Purpose

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.

Condition

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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

Study Design

Phase
Phase 1
Study Type
Interventional
Allocation
Non-Randomized
Intervention Model
Sequential Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Escalation
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
  • Drug: Erdafitinib
    4mg - 8mg
    Other names:
    • JNJ-42756493
  • Drug: Palbociclib
    125 mg
    Other names:
    • Ibrance
  • Drug: Fulvestrant
    500 mg
    Other names:
    • Faslodex
Experimental
Expansion
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
  • Drug: Erdafitinib
    4mg - 8mg
    Other names:
    • JNJ-42756493
  • Drug: Palbociclib
    125 mg
    Other names:
    • Ibrance
  • Drug: Fulvestrant
    500 mg
    Other names:
    • Faslodex

More Details

Status
Active, not recruiting
Sponsor
Vanderbilt-Ingram Cancer Center

Study Contact

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

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.