Fulvestrant, Palbociclib and Erdafitinib in 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.

- 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

Inclusion Criteria:

- Patients must be able to swallow and retain oral medication

- Patients must be ≥ 18 years of age

- Female patients of no childbearing potential must be post-menopausal. Postmenopausal
female subjects should be defined prior to protocol enrollment by any of the
following:

- Participants at least 60 years of age; OR

- Participants under 60 years of age and naturally (spontaneous, no alternative
pathologic or physiological cause) amenorrhea for at least 12 months; OR

- Medical ovarian failure confirmed by follicle-stimulating hormone (FSH) and
estradiol levels in the post menopausal range per local institutional normal
range; OR

- Prior bilateral oophorectomy; OR

- Prior radiation castration with amenorrhea for at least 6 months; OR

- 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

- 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)

- FGFR1 - 4 amplified

- Patients must have evaluable (may have either measurable or non-measurable)
disease

- Patients must have available tissue for FGFR determination

- Patients must have had at least one line of therapy in the metastatic setting

- Current use of any of the drugs listed on the Cautionary Concomitant Med list has to
be approved by the Study Chair

- Patients must have adequate hematologic, hepatic and renal function. All laboratory
tests must be obtained within 2 weeks from study drug initiation. These include:

- ANC ≥ 1,500/mm3

- Platelet count ≥ 100,000/mm3

- HgB ≥ 9.0 g/dL

- Creatinine clearance ≥ 40 mL/min/1.73 m2

- SGOT, SGPT ≤ 2.5 x ULN if no liver metastasis present; SGOT, SGPT ≤ 4 x ULN if
liver metastasis present

- Albumin ≥ 2.0 g/dL

- Total serum bilirubin ≤ 1.5 x ULN (≤ 3 x ULN or direct bilirubin ≤ 1.5 x ULN if
known Gilbert's syndrome)

- Potassium within institutional normal limits

- Phosphorus ≤ institutional upper limit of normal

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

- Major surgery within 4 weeks of enrollment

- 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)

- Known central serous retinopathy (CSR) or retinal vascular occlusion (RVO)

- Uncontrolled intercurrent illness including, but not limited to:

- Malabsorption syndrome significantly affecting gastrointestinal function

- Ongoing or active infection requiring antibiotics/antivirals

- 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 that does not resolve within a few days
when adequately treated with anti-diarrhea medications

- Psychiatric illness/social situations that would compromise patient safety or
limit compliance with study requirements including maintenance of a
compliance/pill diary

- 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)

- Known history of chronic liver or chronic renal failure

- Poor wound healing capacity