First or Second Line HER2-negative Breast Cancer, Metastatic Disease Without Bone Metastasis
Conditions
Keywords
HER2-negative, HER2, Metastatic breast cancer, First Line breast cancer, Second Line breast cancer, Breast cancer, Metastatic, Stage IV breast cancer, Progression free survival, PFS, Circulating Tumor Cells, CTCs, Zoledronic acid, HER2-negative metastatic breast cancer patients without bone metastasis
Brief summary
This study will evaluate zoledronic acid's anti-cancer effects and Circulating Tumor Cell (CTCs) measurements in patients with HER2-negative metastatic breast cancer without bone metastasis.
Interventions
DRUGZoledronic acid
Patients with no bone metastasis (n=150) will receive Standard therapy plus Zoledronic acid administration 4 mg IV monthly during Months 1-18.
DRUGStandard Therapy
Standard Therapy, including chemotherapy and hormonal therapy, was determined at the discretion of the investigator.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent * Female patients (age ≥18 years) * HER2-negative metastatic breast cancer (stage IV) * Patients will be receiving chemotherapy or hormonal therapy * Patients with no bone metastasis and ≤1 prior treatments for metastatic breast cancer. Patients with newly diagnosed metastatic breast cancer may have received adjuvant or neoadjuvant chemotherapy as long as treatment was completed ≥12 months prior to relapse. * Asymptomatic brain metastasis is permitted if all of the following criteria are met: 1. no sign of clinical progression or known progression of brain metastasis 2. off steroids for at least 2 weeks prior to study enrollment * Stable renal function: two serum creatinine determinations of \<3 mg/dL, obtained no less than 7 days apart (one value may be obtained within 6 weeks prior to Screening; the second must be obtained during Screening) * ECOG performance status of 0 or 1 * Life expectancy of ≥ 6 months * Negative serum pregnancy test * Ability and willingness to comply with all study requirements
Exclusion criteria
* Known hypersensitivity to zoledronic acid or other bisphosphonates * Patients with history of another malignancy within the last two years prior to study enrollment, except cured basal cell carcinoma of the skin or excised carcinoma in site of the cervix * Use of concurrent investigational agents is prohibited. Prior use of investigational agents is permitted if discontinued ≥30 days prior to Screening. * No prior therapy with an antiresorptive agent * Patients with active brain metastases or meningeal metastases * Current or recent (in the six months prior to initial study drug treatment) severe cardiovascular disease (defined as uncontrolled congestive heart failure), hypertension refractory to treatment, or poorly controlled Type I/II diabetes mellitus * Current active dental problems including dental abscess or infection of the jawbone (maxilla or mandible) or a current or prior diagnosis of osteonecrosis of the jaw * Patients who have received radiotherapy ≤ 4 weeks prior to study enrollment or who have not recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to study enrollment is allowed * Patients who have undergone major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) ≤ 4 weeks prior to study enrollment or who have not recovered from side effects of such therapy * Diminished renal capacity: calculated creatinine clearance (CrCl) \<30 mL/min (based on Cockcroft-Gault formula) * Corrected (i.e., adjusted for serum albumin) serum calcium of \<8.0 mg/dL (2.00 mmol/L) or ≥ 12 mg/dL (3.00 mmol/L) * Pregnant or breast-feeding females * Women of child-bearing potential who are not willing/able to use effective methods of birth control (e.g., abstinence, oral contraceptives or implants, IUD, vaginal diaphragm or sponge, or condom with spermicide) * History of non-compliance to medical regimens and/or patients who are considered unreliable * History of bone metabolism diseases
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Progression Free Survival (PFS) | up to 18 months | Complete Response (CR): disappearance of all target lesions. Any pathological lymph nodes (target or non-target) must have exhibited a reduction in short axis to \< 10 mm. Partial Response (PR): at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD): at least 20% increase in sum of diameters of target lesions taking as reference the smallest sum on study accompanied by an absolute increase of at least 5 mm or appearance of one or more new lesions. Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference smallest sum diameters. PFS is time from enrollment to date of first documented disease progression or death due to any cause. A participant is considered to be censored when data on time to event is missing due to a subject being lost to follow-up or non-occurrence of the outcome event before the completion of the trial. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Circulating Tumor Cell Levels of at Least 5 Per 7.5 mL of Peripheral Blood by Month | Baseline, Month 1, 2, 4, 6, 9 and 18 | Circulating tumor cells (CTCs) have been associated with poor patient prognosis and outcomes in patients receiving treatment for MBC. CTCs have been evaluated as a potential biomarker for predicting treatment effects and overall survival. Baseline was defined as the last predose measurement for patients who received any study drug and as the later of the screening visit or Visit 2 value for patients who did not receive the study drug. Percentage was calculated as the number of patients with CTC ≥5/7.5 mL against the number of patients with nonmissing CTC values (represented as 'n' in the categories). |
| Time to Progression (TTP) | up to 18 months | Time to progression is defined as the time from the date of enrollment to the date of first documented disease progression or death due to metastatic breast cancer. |
| Change From Baseline in Urine NTX by Month | Baseline, Month 2, Month 4 | NTX= N-telopeptide of type 1 collagen (nmol bce/mmol \[nanomoles of bone collagen equivalents per millimole of creatinine\]). Baseline was defined as the last predose measurement for patients who received any study drug and as the later of the screening visit or visit 2 value for patients who did not receive study drug. |
Countries
United States
Participant flow
Recruitment details
80 patients were screened. 44 patients received treatment.
Participants by arm
| Arm | Count |
|---|---|
| Patients Without Bone Metastases Patients with no bone metastasis were randomized into a 1:1 ratio to standard therapy plus zoledronic acid 4mg IV Zoledronic acid administration monthly during Months 1-18. | 15 |
| Patients With Bone Metastases Patients with bone metastasis received standard therapy + zoledronic acid for 18 months (discontinued upon disease progression/secondary malignancy) | 29 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 0 | 4 |
| Overall Study | Disease Progression | 1 | 4 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Missing Study Completion Status | 2 | 3 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 7 | 4 |
Baseline characteristics
| Characteristic | Patients Without Bone Metastases | Patients With Bone Metastases | Total |
|---|---|---|---|
| Age, Continuous | 53.48 Years STANDARD_DEVIATION 12.293 | 59.47 Years STANDARD_DEVIATION 14.535 | 57.43 Years STANDARD_DEVIATION 13.965 |
| Sex: Female, Male Female | 15 Participants | 29 Participants | 44 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 | 13 / 15 | 28 / 29 |
| serious Total, serious adverse events | 2 / 15 | 7 / 29 |
Outcome results
Primary
Number of Participants With Progression Free Survival (PFS)
Complete Response (CR): disappearance of all target lesions. Any pathological lymph nodes (target or non-target) must have exhibited a reduction in short axis to \< 10 mm. Partial Response (PR): at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD): at least 20% increase in sum of diameters of target lesions taking as reference the smallest sum on study accompanied by an absolute increase of at least 5 mm or appearance of one or more new lesions. Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference smallest sum diameters. PFS is time from enrollment to date of first documented disease progression or death due to any cause. A participant is considered to be censored when data on time to event is missing due to a subject being lost to follow-up or non-occurrence of the outcome event before the completion of the trial.
Time frame: up to 18 months
Population: All Enrolled Patients population, which included all enrolled patients regardless of whether they received study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Patients Without Bone Metastases | Number of Participants With Progression Free Survival (PFS) | Event | 9 Participants |
| Patients Without Bone Metastases | Number of Participants With Progression Free Survival (PFS) | Censor | 6 Participants |
| Patients With Bone Metastases | Number of Participants With Progression Free Survival (PFS) | Event | 19 Participants |
| Patients With Bone Metastases | Number of Participants With Progression Free Survival (PFS) | Censor | 10 Participants |
Secondary
Change From Baseline in Urine NTX by Month
NTX= N-telopeptide of type 1 collagen (nmol bce/mmol \[nanomoles of bone collagen equivalents per millimole of creatinine\]). Baseline was defined as the last predose measurement for patients who received any study drug and as the later of the screening visit or visit 2 value for patients who did not receive study drug.
Time frame: Baseline, Month 2, Month 4
Population: All Enrolled Patients population, which included all enrolled patients regardless of whether they received study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Patients Without Bone Metastases | Change From Baseline in Urine NTX by Month | Change from baseline at Month 2 | -5.25 nmol bce/mmol | Standard Deviation 22.5555 |
| Patients Without Bone Metastases | Change From Baseline in Urine NTX by Month | Change from baseline at Month 4 | -4.750 nmol bce/mmol | Standard Deviation 18.7521 |
| Patients With Bone Metastases | Change From Baseline in Urine NTX by Month | Change from baseline at Month 2 | -27.619 nmol bce/mmol | Standard Deviation 23.3955 |
| Patients With Bone Metastases | Change From Baseline in Urine NTX by Month | Change from baseline at Month 4 | -23.476 nmol bce/mmol | Standard Deviation 26.3526 |
Secondary
Percentage of Patients With Circulating Tumor Cell Levels of at Least 5 Per 7.5 mL of Peripheral Blood by Month
Circulating tumor cells (CTCs) have been associated with poor patient prognosis and outcomes in patients receiving treatment for MBC. CTCs have been evaluated as a potential biomarker for predicting treatment effects and overall survival. Baseline was defined as the last predose measurement for patients who received any study drug and as the later of the screening visit or Visit 2 value for patients who did not receive the study drug. Percentage was calculated as the number of patients with CTC ≥5/7.5 mL against the number of patients with nonmissing CTC values (represented as 'n' in the categories).
Time frame: Baseline, Month 1, 2, 4, 6, 9 and 18
Population: All Enrolled Patients population, which included all enrolled patients regardless of whether they received study drug. n in each category represents the number of patients with non-missing CTC values.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Patients Without Bone Metastases | Percentage of Patients With Circulating Tumor Cell Levels of at Least 5 Per 7.5 mL of Peripheral Blood by Month | Baseline (n=15,28) | 26.7 Percentage of Participants |
| Patients Without Bone Metastases | Percentage of Patients With Circulating Tumor Cell Levels of at Least 5 Per 7.5 mL of Peripheral Blood by Month | Month 1 (n=8,0) | 12.5 Percentage of Participants |
| Patients Without Bone Metastases | Percentage of Patients With Circulating Tumor Cell Levels of at Least 5 Per 7.5 mL of Peripheral Blood by Month | Month 2 (n=12,24) | 8.3 Percentage of Participants |
| Patients Without Bone Metastases | Percentage of Patients With Circulating Tumor Cell Levels of at Least 5 Per 7.5 mL of Peripheral Blood by Month | Month 4 (n=8,20) | 0 Percentage of Participants |
| Patients Without Bone Metastases | Percentage of Patients With Circulating Tumor Cell Levels of at Least 5 Per 7.5 mL of Peripheral Blood by Month | Month 6 (n=7,19) | 0 Percentage of Participants |
| Patients Without Bone Metastases | Percentage of Patients With Circulating Tumor Cell Levels of at Least 5 Per 7.5 mL of Peripheral Blood by Month | Month 9 (n=2,14) | 0 Percentage of Participants |
| Patients Without Bone Metastases | Percentage of Patients With Circulating Tumor Cell Levels of at Least 5 Per 7.5 mL of Peripheral Blood by Month | Month 18 (n=2,1) | 0 Percentage of Participants |
| Patients With Bone Metastases | Percentage of Patients With Circulating Tumor Cell Levels of at Least 5 Per 7.5 mL of Peripheral Blood by Month | Month 4 (n=8,20) | 15.0 Percentage of Participants |
| Patients With Bone Metastases | Percentage of Patients With Circulating Tumor Cell Levels of at Least 5 Per 7.5 mL of Peripheral Blood by Month | Baseline (n=15,28) | 57.1 Percentage of Participants |
| Patients With Bone Metastases | Percentage of Patients With Circulating Tumor Cell Levels of at Least 5 Per 7.5 mL of Peripheral Blood by Month | Month 18 (n=2,1) | 100.0 Percentage of Participants |
| Patients With Bone Metastases | Percentage of Patients With Circulating Tumor Cell Levels of at Least 5 Per 7.5 mL of Peripheral Blood by Month | Month 1 (n=8,0) | NA Percentage of Participants |
| Patients With Bone Metastases | Percentage of Patients With Circulating Tumor Cell Levels of at Least 5 Per 7.5 mL of Peripheral Blood by Month | Month 6 (n=7,19) | 15.8 Percentage of Participants |
| Patients With Bone Metastases | Percentage of Patients With Circulating Tumor Cell Levels of at Least 5 Per 7.5 mL of Peripheral Blood by Month | Month 2 (n=12,24) | 25.0 Percentage of Participants |
| Patients With Bone Metastases | Percentage of Patients With Circulating Tumor Cell Levels of at Least 5 Per 7.5 mL of Peripheral Blood by Month | Month 9 (n=2,14) | 35.7 Percentage of Participants |
Secondary
Time to Progression (TTP)
Time to progression is defined as the time from the date of enrollment to the date of first documented disease progression or death due to metastatic breast cancer.
Time frame: up to 18 months
Population: All Enrolled Patients population, which included all enrolled patients regardless of whether they received study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Patients Without Bone Metastases | Time to Progression (TTP) | 190 Days |
| Patients With Bone Metastases | Time to Progression (TTP) | 297 Days |