Phase I/II Trial of Sorafenib Plus Ixabepilone in HER2-Negative Metastatic Breast Cancer

Study Overview
=================
Brief Summary
-----------------
In this study, patients with metastatic HER2-negative breast cancer will receive treatment with ixabepilone and sorafenib until disease progression or unacceptable toxicity occurs. The Phase I portion of this study will determine the maximum tolerated doses (MTDs) of sorafenib and ixabepilone that may be used in combination for first- or second-line treatment of MBC. The MTDs identified in the Phase I portion of the study will be used in the Phase II portion which will evaluate the efficacy and safety of the combination of sorafenib and ixabepilone in patients who have received at least one prior chemotherapy treatment in either the adjuvant or neoadjuvant setting or following one prior MBC chemotherapy in MBC patients who had not received prior adjuvant or neoadjuvant breast cancer chemotherapy. This will be one of the initial trials investigating the use of this treatment combination for MBC. This trial will be conducted under the leadership of the Sarah Cannon Research Institute (SCRI) Oncology Research Consortium, a community-based, multi-center, clinical trial organization.

Official Title
-----------------
Phase I/II Trial of Sorafenib Plus Ixabepilone in HER2-Negative Metastatic Breast Cancer (MBC)

Conditions
-----------------
Metastatic Breast Cancer

Intervention / Treatment
-----------------
* Drug: Sorafenib
* Drug: Ixabepilone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years. Histologically or cytologically confirmed breast cancer diagnosis with metastatic disease. Patients without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis. 3. Measurable disease, as per RECIST criteria (Therasse et al. 2000). Measurable disease cannot be previously irradiated unless progression was documented. Measurable disease is defined as: at least one lesion that can be accurately measured in at least one dimension [longest diameter to be recorded] as >20 mm with conventional techniques, or as >10 mm with spiral computed tomography (CT) scan. Disease must be measurable, i.e., bone-only disease or evaluable-only disease is not eligible. 4. Patients with brain metastasis may participate if they: • have undergone appropriate treatment, are at least 1 month post-treatment, have no neurologic symptoms, are not on steroids, have a follow-up magnetic resonance imaging (MRI) scan that demonstrates no residual active lesions, and have no new untreated lesions. 5 The following prior therapies are allowed: No prior chemotherapy in the metastatic setting. However, patients must have received prior adjuvant or neo-adjuvant chemotherapy. Prior radiation therapy in either the metastatic or early-stage setting, as long as <25% of the bone marrow has been treated. Radiation therapy must be completed at least 14 days prior to study registration, and all radiation-related toxicities must be resolved to ≤ grade 1 before the patient is eligible for study inclusion. Any number of hormonal therapies in the neo-adjuvant, adjuvant, or metastatic setting is allowed. Patients must discontinue hormonal therapy at least 1 week prior to starting study treatment. •Prior bevacizumab administered >4 weeks before initiation of study treatment is allowed. 6 HER2-negative status. Documentation of HER2 results must be available at the time of study enrollment. HER2-negative is defined as: Immunohistochemical (IHC) 0 or IHC 1+ OR Fluorescence in situ hybridization (FISH) negative (defined by FISH ratio <2.2) OR Silver in-situ hybridization (SISH) negative (defined by SISH ratio <2.2). Patients with an IHC 2+ will need to be validated as HER2-negative by FISH. 7 An Eastern Cooperative Oncology Group (ECOG) performance status of < or = to 2. 8. Normal bone marrow function as defined by: absolute neutrophil count (ANC) >1,500/μL; platelets >100,000/μL; hemoglobin >9 g/dL. 9 Normal hepatic function as defined by: total bilirubin within normal institutional limits; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5 × the institutional upper limit of normal (ULN) for patients without liver metastasis; <5.0 × ULN for patients with liver metastasis. 10. Normal renal function as defined by creatinine <1.5 × ULN. 11. Left ventricular ejection fraction (LVEF) within institutional limits of normal. 12. International normalized ratio (INR) <1.5 or a prothrombin time/partial thromboplastin time (PT/PTT) within normal limits. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate. The INR should be measured prior to initiation of sorafenib, and for patients on warfarin, INR should be monitored at least weekly following initiation of protocol treatment, until the INR is stable and therapeutic. 13. Life expectancy of >6 months. 14. For women of childbearing potential, negative serum pregnancy test within 7 days prior to starting treatment. 15. For women of childbearing potential and men, agreement to use a method of contraception that is acceptable to their physician from time of first signing the informed consent and for the study duration. Men should use adequate birth control for at least three months after the last administration of sorafenib. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she must agree to inform her treating physician immediately. As applicable, patients must agree to discontinue breast-feeding until at least 3 weeks after their last dose of study drug. 16. Recovery to < grade 1 toxicity due to prior therapy. 17. Ability to understand and willingness to sign a written informed consent document. Exclusion Criteria More than one (>1) prior chemotherapy regimen. Treatment with chemotherapy, biologic agents, or targeted agents within the previous 4 weeks. Previous treatment with sorafenib or ixabepilone. Women who are pregnant or breastfeeding. Neuropathy (motor or sensory) greater than grade 1. Uncontrolled intercurrent illness including (but not limited to) ongoing or active infection >grade 2. Known history of human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C infection. History of other non-breast cancer malignancy treated with curative intent within the 5 years preceding study enrollment with the exception of carcinoma in situ of the cervix, non-melanoma skin cancer, or follicular thyroid cancer. Concurrent hormonal therapy, chemotherapy other than ixabepilone, or radiation treatments while on study as well as treatment with other investigational agents while on study. Cardiac disease: •Congestive heart failure (CHF) greater than New York Heart Association (NYHA) Class II (see Appendix B). Unstable angina (anginal symptoms at rest) or new onset angina (i.e., began within the last 3 months). Myocardial infarction within the past 6 months. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy. Uncontrolled hypertension (systolic blood pressure >150 mmHg or diastolic pressure >100 mmHg despite optimal medical management). Thrombolic or embolic events such as cerebrovascular accident, including transient ischemic attacks, within the past 6 months. Pulmonary hemorrhage or bleeding event ≥ grade 2 within 4 weeks of the first dose of study treatment, or any other hemorrhage or bleeding event ≥ grade 3 within 4 weeks of the first dose of study treatment. 14. Serious non-healing wound, ulcer, or bone fracture. 15. Evidence or history of bleeding diathesis or coagulopathy. 16. Major surgery, open biopsy or significant traumatic injury within 4 weeks of the first dose of study drugs or anticipation of the need for major surgical procedure. 17. Chronic use of CYP3A4 inducers and use of the following strong CYP3A4 inhibitors: ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, and voriconazole. Use of these agents should be discontinued at least 72 hours prior to initiation of study treatment. 18. Use of St. John's Wort or rifampin (rifampicin). 19. Any condition that impairs patient's ability to swallow whole pills or gastrointestinal (GI) tract disease that involves an inability to take oral medication, malabsorption syndrome, a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, or uncontrolled inflammatory GI disease (e.g., Crohn's disease or ulcerative colitis). 20. Psychiatric illness/social situations that would limit compliance with study requirements. 21. Known or suspected allergy to sorafenib, Cremophor EL (polyoxyethylated castor oil) or a drug formulated in Cremophor EL such as paclitaxel or any other agent given in the course of this trial. Exclusion Criteria:

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level 1<br>Sorafenib PO BID (200mg), Ixabepilone IV every 21 days (40mg/m^2) | Drug: Sorafenib<br>* Dose Level 1 - Sorafenib PO BID (200mg) Dose Level -1 - Sorafenib PO BID (200mg) Dose Level 1a - Sorafenib PO BID (400mg)<br>* Other names: Nexavar (Sorafenib);Drug: Ixabepilone<br>* Dose Level 1 - Ixabepilone IV every 21 days (40mg/m^2) Dose Level -1 - Ixabepilone IV every 21 days (32mg/m^2) Dose Level 1a - Ixabepilone IV every 21 days (32mg/m^2)<br>* Other names: Ixempra (Ixabepilone);|
| Experimental: Dose Level -1<br>Sorafenib PO BID (200mg), Ixabepilone IV every 21 days (32mg/m^2) | Drug: Sorafenib<br>* Dose Level 1 - Sorafenib PO BID (200mg) Dose Level -1 - Sorafenib PO BID (200mg) Dose Level 1a - Sorafenib PO BID (400mg)<br>* Other names: Nexavar (Sorafenib);Drug: Ixabepilone<br>* Dose Level 1 - Ixabepilone IV every 21 days (40mg/m^2) Dose Level -1 - Ixabepilone IV every 21 days (32mg/m^2) Dose Level 1a - Ixabepilone IV every 21 days (32mg/m^2)<br>* Other names: Ixempra (Ixabepilone);|
| Experimental: Dose Level 1a<br>Sorafenib PO BID (400mg), Ixabepilone IV every 21 days (32mg/m^2) | Drug: Sorafenib<br>* Dose Level 1 - Sorafenib PO BID (200mg) Dose Level -1 - Sorafenib PO BID (200mg) Dose Level 1a - Sorafenib PO BID (400mg)<br>* Other names: Nexavar (Sorafenib);Drug: Ixabepilone<br>* Dose Level 1 - Ixabepilone IV every 21 days (40mg/m^2) Dose Level -1 - Ixabepilone IV every 21 days (32mg/m^2) Dose Level 1a - Ixabepilone IV every 21 days (32mg/m^2)<br>* Other names: Ixempra (Ixabepilone);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | Measured from Day 1 of study drug administration to disease progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) - progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | every 9 weeks until treatment discontinuation or death on study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-month Progression-Free Survival | Measured from Day 1 of study drug administration to disease progression as defined by RECIST v1.1, or death on study. Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | every 9 weeks, up to 6 months | 
| Objective Response Rate | Objective Response will be evaluated in this study using the Response Evaluation Criteria in Solid Tumors (RECIST). | every 9 weeks until discontinuation of treatment | 
| Overall Survival (OS) | Measured from Day 1 of study drug administration to date of death due to any cause. | every 9 weeks until treatment discontinuation or death on study | 
| Number of Patients With Adverse Events as a Measure of of Safety and Tolerability | Assessments are made through analysis of reported incidence of treatment-emergent AEs and SAEs. | every 9 weeks until treatment discontinuation or unacceptable toxicity | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Metastatic Breast Cancer, Sorafenib, Nexavar, Ixabepilone, Ixempra