Metastatic Breast Cancer
Conditions
Keywords
breast cancer, Postmenopausal Women with Hormone Receptor-Positive Locally Advanced Breast Cancer
Brief summary
Letrozole is an aromatase inhibitor that is approved in the first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer. Sorafenib may stop the growth of tumor cells by blocking blood flow to the tumor and by blocking some of the enzymes needed for cell growth. This phase I/II trial is studying the side effects and best dose of sorafenib when given in combination with letrozole and to see how well they work in treating postmenopausal women with metastatic breast cancer.
Interventions
DRUGSorafenib
sorafenib dose will be given at a daily dose to be determined based upon the phase of study that patient is enrolled The phase II dose of sorafenib will be determined from the phase I portion of the study.
DRUGLetrozole
Patients will take letrozole orally at a daily dose of 2.5 mg/day on Days 1 through 28
Sponsors
Rutgers Cancer Institute of New Jersey
National Cancer Institute (NCI)
Bayer
Novartis Pharmaceuticals
Rutgers, The State University of New Jersey
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed invasive breast cancer 2. Stage IIIB, IIIC with T4 lesion or Stage IV disease 3. Breast cancer must be ER-positive and/or PR-positive 4. Age ³ 18 years of age 5. ECOG performance status 0, 1 or 2 6. Able to swallow and oral medication 7. Adequate end organ function 8. Written informed consent
Exclusion criteria
1. Prior hormonal therapy for metastatic disease 2. Prior chemotherapy for metastatic disease 3. Prior treatment with sorafenib 4. Brain metastases or leptomeningeal disease 5. Evidence or history of bleeding 6. Thrombolic or embolic events such as cerebrovascular accident including transient ischemic attacks within the past 6 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sorafenib in Combination With Fixed Dose of of 2.5mg of Letrozole Maximum Tolerated Dose (MTD) | twenty eight days | The highest dose of the drug that does not cause unacceptable side effects. The maximum tolerated dose be testing increasing doses until the highest dose with acceptable side effects is found. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate Using the Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines (Version 1.1) to Letrozole and Sorafenib | 6 months | Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the malignant lymph nodes are used for tumor measurements. Included will be: complete response, partial response or stable disease of letrozole and sorafenib in the treatment of postmenopausal participants with hormone receptor- positive locally advanced or metastatic breast cancer. Clinical Benefit Rate (CBR) = Progressive Free (PF) + Stable Disease (SD) |
| Median Progressive-Free Survival (PFS) | Approximately 4.6 years | PFS based on the Kaplan-Meier method is defined as the time between randomization and documented disease progression (PD) per RECIST 1,0 criteria or death, or is censored at time of last disease assessment. Per RECIST 1.0f or target lesions, PD is at least a 20% increase in sum LD of target lesions, taken as reference the smallest sum LD recorded at treatment started. Based on the time between the first day of treatment and and the date of disease progression. |
| Overall Survival (OS) Assessed as Mean Months | Approximately 4.6 years | From the start of treatment to the end of the study (three years) that participants are still alive. Measured by the mean number. |
Countries
United States
Participant flow
Recruitment details
13 participants in Phase I + 39 participants enrolled in Phase II = 52 participants that appear to be enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| Phase l Sorafenib Dose Escalation and Letrozole 2.5mg po Daily Dose Level -1 Sorafenib: sorafenib dose will be given at a daily dose to be determined based upon the phase of study that patient is enrolled The phase II dose of sorafenib will be determined from the phase I portion of the study.
Dose Level -1: Sorafenib 400mg po every other day. Letrozole: Patients will take letrozole orally at a daily dose of 2.5 mg/day on Days 1 through 28 | 1 |
| Phase l Sorafenib Dose Escalation and Letrozole 2.5mg Daily Dose Level 0:Sorafenib 400mg 1X Daily Sorafenib: s dose will be given at a daily dose to be determined based upon the phase of study that patient is enrolled The phase II dose of sorafenib will be determined from the phase I portion of the study
Dose Level 0: Sorafenib 400mg 1X daily Letrozole: Patients will take letrozole orally at a daily dose of 2.5 mg/day on Days 1 through 28 | 3 |
| Phase l Sorafenib Dose Escalation and Letrozole 2.5mg po Daily Dose Level 1: Sorafenib 400mg 2X Day Sorafenib: sorafenib dose will be given at a daily dose to be determined based upon the phase of study that patient is enrolled The phase II dose of sorafenib will be determined from the phase I portion of the study.
Dose Level 1: Sorafenib 400mg 2X day. Letrozole: Patients will take letrozole orally at a daily dose of 2.5 mg/day on Days 1 through 28 | 9 |
| Phase II Arm - Sorafenib at MTD (400mg) 2x a Day + Letrozole 2.5 mg po Daily Sorafenib 400mg 2X day. Letrozole: Patients will take letrozole orally at a daily dose of 2.5 mg/day | 39 |
| Total | 52 |
Baseline characteristics
| Characteristic | Phase l Sorafenib Dose Escalation and Letrozole 2.5mg po Daily Dose Level -1 | Phase l Sorafenib Dose Escalation and Letrozole 2.5mg Daily Dose Level 0:Sorafenib 400mg 1X Daily | Phase l Sorafenib Dose Escalation and Letrozole 2.5mg po Daily Dose Level 1: Sorafenib 400mg 2X Day | Phase II Arm - Sorafenib at MTD (400mg) 2x a Day + Letrozole 2.5 mg po Daily | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 3 Participants | 5 Participants | 3 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 4 Participants | 36 Participants | 40 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 10 Participants | 10 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 3 Participants | 9 Participants | 25 Participants | 38 Participants |
| Region of Enrollment United States | 1 participants | 3 participants | 9 participants | 39 participants | 52 participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 9 Participants | 39 Participants | 52 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 | 1 / 1 | 2 / 3 | 7 / 9 | 24 / 39 |
| other Total, other adverse events | 1 / 1 | 3 / 3 | 9 / 9 | 39 / 39 |
| serious Total, serious adverse events | 0 / 1 | 1 / 3 | 0 / 9 | 3 / 39 |
Outcome results
Primary
Sorafenib in Combination With Fixed Dose of of 2.5mg of Letrozole Maximum Tolerated Dose (MTD)
The highest dose of the drug that does not cause unacceptable side effects. The maximum tolerated dose be testing increasing doses until the highest dose with acceptable side effects is found.
Time frame: twenty eight days
Population: The primary outcome is the maximum tolerated dose, which is the highest dose of the drug that does not cause unacceptable side effects. The maximum tolerated dose was only analyzed. Then phase 2 added 39 participates.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib in Combination With Fixed Dose of of 2.5mg of Letrozole Maximum Tolerated Dose (MTD) | Sorafenib in Combination With Fixed Dose of of 2.5mg of Letrozole Maximum Tolerated Dose (MTD) | 400 milligrams twice daily |
Secondary
Clinical Benefit Rate Using the Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines (Version 1.1) to Letrozole and Sorafenib
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the malignant lymph nodes are used for tumor measurements. Included will be: complete response, partial response or stable disease of letrozole and sorafenib in the treatment of postmenopausal participants with hormone receptor- positive locally advanced or metastatic breast cancer. Clinical Benefit Rate (CBR) = Progressive Free (PF) + Stable Disease (SD)
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sorafenib in Combination With Fixed Dose of of 2.5mg of Letrozole Maximum Tolerated Dose (MTD) | Clinical Benefit Rate Using the Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines (Version 1.1) to Letrozole and Sorafenib | 0 Participants |
| Phase l Sorafenib Dose Escalation and Letrozole 2.5mg Daily Dose Level 0:Sorafenib 400mg 1X Daily | Clinical Benefit Rate Using the Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines (Version 1.1) to Letrozole and Sorafenib | 3 Participants |
| Phase l Sorafenib Dose Escalation and Letrozole 2.5mg po Daily Dose Level 1: Sorafenib 400mg 2X Day | Clinical Benefit Rate Using the Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines (Version 1.1) to Letrozole and Sorafenib | 4 Participants |
| Phase II Arm - Sorafenib at MTD (400mg) 2x a Day + Letrozole 2.5 mg po Daily | Clinical Benefit Rate Using the Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines (Version 1.1) to Letrozole and Sorafenib | 23 Participants |
Secondary
Median Progressive-Free Survival (PFS)
PFS based on the Kaplan-Meier method is defined as the time between randomization and documented disease progression (PD) per RECIST 1,0 criteria or death, or is censored at time of last disease assessment. Per RECIST 1.0f or target lesions, PD is at least a 20% increase in sum LD of target lesions, taken as reference the smallest sum LD recorded at treatment started. Based on the time between the first day of treatment and and the date of disease progression.
Time frame: Approximately 4.6 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib in Combination With Fixed Dose of of 2.5mg of Letrozole Maximum Tolerated Dose (MTD) | Median Progressive-Free Survival (PFS) | 0 months |
| Phase l Sorafenib Dose Escalation and Letrozole 2.5mg Daily Dose Level 0:Sorafenib 400mg 1X Daily | Median Progressive-Free Survival (PFS) | 10 months |
| Phase l Sorafenib Dose Escalation and Letrozole 2.5mg po Daily Dose Level 1: Sorafenib 400mg 2X Day | Median Progressive-Free Survival (PFS) | 34.5 months |
| Phase II Arm - Sorafenib at MTD (400mg) 2x a Day + Letrozole 2.5 mg po Daily | Median Progressive-Free Survival (PFS) | 11 months |
Secondary
Overall Survival (OS) Assessed as Mean Months
From the start of treatment to the end of the study (three years) that participants are still alive. Measured by the mean number.
Time frame: Approximately 4.6 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sorafenib in Combination With Fixed Dose of of 2.5mg of Letrozole Maximum Tolerated Dose (MTD) | Overall Survival (OS) Assessed as Mean Months | 44 months |
| Phase l Sorafenib Dose Escalation and Letrozole 2.5mg Daily Dose Level 0:Sorafenib 400mg 1X Daily | Overall Survival (OS) Assessed as Mean Months | 21 months |
| Phase l Sorafenib Dose Escalation and Letrozole 2.5mg po Daily Dose Level 1: Sorafenib 400mg 2X Day | Overall Survival (OS) Assessed as Mean Months | 49.6 months |
| Phase II Arm - Sorafenib at MTD (400mg) 2x a Day + Letrozole 2.5 mg po Daily | Overall Survival (OS) Assessed as Mean Months | 24.8 months |