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Clinical Trial Design
This randomized Phase 2 clinical trial is evaluating weekly administration of custirsen (OGX-011) in combination with second-line chemotherapy in patients with metastatic HRPC who were previously treated with a minimum of 2 cycles of a docetaxel-based chemotherapy regimen and progressed during or within 6 months of discontinuation of docetaxel treatment. Because custirsen has been shown to enhance chemotherapy and reverse chemotherapy resistance in preclinical in vitro and in vivo models, the aim of this study was to assess the effect of weekly custirsen treatment on tumor response and disease progression when used in combination with either mitoxantrone or re-treatment with docetaxel (as second-line chemotherapy). This was not a comparative study; the purpose of the randomization was to attempt to assure that equivalent patients were entered into the two treatment groups.
The primary objective was to assess the safety and tolerability of custirsen in combination with either mitoxantrone or docetaxel in patients with metastatic HRPC who had disease progression with first-line docetaxel chemotherapy. The secondary objective was to determine the feasibility of treatment with custirsen in combination with second line chemotherapy in these patients, assessed primarily on PSA response and pain progression but included other criteria such as disease progression and survival.
The preliminary results of this study were presented by Fred Saad, M.D., a medical oncologist at Université Montréal, at the 2008 Genitourinary Symposium of the American Society of Clinical Oncology (ASCO).
Patients were randomized to receive either mitoxantrone or docetaxel. All patients received three loading doses of custirsen (640 mg) during a nine day period immediately prior to receiving chemotherapy. Custirsen was then given weekly. Patients received treatment on a 3 week cycle until disease progression or up to 9 cycles of chemotherapy.
Forty-six (46) patients were randomized (24 to the mitoxantrone plus custirsen treatment group and 22 to the docetaxel plus custirsen treatment group). Of the 46 patients randomized, 42 received at least one cycle of custirsen and chemotherapy and are included in this analysis. Two patients never received treatment (one in each treatment group) and 2 patients received custirsen but did not receive chemotherapy (one patient in the mitoxantrone treatment group withdrew consent and one patient in the docetaxel treatment group withdrew from treatment because of rapid disease progression). Therefore, 20 patients who received docetaxel in combination with custirsen and 22 patients who received mitoxantrone in combination with custirsen were evaluable for treatment response. This was a non-comparative clinical trial and therefore the data from each treatment group are presented separately.
Summary of Preliminary Results of Phase 2 Clinical Trial for the Treatment Group Receiving
Docetaxel Plus Custirsen
The key preliminary results of this clinical trial as of January 03, 2008 for patients who received docetaxel plus custirsen as second-line chemotherapy are summarized as follows:
- The median follow-up time for all study patients (both arms) was 13.3 months; however, 60% of patients were alive and the median survival duration had not yet been reached in the docetaxel/custirsen arm.
- For comparison, a median survival duration of 10 months was observed in the TAX 327 study (one of the studies that was the basis for approval of docetaxel in patients with prostate cancer) in which 237 HRPC patients received either docetaxel or mitoxantrone as second-line chemotherapy and were available for long-term follow up. The median survival duration from the start of second-line therapy for the TAX 327 patients was 10 months for both groups of patients (patients receiving mitoxantrone as second-line chemotherapy after receiving docetaxel as first-line chemotherapy or patients receiving docetaxel as second-line chemotherapy after receiving mitoxantrone as first-line chemotherapy);
- In another study evaluating second-line chemotherapy in HRPC patients, the researchers from British Columbia Cancer Agency (BCCA) reported a median survival duration of 9.6 months for patients who received second-line docetaxel after first-line docetaxel. The patients in the BCCA study had a better prognosis than the patients in our clinical trial because their median time to disease progression after completion of treatment with first-line docetaxel was 11.8 months compared to only a median of 2.1 months for the patients in our clinical trial.
- Docetaxel resistance may have been reversed in a subset of patients who, at the time the clinical trial started, were resistant to docetaxel;
- Pain responses, with a median duration of 6.2 months, were observed in 67% of patients treated with docetaxel plus custirsen arm who were evaluable for pain;
- The frequency and magnitude of the PSA value decline was greater than PSA declines noted for those HRPC patients who received second-line chemotherapy in the TAX 327 study. Preliminary PSA responses in our study, defined as a 50% decrease, have been observed 8 of 20 patients (40%) in the docetaxel plus custirsen arm (4 of these 8 patients had a 90% response with 1 of the 4 patients having a 100% response);
- For comparison, in the TAX-327 study, a 50% decline in PSA values was observed in only 28% of patients receiving docetaxel as second-line chemotherapy after receiving mitoxantrone as first-line chemotherapy.
- In the BCCA study, a 50% decline in PSA values occurred in 32% of patients receiving docetaxel retreatment as second-line chemotherapy.
- Patients in the docetaxel plus custirsen arm received a median of 7.5 cycles (range 1-9). Most studies evaluating second-line treatment in patients with HRPC have reported being able to administer only a median of 3-4 cycles of chemotherapy.
- Adverse events were primarily mild to moderate. The most common adverse events listed in order of decreasing frequency included: fatigue, nausea, diarrhea, anorexia, chills, vomiting, fever, taste disturbance, cough, neuropathy, joint pain, peripheral edema, hair loss, back pain and constipation.
Summary of Preliminary Results of Phase 2 Clinical Trial for the
Treatment Group Receiving Mitoxantrone Plus Custirsen
The key preliminary results of this trial as of January 03, 2008 for patients who received mitoxantrone plus custirsen as second-line chemotherapy are summarized as follows.
- The median follow-up time for all study patients (both arms) was 13.3 months, however, 64% of patients were alive and the median survival duration had not been reached in the mitoxantrone/custirsen arm.
- The median survival duration from the start of second-line therapy was 10 months for patients in the TAX 327 study who received mitoxantrone as second-line chemotherapy after receiving docetaxel as first-line chemotherapy.
- Pain responses, with a median duration of 5.5 months, were observed in 50% of evaluable patients;
- Patients received a median of 6 cycles (range 1-9). Most studies evaluating second-line chemotherapy in patients with HRPC have reported a median of 3-4 cycles of chemotherapy;
- Patients are showing declines in PSA values better than results published by third parties. The frequency of the PSA value declines are greater than PSA declines noted for those HRPC patients who received second-line mitoxantrone in the TAX 327 study. A 50% decline in PSA values occurred in only 15% of patients receiving mitoxantrone as second-line chemotherapy after receiving docetaxel as first-line chemotherapy in the TAX 327 study compared to 27% of patients treated with mitoxantrone plus custirsen as second-line chemotherapy after receiving docetaxel as first-line chemotherapy in our clinical trial.
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Adverse events were primarily mild to moderate. The most common adverse events listed in order of decreasing frequency included: fatigue, nausea, fever, anorexia, vomiting, chills, peripheral edema, bone pain, dyspnea, difficulty sleeping, headache, cough, weight loss, anemia and back pain
Preliminary Results of OGX-011 Treatment on Serum Clusterin Levels: Summary for the Combined Treatment Groups
Comparison of baseline serum clusterin levels to the post-treatment average levels showed a significant reduction (p < 0.0001). In addition, average serum clusterin levels were predictive of survival, with low-average levels predicting median survival time of 14.7 months compared to high-average levels predicting median survival time of 5.5 months. These data suggest that a reduction in clusterin levels may improve survival.
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