scholarly journals A Phase I/II Study of Arsenic Trioxide/Bortezomib/Ascorbic Acid Combination Therapy for the Treatment of Relapsed or Refractory Multiple Myeloma

2007 ◽  
Vol 13 (6) ◽  
pp. 1762-1768 ◽  
Author(s):  
James R. Berenson ◽  
Jeffrey Matous ◽  
Regina A. Swift ◽  
Russell Mapes ◽  
Blake Morrison ◽  
...  
Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2565-2565 ◽  
Author(s):  
James Berenson ◽  
Jeff Matous ◽  
Delina Ferretti ◽  
Regina Swift ◽  
Russell Mapes ◽  
...  

Abstract Background: Both arsenic trioxide and bortezomib as single agents have shown efficacy for patients with relapsed/refractory multiple myeloma (MM). Recently, we have demonstrated synergistic anti-MM effects when these two agents are combined to treat human MM in SCID mice and evaluated in in vitro studies. In addition, we and others have also shown that the addition of ascorbic acid (AA) sensitizes MM cells to the cytotoxic effects of arsenic trioxide both through in vitro and in vivo studies. Thus, the objective of the current Phase I clinical trial was to assess the safety and tolerability of bortezomib + arsenic trioxide + AA treatment for patients with refractory/relapsed MM. Methods: A treatment cycle comprised of intravenous injections of arsenic trioxide, bortezomib and AA on days 1, 4, 8, and 11 followed by a 10-day rest period every three weeks. Bortezomib was given at one of three dose levels (0.7, 1.0, or 1.3 mg/m2), followed by arsenic trioxide at one of two doses (0.125 or 0.25 mg/kg) intravenously followed by AA (1000 mg). Patients were treated for a maximum of eight cycles and were eligible for maintenance therapy with the same treatments given once every other week. Results: Eighteen patients have been enrolled to date, with three patients enrolled in each of the six cohorts. Patients had received a median of three prior therapies (range, 1–6), and five patients had received prior bortezomib therapy. Fifteen patients are evaluable for efficacy to date, and response data are summarized in Table 1. Overall, among the 15 evaluable patients, seven patients responded (2 PR, 5 MR), three patients showed stable disease, and five patients progressed. Among the six patients (in cohorts 1 and 4) enrolled at the lowest (0.7 mg/m2) bortezomib dose level, only one achieved a MR whereas among the nine evaluable patients enrolled at the higher (1.0 and 1.3 mg/m2) bortezomib dose levels six patients responded (2 PR, 4 MR). In general, the regimen was well tolerated. One patient in cohort 3 was removed from study during the first cycle because of the development of an asymptomatic arrhythmia which resolved spontaneously. Other serious adverse events included pneumonia in two patients, chest pain, and abdominal pain (one patient each). Conclusion: These early results from this Phase I/II study indicate that the combination of bortezomib, arsenic trioxide and ascorbic acid has efficacy and is well tolerated in a heavily pretreated population of patients with relapsed or refractory MM. Because of these encouraging clinical results, we plan to further evaluate this combination in a larger group of patients with relapsed/refractory myeloma. Table 1. Dose escalation scheme Cohorts Arsenic trioxide Bortezomib No. of evaluable pts Response *one patient in cohort 3 went off study during cycle 1 (see above), and the other two patients (one each in cohorts 3 and 6) are too early for response evaluation Cohort 1 0.125 mg/kg 0.7 mg/m2 3 1 MR, 2 PD Cohort 2 0.125 mg/kg 1.0 mg/m2 3 1 PR, 1 SD, 1 PD Cohort 3 0.125 mg/kg 1.3 mg/m2 1* 1 PR Cohort 4 0.25 mg/kg 0.7 mg/m2 3 1 SD, 2 PD Cohort 5 0.25 mg/kg 1.0 mg/m2 3 3 MR Cohort 6 0.25 mg/kg 1.3 mg/m2 2* 1 SD, 1 MR


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5129-5129
Author(s):  
Lauren Held ◽  
Jon P. Gockerman ◽  
Louis F. Diehl ◽  
Carlos Manuel de Castro ◽  
Joseph O. Moore ◽  
...  

Abstract Abstract 5129 Purpose: Bortezomib is a well recognized standard therapy, however it is not curative for multiple myeloma. New agents and approaches are needed to overcome resistance in multiple myeloma. Arsenic trioxde (ATO) induces apoptosis of plasma cells through a number of mechanisms, including down regulation of gene overexpression, activating cell cycle arrest by inducing p21 cyclin-dependent kinase inhibitor protein, and by triggering apoptosis through caspase-3 in a dose dependent manner. This phase I study assessed the feasibility and tolerability of concomitant administration of arsenic trioxide (ATO), ascorbic acid (AA), and bortezomib (VelcadeÔ) (AAV) in patients with relapsed/refractory multiple myeloma. Experimental Design: A standard dose of ATO (0.25 mg/kg IV infused over 1–2 hours) and AA (1g IV infused over 15 minutes after infusion of ATO) were given once weekly × 2 with an escalating dose of bortezomib (cohort 1: 1 mg/m2 or cohort 2: 1.3 mg/m2 IV bolus on days 1, 8) of a 21 day cycle). ATO was given at least 1 hour prior to bortezomib and patients were allowed up to a maximum of 6–8 cycles. Results: A total of ten patients (median age, 62 years old) were enrolled with a median follow up of survivors of 25 months. Patients had an average of 4 prior failed therapies. Seven (70%) patients were refractory to bortezomib when previously administered. Despite our patient population being heavily pre-treated, objective responses were observed, with one partial response (Cohort 2), two minimal response (Cohort 1 and 2), and one stable disease (Cohort 2). To date, three of the 10 patients are continuing maintenance therapy 13–43 months from initiating this study. Conclusion: Of the patients that completed the treatment, objective responses were observed despite suboptimal dosing and previous bortezomib treatment failure. Tolerability was observed in most patients as discontinuation was not due to treatment toxicities, but due to aggressiveness of disease. Further studies are warranted with a larger patient population to effectively determine the effectiveness of AAV in relapsed/refractory multiple myeloma. Disclosures: Rizzieri: Cephalon: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Long:Millennium: Speakers Bureau. Gasparetto:Millennium: Speakers Bureau.


2009 ◽  
Vol 15 (3) ◽  
pp. 1069-1075 ◽  
Author(s):  
James R. Berenson ◽  
Ori Yellin ◽  
Ravi Patel ◽  
Herb Duvivier ◽  
Youram Nassir ◽  
...  

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7611-7611 ◽  
Author(s):  
J. R. Berenson ◽  
J. V. Matous ◽  
D. Ferretti ◽  
R. A. Swift ◽  
R. A. Mapes ◽  
...  

7611 Background: The combination of arsenic trioxide (ATO) and bortezomib (B) has shown synergistic anti-tumor activity against human multiple myeloma (MM) cells in preclinical studies, suggesting that this combination may effectively treat patients with MM. In addition, ascorbic acid (AA) can sensitize MM cells to the cytotoxic effects of ATO. Methods: Patients with relapsed or refractory MM were enrolled in this phase I/II dose-escalation trial in 6 cohorts. Patients were given ATO (0.125 or 0.250 mg/kg), B (0.7, 1.0, or 1.3 mg/m2), and a fixed dose of AA (1000 mg) IV on days 1, 4, 8, and 11 of a 21-day cycle for a maximum of 8 cycles. The planned sample size was a maximum of 27 evaluable patients. The primary endpoint was safety and tolerability of the ATO/B/AA regimen in patients with relapsed or refractory MM. Results: At the time of this interim analysis, 22 patients (median age, 63 years) have been enrolled, and accrual has been completed on all cohorts. This group had failed a median of 4 (range, 3–9) prior therapies. One occurrence of grade 4 thrombocytopenia was observed. One occurrence of asymptomatic arrhythmia led to patient withdrawal. All other adverse events were grade 1 or 2. For the 21 patients evaluable for efficacy, objective responses were observed in 10 patients (43%), including 2 complete (CR), 2 partial (PR), and 5 minor (MR) responses. Only 1 (1 MR) of 6 patients receiving the lowest dose of B (0.7 mg/m2) showed a response, whereas 8 (2 CR, 2 PR, and 4 MR) of 15 patients receiving the higher doses (1.0 or 1.3 mg/m2) responded. Conclusions: The ATO/B/AA regimen was well tolerated by the majority of patients, and produced objective responses in 43% of the patients in this heavily pretreated group. The results of this phase I/II study warrant further clinical evaluation of the ATO/B/AA combination regimen for the treatment of patients with relapsed or refractory MM. [Table: see text]


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