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)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 35
- 试验地点
- 6
- 主要终点
- Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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
干预措施: Palbociclib (Drug)
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
干预措施: Erdafitinib (Drug)
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
干预措施: Fulvestrant (Drug)
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
干预措施: Palbociclib (Drug)
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
干预措施: Fulvestrant (Drug)
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
干预措施: Erdafitinib (Drug)
结局指标
主要结局
Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)
时间窗: From the time of randomization up to 4 weeks of treatment (cycle 1), for each patient
Number of participants with DLT in the first cycle for the determination of the MTD.
次要结局
- Progression-free Survival(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(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)(From the time of randomization up to 6 months for each patient)
- Pharmacokinetic Assessment of Erdafitinib - Area Under the Curve (AUC)(From the time of randomization up to 4 weeks of treatment for each patient)
- Pharmacokinetic Assessment of Erdafitinib - Cmax (Maximum Plasma Concentration)(From the time of randomization up to 4 weeks of treatment for each patient)
- Pharmacokinetic Assessment of Erdafitinib - Tmax(From the time of randomization up to 4 weeks of treatment for each patient)
- Pharmacokinetic Assessment of Erdafitinib - CL/F(From the time of randomization up to 4 weeks of treatment for each patient)
- Incidence of Treatment-Emergent Adverse Events [Tolerability](From date of randomization until 28 days post treatment discontinuation from any cause, assessed up to 48 months)
研究者
Brent Rexer
Principal Investigator
Vanderbilt-Ingram Cancer Center