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A Phase I Study of Dasatinib in Combination With Bevacizumab in Advanced Solid Tumors


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Solid Tumors

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Trial Information

A Phase I Study of Dasatinib in Combination With Bevacizumab in Advanced Solid Tumors


Background:

Dasatinib is an inhibitor of SRC family kinases, BCR-ABL, c-KIT, EPHA2 and PDGF beta
receptor.

Bevacizumab is a humanized IgG1 monoclonal antibody (MAb) that binds all biologically active
isoforms of human vascular endothelial growth factor (VEGF, or VEGF-A) with high affinity
(k(d) equal to 1.1nM).

This Phase I trial is open to patients with all solid tumors.

Objectives:

Determine the safety and toxicity of the combination of dasatinib and bevacizumab.

Determine biochemical changes in the src-FAK and src-PLC-. and VEGF signal transduction
pathways in tumor and stromal cells in response to treatment at the MTD, in a pilot fashion,
if those changes are statistically significant.

Eligibility:

Adults with histologically documented solid tumor malignancy that is metastatic or
unresectable and for which standard curative therapies do not exist or are no longer
effective.

Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or biological
therapy for at least 4 weeks.

All patients enrolling in Group 2 must have at least one lesion amenable to biopsy.

ECOG performance status 0 or 1 and adequate organ and marrow function.

Design:

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

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

Tumor biopsies will be obtained from patients in Group 2 before treatment, two weeks into
mono-therapy, and two weeks into combinatorial therapy.

DCE-MRI studies will be obtained on patients in Group 2 before treatment, two weeks into
monotherapy, four weeks into monotherapy, and two weeks into combinatorial therapy.

Patients will be evaluated for toxicity in clinic every 2 weeks for Cycles 1 and 2, and then
every 4 weeks.

Patients will be evaluated for response every 8 weeks using the RECIST criteria.

Approximately 48 patients will be needed to achieve the objectives of the trial.

Inclusion Criteria


- INCLUSION CRITERIA:

3.1.1 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.

3.1.1.1 Patients must have histological documentation of cancer confirmed in the
Laboratory of Pathology/NCI.

3.1.2 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.

3.1.3 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.

3.1.4 Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of dasatinib in combination with bevacizumab in patients
less than 18 years of age, children are excluded from this study, but may be eligible for
future pediatric phase 1 combination trials.

3.1.5 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.

3.1.6 Life expectancy of greater than 3 months.

3.1.7 Patients must have adequate organ and marrow function as defined below:

Table 1: Inclusion criteria laboratory values

Leukocytes greater than 3,000/microl

Hemoglobin greater than or equal to 10g/dl

Absolute neutrophil count greater than 1,200/microl

Platelets greater than 100,000/microl

Total bilirubin less than or equal to 1.5 times institutional upper limits of normal in
the absence of Gilbert's syndrome

AST(SGOT) and ALT(SGPT) less than or equal to 2.5 times institutional upper limit of
normal

creatinine less than or equal to 1.5 mg/dL

OR

Creatinine clearance greater than 45 mL/min/1.73 m(2) for patients with creatinine levels
above institutional normal.

Activated partial thromboplastin time (PTT) less than or equal 1.25 times institutional
upper limits of normal in the absence of lupus anticoagulant

Prothrombin Time (PT) OR INR less than or equal to 1.25 times institutional upper limits
of normal

Spot Urine Protein Creatinine Ratio less than or equal to 0.5; If result is 0.5 or more, a
24-hour urine for protein excretion must be less than or equal to 1000mg

3.1.8 Patients must have recovered from toxicity related to prior therapy to at least CTEP
grade 1 (defined by CTCAE 3.0). Chronic stable grade 2 peripheral neuropathy secondary to
neurotoxicity from prior therapies may be considered on a case by case basis by the
Principal Investigator.

3.1.9 As the effect of dasatinib and bevacizumab in combination on the developing human
fetus is not known, women of child-bearing potential and men must agree to use adequate
contraception (abstinence; hormonal or barrier method of birth control) for the study and
at least 3 months after completion. Pregnant women will not be eligible for study.

3.1.10 Ability to understand and the willingness to sign a written informed consent
document.

3.1.11 Evaluable disease or measurable disease as defined in section 11.1 of greater than
or equal to 1 cm.

3.1.12 Patients may not have any clinically significant cardiovascular disease including
the following:

- myocardial infarction or ventricular tachyarrhythmia within 6 months

- prolonged QTc greater than or equal to 480 msec (Fridericia correction)

- ejection fraction less than institutional normal

- major conduction abnormality (unless a cardiac pacemaker is present)

Patients with any cardiopulmonary symptoms of unknown cause (e.g. shortness of breath,
chest pain, etc.) should be evaluated by a baseline echocardiogram with or without stress
test as needed in addition to electrocardiogram (EKG) to rule out QTc prolongation. The
patient may be referred to a cardiologist at the discretion of the principal investigator.
Patients with underlying cardiopulmonary dysfunction should be excluded from the

study.

EXCLUSION CRITERIA:

3.2.1 Brain metastases

3.2.1.1 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 greater than or equal 6 months will be eligible.

3.2.1.2 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.

3.2.2 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 (less than 3 month history) of venous
thrombotic events will be considered on a case by case basis.

3.2.3 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.

3.2.3.1 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.

3.2.3.2 QTc prolongation (defined as a QTc interval equal to or greater than 480 msecs) or
other clinically significant EKG abnormalities

3.2.3.3 Patients may not have any clinically significant cardiovascular disease including
the following:

- Myocardial infarction or ventricular tachyarrhythmia within 6 months

- Prolonged QTc greater than or equal to 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)

3.2.3.4 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.

3.2.3.5 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 greater than or equal to 7 days is required prior to starting dasatinib
treatment.

Category I drugs that are generally accepted to have a risk of causing Torsades de
Pointes. A wash-out period of greater than or equal to 7 days is required for the
following drugs prior to starting dasatinib treatment:

- Quinidine, procainamide, disopyramide

- Amiodarone, sotalol, ibutilide, dofetilide

- Erythromycin, clarithromycin

- Chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide

- Cisapride, bepridil, droperidol, methadone, arsenic, chlorquine, domperidone,
halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine

3.2.4 HIV-positive patients receiving combination anti-retroviral therapy are excluded
from the study because of possible pharmacokinetic interactions with dasatinib,
bevacizumab, and/or the combination. Appropriate studies will be undertaken in patients
receiving combination antiretroviral therapy when indicated.

3.2.5 Patients who have been treated with dasatinib (any other Src-family kinase
inhibitors) will be excluded

3.2.6 Hypertension defined as systolic blood pressure greater than 140 mmHg or diastolic
pressure greater than 90 mmHg despite optimal medical management.

3.2.7 Proteinuria defined as a spot urine analysis for protein creatinine ratio (UPC) of
greater than 1.0

3.2.8 Therapeutic anticoagulation with coumadin, heparins, or heparinoids. Prophylaxis
doses are permitted.

3.2.9 Serious non-healing wounds (including wounds healing by secondary intention), acute
or non-healing ulcers, or bone fractures within 3 months of fracture. History of abdominal
fistula, major surgery, bowel obstruction, or intra-abdominal abscesses within 28 days
will be excluded. Any patient with history of gastrointestinal perforation will be
excluded due to possibility of increased risk of perforation with bevacizumab.

3.2.10 Evidence of bleeding diathesis

3.2.11 Impairment of swallowing that would preclude administration of dasatinib.

3.2.12 History of hemoptysis or surgery within the past 28 days.

3.2.13 Patients with squamous cell carcinoma of the lungs will be excluded due to risk of
fatal pulmonary hemorrhage. If a patient has a history of any type primary lung cancer and
hemoptysis, they will be excluded.

3.2.14 History of high grade varices.

3.2.15 Use of herbal supplements are not permitted within 7 days of trial commencement and
on study. Vitamin supplement (above a typical single multi-vitamin) usage is discouraged
unless clearly indicated by an existing medical condition. An Associate or Principal
Investigator will have the discretion regarding which vitamin supplements are permitted.

3.2.16 Known hypersensitivity to Chinese hamster ovary cell products or recombinant human
antibodies.

3.2.17 Use of any other concurrent investigational agents for treatment or anticancer
agents including hormonal therapy, except in the case of prostate cancer patients who are
being treated with LHRH agonist at the time of trial entry

3.2.18 Pregnant women are excluded from this study because bevacizumab is an antibody to
VEGF with the potential for teratogenic or abortifacient effects. Dasatinib is a potential
teratogen. Because there is an unknown but potential risk for adverse events in nursing
infants secondary to treatment of the mother bevacizumab or dasatinib, breastfeeding
should be discontinued if the mother is treated on this study.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Determine the safety and toxicity of the combination of dasatinib and bevacizumab in advanced solid tumors that have progressed on standard therapy.

Principal Investigator

Elise C Kohn, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

090019

NCT ID:

NCT01445509

Start Date:

October 2008

Completion Date:

Related Keywords:

  • Solid Tumors
  • Angiogenesis
  • VEGF
  • SRC
  • Targeted Therapy
  • Cancer
  • Solid Tumor
  • Neoplasms

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892