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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
A phase I study of recombinant human leukemia inhibitory factor in patients with advanced cancer
Dishan H Gunawardana1, Russell L Basser, Ian D Davis
1Centre for Developmental Cancer Therapeutics, Parkville, Victoria 3050, Australia. dgunn@ozemail.com
Insights
Recombinant human leukemia inhibitory factor (rhLIF) showed biological effects on blood progenitor cells and improved hemopoietic recovery after chemotherapy in advanced cancer patients. Higher doses accelerated platelet recovery and reduced neutrophil nadir severity.
Area of Science:
- Oncology
- Hematology
- Pharmacology
Background:
- Leukemia inhibitory factor (LIF) is a cytokine in the interleukin 6 family.
- Recombinant human LIF (rhLIF, emfilermin) is being investigated for therapeutic potential.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, and biological effects of rhLIF.
- To assess rhLIF's impact on hemopoietic recovery in advanced cancer patients undergoing chemotherapy.
Main Methods:
- Two-stage study involving 74 patients with advanced cancer.
- rhLIF or placebo administered at various doses and schedules alongside cisplatin and paclitaxel chemotherapy.
- Safety, pharmacokinetic, and hematological parameters were monitored.
Main Results:
- rhLIF increased blood progenitor cells and C-reactive protein levels.
- Higher rhLIF doses (>=4.0 micro g/kg/day) accelerated platelet recovery (P = 0.02) and lessened neutrophil nadir severity.
- Adverse events included autonomic dysfunction (impotence, hypotension) and rigors; dose-limiting toxicities were hypotension and rigors.
- rhLIF exhibited a short half-life (1-5 hours).
Conclusions:
- rhLIF demonstrates biological activity affecting blood progenitor cells and hemopoietic recovery.
- rhLIF shows potential in mitigating chemotherapy-induced myelosuppression.
- Further investigation into rhLIF's efficacy and safety profile is warranted.
Purpose:
Leukemia inhibitory factor (LIF) is a pleiotropic molecule of the interleukin 6 family of cytokines. We aimed to examine the safety, pharmacokinetics, and biological effects of recombinant human LIF (rhLIF, emfilermin) in patients with advanced cancer.
Experimental Design:
In stage 1 of the study, 34 patients received rhLIF or placebo (3:1 ratio) at doses of 0.25-16.0 micro g/kg/day or 4.0 micro g/kg three times daily for 7 days. In stage 2, 40 patients received rhLIF or placebo, either once daily for 14 days commencing the day after chemotherapy (0.25-8.0 micro g/kg/day) or for 7 days commencing the day before chemotherapy (4.0 micro g/kg three times daily). The chemotherapy was cisplatin 75 mg/m(2) and paclitaxel 135 mg/m(2).
Results:
In stage 1, platelet counts increased in most patients, including those who received placebo. Blood progenitor cells increased in response to rhLIF. In stage 2, platelet recovery to baseline levels was earlier for patients receiving higher doses of rhLIF (>/=4.0 micro g/kg/day; P = 0.02). The neutrophil nadir after chemotherapy was less severe in patients receiving >/=4.0 micro g/kg/day of rhLIF. In stages 1 and 2, increases in C reactive protein were seen at higher doses. Several patients developed evidence of autonomic dysfunction, in particular impotence and episodic hypotension. The dose-limiting toxicities were hypotension and rigors. Pharmacokinetic studies demonstrated a short half-life (1-5 h) independent of dose.
Conclusions:
We demonstrated a biological effect of rhLIF on blood progenitor cells, C reactive protein levels, and hemopoietic recovery after chemotherapy.
