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.
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.
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
Inclusion Criteria:
- Patients must be able to swallow and retain oral medication
- Patients must be ≥ 18 years of age
- Patients must be post-menopausal
- Patients must have ECOG performance status 0 - 1
- Patients must have clinical stage IV or inoperable locoregional recurrent invasive
mammary carcinoma that is ER+ and/or PgR+ (≥ 1% positive stained cells) by
immunohistochemistry (IHC), HER2-negative (by IHC or FISH, per ASCO guidelines) and
FGFR1, FGFR2, FGFR3 or FGFR4 amplified (may be determined by local assessment through
either targeted capture next generation sequencing (NGS), plasma cell-free tumor [cf]
DNA or FISH*)
- Patients must have evaluable (may have either measurable or non-measurable) disease
- Patients must have available tissue for FGFR determination
- Patients must have adequate hematologic, hepatic and renal function.
Exclusion Criteria:
- Prior use of an FGFR inhibitor
- More than 2 lines of chemotherapy in the metastatic setting. No limit on endocrine
therapy lines. Prior exposure to CDK4/6 inhibitor acceptable.
- 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
- Current use of any of the prohibited drugs
- Herbal preparations are not allowed throughout the study, and should be discontinued
14 days prior to initiation of study treatment
- Any corneal or retinal abnormality likely to increase the risk of eye toxicity, such
as current corneal pathology such as keratitis, keratoconjunctivitis, keratopathy,
corneal abrasion, inflammation or ulceration, uncontrolled glaucoma despite standard
of care therapy, diabetic retinopathy with macular edema, known active wet,
age-related macular degeneration (AMD), or known central serous retinopathy (CSR) or
retinal vascular occlusion (RVO)
- Malabsorption syndrome significantly affecting gastrointestinal function
- Ongoing or active infection requiring parenteral antibiotics
- Impairment of lung function (COPD > grade 2, lung conditions requiring oxygen therapy)
- Symptomatic congestive heart failure
- Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6
months
- 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]
- QTcF ≥ 480 msec on screening EKG
- Known history of clinically significant QT/QTc prolongation or Torsades de
Pointes(TdP)
- ST depression or elevation of ≥ 1.5 mm in 2 or more leads
- Diarrhea of any cause ≥ CTCAE grade 2
- Psychiatric illness/social situations that would compromise patient safety or limit
compliance with study requirements including maintenance of a compliance/pill diary
lSymptomatic 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)
- Known history of chronic liver or chronic renal failure