Pazopanib and Weekly Topotecan in Patients Recurrent Ovarian Cancer (TOPAZ) - Full Text View - ClinicalTrials.gov

Pazopanib and Weekly Topotecan in Patients Recurrent Ovarian Cancer (TOPAZ) - Full Text View - ClinicalTrials.gov

abstract: Antiangiogenic Agents in Combination With Chemotherapy for the Treatment of Epithelial Ovarian Cancer

Objective: The purpose of this review was to provide an overview of angiogenesis, including the rationale for targeting angiogenesis as a treatment strategy for epithelial ovarian cancer (EOC) and to discuss available clinical trial data with antiangiogenic agents in EOC, with a focus on combinations with chemotherapy.

Methods: This was a literature review of clinical studies evaluating select antiangiogenic agents in combination with traditional cytotoxic chemotherapy for the treatment of EOC.

Results: Several therapies that target angiogenesis-specific pathways are undergoing clinical development for EOC. Although some of these agents have demonstrated single-agent activity for EOC, there is considerable interest in combining this treatment strategy with chemotherapy in an effort to potentially improve treatment benefits in this patient population. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, is the most studied antiangiogenic agent in EOC and has shown efficacy as monotherapy and combined with chemotherapy in both the relapsed/recurrent and first-line settings. However, results from recent phase 3 trials raise questions regarding patient selection and optimal dose, schedule, and duration of bevacizumab therapy. Other agents in various phases of testing include aflibercept (VEGF Trap), a fusion protein that binds all isoforms of VEGF; multitargeted antiangiogenic tyrosine kinase inhibitors (eg, BIBF 1120, cediranib, pazopanib, sorafenib); and AMG 386, a selective angiopoietin inhibitor. Toxicities associated with VEGF inhibition are also a concern with antiangiogenic therapy, including hypertension, proteinuria, thromboses, and gastrointestinal perforation.

Conclusions: Results from recently completed and ongoing clinical trials combining antiangiogenic agents with chemotherapy are awaited in hopes of expanding therapeutic options for patients with EOC.

Access : Open-label feasibility study of pazopanib, carboplatin, and paclitaxel in women with newly diagnosed, untreated, gynaecologic tumours: a phase I|[sol]|II trial of the AGO study group : British Journal of Cancer

 "Severe myelotoxicity was reported in 6 of 12 patients."

Conclusion:

Combining either 800 or 400 mg per day pazopanib with standard carboplatin/paclitaxel chemotherapy is not a feasible treatment option.

NCCN Receives $4 Million in Oncology Research Funding from GlaxoSmithKline

"Pazopanib is currently approved by the FDA to treat patients with advanced renal cell carcinoma. The research grant to NCCN will evaluate the effectiveness of pazopanib in solid tumors including renal, sarcoma, thyroid, neuroendocrine, and ovarian cancers."

Drug Watch a heads-up on pharmaceuticals in late-stage development

New drugs Product type/proposed indication FDA status/notes

abagovomab
Menarini Group
an anti-idiotype antibody, able to mimic a tumor antigen
highly expressed by ovarian cancer cells/used to prevent
or delay the tumor relapse in patients whose disease
responded to the first-line chemotherapy by activating
an immune response toward cancer cells
phase 2/3

karenitecin/BNP1350
BioNumerick Pharmecuticals
in the camptothecin class of chemotherapy drugs/
treatment of advanced ovarian cancer
phase 3

pazopanib (Votrient)
GlaxoSmithKline
multi-kinase angiogenesis inhibitor/maintenance therapy
for the treatment of ovarian cancer
phase 3
 references/sources:

(Pre-)Clinical Pharmacology and Activity of Pazopanib, a Novel Multikinase Angiogenesis Inhibitor

"In a phase I trial, a generally well-tolerated dose was identified at which the majority of patients achieved pazopanib plasma concentrations above the concentration required for maximal in vivo inhibition of VEGFR-2 phosphorylation in preclinical models.
Administered as monotherapy, evidence of antitumor activity was observed in phase II studies in several tumor types, including soft tissue sarcoma, renal cell cancer (RCC), ovarian cancer, and non-small cell lung cancer.
Recently, the U.S. Food and Drug Administration granted approval for treatment with pazopanib in patients with RCC based on the longer progression-free survival time observed with this agent in a placebo-controlled, randomized trial.
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"Furthermore, preliminary data from a small phase II study in women with progressive, platinum-pretreated ovarian cancer showed a cancer antigen 125 response (defined as a confirmed decrease 50% from baseline) in 11 (31%) patients, with a median duration of response of 113 days.*>"

(*Annals of Oncology 19 (Supplement 8): viii211–viii216, 2008
doi:10.1093/annonc/mdn512:
PAZOPANIB (GW786034) IS ACTIVE IN WOMEN WITH
ADVANCED EPITHELIAL OVARIAN, FALLOPIAN TUBE AND
PERITONEAL CANCERS: RESULTS OF A PHASE II STUDY
M. Friedlander1, K.C. Hancock2, B. Benigno3, D. Rischin4, M. Messing5,
C.A. Stringer6, J.P. Hodge7, B. Ma7, G. Matthys7, J.J. Lager7
1Oncology Day Center, Prince of Wales Hospital, Randwick, Sydney/
AUSTRALIA, 2Oncology, Texas Oncology, Fort Worth/UNITED STATES OF
AMERICA, 3Oncology, SE Gynecologic Oncology, Atlanta/UNITED STATES OF
AMERICA, 4Oncology, Mercy Hospital for Women, Melbourne/AUSTRALIA,
5Oncology, Texas Oncology, Bedford/UNITED STATES OF AMERICA,
6Oncology, Texas Oncology, Dallas/UNITED STATES OF AMERICA, 7Scientific
Communications, GlaxoSmithKline, Research Triangle Park/UNITED STATES
OF AMERICA )

" Putting pazopanib into perspective and comparing it with other VEGFR TKIs that have been approved for a longer time are difficult and have to be done on the basis of indirect comparisons, given the lack of data from comparative trials among the several treatment options."

(Pre-)Clinical Pharmacology and Activity of Pazopanib, a Novel Multikinase Angiogenesis Inhibitor

Bridging the Gap between Cytotoxic and Biologic Therapy with Metronomic Topotecan and Pazopanib in Ovarian Cancer

"Pazopanib therapy in combination with metronomic topotecan therapy showed significant antitumor and antiangiogenic properties in preclinical ovarian cancer models and warrants further investigation as a novel therapeutic regimen in clinical trials."