Know Cancer

forgot password

A Phase I/Biomarker Study of Bevacizumab in Combination With CNTO 95 in Patients With Refractory Solid Tumors

Phase 1
18 Years
Open (Enrolling)
Solid Tumors

Thank you

Trial Information

A Phase I/Biomarker Study of Bevacizumab in Combination With CNTO 95 in Patients With Refractory Solid Tumors

Targeting molecular pathways of tumor growth has recently become a major focus of
anti-cancer treatments. The VEGF pathway has demonstrated significant mitogenic activity for
arterial, venous, and lymphatic endothelial cells, induction of vascular permeability for
extracellular remodeling, and activity as an endothelial cell growth factor. The proof of
principle that targeting the VEGF pathway as an anti-cancer therapy was demonstrated by the
phase III trial of the anti-VEGF monoclonal antibody bevacizumab versus placebo in
combination with chemotherapy for metastatic colorectal cancer. In this trial the addition
of bevacizumab to chemotherapy showed a statistically significant improvement in overall
survival for these subjects (11). Since this trial, the addition of bevacizumab to
chemotherapy has been shown to be beneficial in non-small cell lung cancer subjects and
metastatic breast cancer subjects (9, 12).

Integrins have been shown to be essential components of angiogenesis. One of the
best-characterized integrins in tumor-induced angiogenesis is αvβ3. Angiogenesis
dramatically up-regulates integrin αvβ3 expression by endothelial cells (13). Integrin αvβ3
has been linked to cell migration and invasion (14), and cell survival (15). Inhibition of
αvβ3 results in apoptosis of endothelial cells (16) and inhibition of microvascular network
formation (17). The signaling pathways activated by αvβ3 and VEGF act synergistically in the
formation of microvascular networks (17). Both αvβ3 and VEGF activate Src, Ras, PI3K, and
Erk cascades (18). CNTO 95 is a fully humanized monoclonal antibody that blocks integrin
αvβ3 with high affinity.

The combination of different targeted therapies has the potential of providing a more
complete inhibition of angiogenesis. It is our hypothesis that the combination of CNTO 95
and bevacizumab will be a safe and potentially efficacious anti-angiogenesis strategy for
the treatment of adult solid tumors. This combination may have utility directly or may prove
useful when subsequently combined with other anti-angiogenic agents or standard chemotherapy
regimens. We also hypothesize that our clinical dermal wound angiogenesis assay will help
quantify and characterize the anti-angiogenic contribution of each agent in this

Bevicizumab (Avastin) is a humanized monoclonal antibody to VEGF. VEGF is known to play a
pivotal role in tumor angiogenesis and is a significant mitogenic stimulus for arterial,
venous and lymphatic endothelial cells. The addition of bevacizumab to chemotherapy has been
shown to increase overall response rate, duration of response and survival for patients with
metastatic colon cancer (4) and is beneficial in first line non-small cell lung cancer and
metastatic breast cancer [1, 2], and second line metastatic colorectal cancer (7). VEGF
signals through phosphoatidylinositol 3-kinase (PI3K) and Akt as well as through the
extracellular regulated kinase (ERK 1/2), a mitogen activated protein kinase (MAPK). VEGF's
multiple biologic actions may be mediated by different pathways. Erikkson demonstrated that
VEGF induced hyperpermeability was highly dependent on activation of the AKT pathway, while
the angiogenic effect was largely unaffected by blocking this pathway and likely depended on
ERK activation [3].

CNTO 95 is a fully human mAb immunoglobulin G (IgG) of the gamma isotype and kappa light
chain that has been shown to have antiangiogenic and antitumor properties. Results of in
vitro studies demonstrate that CNTO 95 is an anti-αv integrin antibody that binds and blocks
integrin ανβ3 with high affinity. CNTO 95 has also been shown to bind to integrins ανβ1,
ανβ5, and ανβ6. No cross-reactivity of CNTO 95 to glycoprotein IIb/IIIa, ανβ1 or platelets
has been observed. By binding and blocking the ανβ3 and ανβ5 integrins, CNTO 95 can inhibit
cell adhesion, migration, proliferation, and invasion of both tumor and endothelial cells in
vitro. It is known that CNTO 95 binds to other αν integrins. However, the clinical
implications of binding to these integrins are unknown.

Inclusion Criteria:

1. Histologically or cytologically confirmed diagnosis of advanced solid tumor
refractory to standard therapy or for whom there is no standard therapy. Disease must
be measurable by RECIST criteria.

2. Age ≥ 18 years.

3. Karnofsky performance status ≥ 70%.

4. Life expectancy of at least 3 months.

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

Absolute neutrophil count ≥ 1,500/μl Platelets ≥ 100,000/μl Total bilirubin ≤ 1.5 X
upper limit of normal (ULN) AST(SGOT)/ALT(SGPT) ≤ 2.5 X ULN, ≤ 5 X ULN if known
hepatic metastases Creatinine clearance ≥ 50 mL/min/m2 for patients with creatinine
levels (by Cockroft-Gault equation or 24 hour urine) Hemoglobin > 9 g/dL Continuation
of erythropoietin products is permitted. Hemoglobin must be stable above 9 g/dL for
at least 2 weeks without blood transfusion to maintain hemoglobin level.

Calcium (corrected for albumin) > 8.7 mg/dL

6. The effect of the investigational drugs on the developing human fetus is not known,
but these drugs are likely to be embryo- and feto- toxic. Women of child-bearing
potential and men must agree to use adequate contraception (hormonal or barrier
method of birth control) prior to study entry and for the duration of study
participation. Should a woman become pregnant or suspect she is pregnant while she or
her partner are participating in this study, she should inform her treating physician
and study PI immediately. Subjects who are pregnant and/or lactating are excluded
from this study.

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

Exclusion Criteria:

1. Subjects who have had radiation therapy, hormonal therapy, biologic therapy, or
chemotherapy for cancer within the 28 days prior to day 1 of study treatment.
Subjects must not have had major surgery within the 28 days prior to study treatment
day 1 or minor surgical procedures within the 7 days prior to study treatment day 1.

2. Subjects who have received any other investigational agents within the 28 days prior
to day 1 of the study.

3. Subjects with known CNS metastases, centrally located non-small cell lung cancer
(regardless of histologic sub-type), non-small cell lung cancer of squamous
histology, and/or history of hemoptysis (> ½ tsp BRB).

4. Inadequately controlled hypertension (defined as systolic blood pressure >150 and/or
diastolic blood pressure > 100 mmHg). Initiation of antihypertensive is permitted
provided adequate control is documented 3 times over at least 1 week before starting

5. Significant vascular disease (e.g., aortic aneurysm, aortic dissection)

6. Evidence of bleeding diathesis or coagulopathy. Subjects on therapeutic
anticoagulation may be enrolled provided that they have been clinically stable on
anti-coagulation for at least 2 weeks.

7. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to day 1 of study treatment (56 days for hepatectomy, open thoracotomy, major
neurosurgery) or anticipation of need for major surgical procedure during the course
of the study

8. Core biopsy or other minor surgical procedure excluding study-related procedures or
placement of a vascular access device, within 7 days prior to expected start of

9. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to study enrollment

10. Serious, non-healing wound, ulcer, or bone fracture

11. Proteinuria at screening as demonstrated by either urine protein:creatinine (UPC)
ratio ≥ 1.0 or 24hr collection >1g/24hr at screening

12. Any prior history of hypertensive crisis or hypertensive encephalopathy

13. New York Heart Association (NYHA) Grade II or greater congestive heart failure

14. History of myocardial infarction, unstable angina, cardiac or other vascular
stenting, angioplasty, or surgery within 6 months prior to day 1 of study treatment

15. History of stroke or transient ischemic attack within 6 months prior to day 1 of
study treatment

16. History of intolerance or hypersensitivity to prior treatment with bevacizumab or
CNTO 95. Prior treatment with these agents is permitted, as long as prior treatment
was with only one agent at a time (ie - subjects may not have previously received
bevacizumab and CNTO 95 together).

17. Chronic treatment with systemic steroids or another immunosuppressive agent, though
steroids may be used on an as-needed basis - ie - for treatment of nausea. Treatment
with megace or low dose glucocorticoids is permitted for treatment of anorexia.

18. Other known concurrent severe and/or uncontrolled medical disease which could
compromise safety of treatment as so judged by treating physician (i.e., severely
impaired lung function, uncontrolled diabetes (history of consistent blood glucose
readings above 300 mg/dL or less than 50 mg/dL), uncontrolled hypertension (greater
than 150/100), severe infection, severe malnutrition, ventricular arrhythmias active
ischemic heart disease, known active vasculitis of any cause, tumor invasion of any
major blood vessel, chronic liver or renal disease, active upper GI tract ulceration)

19. A known history of HIV seropositivity,hepatitis C virus, acute or chronic active
hepatitis B infection, or other serious chronic infection requiring ongoing

20. Subjects with an active, bleeding diathesis or on oral anti-vitamin K medication
(except coumadin). No history of active GI bleeding or other major bleeding within
previous 6 months.

21. Subjects unwilling to or unable to comply with the protocol

22. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, or psychiatric illness/social situations that would limit safety or
compliance with study requirements or may interfere with the interpretation of the

23. Known history of anaphylaxis allergic reactions to human Ig therapy or polysorbate 80
(components of CNTO 95).

24. Known history of uveitis

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label

Outcome Measure:

To define a recommended phase II dose for the combination of CNTO 95 plus bevacizumab in subjects with advanced solid tumors.

Outcome Time Frame:

Every cycle (21 days)

Safety Issue:


Principal Investigator

Herbert I Hurwitz, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University


United States: Food and Drug Administration

Study ID:




Start Date:

March 2009

Completion Date:

March 2014

Related Keywords:

  • Solid Tumors
  • solid tumors
  • avastin
  • Phase I
  • combination therapy
  • bevacizumab
  • Neoplasms



Duke University Medical Center Durham, North Carolina  27710