Fulvestrant, Palbociclib, and Erdafitinib in Treating Patients with Estrogen Receptor Positive, HER2 Negative, and FGFR Amplified Stage IV Breast Cancer That Is Recurrent or Cannot Be Removed by Surgery
- 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
- Female patients of no childbearing potential must be post-menopausal; post-menopausal female subjects should be defined prior to protocol enrollment by any of the following: * Subjects at least 60 years of age; OR * Subjects 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
- Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1
- Clinical stage IV or inoperable locoregional recurrent invasive mammary carcinoma that is: * ER+ and/or progesterone receptor (PgR)+ (>= 1% positive stained cells) by immunohistochemistry (IHC) * HER2-negative (by IHC or fluorescence in situ hybridization [FISH], per American Society of Clinical Oncology [ASCO] guidelines) * 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: *** The FGFR1/CEN8 ratio is >= 2.0 *** The average number of FGFR1 signals per tumor cell nucleus is >= 6 * Evaluable (may have either measurable or non-measurable disease)
- 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
- 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
- Absolute neutrophil count (ANC) >= 1,500/mm^3 (obtained within 2 weeks from study drug initiation)
- Platelet count >= 100,000/mm^3 (obtained within 2 weeks from study drug initiation)
- Hemoglobin (HgB) >= 9.0 g/dL (obtained within 2 weeks from study drug initiation)
- Creatinine clearance >= 40 mL/min/1.73 m^2 (obtained within 2 weeks from study drug initiation)
- Serum glutamic-oxaloacetic transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT) =< 2.5 x upper limit of normal (ULN) if no liver metastasis present; SGOT, SGPT =< 4 x ULN if liver metastasis present (obtained within 2 weeks from study drug initiation)
- Albumin >= 2.0 g/dL (obtained within 2 weeks from study drug initiation)
- Total serum bilirubin =< 1.5 x ULN (=< 3 x ULN or direct bilirubin =< 1.5 x ULN if known Gilbert’s syndrome) (obtained within 2 weeks from study drug initiation)
- Potassium within institutional normal limits (obtained within 2 weeks from study drug initiation)
- Phosphorus =< institutional upper limit of normal (obtained within 2 weeks from study drug initiation)
- 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 (chronic obstructive pulmonary disease [COPD] > grade 2, lung conditions requiring oxygen therapy) * Symptomatic congestive heart failure (class III or IV of the New York Heart Association classification for heart disease) * 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]) * Fridericia's correction formula (QTcF) >= 480 msec on screening electrocardiography (EKG) * Known history of clinically significant QT/corrected 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 >= Common Terminology Criteria for Adverse Events (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
I. To determine the safety and tolerability of fulvestrant, palbociclib and erdafitinib in patients with estrogen receptor (ER)+/HER2-/FGFR-amplified metastatic breast cancer (MBC).
I. To determine the anti-tumor effect of fulvestrant, palbociclib and erdafitinib in patients with ER+/HER2-/FGFR-amplified MBC.
II. Pharmacokinetic assessments of erdafitinib.
I. To determine pharmacodynamic biomarkers of FGFR inhibition.
II. To determine the therapeutic predictive role of FGFR1-4, CCND1-2, CDK4 and CDK6 amplifications, and RB1 and ESR1 mutations on clinical outcome.
III. To determine if the FGFR1 amplification levels by fluorescence in situ hybridization (FISH) and cell-free deoxyribonucleic acid (cfDNA) is an early surrogate of response.
IV. To determine if the cfDNA results at disease progression show new genomic alterations potentially associated with resistance to CDK4/6 and FGFR inhibition.
OUTLINE: This is a dose-escalation study of erdafitinib.
Patients receive fulvestrant intramuscularly (IM) on days 1 and 15 of cycle 1 and on day 1 of subsequent cycles, palbociclib orally (PO) once daily (QD) on days 1-21, and erdafitinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 28 days.
Trial Phase Phase I
Trial Type Treatment
Vanderbilt University / Ingram Cancer Center
Ingrid Alina Mayer
- Primary ID VICCBRE16126
- Secondary IDs NCI-2017-01346
- Clinicaltrials.gov ID NCT03238196