Recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) given as daily short infusions – a phase I dose-toxicity study

Summary Nitrosoureas are the drugs most effective in the treatment of patients with intracerebral malignant glioma. Their limiting toxicity is delayed myelosuppression. A prospective, randomised crossover study of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was performed in patients receiving BCNU for relapsed glioblastoma, to investigate whether the resulting haematological toxicity profile could be modified by rhGM-CSF. Adequate data for analysis were obtained in 13 patients. Following BCNU, the nadir neutrophil count was higher in 12 out of 13 patients during the rhGM-CSFprotected cycles compared with the unprotected cycles. The median nadir was also significantly higher (1.79, CI 0.76-3.52, P< 0.005). Five episodes of neutropenia ( < 2 x 109 1-) occurred during the unprotected cycles compared with none in the rhGM-CSF-protected cycles (P = 0.076). There was no evidence of any effect on platelets. This result shows that the haematological toxicity profile following therapeutic doses of BCNU can be modified. It suggests that rhGM-CSF and other growth factors should be investigated for clinical efficacy in chemotherapy using nitrosoureas.

supporting

confidence: 66%

rhGM-CSF ameliorates neutropenia in patients with malignant glioma treated with BCNU

Rampling

Steward²,

Paul³

et al. 1994

“…Differential blood counts showed the predominant rise in the WCC to be due to an increase of neutrophil polymorphs but a small increase of eosinophils also occurred in parallel. The striking difference between the effects of GM-CSF given by continuous infusion or daily short injections is illustrated in Figure 2, which shows the haematological responses of one patient who entered both this study and a previous trial (Steward et al, 1989) of GM-CSF alone. After the experience with these initial six patients, a decision was taken that the optimal dose of GM-CSF after melphalan was 10 g kg-' day-' and the final three patients were not entered into the first phase of the study.…”

Section: Patientsmentioning

confidence: 99%

“…These showed a steady rise to a serum level > 1 ng ml-' (the concentration required in vitro to produce >90% of maximal cell proliferation) (Metcalf, 1984) within 3 h of commencing the infusion. Figure 3 shows the serum GM-CSF levels and compares these with those seen after short intravenous administration (measured during previous study (Steward et al, 1989)). Toxicity All nine patients were evaluable for toxicity.…”

Section: Patientsmentioning

confidence: 99%

“…We have carried out a phase I study with recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) and shown that when it was given as daily intravenous half-hour infusions, significant rises in leucocyte counts were obtained, but only at high dose levels (> 30 gg kg-' day-') which were associated with considerable toxicity (Steward et al, 1989). Several trials have shown that haemopoietic growth factors can reduce the myelotoxicity of chemotherapy (Bronchud et al, 1987;Antman et al, 1988;Morstyn et al, 1988) and we therefore decided to combine high-dose melphalan with GM-CSF for patients with metastatic colorectal carcinoma in the hope that we could obtain similar response rates to those of Leff et al…”

mentioning

confidence: 99%

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Granulocyte-macrophage colony stimulating factor (GM-CSF) after high-dose melphalan in patients with advanced colon cancer

Steward

Scarffe²,

Dirix³

et al. 1990

Self Cite

Nine patients with progressive, metastatic disease from primary carcinoma of the colon were entered into a phase I/II study using continuous intravenous infusions of granulocyte-macrophage colony-stimulating factor (GM-CSF) and high dose melphalan (120 mg m-2). GM-CSF was given alone to six patients during the first part of the study to determine a dose that would produce a peripheral leucocyte count (WCC) greater than or equal to 50 X 10(9) 1(-1) and was initially given at 3 micrograms kg-1 day-1 and escalated to 10 micrograms kg-1 day-1 after 10 days. The infusion was discontinued when the WCC exceeded 50 X 10(9) 1(-1) and after a gap of one week, melphalan was given over 30 min. GM-CSF was recommenced 8 h later and was continued until the neutrophil count had exceeded 0.5 X 10(9) 1(-1) for greater than 1 week. One patient achieved a WCC greater than 50 X 10(9) 1(-1) with GM-CSF 3 micrograms kg-1 day-1, but the other five who entered this phase of the study required dose escalation to 10 micrograms kg-1. No toxicity attributed to GM-CSF was seen. After melphalan, the median times to severe neutropenia (less than 0.5 X 10(9) 1(-1] and thrombocytopenia (greater than 20 X 10(9) 1(-1] were 6 and 9 days respectively. The median durations of neutropenia and thrombocytopenia were 14 and 10 days respectively. All patients required intensive support with a median duration of inpatient stay of 24 days. There was one treatment related death due to renal failure. One complete and two partial remissions (33% response rate) were seen but these were of short duration (median of 10 weeks). This study demonstrates that GM-CSF given by continuous intravenous infusion produces significant increments of peripheral granulocyte counts at 3 and 10 micrograms kg-1 day-1 and is not associated with any toxicity. The duration of neutropenia and thrombocytopenia induced by high-dose melphalan appears to be reduced by the subsequent administration of GM-CSF to times which are at least as short as have been reported in historical series which have used autologous bone marrow rescue.

“…Several phase I studies showed that the biological activity of GM-CSF in man is clearly dose dependent and that effective doses are in the range of 1 to 20 ,g kg-' day-1 (Brandt et al, 1988;Antman et al, 1988;Groopman et al, 1987;Steward et al, 1989;Vadhan-Raj et al, 1987). In these studies GM-CSF was administered by intravenous (i.v.…”

mentioning

confidence: 99%

Continuous infusion or subcutaneous injection of granulocyte-macrophage colony-stimulating factor: increased efficacy and reduced toxicity when given subcutaneously

Honkoop

Hoekman²,

Wagstaff³

et al. 1996

Summary Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a haematopoietic growth factor with a wide variety of applications in the clinic. In early phase I studies the continuous intravenous (c.i.) route of administration was often used. Later it was shown that subcutaneous (s.c.) administration was also effective. The optimal route of administration remains, however, poorly defined, and no studies have made a direct comparison between these two routes of administration. We treated patients with advanced breast cancer with moderately high-dose doxorubicin and cylophosphamide and GM-CSF. The first 14 patients received GM-CSF by c.i, while subsequently 47 patients received it s.c. Comparison between the two groups showed that c.i. GM-CSF was more toxic in several respects. There was a higher need for erythrocyte and platelet transfusions and a significant deterioration in the performance status. This study indicates that subcutaneous GM-CSF is the preferred route of administration. Randomised trials are, however, needed to confirm these conclusions.