Can IxMP Be Used as a Second or Third-Line Chemotherapy for Metastatic Castrate Resistant Prostate Cancer?
There was a report recently released about a Phase 2 study from the Department of Defense funded Prostate Cancer Clinical Trials Consortium that suggests that ixabepilone + mitoxantrone + prednisone may have clinically significant activity as a form of second-line chemotherapy in the management of men with docetaxel-refractory, metastatic, castration-resistant advanced prostate cancer (mCRPC)?
In this open-label Phase II trial, men with progressive mCRPC during or after 3 or more cycles of taxane-based (taxotere) chemotherapy were treated with ixabepilone 35 mg/m2 and mitoxantrone 12 mg/m2 on Day 1 every 21 days and with prednisone 5 mg twice daily. Additionally, all the men received pegfilgrastim (Neupogen) to prevent or limit neutropenia (neutropenia is an abnormally low level of neutrophils in the blood. Neutrophils are white blood cells (WBCs) produced in the bone marrow that ingest bacteria) and neutropenia-associated infections at the time of ixabepilone + mitoxantrone infusion. Ixabepilone (Ixempra/Bristol-Myers Squibb) is an epothilone B analog (epothilones are a new class of cancer drugs previously approved for the treatment of locally advanced and metastatic breast cancer that like he taxanes prevent cancer cells from dividing). In early trials epithilones have better efficacy and milder adverse effects than taxanes.
The results of this study are as follows:
* There was a total of 56 evaluable men.
* 25/56 men (45 percent) had a confirmed reduction in their PSA levels of > 50 percent.
* 33/56 men (59 percent) had a confirmed reduction in their PSA levels of > 30 percent.
* 8/36 men with measurable disease (22 percent) experienced objective responses.
* The average (median) time to either PSA or objective progression was 4.4 months.
* The average (median) progression-free survival was 4.4 months.
* The average (median) overall survival was 12.5 months.
* 32 percent of men experienced grade 3 neutropenia.
* 11 percent of men experienced grade 3 or higher neutropenic infections (including 1 treatment-related death).
* Grade 2 and grade 3 neuropathy occurred in 11 and 12.5 percent of men, respectively.
This study suggests that ixabepilone + mitoxantrone + prednisone (IxMP) has some potential as a treatment for taxane-refractory, mCRPC. This regimen clearly needs to be administered in combination with pegfilgrastim and perhaps other supportive care drugs.
The most likely next step will be a Phase 3 clinical trial of this combination of agents. The trial would have to compare IxMP with those of cabazitaxel + prednisone in a randomized group of patients with mCRPC who had progressive disease after earlier taxane therapy. Cabazitaxel + prednisone was approved as a second-line chemotherapy for taxane-refractory, mCRPC based on a 2.4-month median survival benefit compared to prednisone alone.
Since all three of the drugs in the IxMP combination regimen are already approved by the FDA, it is possible for an experienced oncologists to use this regimen today in carefully selected patients — either before or after treatment with cabazitaxel + prednisone. Will insurance cover the treatment is a question.
Joel T Nowak, M.A., M.S.W.