Fulvestrant, Palbociclib and Erdafitinib in ER+/HER2-/FGFR-amplified Metastatic Breast Cancer
Condition: Metastatic Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Erdafitinib; Palbociclib; Fulvestrant
Intervention description: 4mg - 8mg; 125 mg; 500 mg
Intervention MeSH terms: Fulvestrant; Palbociclib
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 35.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: FGFR inhibitor; ER+ metastatic breast cancer; CDK4/6 inhibitor; Endocrine therapy

Summary:

      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.
    

Eligibility criteria:

        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