An Open-Label, Multicenter, Randomized Phase 2 Study Evaluating the Safety and Efficacy of Ramucirumab (IMC 1121B) Drug Product or IMC 18F1 in Combination With Capecitabine or Capecitabine Monotherapy, in Unresectable, Locally Advanced or Metastatic Breast Cancer Patients Previously Treated With Anthracycline and Taxane Therapy
An open-label, multicenter, randomized, Phase 2 trial in which patients with unresectable, locally advanced or metastatic breast cancer who have been previously treated with anthracycline and taxane therapy receive ramucirumab DP or IMC-18F1 administered on an every-21-day cycle (ramucirumab DP on Day 1; IMC-18F1 on Days 1 and 8) in combination with oral capecitabine therapy (given on a 21-day cycle; capecitabine is administered twice a day on Days l-14 of each cycle). Approximately 150 patients will be randomized in a 1:1:1 ratio to either ramucirumab DP or IMC-18F1 in combination with capecitabine (Arm A and Arm B, respectively) or capecitabine monotherapy (Arm C). Randomization will be stratified by triple-negative receptor status (estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor-2 [HER2/neu]-negative) (yes/no) and receipt of prior antiangiogenic therapy (yes/no). Treatment with the study medication(s) will continue until disease progression, the development of unacceptable toxicity, noncompliance or withdrawal of consent by the patient, or investigator decision. Capecitabine dose reductions in the setting of significant myelosuppression, hand-and[?] foot syndrome, or diarrhea will be required.
At the discretion of the investigator, patients in Arm C will be eligible to receive either ramucirumab DP or IMC-18F1 in combination with capecitabine, after radiographic disease progression while on capecitabine (provided that capecitabine has been well tolerated during the conduct of the study). The investigator will decide which investigational product will be given. For all patients in Arm C who cross over to combination treatment (ie, ramucirumab DP or IMC-18F1 in combination with capecitabine), blood collection for immunogenicity analysis is required.
1. The patient has histologically or cytologically confirmed invasive breast cancer which at the time of study entry is either Stage III (locally advanced) disease not amenable to curative therapy or stage IV disease. Histological confirmation of recurrent/metastatic disease is not required if clinical and/or radiographic evidence of advanced or recurrent disease is available.
2. The patient has measurable or nonmeasurable disease (based on Response Evaluation Criteria in Solid Tumors, Version 1.1 [RECIST v 1.1] guidance).
3. The patient has received prior anthracycline therapy and has experienced 1 of the
a. Disease progression within 6 months of the last dose of anthracycline therapy in the
metastatic setting, or
b. Disease progression after receiving an anthracycline in the adjuvant or neoadjuvant
c. Discontinuation of anthracycline therapy in any setting due to intolerable toxicity
provided that there has been evidence of disease progression.
4. The patient has received prior taxane therapy and has experienced 1 of the following:
a. Disease progression within 6 months of the last dose of taxane therapy in the
metastatic setting, or
b. Disease progression within 12 months of the last dose of taxane therapy in the
adjuvant or neoadjuvant setting, or
c. Discontinuation of taxane therapy in any setting due to intolerable toxicity provided
that there has been evidence of disease progression
5. The patient has experienced radiaographic disease progression within 6 months after the last dose of the most recent systemic tratment for locally advansed and unresectable or metastatic breast cancer . Patients who experienced radiographic disease progression within 12 months after the last dose of neoadjuvant/adjuvant anthracycline and taxane therapy may enroll without having received additional therpy for locally advanced and unresectable or metastitaic breast cancer.
6. The patient with HER2-positive disease must have progressed on or following
7. The patient with hormone receptor-positive disease must have progressed on or following hormone therapy.
8. The patient must have received <= 3 prior chemotherapy regimens in any setting (a
regimen is defined as any agent[s] that has been administered for more than 1 cycle;
sequential neoadjuvant/adjuvant treatment is considered 1 regimen).
9. The patient completed any prior radiotherapy >= 4 weeks prior to randomization.
10. The patient has completed any prior hormonal therapy >= 2 weeks prior to randomization.
11. The Patient has completed any prior cytotoxic chemotherapy >= 14 days prior to randomization if the regimen had been administered weekly, and >= 21 days prior to randomization if the regimen had been administered either every 2 or every 3 weeks
12. The patient has AEs that have resolved to Grade <= 1 by the National Cancer Institute
Common Terminology Criteria for Adverse Events, Version 4.02 (NCI-CTCAE v 4.02)
from all clinically significant toxic effects of prior chemotherapy, surgery, radiotherapy,
or hormonal therapy with the exception of peripheral neuropathy which must have
resolved to Grade <= 2 and except where otherwise noted in the eligibility criteria.
13 The patient has an Eastern Cooperative Oncology Group (ECOG) performance status of
14. The patient has adequate hematologic function as defined by absolute neutrophil count
(ANC) >= 1500 cells/[MICRO-SYMBOL]L, hemoglobin >= 9.5 g/dL, and platelets >= 100,000 cells/[MICRO-SYMBOL]L.
15. The patient has adequate coagulation function as defined by International Normalized
Ratio (INR) <= 1.5 and a partial thromboplastin time (PTT) <= 1.5 x upper limit of normal
(ULN) if not receiving anticoagulation therapy. Patients on full-dose anticoagulation
must be on a stable dose of low-molecular weight heparin and must have no active
bleeding (defined as within 14 days prior to randomization) or pathological condition that
carries a high risk of bleeding (eg, tumor involving major vessels or known varices).
16. The patient has adequate hepatic function as defined by total bilirubin <= 1.25 x ULN, and
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 3.0 x ULN, or
<= 5.0 x ULN if the transaminase elevation is due to liver metastases.
17. The patient has adequate renal function defined by creatinine clearance >= 60 mL/min;
either measured by a 24-hour urine collection or calculated by the Cockcroft-Gault
18. The patient[Single Quote]s urinary protein is <= 1+ on dipstick or routine urinalysis; if urine protein
>= 2+, a 24-hour urine collection must demonstrate < 1000 mg of protein in 24 hours to
allow participation in the study.
19. The patient agrees to use adequate contraception during the study period and for
12 weeks after the last dose of study medication.
20. The patient is amenable to compliance with protocol schedules and testing.
21. The patient is able to provide signed informed consent.
22. The patient is >= 18 years of age.
The patient does not have
* cirrhosis at a level of Child-Pugh B (or worse) or
* cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites resulting from cirrhosis and requiring ongoing treatment with diuretics and/or paracentesis.