A Phase 1 Safety Evaluation of Oral Enzastaurin in Combination With Bevacizumab in Patients With Advanced/Metastatic Cancer
A Phase 1 Safety Evaluation of Oral Enzastaurin in Combination With Bevacizumab in Patients With Advanced/Metastatic Cancer
RATIONALE: Enzastaurin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Enzastaurin and bevacizumab may also stop the growth of cancer cells by blocking blood flow to the cancer. Giving enzastaurin together with bevacizumab may kill more cancer cells.
PURPOSE: This phase I trial is studying the side effects and best dose of enzastaurin and bevacizumab in treating patients with locally advanced or metastatic cancer.
OBJECTIVES:
OUTLINE: This is a dose-escalation study of enzastaurin hydrochloride and bevacizumab.
Patients receive oral enzastaurin hydrochloride once, twice, or three times daily on days 1-21 or days 1-28 and bevacizumab IV over 30-90 minutes on day 1 or days 1 and 15. Courses repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity.
Blood samples are collected periodically during study for pharmacokinetic evaluation. Samples are also analyzed for biomarker (GSK3β) by ELISA.
After completion of study treatment, patients are followed for 30 days.
National Cancer Institute (NCI) registered this trial with Eli Lilly as sponsor. NCI did not update the record. In June 2012, NCI transferred the trial to Lilly's clinicaltrials.gov account and Lilly updated the record with the trial status and trial completion dates. This trial is not an applicable trial under Food and Drug Administration Amendments Act of 2007 (FDAAA).
DISEASE CHARACTERISTICS:
PATIENT CHARACTERISTICS:
ECOG performance status 0-2
Life expectancy ≥ 12 weeks
WBC count ≥ 3.0 × 10^9/L
Absolute neutrophil count ≥ 1.5 × 10^9/L
Platelet count ≥ 100 × 10^9/L
Hemoglobin ≥ 10 g/dL (6.21 mmol/L)
Bilirubin ≤ 2 times upper limit of normal (ULN)
Alkaline phosphatase ≤ 3 times ULN (5 times ULN if liver metastases are present)
AST and ALT ≤ 3 times ULN (5 times ULN if liver metastases are present)
Serum creatinine < 1.5 times ULN
No proteinuria at baseline, as demonstrated by either of the following:
No second primary malignancy that could affect compliance with the study or interpretation of the study results
No concurrent serious systemic disorder (e.g., active infection, including HIV) that, in the opinion of the investigator, would compromise the patient's ability to adhere to the study
No known hypersensitivity to bevacizumab or enzastaurin hydrochloride, or to a component of either drug
No prior bevacizumab-related toxicity requiring discontinuation, such as a thromboembolic event, hemorrhage, or serious hypertension
No clinically significant cardiac disease, in the opinion of the investigator, including any of the following:
No evidence of bleeding diathesis or coagulopathy
No nonhealing cutaneous wound or gastrointestinal ulcer
No history of or risk for abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
No hemoptysis requiring medical attention within the past 3 months
No known history of cerebrovascular accidents or transient ischemic attacks
No clinically significant vascular or peripheral vascular disease
No hypertension not controlled by medical management
No history of hypertensive crisis or hypertensive encephalopathy
No significant traumatic injury within the past 28 days
Able to comply with study or study procedures
Able to swallow tablets
Exhibits compliance and geographic proximity that allow adequate follow-up
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for 3 months after completion of study treatment
PRIOR CONCURRENT THERAPY:
Recovered from prior therapy
No prior participation in this study or any other study involving enzastaurin hydrochloride
At least 4 weeks since prior chemotherapy (6 weeks for mitomycin C or nitrosoureas)
At least 4 weeks since prior radiotherapy, anticancer hormone therapy, or other investigational therapy
At least 6 weeks since prior bicalutamide
At least 4 weeks since prior flutamide or nilutamide
More than 10 days since prior and no concurrent aspirin > 325 mg/day
More than 28 days since prior major surgery or open biopsy
More than 7 days since prior core biopsy or other minor surgical procedure, excluding placement of a vascular access device
No concurrent carbamazepine, phenobarbital, or phenytoin
No concurrent systemic anticoagulation
No concurrent chronic use of other nonsteroidal anti-inflammatory drugs
No concurrent routine use of colony-stimulating factors
No concurrent major surgery
No other concurrent chemotherapy, radiotherapy, immunotherapy, or experimental medications
No other concurrent antitumor therapy