phase I study: ABT-888 in Combination With Metronomic Cyclophosphamide

[Guest guest]

Greetings, Calling attention to

A Phase I Study of ABT-888 in Combination With Metronomic Cyclophosphamide

in Adults With Refractory Solid Tumors and Lymphomas*

http://clinicaltrials.gov/ct2/show/NCT00810966

* Leukemia, Lymphoma, Unspecified Adult Solid Tumor, Protocol Specific

** Patients with a history of CNS metastases are eligible, at the discretion

of the principal investigator, provided they have received treatment and

their CNS metastatic disease status has remained stable for ≥ 3 months

without requiring steroids or anti-seizure medications

This investigational protocol combines two approaches to refractory disease:

metronomic dosing of chemo (low continuous dosing) and a targeted agent, so

called ABT-888, which may act on a known mechanism of resistance to

chemotherapy.

It is also hypothesized (not by these investigators) that low dose

cyclophosphamide (cytoxan) is immune modulating [1] and possibly

anti-angiogenic [2]

1 http://cancerres.aacrjournals.org/cgi/content/full/65/12/5027

2 http://www.ncbi.nlm.nih.gov/pubmed/16499874

ABT-888 is thought to be " a potent inhibitor of both PARP-1 and PARP-2 ...

The compound has good oral bioavailability and crosses the blood-brain

barrier. " 3

3 http://clincancerres.aacrjournals.org/cgi/content/abstract/13/9/2728

More on the development strategy of ABT 888:

http://dctd.cancer.gov/MajorInitiatives/Sep0507Phase0Workshop/DrKummar090507.pps

Another slant on the how ABT888 might work:

PARP Inhibitors (ABT-888)

DNA damaging agents remain some of the most successful treatments for

cancer. The enzyme Poly(ADP-ribose)polymerase (abbreviated PARP) can help

repair DNA damage caused by these agents used to treat cancer and render

them ineffective. As PARP activity is often increased in cancer cells, it

provides these cells with a survival mechanism.

ABT-888 is an oral PARP-inhibitor developed by Abbott researchers to prevent

DNA repair in cancer cells and increase the effectiveness of common cancer

therapies such as radiation and alkylating agents.

~ Karl