Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Fulvestrant

Estrogens

Antineoplastic Agents, Hormonal

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Single dose followed by multiple dosing or twice daily dosing for 2 days folllowed by 5 days off each week, or twice daily dosing on the first and fourth day of the week

AZD2014

The purpose of this study is to assess safety and tolerability of AZD2014 when given in combination with Fulvestrant

A Phase I, Open-label, Multicentre, Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of AZD2014 Administered Orally in Combination with Intramuscular (IM) Fulvestrant to Patients with Estrogen Receptor Positive (ER+) Advanced, Metastatic Breast Cancer.

AZD2014 and Fulvestrant in Patients With ER+ Advanced Metastatic Breast Cancer

A Phase I, Open-label, Multicentre, Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of AZD2014 Administered Orally in Combination With Intramuscular (IM) Fulvestrant to Patients With Estrogen Receptor Positive (ER+) Advanced, Metastatic Breast Cancer

Objective Response Rate (ORR) is defined as the number (%) of patients with a confirmed overall response of either complete response (CR) or partial response (PR).

Best objective response was the best response a patient had following start of treatment but prior to starting any subsequent cancer therapy and prior to RECIST v1.1 progression or the last evaluable assessment in the absence of RECIST v1.1 progression.

Duration of response is defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression.

The Clinical Benefit Rate (CBR) at 24 weeks is defined as the percentage of patients who had a confirmed BOR of CR or PR in the first 24 weeks or who demonstrated SD for a minimum interval of 24 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e., 161 days) following the start of treatment.

Baseline was defined as last evaluable assessment prior to starting treatment. Tumour size was the sum of the longest diameters of the target lesions. TLs are measurable tumour lesions.

AstraZeneca

Participants took 35 mg of AZD2014 twice daily continuously in 28 day cycles. Participants also received intramuscular fulvestrant 500 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle.

35 mg BID Continuous

Participants took 50 mg of AZD2014 twice daily continuously in 28 day cycles. Participants also received intramuscular fulvestrant 500 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle.

50 mg BID Continuous

Participants took 75 mg of AZD2014 one time each day continuously in 28 day cycles. Participants also received intramuscular fulvestrant 500 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycles.

75 mg QD Continuous

Participants took 100 mg of AZD2014 one time each day continuously in 28 day cycles. Participants also received intramuscular fulvestrant 500 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycles.

100 mg QD Continuous

Participants took 125 mg of AZD2014 twice daily on Days 1 and 2 of each week in 28 day cycles (4 weeks) in a fasted condition. Participants also received intramuscular fulvestrant 500 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle.

125 mg BID Intermittent Days 1 and 2 (Fasted)

Participants took 125 mg of AZD2014 twice daily on Days 1 and 2 of each week in 28 day cycles (4 weeks) after eating. Participants also received intramuscular fulvestrant 500 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle.

125 mg BID Intermittent Days 1 and 2 (Fed)

Participants took 170 mg of AZD2014 twice daily on Days 1 and 2 of each week in 28 day cycles (4 weeks) in a fasted condition. Participants also received intramuscular fulvestrant 500 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle.

170 mg BID Intermittent Days 1 and 2 (Fasted)

Participants took 170 mg of AZD2014 twice daily on Days 1 and 2 of each week in 28 day cycles (4 weeks) after eating. Participants also received intramuscular fulvestrant 500 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle.

170 mg BID Intermittent Days 1 and 2 (Fed)

Participants took 125 mg of AZD2014 twice daily on Days 1 and 4 of each week in 28 day cycles (4 weeks) in a fasted condition. Participants also received intramuscular fulvestrant 500 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle.

125 mg BID Intermittent Days 1 and 4 (Fasted)

Participants took 170 mg of AZD2014 twice daily on Days 1 and 4 of each week in 28 day cycles (4 weeks) in a fasted condition. Participants also received intramuscular fulvestrant 500 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle.

Total

Age, Continuous

≥18 and <50 years

≥50 to <65 years

≥65 years

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

White

Black or African American

Other

Race/Ethnicity, Customized

United States

Region of Enrollment

Weight

ECOG PS = 0 Fully active; PS = 1 Restricted in physically strenuous activity; PS = 2 Ambulatory and capable of self-care; PS = Capable of only limited self care; PS = 4 Completely disabled

ECOG Performance Status (PS)

G1 = Well differentiated; G2 = Moderately differentiated; G3 = Poorly differentiated; G4 = Undifferentiated; Gx = Not assessable

Tumour Grade

Histology Type

Malignant pleural effusion

Time from Diagnosis to Enrollment

Time from most recent progression to enrollment

Overall disease classification

Estrogen Receptor Positive (ER+)

Progesterone Receptor Positive (PR+)

Human Epidermal Growth Factor Receptor Positive (HER+)

Julie Charlton

Any Adverse Event (AE)

Any AE, Causally Related to AZD2014

Any AE, Causally Related to Fulvestrant Only

Any AE of CTCAE Grade ≥ 3 (G3)

AEs of CTCAE G3, Causally Related to AZD2014

Any AE of CTCAE G3, Related to Fulvestrant Only

Any Adverse Event with Outcome of Death

AE with Outcome of Death, Related to AZD2014

AE Outcome of Death, Related to Fulvestrant Only

Any Serious Adverse Event (SAE)

Any SAE, Causally Related to AZD2014

Any SAE, Causally Related to Fulvestrant Only

Any AE Leading to Discontinuation of AZD2014

Any SAE Leading to Discontinuation of AZD2014

Participants took 75 mg of AZD2014 one time per day continuously in 28 day cycles. Participants also received intramuscular fulvestrant 500 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle.

Participants took 100 mg of AZD2014 one time per day in 28 day cycles (4 weeks). Participants also received intramuscular fulvestrant 500 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle.

The analysis population consisted of all participants who received at least one dose of AZD2014.

Adverse Events

Adverse Events Leading to Dose Reduction of AZD2014

Change in Hemoglobin ≥ 2 CTCAE Grades

Change in Hemoglobin to CTCAE Grade 3 or 4

Change in Leukocytes ≥ 2 CTCAE Grades

Change in Leukocytes to CTCAE Grade 3 or 4

Change in Lymphocytes ≥ 2 CTCAE Grades

Change in Lymphocytes to CTCAE Grade 3 or 4

Change in Neutrophils ≥ 2 CTCAE Grades

Change in Neutrophils to CTCAE Grade 3 or 4

Change in Platelets ≥ 2 CTCAE Grades

Change in Platelets to CTCAE Grade 3 or 4

Change in aPTT ≥ 2 CTCAE Grades

Change in aPTT to CTCAE Grade 3 or 4

Change in INR ≥ 2 CTCAE Grades

Change in INR to CTCAE Grade 3 or 4

Clinically Important Changes in Haematology Parameters

Change in ALT ≥ 2 CTCAE Grades

Change in ALT to CTCAE Grade 3 or 4

Change in AST ≥ 2 CTCAE Grades

Change in AST to CTCAE Grade 3 or 4

Change in Alk Phosphatase ≥ 2 CTCAE Grades

Change in Alk Phosphatase to CTCAE Grade 3 or 4

Change in Albumin ≥ 2 CTCAE Grades

Change in Albumin to CTCAE Grade 3 or 4

Change in Bilirubin ≥ 2 CTCAE Grades

Change in Bilirubin to CTCAE Grade 3 or 4

Change in Creatinine ≥ 2 CTCAE Grades

Change in Creatinine to CTCAE Grade 3 or 4

Change in Phosphate ≥ 2 CTCAE Grades

Change in Phosphate to CTCAE Grade 3 or 4

Change in Urate ≥ 2 CTCAE Grades

Change in Urate to CTCAE Grade 3 or 4

Change in Calcium ≥ 2 CTCAE Grades

Change in Calcium to CTCAE Grade 3 or 4

Change in Sodium ≥ 2 CTCAE Grades

Change in Sodium to CTCAE Grade 3 or 4

Change in Potassium ≥ 2 CTCAE Grades

Change in Potassium to CTCAE Grade 3 or 4

Change in Magnesium ≥ 2 CTCAE Grades

Change in Magnesium to CTCAE Grade 3 or 4

Change in Fasting Glucose ≥ 2 CTCAE Grades

Change in Fasting Glucose to CTCAE Grade 3 or 4

Change in NonFasting Glucose ≥ 2 CTCAE Grades

Change in Non Fasting Glucose to CTCAE Gr.3 or 4

Clinically Important Changes in Clinical Chemistry Parameters

Screening

End of Study

Change from Baseline to End of Study

Left Ventricular Ejection Fraction

Baseline

0.25 Hours Postdose

0.5 Hours Postdose

1 Hour Postdose

1.5 Hours Postdose

2 Hours Postdose

4 Hours Postdose

6 Hours Postdose

8 Hours Postdose

12 Hours Postdose

24 Hours Postdose

QTcF Over 24 Hours

Participants with ≥ 1 post-baseline elevation

Subjects with Max Post-Baseline CTCAE Grade ≥ 1

Subjects with Max Post-Baseline CTCAE Grade ≥ 2

Subjects with Max Post-Baseline CTCAE Grade ≥ 3

Subjects with Max Post-Baseline CTCAE Grade ≥ 4

Post-Baseline Glucose Elevation

Cycle 1, Day 1

Cycle 1, Day 8

Cycle 1, Day 15

Cycle 1, Day 22

Cycle 2, Day 1

Sitting Diastolic Blood Pressure

Sitting Systolic Blood Pressure

Respiratory Rate

Heart Rate

Body Temperature

Oxygen Saturation

Participants took 35 mg of AZD2014 twice daily continuously in Cycle 0 on Days -5 to -1.

Participants took 50 mg of AZD2014 twice daily continuously in Cycle 0 on Days -5 to -1.

Participants took 75 mg of AZD2014 one time each day continuously in Cycle 0 on Days -5 to -1.

Participants took 100 mg of AZD2014 one time each day continuously in Cycle 0 on Days -5 to -1.

AZD2014 Peak Plasma Concentration at Steady State (Cmax,ss) on Cycle 0 Days -5 to -1, Continuous Dosing, no Fulvestrant

AZD2014 Area Under the Plasma Concentration Time Curve (AUC 0-12) Cycle 0 Days -5 to -1, Continuous Dosing, no Fulvestrant

AZD2014 Area Under the Plasma Concentration Time Curve (AUC 0-24) Cycle 0 Days -5 to -1, Continuous Dosing, no Fulvestrant

AZD2014 Area Under the Plasma Concentration Time Curve (AUC 0-t) Cycle 0 Days -5 to -1, Continuous Dosing, no Fulvestrant

AZD2014 Area Under the Plasma Concentration Time Curve (AUC 0-∞) Cycle 0 Days -5 to -1, Continuous Dosing, no Fulvestrant

AZD2014 Peak Plasma Concentration at Steady State (Cmax,ss) on Cycle 1 Day 15, BID Intermittent Dosing, With Fulvestrant

Time to AZD2014 Peak Plasma Concentration at Steady State (Tmax,ss) on Cycle 1 Day 15, BID Intermittent Dosing, With Fulvestrant

AZD2014 Area Under the Plasma Concentration Time Curve (AUC 0-12) Cycle 1 Day 15 Intermittent Dosing, With Fulvestrant

Participants took 100 mg of AZD2014 one time per day continuously in 28 day cycles (4 weeks). Participants also received intramuscular fulvestrant 500 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle.

100 mg QD Continuously

AZD2014 Peak Plasma Concentration at Steady State (Cmax,ss) on Cycle 1 Day 22, Continuous Dosing, With Fulvestrant

Time to AZD2014 Peak Plasma Concentration at Steady State (Tmax,ss) on Cycle 1 Day 22, Continuous Dosing, With Fulvestrant

Participants took 35 mg of AZD2014 twice daily continuously in 28 day cycles (4 weeks). Participants also received intramuscular fulvestrant 500 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle.

Participants took 50 mg of AZD2014 twice daily continuously in 28 day cycles (4 weeks). Participants also received intramuscular fulvestrant 500 mg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent cycle.

AZD2014 Area Under the Plasma Concentration Time Curve (AUC 0-12) Cycle 1 Day 22 Continuous Dosing, With Fulvestrant

Participants received a single dose of 35 mg of AZD2014 in fasted condition.

35 mg

Participants received a single dose of 50 mg of AZD2014 in fasted condition.

50 mg

Participants received a single dose of 75 mg of AZD2014 in fasted condition.

75 mg

Participants received a single dose of 100 mg of AZD2014 in fasted condition.

100 mg

AZD2014 Peak Plasma Concentration (Cmax) Following Single Dose, Fasted, no Fulvestrant.

Time to AZD2014 Peak Plasma Concentration (Tmax) Following Single Dose, Fasted, no Fulvestrant.

Area Under the Plasma Concentration-time Curve for AZD2014 From 0 to 12 Hours (AUC 0-12) Following Single Dose, Fasted, no Fulvestrant.

Area Under the Plasma Concentration-time Curve for AZD2014 From 0 to Infinity (AUC 0-∞) Following Single Dose, Fasted, no Fulvestrant.

Spots Global Cancer Trial Database for estrogen receptor positive advanced metastatic breast cancer