Fosbretabulin disodium

• CAT Number: I002200
• CAS Number: 168555-66-6
• Molecular Formula: C18H19O8P · 2Na
• Molecular Weight: 440.3
• Purity: ≥95%
• Target: Microtubule/Tubulin
• Solubility: Soluble in DMSO, not in water
• Storage: Store at -20°C
• Related CAS: 222030-63-9(acid)
• IC50: 4 nM
• InChIKey: WDOGQTQEKVLZIJ-WAYWQWQTSA-L
• SMILES: COC(C(OP([O-])([O-])=O)=C1)=CC=C1/C=CC2=CC(OC)=C(OC)C(OC)=C2

Fosbretabulin disodium(CAT: I002200) is the disodium salt of a water-soluble phosphate derivative of a natural stilbenoid phenol derived from the African bush willow (Combretum caffrum) with potential vascular disrupting and antineoplastic activities. Upon administration, the prodrug fosbretabulin is dephosphorylated to its active metabolite, the microtubule-depolymerizing agent combretastatin A4, which binds to tubulin dimers and prevents microtubule polymerization, resulting in mitotic arrest and apoptosis in endothelial cells. In addition, this agent disrupts the engagement of the endothelial cell–specific junctional molecule vascular endothelial-cadherin (VE-cadherin) and so the activity of the VE-cadherin/β-catenin/Akt signaling pathway, which may result in the inhibition of endothelial cell migration and capillary tube formation. As a result of fosbretabulin/’s dual mechanism of action, the tumor vasculature collapses, resulting in reduced tumor blood flow and ischemic necrosis of tumor tissue.

Reference

1. Onco Targets Ther. 2016 Nov 30;9:7275-7283. eCollection 2016.

A randomized Phase II trial of the tumor vascular disrupting agent CA4P
(fosbretabulin tromethamine) with carboplatin, paclitaxel, and bevacizumab in
advanced nonsquamous non-small-cell lung cancer.

Garon EB(1), Neidhart JD(2), Gabrail NY(3), de Oliveira MR(4), Balkissoon J(5),
Kabbinavar F(1).

Author information:
(1)Department of Medicine; Department of Hematology and Oncology, David Geffen
School of Medicine at University of California Los Angeles, Los Angeles, CA.
(2)San Juan Oncology Associates, Farmington, NM.
(3)Gabrail Cancer Center, Canton, OH.
(4)Northwest Medical Specialties, Tacoma, WA.
(5)Global Product Development and Immuno-Oncology, PPD, Wilmington, NC, USA.

INTRODUCTION: Combretastatin A4-phosphate, fosbretabulin tromethamine (CA4P) is a
vascular disrupting agent that targets tumor vasculature. This study evaluated
the safety of CA4P when combined with carboplatin, paclitaxel, and bevacizumab in
chemotherapy-naïve subjects with advanced nonsquamous, non-small-cell lung
cancer.
METHODS: Adult subjects with confirmed American Joint Committee on Cancer six
stage IIIB/IV non-small-cell lung cancer and an Eastern Cooperative Oncology
Group performance score of 0 or 1 were randomized to receive six cycles
(treatment phase) of paclitaxel (200 mg/m2), carboplatin (area under the
concentration versus time curve 6), and bevacizumab (15 mg/kg) on day 1 and
repeated every 21 days, or this regimen plus CA4P (60 mg/m2) on days 7, 14, and
21 of each cycle. Subjects could then receive additional maintenance treatment
(excluding carboplatin and paclitaxel) for up to 1 year.
RESULTS: Sixty-three subjects were randomized, 31 to control and 32 to CA4P, and
19 (61.3%) and 17 (53.1%), respectively, completed the treatment phase. Exposure
to study treatment and dose modifications were comparable between the randomized
groups. The overall incidence of treatment-emergent adverse events was similar
between groups, with increased neutropenia, leukopenia, and hypertension in the
CA4P group. Deaths, serious adverse events, and early discontinuations from
treatment were comparable between the randomized treatment groups. The overall
tumor response rate with CA4P was 50% versus 32% in controls. Overall and
progression-free survival rates were comparable between the groups.
CONCLUSION: CA4P plus carboplatin, paclitaxel, and bevacizumab appears to be a
tolerable regimen with an acceptable toxicity profile in subjects with advanced
non-small-cell lung cancer.

2. Surgery. 2012 Dec;152(6):1078-87. doi: 10.1016/j.surg.2012.08.036.

Thyroidectomy followed by fosbretabulin (CA4P) combination regimen appears to
suggest improvement in patient survival in anaplastic thyroid cancer.

Sosa JA(1), Balkissoon J, Lu SP, Langecker P, Elisei R, Jarzab B, Bal CS, Marur
S, Gramza A, Ondrey F.

Author information:
(1)Division of Endocrine Surgery, Department of Surgery, Yale University School
of Medicine, New Haven, CT 06520, USA.

BACKGROUND: Anaplastic thyroid cancer (ATC) is an aggressive neoplasm for which a
paucity of data exist about the relative role of operative procedures in disease
management.
METHODS: The FACT trial was a randomized, controlled phase 2/3 trial assessing
the safety and efficacy of carboplatin/paclitaxel with CA4P (experimental arm) or
without CA4P (control arm) in ATC, 2007-11. Patients were permitted to have had
an operation before enrollment, which was stratified on the basis of exposure to
operation. A subpopulation of patients who had a cancer-related operation
(thyroidectomy) was compared with those who did not, and 1-year and median
survival were estimated.
RESULTS: A total of 80 patients were enrolled; 55% had undergone a cancer-related
operation, of whom 70% had near-total/total thyroidectomy. Baseline
characteristics for operative and nonoperative patients were not substantially
different. Median survival for patients who had cancer-related operation was 8.2
months in the CA4P arm versus 4.0 months in the control arm, resulting in a
hazard ratio of 0.66 (P = .25) and a suggested associated reduction in risk of
death of 35%. 1-year survival was 33.3% in the CA4P arm versus 7.7% in the
control arm.
CONCLUSION: In this largest prospective study ever conducted in ATC,
thyroidectomy followed by CA4P combination regimen showed a nonsignificant trend
toward improvement in patient survival.