Metastatic Breast Cancer
Conditions
Keywords
Breast Cancer, HER2-, HR+, post-menopausal, Locally advanced or metastatic Breast Cancer (HER2-, HR+)
Brief summary
This trial is designed to enroll postmenopausal patients with locally advanced or metastatic, HER2- and HR+ breast cancer not amenable to curative treatment by surgery or radiotherapy, and whose disease has progressed on or after prior endocrine therapy. Patients must undergo molecular pre-screening prior to entry.
Interventions
DRUGDovitinib
Active Dovitinib (in tablet form) taken orally at a dose of 500 mg (i.e., 5 x 100mg tablets) on a 5 days on/2 days off dosing schedule
DRUGFulvestrant
Fulvestrant (in solution) injected intramuscularly at a dose of 500 mg once on Week 1 Day 1, Week 3 Day 1 and Week 5 Day 1 and subsequently once every 4 weeks on Day 1 of the week.
DRUGDovitinib Placebo
Dovitinib Placebo (in tablet form) taken orally at a dose of 500 mg (i.e., 5 x 100mg tablets) on a 5 days on/2 days off dosing schedule
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Postmenopausal women with HER2-, HR+ locally advanced or metastatic breast cancer * Progression on or after endocrine treatment * Measureable disease as per RECIST * ECOG 0, 1 or 2
Exclusion criteria
* Evidence of CNS or leptomeningeal metastases * Previous treatment with fulvestrant * Previous chemotherapy for locally advanced or metastatic breast cancer * Cirrhosis or chronic active/persistent hepatitis Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Based on Local Investigator Assessment | Every 8 weeks assessed up to 34 months | PFS was defined as the time from the date of randomization to the date of the first radiologically documented disease progression or death due to any cause and was assessed based on RECIST v1.1. Responses include: Complete Response: Disappearance of all non-nodal target lesions; Partial Response: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters; Progressive Disease: At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline; Stable Disease: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD; Unknown (UNK) Progression has not been documented and one or more target lesions have not been assessed or have been assessed using a different method than baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Every 8 weeks assessed up to 34 months | ORR was defined as the percentage of patients with a best overall response of Complete Response (CR) or Partial Response (PR) as per RECIST v1.1. Responses include: Complete Response: Disappearance of all non-nodal target lesions; Partial Response: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters; Progressive Disease: At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline; Stable Disease: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD; Unknown (UNK) Progression has not been documented and one or more target lesions have not been assessed or have been assessed using a different method than baseline. |
| Duration of Response (DOR) | From date of first documented efficacy response (CR or PR) to time of documented progression (PD) whichever comes first, assessed up to 24 months | DOR was defined as time from the date of the first documented response (CR or PR) to the date of the first documented or death due to disease. If a patient does not have a progression event, DOR will be censored on the date of the last adequate tumor assessment. |
| Overall Survival (OS) Using Kaplan- Meier Method | From date of randomization to date of death from any cause whichever comes first, assessed up to 34 months | OS was defined as the time from the date of randomization to the date of death from any cause. If a patient is not known to have died at the date of analysis cut-off, the OS will be censored at the last date of contact. |
| Number of Participants With Adverse Events as a Measure of Safety | Screening, Week 2, Week 4 and approximately every 4 weeks during treatment period (approximately 34 months) | The type, frequency and severity of adverse events, laboratory values, and Electrocardiograms (ECGs) experienced by patients will be assessed according to Common Terminology Criteria for Adverse Events. The study enrollment was terminated early due to challenges in enrolling patients with FGF amplified status. See safety section for safety details. |
| Time to Worsening of ECOG Performance Status | Screening, Every 4 weeks during treatment period, and every 8 weeks during follow-up (approximately 9-12 months) | Eastern Cooperative Oncology Group (ECOG) Performance Status (scales and criteria used by doctors and researchers to assess how a patient's disease is progressing and assess how the disease affects the daily living abilities of the patient.) |
Countries
Argentina, Austria, Belgium, Brazil, France, Hungary, Italy, Netherlands, Peru, Poland, Russia, South Africa, Spain, Taiwan, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fulvestrant + Dovitinib Active Fulvestrant in combination with the study drug Dovitinib. | 47 |
| Fulvestrant + Dovitinib Placebo Fulvestrant in combination with a placebo matching Dovitinib. | 50 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 1 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Non-compliance with study treatment | 1 | 0 |
| Overall Study | Progressive Disease | 26 | 40 |
| Overall Study | Study Terminated by Sponsor | 4 | 8 |
| Overall Study | Subject/Guardian Decision | 5 | 0 |
Baseline characteristics
| Characteristic | Fulvestrant + Dovitinib Active | Fulvestrant + Dovitinib Placebo | Total |
|---|---|---|---|
| Age, Continuous | 63.5 Years STANDARD_DEVIATION 9.02 | 61.7 Years STANDARD_DEVIATION 9.51 | 62.6 Years STANDARD_DEVIATION 9.27 |
| Sex: Female, Male Female | 47 Participants | 50 Participants | 97 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 47 / 47 | 45 / 50 |
| serious Total, serious adverse events | 14 / 47 | 10 / 50 |
Outcome results
Primary
Progression Free Survival (PFS) Based on Local Investigator Assessment
PFS was defined as the time from the date of randomization to the date of the first radiologically documented disease progression or death due to any cause and was assessed based on RECIST v1.1. Responses include: Complete Response: Disappearance of all non-nodal target lesions; Partial Response: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters; Progressive Disease: At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline; Stable Disease: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD; Unknown (UNK) Progression has not been documented and one or more target lesions have not been assessed or have been assessed using a different method than baseline.
Time frame: Every 8 weeks assessed up to 34 months
Population: Full Analysis Set (FAS): Consisted of all randomized patients. Following the intent-to-treat principle, patients were analyzed according to the treatment and stratum to which they wereassigned at randomization.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Fulvestrant + Dovitinib Active | Progression Free Survival (PFS) Based on Local Investigator Assessment | All patients (n: 30, 34) | 5.5 Months |
| Fulvestrant + Dovitinib Active | Progression Free Survival (PFS) Based on Local Investigator Assessment | FGF amplified patients (n: 9, 9) | 10.9 Months |
| Fulvestrant + Dovitinib Active | Progression Free Survival (PFS) Based on Local Investigator Assessment | FGF non-amplified patients (n: 21, 25) | 5.5 Months |
| Fulvestrant + Dovitinib Placebo | Progression Free Survival (PFS) Based on Local Investigator Assessment | All patients (n: 30, 34) | 5.5 Months |
| Fulvestrant + Dovitinib Placebo | Progression Free Survival (PFS) Based on Local Investigator Assessment | FGF amplified patients (n: 9, 9) | 5.5 Months |
| Fulvestrant + Dovitinib Placebo | Progression Free Survival (PFS) Based on Local Investigator Assessment | FGF non-amplified patients (n: 21, 25) | 5.5 Months |
Secondary
Duration of Response (DOR)
DOR was defined as time from the date of the first documented response (CR or PR) to the date of the first documented or death due to disease. If a patient does not have a progression event, DOR will be censored on the date of the last adequate tumor assessment.
Time frame: From date of first documented efficacy response (CR or PR) to time of documented progression (PD) whichever comes first, assessed up to 24 months
Population: This outcome measure was not analyzed as the study was terminated before duration of response could be analyzed.
Secondary
Number of Participants With Adverse Events as a Measure of Safety
The type, frequency and severity of adverse events, laboratory values, and Electrocardiograms (ECGs) experienced by patients will be assessed according to Common Terminology Criteria for Adverse Events. The study enrollment was terminated early due to challenges in enrolling patients with FGF amplified status. See safety section for safety details.
Time frame: Screening, Week 2, Week 4 and approximately every 4 weeks during treatment period (approximately 34 months)
Population: Safety Set: Consisted of all patients who received at least one dose of any compound of the study treatment (dovitinib +fulvestrant or placebo+fulvestrant). Patients were analyzed according to the actual study treatment received. Actual treatment received was defined as the treatment the patient received at the first day of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fulvestrant + Dovitinib Active | Number of Participants With Adverse Events as a Measure of Safety | 47 Participants |
| Fulvestrant + Dovitinib Placebo | Number of Participants With Adverse Events as a Measure of Safety | 50 Participants |
Secondary
Overall Response Rate (ORR)
ORR was defined as the percentage of patients with a best overall response of Complete Response (CR) or Partial Response (PR) as per RECIST v1.1. Responses include: Complete Response: Disappearance of all non-nodal target lesions; Partial Response: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters; Progressive Disease: At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline; Stable Disease: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD; Unknown (UNK) Progression has not been documented and one or more target lesions have not been assessed or have been assessed using a different method than baseline.
Time frame: Every 8 weeks assessed up to 34 months
Population: Full Analysis Set (FAS): Consisted of all randomized patients. Following the intent-to-treat principle, patients were analyzed according to the treatment and stratum to which they were assigned at randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fulvestrant + Dovitinib Active | Overall Response Rate (ORR) | All patients | 27.7 Percentage of participants |
| Fulvestrant + Dovitinib Active | Overall Response Rate (ORR) | FGF amplified patients | 20.0 Percentage of participants |
| Fulvestrant + Dovitinib Active | Overall Response Rate (ORR) | FGF non-amplified patients | 31.3 Percentage of participants |
| Fulvestrant + Dovitinib Placebo | Overall Response Rate (ORR) | All patients | 10.0 Percentage of participants |
| Fulvestrant + Dovitinib Placebo | Overall Response Rate (ORR) | FGF amplified patients | 12.5 Percentage of participants |
| Fulvestrant + Dovitinib Placebo | Overall Response Rate (ORR) | FGF non-amplified patients | 8.8 Percentage of participants |
Secondary
Overall Survival (OS) Using Kaplan- Meier Method
OS was defined as the time from the date of randomization to the date of death from any cause. If a patient is not known to have died at the date of analysis cut-off, the OS will be censored at the last date of contact.
Time frame: From date of randomization to date of death from any cause whichever comes first, assessed up to 34 months
Population: Full Analysis Set (FAS): Consisted of all randomized patients. Following the intent-to-treat principle, patients were analyzed according to the treatment and stratum to which they were assigned at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fulvestrant + Dovitinib Active | Overall Survival (OS) Using Kaplan- Meier Method | NA Months |
| Fulvestrant + Dovitinib Placebo | Overall Survival (OS) Using Kaplan- Meier Method | 25.9 Months |
Secondary
Time to Worsening of ECOG Performance Status
Eastern Cooperative Oncology Group (ECOG) Performance Status (scales and criteria used by doctors and researchers to assess how a patient's disease is progressing and assess how the disease affects the daily living abilities of the patient.)
Time frame: Screening, Every 4 weeks during treatment period, and every 8 weeks during follow-up (approximately 9-12 months)
Population: This outcome measure was not analyzed as the study was terminated before time to worsening ECOG performance could be analyzed.