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