Breast Cancer, Metastatic Breast Cancer, Recurrent Breast Cancer
Conditions
Keywords
ER-negative, PgR-negative, Human epidermal growth factor receptor 2 (HER2-negative), Triple Negative Breast Cancer, HER2-negative
Brief summary
This phase 2 clinical trial will evaluate the efficacy of the combination of pemetrexed and sorafenib in patients with recurrent or metastatic Triple Negative Breast Cancer (TNBC). Candidate pharmacodynamic and predictive biomarkers will also be evaluated.
Detailed description
This study is a single-arm, open-label, phase 2 study of a regimen of dose-dense pemetrexed and sorafenib to determine the objective response rate in patients with recurrent or metastatic TNBC. Eligible patients will be those who have had disease progression during or after treatment for recurrent or metastatic disease with one previous cytotoxic chemotherapy regimen. Additionally, patients with disease progression or recurrence during or within 6 months of completion of adjuvant or neoadjuvant therapy are also eligible. Correlative studies will be conducted using blood samples and archived tumor samples. Simon's two-stage design will be utilized in this study. In the first stage, if there are ≤ 3 patients of the first 18 efficacy-evaluable patients who have a partial or complete response, then the trial will end for futility. If ≥ 4 patients have a partial or complete response, patient accrual will continue in the second stage to add 10 more efficacy-evaluable patients. The total sample size for the Simon's two-stage design is 35 patients. Based on enrollment of 2-3 patients per month, the expected enrollment period will be about 12-18 months. Patients were enrolled in 2 sequential groups, referred to as arms for the purposes of reporting results by group. The initial group of patients were enrolled in what is referred to here as Arm A. After a study amendment patients were enrolled in what is referred to here as Arm B.
Interventions
DRUGExperimental Arm A: Pemetrexed
Treatment schedule is administered on day 1 of each 14-day cycle by Intravenous infusion over 10 minutes with a dose of 500 mg/m2. If necessary, the duration of the pemetrexed infusion may be extended to a maximum of 20 minutes.
DRUGExperimental Arm A: Sorafenib
Treatment schedule is administered twice daily by mouth on an empty stomach on days 1-5 of each 14-day cycle with a dose of 400 mg.
DRUGExperimental Arm B: Pemetrexed
Treatment schedule is administered on day 1 of each 21-day cycle by Intravenous infusion over 10 minutes with a dose of 375 mg/m2. If necessary, the duration of the pemetrexed infusion may be extended to a maximum of 20 minutes.
DRUGExperimental Arm B: Sorafenib
Treatment schedule is administered twice daily by mouth on an empty stomach on days 1-5 of each 21-day cycle with a dose of 200 mg.
Sponsors
Eli Lilly and Company
Bayer
Virginia Commonwealth University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Unresectable adenocarcinoma of the breast involving chest wall, regional nodes, or distant site * Breast cancer determined to be estrogen receptor (ER)-negative and progesterone receptor (PgR)-negative defined for this study as \< 10% tumor staining by immunohistochemistry (IHC) (Note: Eligibility should be based on the ER and PgR status reported at the time of the most recent biopsy or resection). * Breast cancer determined to be HER2-negative per current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) HER2 Guidelines (Note: Eligibility should be based on the HER2 status reported at the time of the most recent biopsy or resection). * At least one prior regimen for treatment of recurrent or metastatic disease (Note: Prior regimen for recurrent or metastatic disease is not required if the patient had disease progression or recurrence during or within the first 6 months following completion of adjuvant or neoadjuvant chemotherapy.) * Measurable disease per RECIST v1.1 * Age ≥ 18 years * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Ability to swallow oral medications * Adequate bone marrow function as defined below: * Absolute neutrophil count (ANC) ≥ 1,200/mm3 * Platelet count ≥ 100,000/mm3 * Hemoglobin ≥ 9.0 g/dL, which must be stable in the opinion of the investigator without a history of transfusion dependence. * Adequate renal function as defined below: * Calculated creatinine clearance ≥ 45 mL/min * Adequate hepatic function as defined below: * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for the laboratory * Aspartate aminotransferase (AST) ≤ 3 x ULN for the laboratory, except in the presence of known hepatic metastasis, wherein the AST may be ≤ 5 x ULN * Alanine aminotransferase (ALT) ≤ 3 x ULN for the laboratory, except in the presence of known hepatic metastasis, wherein the ALT may be ≤ 5 x ULN * Serum B12 and folate levels ≥ lower limit of normal (LLN) for the laboratory (Note: Patients may begin B12 and folic acid supplementation and be reconsidered for participation in the study when levels are ≥ LLN for the laboratory). * Ability to take folic acid, vitamin B12, and dexamethasone according to the protocol instructions * Ability to interrupt chronic non-steroidal anti-inflammatory drugs (NSAIDs) beginning 2 days before (5 days before for long-acting NSAIDs) and continuing for 2 days following administration of each pemetrexed dose * Toxicities from previous cancer therapies resolved to ≤ grade 1 unless specified otherwise in the inclusion or
Exclusion criteria
* Women who are not postmenopausal or have not undergone hysterectomy must have a documented negative serum pregnancy test within 7 days prior to initiating study treatment. Note: Postmenopausal is defined as one or more of the following: * Age ≥ 60 years * Age \< 60 years and amenorrheic for at least 1 year with follicle-stimulating hormone (FSH) and plasma estradiol levels in the postmenopausal range * Bilateral oophorectomy * A woman of child-bearing potential (WCBP) and a male patient with partner who is a WCBP must agree to use a medically accepted method for preventing pregnancy for the duration of study treatment and for 2 months following completion of study treatment. * Ability to understand and willingness to sign the consent form written in English
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Patients With Objective Response Either Partial Response (PR) or Complete Response(CR). | 2 years 3 months | The primary endpoint is the percentage of patients with HER2-negative metastatic breast cancer achieving an objective response (either PR or CR). Overall Response = CR+PR, based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Duration of Progression-free Survival (PFS). | 2 years 3 months | Progression-free survival (PFS) defined as the time (in days) from initiation of study treatment until documented disease progression or death, whichever occurs first. |
| The 2-year Survival Rate After Initial Study Treatment. | 2 years 3 months | The proportion of patients who are alive at 2 years following initiation of study treatment. |
| Number of Participants at Risk and Affected by Adverse Events (AEs) | 2 years 3 months | To further characterize the safety and side effect profile of the combination. All participants' AEs will be listed and summary descriptive statistics will be calculated.The Adverse events (AEs) are reported using criteria in the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| A: Pemetrexed + Sorafenib Pemetrexed 500 mg/m2 IV Day 1 + Sorafenib 400mg PO twice each day on Days 1-5 of each 14-day cycle
Experimental Arm A: Pemetrexed: Treatment schedule is administered on day 1 of each 14-day cycle by Intravenous infusion over 10 minutes with a dose of 500 mg/m2. If necessary, the duration of the pemetrexed infusion may be extended to a maximum of 20 minutes.
Experimental Arm A: Sorafenib: Treatment schedule is administered twice daily by mouth on an empty stomach on days 1-5 of each 14-day cycle with a dose of 400 mg. | 9 |
| B: Pemetrexed + Sorafenib Pemetrexed 375mg/m2 intravenously (IV) Day 1 + Sorafenib 200mg by mouth twice daily on days 1-5, every 21 days of each cycle.
Experimental Arm B: Pemetrexed: Treatment schedule is administered on day 1 of each 21-day cycle by Intravenous infusion over 10 minutes with a dose of 375 mg/m2. If necessary, the duration of the pemetrexed infusion may be extended to a maximum of 20 minutes.
Experimental Arm B: Sorafenib: Treatment schedule is administered twice daily by mouth on an empty stomach on days 1-5 of each 21-day cycle with a dose of 200 mg. | 4 |
| Total | 13 |
Baseline characteristics
| Characteristic | A: Pemetrexed + Sorafenib | Total | B: Pemetrexed + Sorafenib |
|---|---|---|---|
| Age, Continuous | 54.89 Years | 55.46 Years | 56.75 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 13 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 9 Participants | 3 Participants |
| Region of Enrollment United States | 9 participants | 13 participants | 4 participants |
| Sex: Female, Male Female | 9 Participants | 13 Participants | 4 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 | 1 / 9 | 0 / 4 |
| other Total, other adverse events | 9 / 9 | 4 / 4 |
| serious Total, serious adverse events | 5 / 9 | 3 / 4 |
Outcome results
Primary
The Percentage of Patients With Objective Response Either Partial Response (PR) or Complete Response(CR).
The primary endpoint is the percentage of patients with HER2-negative metastatic breast cancer achieving an objective response (either PR or CR). Overall Response = CR+PR, based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1).
Time frame: 2 years 3 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| A: Pemetrexed + Sorafenib | The Percentage of Patients With Objective Response Either Partial Response (PR) or Complete Response(CR). | Partial Response | 2 Participants |
| A: Pemetrexed + Sorafenib | The Percentage of Patients With Objective Response Either Partial Response (PR) or Complete Response(CR). | Stable Disease | 1 Participants |
| A: Pemetrexed + Sorafenib | The Percentage of Patients With Objective Response Either Partial Response (PR) or Complete Response(CR). | Progressive Disease | 5 Participants |
| A: Pemetrexed + Sorafenib | The Percentage of Patients With Objective Response Either Partial Response (PR) or Complete Response(CR). | Not Evaluable for Response | 1 Participants |
| B: Pemetrexed + Sorafenib | The Percentage of Patients With Objective Response Either Partial Response (PR) or Complete Response(CR). | Not Evaluable for Response | 2 Participants |
| B: Pemetrexed + Sorafenib | The Percentage of Patients With Objective Response Either Partial Response (PR) or Complete Response(CR). | Partial Response | 1 Participants |
| B: Pemetrexed + Sorafenib | The Percentage of Patients With Objective Response Either Partial Response (PR) or Complete Response(CR). | Progressive Disease | 0 Participants |
| B: Pemetrexed + Sorafenib | The Percentage of Patients With Objective Response Either Partial Response (PR) or Complete Response(CR). | Stable Disease | 1 Participants |
Secondary
Number of Participants at Risk and Affected by Adverse Events (AEs)
To further characterize the safety and side effect profile of the combination. All participants' AEs will be listed and summary descriptive statistics will be calculated.The Adverse events (AEs) are reported using criteria in the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0).
Time frame: 2 years 3 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| A: Pemetrexed + Sorafenib | Number of Participants at Risk and Affected by Adverse Events (AEs) | At Risk | 9 Participants |
| A: Pemetrexed + Sorafenib | Number of Participants at Risk and Affected by Adverse Events (AEs) | Affected | 9 Participants |
| B: Pemetrexed + Sorafenib | Number of Participants at Risk and Affected by Adverse Events (AEs) | At Risk | 4 Participants |
| B: Pemetrexed + Sorafenib | Number of Participants at Risk and Affected by Adverse Events (AEs) | Affected | 4 Participants |
Secondary
The 2-year Survival Rate After Initial Study Treatment.
The proportion of patients who are alive at 2 years following initiation of study treatment.
Time frame: 2 years 3 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| A: Pemetrexed + Sorafenib | The 2-year Survival Rate After Initial Study Treatment. | 1 Participants |
| B: Pemetrexed + Sorafenib | The 2-year Survival Rate After Initial Study Treatment. | 0 Participants |
Secondary
The Duration of Progression-free Survival (PFS).
Progression-free survival (PFS) defined as the time (in days) from initiation of study treatment until documented disease progression or death, whichever occurs first.
Time frame: 2 years 3 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| A: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant C | 28 Days |
| A: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant H | 49 Days |
| A: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant E | 259 Days |
| A: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant I | 56 Days |
| A: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant B | 60 Days |
| A: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant J | NA Days |
| A: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant F | 59 Days |
| A: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant K | NA Days |
| A: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant D | 120 Days |
| A: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant L | NA Days |
| A: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant G | 64 Days |
| A: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant M | NA Days |
| A: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant A | 141 Days |
| B: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant M | 19 Days |
| B: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant A | NA Days |
| B: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant B | NA Days |
| B: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant C | NA Days |
| B: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant D | NA Days |
| B: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant E | NA Days |
| B: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant F | NA Days |
| B: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant G | NA Days |
| B: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant H | NA Days |
| B: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant I | NA Days |
| B: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant J | 22 Days |
| B: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant K | 100 Days |
| B: Pemetrexed + Sorafenib | The Duration of Progression-free Survival (PFS). | Participant L | 160 Days |