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

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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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)

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Erdafitinib
* Drug: Palbociclib
* Drug: Fulvestrant


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Escalation<br>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<br>* 4mg - 8mg<br>* Other names: JNJ-42756493;Drug: Palbociclib<br>* 125 mg<br>* Other names: Ibrance;Drug: Fulvestrant<br>* 500 mg<br>* Other names: Faslodex;|
| Experimental: Expansion<br>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<br>* 4mg - 8mg<br>* Other names: JNJ-42756493;Drug: Palbociclib<br>* 125 mg<br>* Other names: Ibrance;Drug: Fulvestrant<br>* 500 mg<br>* Other names: Faslodex;|

What is the study measuring?
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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 |
| --- | --- | --- |
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FGFR inhibitor, ER+ metastatic breast cancer, CDK4/6 inhibitor, Endocrine therapy