| Full Name: | Trisenox® (arsenic trioxide) |
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| Other Names: | ATO, As203 |
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| Description: | Anti-cancer drug with multiple actions (intravenous) |
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| Phase: | II |
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| Company: | Cephalon, Inc. www.cephalon.com |
What It Is
Trisenox (arsenic trioxide) is a form of arsenic, a naturally occurring element that has been used for therapeutic purposes for more than 2000 years. Trisenox is being investigated as a treatment for myeloma, hematologic cancers, and various solid tumors. It is approved for the treatment of a specific type of leukemia known as acute promyelocytic leukemia (APL) and is on the compendia listing for the therapy of myeloma. Trisenox was originally marketed by Cell Therapeutics, Inc. but was acquired by Cephalon, Inc. in July 2005.
How It Works
Overview
Trisenox is an anticancer drug that exhibits multiple direct and indirect effects against myeloma cells.
Details About Trisenox's Mechanism of Action
Trisenox exhibits its anti-myeloma effects at different levels. It has been shown to
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Inhibit the growth of myeloma cells directly when exposed to the agent in the laboratory
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Induce apoptosis (programmed cell death) of myeloma cells
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Enhance killing of the myeloma cell by cells of the immune system. It does this by inhibiting the expression of CD38 (a cell marker on the surface of the myeloma cell) and the expression of the corresponding CD38 ligand on immune cells (the "key" that the immune cells use to identify the myeloma cell to attack it).
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Block the ability of myeloma cells to "stick" to bone marrow stromal cells. It does this by inhibiting the production of adhesion molecules on the surface of both cell types. This, in turn, inhibits the secretion of interleukin 6 (IL-6), a growth factor for myeloma cells, by the stromal cells
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Inhibit the growth of new blood vessels (angiogenesis) by stimulating apoptosis of tumor-supporting endothelial cells and inhibiting the production of vascular endothelial growth factor (VEGF)
Ascorbic acid (vitamin C) appears to enhance the activity of Trisenox against myeloma cells in the laboratory. It does this by modifying the metabolic pathway (glutathione pathway) that deactivates the arsenic. The combination of the two agents appears to be effective in killing cells that are resistant to other drugs.
Clinical Profile
Dosage and Administration
Trisenox is given as an intravenous infusion over a period of 1 to 4 hours. It is administered 2 to 5 days a week for various lengths of time, sometimes with time off the drug between cycles. It may be given in combination with dexamethasone and/or ascorbic acid.
Side Effects
The side effects seen with Trisenox therapy in myeloma patients appear to be somewhat different than those seen in patients with APL. In myeloma clinical trials, the most common side effects reported with Trisenox include fluid retention and electrolyte imbalances that affect potassium and magnesium. Fluid retention could be related to use of combined use of steroids as well as the disease process itself.
Updated safety experience with Trisenox in patients with hematologic and non-hematologic malignancies was reported in an abstract at the 9th Congress of the European Hematology Association held in June 2004. (Oliva et al., Hematol J. 2004;5(suppl 2).) The data appear to confirm that Trisenox is generally well tolerated and that the observed side effects are manageable and reversible.
Through February 2004, it is estimated that 1040 patients with myeloma received Trisenox in clinical trials (including investigator-sponsored trials) or following its approval for treatment of patients with acute promyelocytic leukemia. During this time, the most commonly reported adverse events in patients with myeloma (n=107) included low blood counts that were not associated with fever and the majority of which did not require treatment with growth factors, fluid retention, increase in weight, difficulty breathing, low blood pressure, ECG abnormalities, and fatigue.
Updated safety experience with Trisenox in patients with hematologic and non-hematologic malignancies was reported in an abstract at the 9th Congress of the European Hematology Association held in June 2004. (Oliva et al., Hematol J. 2004;5(suppl 2).) The data appear to confirm that Trisenox is generally well tolerated and that the observed side effects are manageable and reversible.
Through February 2004, it is estimated that 1040 patients with myeloma received Trisenox in clinical trials (including investigator-sponsored trials) or following its approval for treatment of patients with acute promyelocytic leukemia. During this time, the most commonly reported adverse events in patients with myeloma (n=107) included low blood counts that were not associated with fever and the majority of which did not require treatment with growth factors, fluid retention, increase in weight, difficulty breathing, low blood pressure, ECG abnormalities, and fatigue.
Preclinical Studies
In the laboratory, arsenic trioxide has been shown to induce apoptosis (programmed cell death) of myeloma cell lines and myeloma cells from patients. It also inhibited myeloma cell survival and growth.
Recent preclinical studies have shown that:
Recent preclinical studies have shown that:
- Arsenic trioxide appears to increase the sensitivity of myeloma cells to melphalan.
- Arsenic trioxide shows synergistic anti-myeloma effects when combined with bortezomib (Velcade®, Millennium Pharmaceuticals) in laboratory studies and helps overcome resistance of myeloma cells to these treatments in a mouse model of the disease. (Campbell et al. Blood. 2004;104(11). Abstract 2467.)
- Ascorbic acid overcomes drug resistance in myeloma and significantly increases the anti-myeloma effects of both arsenic trioxide and melphalan in the lab and in animal models. (Campbell et al. Blood. 2004;104(11). Abstract 2470.)
- Arsenic trioxide induces deregulation of molecular mechanisms that are not involved in anti-myeloma activity of conventional therapies, as noted by gene expression profiling. (Maiso et al. Blood. 2004;104(11). Abstract 2457.)
- Apoptosis induced by arsenic trioxide is enhanced by the addition of a component of green tea. (Nakazato et al. Blood. 2004;104(11). Abstract 2475.)
Clinical Trials
Trisenox is currently being evaluated in a number of Phase II trials in relapsed and refractory myeloma. Although Cell Therapeutics Inc. does not plan to pursue a Phase III trial of Trisenox in patients with myeloma, the Phase II data eventually may be used to supplement the current label for use of the agent in myeloma.
Phase II
Single agent. The first Phase II study of Trisenox in relapsed and refractory myeloma included 14 patients who had relapsed or refractory disease and at least 1 autologous stem cell transplant. Patients received a 2-hour daily infusion of Trisenox at the same dose used in the treatment of APL (0.15 mg/kg for 60 days) for 60 days. Patients who responded received retreatment 3 to 6 weeks after the first treatment. (Munshi et al. Leukemia. 2002;16:1835-1837.)
Altogether, 3 patients had reductions in M protein of between 25% and 74%. The results from this study are summarized in the table below. Trisenox therapy was well tolerated in this advanced, heavily-pretreated group of patients (all but 2 patients had received 2 stem cell transplants, and all had failed transplant and salvage therapy). Severe neutropenia (low numbers of white blood cells called neutrophils) developed in 11 patients. However, this may have been related to the many previous therapies received by these patients. Three patients experienced deep vein thrombosis (DVT, formation of blood clots in the deep veins in the body), 2 reported extreme fatigue, and 5 developed infections.
Altogether, 3 patients had reductions in M protein of between 25% and 74%. The results from this study are summarized in the table below. Trisenox therapy was well tolerated in this advanced, heavily-pretreated group of patients (all but 2 patients had received 2 stem cell transplants, and all had failed transplant and salvage therapy). Severe neutropenia (low numbers of white blood cells called neutrophils) developed in 11 patients. However, this may have been related to the many previous therapies received by these patients. Three patients experienced deep vein thrombosis (DVT, formation of blood clots in the deep veins in the body), 2 reported extreme fatigue, and 5 developed infections.
Phase II Study of Trisenox in Relapsed/Refractory Myeloma: Responses |
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| *Included 1 patient with stable disease |
Final results of another Phase II study of Trisenox in relapsed or refractory myeloma were published in 2004. (Hussein et al. Br J Haematol. 2004;125:470-476.) This study evaluated higher, less frequent dosing of Trisenox (up to six 4-week cycles of 0.25 mg/kg 5 days a week for 2 weeks, followed by no therapy for 2 weeks). Twenty-four patients, two-thirds who were refractory to previous therapy, were enrolled in the trial. Eight patients (33%) had an objective response as measured by >25% reduction in M protein. An additional 6 patients (25%) achieved stable disease. Severe (Grade 3 or Grade 4) neutropenia was seen in 16 patients but was not associated with neutropenic fever except for possibly one instance. Other side effects reported, most of which were mild to moderate, included fatigue, shortness of breath, nausea, abdominal pain, infection, or fever.
Several small studies of Trisenox alone or in combination with ascorbic acid or chemotherapy suggest that the agent produces clinically relevant responses in chemotherapy-resistant myeloma.
Melphalan, arsenic trioxide, and vitamin C (MAC).For example, interim results of a small ten-case report of combination treatment with melphalan, arsenic trioxide, and vitamin C (MAC) in relapsed or refractory myeloma reported at the 45th Annual Meeting of the American Society of Hematology (ASH) meeting in December 2003 were promising. (Borad et al. Blood. 2003;102(11). Abstract 827.) All 10 heavily-pretreated patients who received the combination responded with reductions in serum M protein ranging from 29% to 90%. At the time the data was presented, 6 of the 10 patients remained free from disease progression for a median of 10 months (range, 5 to 15 months). The 5 patients who had moderate to severe kidney impairment at the start of the study showed improvement in kidney function with treatment. Side effects reported with the combination are listed in the table below.
Several small studies of Trisenox alone or in combination with ascorbic acid or chemotherapy suggest that the agent produces clinically relevant responses in chemotherapy-resistant myeloma.
Melphalan, arsenic trioxide, and vitamin C (MAC).For example, interim results of a small ten-case report of combination treatment with melphalan, arsenic trioxide, and vitamin C (MAC) in relapsed or refractory myeloma reported at the 45th Annual Meeting of the American Society of Hematology (ASH) meeting in December 2003 were promising. (Borad et al. Blood. 2003;102(11). Abstract 827.) All 10 heavily-pretreated patients who received the combination responded with reductions in serum M protein ranging from 29% to 90%. At the time the data was presented, 6 of the 10 patients remained free from disease progression for a median of 10 months (range, 5 to 15 months). The 5 patients who had moderate to severe kidney impairment at the start of the study showed improvement in kidney function with treatment. Side effects reported with the combination are listed in the table below.
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Case Report of Melphalan, Arsenic Trioxide and Vitamin C (MAC): Interim Safety Results
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The encouraging results from this case report served as the basis for an ongoing multicenter Phase II study of the MAC regimen in relapsed and refractory myeloma. Preliminary data from this study presented at the 10th International Myeloma Workshop indicated that 22 of 37 evaluable patients (60%) achieved an objective response to the regimen. (Berenson et al. Haematologica. 2005;90(suppl.1):156. Abstract #PO.742.) A total of 22% of patients achieved a partial response (≥50% decrease in M protein) and 38% achieved a minor response (≥25%-49% decrease in M protein). Patients had failed an average of 4 prior regimens, including Thalomid® (thalidomide, Celgene) or Revlimid® (lenalidomide, Celgene), Velcade, melphalan, or stem cell transplant. Renal function improved with therapy; serum creatinine levels decreased in 10 of 14 assessable patients with a baseline serum creatinine ≥1.5 mg% and there was disease control in 7 of these patients. The median duration of response and time to progression had not been reached at the time of the presentation. The most common adverse events seen were hematologic in nature (Grade 3 in 12 patients and Grade 4 in 2 patients). There were treatment delays in 4 patients due to low blood counts, 2 patients due to ECG abnormalities (prolonged QT interval), and in 5 patients for other reasons. The study will continue to accrue to a target enrollment of 60 evaluable patients.
Arsenic trioxide, ascorbic acid, and dexamethasone (TAD). Trisenox has been evaluated in combination with ascorbic acid and pulsed dexamethasone (TAD) in a Phase II trial at the Cleveland Clinic involving 20 patients with relapsed, refractory, progressive myeloma. (Abou-Jawde et al. Haematologica. 2005;90(suppl. 1):156. Abstract PO.741.) The TAD regimen included one induction cycle followed by two consolidation cycles in which the dexamethasone frequency was reduced to once a month. Patients achieving stable disease or better received maintenance (the regimen administered for 5 weeks with a 2-month break and steroids once a month). Patients have had a mean duration of therapy of approximately 2 years.
Two patients (10%) achieved near CR (<90% decrease in M protein), 4 patients (20%) had partial response, and 10 (50%) had stable disease, for an overall response of 30% (SWOG criteria). Patients achieving stable disease had improvement in performance status as well as improvement in end organ damage. The median duration of response was 357 days (range, 21-701 days). The median progression-free survival (PFS) and overall survival (OS) were 316 days and 962 days respectively.
Most adverse events were mild to moderate. Grade 1 and Grade 2 fatigue, edema, nausea, elevated blood sugar, and neuropathy constituted more than 10% of the total grade 1 and 2 adverse events. Nine patients developed a Grade 3 event and one patient had a Grade 4 event that were considered treatment related. Most of these events were non-hematological; only one patient (5%) developed Grade 3 neutropenia without documented fever or infection. No patient on the study required growth factor support. One patient each experienced headache, fatigue, low sodium levels, dehydration, intravenous site burning, or fainting.
A multicenter Phase II trial evaluating the safety and efficacy of this combination is being conducted in Europe.
Ongoing Clinical Trials
Trisenox is currently being evaluated in patients with relapsed or refractory myeloma in a variety of ongoing clinical trials, several of which are listed in the table below. Several of these trials are evaluating Trisenox in combination with agents such as ascorbic acid, dexamethasone, melphalan, thalidomide, or bortezomib. A trial of Trisenox in combination with Doxil® (doxorubicin HCl liposome injection, Ortho Biotech), vincristine, and dexamethasone (DVd) has been initiated where the role of arsenic trioxide in enhancing the effects of DVd is being investigated. Moreover, the role of arsenic trioxide as a sensitizer for high-dose melphalan as an autologous stem cell transplant preparative regimen is currently in active trials.
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Ongoing Trisenox Clinical Trials as of August 2005
Phase II
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For More Information on Clinical Trials:
1-800-715-0944
Reviewed by:
Mohamad Hussein
Director, Myeloma Multidisciplinary Clinical Research Program
Cleveland Clinic