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

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ClinicalTrials.gov Identifier: NCT03238196
Recruitment Status : Recruiting
First Posted : August 3, 2017
Last Update Posted : January 23, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Ingrid Mayer, MD, Vanderbilt-Ingram Cancer Center

Brief 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.

Condition or disease Intervention/treatment Phase
Metastatic Breast Cancer Drug: Erdafitinib Drug: Palbociclib Drug: Fulvestrant Phase 1

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : August 10, 2017
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : September 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

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 Name: JNJ-42756493

Drug: Palbociclib
125 mg
Other Name: Ibrance

Drug: Fulvestrant
500 mg
Other Name: 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 Name: JNJ-42756493

Drug: Palbociclib
125 mg
Other Name: Ibrance

Drug: Fulvestrant
500 mg
Other Name: Faslodex




Primary Outcome Measures :
  1. 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 ]
    Assessment of DLT and determination of MTD


Secondary Outcome Measures :
  1. 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 ]
    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.

  2. 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 ]
    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

  3. 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 ]
    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

  4. 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 ]
    The area under the plasma concentration-time curve from time zero to the last measurable concentration

  5. Pharmacokinetic assessment of erdafitinib - Cmax (maximum plasma concentration) [ Time Frame: From the time of randomization up to 4 weeks of treatment for each patient ]
    The maximum (peak) observed plasma drug concentration after oral dose administration

  6. Pharmacokinetic assessment of erdafitinib - Tmax [ Time Frame: From the time of randomization up to 4 weeks of treatment for each patient ]
    Time to reach maximum (Cmax) plasma drug concentration after oral dose administration (time)

  7. Pharmacokinetic assessment of erdafitinib - CL/F [ Time Frame: From the time of randomization up to 4 weeks of treatment for each patient ]
    Apparent total body clearance of drug from the plasma after oral administration

  8. 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 ]
    Assessment of adverse events throughout the study


Other Outcome Measures:
  1. Serial measurements of serum phosphate, calcium, vitamin D, parathyroid hormone (PTH), FGF23, sFGFR2, sFGFR3, and sFGFR4 [ Time Frame: During the first 8 weeks of treatment (days 1, 8, 15, 22 of cycle 1 and days 1 and 15 of cycle 2) ]
    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).

  2. FGFR1 amplification levels by FISH and cfDNA [ Time Frame: At study entry (baseline) ]
    The level of FGFR1 amplification assessed in tumors by fluorescence in situ hybridization (FISH) will be correlated with clinical outcome.

  3. Next Generation Sequencing [ Time Frame: At study entry (baseline) ]
    Will determine if other genomic alterations other than FGFR amplifications correlate with clinical outcome.

  4. Plasma cell-free deoxyribonucleic acid (cfDNA) [ Time Frame: At study entry (baseline), at 4 weeks, and at study discontinuation from disease progression (for each patient), assessed up to 48 months. ]
    Will determine if the cfDNA results at disease progression show new genomic alterations potentially associated with resistance to CDK4/6 and FGFR inhibition.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03238196


Contacts
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Contact: Clinical Trials Information Program 800-811-8480 cip@vanderbilt.edu

Locations
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United States, Alabama
University of Alabama Not yet recruiting
Birmingham, Alabama, United States, 35233
United States, California
University of California San Francicso Not yet recruiting
San Francisco, California, United States, 94158
United States, New York
Memorial Sloan Kettering Not yet recruiting
New York, New York, United States, 10065
United States, Pennsylvania
University of Pittsburgh Medical Center Not yet recruiting
Pittsburgh, Pennsylvania, United States, 15213
United States, Tennessee
Vanderbilt-Ingram Cancer Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Clinical Trials Information Program    800-811-8480      
Principal Investigator: Ingrid Mayer, MD         
United States, Texas
University of Texas Southwestern Simmons Comprehensive Cancer Center Not yet recruiting
Dallas, Texas, United States, 75235
Sponsors and Collaborators
Vanderbilt-Ingram Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Ingrid Mayer, MD Vanderbilt-Ingram Cancer Center

Additional Information:
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Responsible Party: Ingrid Mayer, MD, Principal Investigator, Vanderbilt-Ingram Cancer Center
ClinicalTrials.gov Identifier: NCT03238196     History of Changes
Other Study ID Numbers: VICC BRE 16126
First Posted: August 3, 2017    Key Record Dates
Last Update Posted: January 23, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Ingrid Mayer, MD, Vanderbilt-Ingram Cancer Center:
FGFR inhibitor
ER+ metastatic breast cancer
CDK4/6 inhibitor
Endocrine therapy

Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Fulvestrant
Palbociclib
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action