcutaneous 
tissue disorders  
Skin, mucosal or nail toxicity CTCAE Grade ≥ 3 for > 72 hours 
 
Hyperphosphatemia 
Phosphorus level ≥ 7.0 mg/dL for > 14 days despite treatment 
 
GI disordersa 
Diarrhea CTCAE Grade ≥ 3 for ≥ 48 hrs, despite the use of anti-
diarrhea therapy  
Nausea/vomiting CTCAE Grade ≥ 3 for ≥ 48 hrs, despite the use of 
anti-emetic therapy  
Constipation CTCAE Grade ≥ 3 for ≥ 48 hrs, despite the use of 
anti-constipation therapy 
 
Investigationsb 
Blood bilirubinc CTCAE Grade 2 for > 7 consecutive days or ≥ 
Grade 3 
AST or ALT CTCAE ≥ Grade 3  
Alkaline phosphatase CTCAE ≥ Grade 3  
 
Other hematologic and 
non-hematologic 
toxicities 
Any other CTCAE ≥ Grade 3 toxicity for > 7 consecutive days  
(except decreased lymphocyte count [lymphopenia] that is not 
clinically significant) 


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TOXICITY 
DLT CRITERIA 
a Patients will not initially receive prophylactic treatment for nausea/vomiting during Cycle 1. 
However, prophylactic treatment may be initiated in all patients at the dose level where these 
toxicities have been observed and in all further patients if at least 1 patient has experienced 
nausea/vomiting CTCAE Grade ≥ 3 or if at least 2 patients experienced nausea/vomiting 
CTCAE Grade ≥ 2. However, anti-emetics may be applied for treatment if the patient has 
experienced nausea/vomiting CTCAE Grade ≥ 1 at the discretion of the treating physician.  
b For any hepatic toxicity CTCAE Grade 4, or CTCAE Grade 3 that does not resolve within 7 
days to CTCAE Grade ≤ 1 (or CTCAE Grade ≤ 2 if liver infiltration with tumor present), an 
abdominal CT scan should be performed to assess if it is related to disease progression. 
c Refers to total bilirubin. 
 
Apart from the criteria listed above, if a lower grade AE leads to a dose interruption of more 
than 14 consecutive days of erdafitinib, this AE may be considered as DLT (the determination 
will be based on clinical significance and patient risk; discussion with the Protocol Chair will 
determine if the event should or should not count as a DLT). 
Patients whose treatment is interrupted or permanently discontinued due to an AE or clinically 
significant laboratory value, must be followed as outlined in the table below, at least once a week 
for 4 weeks, and subsequently at 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Patients that require a dose delay of > 28 days due to a cause unrelated 
to study participation will have the opportunity to continue study if deemed eligible to do so by the 
Protocol Chair of the study. 
TOXICITY 
FOLLOW-UP EVALUATION 
Hematology 
If ≥ CTCAE grade 3 neutropenia or ≥ CTCAE grade 3 
thrombocytopenia have been demonstrated, these parameters 
must be repeated at least once a week until resolution to ≤ CTCAE 
grade 1 neutropenia or ≤ CTCAE grade 1 thrombocytopenia to 
allow for initiation of re-treatment. 
 
Renal 
If creatinine ≥ 2 x ULN has been demonstrated, this parameter 
must be evaluated at least twice a week until resolution to ≤ 
CTCAE grade 1 to allow for initiation of re-treatment, and then at 
least weekly until either resolution or until stabilization. 
Creatinine ≥ 2.0 x ULN and 3+ proteinuria or hematuria ≥ CTCAE 
grade 2 has been demonstrated, a 24-hour urine collection for 
total protein and total creatinine must be repeated at least weekly 
until either parameter returns to baseline value or until 
stabilization. Whenever a measured CrCl is obtained, a creatinine 
should be obtained within ≤ 72 h of the urine collection. 
 
Hepatic 
If total bilirubin ≥ 2 x ULN or ≥ CTCAE grade 3 AST/ALT has been 
demonstrated, these parameters must be repeated daily until 
resolution to ≤ CTCAE grade 1 (or ≤ grade 2 for AST or ALT, if liver 
metastasis are present) to allow for initiation of re-treatment, and 
then at least weekly until either resolution or until stabilization 
Patients with total bilirubin > ULN (any duration) should have 
fractionation of bilirubin into total/direct or indirect/direct 
components and any additional work-up as clinically indicated by 


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these results. Follow-up of hyperbilirubinemia should proceed as 
per the guidelines above, irrespective of the results of 
fractionation. 
 
Metabolic/Laboratory 
Parameters of metabolic/ laboratory abnormalities ≥ CTCAE grade 
3 must be assessed once at 2 to 4 days and once again at 7 days 
(± 1 day) and be repeated twice a week until resolution to ≤ CTCAE 
grade 2 to allow for initiation of re-treatment, and then at least 
weekly until either resolution to ≤ CTCAE grade 1 or until 
stabilization. 
A CT scan or other imaging study to assess the pancreas, liver, 
and gallbladder must be performed within 1 week of the first 
occurrence of any ≥ CTCAE grade 3 of amylase or lipase levels. 
In patients with triglycerides ≥ 500 mg/dL, urine amylase needs to 
be tested in addition. 
 
Ocular toxicity 
Patients who experience ocular toxicity should be followed as per 
Dose Modification guidelines (Section 8) 
 
Non-Laboratory 
Patients who experience non-laboratory DLTs must be evaluated 
at least once a week following demonstration of the toxicity until 
resolution of the toxicity to allow for re-treatment, stabilization of 
the toxicity, or study treatment completion. 
 
7.5 
Definition of Maximum Tolerated Dose (MTD) 
The MTD will be defined as the highest dose at which 20% of the patients experienced a DLT. 
The first cohort of patients (3 patients) will be started at dose level 1, and each patient will be 
observed for 4 weeks on the specified dose. No new cohort of patients will be treated until the 
previous cohort has been fully evaluated for toxicity and a dose escalation decision has been 
made. Routine updates regarding patient and study status will be conducted.   
Once the MTD is reached, the safety data will be analyzed and the expansion component of the 
study will be completed to assess tolerability and efficacy. Patients in the phase II portion of the 
study will initiate study treatment at the MTD defined in the escalation component of the trial. Note 
that dose reduction within patients (individually) is allowed after the 4 week DLT observation 
period in the escalation and in the expansion components of the study (see Dose Modification 
guidelines, Section 8). Intrapatient dose escalation will not be allowed. Dose reduction will be 
required for a given patient in case of: 
• 
Grade 3 or 4 toxicities 
• 
Grade ≥ 2 hyperphosphatemia lasting more than 21 days despite medical treatment, or  
• 
Grade ≥ 2 ocular toxicity lasting more than 28 days despite medical treatment, or 
• 
Grade ≥ 2 elevation of creatinine, bilirubin, AST, or ALT lasting more than 14 days despite 
medical treatment, or 
• 
Grade ≥ 2 skin or nail toxicity for more than 28 days in a row despite optimal medical treatment, 
or 


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• 
Grade ≥ 2 GI toxicity lasting more than 14 days despite medical treatment.  
7.6 
Concomitant Treatment and Supportive Care Guidelines 
Because there is a potential for interaction of erdafitinib and palbociclib with other concomitantly 
administered drugs through the cytochrome P450 system, the case report form must capture the 
concurrent use of all other drugs, over-the-counter medications, or alternative therapies. The 
Protocol Chair should be alerted if the patient is taking any agent known to affect or with the 
potential to affect selected P450 isoenzymes (Cautionary Concomitant Medications list). Patients 
taking any of the medications on the Cautionary Concomitant Medications list are enrouraged to 
seek alternative medications; if not possible, patient will not necessarily be excluded from entering 
the study, but approval by the Study Chair has to be obtained prior to enrollment. Patients already 
enrolled in the study that initiate and persist taking any of the medications on the Cautionary 
Concomitant Medications list will also require approval from the Study Chair. 
Patients on chronic medications that can be given concomitantly with erdafitinib and palbociclib 
should be maintained on the same dose and dose schedule throughout the study period, as 
medically feasible. The investigator should instruct the patient to notify the study site about any 
new medications he/she takes after the start of the study drug. All medications (other than study 
drug) and significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient starts treatment with study drug, and any changes in dosing should 
be recorded. 
All supportive measures consistent with optimal patient care can be given throughout the study 
at the discretion of the treating physician, as long as they are not part of the list of prohibited 
medications. In general, the use of any concomitant medication/therapies deemed necessary for 
the care of the patient is permitted with the following considerations: 
• 
Prophylactic anti-emetics should be started only once the patient experienced nausea or 
vomiting at the discretion of the investigator.  
• 
There are no concurrent supportive or prophylactic growth factor support regimens 
recommended for palbociclib. While the rates of grade III/IV neutropenia are considerable with 
CDK4/6 inhibitors, the rates of febrile neutropenia (FN) are quite low, and well below the 20% 
threshold for which FN prophylaxis with G-CSF is recommended. Nonetheless, G-CSF 
support will be allowed at the treating physician’s discretion. Hematopoietic growth factors 
may be used according to ASCO guidelines 
• 
Bone directed therapy to prevent skeletal related events (SRE’s) or to treat osteoporosis with 
bisphosphonates or denosumab is permitted. While the use of bisphosphonates has been 
found to reduce the incidence of new bone metastases in patients with metastatic breast 
cancer, we do not anticipate this to affect the results of this trial. Thus, treatment initiated prior 
to registration or after registration with these agents is permitted. The time of initiation of bone 
directed therapy should be clearly recorded on the case report forms 
• 
Local radiotherapy required for life-threatening situations (e.g., superior vena cava syndrome, 
spinal cord compression, central nervous system metastases) will require the patient to 
discontinue protocol treatment due to symptomatic deterioration. However, limited palliative 
radiotherapy (i.e., to bone metastasis) in subjects who are otherwise benefiting from study 
treatment will be allowed during the study but must be discussed with the Protocol Chair. 
Study treatment should be withheld until palliative radiotherapy is terminated. This treatment 
break should not be considered as treatment interruption. Palliative radiation is permitted if 
done solely for bone pain relief. It should not be delivered to a target lesion and it should not 
encompass more than 25% of irradiated bone marrow. If palliative radiotherapy is initiated 


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after the start of study treatment, the reason for its use must be clearly documented and 
progression as per RECIST 1.1 must be ruled out 
• 
Other investigational therapies must not be used while the patient is on the study 
• 
Anticancer systemic therapy other than the study treatments must not be given to patients 
while on the study. If such agents are required for a patient then the patient must be 
discontinued from the study 
• 
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 
• 
Herbal preparations are not allowed throughout the study. These herbal preparations include, 
but are not limited to: St. John’s wort, Kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Patients should stop 
using these herbal preparations 14 days prior to first dose of study drug  
7.7 
Duration of Therapy 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse events, treatment may continue 
until one of criteria in Section 7.9 applies. 
7.8 
Duration of Follow-Up  
Participants will have a follow up at 28 days (± 7days) after discontinuation of study drugs 
for any reason (unacceptable adverse events or disease progression) for toxicity 
assessments.  
• 
Participants removed from study for unacceptable adverse events will be followed weekly 
until resolution or stabilization of a serious adverse event, and will be followed every three 
months (chart review) until disease progression, or until death from any cause (whichever 
occurs first)Patients continuing fulvestrant who have discontinued erdafitinib or palbociclib 
for any reason other than disease progression will be followed until disease progression 
as stated above 
7.9 
Criteria for Removal from Study  
Participants will be removed from study when any of the criteria listed in Section 7.10 applies. All 
patients who initiate protocol treatment will be included in the safety analysis, and all patients who 
initiate protocol treatment and receive at least 8 weeks of treatment will be included in overall 
evaluation of response. All reasons for discontinuation of therapy should be documented clearly 
in the medical record.  
7.10 Discontinuation of Treatment 
The reasons for discontinuation or protocol treatment include: 
 
• 
Evidence of disease progression during treatment at the discretion of the treating investigator 
• 
Non-compliance with the study protocol, including, but not limited to not attending the majority 
of scheduled visits. The Protocol Chair will determine when non-compliance should lead to 
removal from study. Note: These patients will still be included in the overall evaluation of safety 
and response 
• 
Unacceptable major toxicity. Note: These patients will still be included in the overall evaluation 
of safety and response 


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• 
Intercurrent illness or condition that would, in the judgment of the treating investigator, affect 
assessment of clinical status to a significant degree or require discontinuation of study 
treatment 
• 
At subject’s own request. Note: The reason for discontinuation from the study must be 
documented. These patients will be included in the overall evaluation of safety and response 
if any protocol therapy was administered prior to withdrawal 
• 
Study is closed for any reason (e.g. new information shows that the patient’s welfare would 
be at risk if she continued study treatment) 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator 
• 
Patients that require a dose delay of > 28 days. If the delay is due to a cause unrelated to 
study participation, the patient will have the opportunity to continue study if beyond the first 8 
weeks of treatment, if clinical benefit is seen, and if deemed eligible to do so by the Protocol 
Chair of the study 
• 
If the patient requires dose reduction below dose level -1, the patient should be discontinued 
from the study unless deemed to have clinical benefit that would outweigh the risk. A 
discussion with the Protocol Chair should be carried out prior to final decision on 
discontinuation  
7.11 Replacement of Patients Who Discontinue Early 
In general, the study intends that patients would be treated until disease progression or 
intolerable toxicity.  During the phase Ib dose escalation period and phase II portion of the study, 
if a patient discontinues study treatment for reasons clearly not related to study treatment, after 
completing fewer than one planned cycle of study, and/or receiving <75% of the total intended 
dose of study drugs over the first cycle of treatment, then that patient will be considered not 
evaluable and may be replaced with a new patient.   
7.12 Withdrawal from Study 
The reasons for withdrawal from the study include: 
• 
Subject withdraws consent for follow-up 
• 
Subject is lost to follow-up 
• 
Study is terminated for any reason 
8. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS 
8.1 
Erdafitinib 
8.1.1 Most common anticipated toxicities (refer to IB for further details) 
• 
Hyperphosphatemia  
• 
Decrease in appetite 
• 
Dry mouth   
• 
Nail and skin toxicities  
• 
Palmar-plantar erythrodysthesia  
• 
Mucositis (mouth sores) 
• 
Dysgeusia 
• 
Constipation  
• 
Diarrhea 
• 
Fatigue/asthenia  


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• 
Reversible retinal pigment epithelial detachment (RPED or central serous retinopathy [CSR])  
• 
Nausea 
8.1.2 Adverse events of special interest 
Central serous retinopathy was reported in 52 subjects (10.4%)  across 5 studies at all doses and 
32 subjects (14.4%) at the 8 or 9 mg dose.  Events of CSR included preferred terms of , retinal 
detachment (18 subjects), chorioretinopathy (15 subjects), detachment of retinal pigment 
epithelium (11 subjects) and retinal edema (5 subjects). Most  events were Grade 1 or Grade 2 
(data cut-off 4 June 2019, IB v. 8).  Drug-induced CSRs are generally reversible. 
8.1.3 Adverse events of clinical importance 
8.1.3.1 
Skin, mucosal, and nail changes 
Skin, mucosal and nail toxicities are commonly reported in erdafitinib studies. Nail toxicity were 
reported in 44.3% of subjects at all doses (56.8% at the 8 or 9 mg dose) and skin toxicityin 42.3% 
of subjects  (45.9% at the 8 or 9 mg dose) from 5 poled studies (data cut-off June 2019, IB v 8). . 
While frequent and known to be associated with FGFR inhibitors, these toxicities respond well to 
medical management and did not necessitate permanent changes in treatment. 
General recommendations to avoid skin toxicities: 
• 
Avoid unnecessary exposure to sunlight and excessive use of soap. 
• 
Avoid bathing in excess; use tepid rather than hot water.   
• 
Use moisturizers regularly; apply thick, alcohol-free and oil-in-water based emollient cream 
on exposed and dry areas of the body.   
• 
Avoid perfumed products, bubble bath, perfumed soaps, and take breaks from shaving.   
• 
Use broad-spectrum sunscreen with a skin protection factor (SPF) ≥15. 
• 
Wear cotton clothes next to skin rather than wool, synthetic fibers, or rough clothing. 
• 
Use occlusive alcohol-free emollient creams (jar or tub) for treatment of mild/moderate 
xerosis. 
• 
For scaly areas, use exfoliants (ammonium lactate 12% or lactic acid cream 12%). 
General recommendations to prevent mucositis:  
• 
Good oral hygiene 
• 
Use a soft toothbrush 
• 
Avoidance of spicy, acidic, hard, and hot food and beverages 
• 
Use of mild-flavored toothpastes 
• 
Use of saline-peroxide or salt and soda mouthwashes 3 or 4 times per day 
• 
Water soluble lubrication agents like artificial saliva (for xerostomia or dry mouth) 
General recommendations to prevent nail toxicities: 
• 
Good hygienic practices, keep fingers and toes clean. 
• 
Keep nails trimmed 
• 
Use gloves for housecleaning and gardening to minimize damage and prevent infection 
• 
Nail polish and imitation fingernails should not be worn until the nails have grown out and 
returned to normal 
• 
Wearing comfortable shoes (wide sized shoes with room for the toes) 
• 
Trimming nails but avoiding aggressive manicuring 


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8.1.3.2 
Hyperphosphatemia 
Hyperphosphatemia, an expected class effect of FGFR inhibitors, was the most frequently 
reported AE of clinical importance in Study EDI1001 (65.2% of subjects, Table 49 of IB) and in 
Study BLC2001 (54.3% of subjects,Table 50 of IB). To further understand the occurrence of 
hyperphosphatemia, an analysis of serum phosphate levels was conducted in Study EDI1001. 
The average baseline phosphate level for 187 subjects across tumor types was 3.4 mg/dL with a 
median of 3.4 mg/dL and range of 1.5-5.2 mg/dL. The profile of mean percent change in 
phosphate levels over time showed phosphate levels peaked between Cycles 1 and 2 of 
treatment with erdafitinib. Increases in phosphate were dose dependent; at 9 mg daily, the 
maximum mean phosphate concentration was 7.3 mg/dL on Cycle 1 Day 21. The trend in mean 
phosphate levels showed a decline in phosphate level changes from baseline over time beginning 
at approximately Cycle 3 of treatment. Thus maximum phosphate elevations were transient and 
serum phosphate levels stabilized even with continued exposure to erdafitinib. If use of a 
phosphate binder is required and sevelamer hydrochloride (Renagel) is not available, use of other 
phosphate binders (non-calcium containing) based on the local standard is recommended, 
including Sevelamer carbonate (Renvela) or lanthanum carbonate (Fosrenol).  
8.1.3.3 
Arrhythmias 
Arrythmia is no longer an AE of clinical importance.  Due to the preclinical signal, arrhythmias 
remain were designtated as  clinically important; however, the potential cardiac liability of 
erdaftinib has not been observed in clinical studies. A review of the QTcF intervals and the 
pharmacokineticpharmacodynamic relationships for erdafitinib revealed no effects of erdafitinib 
on cardiac repolarization or other electrocardiographic parameters. Thus the potential cardiac 
liability of erdafitinib has, to date, not been observed in clinical studies. 
8.1.3.4 
Ocular toxicities  
Ocular toxicities such as dry eyes, keratitis and reversible retinal pigment epithelial detachment 
(RPED or central serous retinopathy [CSR]/ choroidopathy) have been noted with erdafitinib and 
other FGFR inhibitors. Eye toxicity was reported by 41.1% of subjects in  at all doses from 5 
studies(data cut-off June 2019, IB v8), the most common events (≥ 5% overall were dry eye, 
lacrimation increased, vision blurred, and conjunctivitis. 
Retinal pigment epithelial detachment is the separation of the retinal pigment epithelium (RPE) 
from the Bruch’s membrane due to the presence of sub-RPE fluid, blood, fibrovascular 
membrane, or drusenoid material and is attributed to the disruption of the ionic pump of the RPE 
cells or hyperpermeability of the choroidal vasculature. Drug- induced RPED/CSRs are generally 
reversible.  
8.1.3.4.1 Assessment and evaluation plan for new subjects and subjects during study without 
ocular symptoms 
All patients exposed to erdafitinib should have a baseline assessment of visual acuity, tonometry, 
fundoscopy (examination of both central and peripheral zones should be performed) and Amsler 
Grid test, and, where available, an optical coherence tomography (OTC) should be performed. 
The ophthalmological test should be performed once during screening. Additional exams should 
be performed as clinically necessary based on the findings of the Amsler grid test and clinical 
assessment. 


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An Amsler grid test should be performed at the beginning of every new cycle and at the end of 
treatment, to identify any new abnormalities (observation of wavy, broken or distorted lines or a 
blurred or missing area of vision). 
• 
If the subject is asymptomatic and the Amsler grid test is negative, patient will continue study 
medication at current dose and schedule. 
• 
If the subject is asymptomatic and the Amsler grid test is positive (observation of wavy, broken 
or distorted lines or a blurred or missing area of vision) then the subject should have a full 
ophthalmological exam as described, within 7 days. If this is not possible then the study drug 
should be withheld until a full ophthalmological exam is performed. 
• 
If the subject has ocular abnormalities, manage as per the Dose Modification guidelines for 
ocular toxicity (Section 8.4). 
8.1.3.4.2 Assessment and evaluation plan for any subject during study with ocular symptoms 
Subjects that have ocular symptoms at any time should be managed as per the “Management 
Guidelines for Eye Toxicity Associated with Vision Changes”. 
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. 
When central serous retinopathy (CSR)/retinal pigment epithelial detachments (RPED) is 
suspected then an OCT should be performed. Fluorescein angiography could be considered 
appropriate in conditions such as suspected retinal vein occlusion (RVO). It is also recommended 
that color fundus photos or OCT images be obtained and stored in the patient’s file for future 
reference. In patients with suspected retinal pathology such as CSR or RVO a consultation with 
a retina specialist should be considered. 
8.1.3.4.3 Management Guidelines for Eye Toxicity Associated With Vision Changes 
Eye toxicities considered a consequence of dry eye should be managed as per the standard 
clinical practice and as per the standard toxicity management guidelines described in the protocol. 
Subjects with confirmed new corneal or retinal abnormality while taking the study medication 
should be reported with an AE of special interest (Grade 1 and 2) or SAE (Grade ≥3) as 
appropriate. 
Any new eye symptoms of clinical significance such as but not limited to blurred vision, partial or 
complete loss of vision, double vision, floaters or color spots or halos around light, change in color 
or night vision, photophobia, ocular pain or stinging sensation, and foreign body sensation should 
be further evaluated and managed as per the Dose Modification guidelines for ocular toxicity 
(Section 8.4). 
8.1.3.4.4 Guidelines for the management of dry eye 
• 
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  


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
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8.2 
Fulvestrant 
8.2.1 Most common anticipated toxicities (refer to package insert for further details) 
• 
Hot flashes 
• 
Joint disturbances 
• 
Injection site reactions 
• 
GI disturbances 
There is considerable clinical experience with fulvestrant 500 mg intramuscular dosing every 4 
weeks (with an initial loading dose phase at cycle 1 day 15); it is generally very well tolerated. As 
was clearly established in the CONFIRM trial, the higher dose of fulvestrant 500 mg is more 
efficacious than the lower dose of 250 mg, with essentially no difference in adverse event rates. 
Dose reduction to 250 mg is left to the discretion of the treating physician, but it is not anticipated 
that dose reduction will improve adverse effects and it should generally be avoided given the 
inferior efficacy. However, dose reduction to fulvestrant 250 mg can be considered in patients 
with moderate hepatic impairment. 
8.3 
Palbociclib 
8.3.1 Most common anticipated toxicities (refer to package insert for further details) 
• 
Neutropenia 
• 
Leukopenia 
• 
Anemia 
• 
Thrombocytopenia 
• 
Fatigue 
• 
Nausea 
The primary anticipated toxicity of palbociclib is neutropenia. In the phase I trials of palbociclib 
alone in patients with advanced cancers, neutropenia was the only dose-limiting toxicity (DLT). 
Grade 3 neutropenia during cycle 1 was observed in 3/22 patients receiving palbociclib 125 mg 
PO daily, with no grade 4 neutropenic events observed. Based on this result, 125 mg PO daily 
became the recommended phase II dose (RP2D). Other hematologic AEs of grade 3 or greater 
during cycle 1 were anemia and leukopenia, occurring in 1 and 4 of 41 patients, respectively. The 
most common non-hematologic AEs of grade 3 or greater during cycle 1 were fatigue, nausea, 
and abdominal pain (each occurring in 2 of 41 patients). Of note, there were no complicated 
hematologic AEs documented, and all hematological AEs resolved during the off drug period of a 
3 week on/1 week off schedule, and were non-cumulative. 
In a phase II trial of palbociclib alone for advanced breast cancer, the only toxicities grade ≥3 
observed were transient neutropenia (50%) and thrombocytopenia (21%). In a phase II trial of 
palbociclib plus letrozole for first-line therapy of ER+ MBC, the most common AEs reported were 
neutropenia, leukopenia, and fatigue. The median time to first treatment delay for neutropenia 
was 58 days, and the median duration of treatment delay until recovery was 5 days (range 1-16 
days). In general, hematological abnormalities were adequately managed with standard 
supportive care, were not complicated, and resolved during the drug hold with no cumulative 
toxicity noted. In the phase I dose-escalation trial of palbociclib alone, QT interval changes were 
also evaluated in detail. While 26 of 41 patients had a maximum increase of <30 msec from 
baseline QTc, no patients had an on-treatment value exceeding 500 msec. 


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8.3.2 Dose Modification/ Delays and Toxicity Management 
In the event of significant treatment-related toxicity, palbociclib and erdafitinib dosing may be 
interrupted or delayed and/or reduced as described below. In the event of multiple toxicities, dose 
modification should be based on the worst toxicity observed. Patients are to be instructed to notify 
investigators at the first occurrence of any adverse sign or symptom. Patients should not hold or 
discontinue palbociclib and erdafitinib for side effects potentially or likely related to concomitant 
anti-hormonal therapy (e.g., grade 3 or long lasting grade 2 joint pain) as per the investigator’s 
judgment. 
Missed doses are not made up. When the adverse event resolves, the cycle will continue as 
scheduled. However, if palbociclib or erdafitinib start for a specific cycle is delayed for toxicity, 
fulvestrant will continue without change.  
The need for a dose reduction at the time of treatment resumption should be based on the table 
criteria below unless expressly agreed otherwise following discussion between the investigator 
and the Protocol Chair. If a dose reduction is applied, the patient may need to return to the clinic 
to receive new drug supply. 
8.4 
Palbociclib and Erdafitinib Dose Modifications and Management of Toxicities 
Palbociclib dose level reductions 
Starting 
dose 
First 
reduction 
Second  
reduction 
Third   
reduction 
125 mg  
100 mg  
75 mg 
Discontinue if no clinical benefit has been seen 
Erdafitinib dose level reductions 
Starting 
dose 
First 
reduction 
Second  
reduction 
Third   
reduction 
Fourth  
reduction 
8 mg 
6 mg 
5 mg 
4 mg 
Discontinue if no clinical benefit has been seen 
6 mg 
5 mg 
4 mg 
Discontinue if no clinical benefit has been seen 
5 mg 
4 mg 
Discontinue if no clinical benefit has been seen 
Investigations – Hematology (for palbociclib only) 
ANC decreased (Neutropenia) 
Grade 1 / 2 
Maintain dose level of palbociclib. 
Grade 3 
Omit dose of palbociclib until ANC ≥ 1000/mm3, then 
- If resolved in ≤ 7 days, then maintain dose level of palbociclib. 
- If resolved in > 7 days, then ↓ 1 dose level of palbociclib.  
Grade 4 
Omit dose of palbociclib until ANC ≥ 1000/mm3, then ↓ 1 dose level of palbociclib. Erdafitinib 
should be omitted as well if the treating physician considers that the safety of the patient is 
compromised. 
Anemia 
Grade 1 / 2 
Maintain dose level of palbociclib. 
Grade 3  
Omit dose of palbociclib until resolved to CTCAE Grade ≤ 2, then maintain dose level of 
palbociclib 
Grade 4 
Discontinue palbociclib. 
Febrile neutropenia  
Grade 3  
Omit dose of palbociclib, then  


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- If resolved by ≤ 7 days, then, ↓ 1 dose level of palbociclib. 
- If not resolved within 7 days discontinue palbociclib. 
Grade 4 
Discontinue palbociclib. Erdafitinib shoud be omitted as well if the treating physician considers 
that the safety of the patient is compromised. 
Platelet count decreased (Thrombocytopenia) 
Grade 1 / 2 
Maintain dose level of palbociclib. 
Grade 3 
Omit dose of palbociclib until resolved to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, then ↓ 1 dose level of palbociclib.  
- If resolved in > 7 days and/or with signs of bleeding, then discontinue patient from palbociclib.  
Grade 4 
Discontinue palbociclib. 
Bleeding 
Any bleeding (related 
to palbociclib) resulting 
in platelet transfusion 
Omit dose of palbociclib until no further bleeding has been observed. Continuation of 
study treatment may be considered based on the thrombocytopenia 
recommendations. 
Investigations – Hepatic 
Total bilirubin (for patients with Gilbert syndrome these dose modifications apply to changes in direct bilirubin only)  
Grade 1  
Maintain dose level of palbociclib and erdafitinib. 
Grade 2 
Omit dose of palbociclib and erdafitinib, and check bilirubin daily until resolved to CTCAE Grade 
≤ 1, then: 
- If resolved in ≤ 7 days, then maintain dose level of palbociclib and erdafitinib. 
- If resolved in > 7 days, then ↓ 1 dose level of palbociclib and erdafitinib. Start palbociclib first, 
and recheck bilirubin level in 7 days. If level remains CTCAE Grade ≤ 1, then reintroduce 
erdafitinib. 
Grade ≥ 3 
Discontinue palbociclib and erdafitinib. 
Note: If CTCAE Grade 3 or 4 hyper-bilirubinemia is due to the indirect (non-conjugated) component only, and 
hemolysis as the etiology has been ruled out as per institutional guidelines (e.g. review of peripheral blood 
smear and haptoglobin determination), then ↓ 1 dose level of palbociclib and erdafitinib and continue treatment 
at the discretion of the Investigator. 
AST or ALT 
Grade 1   
Maintain dose level of palbociclib and erdafitinib. 
Grade 2 
Omit dose of palbociclib and erdafitinib, and check AST and ALT daily until resolved to CTCAE 
Grade ≤ 1, then 
- If resolved in ≤ 7 days, then maintain dose level of palbociclib and erdafitinib 
- If resolved in > 7 days, then ↓ 1 dose level of palbociclib and erdafitinib. Start palbociclib first, 
and recheck AST and ALT levels in 7 days. If levels remain CTCAE Grade ≤ 1, then reintroduce 
erdafitinib. 
Grade 3 
Omit dose of palbociclib and erdafitinib, and check AST and ALT daily until resolved to CTCAE 
Grade ≤ 1 (or CTCAE Grade ≤ 2 in case of liver metastasis), then 
- If resolved in ≤ 7 days, then ↓ 1 dose level of palbociclib and erdafitinib. Start palbociclib first, 
and recheck AST and ALT levels in 7 days. If levels remain CTCAE Grade ≤ 1, then reintroduce 
erdafitinib. 
- If resolved in > 7 days, then discontinue patient from palbociclib and erdafitinib 
Grade 4 
Discontinue palbociclib and erdafitinib. 


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AST or ALT and Bilirubin 
AST or ALT > 3.0 – 
5.0 ULN and total 
bilirubin > 2.0 x ULN   
Omit dose of palbociclib and erdafitinib, , and check bilirubin, AST and ALT daily until 
resolved to CTCAE Grade ≤ 1, then  
- If resolved in ≤ 7 days, then ↓ 1 dose level of palbociclib and erdafitinib. Start 
palbociclib first, and recheck bilirubin, AST and ALT levels in 7 days. If levels remain 
CTCAE Grade ≤ 1, then reintroduce erdafitinib. 
- If resolved in > 7 days, then discontinue patient from palbociclib and erdafitinib. 
AST or ALT > 5.0 ULN 
and total bilirubin > 
2.0 x ULN 
Discontinue palbociclib and erdafitinib. 
Metabolism and nutrition disorders (for erdafitinib only) 
Phosphorus elevationa  
5.5-6.9 mg/dL 
Maintain dose level of erdafitinib. May consider sevelamer 800 mg to 1,600 mg 3 times a day 
(with food). 
7.0-9.0 mg/dL 
Omit erdafitinib.  
Sevelamer 800 to 1,600 mg 3 times a day with food until phosphate level is <5.5 mg/dL.  
Once serum phosphate level returns to <5.5 mg/dL, restart erdafitinib at same dose level. 
A dose reduction may be implemented for persistent hyperphosphatemia (≥7 mg/dL) if 
clinically necessary 
>9.0 mg/dL 
Omit erdafitinib. 
Sevelamer up to 1,600 mg 3 times a day with food 
AND  
Acetazolamide 250 mg 2 or 3 times a day only until serum phosphate level returns to 
<5.5 mg/dL. 
Once serum phosphate level returns to <5.5 mg/dL, restart treatment at the first reduced dose 
level.  
A second dose reduction may be implemented if needed or clinically indicated for persistent 
hyperphosphatemia (≥7 mg/dL) at every cycle 
>10.0 mg/dL 
and/or 
significant 
alteration in 
baseline renal 
function and/or 
Grade 3 
hypocalcemia 
Erdafitinib should be discontinued permanently. (In situations where the subject is having 
clinical benefit and the investigator and the Study Chair agree that re-starting drug is in the 
best interest of the subject, the drug may be re-introduced at 2 dose levels lower if 
appropriate. Follow other recommendations described above. 
aNote: Restriction of phosphate intake to 600 – 800 mg/day is recommended to all subjects in the study 
Ocular toxicity (for erdafitinib only) 
Grade 1 
Refer to ophthalmologic exam. If this cannot be performed within 7 days, omit erdafitinib until an 
exam can be performed. 
If no evidence of eye toxicity, continue erdafitinib at same dose level. 


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If keratitis or retinal abnormality are detected, omit erdafitinib until signs and symptoms have 
resolved; follow specific treatment as per ophthalmologist’s recommendations. 
For retinal pathology perform OTC as appropriate and consider referral to a retina specialist for 
further evaluation. 
If toxicity is reversible (complete resolution or stabilization and asymptomatic) in 4 weeks according 
to ophthalmologic exam, resume erdafitinib at the next lower dose level after consultation with 
Protocol Chair. 
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. 
If there is no evidence of eye toxicity, continue erdafitinib therapy at the same dose level. 
Grade 2 
Immediately omit erdafitinib and refer to ophthalmologic exam.  
If keratitis or retinal abnormality are detected, omit erdafitinib until signs and symptoms have 
resolved; follow specific treatment as per ophthalmologist’s recommendations. 
For retinal pathology perform OTC as appropriate and consider referral to a retina specialist for 
further evaluation. 
 
Monitor for recurrence every 1-2 weeks for a month and as clinically appropriate thereafter. 
 
If toxicity is reversible (complete resolution or stabilization and asymptomatic) in 4 weeks according 
to ophthalmologist exam, resume erdafitinib at the next lower dose level if patient is deriving clinical 
benefit from treatment, after consultation with Protocol Chair. 
Grade 3 
Immediately discontinue erdafitinib, refer to ophthalmologic exam, report as SAE. 
If keratitis or retinal abnormality are detected, omit Erdafitinib until signs and symptoms have 
resolved; follow specific treatment as per ophthalmologist’s recommendations. 
For retinal pathology perform OTC as appropriate and consider referral to a retina specialist for 
further evaluation. 
If toxicity is reversible (complete resolution or stabilization and asymptomatic) in 4 weeks according 
to ophthalmologist exam, resume erdafitinib at 2 lower dose levels if patient is deriving clinical 
benefit from treatment, after consultation with Protocol Chair. 
Continue to monitor for recurrence of toxicity every 1-2 weeks for a month and as clinically 
appropriate thereafter, using appropriate investigations. For cases of recurrence, permanently 
discontinue erdafitinib. 
Grade 4 
Immediately discontinue erdafitinib permanently, refer to ophthalmologic exam, report as SAE. 
Continue to monitor for recurrence of toxicity every 1-2 weeks for a month and as clinically 
appropriate thereafter, using appropriate investigations. 
GI disorders 
Constipation (for erdafitinib only) 
Grade 1 
Maintain dose level of erdafitinib, but initiate anti-constipation treatment. 
Grade 2 
Omit dose of erdafitinib until resolved to CTCAE Grade ≤ 1, then maintain dose level of erdafitinib. 


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Grade 3 
Omit dose of erdafitinib until resolved to CTCAE Grade ≤ 1, then reduce dose of erdafitinib by 1 
dose level. 
Grade 4 
Discontinue erdafitinib. 
Diarrhea (for palbociclib only) 
Grade 1 
Maintain dose level of palbociclib, initiate anti-diarrhea treatment per standard practice. 
Grade 2 
Initiate anti-diarrhea treatment per standard practice. 
Omit dose of palbociclib until resolved to CTCAE Grade ≤ 1, then maintain dose level of palbociclib. 
For 2nd occurrence of diarrhea CTCAE Grade 2, omit dose of palbociclib until resolved to CTCAE 
Grade ≤ 1, then reduce palbociclib by 1 dose level. 
Grade 3 
Initiate anti-diarrhea treatment per standard practice. 
Omit dose of palbociclib until resolved to CTCAE Grade ≤ 1, then reduce dose of palbociclib by 1 
dose level. 
For 2nd occurrence of diarrhea CTCAE Grade 3, discontinue palbociclib. 
Grade 4 
Initiate anti-diarrhea treatment per standard practice. 
Discontinue palbociclib. 
Note: Antidiarrheal medication per standard practice is recommended at the first sign of abdominal cramping, 
loose stools or overt diarrhea. 
Mucositis  
Grade 1 
Continue palbociclib and erdafitinib at same doses. 
Topical steroid moderate strength and lidocaine 2-5% jelly or solution QID. 
Grade 2 
Continue palbociclib and erdafitinib at current dose.  
Dexamethasone solution (3.3 mg/5 mL) swish and spit QID and lidocaine 2-5% jelly or solution 
QID.  
Consider study drug holding if no improvement in 1 week.  
When resolves to ≤Grade 1 or baseline, restart at same or 1 dose level below in consultation with 
the medical monitor. 
Grade 3 
Hold palbociclib and erdafitinib (for up to 28 days), with weekly reassessments of clinical condition.  
Dexamethasone solution (3.3 mg/5 mL) swish and spit QID and lidocaine 2-5% jelly or solution QID 
When resolves to ≤Grade 1 or baseline, restart at 1 dose level below in consultation with the 
medical monitor. 
Grade 4 
Discontinue palbociclib and erdafitinib; evaluation and therapy as clinically indicated. 
Skin and subcutaneous disorders (for erdafitinib only) 
Skin toxicity 
Grade 1 
Maintain dose level of erdafitinib. 
Use fragrance free moisturizing cream or ointment BID over entire body. 
Use ammonium lactate 12% cream or salicylic acid 6% cream BID over dry/scaly/hyperkeratotic 
areas such as palms and soles. 


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Grade 2 
Maintain dose level of erdafitinib. 
Use fragrance free moisturizing cream or ointment BID over entire body. 
Use ammonium lactate 12% cream or salicylic acid 6% cream BID over dry/scaly/hyperkeratotic 
areas such as palms and soles. 
Use zinc oxide 13-40% at night for areas with fissures. 
Grade 3 
Omit erdafitinib doses for up to 28 days, with weekly assessments of clinical condition. 
Use topical steroid ointment or cream (Clobetasol 0.05%, Betamethasone 0.05%, Fluocinonide 
0.05%) BID and zinc oxide 13-40% at night for areas with fissures. 
Once resolved to grade ≤ 1 then: 
- If resolved in ≤ 14days, ↓ 1 dose level of erdafitinib. 
- If resolved in > 14 days, discontinue patient from erdafitinib. 
Grade 4 
Discontinue erdafitinib; therapy as clinically indicated. 
Nail toxicity 
Grade 1 
Maintain dose level of erdafitinib. 
Over the counter nail strengthener OR poly-urea urethane nail lacquer (Nuvail) OR diethylene 
glycol monoethylether nail lacquer daily (Genadur). 
Grade 2 
Maintain dose level of erdafitinib. 
For signs of infection (periungal edema/erythema/ tenderness and/or discharge), start the following:  
- treatment with oral antibiotic for 2 weeks (cefadroxil 500 mg BID, ciprofloxacin 500 mg BID, or 
sulfamethoxazole/ trimethoprim (Bactrim®) DS BID)  
AND  
- topical antifungal lacquer daily for 6+ weeks (ciclopirox olamine 8% OR efinaconazole 10% OR 
amorolfine 5% weekly OR bifonazole/urea ointment daily) 
Consider study drug holding if no improvement in 1 to 2 weeks.  
When resolved to ≤ Grade 1 or baseline, restart at same or 1 dose level below in consultation with 
the medical monitor. 
Grade 3 
Hold erdafitinib (for up to 28 days), with weekly reassessments of clinical condition.  
Silver nitrate application weekly AND topical antibiotics (Mupirocin 2%, gentamycin, bacitracin 
zinc/polymixin B) AND vinegar soaks (soaking fingers or toes in a solution of white vinegar in water 
1:1 for 15 minutes every day). 
For signs of infection (periungal edema/erythema/ tenderness and/or discharge), start the following: 
treatment with oral antibiotic for 2 weeks (cefadroxil 500 mg BID, ciprofloxacin 500 mg BID, or 
sulfamethoxazole/trimethoprim (Bactrim®) DS BID). 
For cases of severe/refractory infection consider intravenous antibiotics.   
Consider dermatological and/or surgical evaluation if necessary. 
When resolved to ≤Grade 1 or baseline, restart at 1 dose level below in consultation with the 
medical monitor. 


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Grade 4 
Discontinue erdafitinib, evaluation and therapy as clinically indicated. 
General disorders (for erdafitinib only) 
Fatigue/ asthenia 
Grade 1 / 2 
Maintain dose level of erdafitinib. 
Grade 3 
Omit dose of erdafitinib until resolved to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, maintain dose level of Erdafitinib. 
- If resolved in > 7 days, discontinue patient from Erdafitinib. 
Other AEs 
Grade 1 / 2 
Maintain dose level of palbociclib and erdafitinib. 
Grade 3 
Omit dose of palbociclib and erdafitinib until resolved to CTCAE Grade ≤ 1, then ↓ dose level 
of palbociclib and erdafitinib. 
Grade 4 
Discontinue palbociclib and erdafitinib. 
• All dose modifications should be based on the worst preceding toxicity. Once a dose has been reduced it will 
not be increased at a later time even if there is no toxicity. Patients who require dose reductions of palbociclib 
and erdafitinib past the lowest dose level will be discontinued from study drugs treatment. 
• If a patient requires a dose delay of > 28 consecutive days from the intended day of the next scheduled dose 
of palbociclib and erdafitinib, due to study related interventions, then the patient must be discontinued from 
the study treatment. Patients that require a dose delay of > 28 days due to a cause unrelated to study 
participation will have the opportunity to continue study if deemed eligible to do so by the Protocol Chair of 
the study. Patients who discontinue from the study for a study-related AE or an abnormal laboratory value 
must be followed at least once a week for 4 weeks and subsequently at 4-week intervals, until resolution or 
stabilization of the event, whichever comes first, except specifically mentioned. 
8.5 
Special Considerations 
• 
If erdafitinib needs permanent discontinuation, patients may continue fulvestrant and 
palbociclib treatment under study procedures 
• 
If palbociclib needs permanent discontinuation, patients may continue fulvestrant and 
erdafitinib treatment under study procedures 
• 
If both erdafitinib and palbociclib need permanent discontinuation, patients should discontinue 
all study drugs 
• 
For toxicities considered (by the treating investigator) unlikely to develop into serious or life-
threatening events (e.g. alopecia, dysgeusia), treatment may be continued at the same dose 
without reduction or interruption 
• 
The treating investigator may reduce a subject’s dose for a toxicity of any grade/duration 
where s/he believes it to be in the best interest of the subject 
• 
Any consideration to alter the above dose modification guidelines should be discussed with 
the Protocol Chair for approval or disapproval in advance 
 
 


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9. 
DRUG FORMULATION/STORAGE/SUPPLY 
9.1 
Erdafitinib 
Erdafitinib is an investigational agent and will be supplied free-of-charge from Janssen Research 
& Development.  
Classification 
Erdafitinib (JNJ-42756493) is an oral pan-FGFR tyrosine kinase inhibitor. 
Mechanism of Action 
Erdafitinib (JNJ-42756493) is a potent, oral pan-FGFR tyrosine kinase inhibitor with the 
biochemical inhibitory IC50 values <1 nM for FGFR1, <1 nM for FGFR2, 1.05 nM for FGFR3, and 
<1nM for FGFR4. It has demonstrated potent inhibition of cell proliferation with IC50 values ranging 
from <1 to <1000 nM in FGFR pathway-activated cancer cell lines including squamous NSCLC, 
gastric, breast, HCC, endometrial, bladder, multiple myeloma, and acute myeloid leukemia. 
Metabolism  
Erdafitinib exhibited a dose-related increase in Cmax and area under the analyte concentration-
time curve (AUC) and time-independent PK within the dose range of 0.5 to 12 mg, both after 
single and multiple daily dosing. The actual sampling time to reach maximum concentration (tmax) 
ranged between 2-4 hours (erdafitinib as tablet), independent of the studied formulations. PK was 
characterized by moderate intersubject variability (CV% 31-39%) and low intra-subject variability 
(9-10%). Erdafitinib is primarily excreted in feces either as unchanged drug or as metabolites. In 
vitro data indicated that CYP3A and 2C9 are involved in erdafitinib metabolism. 70% and 20% of 
the radioactivity was recovered in feces and urine, respectively, with approximately 11% of 
unchanged drug recovered in urine. Erdafitinib is highly bound to plasma proteins, especially to 
α1-AGP (fraction unbound in oplsma being 0.36% and 0.50% in patients and healthy subjects, 
respectively. Apparent volume of distribution (Vd/F) of the terminal phase based on total plasma 
erdafitinib in healthy subjects is small (approximately 31 L), suggesting it is limited by the binding 
to plasma protein. Erdafitinib has low total plasma oral clearance (mean CL/F in subjects with 
cancer averaged 0.29 L/h; the corresponding value for healthy subjects was 0.43 L/h), likely 
restricted by protein binding. As a consequence, the apparent elimination half-life (t1/2) of 
erdafitinib is long (approximately 50 hours in healthy subjects) resulting an approximately 3- to 4-
fold accumulation in Cmax and AUC following multiple daily dosing. 
Precautions and Warnings 
Erdafitinib is an investigational drug, with safety data available from nonclinical studies and three 
Phase 1 clinical studies. All subjects should be closely monitored with special attention to 
evidence of disturbance of phosphate homeostasis and bone pathology and ocular symptoms 
until sufficient clinical experience is obtained. For the most up-to-date recommendations on 
management of common adverse events, please refer to the protocols of ongoing clinical trials in 
the investigator brochure. 
Contraindications 
Phase 1 and 2 clinical trials with erdafitinib are still ongoing and there are currently limited data 
regarding the use of erdafitinib in humans, so no conclusions regarding existing contraindications 
can be drawn. Subjects enrolled into clinical studies with erdafitinib should adhere to specific 
inclusion and exclusion criteria as defined by the study protocol. 
Drug-drug Interactions 


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Based on preliminary in vitro data, erdafitinib is metabolized by cytochrome CYP3A4 and 
CYP2C9. No in vivo or clinical data are available to date. For this reason, strong CYP3A4/5 and 
CYP2C99 inhibitors/ inducers should be used with caution; subjects should be closely monitored 
for potential toxicities, and appropriate action, including temporary interruption of erdafitinib, 
should be taken. Alternatives to concurrent administration of erdafitinib and strong or mixed 
CYP3A4 and CYP2C9 inhibitors (such as orally or parenterally administrated clarithromycin, 
ketoconazole, itraconazole, ritonavir and fluconazole) should potentially be sought, and, if no 
alternative treatment is available, the Study Chair should be consulted. Erdafitinib was also 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 coadministered drugs that are P-gp substrates, such 
as digoxin, dabigatran, apixaban, etc.  
Overdosage 
Dose limiting toxicities were observed at 12 mg daily and 12 mg intermittent (7 days on/7 days 
off), but the maximum tolerated dose was not reached. 
Dosage and Administration 
The clinically effective dose of erdafitinib has not yet been determined.  Recommended starting 
dose of single agent erdafitinib is 8 mg orally once daily. This dose should be maintained and 
serum phosphate (PO4) level should be assessed at approximately Day 14, when the dose can 
be increased to 9 mg once daily in absence of severe hyperphosphatemia and significant drug-
related toxicity. 
Storage and handling 
Tablets should be stored at room temperature, as specified at delivery and in the original 
packaging. 
How Supplied 
Detailed information on preparation, handling, and storage conditions will accompany the clinical 
drug supplies to the clinical study site(s). The storage conditions and expiration dates will be 
indicated on the label of the drug product.  Erdafitinib will be supplied as 3 mg, 4 mg and 5 mg 
oral film coated tablets. 
Disposal and destruction 
The drug supply will be destroyed/ disposed of as per institutional guidelines. 
9.2 
Fulvestrant 
Fulvestrant is commercially available and available in 50 mg/mL solution in a single use-vial for 
intramuscular administration. 
Classification 
An estrogen receptor antagonist indicated for the treatment of hormone receptor positive 
metastatic breast cancer in postmenopausal women with disease progression following 
antiestrogen therapy. 
Mechanism of Action 
Fulvestrant is an estrogen receptor antagonist that binds to the estrogen receptor in a competitive 
manner with affinity comparable to that of estradiol and downregulates the ER protein in human 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
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breast cancer cells. In vitro studies demonstrated that fulvestrant is a reversible inhibitor of the 
growth of tamoxifen resistant, as well as estrogen-sensitive human breast cancer (MCF-7) cells. 
In in vivo tumor studies, fulvestrant delayed the establishment of human breast cancer MCF-7 
xenografts in nude mice. Fulvestrant inhibited the growth of established MCF-7 xenografts and of 
tamoxifen-resistant breast xenografts. Fulvestrant showed no agonist-type effects in uterotropic 
assays in immature or ovariectomized mice and rats. In studies in immature rats and 
ovariectomized monkeys, fulvestrant blocked the uterotrophic action of estradiol. In post-
menopausal women, the absence of changes in plasma concentrations of FSH and LH in 
response to fulvestrant treatment (250 mg monthly) suggests no peripheral steroidal effects. 
Metabolism 
Biotransformation and disposition of fulvestrant in humans have been determined following 
intramuscular and intravenous administration of 14C-labeled fulvestrant. Metabolism of 
fulvestrant appears to involve combinations of a number of possible biotransformation pathways 
analogous to those of endogenous steroids, including oxidation, aromatic hydroxylation, 
conjugation with glucuronic acid and/or sulphate at the 2, 3 and 17 positions of the steroid nucleus, 
and oxidation of the side chain sulphoxide. Identified metabolites are either less active or exhibit 
similar activity to fulvestrant in models of antiestrogen action. Studies using human liver 
preparations and recombinant human enzymes indicate that cytochrome P-450 3A4 (CYP 3A4) 
is the only P-450 isoenzyme involved in the oxidation of fulvestrant; however, the relative 
contribution of P-450 and non-P-450 routes in vivo is unknown.  
Excretion 
Fulvestrant was rapidly cleared by the hepatobiliary route with excretion primarily via the feces 
(approximately 90%). Renal elimination was negligible (less than 1%). After an intramuscular 
injection of 250 mg, the clearance (mean ± SD) was 690 ± 226 mL/min with an apparent half-life 
about 40 days. 
Contraindications 
Fulvestrant is contraindicated in pregnant women and in patients with a known hypersensitivity to 
the drug or to any of its components. 
Drug-drug Interactions 
There are no known drug-drug interactions. Although fulvestrant is metabolized by CYP 3A4 in 
vitro, drug interactions studies with ketoconazole or rifampin did not alter fulvestrant 
pharmacokinetics. Dose adjustment is not needed in patients co-prescribed CYP3A4 inhibitors or 
inducers. 
Storage and handling 
Refrigerate, 2°-8°C (36°-46°F). Protect from light, store in the original carton until time of use. 
How Supplied 
Commercial supplies of fulvestrant (AstraZeneca PLC) will be used in this study and billed to third 
party payers or to the subject. Complete and updated adverse event information is available in 
product package insert. 
9.3 
Palbociclib 
Palbociclib is available in 75 mg, 100 mg and 125 mg capsules for oral administration.  Palbociclib 
will be provided free of charge by Pfizer. 
Classification 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
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Palbociclib is a cyclin-dependent kinase (CDK) 4/6 inhibitor with antineoplastic activity indicated 
for the treatment of hormone receptor positive metastatic breast cancer in postmenopausal 
women, in conjunction with letrozole (1st line treatment) or with fulvestrant (2nd line treatment). 
Mechanism of Action 
Palbociclib selectively inhibits CDK4 and CDK6, thereby dephosphorylating and inhibiting 
retinoblastoma (Rb) protein early in the G1 phase of the cell cycle, thus leading to suppression of 
DNA replication and cell cycle arrest. CDK4 and 6 are serine/threonine kinases that are 
upregulated in many tumor cell types and play a key role in the regulation of cell cycle progression. 
Metabolism 
To date, pharmacokinetic data have been collected in 4 clinical studies for a total of 138 cancer 
patients. The exposure and Cmax increased in a dose-proportional manner over the range of 25 
to 225 mg once daily (QD) following palbociclib administration on days 1 and 8 of cycle 1, although 
some low to moderate variability around these doses was observed, particularly at the 150 mg 
QD dose level. Following repeated daily dosing to day 15 and day 21 (assumed to be steady 
state), palbociclib was absorbed with a median Tmax of ~4 h. The mean palbociclib Vz/F was 
3103 L, which is significantly greater than total body water (42 L), indicating that palbociclib 
extensively penetrates into peripheral tissues. Palbociclib was eliminated slowly; the mean t½ 
was 26.5 h (range 15.8 to 36.2 h) and the mean CL/F was 86.1 L/h. Palbociclib accumulated 
following repeated dosing with a median Rac of 2.4, which is consistent with a half-life of ~27 h. 
Preliminary results from the recently performed food effect study (A5481021) suggested that the 
administration of palbociclib with food results in more consistent drug absorption and exposure 
than administration of palbociclib in a fasted state. As a result of these findings, patients should 
be instructed to take palbociclib with food. CYP3A4 inhibitors/ inducers should be avoided. 
Drug-drug Interactions 
The strong CYP3A inhibitor itraconazole increased palbociclib AUCinf  by approximately 87%, 
relative to palbociclib given alone. As expected, coadministration of rifampin, a strong CYP3A 
inducer, decreased palbociclib AUCinf by 85% relative to palbociclib given alone. Palbociclib is a 
weak time-dependent inhibitor of CYP3A following administration of the clinical 125 mg dose: 
palbociclib increased the midazolam AUCinf values by 61%, as compared with midazolam alone. 
In vitro, palbociclib is not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, and 2D6, and is not 
an inducer of CYP1A2, 2B6, 2C8, and 3A4 at clinically relevant concentrations.  In vitro 
evaluations indicated that palbociclib has a low potential to inhibit the activities of drug 
transporters at clinically relevant concentrations. 
Storage and handling 
Palbociclib capsules should be stored at controlled room temperature (15-30°C, 59-86°F) in their 
original container. 
Side Effects 
The most frequently reported treatment-related adverse events included neutropenia, leukopenia, 
anemia, and fatigue. A phase II study of palbociclib showed toxicities that were mostly Grade 1 
and 2; Grade 3 and 4 toxicities were limited to transient neutropenia (50%) and thrombocytopenia 
(21%). A large phase II study of palbociclib combined with letrozole found a 54% rate of grade 
3/4 neutropenia but no increase in febrile neutropenia. Neutropenia was easily managed with 
dose delay and dose reduction.  
How Supplied 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
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Pfizer provides supplies of palbociclib (Pfizer) that are to be  used in this study and will not be 
billed to third party payers or to the subject. 
Disposal and destruction 
The drug supply will be destroyed/ disposed of as per institutional guidelines.  
9.4 
Drug Accountability 
Clinical drug supply must be accounted for and patients will be asked to return all unused study 
drug and packaging on a regular basis, at the end of the study or at the time of study drug 
discontinuation. Accountability for the drug at all study sites is the responsibility of the principal 
investigator and designated Pharmacy representative. The investigator will ensure that the 
investigational drug is used only in accordance with this protocol. Drug accountability records 
indicating the drug’s delivery date to the site, inventory at the site, use by each patient, and 
destruction/disposal per institutional policy will be maintained by the clinical site. Accountability 
records will include dates, quantities, lot numbers, expiration dates, and patient numbers. 
 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
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10. CORRELATIVE/SPECIAL STUDIES  
10.1 Overview 
Correlate/ 
Sample 
Source 
Local/ On-Site Processing 
Central 
Processing 
Shipping 
FGFR1 
testing 
FFPE from 
archival 
tumor tissue 
(primary or 
metastatic)  
Submission of FFPE archival 
tumor tissue block  
OR  
Submission of 5 unstained 
slides cut at 4 microns each 
placed on charged (plus) slides 
 
Yes 
(FGFR1 
FISH) 
Freq: 
Same day 
 
Temp: 
Ambient 
 
Lab: 
VUMC 
Note: Known FGFR amplification by FISH, NGS or cfDNA are acceptable for 
enrollment if previously done locally 
Next 
Generation 
Sequencing 
(NGS) 
FFPE from 
archival 
tumor tissue 
(primary or 
metastatic) 
Submission of FFPE archival 
tumor tissue  
OR  
Submission of: 
- 1 H&E (or an unstained 4 
micron section on a plus 
[charged] slide) followed by,  
- 6 serial 20 micron peels placed 
in a DNAse-RNAse free tube 
(wrapped in parafilm to exclude 
moisture) followed by, 
- 1 H&E (or an unstained 4 
micron section on a plus 
[charged] slide)   
- Peels should be placed in the -
80 freezer upon receipt until 
extraction is to take place 
Yes (DNA 
extraction 
for NGS) 
Freq: 
Batched 
 
Temp: 
Ambient 
 
Lab: 
VUMC 
(VUMC will 
subsequently 
be 
responsible to 
batch ship to 
MSKCC for 
NGS 
analyses) 
Whole 
Blood (NGS 
control) 
Blood- 
1 tube, 8 
mL, 
PAXgene or 
EDTA 
(purple top) 
-Mix by gentle inversion 8 or 10 
times 
- Freeze and store in 20C 
freezer until ready to ship to 
MSKCC 
Yes 
Freq: 
Batched 
 
Temp: 
Ambient 
 
Lab: 
VUMC 
(VUMC will 
subsequently 
be 
responsible to 
batch ship to 
MSKCC for 
NGS 
analyses) 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
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Note: For patients in which archival tumor is not available and a fresh tumor biopsy is 
obtained, the main core should be fixed for IHC analysis on site. If additional cores are 
collected, they can be snap-frozen and submitted as such. The invasive tumor area in the 
FFPE should be at least 5 mm x 5 mm and contain 20% tumor cellularity. 
cfDNA 
Blood- 
1 tube, 
10mL, 
Streck 
-Mix by gentle inversion 8 or 10 
times 
-Do not refrigerate or freeze 
 
cfDNA Samples collected at 
VUMC only are to be pre- 
processed as follows: 
-Needed supplies: 2 x 15 ml 
conical tubes, 1 x 5 ml screw-
cap, 3 x 5 ml pipettes  
-Transfer entire volume of blood 
from Streck tube to a 15 ml 
conical tube using 5 ml pipette.  
-Centrifuge 15 ml conical tubes 
at 1600xg for 10 minutes at 
10˚C  
- Transfer supernatant to a fresh 
15 ml conical tube without 
disturbing the cellular layer 
using a disposable 5 ml 
- Centrifuge the plasma in the 
second 15 ml conical tube for 
3200xg for 10 minutes at 10˚C 
-Transfer the supernatant to 1 x 
5 ml screw top tube without 
disturbing the cellular layer 
using a 5 ml pipette Leave a 
residual volume of about 0.3 ml 
(7 mm) in the bottom of the 15 
ml tube to avoid cellular 
contamination.  
-Freeze supernatant at -80˚C 
Yes (cfDNA 
analysis) 
Freq: 
Same day 
 
Temp: 
Ambient 
 
Lab: 
VUMC 
PK 
Blood- 
1 tube, 6 
mL, 
Lavender-
top K2EDTA 
vacutainer 
tube 
- Mix by gentle inversion at least 
10 times 
- Place tube in an ice/water bath 
and maintain chilled until 
centrifugation 
- Within 30 minutes of collection, 
centrifuge collection tubes in a 
refrigerated centrifuge (set to 2-
80C) at a minimum of 1500 x g 
for 15 minutes 
- Use standard laboratory 
technique to transfer all the 
plasma equally into 2 
appropriately labeled 
Yes (PK 
Analysis) 
Freq: 
Batched 
 
Temp: 
Frozen 
 
Lab: 
VUMC 
PD 
Blood- 
1 tube, 6 
mL, 
Lavender-
top K2EDTA 
vacutainer 
tube 
Yes 
(FGF23, 
sFGFR2, 
sFGFR3 
and 
sFGFR4 
analyses) 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
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Protocol number BRE 16126 
 
 
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polupropylene screw-cap 
cryovials (one is the primary 
sample and the other the back-
up sample) 
- Label cryovials accordingly 
- Store both plasma aliquot 
samples in a freezer set to 
maintain a temperature of -700C 
 
Note: PTH, Calcium, Phosphate and vitamin D will be assessed locally per institutional 
collection/ processing guidelines 
10.2 Blood Samples for Pharmacodynamic Assessments 
Blood collection for pharmacodynamic assessments (serum phosphate, calcium, vitamin D, 
parathyroid hormone [PTH], FGF23, sFGFR2, sFGFR3 and sFGFR4) will be performed on Days 
1 and 15 of Cycle 1 and 2 in all patients participating in the phase Ib portion of the study, to 
determine pharmacodynamic biomarkers of FGFR inhibition. 
Serum FGFR2, FGFR3 and FGFR4 will be measured using an enzyme-linked immunosorbent 
assay developed at Janssen Research & Development (Raritan, NJ). 
Tubes should be packed and sent according to the Lab manual. 
If not retrieved on site by VICC CTO personnel, outside sites should ship specimens along with 
Tissue/Blood Registration Form directly to:  
Dr. Melinda Sanders 
c/o Violeta Sanchez 
Vanderbilt University Medical Center 
Department of Pathology 4912 TVC 
1301 Medical Center Drive  
Nashville, TN 37232-5310 
      615-343-9115  
 
 
**Specimens should be mailed to arrive at VUMC from Monday 8AM through Friday 1PM** 
**Specimens collected from Vanderbilt patients will be pre-processed by VICC CTO and 
subsequently delivered to Melinda Sanders/Violeta Sanchez for storage until processing** 
10.3 Blood Samples for cfDNA 
To determine if the FGFR1 amplification levels is an early surrogate of response, and to determine 
if the cfDNA results at disease progression show new genomic alterations potentially associated 
with resistance to CDK4/6 and FGFR inhibition, blood collection for cfDNA will be performed in all 
patients at: baseline (Cycle 1 Day 1), Day 1 of every even cycle, and at disease progression 
(end-of-treatment). Initially, the baseline, 4-week and end-of-treatment timepoints will be 
submitted for cfDNA analysis; the other time points will be stored for future research. 
One vial of whole blood should be collected in a Cell-Free DNA BCT tube (Streck tube). Fill the 
tube completely. Remove the tube from the adapter and immediately mix by gentle inversion 8 to 
10 times.  


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
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Tubes should be packed according to the Lab manual and sent immediately (within 24 h). Do 
not freeze or refrigerate specimens collected in Streck tubes as this will compromise 
measurements of cfDNA. 
If not retrieved on site by VICC CTO personnel, outside sites should ship specimens along with 
Tissue/Blood Registration Form directly to:  
Dr. Melinda Sanders 
c/o Violeta Sanchez 
Vanderbilt University Medical Center 
Department of Pathology 4912 TVC 
1301 Medical Center Drive  
Nashville, TN 37232-5310 
      615-343-9115  
 
 
 
**Specimens should be mailed to arrive at VUMC from Monday 8AM through Friday 1PM** 
**Specimens collected from Vanderbilt patients will be pre-processed by VICC CTO and 
subsequently delivered to Melinda Sanders/Violeta Sanchez for storage until processing** 
10.4 Blood Samples for NGS control 
Whole blood collection will be performed on Days 1 of Cycle 1 in all patients participating in the 
study, to be used as germline control once NGS analysis is done in tumor tissue. 
Tubes should be packed and sent according to the Lab manual. 
If not retrieved on site by VICC CTO personnel, outside sites should ship specimens along with 
Tissue/Blood Registration Form directly to:  
Dr. Melinda Sanders 
c/o Violeta Sanchez 
Vanderbilt University Medical Center 
Department of Pathology 4912 TVC 
1301 Medical Center Drive  
Nashville, TN 37232-5310 
      615-343-9115  
 
 
**Specimens should be mailed to arrive at VUMC from Monday 8AM through Friday 1PM** 
**Specimens collected from Vanderbilt patients will be pre-processed by VICC CTO and 
subsequently delivered to Melinda Sanders/Violeta Sanchez for storage until processing** 
10.5 Tissue Samples  
To determine the therapeutic predictive role of FGFR1-4, CCND1-2, CDK4 and CDK6 
amplifications, and RB1 and ESR1 mutations on clinical outcome, FFPE tissue from primary 
tumor or from a metastatic tumor biopsy will be collected for FGFR1 FISH analysis and Next 
Generation Sequencing in all patients enrolled in the study at the time of registration.  
Collection of fresh frozen tissue from a metastasis at any point prior, during or after study drugs, 
is encouraged and desirable, especially in patients that achieve a good clinical response and 
subsequently have disease progression. The fresh biopsy will follow guidelines as listed in Section 
10.4.3.   
Summary of required tissue: 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
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Protocol number BRE 16126 
 
 
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A) FFPE block from primary tumor or metastatic tumor biopsy, with adequate tissue to cut the 
tissue sections described in B) and C) below. Ideally, the invasive tumor area should be at 
least 5 mm x 5 mm and contain 20% tumor cellularity. 
 
If participating institutions are not allowed to release FFPE blocks,the following should be 
prepared: 
 
B) To perform FGFR1 FISH for either pre-screening or central confirmation: 5 unstained slides 
cut at 4 microns each placed on charged (plus) slides. Do not bake on a hot plate (see 10.3.1). 
 
C) To perform next generation sequencing cut in this order: 
 
1. From a tumor block containing greater than 25 mm2 of tumor with at least 20% tumor cellularity 
please provide: 
a. 1 H&E (or an unstained 4 micron section on a plus [charged] slide) followed by,  
b. 3 serial 20 micron peels placed in a DNAse-RNAse free tube (wrapped in parafilm to 
exclude moisture) followed by,  
c. 1 H&E (or an unstained 4 micron section on a plus [charged] slide)   
d. Peels should be placed in the -80 freezer upon receipt until extraction is to take place. 
 
2. Tumor blocks containing 5-20 mm2 of tumor with at least 20% tumor cellularity please provide: 
a) 1 H&E (or an unstained 4 micron section on a plus [charged] slide) followed by,  
b) 6 serial 20 micron peels placed in a DNAse-RNAse free tube (wrapped in parafilm to 
exclude moisture) followed by, 
c)  1 H&E (or an unstained 4 micron section on a plus [charged] slide)   
d) Peels should be placed in the -80 freezer upon receipt until extraction is to take place. 
 
All formalin-fixed paraffin embedded tissue and/or slides should be sent with a cold pack 
(except in winter months) to avoid melting that could compromise tissue analysis. 
 
**Paraffin blocks retrieved on site by VICC CTO personnel along with Tissue/Blood 
Registration Form should be delivered directly to the persons below who will prepare the 
samples listed above: 
 
Dr. Melinda Sanders 
c/o Violeta Sanchez 
Vanderbilt University Medical Center  
Department of Pathology  
4912 TVC 1301 Medical Center Drive 
Nashville, TN 37232-5310 
615-343-9115 
 
**Paraffin blocks, s l i d e s  a n d  t i s s u e  p e e l s  f r o m  outside sites should ship 
specimens along with Tissue/Blood Registration Form directly to: 
 
Dr. Melinda Sanders 
c/o Violeta Sanchez 
Vanderbilt University Medical Center  
Department of Pathology  


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
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4912 TVC 1301 Medical Center Drive 
Nashville, TN 37232-5310 
615-343-9115 
 
10.5.1 FGFR1 Fluorescence In Situ Hybridization (FISH) 
Patients with known (i.e. local determination of) FGFR1-4 amplification (by NGS, cfDNA or FISH) 
are eligible for study participation. For patients with FGFR1 amplification, central confirmation of 
FGFR1 amplification by FISH will be performed, but will not be required for study treatment 
initiation. Patients without known FGFR1 amplification can send tissue for FGFR1 amplification 
screening via FISH analysis at the Vanderbilt-Ingram Cancer Center (VICC) in the CLIA-certified 
Vanderbilt University Medical Center Cytogenetics Laboratory. Patients with known FGFR2-4 
amplifications (by local determination of NGS, cfDNA or FISH) will not have central confirmation 
of amplification status by FISH due to their overall low prevalence. From the time tissue arrives 
at the Coordinating Center Breast Cancer Tissue Core (Dr. Melinda Sanders), a turn-around time 
of no longer than 7 days should be expected for the FISH results to become available thus 
determining if a patient is eligible or not.  
FGFR1 FISH will be performed as follows: three to four-μm tissue sections will be mounted on 
sialinized slides and hybridized overnight with the ZytoLight SPEC FGFR1/CEN 8 Dual Color 
Probe (ZytoVision, Bremerhaven, Germany). Briefly, after deparaffinization, the slides are 
denatured in the presence of 10 μl probe for 6 min at 73°C and hybridized at 37°C overnight in 
StatSpin (Thermobrite, Abbott Molecular, Inc.). Post-hybridization SSC washes are performed at 
72°C and then the slides are stained with DAPI before analysis. Slides are analyzed with 
Reflected light fluorescent microscope (Olympus BX60) at 100X for hot spots. Representative 
images of tumor cells are captured using Cytovision software. Thirty tumor cell nuclei from hot 
spots or random areas are individually evaluated with the Olympus BX60 at 100X by counting 
green FGFR1 and orange centromer 8 (CEN8) signals. The average of FGFR1 copy number and 
the FGFR1/CEN8 is then calculated. Tumors are considered as FGFR1 positive (‘amplified’) 
under one of the following conditions: 
• 
The FGFR1/CEN8 ratio is ≥2.0; 
• 
The average number of FGFR1 signals per tumor cell nucleus is ≥640. 
10.5.2 Next Generation Sequencing 
DNA will be extracted using DNEasy or QiaAMP DNA tissue kits from FFPE archival tumor 
sections or snap-frozen biopsies of metastases, respectively. Tumor cellularity is assessed by an 
expert breast pathologist (MES); specimens with ≥ 20% tumor nuclei are considered evaluable. 
In the few cases with paucicellular samples (< 20% tumor cells), multiple sections were macro-
dissected to achieve ≥ 20% tumor cellularity.  
Subsequently, Next Generation Sequencing (NGS) will be performed using the MSK-IMPACT™ 
(Memorial Sloan Kettering - Integrated Mutation Profiling of Actionable Cancer Targets)46, a 
hybridization capture-based assay for targeted deep sequencing of all exons and selected introns 
of 341 key cancer genes in DNA from FFPE tumor sections. Custom DNA probes targeting exons 
and selected introns of 341 genes are synthesized using the NimbleGen SeqCap EZ library 
custom oligo system and biotinylated to allow for sequence enrichment by capture using 
streptavidin-conjugated beads. Pooled libraries containing captured DNA fragments are 
subsequently sequenced on the Illumina HiSeq 2500 system (rapid-run mode) as 2 × 100-bp 
paired-end reads.  


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
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10.5.3 Guidelines for Tissue Acquisition on Biopsies of Metastatic Lesions (when applicable) 
Tissue specimens, when feasible, will be collected from recurrent or metastatic lesions using 
standard institutional procedures. The amount of tissue collected will follow the guidelines listed 
below. If a patient has more than one site of disease, only one site needs to be biopsied, and the 
site is left to the discretion of the patient and her treating physician. If a patient is undergoing 
resection of a lesion for clinical reasons (i.e. wedge resection of a new lung lesion for confirmation 
of diagnosis or re-testing of hormone receptor and/or HER2 status, or, resection of a chest wall 
lesion, or, resection of a lymph node), then the patient may opt to have a portion of that tissue 
(roughly equivalent to the goal amount of tissue listed in the guidelines above, i.e. the equivalent 
of two 5-mm punch biopsies of the skin, or 3-6 18-gauge core biopsies) stored for research at the 
time of the procedure. 
Core biopsies are always preferred over fine needle aspirates when both are technically feasible 
and safe. Fine needle aspirates (FNA) are acceptable and may be used for the baseline tissue 
sample but may not provide enough or adequate DNA for NGS.  
 
Listed below are the goal amounts of tissue for patients who undergo core biopsy or punch biopsy, 
or who have either ascites fluid or pleural fluid accessible for collection. Please note that the 
guidelines below are for the amount of tissue to be obtained at the baseline biopsy, and are not 
meant to replace clinical judgment at the time the procedure is performed. Less than the goal 
quantity of tissue is accepted for each type of biopsy, and will be left to the clinical judgment of 
the physician performing the procedure. 
• 
Breast: A goal of 3-6 core biopsy specimens will be obtained using standard institutional 
guidelines for a diagnostic core biopsy of a breast mass  
• 
Skin/chest wall: A goal of one to two 5-mm punch biops(ies)  
• 
Lymph node: A goal of 3-6 core biopsy specimens will be obtained using an 18-gauge needle  
• 
Liver: A goal of 3-6 core biopsy specimens will be obtained using an 18-gauge needle  
• 
Lung: Because of the risk of pneumothorax associated with core needle biopsies of lung 
nodules, no core biopsies of lung nodules will be performed on this protocol  
• 
Bone: Because the yield of malignant tissue from bone biopsies tends to be relatively low, if 
a patient has another accessible site of disease (i.e. skin, lymph node, liver), that site should 
be biopsied preferentially. If bone is the only biopsy-accessible site, then a goal of 3-6 core 
biopsy specimens will be obtained using an 18-gauge needle.  It is critical that every attempt 
be made to process a portion of the specimen without decalcification or decalcification with 
EDTA instead of Formic acid as the mutational analysis cannot be performed on decalcified 
specimens.  
• 
Pleural Fluid: A goal of 500 mL of pleural fluid will be obtained with a standard thoracentesis 
procedure, with or without image guidance, according to the clinical judgment of the treating 
physician and clinician performing the procedure. Less than the goal amount is acceptable, 
and should be based upon the clinical judgment of the Investigator and the clinician performing 
the procedure. If more than the goal amount of fluid is obtained, then the entire specimen 
(with the exception of what is needed for clinical purposes, if applicable) will be stored in the 
tissue bank.  
• 
Ascites fluid: A goal of 500 mL of ascites fluid will be obtained with a standard paracentesis 
procedure, with or without image guidance, according to the clinical judgment of the treating 
physician and clinician performing the procedure. Less than the goal amount is acceptable, 


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and should be based upon the clinical judgment of the Investigator and the clinician performing 
the procedure. If more than the goal amount of fluid is obtained, then the entire specimen 
(with the exception of what is needed for clinical purposes, if applicable) will be stored in the 
tissue bank.  
• 
For patients in whom a core biopsy is not possible and who thus undergo FNA, 3 passes 
should be collected.  
10.5.4 Instructions on fresh tissue specimen handling 
If feasible, at least four core biopsy specimens should be obtained:   
• 
Two core biopsy specimens should be snap-frozen in liquid nitrogen 
• 
Two core biopsies should be suspended in freshly prepared 10% buffered formalin 
• 
If additional core biopsies are obtained, 1-2 cores should be snap-frozen 
• 
If only 1 core biopsy is obtained, it should be snap-frozen in liquid nitrogen 
• 
If only 2 core biopsies are obtained, one should be snap-frozen in liquid nitrogen and the other 
should be suspended in freshly prepared 10% buffered formalin 
• 
Do not put tissue into any solution. 
For patients in whom a core biopsy is not feasible and who thus undergo FNA:  
• 
3 passes should be collected  
• 
All passes should be evacuated and rinsed directly into 10% buffered formalin in the same 
container  
10.5.5 Tissue specimen labeling and documentation  
• 
Label ALL specimens before freezing 
• 
If sample comes in contact with contaminate, make note in information section of paperwork. 
• 
Enter time core biopsy was collected on paperwork. 
• 
Label each collection containers with Patient ID sequence number/code letter, Medical 
Record #, site and location of biopsy, date and time. 
• 
If not retrieved on site by VICC CTO personnel, outside sites should ship specimens along 
with Tissue/Blood Registration Form directly to:  
 
Dr. Melinda Sanders 
c/o Violeta Sanchez 
Vanderbilt University Medical Center 
Department of Pathology, 4912 TVC 
1301 Medical Center Drive  
Nashville, TN 37232-5310 
615-343-9115  
 
 
The specimens will be logged in as a consented specimen and either be stored frozen or as 
paraffin-embedded tissue and available for molecular pathology studies. Ship ALL frozen 
samples packed with dry ice. 
**Specimens should be mailed to arrive at VUMC from Monday 8AM through Friday 1PM** 
10.6 Pharmacokinetics 
Full pharmacokinetic (PK) sampling of erdafitinib and palbociclib in combination with fulvestrant 
will be performed on Days 1 and 15 of Cycles 1 and 2 in all patients participating in the phase Ib 


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dose escalation portion of the trial treated on the daily dosing schedule. Of note, PK samples 
could be obtained from additional patients if there are concerns about the PK profiling and/or 
clinical safety based on the available results.    
The collection time of all samples must be documented in the PK Blood Collection eCRF pages. 
The exact time of oral erdafitinib dosing, date sample was taken and actual time of sampling must 
be entered on the eCRF. Any sampling problems (e.g., patient took study drug before a pre-dose 
sample) must be noted in the comments section of the eCRF. On days and time-points when 
blood samples for biomarkers and pharmacokinetics are to be performed, the pharmacokinetic 
sample must be drawn first. A meal record, if feasible, should be completed on the eCRF on days 
of PK assessment. 
On the days of full pharmacokinetic sampling, patients should take their medication at the clinic. 
Patients who forget to postpone their dose on these days and take their medication at home will 
be excluded from pharmacokinetic blood sampling for that day and they should not have blood 
samples collected. On the days of full pharmacokinetic sampling, the exact time of any episodes 
of vomiting within the first 24 h post-dosing on that day must be noted in a separate section of the 
eCRF. Similarly, in case of any increase of stool frequency (i.e. diarrhea) within the first 24 h post-
dosing on that day, this should also be documented in a separate section of the eCRF. 
The days of full pharmacokinetic blood sampling should be representative of the other study days 
with regard to the use of the chronically administered concomitant medications. Therefore, 
patients taking medication chronically should be maintained on the same dose and dose schedule 
throughout the study period, as medically feasible. An intermittent concomitant medication should 
be avoided on the days of full pharmacokinetic sampling. 
All pharmacokinetic blood samples will be taken by either direct venipuncture, an indwelling 
cannula inserted in a forearm vein, or via a port-a cath. Please refer to the Lab Manual for detailed 
instructions for the collection (including sampling schedule if an alternative dosing schedule is 
adopted), handling, and shipping of samples.  
The sampling regimen assumes that both erdafitinib and palbociclib will be swallowed 
concomitantly, or less than 5 minutes apart, and that both drugs will be taken at the same time 
every day. When patients come for the pre-dose PK (except for Cycle 1, Day 1), the time when 
erdafitinib and palbociclib were taken the day before should be noted. The blood sampling 
regimen for determining the pharmacokinetics of erdafitinib and palbociclib is given in Table 
10.5.1 and 10.5.2. If the evaluation of emerging data of erdafitinib indicates that it may be 
desirable to explore different doses or schedules of erdafitinib, then new cohorts of patients will 
be enrolled. A dosing schedule modification would be based on PK, PD and/or safety 
assessments. The collection time of all samples must be documented in the PK Blood Collection.  
Table 10.5.1: PK blood collection plan daily dosing schedule 
PK blood draws 
Cycle 1 
Cycle 2 
Day 1 
Day 15 
Day 1 
Day 15 
Pre-dose 
X 
X 
X 
X 
Post-dose 
1h ± 15 min 
X 
X 
X 
 
2h ± 15 min 
X 
X 
X 
 
4h ± 15 min 
X 
X 
X 
 


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8h ± 1 hour 
X 
X 
X 
 
 
Table 10.5.2:  PK Sample Numbers Labeling 
Cycle 
Day 
Time 
(hr.) 
Sample number 
Description 
1 
Day 1 
0 
US101 
Pre-erdafitinib and palbociclib dose 
1 
Day 1 
1h 
US103 
1h post-erdafitinib and palbociclib dose 
1 
Day 1 
2h 
US104 
2h post-erdafitinib and palbociclib dose 
1 
Day 1 
4h 
US106 
4h post-erdafitinib and palbociclib dose 
1 
Day 1 
8h 
US107 
8h post-erdafitinib and palbociclib dose 
1 
Day 15 
0 
US108 
Pre-erdafitinib and palbociclib dose 
1 
Day 15 
1h 
US110 
1h post-erdafitinib and palbociclib dose 
1 
Day 15 
2h 
US111 
2h post-erdafitinib and palbociclib dose 
1 
Day 15 
4h 
US113 
4h post-erdafitinib and palbociclib dose 
1 
Day 15 
8h 
US114 
8h post-erdafitinib and palbociclib dose 
2 
Day 1 
0 
US115 
Pre-erdafitinib and palbociclib dose 
2 
Day 1 
1h 
US117 
1h post-erdafitinib and palbociclib dose 
2 
Day 1 
2h 
US118 
2h post-erdafitinib and palbociclib dose 
2 
Day 1 
4h 
US120 
4h post-erdafitinib and palbociclib dose 
2 
Day 1 
8h 
US121 
8h post-erdafitinib and palbociclib dose 
2 
Day 15 
0 
US122 
Pre-erdafitinib and palbociclib dose 
10.6.1 Analytical method 
Erdafitinib concentrations in plasma will be determined by a validated bioanalytical method with 
an anticipated lower limit of quantification (LLOQ) of approximately 1 ng/mL which may be 
improved according to eventual needs for a higher sensitivity. In addition to erdafitinib analysis, 
exploratory erdafitinib metabolite analysis on remaining plasma material may be performed using 
a non-validated, semi-quantitative or qualitative LCMS/MS method, if deemed appropriate. 
10.7 Genetic Testing 
Participants will be given information as part of the informed consent process that samples will be 
used for research tests that will include genetic studies and testing.  The intent is not to give 
participants (or his/her medical providers) the results of any testing done for research purposes; 
however, incidental germline (heritable) mutations may be identified of which a participant may or 
may not already be aware.  In the case that an incidental genetic finding is identified, the Protocol 
Chair of this project will be notified.  The possible decisions for handling incidental findings may 
include notification of the participant (and provider); recommendation for genetic counseling, 
which may or may not include genetic testing (e.g., if the finding was not done in a CLIA certified 
laboratory); or, neither.  In general, a member of the participant’s treating team will be given the 
information to help with notification.  In all cases, the current policy of the Vanderbilt-Ingram 
Cancer Center and local/participating site IRB, as applicable, will be followed and any additional 
approvals that may be required prior to participant notification will be secured in advance. 
 
 


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11. SPECIMEN BANKING 
 
The study Protocol Chair and collaborators have approval by the TBCRC to use all research bio-
specimens collected during the conduct of this trial to address the research questions described 
in the protocol document.  All future use of residual or repository specimens collected in this trial 
for purposes not prospectively defined will require review and approval by the TBCRC according 
to its established policies, whether the specimens are stored in a central site or at a local institution 
in a virtual repository. Secondary use of biospecimens for new endpoints must be submitted to 
the TBCRC Central Office for possible review by the TBCRC Correlative Science Review 
Committee. 


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12.  MEASUREMENT OF EFFECT 
For the purposes of this study, patients should be re-evaluated for response after every 2 cycles. 
Response and progression will be evaluated in this study using the international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) Committee (version 1.1)47. 
Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are 
used in the RECIST criteria. 
12.1 Definitions 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
administration of study treatment drugs.  
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below.  
12.2 Disease Parameters 
12.2.1 Measurable 
12.2.1.1 Tumor lesions: Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
 
• 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
• 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
• 
20 mm by chest X-ray 
12.2.1.2 Malignant lymph nodes: To be considered pathologically enlarged and measurable, 
a lymph node must be ≥15mm in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm). At baseline and in follow-
up, only the short axis will be measured and followed.  
12.2.2 Non-measurable 
All other lesions, including small lesions (longest diameter <10mm or pathological lymph 
nodes of ≥10 to <15 mm in the short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
and abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
12.2.3 Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 
12.2.3.1 Bone lesions: 


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• 
Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above 
• 
Blastic bone lesions are non-measurable 
12.2.3.2 Cystic lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts 
• 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non cystic 
lesions are present in the same patient, these are preferred for selection as target lesions 
           13.2.3.3  Lesions with prior local treatment: 
• 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless disease progression there 
has been demonstrated 
12.2.4 Specifications by methods of measurements 
12.2.4.1 Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
12.2.4.2 Method of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but is/are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial and 
≥ 10 mm in diameter as assessed using calipers (e.g., skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. When lesions can be evaluated by both clinical exam and imaging, imaging evaluation 
should be undertaken since it is more objective and may also be reviewed at the end of the study. 
 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, 
lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded 
by aerated lung.  
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. Guidelines have defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is 5mm or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g. for body scans).  


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Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
 
Endoscopy, laparoscopy: The utilisation of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm complete pathological response when biopsies 
are obtained or to determine relapse in trials where recurrence following complete response or 
surgical resection is an endpoint. 
 
Tumor markers:  Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalise for a patient to 
be considered in complete response.  
 
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (e.g. with taxanes or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment can 
be considered, if measurable lesions have met criteria for response or stable disease, in order to 
differentiate between response (or stable disease) and progressive disease. 
12.3 Response Criteria 
12.3.1 Target lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline. 
This means that in instances where patients have only one or two organ sites involved, a 
maximum of two and four lesions, respectively, will be recorded. 
12.3.2 Evaluation of Target Lesions 
12.3.2.1 Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
12.3.2.2 Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 
12.3.2.3 Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one 
or more new lesions is also considered progression). 
12.3.2.4 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 


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to qualify for PD, taking as reference the smallest sum of diameters while on study. 
12.3.3 Non-target lesions:  
All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are not 
required and these lesions should be followed as ‘present’, ‘absent’, or, in rare cases 
‘unequivocal progression’. In addition, it is possible to record multiple non-target lesions 
involving the same organ as a single item on the case record form (e.g. ‘multiple enlarged 
pelvic lymph nodes’ or ‘multiple liver metastases’). 
12.3.4 Evaluation of Non-Target Lesions 
12.3.4.1 Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker levels. All lymph nodes must be non-pathological in size (<10 mm in their 
short axis). 
12.3.4.2 Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker levels above the normal limits. 
12.3.4.3 Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 
(Note: the appearance of one or more new lesions is also considered progression). 
12.3.5 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment 
until the end of treatment taking into account any requirement for confirmation. On occasion 
a response may not be documented until after the end of therapy so protocols should be clear 
if post-treatment assessments are to be considered in determination of best overall response. 
Protocol must specify how any new therapy introduced before progression will affect best 
response designation. The patient’s best overall response assignment will depend on the 
findings of both target and non-target disease and will also take into consideration the 
appearance of new lesions. Furthermore, depending on the nature of the study and the 
protocol requirements, it may also require confirmatory measurement. Specifically, in non-
randomized trials where response is the primary endpoint, confirmation of PR or CR is needed 
to deem either one as the ‘best overall response’. 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non CR/Non PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non PD or not all evaluated 
No 
PR 
SD 
Non PD or not all evaluated 
No 
SD 
Not all 
evaluated 
Non PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
 
CR=complete response, PR=partial response, PD=progressive disease, SD=stable disease, 
NE=not evaluable. 


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* In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported 
as “symptomatic deterioration”. In these patients, every effort should be made to document 
the objective progression even after discontinuation of treatment. 
12.4 Duration of Response 
12.4.1 Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented. 
12.4.2 Duration of stable disease: Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started. 
13. ADVERSE EVENT REPORTING REQUIREMENTS 
13.1 General 
Adverse event collection and reporting is a routine part of every clinical trial. This study will use 
the descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events version 4.03 (CTCAE v4.03) that is available at http://ctep.cancer.gov/reporting//ctc.html.  
Information on all adverse events, whether reported by the participant, directly observed, or 
detected by physical examination, laboratory test or other means, will be collected, recorded, 
followed and reported as described in the following sections.  
Adverse events, special situations including pregnancies and product quality complaints 
experienced by participants will be collected and reported from initiation of study-related 
procedures (i.e from time of consent form signature), throughout the study, and within 30 days of 
the last documented dose of study medication. Participants who experience an ongoing adverse 
event related to a study procedure and/or study medication beyond 30 days will continue to be 
contacted by a member of the study team until the event is resolved, stabilized, or determined to 
be irreversible by the participating investigator.  
For the purposes of this study, the J&J medicinal product is: Balversa (Erdafitinib (JNJ-42756493) 
Participants should be instructed to report any serious post-study event(s) that might reasonably 
be related to participation in this study. The investigator should notify the IRB and any other 
applicable regulatory agency of any unanticipated death or adverse event occurring after a 
participant has discontinued or terminated study participation that may reasonably be related to 
the study drugs.  
13.2 Definitions 
13.2.1 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 


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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. 
 
13.2.2 Serious adverse event (SAE) 
A serious adverse event is an undesirable sign, symptom or medical condition which: 
 
• 
is fatal or life-threatening (the subject was at risk at the time of the event. It does not refer to 
an event that hypothetically may have caused death if it were more severe); 
• 
requires or prolongs inpatient hospitalization; 
• 
results in persistent or significant disability/incapacity; 
• 
constitutes a congenital anomaly or birth defect; or 
• 
is a suspected transmission of any infectious agent fia a medicinal product 
• 
jeopardizes the participant and requires medical or surgical intervention to prevent one of the 
outcomes listed above.  
• 
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. 
 
Events not considered to be serious adverse events are hospitalizations for: 
• 
routine treatment or monitoring of the studied indication, not associated with any deterioration 
in condition, or for elective procedures 
• 
elective or pre-planned treatment for a pre-existing condition that did not worsen 
• 
emergency outpatient treatment for an event not fulfilling the serious criteria outlined above 
and not resulting in inpatient admission 
• 
respite care 
13.2.3 Expectedness  
• 
Expected: Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, an adverse event is 
considered expected when it appears in the current adverse event list, the Investigator’s 
Brochure, the package insert or is included in the informed consent document as a potential 
risk. 
• 
Unexpected: An adverse event is considered unexpected when it varies in nature, intensity or 
frequency from information provided in the current adverse event list, the Investigator’s 
Brochure, the package insert or when it is not included in the informed consent document as 
a potential risk 


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13.2.4 Attribution  
Attribution is the relationship between an adverse event or serious adverse event and the study 
treatment. Attribution will be assigned as follows: 
 
• 
Definite – The AE is clearly related to the study treatment 
• 
Probable – The AE is likely related to the study treatment 
• 
Possible – The AE may be related to the study treatment 
• 
Unlikely - The AE is doubtfully related to the study treatment 
• 
Unrelated - The AE is clearly NOT related to the study treatment 
13.3 Reporting Procedures 
13.3.1 General Considerations 
All adverse events will be captured on a centralized electronic case report form called ON-line 
Clinical Oncology Research Environment = Oncore 
 (http://www.vicc.org/ct/research/oncore.php).  
Oncore is a highly secure, web based, cancer specific, and customizable system that provides 
fully integrative clinical data management and study administration capabilities developed in an 
ongoing collaborative effort with NCI designated Comprehensive Cancer Centers. It fully 
integrates study administration functionality including protocol tracking, patient registration, NCI 
reporting, review committee tracking, and SAE tracking, with clinical data management 
functionality including electronic case report forms (eCRF) design, clinical data capture, protocol 
and regulatory compliance monitoring. Specified members at each TBCRC participating site will 
submit all regulatory documents to the Coordinating Center Data Manager, who will upload them 
on Oncore. 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs, and 
avoid colloquialisms and abbreviations. If known at the time of reporting, a diagnosis should be 
reported rather than individual signs and symptoms (e.g. record only liver failure or hepatitis rather 
than jaundice, asterixis, and elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or syndrome at the time of 
reporting, it is acceptable to report the information that is currently available. If a diagnosis is 
subsequently established, it should be reported as follow-up information. 
All deaths that occur during the protocol-specified AE reporting period, regardless of attribution, 
will be reported to the appropriate parties.  When recording a death, the event or condition that 
caused or contributed to the fatal outcome should be reported as the single medical concept.  If 
the cause of death is unknown and cannot be ascertained at the time of reporting, report 
“Unexplained Death.” Deaths that occur during the protocol specified adverse event reporting 
period that are attributed by the investigator solely to progression of disease should be recorded 
only in the study eCRF. 
NOTE: Death for any reason should be reported as a Serious Adverse event. 
The cause of death of a subject in a study within 30 days of the last dose of study drug, whether 
or not the event is expected or associated with the study drug, is considered a serious adverse 
event. 
A pre-existing medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A pre-existing medical condition should be 
re-assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 


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character of the condition worsens during the study. When reporting such events, it is important 
to convey the concept that the pre-existing condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”). 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE. If a patient is hospitalized to undergo a medical or surgical procedure as a 
result of an AE, the event responsible for the procedure, not the procedure itself, should be 
reported as the SAE. For example, if a patient is hospitalized to undergo coronary bypass surgery, 
record the heart condition that necessitated the bypass as the SAE. 
Hospitalizations for the following reasons do not require reporting: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for 
pre-existing conditions; or 
• 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study; or 
• 
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of the 
study; or 
• 
Hospitalizations not intended to treat an acute illness or adverse event (e.g., social reasons 
such as pending placement in long-term care facility); or 
• 
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.] 
 
13.3.2 Serious Adverse Events 
All serious adverse events, regardless of causality to study drug, will be reported to the Principal 
Investigator and/or the Study Coordinator at each institution, and also to the Coordinating Center. 
All serious adverse events must be reported to the Coordinating Center within 24 hours of the site 
becoming aware of the event. Sites will email or fax the SAE forms to the cooridinating center at: 
coordinating.center@vvumc.org.  The coordinating center will report SAEs to the FDA via 
MedWatch form (3500).   
 
ATTN:  VICC CTO Personnel 
EMAIL:  Coordinating.center@vumc.org  
FAX:  (615) 875-0040 
 
Follow-up information must also be reported within 1 business day of receipt of the information 
by the investigator. 
The Coordinating Center will disseminate information regarding serious adverse events to the 
participating sites within 5 days of review of the information by the Protocol Chair (or her designee 
in the event of extended absence) only in the case that the event(s) is/are believed to be related 
(i.e., possibly, probably or definitely) to the study medication. The Coordinating Center will be 
responsible for reporting of events to the FDA and supporters, as appropriate (outlined below). 


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13.3.3 Adverse Events of Special Interest 
For erdafitinib, adverse events of special interest include: 
• 
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  
 
13.3.4 Institutional Review Board 
All adverse events and serious adverse events will be reported to the IRB per current institutional 
standards. If an adverse event requires modification of the informed consent, these modifications 
will be provided to the IRB with the report of the adverse event. If an adverse event requires 
modification of the study protocol, these modifications will be provided to the IRB as soon as is 
possible. 
13.3.5 Food and Drug Administration (FDA) 
In this trial, unexpected adverse events believed to be definitely, probably, or possibly related to 
the medications will be reported to the FDA via MedWatch (using the online form available at 
https://www.accessdata.fda.gov/scripts/medwatch/; by telephone 1-800-FDA-1088; or by fax 1-
800-FDA-0178 using form available at http://www.fda.gov/medwatch/report/hcp.htm). The 
Coordinating Center will be responsible for correspondence regarding adverse events with the 
FDA for all participating sites. 
13.3.6 Pfizer, Inc. 
The Coordinating Center will receive information from participating sites of all SAEs and other 
reportable events, and will report to Pfizer as detailed below: 
• 
If an SAE occurs, Pfizer is to be notified within 24 hours of coordinator center awareness of 
the event. In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be 
made immediately, irrespective of the extent of available AE information. This timeframe also 
applies to additional new information (follow-up) on previously forwarded SAE reports as well 
as to the initial and follow-up reporting of exposure during pregnancy, exposure via 
breastfeeding and occupational exposure cases. 
• 
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (e.g., if an outpatient study patient initially seeks treatment elsewhere), the 
coordinating center is to report the event within 24 hours after learning of it and document the 
time of his/her first awareness of the AE.   
• 
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the timeframes for reporting specified above. In addition, an investigator may 
be requested by Pfizer to obtain specific additional follow-up information in an expedited 
fashion. This information collected for SAEs is more detailed than that captured on non-SAEs. 
In general, this will include a description of the AE in sufficient detail to allow for a complete 
medical assessment of the case and independent determination of possible causality. 
Information on other possible causes of the event, such as concomitant medications, 
vaccines, and/or illnesses must be provided. In the case of a patient death, a summary of 
available autopsy findings must be submitted as soon as possible to Pfizer or its designated 
representative. 


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13.3.7 Janssen Research & Development 
The Coordinating Center will report any safety information that meets the criteria noted to 
Janssen on a Serious Event Report Form within 24 hours of the coordinating center becoming 
aware of the event 
 
All adverse events, adverse events of interest (section 13.3.3), product quality complaints and 
safety events of interest (including pregnancy) (listed below) whether serious or non-serious, 
related or not related, following initiation of study procedures (i.e. from time of informed 
consent signature) 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 a J&J  medicinal product.  
All (serious and non-serious) adverse events reported for a J&J medicinal product should be 
followed-up in accordance with clinical practice. 
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 
• 
Inadvertent or accidental exposure to a J&J medicinal product  
• 
Medication error, intercepted medication error or potential medication error 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 thereapeutic or clinical benefit from use of a J&J medicinal product 
• 
Any failure of expected pharmacological action (i.e. lack of effect of a K&J medicinal 
product 
These safety events may not meet the definition of an adverse event; however, from 
Janssen’s 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 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 within 24 hours of the 
coordinating center becoming aware of the event. 
 
Individual Case Safety Report (ICSR) 
A valid ICSR must contain the four minimum criteria required to meet regulatory 
reporting requirements. 
• 
an identifiable subject (but not disclosing personal information such as the subject’s 
name, initials or address) 


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• 
an identifiable reporter (investigational site) 
• 
a J&J medicinal product 
• 
an adverse event, outcome, or certain special situations 
 
The minimum information required is: 
• 
suspected J&J medicinal product (doses, indication) 
• 
date of therapy (start and end date, if available) 
• 
batch or lot number, if available 
• 
subject details (subject ID and country) 
• 
gender 
• 
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 
 
Pregnancy  
 
All initial reports of pregnancy must be reported to the the Coordinating Center within 24 hours of 
becoming aware of the event using the Serious Adverse Event Form. Abnormal pregnancy 
outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital anomaly, ectopic pregnancy) 
are considered serious adverse events and must be reported. 
 
Any subject who becomes pregnant during the study must be promptly withdrawn from the study and 
discontinue further study treatment. 
 
Because the J&J medicinal product may have an effect on sperm, pregnancies in partners of male 
subjects exposed to a J&J medicinal product will be reported to Janssen within within 24 hours of 
Coordinating Center knowledge of the event using the Serious Adverse Event Form.  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 
Safety Data and Product Quality Complaints (PQCs) for Janssen Medicinal Products  
 
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 
• 
Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules 
• 
Potential Dosing Device Malfunction: e.g., autoinjector button not working, needle 
detaching from syringe 
• 
Suspected Contamination 
• 
Suspected Counterfeit 
 


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PQC 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, J&J and are mandated by regulatory agencies worldwide. 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 a J&J medicinal product under study must be reported to to Janssen 
within within 24 hours of Coordinating Center being made aware of the event.  
 
If the defect for a J&J medicinal product under study is combined with either a serious adverse 
event or non-serious adverse event, the PQC must reported to Janssen by the the Coordinating 
Center according to the serious adverse event reporting timelines.  A sample of the suspected 
product should be maintained for further investigation if requested. 
 
All adverse events and special situations, whether serious or non-serious, related or not related, following 
exposure to a J&J medicinal product 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 a J&J medicinal product.  
All (serious and non-serious) adverse events reported for a J&J medicinal product should be followed-up 
in accordance with clinical practice. 
 
AE Reports (Incoming) Single Case AE/SAE Reports should be sent via SecureEmail to 
Janssen: 
• 
Enter the following web address into your web browser (personnel need to have been 
registered with Cisco AND have their email/password):  
 https://res.cisco.com/websafe/root 
• 
In the “To” box, enter IIS-BIO-VIRO-GCO@its.jnj.com 
 
14. DATA AND SAFETY MONITORING 
14.1 Data Management and Reporting 
Data will be collected using a centralized electronic case report form called ON-line Clinical 
Oncology Research Environment (Oncore), located at  
< http://www.vicc.org/ct/research/oncore.php >. 
Oncore is a highly secure, web based, cancer specific, and customizable system that provides 
fully integrative clinical data management and study administration capabilities developed in an 
ongoing collaborative effort with NCI designated Comprehensive Cancer Centers.  The system is 
capable of storing basic protocol information (e.g. IRB approval dates, dates for annual renewals) 
and clinical trials research data. It fully integrates study administration functionality including 
protocol tracking, patient registration, NCI reporting, review committee tracking, and SAE tracking 
with clinical data management functionality including electronic case report forms (eCRF) design, 
clinical data capture, protocol and regulatory compliance monitoring.   


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Oncore allows the investigator to define specific protocol requirements and generate data 
collection forms. Creation of the data collection form is done with a single button click after the 
parameters of an individual protocol have been specified. Oncore also permits specification of 
study protocols, management of patient enrollment, clinical data entry and viewing, and the 
generation of patient or study-specific reports based on time stamping. OnCore is embedded with 
a comprehensive domain repository of standard reference codes and forms to promote 
standardization. The sources for the repository include CDUS, CTC, CDEs from NCI, ICD, 
MedDRA and various best practices from contributing NCI-designated Comprehensive Cancer 
Centers. OnCore provides several reporting features specifically addressing NCI Summary 3 and 
Summary 4 and other reporting requirements. Data may also be exported in a format suitable for 
import into other database, spreadsheets or analysis systems (such as SPSS).  This system will 
be used to manage all VICCC clinical trials data. OnCore is maintained and supported in the VICC 
Clinical and Research Informatics Resource.  
Specified site members will submit all pertinent regulatory documents to the Coordinating Center 
Data Manager, who will store it in a secure location. 
The Principal Investigator or designee will inform Janssen Research & Development as defined 
in established Safety and Data Exchange Agreement (SDEA) of any serious adverse event, and 
will inform the Vanderbilt IRB in accordance with IRB policy.  The Principle Investigator is 
responsible for the detection and documentation of events meeting the criteria and definition of 
an AE or SAE, as specified in this protocol. Whenever there is a safety evaluation during the 
study, the treating investigator or site staff will be responsible for detecting, documenting and 
reporting AEs and SAEs, as detailed in the protocol. If any problem is identified related to the 
conduct of this research, the VICC Data Safety and Monitoring Committee (DSMC) will be formally 
asked to review the study and the situation that required DSMC intervention. 
14.2 Data Handling and Record Keeping 
An electronic case report form (Oncore eCRF) is required and must be completed for each 
included participant.   
The investigator or designee may maintain records separate from the case report forms in the 
forms of clinic charts, medical records, original laboratory, radiology and pathology reports, 
pharmacy records, etc. The investigator will document in the clinic chart or medical record the 
date on which the patient signed informed consent prior to the patient’s participation in the trial.  
Source documents must completely reflect the nature and extent of the patient’s medical care, 
and must be available for source document verification against entries in the case report forms. 
Source documents regarding procedures such as scans and laboratory evaluations performed as 
part of the standard of care prior to enrollment in the study can be used to fulfill certain screening 
and baseline assessments. All information obtained from source documents will be kept in strict 
confidentiality. Source data sent as supporting documentation to regulatory authorities for serious 
adverse events will be de-identified to preserve confidentiality. 
To enable evaluations and/or audits from Health Authorities and Vanderbilt the investigator 
agrees to keep records including: The identity of all participants (sufficient information to link 
records; e.g., hospital records), all original signed informed consent forms, copies of all source 
documents, and detailed records of drug disposition. To comply with international regulations, the 
records should be retained by the investigator in compliance with regulations.  
During data entry, range and missing data checks will be performed online. The checks to be 
performed will be documented in the Data Monitoring Plan for the study. A summary report (QC 
Report) of these checks together with any queries resulting from manual review of the eCRF's will 


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be generated and transmitted to the site and the site monitor. Corrections will be made by the 
study site personnel. This will be done on an ongoing basis. 
14.3 Meetings 
This trial will be monitored by the VICC Breast Cancer Research Team. The Breast Cancer 
Research Team is composed of the Clinical Core Director of the Breast Cancer Program and 
Team Leader, surgical oncologists, radiation oncologists, medical oncologists, research nurses, 
data managers, and our regulatory specialist. The Breast Cancer Research Team meets 
informally weekly and officially on a monthly basis to discuss all AEs/SAEs, accrual, compliance, 
safety issues, adherence to protocol, data reviews, etc. pertaining to all breast cancer clinical 
trials. This particular study will be thoroughly reviewed during these meetings. The monthly 
meetings have minutes recorded each time, those are also reviewed on a monthly basis by the 
Breast Cancer Research Team Physician Leader. 
Teleconferences between TBCRC participants and the Breast Cancer research team at 
Vanderbilt will be held every other week during escalation phase and monthly during expansion 
phase, to discuss all issues related to the trial (AEs/SAEs, accrual, compliance, safety issues, 
adherence to protocol, data reviews, etc.). 
14.4 Monitoring 
The Vanderbilt-Ingram Cancer Center (VICC) oversees patient safety and data monitoring for its 
investigator-initiated and NIH-NCI funded clinical trials through its Data and Safety Monitoring 
Committee (DSMC). The purpose of the DSMC is to ensure the efficient implementation and 
management of VICC Data and Safety Monitoring Plan (DSMP). The Committee maintains 
authority to intervene in the conduct of studies as necessary to ensure clinical research performed 
at VICC achieves the highest quality standards. 
The VICC DSMC meets on a quarterly basis and ad hoc to discuss data and safety monitoring of 
clinical trials and to oversee the VICC DSMP. Internal audits for compliance with adverse event 
reporting, regulatory and study requirements, and data accuracy and completion are conducted 
according to the VICC DSMP according to study phase and risk. The committee reviews all 
serious adverse events (SAE) on Vanderbilt sponsored investigator-initiated studies on a 
quarterly basis and provides DSMC SAE review reports to the Vanderbilt IRB. 
The investigator will allow the VICC-DSMC designee access to all pertinent medical records, as 
required by federal regulations, in order to allow for the verification of data gathered in the 
electronic data case report forms (eCRFs) and for the review of the data collection process.  The 
VICC-DSMC designee will review various aspects of the trial including, but not limited to:  
screening and enrollment logs; compliance with the protocol and with the principles of Good 
Clinical Practice; completion of case report forms; source data verification; study drug 
accountability and storage; facilities and staff. The investigator and the investigational site staff 
must be available to meet with the VICC-DSMC designee in order to discuss the progress of the 
trial, make necessary corrections to case report form entries, respond to data clarification 
requests and respond to any other trial-related inquiries of the monitor. 
In addition to the above, the FDA may review the conduct or results of the study at the 
investigational site.  
 
In accordance with HIPAA and associated privacy regulations, a subject’s authorization to use 
personally identifiable health information may be required from each subject before 
commencement of research activities. This authorization document must clearly specify what 


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parties will have access to a subject’s personal health information, for what purpose and for what 
duration. 
 
The trial additionally will be monitored by the VICC Multi-Institutional Coordinating Center. The 
actual frequency of monitoring will depend on the enrollment rate and performance of the site. 
Monitoring will be conducted through onsite and/or remote monitoring, teleconferences with the 
Investigator and site staff, and appropriate communications by mail, fax, email, or telephone. The 
purpose of monitoring is to ensure that the study is conducted in compliance with the protocol, 
standard operating procedures (SOPs), and other written instructions, and to ensure the quality 
and integrity of the data. 
 
During scheduled monitoring visits, investigators and the investigational site staff must be 
available to discuss the progress of the trial, make necessary corrections to case report form 
entries, respond to data clarification requests, provide required regulatory documents, and 
respond to any other trial-related inquiries of the monitor. 
 
In addition to the above, the FDA may review the conduct or results of the study at the 
investigational site. 
 
 
 
 


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15. REGULATORY CONSIDERATIONS 
15.1 Pre-Study Documentation 
Each participating site is responsible for submitting copies of all relevant regulatory 
documentation to the Coordinating Center. The Coordinating Center will provide each 
participating site with a comprehensive list of the necessary documents. It is the responsibility of 
the participating sites to maintain copies of all documentation submitted to the Coordinating 
Center. 
 
The required documents include but are not limited to the following: 
• 
A signed FDA Form 1572 
• 
A current curriculum vitae and medical license of the Principal Investigator and each sub-
investigator listed on the FDA Form 1572 
• A letter from the IRB stipulating approval of the protocol, the informed consent 
document and any other material provided to potential trial participants with information 
about the trial (e.g. advertisements) 
• 
A copy of the IRB-approved informed consent document 
• 
The current IRB membership list for the reviewing IRB 
• 
A completed financial disclosure form for the investigator and all sub- investigators 
• 
Current laboratory certification for the reference laboratory and curriculum vitae of the 
laboratory director 
• 
A list of current laboratory normal values for the reference laboratory 
The requirements for data management, submissions, and monitoring are outlined below. The 
participating sites will submit all the research related information inclusive of:  
• 
Source documents (patient registration list, CRF info, toxicity assessments, tumor 
measurements / responses, etc.)  are required to be provided within 30 days of visit or 10 
days in advance of a monitoring visit or audit,   
• 
Essential Documents (IRB approval documents, financial disclosure forms, 1572, 
delegation of authority log, protocol training, etc.) are required to be provided within one 
week of receiving the updated documents.    
 
Personnel from the VICC Clinical Trials Office will monitor the trial and may periodically visit the 
investigative site to assure proper conduct of the trial and proper collection of the data. The 
investigators at other sites will allow the monitor to review all source documents used in the 
preparation of the case reports. 
 
15.2 Protocol Review and Amendments 
Information regarding study conduct and progress will be reported to the Institutional Review 
Board (IRB) per the current institutional standards of each participating center. Any changes to 
the protocol will be made in the form of an amendment and must be approved by the IRB of each 
institution prior to implementation.   
The Protocol Chair (or designee) is responsible for the coordination and development of all 
protocol amendments, and will disseminate this information to the participating centers. 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 


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Board/Independent Ethics Committee (IRB/IEC/REB). Any amendments to the protocol, other 
than administrative ones, must be approved by this committee. 
Amendments significantly affecting the safety of subjects, the scope of the investigation or the 
scientific quality of the study, require additional approval by the IRB/IEC/REB. Amendments 
affecting only administrative aspects of the study do not require formal protocol amendments or 
IRB/IEC/REB approval but the IRB/IEC/REB of each center must be kept informed of such 
administrative changes.  
15.3 Informed Consent 
The investigator (or his/her designee) will explain to each subject the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits involved 
and any discomfort it may entail.  Each subject will be informed that participation in the study is 
voluntary, that s/he may withdraw from the study at any time, and that withdrawal of consent will 
not affect her subsequent medical treatment or relationship with the treating physician(s) or 
institution.  The informed consent will be given by means of a standard written statement, written 
in non-technical language, which will be IRB approved.  The subject should read and consider 
the statement before signing and dating it, and will be given a copy of the document.  No subject 
will enter the study or have study-specific procedures done before his/her informed consent has 
been obtained. 
In accordance with the Health Information Portability and Accountability Act (HIPAA), the written 
informed consent document (or a separate document to be given in conjunction with the consent 
document) will include a subject authorization to release medical information to the Coordinating 
Center and supporting agencies and/or allow these bodies, a regulatory authority, or Institutional 
Review Board access to subjects’ medical information that includes all hospital records relevant 
to the study, including subjects’ medical history. 
15.4 Confidentiality and Disclosure 
The investigator agrees to keep all information provided by this study in strict confidence and to 
request similar confidentiality from his/her staff and the IRB/IEC/REB. Study documents provided 
(protocols, investigators' brochures, CRFs and other material) will be stored appropriately to 
ensure their confidentiality.  
Patient medical information obtained by this study is confidential, and disclosure to third parties 
other than those noted below is prohibited. Upon the patient’s permission, medical information 
may be given to his or her personal physician or other appropriate medical personnel responsible 
for his or her welfare.  This medical information must be made available to the IRB and DSMC, 
upon request, for source verification of study documentation.  Data generated by this study must 
be available for inspection upon request by representatives of the U.S. FDA, local health 
authorities, Dr. Vandana Abramson and her authorized representative(s), collaborators and 
licensees, and the IRB for each study site, if appropriate. We will make all reasonable efforts to 
keep patient’s protected health information (PHI) private and confidential. We will only utilize or 
relinquish this kind of information according to federal privacy guidelines. There are many 
safeguards in place to prevent the unintentional disclosure of information obtained for or produced 
by this study.  Research data, including the data collected from the medical charts will be entered 
into a password-protected database.  Any publications or public disclosure of data relating to the 
patient’s tumor will be done without any identifying information.   
PHI will be collected and stored in the ONCORE research database.  The coordinating center will 
have access to all research data, which will be kept for at least 2 years after the study is 


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Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
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completed. Any research data entered in a patient medical record will be stored for an indefinite 
amount of time. There are no plans to destroy data at this time. 
Confidentiality and security will be maintained for the tissue collection within this study. All tissue 
samples obtained for this study will be assigned a code and this code used to identify the sample. 
The samples will not be labeled with the patient’s name, address or other information that would 
identify them. All information will be coded to maintain privacy. Research data, including the data 
collected from the medical charts will be entered into a password-protected database. The 
database (Breast Cancer Program Database) in which this study data are going to be stored has 
a firewall (in addition to the institutional firewall) with the highest level of protection, i.e. the same 
level of protection as the on-line hospital information system at Vanderbilt.  This means that users 
must log on to a web server that sits between the institutional firewall and the firewall to the 
database, and only this application server is allowed to query the database. Information, including 
the identifier and password for the authorized users, is transmitted via a secure shell protocol 
using 128k encryption. Only Dr. Vandana Abramson, the PI, and the Breast Team Data Manager, 
approved through our IRB will be allowed access to patient identifiers. Other levels of 
authorization may exist for approved users, e.g. access to de-identified data. This database will 
store a de-identified link to the patient data and will not otherwise store patient data, even de-
identified data.  The safety monitoring will be performed by the groups deemed appropriate by 
the Vanderbilt University Medical Center IRB for reviewing the clinical trials procedure.  Safety 
monitoring for the database is also performed by the Networking and Security Services of the 
Vanderbilt University Medical Center. Audit trails for access to the web server and the databases 
behind the dual firewall system are maintained in accordance with the practices of the Networking 
and Security Services of the Vanderbilt University Medical Center. 
The investigator agrees to keep all information provided by Janssen Research & Development in 
strict confidence and to request similar confidentiality from his/her staff and the IRB/IEC/REB. 
Study documents provided by Janssen Research & Development (investigators' brochures and 
other material) will be stored appropriately to ensure their confidentiality. The information provided 
by Janssen Research & Development to the investigator may not be disclosed to others without 
direct written authorization from Janssen Research & Development, except to the extent 
necessary to obtain informed consent from patients who wish to participate in the trial. 
15.5 Records Retention 
The investigator will retain the records of the clinical trial (including, but not necessarily limited to, 
CRFs, source documents, informed consent forms, drug accountability records, IRB 
correspondence, etc.) for at least 2 years after all investigations have been discontinued.  Study 
records must be stored in a safe and secure location permitting timely retrieval, if necessary. 
Study records that must be retained include case report forms, signed informed consents, 
correspondence with the IRB, study drug dispensing and inventory records, source documents 
(clinic charts, medical records, laboratory results, radiographic reports) and screening/ enrollment 
logs. 
15.6 Study Termination 
The investigator reserves the right to terminate the study at any site and at any time.  Reasons 
for study termination may include, but are not limited to, the following: 
• 
Investigator non-compliance with the protocol, GCP or regulatory requirements 
• 
Insufficient enrollment 
• 
Safety concerns 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
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• 
Decision by Janssen Research & Development to modify or discontinue the development or 
manufacturing of erdafitinib  
• 
A request to discontinue the study by the IRB or FDA 
The investigator will promptly notify Pfizer, Janssen Research & Development, the IRB and FDA 
if the study is terminated for any reason. 
15.7 Ethics and GCP 
This study will be carried out in compliance with the protocol and Good Clinical Practice, as 
described in: 
• 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996 
• 
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations) 
• 
Declaration of Helsinki, concerning medical research in humans (Recommendations Guiding 
Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, amended 
Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996) 
The investigator agrees to adhere to the instructions and procedures described in it and thereby 
to adhere to the principles of Good Clinical Practice to which it conforms. 
15.8 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food 
and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. Information posted will 
allow subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and study site contact information. 
16. MULTI-CENTER GUIDELINES 
16.1 Study Documentation 
Each participating site is responsible for submitting copies of all relevant regulatory 
documentation to the Coordinating Center. The required documents include, but are not limited 
to the following: local IRB approvals (i.e., protocol, consent form, amendments, patient brochures 
and recruitment material, etc.), each participant’s informed consent, enrollment form, eligibility 
checklist and tissue block registration, summary of unanticipated problems or protocol deviations, 
and documentation of expertise of the investigators. The Coordinating Center will provide each 
participating site with a comprehensive list of the necessary documents. It is the responsibility of 
the participating sites to maintain copies of all documentation submitted to the Coordinating 
Center. 
The requirements for data management, submissions, and monitoring are outlined below. The 
TBCRC participating sites will submit all the research related information (source documents and 
research records – IRB approval documents, patient registration list, CRF info, toxicity 
assessments, tumor measurements/ responses, etc.) within 2 weeks of the patient’s visit to the 
Coordinating Center Data Manager, who will upload it on Oncore at the appropriate time points: 
prior to study initiation, when patients are enrolled, and monthly throughout the study. The 
Coordinating Center Data Manager will have data entered into Oncore within 1 week of receiving 
the information.  Personnel from the VICC Clinical Trial Shared Resource will monitor the trial and 
may periodically visit the investigative site to assure proper conduct of the trial and proper 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
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collection of the data.  The investigators at other sites will allow the monitor to review all source 
documents used in the preparation of the case reports. 
16.2 Records Retention 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including CRFs, consent forms, 
laboratory test results, and medication inventory records, must be retained by each Principal 
Investigator for 2 years after marketing application approval.  If no application is filed, these 
records must be kept 2 years after the study is discontinued and the U.S. FDA and the applicable 
national and local health authorities are notified. 
Following closure of the study, each participating center will maintain a copy of all site study 
records in a safe and secure location. The Coordinating Center will inform the investigator at each 
site at such time that the records may be destroyed. 
16.3 Publication 
It is understood that any manuscript or releases resulting from the collaborative research will be 
circulated to all participating sites prior to submission for publication or presentation. 
Any formal presentation or publication of data from this trial may be published after review and 
comment by Janssen Research & Development and prior to any outside submission.  Janssen 
Research & Development will receive copies of any intended communication in advance of 
publication (at least twenty-one working days for presentational materials and abstracts and thirty 
working days for manuscripts). Principal Investigator/Institution shall have the final authority to 
determine the scope and content of its publications, provided such authority shall be exercised 
with reasonable regard for the interests of Janssen Research & Development and, in accord with 
the trial contract shall not permit disclosure of Pfizer, Inc. and Janssen Research & Development 
confidential or proprietary information. Additionally, any publication of study data and results must 
conform to the publications policy as stated the Translational Breast Cancer Research 
Consortium’s (TBCRC) “Policies and Procedures”.  
17. STATISTICAL CONSIDERATIONS 
17.1 Study Design/ Endpoints 
This is an open-label phase Ib multi-institution trial that evaluates the safety profile/tolerability 
(DLT, MTD and RP2D determination) and anti-tumor effect (PFS, CBR and ORR determination) 
of the combination of palbociclib, fulvestrant and erdafitinib in post-menopausal patients with 
ER+/HER2-/FGRF-amplified metastatic breast cancer. Since a phase II study is currently being 
planned, tolerability and experience with this combination over a period of time of at least 8-16 
weeks is desirable.  Hence, in addition to an MTD, we are proposing a “highest tolerable dose”, 
to minimize the risk for unexpected DLT and ensure good tolerability of study drugs in future 
phase II trials. 
17.2 Sample Size and Statistical Analysis  
17.2.1 Primary endpoint 
Demographic and baseline patient characteristics will be summarized.  Adverse events will be 
classified by type, incidence, severity, and causality.  All adverse events will be summarized by 
patient, dose level, and disease.  All patients who received at least 4 weeks of study treatment 
drugs (unless DLTs observed) will be included in the safety portion of the trial, and all patients 
who received at least 8 weeks of erdafitinib will be included in the tolerability portion of the trial.  


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
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In the phase Ib escalation component of the trial, the MTD will be defined using the recently 
developed adaptive design known as the modified toxicity probability interval (mTPI) method48. 
The mTPI design uses a Bayesian framework with a beta/binomial hierarchical model to compute 
the posterior probabilities of three intervals that reflect the relative distance between the toxicity 
rate of each dose level to the target toxicity probability. That is, the mTPI design replaces the 3 + 
3 rules with a model-based inference on the toxicity probability intervals and has been shown to 
be safer and more reliable than the 3+3 design. The first cohort of patients (3 patients) in each 
arm will be started at dose level 1, and each patient will be observed for 4 weeks on the specified 
dose. The maximum tolerated dose (MTD) will be defined as the highest dose at which 20% of 
the patients experienced a DLT. The levels of uncertainty around the true target toxicity pT are 
(0.05, 0.05), which deifine the proper dosing interval as  (pT – 0.05, pT + 0.05). Each cohort has 3 
patients. In Table 17.2.1, the columns are the numbers of patients treated so far at the current 
dose level, and the rows are the corresponding numbers of patients experiencing toxicity. The 
entries of the table are dose-finding decisions—E, S, and D—representing escalating the dose, 
staying at the same dose, and de-escalating the dose, respecitvely. In addition, decision U means 
that the current dose level is unacceptable because of high toxicity and should be excluded from 
the trial. For example, when one of three patients experiences toxicity, the decision is to stay at 
the current dose level. This means that the next cohort of 3 patients will be treated at the same 
dose level currently being used. If zero of three patients experiences toxicity, the decision is to 
escalate. This means that the next cohort of 3 patients will be treated at the next-higher dose 
level. If three of three patients experiences toxicity, the decision is DU—to de-escalate to the next-
lower dose level and exclude the current dose from the trial which is considered unacceptably 
toxic.  
Table 17.2.1 
Number of Patients 
Number 
of 
Patients 
with 
DLTs 
 
1 2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
0 
E E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
1 
D D 
S 
S 
S 
S 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
2 
  
D 
DU 
D 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
E 
E 
3 
  
  
DU 
DU 
DU 
DU 
D 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
4 
  
  
  
DU 
DU 
DU 
DU 
DU 
DU 
D 
S 
S 
S 
S 
S 
S 
S 
S 
5 
  
  
  
  
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
S 
S 
S 
S 
S 
6 
  
  
  
  
  
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
S 
S 
7 
  
  
  
  
  
  
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
8 
  
  
  
  
  
  
  
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
9 
  
  
  
  
  
  
  
  
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
10 
  
  
  
  
  
  
  
  
  
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
11 
  
  
  
  
  
  
  
  
  
  
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
12 
  
  
  
  
  
  
  
  
  
  
  
DU 
DU 
DU 
DU 
DU 
DU 
DU 
13 
  
  
  
  
  
  
  
  
  
  
  
  
DU 
DU 
DU 
DU 
DU 
DU 
14 
  
  
  
  
  
  
  
  
  
  
  
  
  
DU 
DU 
DU 
DU 
DU 
15 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
DU 
DU 
DU 
DU 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
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16 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
DU 
DU 
DU 
17 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
DU 
DU 
18 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
DU 
 
E: Escalate to the next higher dose; S: Stay at the same dose; D: De-escalate to the 
previous lower dose; DU: De-escalate to the previous lower dose and the current dose will 
never be used again in the trial; 
 
No new cohort of patients will be treated until the previous cohort has been fully evaluated for 
toxicity. All patients treated to determine the MTD will be part of the escalation portion of the trial. 
Once the MTD is reached, the safety data will be analyzed and the expansion component of the 
study will be completed to assess tolerability and efficacy. Patients in the expansion component 
of the study will initiate study treatment at the respective MTD. Note that dose reduction within 
individual patients is allowed in the expansion component of the study. Dose reduction will be 
required for a given patient in case of grade 3 or 4 toxicities, or if grade 2 creatinine, bilirubin, 
AST, ALT, hyperphosphatemia or grade 2 GI toxicity lasting more than 2 weeks.  
Since a phase II study is currently being planned, tolerability and experience with these 
combinations over at least 8-16 weeks is desirable. A period of 8 weeks was deemed acceptable 
for assessment of study drug tolerability.  Hence, we are proposing a modified definition of an 
MTD, to ensure tolerability of study drugs for a more prolonged period of time in anticipation of 
future phase II trials. We plan to treat at least 20 patients as part of the expansion portion of the 
study. For tolerability assessment, patients in the escalation portion of the trial that are treated at 
the MTD will be included in the tolerability analysis.  
Justification for RP2D based on ≥ 15 out of 20 Tolerant Patients  
 
 
 
True probability of tolerability at MTD 
0.3 
0.5 
0.7 
0.75 
0.8 
0.9 
0.99 
Probability of observing ≥ 15/20 tolerable 
patients 
0.00004 0.02 0.42 
 
0.62 0.80 0.99 
 
1.00 
 
Two-sided 95% Wilson Confidence Intervals* for the Probability of Treatment Tolerance 
based on ≥15 Tolerant Patients out of 20   
 
Observed # of tolerant patients 
 
95% Wilson confidence interval 
Lower bound 
Upper bound 
15 
0.53 
0.89 
16 
0.58 
0.92 
17 
0.64 
0.95 
18 
0.70 
0.97 
19 
0.76 
0.99 
20 
0.84 
1.00 
* We chose to calculate and report the Wilson score confidence intervals49 because of their 
good coverage properties, especially when the true proportions are at extreme values such as 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
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being equal to or close to 1 
50(http://en.wikipedia.org/wiki/Binomial_proportion_confidence_interval).  
 
The recommended dose for phase II trials will be defined as the highest dose (at or below the 
MTD) at which ≥ 15 patients treated at the MTD (including patients from the escalation portion 
treated at that same dose level) can tolerate treatment for a minimum of 8 weeks in a row without 
development of the previously cited toxicities. The dose that will be used in the phase II study will 
be the most tolerable (i.e. with the least amount of ≥ Grade 2 toxicities), as tested in this study. 
Study drugs will be given at the specified doses above until disease progression or unacceptable 
toxicity. As long as the above parameters are fulfilled (i.e. at least 15 out 20 patients are able to 
safely tolerate the combination at a given dose level stipulated by the study for 8 weeks in a row) 
the dose of study drugs in the expansion portion of the study (i.e. the highest tolerable dose; not 
necessarily the MTD) will move forward in phase II studies.  
17.2.2. Secondary endpoints 
Secondary endpoints defined in terms of percentages such as Overall Response Rate (ORR), 
Clinical Benefit Rate (CBR), and Progression-Free Survival (PFS) will be summarized and 95% 
CI for each percentage will be reported.  The distribution of PFS will be estimated using the 
Kaplan-Meier method with censoring used as needed (e.g. if a patient is lost to follow-up, or 
analysis is done before all patients have had the event of interest).  Median time to event and 
corresponding  95% CI will be reported along with Kaplan-Meier curves. The duration of PFS for 
patients who progress and then subsequently die will be the number of days between initiation of 
the study treatment and the date of when disease progression is first observed. Demographic and 
clinical characteristics will be summarized for all patients as percentages for categorical variables 
and as mean, standard deviation, median, minimum and maximum for continuous measures. 
Data will be collected using a centralized electronic case report form called ON-line Clinical 
Oncology Research Environment = Oncore (http://www.vicc.org/ct/research/oncore.php). An 
exploratory objective of this study is to determine the pharmacokinetics of the combination of 
erdafitinib, palbociclib and fulvestrant. The plasma samples from all patients will be assayed for 
erdafitinib and palbociclib concentrations using methods described in the Laboratory manual. 
Values below the assay LLOQ will be reported as 0.00 ng/mL. Missing values will be labeled 
accordingly. All concentrations below the LLOQ or missing data will be labeled as such in the 
concentration data listings. Concentrations below the LLOQ will be treated as zero in summary 
statistics. Calculation of PK parameters will include up to the last measurable concentration tlast. 
Pharmacokinetic parameters will be determined for all patients using non-compartmental 
method(s) using WinNonlin® Pro (Version 5.2 - Pharsight, Mountain View, CA). PK parameters 
listed in the table below will be estimated and reported.  
 
AUC0-last 
The area under the plasma concentration-time curve from time zero to the last 
measurable concentration (Tlast) (mass x time x volume -1) 
AUC0-Inf 
The area under the plasma concentration-time curve from time zero to infinity 
(mass x time x volume -1) 
AUC0-24 
The area under the plasma concentration-time curve from time zero to 24 hours 
(mass x time x volume -1) 
AUCex1 
Area under the plasma concentration-time curve extrapolated from the time t to 
infinity as a percentage of total AUC (%) 
Cav 
The average drug concentration in plasma during the dosing interval (mass x 
volume -1) 
Clast 
Last measurable plasma concentration 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
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Cmax 
The maximum (peak) observed plasma drug concentration after oral dose 
administration (mass x volume -1) 
Tlast 
Time to reach the last measurable plasma concentration 
Tmax 
The time to reach maximum (Cmax) plasma drug concentration after oral dose 
administration (time) 
CL/F 
Apparent total body clearance of drug from the plasma after oral administration 
(volume x time -1) 
Vz/F 
The apparent volume of distribution during terminal phase after a (single) oral 
administration (associated with λz) (volume) 
Rsqadj1 
Square of the correlation coefficient associated with λz 
1 AUCex and Rsqadj will be used in interpretation of the primary PK parameters and therefore 
will be included in the listings only 
 
Exploratory PK analysis will be conducted using compartmental modeling when necessary. 
Descriptive graphical plots of individual and mean plasma concentration (per treatment) along 
with its time course will be generated. Further graphical exploratory analyses will be carried out if 
deemed appropriate. Pharmacokinetic parameters for each dose cohort will be analyzed by 
descriptive statistics, including the mean, SD, CV% or median (range). Since tmax is generally 
evaluated by a non-parametric method, median values and ranges will be given for this 
parameter. Assessment of dose-proportionality, inter- and intra-individual variability and steady-
state attainment will be conducted. If appropriate, an analysis of variance (ANOVA) will be 
performed on log-transformed AUCs and Cmax using a linear mixed effect model to assess day 
effect. Exploratory metabolite analysis on remaining plasma material from samples collected 
during the study will be performed, if deemed appropriate. Non-compartmental parameters, 
including but not limited to AUC (AUC0-tlast and/or AUC0-inf), T1/2, Cmax and Tmax will be 
reported. 
17.3 Reporting and Exclusions 
All patients included in the study must be assessed for safety, tolerability, and response to 
treatment, even if there are major protocol treatment deviations or if they are ineligible. Each 
patient will be assigned one of the following categories: 1) complete response, 2) partial response, 
3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death 
from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, insufficient 
data). All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate. 
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression). Thus, an incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response and clinical benefit rate. 
 
 
 
 
 
 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
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18. REFERENCES 
1. 
American Cancer Society Cancer Facts and Figures Atlanta, GA: American Cancer 
Society, 2011. 
2. 
Sorlie, T., et al. Gene expression patterns of breast carcinomas distinguish tumor 
subclasses with clinical implications. Proc Natl Acad Sci U S A 98, 10869-10874 (2001). 
3. 
Howell, A. & Abram, P. Clinical development of fulvestrant ("Faslodex"). Cancer 
treatment reviews 31 Suppl 2, S3-9 (2005). 
4. 
Dowsett, M., Nicholson, R.I. & Pietras, R.J. Biological characteristics of the pure 
antiestrogen fulvestrant: overcoming endocrine resistance. Breast Cancer Res Treat 93 
Suppl 1, S11-18 (2005). 
5. 
Miller, T.W., et al. ERalpha-dependent E2F transcription can mediate resistance to 
estrogen deprivation in human breast cancer. Cancer discovery 1, 338-351 (2011). 
6. 
Huang, B., Warner, M. & Gustafsson, J.A. Estrogen receptors in breast carcinogenesis 
and endocrine therapy. Mol Cell Endocrinol 418 Pt 3, 240-244 (2015). 
7. 
Ishida, N., et al. Fulvestrant 500 mg in postmenopausal patients with metastatic breast 
cancer: the initial clinical experience. Breast Cancer (2015). 
8. 
Agrawal, A., et al. Biological effects of fulvestrant on estrogen receptor positive human 
breast cancer: short, medium and long-term effects based on sequential biopsies. Int J 
Cancer 138, 146-159 (2016). 
9. 
Tan, P.S., Haaland, B., Montero, A.J. & Lopes, G. A meta-analysis of anastrozole in 
combination with fulvestrant in the first line treatment of hormone receptor positive 
advanced breast cancer. Breast Cancer Res Treat 138, 961-965 (2013). 
10. 
Di Leo, A., et al. Final overall survival: fulvestrant 500 mg vs 250 mg in the randomized 
CONFIRM trial. J Natl Cancer Inst 106, djt337 (2014). 
11. 
Yardley, D.A., et al. Everolimus plus exemestane in postmenopausal patients with HR(+) 
breast cancer: BOLERO-2 final progression-free survival analysis. Advances in therapy 
30, 870-884 (2013). 
12. 
Turner, N.C., et al. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. 
N Engl J Med 373, 209-219 (2015). 
13. 
Fry, D.W., et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and 
associated antitumor activity in human tumor xenografts. Mol Cancer Ther 3, 1427-1438 
(2004). 
14. 
Schwartz, G.K., et al. Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, 
administered in 3-week cycles (Schedule 2/1). Br J Cancer 104, 1862-1868 (2011). 
15. 
Dean, J.L., Thangavel, C., McClendon, A.K., Reed, C.A. & Knudsen, E.S. Therapeutic 
CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene 
29, 4018-4032 (2010). 
16. 
Finn, R.S., et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially 
inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines 
in vitro. Breast Cancer Res 11, R77 (2009). 
17. 
Finn, R.S., et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination 
with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, 
HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 
study. Lancet Oncol 16, 25-35 (2015). 
18. 
Wardell, S.E., et al. Efficacy of SERD/SERM Hybrid-CDK4/6 Inhibitor Combinations in 
Models of Endocrine Therapy-Resistant Breast Cancer. Clin Cancer Res 21, 5121-5130 
(2015). 
19. 
Flaherty, K.T., et al. Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 
inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced 
cancer. Clin Cancer Res 18, 568-576 (2012). 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
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Protocol number BRE 16126 
 
 
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20. 
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cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res 
21, 995-1001 (2015). 
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Finn, R.S., et al. PALOMA-2: Primary results from a phase III trial of palbociclib (P) with 
letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2– 
advanced breast cancer (ABC). J Clin Oncol 34 (suppl; abstract 507)(2016). 
22. 
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Positive Advanced Breast Cancer. N Engl J Med 373, 1672-1673 (2015). 
23. 
Cristofanilli, M., et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for 
treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that 
progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, 
double-blind, phase 3 randomised controlled trial. Lancet Oncol (2016). 
24. 
Chia, S., et al. Double-blind, randomized placebo controlled trial of fulvestrant compared 
with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal 
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targeted therapies in solid tumors. Ann Oncol 25, 552-563 (2014). 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
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40. 
Schildhaus, H.U., et al. Definition of a fluorescence in-situ hybridization score identifies 
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Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
 Protocol Version:11/4/21 
CONFIDENTIAL 
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19. MEDICATIONS TO BE USED WITH CAUTION 
Please note this is not an exhaustive list. Alternatives to concurrent administration of 
erdafitinib and the below medications should be sought; if no alternative treatment is 
available, the Study Chair should be consulted. 
 
 
Moderate and Strong CYP3A4 Inhibitors:  Moderate and Strong CYP3A4 Inducers: 
 
 
Aprepitant 
 
 
 
 
 
Bosentan 
 
Atazanavir 
 
 
 
 
 
Carbamazepine 
 
Boceprevir 
 
 
 
 
 
Efavirenz 
 
Clarithromycin  
 
 
 
 
Enzalutamide 
 
Cobicastat 
 
 
 
 
 
Fosphenytoin 
 
Conivaptan 
 
 
 
 
 
Lumacaftor 
 
Diltiazem 
 
 
 
 
 
Mitotane 
 
Erythromycin  
 
 
 
 
Modafanil 
 
Fluconazole 
 
 
 
 
 
Nafcillin 
 
Fosamprenavir 
 
 
 
 
Phenytoin 
 
Grapefruit Juice 
 
 
 
 
Phenobarbital 
 
Idelalisib 
 
 
 
 
 
Primidone 
 
Imatinib 
 
 
 
 
 
Rifampin 
 
Indinavir 
 
 
 
 
 
Rifapentin 
 
Itraconazole 
 
 
 
 
 
St. John’s Wort 
 
Ketoconazole 
 
Lopinavir 
 
Nefazodone 
 
Nelfinavir 
 
Nilotinib 
 
Posaconazole 
 
Ritonavir 
 
Saquinavir 
 
Suboxone 
 
Telaprevir 
 
Telithromycin 
 
Verapamil 
 
Voriconazole 
 
Moderate and Strong CYP2C9 Inhibitors:  
Moderate and Strong CYP2C9 Inducers: 
 
 
Amiodarone 
 
 
 
 
 
Enzalutamide 
 
Delaviridine 
 
 
 
 
 
Phenobarbital 
 
Efavirenz 
 
 
 
 
 
Primidone 
 
Fluconazole 
 
 
 
 
 
Rifapentin 
 
Fluvastatin 
 
Miconazole 
 
Moderate and Strong P-gp Inhibitors: 
 
Moderate and Strong P-gp Inducers: 
 
 
Amiodarone 
 
 
 
 
 
Carbamazepine 
 
Clarithromycin  
 
 
 
 
Rifampin 
 
Erythromycin  
 
 
 
 
St. John’s wort 


Fulvestrant, palbociclib and erdafitinib in ER+/HER2–/FGFR-amplified MBC 
Protocol Chair:  Vandana Abramson, MD  
Protocol number BRE 16126 
 
 
 Protocol Version:11/4/21 
CONFIDENTIAL 
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Do not disclose or use except as authorized 
 
 
Ketoconazole  
 
 
 
 
Tipranavir 
 
Quinidine 
 
Saquinavir 
 
Verapamil