A Phase I/Biomarker Study of Bevacizumab in Combination With CNTO 95 in Patients With Refractory Solid Tumors
概览
- 阶段
- 1 期
- 干预措施
- CNTO 95 and avastin
- 疾病 / 适应症
- Solid Tumors
- 发起方
- Herbert Hurwitz, MD
- 入组人数
- 13
- 试验地点
- 1
- 主要终点
- To define a recommended phase II dose for the combination of CNTO 95 plus bevacizumab in subjects with advanced solid tumors.
- 状态
- 已完成
- 最后更新
- 11年前
概览
简要总结
The purpose of this research study is to find out what side effects the combination of the two study drugs, bevacizumab (Avastin) and CNTO 95 have on the body and to determine the highest dose of CNTO 95 that can be given with bevacizumab that is safe and well tolerated.
详细描述
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 combination. Bevacizumab (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 phosphotidylinositol 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.
研究者
Herbert Hurwitz, MD
Associate Professor of Medicine
Duke University
入排标准
入选标准
- •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.
- •Age ≥ 18 years.
- •Karnofsky performance status ≥ 70%.
- •Life expectancy of at least 3 months.
- •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
- •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.
- •Ability to understand and the willingness to sign a written informed consent document.
排除标准
- •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
- •Subjects who have received any other investigational agents within the 28 days prior to day 1 of the study.
- •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).
- •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 treatment.
- •Significant vascular disease (e.g., aortic aneurysm, aortic dissection)
- •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.
- •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
- •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 treatment.
- •History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment
- •Serious, non-healing wound, ulcer, or bone fracture
研究组 & 干预措施
I
CNTO 95 and avastin
干预措施: CNTO 95 and avastin
结局指标
主要结局
To define a recommended phase II dose for the combination of CNTO 95 plus bevacizumab in subjects with advanced solid tumors.
时间窗: Every cycle (21 days)
To evaluate dose limiting as well as non-dose limiting toxicities of this combination.
时间窗: Every cycle (21 days)
次要结局
- To explore the effect of the combination versus each agent individually on dermal wound angiogenesis in a skin biopsy, the clinical activity of this combination, and the association between blood- and urine-based biomarkers and clinical outcome.(Every cycle (21 days))