Imatinib & Docetaxel Produce Modest Response Against Recurrent Platinum Resistant/Refractory Ovarian Cancer

A combination of imatinib mesylate (Gleevec®) and docetaxel (Taxotere®) produced only a modest response in patients with recurrent, platinum-resistant or refractory ovarian cancer, according to the results of a Phase II clinical trial conducted by the Hoosier Oncology Group at Indiana University Cancer Center.

Background

A combination of imatinib mesylate (Gleevec®) and docetaxel (Taxotere®) produced only a modest response in patients with recurrent, platinumresistant or refractory ovarian cancer, according to the results of a Phase II clinical trial conducted by the Hoosier Oncology Group at Indiana University Cancer Center.

Imatinib mesylate (Imatinib) is an inhibitor of the (i) receptor tyrosine kinases (RTKs) for platelet-derived growth factor (PDGF) and stem cell factor (SCF), and (ii) c-Kit. RTKs are key regulators of normal cellular processes, and may play a critical role in the development and progression of many types of cancer. PDGF is one of the numerous growth factors, or proteins, that regulate cell growth and division. In particular, it plays a significant role in new blood vessel formation (angiogenesis) from existing blood vessels. SCF is a growth factor, or protein, important for the survival, proliferation, and differentiation of hematopoietic stem cells that give rise to all types of blood cells. C-kit is a protein that is expressed on the surface of hematopoietic stem cells as well as other cell types, and binds to stem cell factor (a substance that causes certain types of cells to grow). Docetaxel, a chemotherapy drug, promotes cell growth arrest.

Based upon the foregoing, the trial investigators hypothesized that use of imatinib (in tandem with docetaxel) would inhibit or block the RTKs for PDGF & SCF and the c-kit receptor, and cause tumor disruption by enhancing the effect of chemotherapy while controlling tumor angiogenesis. Also, the combination of imatinib and docetaxel previously produced synergistic effects in-vitro (in the laboratory) and in-vivo (in mice). As a monotherapy, and prior to this trial, docetaxel produced single agent activity in ovarian cancer with response rates of 30% to 40% in the platinum refractory setting.

The Imatinib/Docetaxel Phase II Clinical Trial

Pursuant to trial eligibility criteria, all patients had recurrent, platinum-resistant, or refractory epithelial ovarian cancer that expressed PDGFR or c-kit, as determined by immunohistochemistry. This screening resulted in the enrollment of 23 patients with the following tumor characteristics: 4 patients had c-kit-positive/PDGFR-negative tumors, 11 patients had PDGFR-positive/c-kit-negative tumors, and 8 patients had c-kit-positive/PDGFR-positive tumors. The median patient age was 56 years (ranging from 33 to 76 years). Enrolled patients had received a median of 3 prior lines of treatment.

The overall response rate was 21.7%, which included 1 complete response (CR) and 4 partial responses (PR). An additional 3 patients had stable disease for more than 4 months. The trial investigators determined that the expression of PDGFR and/or c-kit, did not predict response to this combination therapy. The most common adverse events encountered were fatigue (83%), nausea (74%), diarrhea (61%), anorexia (52%), and edema (65%), and the majority of those events were grade 1 or 2 events.

Based upon the foregoing, the trial investigators concluded that the combination treatment of imatinib and docetaxel was tolerated in patients with heavily pretreated epithelial ovarian cancer that expressed c-kit or PDGF, but found that few patients had sustained responses or stable disease, when compared with the 30% to 40% response rate of docetaxel used as a monotherapy in a platinum refractory setting.

Sources:

2 thoughts on “Imatinib & Docetaxel Produce Modest Response Against Recurrent Platinum Resistant/Refractory Ovarian Cancer

  1. Mike,

    You raise an interesting point with respect to the measurement of tyrosine kinase function in the plasma. I believe that your idea to measure plasma tyrosine kinase function is analogous to the measurement of shed HER-2 ECD in the plasma to determine the immediate or short-term effectiveness of trastuzamab (Herceptin), albeit in an immunology context. I do not know if a tyrosine kinase measurement(s) was performed on plasma samples, but I could check with the trial investigator at the Univ. of Indiana Cancer Center. IHC testing was performed on the tumors so as to detect PDGFR and c-kit expression, in the hope that the biological activity of imatinib (Gleevec) would prevail. It seems that there is a potential issue as to the reliability of IHC testing to accurately measure expression, in tandem with the necessary level of expression (or overexpression) that allows imatinib to achieve maximum effect. From a practical perspective, once the response rate for the combination of imatinib and docetaxel fell below that of docetaxel monotherapy, the work may have stopped without further detailed measurement of drug activity.

    You are correct, imatinib is a miracle drug for use against chronic myelogenous leukemia (CML). Best, Paul

    Like

  2. Sounds like about the response rate you’d expect from taxotere single agent, though I’d have to look it up. I’d also like to know if they looked at a biochemical endpoint, like tyrosine kinase function in plasma.
    This is about what we would expect from Gleevec in solid tumors–there have been papers for at least five years in a host of other types of tumors, with pretty minimal efficacy, except in gastrointestinal stromal tumors.

    Having said that, the impact of Gleevec in CML cannot be overstated.

    Another nice post. Thanks.

    Like

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s