Clinical Trials /

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

NCT03238196

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Fulvestrant, Palbociclib and Erdafitinib in ER+/HER2-/FGFR-amplified Metastatic Breast Cancer
  • Official Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: VICC BRE 16126
  • NCT ID: NCT03238196

Conditions

  • Metastatic Breast Cancer

Interventions

DrugSynonymsArms
ErdafitinibJNJ-42756493Escalation
PalbociclibIbranceEscalation
FulvestrantFaslodexEscalation

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.

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.

      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
    

Trial Arms

NameTypeDescriptionInterventions
EscalationExperimentalFulvestrant - 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
  • Erdafitinib
  • Palbociclib
  • Fulvestrant
ExpansionExperimentalFulvestrant - 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
  • Erdafitinib
  • Palbociclib
  • Fulvestrant

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must be able to swallow and retain oral medication

          -  Patients must be ≥ 18 years of age

          -  Patients must be post-menopausal

          -  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) and
             FGFR1, FGFR2, FGFR3 or FGFR4 amplified (may be determined by local assessment through
             either targeted capture next generation sequencing (NGS), plasma cell-free tumor [cf]
             DNA or FISH*)

          -  Patients must have evaluable (may have either measurable or non-measurable) disease

          -  Patients must have available tissue for FGFR determination

          -  Patients must have adequate hematologic, hepatic and renal function.

        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

          -  Current use of any of the prohibited drugs

          -  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), or known central serous retinopathy (CSR) or
             retinal vascular occlusion (RVO)

          -  Malabsorption syndrome significantly affecting gastrointestinal function

          -  Ongoing or active infection requiring parenteral antibiotics

          -  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

          -  Psychiatric illness/social situations that would compromise patient safety or limit
             compliance with study requirements including maintenance of a compliance/pill diary
             lSymptomatic 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Treatment-Emergent Adverse Events [Safety]
Time Frame:From the time of randomization up to 4 weeks of treatment (cycle 1), for each patient
Safety Issue:
Description:Assessment of DLT and determination of MTD

Secondary Outcome Measures

Measure:Progression-free survival
Time Frame: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
Safety Issue:
Description: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.
Measure:Overall response rate
Time Frame: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
Safety Issue:
Description: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
Measure:Clinical benefit rate (CBR; complete response + partial response + stable disease without disease progression at 6 months)
Time Frame:From the time of randomization up to 6 months for each patient
Safety Issue:
Description: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
Measure:Pharmacokinetic assessment of erdafitinib - Area Under the Curve (AUC)
Time Frame:From the time of randomization up to 4 weeks of treatment for each patient
Safety Issue:
Description:The area under the plasma concentration-time curve from time zero to the last measurable concentration
Measure:Pharmacokinetic assessment of erdafitinib - Cmax (maximum plasma concentration)
Time Frame:From the time of randomization up to 4 weeks of treatment for each patient
Safety Issue:
Description:The maximum (peak) observed plasma drug concentration after oral dose administration
Measure:Pharmacokinetic assessment of erdafitinib - Tmax
Time Frame:From the time of randomization up to 4 weeks of treatment for each patient
Safety Issue:
Description:Time to reach maximum (Cmax) plasma drug concentration after oral dose administration (time)
Measure:Pharmacokinetic assessment of erdafitinib - CL/F
Time Frame:From the time of randomization up to 4 weeks of treatment for each patient
Safety Issue:
Description:Apparent total body clearance of drug from the plasma after oral administration
Measure:Incidence of Treatment-Emergent Adverse Events [Tolerability]
Time Frame:From date of randomization until 28 days post treatment discontinuation from any cause, assessed up to 48 months
Safety Issue:
Description:Assessment of adverse events throughout the study

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Vanderbilt-Ingram Cancer Center

Trial Keywords

  • FGFR inhibitor
  • ER+ metastatic breast cancer
  • CDK4/6 inhibitor
  • Endocrine therapy

Last Updated

August 11, 2017