1. Carlson, Robert H.

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NEW YORK CITY-The immunomodulatory agent lenalidomide is showing promise in patients with castration-resistant prostate cancer when combined with docetaxel.

Chemotherapy Foundat... - Click to enlarge in new windowChemotherapy Foundation Symposium

Lenalidomide is a derivative of thalidomide, and both compounds have anti-angiogenic and immune modulatory moieties. Speaking here at the Chemotherapy Foundation Symposium, Daniel Petrylak, MD, Director of the Prostate Cancer Program of the Herbert Irving Comprehensive Cancer Center and Professor of Medicine at New York Presbyterian Hospital/Columbia University Medical Center, noted that it is thought that lenalidomide, which has an effect on CD8 cells, may be more immune stimulatory than thalidomide is. And besides being anti-angiogenic, both of these small-molecule drugs are orally bioavailable, immunomodulatory, and affect inflammatory cytokines and the immune response.


Both also inhibit TNF-alpha, IL1-beta, and IL-6; stimulate IL-10; and augment interleukin-2 and interferon gamma.


Dr. Petrylak reviewed the development of regimens combining an immunomodulatory drug with chemotherapy. Single-agent thalidomide was found to produce durable responses in several trials, with a PSA decline of 50% or more in 18 to 40 percent of patients with castration-resistant prostate cancer.


Thalidomide is generally well-tolerated, he said, noting that the most commonly seen drug-related side effects are fatigue and neuropathy, and patients also experience constipation, dizziness, and edema.


When thalidomide was combined with docetaxel a PSA decline of 50% or more was seen in 51% to 66% of patients, versus only 32% to 37% in patients receiving docetaxel alone.


When researchers at MD Anderson Cancer Center tested a triplet combination of thalidomide with paclitaxel and estramustine in men with chemorefractory androgen-independent prostate cancer, 55% of patients experienced a PSA decrease of 50% or more, while 21% saw PSA drop by 80% or more. The safety profile was acceptable, Dr. Petrylak said.


The combination was therefore considered promising for men with androgen-independent prostate cancer.


Dr. Petrylak said the early combination regimens used primarily weekly administration of docetaxel before it was recognized that the every-three-week regimen produced longer survival than weekly administration did.


Then a trial from the National Cancer Institute presented intriguing data. The primary endpoint was progression-free survival, and there did not appear to be a large difference between weekly docetaxel versus weekly docetaxel with thalidomide.


"But when we looked at the survival data in a subsequent analysis, there actually was a significant difference in favor of the combination therapy," he said.


Lenalidomide was first evaluated as a single agent in castration-resistant prostate cancer. Dr. Petrylak said a small study presented at the American Society of Clinical Oncology's 2003 Annual Meeting, with 12 such patients, used slightly lower doses of lenalidomide than are used for treating multiple myeloma or myelodysplastic syndromes. The drug was well tolerated, although deep-vein thrombosis and hypotension were seen in patients and were considered the dose-limiting side effects. The maximum tolerated dose was determined to be 10 mg.


No partial or complete responses were seen in that trial, he said, and responses were primarily in PSA stabilization.


A Phase I/II trial conducted by Dr. Petrylak and colleagues tested docetaxel-lenalidomide in men with castration-resistant prostate cancer who had prior treatment with docetaxel as well as men who had not received docetaxel.


Docetaxel was administered every three weeks as standard dosage and lenalidomide on days 1 and 14.


"What got us excited was the fact that there were responses in progression in patients who had immediately come off docetaxel," Dr. Petrylak said.


He said 15 patients (44%) had a PSA decline of 50% or more, including 10 of 18 patients with no prior chemotherapy and five of 16 with prior chemotherapy. And seven additional patients had a PSA decline of 30% or more.


Chemotherapy-naive patients had a median time to progression of 233 days, and previously treated patients, 162 days.


He said it was very interesting that three patients in this trial have gone past 20 cycles, suggesting that the lenalidomide-docetaxel regimen is well tolerated. This might have to do with the cytokines, he said, adding, though that this is a small group of patients and could be subject to selection bias.


Dr. Petrylak said he had just received PSA data from an expanded cohort of that trial at the Phase II/III dose, which showed that 50% of all patients experienced a PSA decrease of 50% or more, and the same was seen in 40% of those patients with prior therapy.


'Most Exciting Ongoing Trial with Lenalidomide'

Dr. Petrylak said the most exciting ongoing trial with lenalidomide in castration-resistant prostate cancer is from the NCI, using docetaxel at the standard dose, bevacizumab on day 1, and lenalidomide on days 1-14.


"There are patients who have had significant PSA declines and the response rate overall was 87.5%, which is very similar to what we've seen with the triplet regimen with thalidomide," he said.


A high rate of osteonecrosis of the jaw is concerning, he said, and it is not clear whether this was related to bisphosphonate therapy or not.


"But certainly we do see a very high response rate," Dr. Petrylak said.


Phase III Study Underway

Dr. Daniel Petrylak concluded by describing the Phase III "Mainsail" study that compares the standard regimen of docetaxel-prednisone with docetaxel-prednisone-lenalidomide. The trial, opened in 2009, is almost fully accrued to its goal of 1,015 patients. Patients have had no prior therapy.


The primary endpoint is overall survival, and secondary endpoints are safety, progression-free survival, and response.