3.1.1. Background

Oprelvekin is a recombinant form of IL-11 produced in E. coli by recombinant DNA technology (10) and approved by the Food and Drug Administration (FDA) to prevent severe thrombocytopenia and reduce the need for platelet transfusions after myelosuppressive chemotherapy in patients with nonmyeloid cancers. rHuIL-11 increases the size and DNA content of megakaryocytes and stimulates throm-bopoiesis, increasing production and release of normally functioning platelets (10,11). Its nonhematologic effects include the modulation of intestinal epithelial growth that leads to increased rates of intestinal healing, enhanced fat deposition, an increase in the synthesis of acute-phase proteins, and osteoclastic maturation (10-13). rHuIL-11 may promote the growth of myeloid and megakaryocytic and plasma cell lines (14-16).

3.1.2. Studies

In a review by Smith (17), the safety and tolerability of rHuIL-11 administered sc at the recommended dose of 50 ^g/kg/d was compared with placebo in two phase 2 studies. The dataset included 308 patients, ranging from 8 mo to 75 yr of age, who received up to eight sequential 1-28-d courses of oprelvekin. In this group, aside from complications associated with underlying malignancy or cytotoxic chemotherapy, most adverse events were of mild or moderate severity and were reversible after cessation of the growth factor. The incidence and type of adverse events were similar between patients who received oprelvekin and those who received placebo. Edema, dyspnea, tachycardia, conjunctival injection, palpitations, and pleural effusion occurred more frequently in the oprelvekin-treated patients. Adverse events that occurred in >10% of patients and were observed in equal or greater frequency among patients receiving placebo included asthenia, pain, chills, abdominal pain, infection, anorexia, constipation, dyspepsia, ecchymosis, myalgia, bone pain, and alopecia. Patient withdrawal owing to an adverse event (most commonly atrial fibrillation/flutter) was more frequent among those receiving oprelvekin compared with placebo (11% vs 6%). An analysis of data derived from these patients has led to the speculation that oprelvekin treatment, along with age, history of atrial arrythmias or cardiac disease, or alcohol use, are risk factors for the development of these arrythmias. Thrombotic events, the number of red blood cell (RBC) transfusions, and the duration of neutropenia (absolute neutrophil count [ANC] < 0.5 x 109/L) were similar in both groups. The incidence of >grade 3 adverse events was similar in oprelvekin-treated and placebo-treated patients. Although the incidence of asthenia was similar between these two groups (65% vs 64%, p = 1.0), >grade 3 was more common in the former (14% vs 3%, p = 0.03).

Retrospective analysis of the phase 2 placebo-controlled chemotherapy studies (studies 1 and 2) showed a significantly (p < 0.01) lower incidence of bleeding complications—primarily ecchymosis and epitaxis—among patients in the oprelvekin group (28%) compared with those in the placebo group (51%). None of the patients treated with oprelvekin (n = 69) developed severe or life-threatening bleeding complications (grade 3 hemorrhage, hemorrhagic cystitis, or vaginal hemorrhage); these occurred only among placebo-treated patients (3/67, 4.5%).

In the two phase 2 placebo-controlled chemotherapy studies, the only biochemical laboratory abnormalities that occurred significantly more frequently with oprelvekin than with placebo were decreases in serum albumin and total protein concentrations. These changes were without clinical consequence, and laboratory values returned to baseline levels after drug discontinuation. Mean decreases in serum albumin of up to 0.6 g/dL (10-15%) were noted in the first phase 2 study.

In the second phase 2 study, the observed mean decreases in serum albumin and total protein concentrations were 22% in the oprelvekin group vs 6% in the placebo group (p = 0.0006). The investigators determined that these changes seem to have resulted from the combined effects of oprelvekin-induced increased plasma volume and decreased nutritional intake by the patients because of the gastrointestinal and central toxicity of chemotherapeutic agents.

In a later representative phase 3 trial (n = 133), all grades of edema, dyspnea, and dizziness were more frequent among patients who received oprelvekin than among those who received placebo (45% vs 20%; 34% vs 13%; 44; 34% vs 13%; 44% vs 20%, respectively), although the proportion of patients with >grade 3 was similar between the two groups (4% vs 2%; 2% vs 4%; 2% vs 0%, respectively). In this trial, metabolic abnormalities led to drug discontinuation in 5% of the oprelvekin-treated patients. Hypokalemia was more frequent in this group (7% vs 4%); the investigators concluded that this difference was probably owing to diuretic use.

The incidence and type of adverse events in the phase 3 chemotherapy study were similar to those seen in the two placebo-controlled phase 2 studies, with the exception of dizziness, which was attributed to concomitant diuretic use (18). As in the phase 2 placebo-controlled trials, most adverse events in the phase 3 trial were mild or moderate in severity (grade 1 or 2) and resolved without sequelae after discontinuation of the study drug. The oprelvekin and placebo groups did not differ significantly in overall incidence of grade 3 and 4 adverse events (36% [oprelvekin] and 38% [placebo]); however, the incidence of grade 3 or 4 chills was reported significantly (p = 0.04) more frequently in the placebo group (n = 3, 7%) than in the oprelvekin group (n = 0). In addition, the only episodes of grade 3 or 4 gastrointestinal hemorrhage (two patients) or pulmonary infarct (one patient) occurred in the placebo group.

As in the phase 2 patients, in the phase 3 study, bleeding events contributing to hos-pitalization occurred in a higher percentage of patients in the placebo group (5/45, 11.1%) than in the oprelvekin group (3/88, 3.4%). These observations reflect the lack of adverse effects of oprelvekin on platelet function or blood coagulation.

Most adverse events associated with oprelvekin (e.g., edema, dyspnea, pleural effusions, and conjunctival injection) are believed to be the result of fluid retention and increased plasma volume (19). Mild, reversible dilutional anemia characterized by moderate decreases in hemoglobin (Hb) concentration (15-19% reductions from baseline) and hematocrit levels (approx 20% reduction from baseline) secondary to plasma volume expansion has occurred during oprelvekin therapy in phase 1 studies in healthy volunteers (19) and in nonmyelosuppressed patients with cancer (20). In the latter population, anemia developed within 2-3 d of initiation of oprelvekin therapy and reached a nadir during the second week of administration (20). Hb concentrations returned to baseline levels within 2 wk after the completion of oprelvekin therapy. Although this dilutional anemia occurred in approx 20% of patients who received oprelvekin in phase 1 trials, it was not associated with statistically significant increases in the incidence of clinically significant anemia or with mean requirements for RBC transfusions in those who received oprelvekin compared with those who received placebo (21,22). Across the phase 2 studies, anemia was reported in only 10% of oprelvekin-treated patients, compared with 6% of placebo patients (17). The mean number of RBC units transfused per patient was 1.9 in the oprelvekin group and 1.7 in the placebo group.

3.1.3. Other Hematologic Effects rHuIL-11 increases fibrinogen and von Willebrand factor levels. Nevertheless, in the placebo-controlled studies with oprelvekin, thrombotic and thromboembolic events occurred infrequently and with similar incidence in oprelvekin and placebo groups.

Thromboembolic sequelae such as stroke have been observed in patients receiving oprelvekin who experienced atrial arrythmias. Since patients with histories of thrombotic events or disseminated intravascular coagulation have been excluded from most clinical protocols, it is difficult to determine whether oprelvekin heightens their risk. Postmarketing surveillance has shown spontaneous reports of thrombotic events in patients receiving oprelvekin (17); however, a causal relationship has not been ascertained.

Cumulative toxicity and bone marrow exhaustion are not a consequence of repetitive treatment with oprelvekin. The frequency and severity of adverse events appear to be stable after prolonged administration. Maintenance of platelet nadirs, neutrophil recovery times, and requirements for RBC transfusion have not been seen to increase during sequential treatments (22).

Oprelvekin is occasionally recognized as a foreign protein. The incidence of Ab reactivity to oprelvekin among subjects who have received more than one dose of oprelvekin is reported to be 1.4-4%. The development of these Abs has not been associated with anaphylactoid reactions or neutralizing properties. Specifically, no unexpectedly prolonged thrombocytopenia has been described.

No significant differences between patients receiving oprelkevin or placebo are reported with respect to median time to neutrophil recovery after chemotherapy, the duration of neutropenia, or the incidence of neutropenic fever (48% vs 42%; p = 0.5).

3.1.4. Oprelvekin and Tumor Growth

In placebo-controlled chemotherapy studies, the rate of disease progression was similar between groups treated with oprelvekin or placebo, suggesting that oprelvekin does not interfere with the antitumor effectiveness of cytotoxic therapy and has no inherent tumorigenic effects. Preclinical observations suggest that oprelvekin does not stimulate the growth of cells from human primary solid tumors in vitro (17). Furthermore, retrospective analysis of follow-up data from three randomized studies showed no adverse effects on overall survival or progression-free survival.

3.1.5. Concomitant Administration

Almost all patients treated with oprelvekin have been treated concurrently with rHuG-CSF (filgrastim) without evidence of an adverse pharmacodynamic interaction between these two cytokines.

Oprelvekin has been administered concomitantly with acetaminophen, ondansetron, prochlorperazine, diphenhydramine, dexamethasone, lorazepam, ciprofloxacin, or furosemide in most (>65%) patients involved in the two phase 2 placebo-controlled chemotherapy studies (n = 69), with no evidence of significant drug interactions. At the recommended dose, there does not appear to be any effect of oprelkevin on the liver cytochrome P450 microsomal enzyme system (17).

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