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3.2.1. Background

SCF, also referred to as Steel locus factor, mast cell growth factor, and c-kit ligand, is a glycoprotein growth factor that modulates the proliferation of hematopoietic progenitor cells and mast cells. The action of SCF is based on its interaction with the tyrosine kinase receptor encoded by the c-kit proto-oncogene (23), resulting in the stimulation of mature and immature hematopoietic cells of multiple lineages (myeloid, erythroid, and megakaryocytic progenitors) and the expansion of the stem cell compartment (24-26). SCF alone appears to have a modest effect on its target cell's proliferation and mobilization and has an enhanced influence in the presence of other HGFs (27,28). It was the ability of SCF alone and in combination with other growth factors to induce proliferation, prolong survival, encourage lineage commitment, and stimulate the mobilization of hematopoietic progenitor cells that led to the development of rHuSCF and its further development in nonhuman primate and human clinical trials. rHuSCF is produced by DNA technology and expressed in E. coli as a 166-amino acid nonglycosylated protein with methionine included at the N-terminus.

3.2.2. Studies

The adverse event profile associated with r-metHuSCF was first defined in two small phase 1 clinical trials investigating its utility in patients with cancer receiving chemotherapy (29,30). When administered to 17 patients with nonsmall-cell lung cancer in incremental doses of 10, 25, and 50 ^g/kg/d before the administration of chemotherapy, a specific pattern of adverse events emerged. At the lowest dose level, adverse events were limited to the injection site. At dose levels > 10 ^g/kg/d, adverse events occurred as multisystem systemic reactions. Dose-related mild-to-moderate reactions occurred in all patients at all dose levels and included edema, urticaria, erythema, and pruritus. These reactions, mild to severe, as well as angioedema and der-matographia, occurred at distant cutaneous sites. Cough, throat tightness, sore throat, dyspepsia, and hypotension were transient and did not result in patient withdrawal from the study (29). In another phase 1 trial of identical design, rHuSCF was administered to patients (n = 17) with advanced breast cancer. The adverse event profile was similar to that described above (30).

Larger phase 2 and phase 3 clinical trials investigating the value of combining rHuSCF with rHuG-CSF (filgrastim) for the mobilization of bone marrow progenitor cells have demonstrated adverse event patterns like those seen in the earlier phase 1 trials. In a phase 1-2 trial (n = 38) of rHuSCF plus filgrastim in patients with non-Hodgkin's lymphoma (NHL), >80% of those who received rHuSCF had local injection site reactions, and 12% (three patients) had cough, dyspnea, and chest tightness with distant urticaria that resolved with the continuation of filgrastim (31). In a small randomized apheresis study comparing filgrastim alone with filgrastim plus dose-escalated rHuSCF in patients with breast cancer (n = 62), rHuSCF-related injection site reactions occurred in 89% (n = 39) of patients (32). These local reactions consisted of erythema, urticaria, and pruritus and were of mild-to-moderate severity. All occurred within 24 h of start of therapy and resolved within 96 h of onset. Six patients (14%) developed similar reactions at distant sites; these followed the same time sequence as those seen at the local injection site. Other adverse events that occurred more frequently among patients receiving rHuSCF compared with placebo included mild transient decreases in blood pressure (n = 4), fever (n = 6), and nausea (n = 5). One patient developed angioedema (periorbital, perioral, and tongue edema, hoarseness) with generalized urticaria and pruritus requiring treatment with corticosteroids and H1 antagonists.

A randomized phase 2 trial comparing cyclophosphamide plus filgrastim alone vs the same with filgrastim plus rHuSCF for the mobilization of progenitor cells in patients with breast cancer (n = 215) showed that 88% of patients receiving rHuSCF had drug-related injection site reactions and 4% pruritus, 3% rash, and 3% dyspnea (33). In a similarly designed phase 3 trial for patients with breast cancer (n = 203), rHuSCF-related injection site reactions occurred in 92% of patients, dyspnea in 8%, and pruritus in 6% (34). Another phase 3 trial that compared progenitor cell mobilization with cyclophos-phamide plus filgrastim or the same with rHuSCF in patients with multiple myeloma (n = 102) found that injection site erythema and reaction occurred in 44% (n = 24) and 22% (n = 12) of patients receiving rHuSCF. Distant rash and erythema, respectively, were seen in 13% (n = 7) and 5% (n = 3) of rHuSCF-treated patients and 0% and 2% (n = 1) of filgrastim alone-treated patients. Although the number of patients experiencing skeletal pain was small, rHuSCF appeared to increase its frequency compared with placebo (7% vs 2%) (35). This adverse event profile associated with rHuSCF administration, which is consistently demonstrated in multiple clinical trials, appears to be mast cell-related. SCF (mast cell growth factor) has been shown to stimulate cutaneous mast cell proliferation and degranulation (36,37), and the occurrence of injection site and distant erythema, rash, and urticaria as well angioedema strongly supports this finding. Therapeutic evidence of this mast cell effect includes the fact that H1 and H2 receptor blockers favorably influence the severity of rHuSCF-induced cutaneous and systemic reactions.

c-kit or a c-kit variant is found in a variety of normal and neoplastic hematopoietic and nonhematopoietic tissues (38-50). In particular, a mutation of codon 816 (Asp816) has been identified in mast cell leukemia, acute myeloblastic leukemia (AML), and germ cell tumors (51) that confers cytokine independence and constitutive activation of signal transducer and activator of transcription 3 (STAT3). The presence of both normal and abnormal c-kit offers an opportunity for therapeutic intervention and the risk that treatment with rHuSCF may accelerate the neoplastic process. The c-kit tyrosine kinase inhibitor (ST1571) has significant activity in patients with chronic myelocytic leukemia and gastrointestinal stromal tumors (52). Likewise, the inhibition of c-kit tyrosine kinase decreases the proliferation of human colorectal and small cell lung cancer cell lines (52,53). Cell lines derived from patients with mastocytosis demonstrate the presence of an activating c-kit mutation that is supersensitive to the presence of SCF, resulting in an increase in the rate of progenitor proliferation and the accumulation of mast cells in an SCF concentration-dependent manner (54,55). The neoplastic process has not been reported to be worsened by exposure to rHuSCF.

No rHuSCF-related neutralizing Abs have been reported in patients who have received either rHuSCF alone or in combination with other HGF.

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