forodesine and Skin-Neoplasms

Cutaneous T-cell lymphoma (CTCL) is characterized by the accumulation of neoplastic CD4+ T lymphocytes in the skin. Given the lack of curative treatments for CTCL, there is a significant need for new, superior therapies. Forodesine is a transition-state analogue that inhibits purine nucleoside phosphorylase. Because it selectively targets T lymphocytes, it represents a drug of interest for the treatment of CTCL. Areas covered: Phase I/II dose-ranging studies of intravenous (IV) and oral forodesine demonstrated its activity, safety, and tolerability for refractory CTCL. Response rates were 31% and 27%, respectively. No dose-limiting toxicities were observed. These studies were followed by a phase II trial of oral forodesine 200 mg daily. This oral formulation showed only partial activity, with a response rate of 11%, likely attributable to underdosing. Common adverse events in these trials included infection, fatigue, peripheral edema, nausea, pruritus, headache, and insomnia. Expert opinion: IV and oral formulations of forodesine have demonstrated partial activity and an acceptable safety profile in patients with refractory CTCL. A higher oral dose, or sequential therapy consisting of IV forodesine followed by maintenance oral forodesine, may be more effective. With proper dosing, forodesine may emerge as a safe and effective treatment for refractory CTCL.

Topics: Administration, Intravenous; Administration, Oral; Animals; Antineoplastic Agents; Dose-Response Relationship, Drug; Humans; Lymphoma, T-Cell, Cutaneous; Purine Nucleosides; Pyrimidinones; Skin Neoplasms

There are few approved therapies for cutaneous T-cell lymphoma (CTCL). The retinoids are the major biologic response modifiers used in CTCL, producing good response rates but few complete responses. For patients with early-stage disease, the oral retinoids can be combined with other therapies, such as psoralen plus ultraviolet A or interferon alpha, to improve response rates. Combined-modality therapy with oral retinoids, combined chemotherapy, electron-beam therapy, and topical mustargen has also proved effective. For the treatment of advanced-stage disease, the targeted therapy denileukin diftitox (Ontak) provides a nonimmunosuppressive alternative to conventional chemotherapy or radiation therapy. Of the conventional chemotherapies that have been tested in CTCL, gemcitabine (Gemzar) has demonstrated good efficacy in producing responses, particularly in patients with tumors. This agent can be used in combination with a maintenance therapy of bexarotene (Targretin) to manage the plaques and patches of mycosis fungoides. Several other targeted therapies are now also in testing, for example, alemtuzumab (CamPath), HuMax-CD4, several histone deacetylase inhibitors, and the transition-state inhibitor forodesine. These drugs, in combination with currently used therapies, may increase the number and combinations of therapies available for the treatment of this chronic condition to optimize long-lasting responses in CTCL.

Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Diphtheria Toxin; Dose-Response Relationship, Drug; Humans; Hydroxamic Acids; Immunologic Factors; Interferon-alpha; Interleukin-2; Lymphoma, T-Cell, Cutaneous; Mechlorethamine; Purine Nucleosides; Pyrimidinones; Radiotherapy, Adjuvant; Recombinant Fusion Proteins; Retinoids; Sezary Syndrome; Skin Neoplasms; Vorinostat

Primary cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of non-Hodgkin's lymphomas characterized by skin infiltration of neoplastic T lymphocytes. Mycosis fungoides and its leukemic variant Sézary syndrome represent the most common CTCL subtypes. Current treatment for patients with mycosis fungoides involves topical and systemic therapies for the cutaneous manifestations. However, no therapy is curative and patients often progress to advanced extracutaneous CTCL with visceral organ complications or relapsed disease that is frequently refractory to most topical and aggressive systemic regimens. The emergence of novel targeted therapies such as biologic agents, histone deacetylase inhibitors, and purine nucleoside phosphorylase inhibitors offers promise for more effective and safer treatment strategies for refractory CTCLs.

Topics: Clinical Trials as Topic; Histone Deacetylases; Humans; Immunologic Factors; Mycosis Fungoides; Purine Nucleosides; Purine-Nucleoside Phosphorylase; Pyrimidinones; Sezary Syndrome; Skin Neoplasms

Forodesine is a potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to intracellular accumulation of deoxyguanosine triphosphate (dGTP) in T and B cells, resulting in apoptosis. Forodesine has demonstrated impressive antitumor activity in early phase clinical trials in cutaneous T-cell lymphoma (CTCL).. In this phase II study, patients with CTCL who had already failed three or more systemic therapies were recruited. We investigated the response rate, safety and tolerability of oral forodesine treatment in subjects with cutaneous manifestations of CTCL, stages IB, IIA, IIB, III and IVA. The safety population encompassing all stages was used for analysis of accountability, demographics and safety. The efficacy population differed from the safety population by exclusion of stage IB and IIA patients.. All 144 patients had performance status 0-2. The median duration of CTCL from diagnosis was 53 months (5-516 months). The median number of pretreatments was 4 (range: 3-15). No complete remissions were observed. In the efficacy group of patients, 11% achieved partial remission and 50% had stable disease. The median time to response was 56 days and the median duration of response was 191 days. A total of 96% of all treated patients reported one or more adverse events (AEs) and 33% reported a serious AE. The majority of AEs were classified as mild or moderate in severity. The most commonly reported AEs (>10%) were peripheral edema, fatigue, insomnia, pruritus, diarrhea, headache and nausea. Overall eight patients died during the study: five due to sepsis and infections, one due to a second malignancy (esophageal cancer), one due to disease progression and one due to liver failure.. Oral forodesine at a dose of 200 mg daily is feasible and shows partial efficacy in this highly selected CTCL population and some durable responses.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Apoptosis; Female; Humans; Male; Middle Aged; Mycosis Fungoides; Purine Nucleosides; Purine-Nucleoside Phosphorylase; Pyrimidinones; Sezary Syndrome; Skin Neoplasms; Treatment Failure

BCX1777 (forodesine), a novel purine nucleoside phosphorylase inhibitor, induces apoptosis, mainly in T cells. To evaluate the safety, tolerability, and pharmacokinetics of BCX1777, we conducted a phase I study in patients with relapsed or refractory peripheral T/natural killer-cell malignancies. Eligible patients had relapsed or refractory peripheral T/natural killer-cell malignancies without any major organ dysfunction. BCX1777 was administered orally once daily (dose escalation: 100, 200, and 300 mg) until disease progression requiring new therapy or unacceptable adverse events occurred. A total of 13 patients were enrolled and treated in three dose cohorts (100 mg/day, five patients; 200 mg/day, three patients; 300 mg/day, five patients). Although none of the patients developed dose-limiting toxicities, further dose escalation was not performed based on data from overseas. Therefore, the maximum tolerated dose was not determined. Adverse events of grade 3 or greater (≥2 patients) included lymphopenia (62%), anemia (15%), leukopenia (8%), and pyrexia (8%). Plasma pharmacokinetics parameter of BCX1777 (area under the plasma concentration-time curve) at day 1 in each cohort was 1948 ± 884, 4608 ± 1030, and 4596 ± 939 ng•h/mL, respectively. Disease control was achieved in approximately half of patients. One patient with anaplastic large cell lymphoma, which was negative for anaplastic lymphoma kinase, achieved a complete response, and two patients with cutaneous T-cell lymphoma achieved partial responses. BCX1777 was well tolerated at doses up to 300 mg once daily and showed preliminary evidence of activity in relapsed or refractory peripheral T/natural killer-cell malignancies, warranting further investigation.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Area Under Curve; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Exanthema; Female; Humans; Lymphoma, Large-Cell, Anaplastic; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Lymphopenia; Male; Metabolic Clearance Rate; Middle Aged; Mycosis Fungoides; Natural Killer T-Cells; Purine Nucleosides; Pyrimidinones; Recurrence; Skin Neoplasms; Treatment Outcome