- To compare the progression-free survival of patients with HER2-positive stage IIIB, IIIC, or IV breast cancer treated with lapatinib ditosylate and capecitabine with vs without cixutumumab.
- To assess the safety and tolerability of these regimens in these patients.
- To compare the overall survival time, time to treatment failure, confirmed tumor response rate, and duration of response in patients treated with these regimens.
- To assess patient compliance.
- To compare overall quality of life and treatment side effects via patient-reported outcomes.
- To determine expression patterns and/or activation of IGF- and ErbB family of receptors and signaling molecules in formalin-fixed, paraffin-embedded tumor tissue and in circulating tumor cells.
- To determine changes in expression patterns and/or activation of IGF- and ErbB receptors and signaling molecules in circulating tumor cells after treatment with these regimens.
- To determine expression patterns and changes in expression patterns of IGF-I, IGF-II, insulin, growth hormone, and the IGF binding proteins in serum.
- To assess the proportion of patients whose pathologic specimens were correctly diagnosed as HER2-positive (according to 2007 ASCO CAP guidelines) metastatic breast cancer.
OUTLINE: This is a multicenter study. Patients are stratified according to hormone receptor status (estrogen receptor- or progesterone receptor-positive vs other) and number of prior chemotherapy regimens in the metastatic setting (2 or more vs 1 vs none). The first 10 patients enrolled on this study are assigned to cohort 1 (safety analysis). All other patients are assigned to cohort 2 (randomized treatment).
- Cohort 1 (safety analysis): Patients receive cixutumumab IV over 1-1½ hours on days 1, 8, and 15. Patients also receive oral capecitabine twice daily on days 1-14 and oral lapatinib ditosylate once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
- Cohort 2 (randomized treatment): Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients receive oral capecitabine twice daily on days 1-14 and oral lapatinib ditosylate once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
- Arm II: Patients receive capecitabine and lapatinib ditosylate as in arm I. Patients also receive cixutumumab IV over 1-1½ hours on days 1, 8, and 15. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Blood samples are collected at baseline and on day 8 of courses 1 and 2 for biomarker laboratory studies. Serum and circulating tumor cell biomarkers are analyzed by immunohistochemistry or immunofluorescence for changes in protein expression (total and phosphorylated). Tumor tissue samples obtained at the time of original diagnosis are analyzed by immunohistochemistry for protein biomarkers.
Patients complete quality of life questionnaires periodically.
After completion of study treatment, patients are followed every 3 months until disease progression and then every 6 months for up to 5 years.
- Histologically confirmed breast cancer, meeting one of the following criteria:
- Locally advanced disease (i.e., stage IIIB or IIIC [T4 primary tumor] disease)
- Metastatic disease
- Disease progressed after treatment with regimens that included trastuzumab (Herceptin®) in combination with an anthracycline and/or a taxane
- Agents need not have been given concurrently, nor in the same regimen
- Prior chemotherapy regimens in the neoadjuvant, adjuvant, or metastatic setting allowed
- Unlimited prior chemotherapy is allowed
- Prior treatment with trastuzumab required unless there is a contraindication for trastuzumab treatment
- HER2-positive disease, defined by any of the following:
- Validated IHC assay score of 3+ (defined as uniform, intense staining of > 30% of invasive tumor cells)
- Average HER2 gene copy number > 6
- Gene amplified (HER2:D17Z1 ratio > 2.20)
- Measurable disease according to RECIST criteria
- No evidence of active brain metastases, including leptomeningeal involvement
- CNS metastasis controlled* by prior surgery and/or radiotherapy is allowed NOTE: *To be considered controlled, there must have been no symptoms for at least 2 months or no evidence of progression prior to study entry AND corticosteroid therapy must have been discontinued
- Hormone receptor status not specified
- Menopausal status not specified
- ECOG performance status 0-2
- Life expectancy > 3 months
- WBC ≥ 3,000/mm³
- ANC ≥ 1,500/mm³
- Platelet count ≥ 75,000/mm³
- Hemoglobin > 9.0 g/dL
- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
- AST and ALT ≤ 2.5 times ULN (5 times ULN if elevations are due to liver metastases)
- Serum creatinine ≤ 1.5 times ULN
- Creatinine clearance ≥ 30 mL/min
- Fasting glucose < 120 mg/dL
- Diabetes allowed provided blood glucose level meets the above criterion
- INR ≤ 1.5 times ULN
- LVEF ≥ 50% by MUGA or ECHO
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- Willing to provide tissue and blood samples for research purposes
- Able to complete questionnaires by self or with assistance
- No other stage III or IV invasive cancer within the past 5 years
- No other malignancy requiring active treatment, except nonmelanoma skin cancer or carcinoma in situ of the cervix
- History of prior malignancy allowed provided patient is not receiving other specific treatment for their malignancy
- No current, active hepatic or biliary disease, except Gilbert syndrome's or asymptomatic gallstones
- No New York Heart Association class III or IV cardiovascular disease
- No concurrent uncontrolled illness including, but not limited to, any of the following:
- Poorly controlled diabetes
- Ongoing or active infection
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Cardiac arrhythmia
- Psychiatric illness/social situation that would preclude compliance with study requirements
- No co-morbid systemic illness or other severe concurrent disease that, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of the safety of the prescribed study regimens
- Not immunocompromised (other than that related to the use of corticosteroids), including known HIV-positivity with an AIDS-defining illness
- HIV-positive patients with a CD4 count within normal range and who have no history of an AIDS-defining illness are eligible
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- Prior hormonal therapy in the neoadjuvant, adjuvant, or metastatic setting allowed
- More than 4 weeks since prior major surgery, chemotherapy, or immunologic therapy
- More than 4 weeks since prior radiotherapy, except a single dose of palliative radiotherapy or radiotherapy to a non-target lesion
- Prior radiotherapy to a target lesion is allowed only if there has been clear progression of the lesion since completion of radiotherapy
- Recovered from prior radiotherapy
- No more than 2 prior chemotherapy regimens for metastatic disease
- No prior treatment with any therapy targeting IGF-I, IGF-II, or its receptors (either monoclonal antibody or tyrosine kinase inhibitor) including, but not limited to, any of the following:
- MK-0646 (h7C10)
- No other prior therapy targeting HER1 (EGFR) and/or HER2 (either monoclonal antibody or tyrosine kinase inhibitor) including, but not limited to, any of the following:
- Lapatinib ditosylate
- Erlotinib hydrochloride
- No concurrent agents that would contraindicate study treatment, including any of the following:
- CYP3A4 inhibitors and inducers, including grapefruit and grapefruit juice
- Warfarin, cimetidine, allopurinol, sorivudine or brivudine, ketoconazole, itraconazole, ritonavir, amprenavir, or indinavir
- No concurrent treatment in another clinical study in which investigational procedures are performed or investigational therapies are administered
- No other concurrent chemotherapeutic agents, biologic agents, or radiotherapy
- No other concurrent trastuzumab
Last updated: 06/17/2012