Sunday, December 5, 2004, 06:00 PM
[2398] A Phase I/II Multicenter, Safety and Efficacy Study of Combination Treatment with Melphalan, Arsenic Trioxide and Vitamin C (MAC) in Patients with Relapsed or Refractory Multiple Myeloma.
Session Type: Poster Session 611-II
James R. Berenson. Oncology, Oncotherapeutics, Inc., Los Angeles, CA, USA
Background: An urgent need exists for new treatments to overcome chemoresistance in MM patients. Recent in vitro and In vivo studies in our laboratory show that arsenic trioxide (ATO) can sensitize chemoresistant MM cells to melphalan-induced cytotoxic effects. Pre-clinical studies also show the most profound anti-MM effects when ATO, ascorbic acid and melphalan are used in combination compared with the effects observed when the drugs are used alone or combinations of any two of these agents. Based on encouraging results from a pilot study1, a larger, multicenter trial was recently started.
Methods: MM patients who showed relapse after responding to first-line chemotherapy and/or having proved to be refractory to chemotherapy are enrolled. Patients received a loading dose of ATO at 0.25 mg/kg IV followed by ascorbic acid 1 g IV days 1-4 of week 1 of each six-week cycle. ATO/ascorbic acid was given twice-weekly for the next 4 weeks of each cycle. Low-dose melphalan (0.10 mg/kg) was administered orally for the first 4 days of each cycle. Patients received a maximum of 6 cycles followed by weekly maintenance treatment with weekly ATO followed by ascorbic acid. The primary objectives of this study are to determine response rate and safety and tolerability of MAC therapy.
Results: Twenty patients have received at least one treatment cycle. Preliminary data show that eight (4 PR, 4 MR) of the 14 evaluable patients (57%) had an objective response, an additional three patients achieved stable disease, resulting in a total of 11 patients (79%) with disease control. Since responses were seen after 2 to 5 treatment cycles, it is possible that some patients with stable disease may experience additional disease response. Seven of the eight responding patients had failed two or more treatments: five patients had received prior thalidomide therapy, two had received melphalan and bortezomib, and two patients had undergone autologous peripheral stem cell transplantation. Of the six patients who have now completed the maximal numbers of cycles, four achieved PR, one MR, and one SD. The regimen was well tolerated with few significant side effects reported; mild cytopenias were reported as reversible.
Conclusions: These preliminary results in this treatment group of heavily pre-treated MM patients who had either relapsed or were refractory to standard and/or investigational multiple myeloma treatments suggests that the MAC treatment regimen (1) shows efficacy using a low dose of melphalan supporting the preclinical evidence that ATO can sensitize tumors to chemotherapy; (2) is well tolerated; (3) may require multiple cycles before response.
References:
1. Borad M, Swift R, Sadler K, Yang H, Berenson JR. Melphalan, Arsenic Trioxide and Ascorbic Acid (MAC) is Effective in the Treatment of Refractory and Relapsed Multiple Myeloma (MM). ASH 2003.
Abstract #2398 appears in Blood, Volume 104, issue 11, November 16, 2004
Keywords: Relapse|Trisenox|Myeloma
Poster Session: Myeloma Therapy - Non-Transplant III (6:00 PM-7:30 PM)
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Sunday, December 5, 2004, 06:00 PM
[2419] Arsenic Trioxide (Trisenox® ATO), Ascorbic Acid (AA) and Dexamethasone (Dex) Pulses (TAD) for Relapsed Refractory Progressive Multiple Myeloma (MM) Patients (pts); a Final Report.
Session Type: Poster Session 632-II
Rony M. Abou-Jawde, Janice Reed, Megan Kelly, Luba Platt, Mary Ann Karam, Mary Ruth Kovak, Gordan Srkalovic, Mohamad A. Hussein. Multiple Myeloma Research Program, Cleveland Clinic, Cleveland, OH, USA; Cell Therapeutics, Seattle, WA, USA; Oncology, Sparrow Cancer Center, Lancing, MI, USA
ATO is a novel anticancer agent whose unique multifaceted mechanisms of action offer a scientific rationale for investigation in different hematologic malignancies. 2 phase II studies of ATO in advanced,heavily treated MM reported =25% decrease(40-50% of treated pts) in serum M-protein concentrations. Data from both studies suggest that long term therapy might result in enhanced quality of responses. It has been shown that ATO sensitizes myeloma cells to Dex in-vitro and AA potentiates the effect of ATO on different myeloma and human cell lines. We therefore initiated a phase II trial combining ATO with Dex & AA. MM pts with active,progressive disease who failed < 2 different regimens were eligible for enrollment. SWOG response criteria was used to assess efficacy to therapy. Treatment regimen consisted of 12 weeks (wks) treatment blocks with the 1st block considered induction,containing intense steroid schedule,and 1-2 more 12 wks blocks for consolidation with reduced steroid schedule. Regimen details;Cycle 1:Wk 1, loading with ATO at 0.25mg/kg IV d1-5,AA 1000mg IV within 30 minutes after each ATO infusion & Dex 40 mg orally d1-4. Wks 2 through 12; ATO at 0.25mg/kg IV twice weekly,AA 1000mg IV within 30 minutes after each ATO infusion & Dex 40 mg orally d11-14,29-32,39-42,57-60,& 67-70. Wks 13 through 15,is a rest period. Cycles 2 & 3 are the same as cycle 1 except Dex frequency is reduced to once a month (m) as follows;Dex 40 mg orally d1-4,29-32,57-60,& 67-70. Pts achieving SD or better were initiated on maintenance with the regimen administered for 5 wks with a 2m break and steroids given once a month. 20 pts were enrolled & evaluable for response and toxicity. Median age is 64,ß2 microglobulin 3.2mg/dl & median serum albumin is 3.85. Six,7,2 & 5 patients were on study for a median duration of 58, 151, 351 and 511 days respectively.17 pts were taken off study;14 for disease progression,1 for grade 4 painful neuropathy,1 for refusal of therapy &1 developed colon cancer. Median survival for the 14 pts alive is 18.3 m (2.5-24.2). The regimen was well tolerated with 6 pts experiencing either grade 3 hyperglycemia,headaches,burning at IV site,neutropenia,dehydration,syncope,or fatigue. 1 patient experienced grade 4 painful neuropathy and was taken off study with the event resolving in 4 wks without any therapy. 3/5 pts who proceeded to maintenance decided against the 3rd consolidation cycle because of travel logistics,absence of further reduction of protein,or normalization of performance status. The most common cause to reduce the number of loading dose days and the biweekly treatment during maintenance is grade 2 paraesthesia that resolved with dose reduction. 8 pts achieved >50% reduction of the m-protein following cycle 1 of therapy;2CR,1NCR,5PR,10SD & 3PD. None of the pts but 1 showed further improvement in the m-protein after the1st cycle of therapy. Mean duration of therapy was 1.9 years. TAD results in an over all response rate of 45% & 85% SD or better with a mean survival of 18.3 months. Further expansion of the study to confirm this data is warranted,and utilizing the complementary mechanism of action of other immunomodulatory agents such as thalidomide with this regimen is ongoing.
Abstract #2419 appears in Blood, Volume 104, issue 11, November 16, 2004
Keywords: Multiple myeloma|Arsenic trioxide|Phase II
Poster Session: Myeloma Therapy - Non-Transplant III (6:00 PM-7:30 PM) |
