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The Oncologist, Vol. 6, Suppl 2, 22-28, April 2001
© 2001 AlphaMed Press

SUPPLEMENT

Clinical Trials of Arsenic Trioxide in Hematologic and Solid Tumors: Overview of the National Cancer Institute Cooperative Research and Development Studies

Anthony J. Murgo

Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA

Correspondence: Anthony J. Murgo, M.D., Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, 6130 Executive Blvd., EPN Suite 7131, Rockville, Maryland, 20852-4910, USA. Telephone: 301-496-1196; Fax: 301-402-0428; e-mail: Murgoa{at}ctep.nci.nih.GOV


   ABSTRACT
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 Abstract
The National Cancer Institute...
 Rationale for Clinical...
 NCI-Sponsored Trials with...
 Conclusions
 References
 
Arsenic trioxide inhibits growth and promotes apoptosis in many different cancer cell lines. The National Cancer Institute is working cooperatively with research centers across the U.S. to evaluate its clinical activity in hematologic malignancies, such as acute promyelocytic leukemia, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, chronic lymphocytic leukemia, myelodysplastic syndrome, and multiple myeloma. It is also supporting research in solid tumors, such as advanced hormone-refractory prostate cancer and renal cell cancer and in cervical cancer and refractory transitional cell carcinoma of the bladder. The safety and pharmacokinetics of arsenic trioxide are also being evaluated in pediatric patients with refractory leukemia and lymphoma. The results of these ongoing studies should provide important insights into the clinical utility of arsenic trioxide in these diseases.

Key Words. Arsenic trioxide • National Cancer Institute • Hematologic malignancy • Solid tumor


   THE NATIONAL CANCER INSTITUTE COOPERATIVE RESEARCH AND DEVELOPMENT PROGRAM
Top
 Abstract
 The National Cancer Institute...
Rationale for Clinical...
 NCI-Sponsored Trials with...
 Conclusions
 References
 
The National Cancer Institute (NCI) partners with investigators from industry and academia on research projects of mutual interest through the use of Cooperative Research and Development Agreements (CRADAs). Because of promising preclinical findings and clinical results in acute promyelocytic leukemia (APL) with arsenic trioxide, the NCI has been interested in assisting in the development of this compound. In October 1998, the NCI Decision Network approved the use of government resources for the clinical development of arsenic trioxide formulated in the U.S. Shortly thereafter, the NCI solicited proposals for clinical trials in hematologic malignancies other than refractory APL and in selected solid tumors. The NCI filed an Investigational New Drug application for arsenic trioxide in March 1999, and executed a CRADA agreement with PolaRx (now Cell Therapeutics, Inc., Seattle, WA) in May 1999.

The NCI is sponsoring a randomized, intergroup, phase III trial in patients with newly diagnosed APL to evaluate the role of arsenic trioxide following induction with all-trans retinoic acid (ATRA) plus chemotherapy. The NCI is also sponsoring phase II investigations of arsenic trioxide for other malignancies, including the hematologic malignancies acute non-APL myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), low-, intermediate-, and high-grade non-Hodgkin's lymphoma (NHL), Hodgkin's disease, chronic lymphocytic leukemia (CLL), and multiple myeloma. The solid tumors in which preclinical studies suggest a role for arsenic trioxide therapy include those of the prostate, kidney, cervix, and bladder.


   RATIONALE FOR CLINICAL EVALUATION OF ARSENIC TRIOXIDE IN NON-APL HEMATOLOGIC MALIGNANCIES AND SOLID TUMORS
Top
 Abstract
 The National Cancer Institute...
 Rationale for Clinical...
NCI-Sponsored Trials with...
 Conclusions
 References
 
Observations of the clinical utility of arsenic trioxide in APL have prompted investigations into the mechanisms of action by which arsenic produces clinical benefit. Chen et al. determined that, at low concentrations, arsenic trioxide promotes differentiation of APL cells and, at higher concentrations, triggers apoptosis and downregulates Bcl-2 expression [1]. Subsequently, an intense research effort focused on whether these effects were unique to APL cells or to a more generalized response by different types of neoplastic cells.

Considerable preclinical evidence supports the potential of arsenic trioxide against a number of different malignancies (Table 1Go). Studies in cultured cells show that it inhibits growth and promotes apoptosis in myeloid leukemia, multiple myeloma, lymphoma, and lymphocytic leukemia, and solid tumor cell lines.


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  		Table 1. Preclinical activity of arsenic trioxide against malignancies other than APL
 
Antitumor effects may be enhanced when arsenic trioxide is combined with other agents. In vitro, ATRA induces differentiation, causing partial degradation of the promyelocytic leukemia retinoic acid receptor alpha (PML RAR{alpha}) fusion protein in APL cells. When such cells are cultured with arsenic trioxide, apoptosis is induced, and PML RAR{alpha} is totally degraded. These effects are synergistic, and alternating treatment with arsenic trioxide and ATRA improved survival in severe combined immunodeficient mice injected with APL cells [2, 3]. Arsenic trioxide also exhibits synergistic effects with interferon-{alpha} (IFN-a). In a model of human T-cell lymphotropic virus type 1 (HTLV-1)-transformed cells, Bazarbachi et al. showed that this combination inhibits cell proliferation, arrests cells in G1, and induces apoptosis [4]. The mechanisms by which these agents work together have been partially elucidated. Expression of the viral transactivator protein Tax, critical for viral transformation by HTLV-1, is downregulated, altering the NF-{kappa}B pathway [5]. Other mediators are involved as well. Ceramide is a sphingolipid that induces cell cycle arrest and apoptosis. HTLV-1 cells treated with IFN-{alpha} alone showed no increase in ceramide levels, and those treated with arsenic trioxide alone showed only a modest increase. However, levels were markedly increased in response to the combination of IFN-{alpha} and arsenic trioxide, suggesting that these agents work synergistically to promote apoptosis [6].

Arsenic trioxide exerts its cytotoxic effects on neoplastic cells by inhibiting proliferation, inducing apoptosis, and promoting cellular differentiation. Anecdotal and preliminary clinical data from China suggest a broad therapeutic potential for arsenic trioxide in the treatment of cancer. These findings support further investigation of the clinical utility of arsenic trioxide for the treatment of hematologic and solid tumor malignancies other than APL. A major objective of the NCI CRADA clinical trials program is to determine whether these preclinical and early clinical results can be translated into significant clinical benefit.


   NCI-SPONSORED TRIALS WITH ARSENIC TRIOXIDE
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 Abstract
 The National Cancer Institute...
 Rationale for Clinical...
 NCI-Sponsored Trials with...
Conclusions
 References
 
Most of the clinical studies described here were recently activated or are soon to be activated. Therefore, results are not available at the time of this writing. Response rate is the primary efficacy end point for all of these phase II studies. Most studies also include laboratory correlates to expand our understanding of the mechanisms of action of arsenic trioxide and help elucidate its pharmacokinetics and pharmacodynamics. Essentially, these are proof-of-concept trials to evaluate the clinical activity of arsenic and identify and characterize the molecular targets on which it acts. The doses and dosing schedules of arsenic trioxide necessary to achieve clinical benefit in these trials will likely differ from those used in trials with APL. A variety of doses and regimens were selected for these studies based on preclinical work or preliminary clinical investigations.

Phase II Studies in Hematologic Malignancies
Initial work with arsenic trioxide focused on APL and the current phase III NCI-sponsored intergroup trial of arsenic for consolidation therapy in patients with newly diagnosed APL has already been described. Table 2Go summarizes the clinical trials of arsenic trioxide in other hematologic malignancies.


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  		Table 2. Phase II studies of arsenic trioxide in hematologic malignancies other than APL
 
In a study of arsenic trioxide for the treatment of AML, patients older than 65 years with refractory, relapsed, or newly diagnosed AML were eligible for this trial. The Eastern Cooperative Oncology Group recently activated a trial of the compound in patients with relapsed or refractory ALL. Another multicenter study will investigate its activity in patients with relapsed or refractory Philadelphia chromosome positive ALL or CML in blast crisis. Two other studies are under way in patients with CML. Memorial Sloan-Kettering Cancer Center (New York, NY) has initiated a trial of arsenic trioxide administered at 0.25 mg/kg/day for 25 days in patients with relapsed or refractory CML. In a study at M.D. Anderson Cancer Center (Houston, TX), investigators are using the same dose for 15-30 days to treat patients with chronic-phase CML who are refractory to or intolerant of IFN-{alpha}. Although these doses are higher than those usually given in APL, preclinical data suggest that AML [7, 8] and malignant lymphoid cells [9] may require higher levels of arsenic to inhibit growth and induce apoptosis.

The utility of arsenic trioxide in the treatment of a number of lymphoid malignancies is being evaluated as well. At Memorial Sloan-Kettering Cancer Center, patients with relapsed or refractory intermediate- or high-grade NHL are being treated with arsenic trioxide, 0.25 mg/kg/day, 5 days a week for 5 weeks. In a trial at Mount Sinai Hospital (New York, NY), patients with relapsed or refractory low-grade NHL or CLL are eligible for treatment with arsenic trioxide. Investigators at Northwestern University (Evanstown, IL) have undertaken a trial of arsenic trioxide 0.25 mg/kg/day for 60 days in patients with relapsed or refractory Hodgkin's disease. M.D. Anderson Cancer Center is the setting for an investigation of arsenic trioxide in patients with relapsed or refractory CLL.

Clinical evaluation of arsenic trioxide for the treatment of multiple myeloma is under way and is the subject of a separate article in this supplement [10]. Combination therapy with arsenic trioxide and ascorbic acid is also being studied in patients with relapsed or refractory multiple myeloma (Table 2Go). The addition of ascorbic acid is linked to observations that, at least in part, the glutathione redox system mediates the inhibition of growth and induction of apoptosis that follow exposure to arsenic trioxide. Earlier work showed that ascorbic acid decreases glutathione levels and renders malignant cells, but not normal cells, more sensitive to arsenic trioxide-induced apoptosis. In a mouse model, ascorbic acid enhanced the antilymphoma effect observed in response to arsenic treatment, without additional toxicity [11].

Phase II Studies in Solid Tumors
Based on promising preclinical data, NCI-sponsored clinical trials to examine the potential of arsenic trioxide for the treatment of solid tumors are under way or in the final planning stages (Table 3Go).


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  		Table 3. Phase II studies of arsenic trioxide in solid tumors
 
Androgen-dependent and -independent prostate cancer cell lines are equally susceptible to apoptosis induced by arsenic trioxide exposure [12], whereas most chemotherapeutic agents are far better at inhibiting the growth of androgen-independent cells. These interesting in vitro results led to the development of a trial in patients with advanced hormone-refractory prostate cancer at Montefiore Hospital (New York, NY) and Mount Sinai Hospital. Patients will receive arsenic trioxide, 0.2 mg/kg/day on days 1-5 and 8-12 of a 4-week cycle.

At Memorial Sloan-Kettering Cancer Center, patients with advanced renal cell carcinoma will be treated with arsenic trioxide, 0.3 mg/kg/day on days 1-5 of a 4-week cycle. Another study at the same center focuses on patients with advanced cervical cancer. The role of human papilloma viruses (HPV) in the development of cervical cancer is well known. Zheng et al. showed that arsenic trioxide induces apoptosis in HPV 16 DNA-immortalized human cervical epithelial cells in vitro and selectively inhibits early viral gene expression [13]. Inclusion of arsenic in the media proved cytotoxic for a variety of cell lines, including those for bladder and cervical cancers [14]. These preclinical findings provide the rationale for a trial being planned by Cancer and Leukemia Group B for patients with refractory transitional cell carcinoma of the bladder.

Clinical Trials of Arsenic Trioxide in Pediatric Patients
The Pediatric Oncology Group and the Children's Cancer Group are conducting a recently activated NCI-sponsored phase I trial of arsenic trioxide in children with refractory leukemia or lymphoma. A major aim of this study is to improve our understanding of the pharmacokinetics and safety of arsenic trioxide in the pediatric population.

The previously described phase III study in newly diagnosed APL will also include children. Although survival is generally good in children with APL treated with the currently available regimens, arsenic trioxide may provide additional survival benefits.


   CONCLUSIONS
Top
 Abstract
 The National Cancer Institute...
 Rationale for Clinical...
 NCI-Sponsored Trials with...
 Conclusions
References
 
Abundant preclinical evidence shows that arsenic trioxide inhibits growth and promotes apoptosis in many different cancer cell types. This broad mechanism of action supports a potential for clinical activity in numerous neoplastic diseases other than APL and provides a basis for further clinical evaluation of arsenic trioxide in hematologic malignancies and solid tumors. The dose and dosing regimen required for clinical response in such cancers may be different from those for APL. The ongoing NCI Cooperative Research and Development program with industry and academia should provide important insights into the clinical potential of arsenic trioxide for malignancies beyond APL.


   REFERENCES
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 Abstract
 The National Cancer Institute...
 Rationale for Clinical...
 NCI-Sponsored Trials with...
 Conclusions
 References
 

  1. Chen G-Q, Shi X-G, Tang W et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells. Blood 1997;89:3345-3353.[Abstract/Free Full Text]
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Received February 21, 2001; accepted for publication February 22, 2001.




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