Fulvestrant, Palbociclib and Erdafitinib in ER+/HER2-/FGFR-amplified Metastatic Breast Cancer

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)

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.
• 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