New Multiple Myeloma Treatments On The Horizon (ASCO 2012)
Published: May 23, 2012 12:20 pm
During the upcoming annual meeting of the American Society of Clinical Oncology (ASCO), results will be presented from clinical trials involving potential new drugs under development for the treatment of multiple myeloma.
In particular, results for newer, lesser known agents that are in the early stages of clinical development will take center stage. These agents include obatoclax, siltuximab, daratumumab, and SNS01-T.
According to the recently released ASCO abstracts, the agents showed varying degrees of activity in relapsed and refractory myeloma patients. So it will be particularly interesting to see and hear how the myeloma experts react to the initial findings for these compounds.
The current article summarizes the preliminary results from these agents, based on the data available in the meeting abstracts.
Obatoclax is being developed by the pharmaceutical company Cephalon, a subsidiary of Teva Pharmaceuticals (NASDAQ: TEVA). It is an inhibitor of the Bcl-2 family of proteins. This inhibition causes cell death in cancer cells, preventing tumor growth. Obatoclax is currently being investigated as a treatment for solid tumors as well as for a variety of blood cancers, including multiple myeloma, leukemia, and lymphoma.
At ASCO, Dr. A. K. Stewart from the Mayo Clinic in Arizona will discuss results of a Phase 1 study of obatoclax in combination with Velcade (bortezomib) for the treatment of relapsed multiple myeloma.
Since it is a Phase 1 trial, the study population is small. The abstract contains data from 11 patients. The median patient age was 62 years. The median time from diagnosis was 4.7 years.
Patients received a starting dose of 14 mg/m2 of obatoclax as a 24-hour continuous infusion on days 1, 8, and 15 of a 21-day treatment cycle, which was then amended to either 30 mg/m2 or 40 mg/m2 of obatoclax as a three-hour continuous infusion on days 1, 8, and 15. In addition, patients received 1.3 mg/m2 of Velcade on days 1, 4, 8, and 11.
Ten patients were evaluable for response; 40 percent of patients achieved a partial response and 10 percent achieved a minor response. None of the patients who received 40 mg/m2 of obatoclax as a three-hour continuous infusion responded.
The researchers did not observe any dose-limiting side effects at the 30 mg/m2 dose level, so it was determined to be the maximum tolerated dose.
The most commonly observed side effects were blood-related or neurologic in nature.
Siltuximab is a compound that blocks the activity of IL-6, a protein that facilitates myeloma cell growth and resistance to dexamethasone (Decadron). It is being developed by Janssen Biotech, a Johnson & Johnson company (NYSE: JNJ), and has been investigated for the treatment of prostate cancer, ovarian cancer, metastatic renal cell cancer, and Castleman’s disease (excessive growth of lymphatic cells).
At ASCO, Dr. Robert Orlowski from the MD Anderson Cancer Center in Houston will present results from a Phase 2 study comparing siltuximab plus Velcade to Velcade alone in relapsed and refractory myeloma patients.
The study included 286 patients who received either 6 mg/kg of intravenous siltuximab twice weekly plus 1.3 mg/m2 of Velcade on days 1, 4, 8, 11, 22, 25, 29, and 32 in a 42-day treatment cycle or Velcade alone for a maximum of four treatment cycles. After that, Velcade was reduced to once weekly in 35-day treatment cycles.
Patients who progressed discontinued Velcade and could receive 40 mg of dexamethasone daily on days 1 through 4, 9 through 12, and 17 through 20 of a 28-day treatment cycle for a maximum of four cycles. In subsequent treatment cycles, dexamethasone was administered on days 1 through 4 until disease progression.
Patients who received siltuximab plus Velcade were slightly older (median age 64 years) than patients receiving Velcade alone (61 years).
The median treatment duration was five months in both treatment groups, and the median follow-up time was 24.5 months.
More patients on siltuximab plus Velcade responded to treatment (55 percent) than patients on Velcade alone (47 percent). Complete response rates were 11 percent for patients receiving siltuximab plus Velcade and 7 percent for patients receiving Velcade alone.
The median progression-free survival time was longer for patients receiving siltuximab plus Velcade (8.1 months), compared to patients receiving Velcade alone (7.6 months).
However, the median overall survival was longer for patients receiving Velcade alone (36.9 months), compared to those receiving siltuximab plus Velcade (30.8 months).
More patients receiving siltuximab plus Velcade experienced severe or life-threatening side effects (91 percent) than patients receiving Velcade alone (74 percent).
Daratumumab is being developed by the Danish pharmaceutical company Genmab. It is a monoclonal antibody that binds to the CD38 molecule, which is found on the surface of multiple myeloma cells. Daratumumab then signals for the immune system to kill the myeloma cells.
At ASCO, Dr Torben Plesner from Vejle Hospital in Vejle, Denmark, will present preliminary efficacy results from a Phase 1/2 study of daratumumab in relapsed and refractory myeloma patients.
Study participants received escalating doses of daratumumab ranging from 0.005 mg/kg to 24 mg/kg.
The data included in the abstract is based on data from 23 patients who received up to 4 mg/kg of daratumumab.
Daratumumab’s preliminary efficacy evaluation is based on the change in monoclonal (M) protein in the blood or urine.
Of the patients receiving up to 1 mg/kg of daratumumab, 18 percent of patients achieved a reduction in M-protein ranging from 12 percent to 19 percent. Of the patients receiving 2 mg/kg, a third achieved a reduction in M-protein of 55 percent. In the 4 mg/kg group, all patients achieved a reduction in the M-protein ranging from 49 percent to 64 percent.
In addition, all patients in the 4 mg/kg group showed a marked reduction in the percentage of plasma cells in the bone marrow ranging from 80 percent to 97 percent.
According to the researchers, the drug’s side effects at these doses are manageable.
SNS01-T is being developed by the pharmaceutical company Senesco (NYSEAMEX: SNT). It selectively causes cells to die by targeting a protein called eIF5A, which is believed to be an important regulator of cell growth and cell death. SNS01-T is a nanoparticle that has three components: the first part targets myeloma cells with the natural form of eIF5A; the second part causes the cells to create an ineffective version of eIF5A; and the third part is a polymer that is used to deliver the complex to the myeloma cells.
During a poster session on Monday, June 4, results will be presented from a Phase 1/2 trial investigating the safety and tolerability of SNS01-T in relapsed and refractory multiple myeloma patients.
The abstract currently does not include any study results. Dr. John Lust from the Mayo Clinic, the study’s lead investigator, stated to The Myeloma Beacon in request for further information that the study is a 'trial in progress' and that he cannot provide more information at this time than what is included in the abstract.
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