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.

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Breast Cancer
• Intervention / Treatment: Drug: Erdafitinib; Drug: Palbociclib; Drug: Fulvestrant

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

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Tennessee
    • Memphis, Tennessee, United States, 38120
      • Baptist Memorial Hospital Memphis
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Simmons Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)	Number of participants with DLT in the first cycle for the determination of the MTD.	From the time of randomization up to 4 weeks of treatment (cycle 1), for each patient

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events [Tolerability]	Assessment of adverse events throughout the study	From date of randomization until 28 days post treatment discontinuation from any cause, assessed up to 48 months
Progression-free Survival	Assessment of clinical impact [anti-tumor effect] of the combination of erdafitinib, palbociclib and fulvestrant in patients with ER+/ FGFR amplified metastatic breast cancer will be assessed by measuring the interval (in months) between treatment initiation and disease progression.	Imaging studies will be performed every 8 weeks from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months
Overall Response Rate	Assessment of clinical impact [anti-tumor effect] of the combination of erdafitinib, palbociclib and fulvestrant in patients with ER+/ FGFR amplified metastatic breast cancer by measure the rate (%) of complete and partial responses seen in patients with measurable disease	Imaging studies will be performed every 8 weeks from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months
Clinical Benefit Rate (CBR; Complete Response + Partial Response + Stable Disease Without Disease Progression at 6 Months)	Assessment of clinical impact [anti-tumor effect] of the combination of erdafitinib, palbociclib and fulvestrant in patients with ER+/ FGFR amplified metastatic breast cancer by measure the rate (%) of complete and partial responses + stability of disease at 6 months seen in patients with measurable disease	From the time of randomization up to 6 months for each patient
Pharmacokinetic Assessment of Erdafitinib - Area Under the Curve (AUC)	The area under the plasma concentration-time curve from time zero to the last measurable concentration	From the time of randomization up to 4 weeks of treatment for each patient
Pharmacokinetic Assessment of Erdafitinib - Cmax (Maximum Plasma Concentration)	The maximum (peak) observed plasma drug concentration after oral dose administration	From the time of randomization up to 4 weeks of treatment for each patient
Pharmacokinetic Assessment of Erdafitinib - Tmax	Time to reach maximum (Cmax) plasma drug concentration after oral dose administration (time)	From the time of randomization up to 4 weeks of treatment for each patient
Pharmacokinetic Assessment of Erdafitinib - CL/F	Apparent total body clearance of drug from the plasma after oral administration	From the time of randomization up to 4 weeks of treatment for each patient

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Next Generation Sequencing	Will determine if other genomic alterations other than FGFR amplifications correlate with clinical outcome.	At study entry (baseline)
Serial Measurements of Serum Phosphate, Calcium, Vitamin D, Parathyroid Hormone (PTH), FGF23, sFGFR2, sFGFR3, and sFGFR4	Serial measurements of serum phosphate, calcium, vitamin D, PTH), FGF23, sFGFR2, sFGFR3, and sFGFR4 will be assessed to detect on target effects of FGFR inhibition (pharmacodynamic assessments).	During the first 8 weeks of treatment (days 1, 8, 15, 22 of cycle 1 and days 1 and 15 of cycle 2)
FGFR1 Amplification Levels by FISH and cfDNA	The level of FGFR1 amplification assessed in tumors by fluorescence in situ hybridization (FISH) will be correlated with clinical outcome.	At study entry (baseline)
Plasma Cell-free Deoxyribonucleic Acid (cfDNA)	Will determine if the cfDNA results at disease progression show new genomic alterations potentially associated with resistance to CDK4/6 and FGFR inhibition.	At study entry (baseline), at 4 weeks, and at study discontinuation from disease progression (for each patient), assessed up to 48 months.

Collaborators and Investigators

• Sponsor: Vanderbilt-Ingram Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Brent Rexer, MD, PhD, Vanderbilt-Ingram Cancer Center

Publications and helpful links

Helpful Links

• Clinical Trials Webpage - Vanderbilt-Ingram Cancer Center
• Mycancergenome - FGFR1 Webpage

Study record dates

Study Major Dates

• Study Start (Actual): August 18, 2017
• Primary Completion (Actual): April 30, 2021
• Study Completion (Estimated): September 25, 2024

Study Registration Dates

• First Submitted: July 24, 2017
• First Submitted That Met QC Criteria: August 2, 2017
• First Posted (Actual): August 3, 2017

Study Record Updates

• Last Update Posted (Actual): February 1, 2024
• Last Update Submitted That Met QC Criteria: January 30, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Endocrine therapy; CDK4/6 inhibitor; FGFR inhibitor; ER+ metastatic breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protein Kinase Inhibitors; Hormone Antagonists; Estrogen Antagonists; Estrogen Receptor Antagonists; Fulvestrant; Palbociclib
• Other Study ID Numbers: VICC BRE 16126

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No