Phase I Clinical Trial of Recombinant Human Interleukin-3 Combined With Carboplatin in the Treatment of Patients With Recurrent Ovarian Carcinoma

Rusthoven, James J.; Eisenhauer, Elizabeth; Mazurka, John; Hirte, H.; O'Connell, Greg; Muldal, A.; Lu, Hai-xiao; Onetto, Nicole; Swenerton, Kenneth D.; Jeffrey, John

doi:10.1093/jnci/85.10.823

Cited by 10 publications

(4 citation statements)

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“…The toxicity profile of rhIL-3 observed in this study was almost identical to that reported by others [26,27,30,[33][34][35]. However, an increase in the severity of toxicity was observed during rhIL-3 treatment over several cycles.…”

Section: Discussionsupporting

confidence: 88%

Recombinant human interleukin-3 to dose-intensify carboplatin and cyclophosphamide chemotherapy in epithelial ovarian cancer: a phase I trial.

Veldhuis¹,

Willemse²,

Gameren³

et al. 1995

JCO

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Section: Discussionsupporting

confidence: 88%

Recombinant human interleukin-3 to dose-intensify carboplatin and cyclophosphamide chemotherapy in epithelial ovarian cancer: a phase I trial.

Veldhuis¹,

Willemse²,

Gameren³

et al. 1995

JCO

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“…IL-3 stimulates the proliferation and differentiation of multi potent haemopoietic stem cells and committed progenitor cells of the granulocyte, macrophage, eosinophil, basophil, erythroid, megakaryocyte and mast celllineages.lI69-17IJ Increases in bone marrow cellularity and peripheral multilineage haemopoietic effects following IL-3 administration have been confirmed in early clinical trialsl172-176J and in healthy volunteers.l 177J IL-3 used in humans is produced by recombinant DNA technology using yeast or E. coli systems and is currently under clinical investigation, with dosages usually ranging from 0.5 to 15 Ilg/kg/day via subcutaneous injection. Several phase 1111 trials have been performed, primarily in patients with chemotherapy-induced myeIotoxicity, [178][179][180][181][182][183][184] myelodysplastic syndrome or aplastic anaemia,l173-175, 185, 186J c Five patients also chose to discontinue therapy because of uncomfortable fever and chills. Diamond-Blackfan anaemia [187,188] and in the setting of autologous bone marrow transplantation [189] or peripheral stem cell harvesting.l 1691…”

Section: Interleukin-3 (Il-3)mentioning

confidence: 99%

“…Mild to severe skin rash or urticaria were also sometimes observed, [178,179,[180][181][182][183][184][185][186] but responded to corticosteroid and systemic antihistamine drugs.l I 84] Although in vitro and in vivo studies have shown that IL-3 increased histamine release and enhanced the formation of basophils and eosinophils, the mechanism of IL-3-induced urticaria is not well understood. Indeed, no clear relationship between histamine level, eosinophil and basophil counts has been established in patients with cutaneous reactions.l178,183-1851 In addition, recurrence after IL-3 readministration is not always observed.…”

Section: 1 General Toxicitymentioning

confidence: 99%

“…[186] Although the maximum tolerated IL-3 dosage has not been strictly defined, dosages of 5 to 10 /lg/kg/day by subcutaneous injection have been suggested acceptable by most patients for further studies. Overall, treatment discontinuation because of adverse effects ranges from 17 to 50% of patients when using 10 /lg/kg/day [183,184] and was most often required after several cycles of IL-3 treatment in the setting of chemotherapy-induced myelotoxicity.l184] By contrast, with studies in healthy volunteers, several investigators have found the incidence or severity of feverlflu-Jike symptoms, [173,175,182,183] headache [178, 181 ,182,185,189] and generalised skin reaction or facial oedema [184,185] as dose-limiting adverse events. In patients undergoing autologous bone marrow transplantation and receiving IL-3 via a 20-day regimen of 2-hour intravenous infusions, about 75% of patients were removed from the studies at dosages ~5 /lg/kg/day because of grade III toxicity or subjectively intol- Table II Drug Safety 13 (6) 1995 erable malaise.ll891 In this setting, the maximum tolerated dosage was thus only 2 Ilg/kg/day.…”

Section: 1 General Toxicitymentioning

confidence: 99%

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Clinical Toxicity of Cytokines Used As Haemopoietic Growth Factors

1995

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A number of cytokines are used as haemopoietic growth factors and this review focuses on toxicities associated with granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-1, IL-3, IL-4, IL-6 and macrophage colony-stimulating factor (M-CSF). Both GM-CSF and G-CSF, currently approved for clinical use, are generally well tolerated by the majority of patients during short term administration. Constitutional symptoms and bone pain are the most frequently reported adverse effects, but they are rarely treatment-limiting. Reactivation of rheumatoid symptoms, and exacerbation of autoimmune thyroiditis or autoimmune haematological disorders have sometimes been described. Severe cardiovascular complications include the possibility for arterial thromboses and the vascular leak syndrome, which is more specifically observed with GM-CSF. Reports of several cases and small series of patients have suggested that growth factors might increase the pulmonary toxicity of chemotherapy, a possibility that remains debated and requires further attention. Generalised or local cutaneous reactions are frequently noted with GM-CSF. Leukocytoclastic vasculitis was observed with both growth factors, while neutrophilic dermatoses have been mostly described with G-CSF. Exacerbation of psoriasis and isolated anaphylactic reactions have appeared with GM-CSF and G-CSF. The hepatotoxic potential of the growth factors is not clearly established, but the occurrence of coagulation abnormalities has recently been reported. Renal and biological disturbances are usually transient. Long term treatment with GM-CSF and G-CSF also seems to be well tolerated, but the possible occurrence of several adverse events, i.e. bone disorders, leukaemia, unmasking or acceleration of underlying disease, require further investigation in patients receiving prolonged treatment, as in myelodysplasia. Finally, antibodies against growth factors have been reported only with GM-CSF. Other cytokines are still under investigation. Flu-like and constitutional symptoms, sometimes dose-limiting, have been reported with IL-1, IL-3, IL-4 and IL-6, while M-CSF was occasionally associated with such adverse effects. More specific adverse events, also frequently considered as dose-limiting toxicities, include hypotension with IL-1, severe headache or skin rash with IL-3, and nasal congestion and gastroduodenal lesions with IL-4. Severe capillary leak syndrome has been reported only with IL-4. M-CSF toxicity is minimal and limited to reversible but sometimes dose-limiting thrombocytopenia and ophthalmological symptoms with the recombinant product. Again, the safety of long term administration of these cytokines has not yet been determined, and IL-3-induced disease progression in myelodysplastic patients has been suggested.

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Hematopoietic growth factors in autologous transplantation

1998

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Hematopoietic growth factors (HGFs) sustain the survival, proliferation and differentiation of hematopoietic stem cells and some functions of mature blood cells. In man several HGFs have been characterised and cloned so far, and this has allowed investigators to confer the rationale for the clinical application of these molecules in hematology and oncology. In particular G-CSF and GM-CSF are currently utilised to abrogate the hematological toxicity of chemotherapy for standard and dose-intensified therapy, neutropenia following bone marrow and peripheral blood stem cell transplantation. Moreover there has recently been great interest in the ex vivo expansion of hematopoietic stem and progenitor cells for a variety of applications, such as in vitro tumor cell purging or for reducing the volume of blood processed by the leukapheresis. Several combinations of HGFs have been described to sustain the ex vivo survival and proliferation of these cells disclosing new opportunities in the field of stem cells transplants.

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Phase I Clinical Trial of Recombinant Human Interleukin-3 Combined With Carboplatin in the Treatment of Patients With Recurrent Ovarian Carcinoma

Cited by 10 publications

References 0 publications

Recombinant human interleukin-3 to dose-intensify carboplatin and cyclophosphamide chemotherapy in epithelial ovarian cancer: a phase I trial.

Recombinant human interleukin-3 to dose-intensify carboplatin and cyclophosphamide chemotherapy in epithelial ovarian cancer: a phase I trial.

Clinical Toxicity of Cytokines Used As Haemopoietic Growth Factors

Hematopoietic growth factors in autologous transplantation

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