Phase II Evaluation of Carboplatin, Paclitaxel and Bevacizumab as First Line Chemotherapy and Consolidation for Advanced Ovarian Cancer
Ovarian cancer is diagnosed in approximately 26,000 American women each year, and is the
leading cause of death from gynecologic cancers. Difficult to detect, the disease typically
presents only when advanced. Ovarian cancer is among the most sensitive of solid tumors to
chemotherapy. However, the majority of patients with ovarian cancer who achieve a complete
remission with first line platinum-based chemotherapy will ultimately develop recurrent
disease. The combination of carboplatin and paclitaxel is the standard first line
combination in the US.
In patients with advanced ovarian cancer, carboplatin plus paclitaxel results in less
toxicity, is easier to administer, and is not inferior, when compared with cisplatin plus
paclitaxel. The randomized trial, GOG-158 finally confirmed the adoption of this standard
with an improved toxicity profile of the combination of cisplatin and paclitaxel, a doublet
that had been previously demonstrated to have a substantially better progression free and
overall survival advantage compared with cisplatin and cyclophosphamide in advanced-stage
epithelial ovarian cancer. Although in nonrandomized trials, carboplatin and paclitaxel was
a less toxic and highly active combination regimen, there remained concern regarding its
efficacy in patients with good prognosis completely resected advanced disease.
In parallel European, multicentre, randomised trials, between January, 1996, and March,
2002, 802 patients with platinum-sensitive ovarian cancer relapsing after 6 months of being
treatment-free were enrolled from 119 hospitals in five countries (ICON III). Patients were
randomly assigned paclitaxel plus platinum chemotherapy or conventional platinum-based
chemotherapy. Survival curves demonstrated a difference in favor of paclitaxel plus platinum
(hazard ratio 0.82 [95% CI 0.69-0.97], p=0.02), corresponding to an absolute difference in
2-year survival of 7% between the paclitaxel and conventional treatment groups (57 vs 50%
[95% CI for difference 1-12]), and median survival of 5 months (29 vs 24 months [1-11]).
Since the hypothesis of targeting angiogenesis to treat cancer was first described in 1971
by Judah Folkman, there has been intense research into the development of antiangiogenic
cancer therapies. Tumors are dependent on their development of a vascular supply. Recent
work has shown that, if cells are already transformed, angiogenesis can be initiated with a
tumor mass comprising as few as 100-300 cells.
VEGF actions are mediated through binding to two receptor tyrosine kinases, VEGF-R-1 (Flt-1)
and VEGF-R- 2 (KDR; whose murine form is known as Flk-1). Activation of these receptors by
VEGF triggers the phosphorylation of a multitude of proteins that are active in signal
transduction cascades. VEGF gene expression is upregulated by a wide range of stimuli
including hypoxia, nitric oxide, estrogen, a variety of growth factors (e.g., FGF-4, PDGF,
TNF, TGF-b, EGF, IL-6, IL-1b, #76) and common genetic events associated with the malignant
phenotype (loss of tumor suppressor genes such as p53 and activation of oncogenes such as
ras, v-src and HER2/neu). Beside major angiogenic properties, VEGF is a potent mitogen for
vascular endothelium, inhibits endothelial apoptosis and mobilizes bone marrow-derived
endothelial cell precursors. VEGF also mediates the secretion of enzymes involved in the
degradation of extracellular matrix, modulates migration, increases vascular permeability,
upregulates hexose transport and induces monocyte migration.
Ovarian cancers secrete large amounts of VEGF in vitro and in vivo, and VEGF appears to play
a crucial role in angiogenesis and tumor induced immunosuppression in ovarian cancer
patients. Indeed, VEGF has been confirmed as an independent prognostic indicator by
multivariate analysis of survival.
Angiogenesis is crucial in the development of ovarian cancer. VEGF is closely linked to
normal ovarian function and is required for the development of the corpus luteum and the
maturation of the endometrium. Elevated VEGF expression occurs in all stages of ovarian
cancer and is associated with poor prognosis. In fact, VEGF levels appear to be
prognostically important. In addition to its role in ovarian-cancer-associated angiogenesis,
VEGF overexpression is directly associated with the production of ascitic fluid, a feature
probably related to its ability to induce endothelial hyperpermeability. In studies
monitoring VEGF after tumor resection, VEGF appears to be a valid tumor marker, following a
dramatic decline after surgery, the levels rise at recurrence.
The parent murine antibody of bevacizumab, A.4.6.1, demonstrated promising antitumor
activity in a subcutaneous SKOV-3 human ovarian cancer xenograft model. Interestingly, in
the intraperitoneal model of the same cell line, A.4.6.1 produced only partial inhibition of
tumor growth, but was associated with almost complete inhibition of ascites production.
These data provided the rationale for evaluation of bevacizumab in ovarian cancer. A
Gynecologic Oncology Group (GOG) phase II study of bevacizumab monotherapy is ongoing, and a
second trial will examine the combination of bevacizumab with daily, low-dose, oral
cyclophosphamide, using metronomic dosing in the hope that 'less is more'.
Bevacizumab (rHumAb VEGF; Genentech, Inc., CA), a recombinant humanized monoclonal antibody
directed to VEGF, and neutralizes the biological properties of human VEGF. Bevacizumab,
derived from the murine antibody A.4.6.1, comprises 93% human IgG frameworks and 7%
murine-derived antigen-binding regions, the humanization providing a longer half-life and
Based on preclinical data, a phase I/II program with bevacizumab was initiated. The initial
phase I trial enrolled 25 patients in a dose-escalation fashion (0.1-10.0 mg/kg on days 0,
28, 35, and 42). No grade 3 or 4 toxicity was seen that was directly attributable to
therapy. There were three episodes of tumor-related bleeding, including a hemorrhage in a
previously undetected cerebral metastasis. Grade 1 and 2 toxicities, possibly or probably
related to treatment, included asthenia, headache, and nausea. There were no complete or
partial responses seen, although one patient with renal cell carcinoma achieved a mixed
The material use in this study is NOT commercially available Avastin™ (Genentech, Inc.;
South San Francisco, CA), and may differ from that product.
Bevacizumab demonstrated preclinical and clinical activity in colorectal cancer and
Genentech chose this as the disease for their registration studies. At ASCO 2003 Hurwitz et
al reported the results of their phase III study of standard bolus irinotecan/5-FU/LV (IFL)
plus bevacizumab (5 mg/kg). An impressive median survival advantage (20.3 months vs. 15.6
months [p=0.00003]) was reported in 925 patients receiving first line therapy with
irinotecan, 5-fluorouracil, leucovorin treatment for metastatic colorectal cancer. Only
grade 3 hypertension (11%), easily managed with oral medications, was clearly increased in
this Phase III study. Gastrointestinal perforation, although rare, was possibly seen more
Importantly, this was the first phase III validation of an antiangiogenic approach for the
treatment of human cancer. Several further, large phase III trials of bevacizumab in
metastatic colorectal cancer are under way. These include a first-line study of standard
5-FU/LV with or without bevacizumab in patients who are not appropriate for irinotecan
therapy. A further phase III study will assess the FOLFOX regimen with or without
bevacizumab in the second-line setting for patients who have failed previous irinotecan plus
5-FU treatment. These results will help to define the benefit of anti-VEGF therapy.
Other studies are awaited, notably ECOG 4599 a randomized comparison of Taxol and
carboplatin with and without bevacizumab, in patients with non-small cell lung cancer has
completed accrual with over 600 patients.
There are three reasons to investigate protracted exposure to bevacizumab. Firstly, the
agent, while inducing apoptosis, is considered a cytotoxic and protracted exposure is
thought to be necessary to maintain tumor dormancy. Secondly, the studies in colorectal
cancer treated patients until tumor progression. Lastly, there is an evolving paradigm in
the treatment of ovarian cancer. It is now widely accepted that continual rather than
intermittent palliative chemotherapy translates into a better quality of life. The
Gynecologic Oncology Group have recently reported a provocative randomized controlled trial
that confirmed a significant and large improvement in progression free survival (GOG 178),
considered the most important end point in the patients with advanced ovarian cancer.
Furthermore, in the preclinical studies of ovarian cancer, the ovarian cancer model
presented a compelling argument for prolonged bevacizumab administration. Having inoculated
the human ovarian carcinoma cell line SKOV-3 within the peritoneal cavity of immunodeficient
mice, tumor engrafted in 7 to 10 days. The function-blocking VEGF antibody, A4.6.1
significantly inhibited subcutaneous SKOV-3 tumor growth approximately 20 fold compared with
controls (P < 0.05), and similarly in the intraperitoneal model. Importantly, within 2 to 3
weeks of cessation of A4.6.1 treatment, effectively treated mice developed severe ascites,
became cachectic, and had to be killed, and subsequent tumor burden in these animals varied
from moderate to high. It should be clarified that the murine study utilized A4.6.1 the
murine precursor of bevacizumab, but that the results can be extrapolated to the actions of
OVERVIEW OF TRIAL DESIGN Study Design: Open label phase II study. Subjects: Patients with
chemotherapy naive epithelial ovarian cancer; or fallopian, primary peritoneal and papillary
serous mullerian tumors .
CHEMOTHERAPY Carboplatin and paclitaxel administered concurrently with bevacizumab after
surgery for for 6-8 cycles q21 days. Bevacizumab will be omitted in the first cycle,
immediately post-operatively and continued for one year of consolidation therapy.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To examine the toxicity, estimate the objective response rate, and progression free survival of carboplatin, paclitaxel, and bevacizumab followed by single agent bevacizumab as consolidation for advanced mullerian cancer
Richard T Penson, MRCP MD
United States: Food and Drug Administration