Dasatinib in Combination With Bevacizumab to Treat Advanced Solid Tumors

NCT01445509 | Completed Phase 1 FDA Drug

• 2 other identifiers: 09001909-C-0019
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

Background:

• Bevacizumab inhibits blood vessel growth in cancer cells by blocking a growth factor called VEGF. Dasatinib inhibits the action of proteins called tyrosine kinases, which promote and stimulate blood vessel formation and cancer growth and spread.
• Using the two drugs in combination may provide a more effective cancer treatment than either drug used alone.
• Both drugs have been approved by the Food and Drug Administration for different cancer types, but their use in combination sis experimental. Objectives: \- To determine the highest doses of the combination of dasatinib and bevacizumab that can be safely given to patients with different cancers and to find out what effects, good and bad, these drugs may have on the patient and the disease. Eligibility: \- Adult patients with an advanced solid tumor cancer that cannot be treated successfully with standard therapies. Design:
• Patients in Group 1 receive dasatinib and bevacizumab together throughout the study. The dose is increased in successive groups of three to six patients until the optimum safe dose is determined. Patients take dasatinib by mouth once a day and receive bevacizumab as an infusion through a vein once every 2 weeks in 28-day treatment cycles.
• Patients in Group 2 are randomly assigned to receive either dasatinib or bevacizumab for cycle one, and then both drugs for all subsequent cycles. The drug doses are based on the optimum doses found in Group 1 patients.
• Patients have a physical examination and blood and urine tests every 2 weeks for cycles 1 and 2, and then every 4 weeks for the duration of treatment.
• Patients have CT or MRI scans or another imaging test such as ultrasound every 8 weeks to monitor the cancer s response to treatment.
• Tumor biopsies are obtained from patients in Group 2 before treatment, 2 weeks into the first treatment cycle, and 2 weeks into the second cycle.
• Dynamic, contrast-enhanced MRI (DCE-MRI) tests are done on patients in Group 2 before treatment, 2 weeks into the first cycle and 4 weeks into the second cycle. This MRI test uses a special non-radioactive dye that shows blood flow in a certain part of the body.
• For patients who have been on the study over 2 years, the cycle may be lengthened to 6 or 8 weeks at the discretion of the investigator.

Conditions

Solid Tumors

Keywords

Angiogenesis; VEGF; SRC; Targeted Therapy; Cancer; Solid Tumor

Outcome Measures

Primary Outcomes (3)

• Determine the toxicity profile of the combination of dasatinib and bevacizumab

  A safety and toxicity profile of the combination of dasatinib and bevacizumab

  end of treatment

• Maximjum Tolerated Dose (MTD) of the combination of dasatinib and bevacizumab

  Determine the MTD of the combination of dasatinib and bevacizumab

  every 2 weeks for cycles 1 and 2; then every 4 weeks

• Estimates of biochemical changes in the src-FAK and src-PLC- and VEGF signal transduction pathways

  A describe of biochemical changes in the src-FAK and src-PLC- and VEGF signal transduction pathways in tumor and stromal cells in response to treatment for Group 2.

  at the MTD

Secondary Outcomes (1)

• Efficacy of the combination of bevacizumab and dasatinib.

  End of treatment

Study Arms (2)

Arm 1

EXPERIMENTAL

Group 1 will receive dasatinib and bevacizumab together at the start of study in a dose escalation fashion

Drug: Bevacizumab; Drug: Dasatinib

Arm 2

EXPERIMENTAL

Group 2 will be randomized as to which agent they receive for cycle one. Cycles 2 and beyond are treated using both agents.

Drug: Bevacizumab; Drug: Dasatinib

Interventions

Dasatinib DRUG

We will start dasatinib at 50 mg PO QD which is less than half the recommended Phase 2 dose as well as bevacizumab at 5 mg/kg IV every two weeks, which is half the single agent dose. If this is well-tolerated, study drugs will be escalated per schema to maximize the dose of dasatinib when given concurrently.

Arm 1; Arm 2

Bevacizumab DRUG

Once the MTD of dasatinib with bevacizumab 5 mg/kg IV every two weeks is determined, one final dose level will be accrued with that MTD dose of dasatinib with bevacizumab at 10 mg/kg IV every two weeks in order to determine if we can safely escalate bevacizumab to full dose with dasatinib concurrently.

Arm 1; Arm 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have a solid tumor malignancy that is metastatic or unresectable and for which standard curative therapies do not exist or are no longer effective.
• Patients must have histological documentation of cancer confirmed in the Laboratory of Pathology/NCI.
• Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or biological therapy for at least 4 weeks. Patients who were receiving mitomycin C, nitrosoureas, bevacizumab or carboplatin must be 6 weeks from the last administration of chemotherapy. Patients with prostate cancer must continue to receive LHRH agonist (unless orchiectomy has been performed). Patients should not be receiving complementary/alternative therapy while on study. Any patient who has undergone therapy with a monoclonal antibody must be at least 4 weeks from the last treatment.
• All patients enrolling in group 2 must have at least one lesion deemed safe to biopsy and be willing to undergo the three mandatory biopsies. This determination will be made by a member of the interventional radiology team or surgical associate investigator and an associate investigator. This requirement is not necessary for patients in group 1.
• Age \>=18 years. Because no dosing or adverse event data are currently available on the use of dasatinib in combination with bevacizumab in patients \<18 years of age, children are excluded from this study, but may be eligible for future pediatric phase 1 combination trials.
• ECOG performance status 0 or 1. ECOG performance status of 2 will be considered on a case by case basis with a focused assessment on risk of perforation.
• Life expectancy of greater than 3 months.
• Patients must have adequate organ and marrow function as defined below:
• Leukocytes \>3,000/microl
• Hemoglobin \>= 10g/dl
• Absolute neutrophil count \>1,200/microl
• Platelets \>100,000/microl
• total bilirubin \<=1.5 X institutional upper limits of normal in the absence of Gilbert's syndrome
• AST(SGOT) and ALT(SGPT) \<=2.5 X institutional upper limit of normal
• creatinine \<=1.5 mg/dL OR Creatinine clearance \>45 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal.

You may not qualify if:

• Brain metastases
• Patients who have a history of remote CNS metastases that have undergone "curative therapy" by radiation therapy, gamma knife therapy, or surgery and have remained without recurrence for a period of \>=6 months will be eligible.
• CNS imaging will not be mandated for all patients. However, if there is clinical suspicion of CNS involvement, a contrast CT or MRI of the brain will be required. Screening CNS scans should be required for certain tumor types with relatively high risk of CNS metastases, including but not limited to melanoma, renal cell carcinoma, breast, lung.
• Thrombotic or embolic events within the past 6 months such as a cerebrovascular accident (including transient ischemic attacks), pulmonary embolism, unstable angina, or myocardial infarction. Patients with recent (\< 3 month history) of venous thrombotic events will be considered on a case by case basis.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (AHA Class II or worse), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients with evidence of active infection must have completed antibiotic therapy and be without clinical or laboratory evidence of infection for seven days after treatment has concluded.
• QTc prolongation (defined as a QTc interval equal to or greater than 480 msecs) or other clinically significant EKG abnormalities
• Patients may not have any clinically significant cardiovascular disease including the following:
• Myocardial infarction or ventricular tachyarrhythmia within 6 months
• Prolonged QTc \>= 480msec (Fridericia correction)
• Ejection fraction less than institutional normal (should be done if clinically indicated and for patients with congestive heart failure on medication)
• Major conduction abnormality (unless a cardiac pacemaker is present)
• Patients who have an active pleural effusion may be considered if tapped prior to study. Patients with pleural effusions that are too small to be removed may be considered on a case by case basis. Patients with a Grade 2, asymptomatic pericardial effusion found incidentally on imaging studies may be considered on a case by case basis.
• Dasatinib is metabolized primarily by the CYP3A4 liver enzyme. Consideration should be given to using alternative medications not impacting CYP3A4 while on dasatinib therapy.
• Patients may not be receiving any prohibited potent CYP3A4 inhibitors. For these drugs, a wash-out period of \>= 7 days is required prior to starting dasatinib treatment.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Avizienyte E, Wyke AW, Jones RJ, McLean GW, Westhoff MA, Brunton VG, Frame MC. Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signalling. Nat Cell Biol. 2002 Aug;4(8):632-8. doi: 10.1038/ncb829.

  PMID: 12134161 BACKGROUND

• Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2007 Nov 20;25(33):5165-71. doi: 10.1200/JCO.2007.11.5345.

  PMID: 18024863 BACKGROUND

• Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003 May 21;289(19):2560-72. doi: 10.1001/jama.289.19.2560. Epub 2003 May 14.

  PMID: 12748199 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Neoplasms

Interventions

Bevacizumab; Dasatinib

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Study Officials

• Stanley Lipkowitz, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 30, 2011
• First Posted: October 3, 2011
• Study Start: December 29, 2008
• Primary Completion: December 18, 2017
• Study Completion: September 20, 2018
• Last Updated: May 1, 2026

Record last verified: 2026-01-13

Locations

US (1)