Phase I/II Trial of Sorafenib Plus Ixabepilone in HER2-Negative Metastatic Breast Cancer (MBC)
Phase I/II Trial of Sorafenib Plus Ixabepilone in HER2-Negative Metastatic Breast Cancer (MBC)
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.
Inclusion Criteria:
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,
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.
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.
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:
FISH ratio <2.2) OR
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: