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.

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.

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

Exclusion Criteria

• Any investigational agent within 4 weeks prior to initiating study treatment

• Anticancer therapy within 2 weeks prior to initiating study treatment

• Plans for concurrent anticancer therapy except as permitted in Section 6.7.11

• Known or presumed intolerance of pemetrexed or sorafenib

• Known or suspected malabsorption condition or obstruction

• Brain metastases meeting either of the following exclusion criteria:

• Untreated brain metastases

• After completion of brain-directed therapy, the patient has not been able to tolerate discontinuation of steroids or a decrease in steroid dose

• Leptomeningeal metastasis

• Any documented history of clinically identifiable thrombotic, embolic, venous, or arterial events such as cerebrovascular accident, transient ischemic attack, deep vein thrombosis, or pulmonary embolism within 6 months prior to initiating study treatment (Note: Patients with an asymptomatic catheter-related thrombus or a tumor-associated thrombus of locally-involved vessels or with incidental asymptomatic filling defects identified on imaging are not excluded.)

• Contraindication to antiangiogenic agents, including:

• Serious non-healing wound, non-healing ulcer, or bone fracture

• Major surgical procedure or significant traumatic injury within 4 weeks prior to initiating study treatment

• Pulmonary hemorrhage/bleeding event ≥ grade 2 (CTCAE v4.0) within 12 weeks prior to initiating study treatment

• Any other hemorrhage/bleeding event ≥ grade 3 (CTCAE v4.0) within 12 weeks prior to initiating study treatment

• Systolic blood pressure (BP) > 160 mmHg or diastolic BP > 100 mmHg despite optimal medical management

• QT interval, corrected (QTc) > 480 ms (≥ grade 2) on a 12-lead electrocardiogram (ECG)

• If baseline QTc on screening ECG is ≥ grade 2:

• Check potassium and magnesium serum levels

• Correct any identified hypokalemia and/or hypomagnesemia and repeat ECG to confirm exclusion of patient due to QTc

• For patients with heart rate < 60 bpm or > 100 bpm, manual read of the QT interval by a cardiologist is required, with Fridericia correction applied to determine QT interval with correction using Fridericia's formula (QTcF) which must be used to determine eligibility (Note: If heart rate is 60-100 bpm, manual read of the QT interval and correction to QTcF is not required).

• Active or clinically significant cardiac disease including any of the following:

• Unstable angina (eg, anginal symptoms at rest) or onset of angina within 3 months prior to initiating study treatment

• Myocardial infarction within 6 months prior to initiating study treatment

• Ventricular arrhythmias requiring anti-arrhythmic therapy other than beta blockers

• New York Heart Association (NYHA) class III or IV congestive heart failure

• Serious (ie, ≥ grade 3) uncontrolled infection

• Uncontrolled effusion

• Known human immunodeficiency virus (HIV) seropositivity (Note: HIV testing is not required)

• Chronic or active hepatitis B or C infection requiring treatment with antiviral therapy

• Seizure disorder requiring enzyme-inducing anti-epileptic drugs (EIAEDs) (Note: If the seizure disorder can be managed with agents that are not EIAEDs (eg, levetiracetam or valproate), the patient should not be excluded).

• Planned ongoing treatment with other drugs thought to potentially have adverse interactions with either of the study drugs; if such drugs have been used, patients must have discontinued these agents at least 2 weeks (or as noted below) prior to initiating study treatment. Examples include:

• STRONG CYP3A4 inducers

  *Note: Examples of clinical inducers of cytochrome p450 (CYP) isozymes and classification of strong, moderate, and weak interactions are available through the FDA website (Table 3-3 of website:): http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm

• Immunosuppressants (eg, tacrolimus, leflunomide, tofacitinib, roflumilast, pimecrolimus)

• NSAIDs (Note: NSAIDs must be discontinued within 5 days prior to initiating study treatment)

• Pregnancy or breastfeeding

• Previous malignancy with the following exceptions: adequately treated basal cell carcinoma or squamous cell carcinoma of the skin; any in situ malignancy; adequately treated Stage 1 and Stage 2 cancer from which the patient is currently in remission; any other cancer from which the patient has been disease-free for 3 years

• Medical, psychological, or social condition that, in the opinion of the investigator, may increase the patient's risk or limit the patient's adherence with study requirements