Metastatic Breast Cancer
Conditions
Keywords
FGFR inhibitor, ER+ metastatic breast cancer, CDK4/6 inhibitor, Endocrine therapy
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.
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
Interventions
DRUGErdafitinib
4mg - 8mg
DRUGPalbociclib
125 mg
DRUGFulvestrant
500 mg
Sponsors
National Cancer Institute (NCI)
Vanderbilt-Ingram Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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. Response of a patient was evaluated using Solid Tumor Response Criteria -RECIST v1.1. |
| Pharmacokinetic Assessment of Erdafitinib - Cmax (Maximum Plasma Concentration) | 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 |
| Pharmacokinetic Assessment of Erdafitinib - Tmax | 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) |
| Pharmacokinetic Assessment of Erdafitinib - CL/F | 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 |
| 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 | Assessment of adverse events throughout the study. The number of patients who had any grade of adverse events were reported. |
| 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 | 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. Progression-free survival (PFS) time is defined as the time from treatment initiation to progression date or death (whichever comes first). Those alive without prpgression is censored at the last date of known alive. Median PFS time and 95% confidence intervals are obtained using Kaplan-meier method. |
| 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 | 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. The response of a patient will be evaluated using Solid Tumor Response Criteria RECIST v1.1. |
| Pharmacokinetic Assessment of Erdafitinib - Area Under the Curve (AUC) | 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Next Generation Sequencing | At study entry (baseline) | Will determine if other genomic alterations other than FGFR amplifications correlate with clinical outcome. |
| Plasma Cell-free Deoxyribonucleic Acid (cfDNA) | 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. |
| Serial Measurements of Serum Phosphate, Calcium, Vitamin D, Parathyroid Hormone (PTH), FGF23, sFGFR2, sFGFR3, and sFGFR4 | 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). |
| FGFR1 Amplification Levels by FISH and cfDNA | At study entry (baseline) | The level of FGFR1 amplification assessed in tumors by fluorescence in situ hybridization (FISH) will be correlated with clinical outcome. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited to this trial from August 2017 to January 2021 at five medical centers.
Participants by arm
| Arm | Count |
|---|---|
| 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
Erdafitinib: 6mg
Palbociclib: 125 mg
Fulvestrant: 500 mg | 22 |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) Participants who were treated with Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 5mg. | 3 |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 6mg (Escalation) Participants who were treated with Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 6mg. | 6 |
| Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 8mg (Escalation) Participants who were treated with Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 8mg. | 4 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 | 2 | 2 |
| Overall Study | Disease progression | 14 | 2 | 3 | 2 |
| Overall Study | Still on treatment | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Expansion | Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 6mg (Escalation) | Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 8mg (Escalation) | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 1 Participants | 1 Participants | 1 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 2 Participants | 5 Participants | 3 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 3 Participants | 3 Participants | 1 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 0 Participants | 3 Participants | 3 Participants | 13 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) White | 17 Participants | 2 Participants | 3 Participants | 2 Participants | 24 Participants |
| Region of Enrollment United States | 22 participants | 3 participants | 6 participants | 4 participants | 35 participants |
| Sex: Female, Male Female | 22 Participants | 3 Participants | 6 Participants | 4 Participants | 35 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 3 / 22 | 6 / 6 | 2 / 4 |
| other Total, other adverse events | 3 / 3 | 22 / 22 | 6 / 6 | 4 / 4 |
| serious Total, serious adverse events | 1 / 3 | 5 / 22 | 1 / 6 | 1 / 4 |
Outcome results
Primary
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.
Time frame: From the time of randomization up to 4 weeks of treatment (cycle 1), for each patient
Population: Participants who were treated with Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib in Escalation phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 0 participants |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 6mg (Escalation) | Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 0 participants |
| Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 8mg (Escalation) | Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 2 participants |
Secondary
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. Response of a patient was evaluated using Solid Tumor Response Criteria -RECIST v1.1.
Time frame: From the time of randomization up to 6 months for each patient
Population: Participants received the treatment and had evaluable response data. This study was a single-arm dose escalation/dose expansion study. Therefore we did not subdivide the dose level groups for the secondary outcomes as the study was not powered for any intra-arm comparisons of clinical benefit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Clinical Benefit Rate (CBR; Complete Response + Partial Response + Stable Disease Without Disease Progression at 6 Months) | 64.5 percentage of participants |
Secondary
Incidence of Treatment-Emergent Adverse Events [Tolerability]
Assessment of adverse events throughout the study. The number of patients who had any grade of adverse events were reported.
Time frame: From date of randomization until 28 days post treatment discontinuation from any cause, assessed up to 48 months
Population: All patients treated. This study was a single-arm dose escalation/dose expansion study. Therefore we did not subdivide the dose level groups for the secondary outcomes as the study was not powered for any intra-arm comparisons of clinical benefit.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Oral mucositis, any grade | 27 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Hyperphosphatemia, any grade | 29 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Palmar-plantar erythrodysesthesia syndrome, any grade | 18 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Diarrhea, any grade | 14 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Constipation, any grade | 19 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Dysgeusia, any grade | 19 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Dry mouth, any grade | 18 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Nail alterations, any grade | 13 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Sore throat, any grade | 8 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Alopecia, any grade | 13 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Dry skin, any grade | 12 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Anorexia, any grade | 7 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Epistaxis, any grade | 9 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Dry eye, any grade | 10 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Skin ulceration, any grade | 2 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Vision changes/alterations, any grade | 6 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Neutrophil count decreased, grade 4 | 1 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Palmar-plantar erythrodysesthesia syndrome, grade 3 | 2 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Abdominal pain, any grade | 5 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Dizziness, any grade | 3 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Gastroesophageal reflux disease, any grade | 5 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Hypotension, any grade | 3 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Elevated ALT, any grade | 1 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Elevated AST, any grade | 3 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Colitis, any grade | 1 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Esophagitis, any grade | 2 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Eye keratopathy, any grade | 1 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Hyperkeratosis, any grade | 1 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Syncope, any grade | 1 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Neutropenia, any grade | 25 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Leucopenia, any grade | 15 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Anemia, any grade | 12 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Thrombocytopenia, any grade | 2 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Lymphopenia, any grade | 1 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Febrile neutropenia, any grade | 1 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Neutrophilia, any grade | 1 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Thromboembolic event, any grade | 1 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Fatigue, any grade | 15 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Nausea, any grade | 6 patients |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Incidence of Treatment-Emergent Adverse Events [Tolerability] | Vomiting, any grade | 6 patients |
Secondary
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. The response of a patient will be evaluated using Solid Tumor Response Criteria RECIST v1.1.
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
Population: Patients received the treatment and had valuable response data. This study was a single-arm dose escalation/dose expansion study. Therefore we did not subdivide the dose level groups for the secondary outcomes as the study was not powered for any intra-arm comparisons of clinical benefit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Overall Response Rate | 9.7 percentage of participants |
Secondary
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
Time frame: From the time of randomization up to 4 weeks of treatment for each patient
Population: Patients who actually received erdafitinib 5m, 6 mg and 8mg and participated the PK study by measuring the blood plasma concentration. One patients could have PK data at different cycles and days.~For dose 5mg, 7 patients had 14 PK data. For daose 6mg, 6 patients had 11 PK data. For dose8mg, 4 patients had 8 PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Pharmacokinetic Assessment of Erdafitinib - Area Under the Curve (AUC) | 1128 ng/ml.hr | Standard Deviation 608 |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 6mg (Escalation) | Pharmacokinetic Assessment of Erdafitinib - Area Under the Curve (AUC) | 718 ng/ml.hr | Standard Deviation 521 |
| Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 8mg (Escalation) | Pharmacokinetic Assessment of Erdafitinib - Area Under the Curve (AUC) | 1268 ng/ml.hr | Standard Deviation 827 |
Secondary
Pharmacokinetic Assessment of Erdafitinib - CL/F
Apparent total body clearance of drug from the plasma after oral administration
Time frame: From the time of randomization up to 4 weeks of treatment for each patient
Population: Patients who actually received erdafitinib 5m, 6 mg and 8mg and participated the PK study by measuring the blood plasma concentration. One patients could have PK data at different cycles and days.~For dose 5mg, 7 patients had 14 PK data. For daose 6mg, 6 patients had 11 PK data. For dose8mg, 4 patients had 8 PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Pharmacokinetic Assessment of Erdafitinib - CL/F | 5.5 l/hr | Standard Deviation 2.6 |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 6mg (Escalation) | Pharmacokinetic Assessment of Erdafitinib - CL/F | 11.3 l/hr | Standard Deviation 5.5 |
| Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 8mg (Escalation) | Pharmacokinetic Assessment of Erdafitinib - CL/F | 8.6 l/hr | Standard Deviation 4.6 |
Secondary
Pharmacokinetic Assessment of Erdafitinib - Cmax (Maximum Plasma Concentration)
The maximum (peak) observed plasma drug concentration after oral dose administration
Time frame: From the time of randomization up to 4 weeks of treatment for each patient
Population: Patients who actually received erdafitinib 5m, 6 mg and 8mg and participated the PK study by measuring the blood plasma concentration. One patients could have PK data at different cycles and days.~For dose 5mg, 7 patients had 14 PK data. For daose 6mg, 6 patients had 11 PK data. For dose8mg, 4 patients had 8 PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Pharmacokinetic Assessment of Erdafitinib - Cmax (Maximum Plasma Concentration) | 875 ng/ml | Standard Deviation 625 |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 6mg (Escalation) | Pharmacokinetic Assessment of Erdafitinib - Cmax (Maximum Plasma Concentration) | 668 ng/ml | Standard Deviation 528 |
| Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 8mg (Escalation) | Pharmacokinetic Assessment of Erdafitinib - Cmax (Maximum Plasma Concentration) | 737 ng/ml | Standard Deviation 348 |
Secondary
Pharmacokinetic Assessment of Erdafitinib - Tmax
Time to reach maximum (Cmax) plasma drug concentration after oral dose administration (time)
Time frame: From the time of randomization up to 4 weeks of treatment for each patient
Population: Patients who actually received erdafitinib 5m, 6 mg and 8mg and participated the PK study by measuring the blood plasma concentration. One patients could have PK data at different cycles and days.~For dose 5mg, 7 patients had 14 PK data. For daose 6mg, 6 patients had 11 PK data. For dose8mg, 4 patients had 8 PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Pharmacokinetic Assessment of Erdafitinib - Tmax | 2.8 hour | Standard Deviation 2.5 |
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 6mg (Escalation) | Pharmacokinetic Assessment of Erdafitinib - Tmax | 2.5 hour | Standard Deviation 1.8 |
| Fulvestrant 500mg, Palbociclib 125mg and Erdafitinib 8mg (Escalation) | Pharmacokinetic Assessment of Erdafitinib - Tmax | 2.8 hour | Standard Deviation 2.5 |
Secondary
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. Progression-free survival (PFS) time is defined as the time from treatment initiation to progression date or death (whichever comes first). Those alive without prpgression is censored at the last date of known alive. Median PFS time and 95% confidence intervals are obtained using Kaplan-meier method.
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
Population: All participants. This study was a single-arm dose escalation/dose expansion study. Therefore we did not subdivide the dose level groups for the secondary outcomes as the study was not powered for any intra-arm comparisons of clinical benefit.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fulvestrant 500mg/Palbociclib 125mg/Erdafitinib 5mg (Escalation) | Progression-free Survival | 12.4 weeks |
Other Pre-specified
FGFR1 Amplification Levels by FISH and cfDNA
The level of FGFR1 amplification assessed in tumors by fluorescence in situ hybridization (FISH) will be correlated with clinical outcome.
Time frame: At study entry (baseline)
Other Pre-specified
Next Generation Sequencing
Will determine if other genomic alterations other than FGFR amplifications correlate with clinical outcome.
Time frame: At study entry (baseline)
Other Pre-specified
Plasma Cell-free Deoxyribonucleic Acid (cfDNA)
Will determine if the cfDNA results at disease progression show new genomic alterations potentially associated with resistance to CDK4/6 and FGFR inhibition.
Time frame: At study entry (baseline), at 4 weeks, and at study discontinuation from disease progression (for each patient), assessed up to 48 months.
Other Pre-specified
Serial Measurements of Serum Phosphate, Calcium, Vitamin D, Parathyroid Hormone (PTH), FGF23, sFGFR2, sFGFR3, and sFGFR4
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).
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)