Circularly Permuted TRAIL May Be Effective For Relapsed/Refractory Multiple Myeloma (ASH 2012)
Published: Dec 17, 2012 2:29 pm
Results from three Chinese clinical trials indicate that the investigational drug circularly permuted TRAIL may be effective alone or in combination with thalidomide in relapsed and refractory multiple myeloma patients.
However, further testing of the drug is necessary to determine its optimal dose.
Dr. Wenming Chen from the Chaoyang Hospital of Capital Medical University in Beijing presented the findings from the three studies last week at the American Society of Hematology (ASH) annual meeting in Atlanta.
Circularly Permuted TRAIL (CPT) is being developed by Beijing Sunbio Biotech as a treatment for multiple myeloma and other blood cancers. It activates receptors in the body, known as TRAIL, that trigger cell death.
Preclinical studies have shown that CPT kills cancers cells, but does not affect most healthy cells.
During an oral presentation session at ASH, Dr. Chen presented the results of a Phase 2 study of CPT as a single-agent treatment in relapsed/refractory myeloma patients.
The study included 27 relapsed and refractory multiple myeloma patients who had been treated with a median of three prior lines of therapy. The median patient age was 59 years.
Patients received 2.5 mg/kg of CPT once daily for 14 days of a 21-day treatment cycle. All patients received two cycles of therapy.
Overall, 21 of the 27 patients completed the study. Two patients withdrew from the trial due to progressive disease; two others withdrew for administrative reasons; and two withdrew for “other reasons.”
Of the 21 patients who completed the study, 33 percent of the study participants responded to CPT treatment, including 4 percent who achieved a near complete response and 30 percent who achieved a partial response.
About half the patients in the trial had previously been treated with Velcade (bortezomib), and overall response rates among those patients were slightly higher than in those who had not been previously treated with Velcade (36 percent versus 31 percent, respectively).
Dr. Chen pointed out that responses were achieved within one to two treatment cycles, indicating that CPT is a rapid-acting antitumor agent.
According to Dr. Chen, CPT was well tolerated. Almost all patients (90 percent) reported at least one side effect from the treatment, but most side effects were mild in nature.
The most common side effects of any severity included fever (48 percent), elevated liver enzymes (41 percent), and low white blood cell counts (26 percent).
Severe side effects were reported by 37 percent of the patients, with the most common being elevated liver enzymes (11 percent).
Dr. Chen pointed out that the elevated liver enzymes were related to the dosing schedule. The rate of elevated liver enzymes was significantly lower in a separate trial where CPT was given only five days per treatment cycle.
CPT Efficacy At Different Doses
A poster presentation by Dr. Chen and his colleagues summarized the results from a Phase 1b clinical trial assessing CPT at different doses.
This trial aimed to establish an optimal dosage for CPT and to determine its efficacy and safety profiles.
The study included 29 patients with relapsed/refractory myeloma. The patients had a median age of 57 years and had been treated with a median of four prior lines of therapy.
Patients were treated intravenously with one of five doses of CPT, ranging from 5 mg/kg to 15 mg/kg. The CPT was administered once daily on the first five days of a 21-day cycle, and patients received a median of two cycles of treatment (range: 1-9).
Among the patients treated with at least the 8 mg/kg dose of CPT, 28 percent responded, with 6 percent achieving a complete response and 22 percent achieving a partial response.
Below 8 mg/kg of CPT, the highest response was a minimal response. Therefore, the investigators concluded that the optimal CPT dose is between 8 mg/kg and 15 mg/kg.
The investigators determined that CPT was safe at all doses tested. The most common side effects of any severity were fever (21 percent), low white blood cell counts (17 percent), fatigue (14 percent), vomiting (10 percent), and elevated liver enzymes (14 percent).
The most common severe side effects were low red blood cell counts (14 percent) and low white blood cell counts (10 percent).
CPT in Combination With Thalidomide
Dr. Chen and his colleagues also studied CPT in combination with thalidomide (Thalomid). Results from this Phase 2 clinical trial also were presented during a poster session at ASH.
The study included 43 relapsed/refractory myeloma patients, most of whom (78 percent) were less than 65 years of age. The study participants had been treated with a median of four prior lines of therapy, and all participants had been previously treated with — and no longer responded to — thalidomide.
Study participants were treated with one of three doses of CPT (5 mg/kg, 8 mg/kg, or 10 mg/kg) on days 1 to 5 of a 21-day cycle, for up to six cycles.
All patients also received 100 mg of thalidomide daily throughout each 21-day cycle.
Overall, 22 percent of patients responded, with 5 percent achieving a complete response, 7 percent a near complete response, and 10 percent a partial response. Patients treated with 10 mg/kg of CPT had the highest overall response rate (27 percent).
The researchers concluded that CPT with thalidomide was well-tolerated and that the side effects were similar for each of the dose groups.
The most common severe side effects were low white blood cell counts (19 percent), low platelet counts (5 percent), low red blood cell counts (5 percent), and elevated liver enzymes (5 percent). One patient died from a stroke that was thought to be disease-related rather than treatment-related.
The researchers concluded that CPT plus thalidomide was more effective than CPT alone (based on data from previous studies), despite the patients in this study being resistant to prior thalidomide therapy.
Based on their results, the researchers recommended that 10 mg/kg of CPT be used in future clinical trials.
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