Breast Neoplasms
Conditions
Keywords
Breast cancer, Anti tumor potential, Letrozole, Zoledronic acid, Neoadjuvant treatment, Hormone responsive breast cancer
Brief summary
This study will evaluate the safety/efficacy of zoledronic acid when given by intravenous infusion every 4 weeks in addition to letrozole as endocrine therapy in postmenopausal patients with hormone responsive breast cancer
Detailed description
Open-label, multicenter, randomized phase II trial over approx 6.5 months of neoadjuvant treatment with letrozole with or without zoledronic acid in postmenopausal patients with primary breast cancer. A total of approximately 850 patients were originally planned to be enrolled; primary study endpoint was the objective response rate (according to modified RECIST criteria) after 6 months of treatment. After the core study, patients willing to participate were followed-up for further 5 years.
Interventions
DRUGLetrozole
2.5 mg.tablet.
DRUGZolendronic Acid
4 mg or an adjusted dose based on renal function in 100 ml physiologic (o.9%) normal saline, (as an intravenous infusion over no less than 15 minutes)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Open-label, multicenter, randomized
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Postmenopausal women with primary invasive breast cancer, histologically confirmed by core needle biopsy, whose tumors are estrogen (ER) and / or progesterone (PgR) positive * Clinical Stage T1c (Size ≥ 1.5 cm), T2, T3, T4a, b, c, N0 or N1, M0 (TNM Classification). According to the modified RECIST criteria, tumors of size ≥ 1.5 cm are considered measurable by mammography and can be determined as target lesions). * Tumor measurable by mammography, sonography and clinical examination. * Adequate bone marrow, renal and hepatic function * Good health status (ECOG Performance status of 0, 1 or 2)
Exclusion criteria
* Prior treatment with letrozole or bisphosphonates. Prior and concomitant anti-breast-cancer treatments such as chemotherapy, immunotherapy / biological response modifiers (BRM's), endocrine therapy other than letrozole (including steroids), and radiotherapy. Patients who have received hormone replacement therapy (HRT) will NOT be excluded, provided that HRT is discontinued at least 2 weeks prior to entry into the study. * Patients with unstable angina, or uncontrolled cardiac disease (e.g. Class III and IV New York Heart Association's Functional Classification, see Appendix 9) or uncontrolled endocrine disorders. * Evidence of inflammatory breast cancer or distant metastasis. * Current active dental problems including infection of the teeth or jawbone (maxilla or mandibular); dental or fixture trauma, or a current or prior diagnosis of osteonecrosis of the jaw (ONJ), of exposed bone in the mouth, or of slow healing after dental procedures. Recent (within 6 weeks) or planned dental or jaw surgery (e.g. extraction, implants). * History of diseases with influence on bone metabolism, such as Paget's disease, Osteogenesis Imperfecta, and primary or secondary hyperthyroidism within the 12 months prior to study entry Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Response Rate (Complete Response (CR) or Partial Response (PR)) Based on MRI- or Mammography and/or Sonography According to Modified RECIST Criteria at Month 6 | 6 months | Sum of longest diameter for all target lesions was reported as baseline sum LD. Baseline sum LD was used as reference to characterize objective tumor response. Response Evaluation Criteria in Solid Tumors has 4 response categories. CR (complete response) = disappearance of all target lesions, PR (partial response)= 30% decrease in sum of longest diameter of target lesions, PD (progressive disease) = 20% increase in the sum of the longest diameter of target lesions and SD(stable disease)=small changes that do not meet criteria. Analysis was underpowered due to insufficient recruitment rate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best RECIST Response Based on Central Review at 6 Mos | 6 Months | Best response is defined as the best response the patients has reached during the 6 months of treatment. Response Evaluation Criteria in Solid Tumors (RECIST) has 4 response categories. CR (complete response) = disappearance of all target lesions, PR (partial response) = 30% decrease in the sum of the longest diameter of target lesions, PD (progressive disease) = 20% increase in the sum of the longest diameter of target lesions and SD (stable disease) = small changes that do not meet criteria. |
| Number of Patients With Breast Conserving Surgery at 6 Months | Every 6 months | — |
| Change From Baseline in Tumor Size (Longest Diameter) at Month 6 | Baseline, Month 6 | Tumor size (sum of longest diameter)was analyzed based on the diameters values provided with the central review. |
| Mean Changes From Baseline in FACT-B Total Score at 6 Months (ITT, Data as Observed) | baseline and 6 mos | The FACT-B total score is calculated by summing all five unweighted subscale scores, with total scores in the range of 0-144.To Derive a FACT-B total score: all sections added together The higher the score the better the QoL * \+ \_\_\_\_\_\_\_\_\_\_ + \_\_\_\_\_\_\_\_\_\_ + \_\_\_\_\_\_\_\_\_\_ + \_\_\_\_\_\_\_\_\_\_ =\_\_\_\_\_\_\_\_=FACT-B Total score (PWB score) (SWB score) (EWB score) (FWB score) (BCS score) |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Letrozole (LET) Letrozole 2.5 mg/day oral letrozole for approximately 6.5 months neoadjuvent treatment. | 79 |
| Letrozole +Zoledronic Acid (LET+ZOL) 2.5 mg/day oral letrozole for approximately 6.5 months neoadjuvant treatment plus zoledronic acid 4 mg i.v. q4w | 89 |
| Total | 168 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal Laboratory Value(s) | 1 | 1 |
| Overall Study | Administrative Problems | 0 | 1 |
| Overall Study | Adverse Event | 1 | 6 |
| Overall Study | Lack of Efficacy | 4 | 4 |
| Overall Study | Protocol Violation | 0 | 2 |
| Overall Study | Withdrawal by Subject | 6 | 1 |
Baseline characteristics
| Characteristic | Letrozole (LET) | Letrozole +Zoledronic Acid (LET+ZOL) | Total |
|---|---|---|---|
| Age, Continuous | 70.5 years STANDARD_DEVIATION 8.4 | 71.3 years STANDARD_DEVIATION 9.2 | 70.9 years STANDARD_DEVIATION 8.8 |
| Sex: Female, Male Female | 79 Participants | 89 Participants | 168 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 | 56 / 79 | 67 / 89 |
| serious Total, serious adverse events | 3 / 79 | 14 / 89 |
Outcome results
Primary
Tumor Response Rate (Complete Response (CR) or Partial Response (PR)) Based on MRI- or Mammography and/or Sonography According to Modified RECIST Criteria at Month 6
Sum of longest diameter for all target lesions was reported as baseline sum LD. Baseline sum LD was used as reference to characterize objective tumor response. Response Evaluation Criteria in Solid Tumors has 4 response categories. CR (complete response) = disappearance of all target lesions, PR (partial response)= 30% decrease in sum of longest diameter of target lesions, PD (progressive disease) = 20% increase in the sum of the longest diameter of target lesions and SD(stable disease)=small changes that do not meet criteria. Analysis was underpowered due to insufficient recruitment rate.
Time frame: 6 months
Population: The modified intent-to-treat (mITT) population included all patients of the ITT population for whom at least one post-baseline assessment of tumor response according to modified RECIST made by central review was available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letrozole (LET) | Tumor Response Rate (Complete Response (CR) or Partial Response (PR)) Based on MRI- or Mammography and/or Sonography According to Modified RECIST Criteria at Month 6 | 54.5 percentage of participants |
| Letrozole +Zoledronic Acid (LET+ZOL) | Tumor Response Rate (Complete Response (CR) or Partial Response (PR)) Based on MRI- or Mammography and/or Sonography According to Modified RECIST Criteria at Month 6 | 69.2 percentage of participants |
p-value: 0.10695% CI: [-1.8, 31.1]Fisher Exact
Secondary
Best RECIST Response Based on Central Review at 6 Mos
Best response is defined as the best response the patients has reached during the 6 months of treatment. Response Evaluation Criteria in Solid Tumors (RECIST) has 4 response categories. CR (complete response) = disappearance of all target lesions, PR (partial response) = 30% decrease in the sum of the longest diameter of target lesions, PD (progressive disease) = 20% increase in the sum of the longest diameter of target lesions and SD (stable disease) = small changes that do not meet criteria.
Time frame: 6 Months
Population: The modified intent-to-treat (mITT) population included all patients of the ITT population for whom at least one post-baseline assessment of tumor response according to modified RECIST made by central review was available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Letrozole (LET) | Best RECIST Response Based on Central Review at 6 Mos | Complete Response (CR) | 0 Participants |
| Letrozole (LET) | Best RECIST Response Based on Central Review at 6 Mos | at least Paratial Response (PR) | 36 Participants |
| Letrozole (LET) | Best RECIST Response Based on Central Review at 6 Mos | at least Stable Disease (SD) | 30 Participants |
| Letrozole (LET) | Best RECIST Response Based on Central Review at 6 Mos | Progressive Disease | 0 Participants |
| Letrozole +Zoledronic Acid (LET+ZOL) | Best RECIST Response Based on Central Review at 6 Mos | Progressive Disease | 1 Participants |
| Letrozole +Zoledronic Acid (LET+ZOL) | Best RECIST Response Based on Central Review at 6 Mos | Complete Response (CR) | 2 Participants |
| Letrozole +Zoledronic Acid (LET+ZOL) | Best RECIST Response Based on Central Review at 6 Mos | at least Stable Disease (SD) | 19 Participants |
| Letrozole +Zoledronic Acid (LET+ZOL) | Best RECIST Response Based on Central Review at 6 Mos | at least Paratial Response (PR) | 43 Participants |
Secondary
Change From Baseline in Tumor Size (Longest Diameter) at Month 6
Tumor size (sum of longest diameter)was analyzed based on the diameters values provided with the central review.
Time frame: Baseline, Month 6
Population: The modified intent-to-treat (mITT) population included all patients of the ITT population for whom at least one post-baseline assessment of tumor response according to modified RECIST made by central review was available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Letrozole (LET) | Change From Baseline in Tumor Size (Longest Diameter) at Month 6 | -1.12 cm | Standard Deviation 0.92 |
| Letrozole +Zoledronic Acid (LET+ZOL) | Change From Baseline in Tumor Size (Longest Diameter) at Month 6 | -1.37 cm | Standard Deviation 0.96 |
Secondary
Mean Changes From Baseline in FACT-B Total Score at 6 Months (ITT, Data as Observed)
The FACT-B total score is calculated by summing all five unweighted subscale scores, with total scores in the range of 0-144.To Derive a FACT-B total score: all sections added together The higher the score the better the QoL * \+ \_\_\_\_\_\_\_\_\_\_ + \_\_\_\_\_\_\_\_\_\_ + \_\_\_\_\_\_\_\_\_\_ + \_\_\_\_\_\_\_\_\_\_ =\_\_\_\_\_\_\_\_=FACT-B Total score (PWB score) (SWB score) (EWB score) (FWB score) (BCS score)
Time frame: baseline and 6 mos
Population: ITT
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Letrozole (LET) | Mean Changes From Baseline in FACT-B Total Score at 6 Months (ITT, Data as Observed) | Baseline | 113.3 score on a scale | Standard Deviation 16.6 |
| Letrozole (LET) | Mean Changes From Baseline in FACT-B Total Score at 6 Months (ITT, Data as Observed) | Month 6 | 112.0 score on a scale | Standard Deviation 19.6 |
| Letrozole +Zoledronic Acid (LET+ZOL) | Mean Changes From Baseline in FACT-B Total Score at 6 Months (ITT, Data as Observed) | Baseline | 109.5 score on a scale | Standard Deviation 20.2 |
| Letrozole +Zoledronic Acid (LET+ZOL) | Mean Changes From Baseline in FACT-B Total Score at 6 Months (ITT, Data as Observed) | Month 6 | 108.2 score on a scale | Standard Deviation 20.5 |
Secondary
Number of Patients With Breast Conserving Surgery at 6 Months
Time frame: Every 6 months
Population: The intent-to-treat (ITT) population included all patients of the safety population for whom at least one post-baseline assessment of tumor response according to the modified RECIST (local or central assessment) was available. During different time points, participants with observations at that timepoint were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Letrozole (LET) | Number of Patients With Breast Conserving Surgery at 6 Months | Radical mastectomy | 10 Participants |
| Letrozole (LET) | Number of Patients With Breast Conserving Surgery at 6 Months | Lumpectomy/Quadrantectomy | 50 Participants |
| Letrozole (LET) | Number of Patients With Breast Conserving Surgery at 6 Months | Other | 2 Participants |
| Letrozole (LET) | Number of Patients With Breast Conserving Surgery at 6 Months | Lumpectomy/Quadrantectomy + Other | 1 Participants |
| Letrozole (LET) | Number of Patients With Breast Conserving Surgery at 6 Months | Modfied radical mastectomy | 3 Participants |
| Letrozole (LET) | Number of Patients With Breast Conserving Surgery at 6 Months | Surgery performed | 66 Participants |
| Letrozole +Zoledronic Acid (LET+ZOL) | Number of Patients With Breast Conserving Surgery at 6 Months | Other | 0 Participants |
| Letrozole +Zoledronic Acid (LET+ZOL) | Number of Patients With Breast Conserving Surgery at 6 Months | Surgery performed | 77 Participants |
| Letrozole +Zoledronic Acid (LET+ZOL) | Number of Patients With Breast Conserving Surgery at 6 Months | Radical mastectomy | 12 Participants |
| Letrozole +Zoledronic Acid (LET+ZOL) | Number of Patients With Breast Conserving Surgery at 6 Months | Modfied radical mastectomy | 8 Participants |
| Letrozole +Zoledronic Acid (LET+ZOL) | Number of Patients With Breast Conserving Surgery at 6 Months | Lumpectomy/Quadrantectomy | 56 Participants |
| Letrozole +Zoledronic Acid (LET+ZOL) | Number of Patients With Breast Conserving Surgery at 6 Months | Lumpectomy/Quadrantectomy + Other | 1 Participants |