Cairo, M.S., Davenport, V., Bessmertny, O., Goldman, S.C., Berg, S.L., Kreissman, S.G., . . . Reaman, G.H. (2005). Phase I/II dose escalation study of recombinant human interleukin‐11 following ifosfamide, carboplatin and etoposide in children, adolescents and young adults with solid tumours or lymphoma: A clinical, haematological and biological study. British Journal of Haematology, 128, 49–58.

• Ifosfamide 1800 mg/m² for five days, carboplatin 400 mg/m² for two days, and etoposide 100 mg/m² for five days with recombinant human interleukin-11 (rhIL-11) subcutaneous (SC) at 25–125 mcg/kg/day on days 6–33
• Chemotherapy repeated every 21 + days or when hematologic recovery was achieved (absolute neutrophil count greater than 100z10/9 and platelet count greater than 100x10/9 for two days without platelet transfusion or a maximum of 28 days). No chemotherapy dose change was permitted in cycles one and two.
• For six cycles, until tumor progression or inadequate hematologic recovery by day 60 in cycle one or day 35 in subsequent cycles
• Select patients who received rhIL-11 with six cycles of chemotherapy and who benefited in the investigators’ opinions were able to receive subsequent doses.
• G-CSF was administered SC beginning day six and until post nadir
• Primary endpoints for safety were AE, lab, and radiologic findings.
   

• N = 47
• MEDIAN AGE = 10.5 years
• AGE RANGE = 8 months–24 years
• MALES: 30, FEMALES: 17
• KEY DISEASE CHARACTERISTICS: Children, adolescents, and young adults with solid tumors or lymphoma
• OTHER KEY SAMPLE CHARACTERISTICS: 53% white; three weeks since last chemotherapy and six weeks since last nitrosourea chemotherapy. Excluded primary/mets intracranial tumors greater than 50% infiltration of tumor into bone marrow, craniospinal xRT or xRT greater than 50% of bone marrow space
   

• Phase I/II dose escalation study

• Dose-limiting toxicities include grade 4 nonhematologic toxicity or papilloedema.
• Tolerated dose defined as dose level at which no more than 1 of 10 patients experienced dose-limiting toxicity
• Serum IL-11 concentrations measured at genetic institute
• Blood collected at 0 (predose),1, 2, 2.5, 3, 4, 6, 8,10,12, and 14 hours after IL-11
• Pharmacokinetic measures done
• Progenerator cells evaluated by colony formation assays as well as flow
• Cytokine receptor expression measured by flow
• Primary endpoints for safety were AE, lab, and radiologic findings.
• Secondary objectives to evaluate and estimate hematologic responses

Three of 47 patients withdrew. Also, 24 of 44 discontinued before receiving two cycles (9 because of disease progression; 3 for adverse events [papilloedema]; 2 for therapy changes; 10 for other reasons; 1 died). Twenty patients completed two cycles of therapy. Median time to platelet recovery was reduced (24.5–20 days in similar historical cohort). One patient developed incidence of anti-IL-11 antibody formation. Number of platelet transfusions was three versus six in historical controls. IL-11 was well-tolerated at doses less than 50; the maximum tolerated dose is 50 mcg/kg/day. Doses above this increased side effects of papilloedema in 6 of 26 patients, periosteal bone changes in 4 of 26 patients, and cardiomegaly.

• Dose-limiting side effects at greater than or equal to 75 mc
• Tachycardia—45%
• Conjunctival infection—45%
• Edema—29%
• Pain—23%
• Rhinitis—20.5%
• Diarrhea—20.5%
• Cardiomegaly—20.5%
• Papilloedema—16%
• Periosteal bone changes—11%
• Small N
• Follow-up one year out
• Large range in age/size
• Not randomized—compared to historic controls