2056 Vol. 9, 2056–2065, June 2003 Clinical Cancer Research A Phase I Study of Recombinant Human Leukemia Inhibitory Factor in Patients with Advanced Cancer1 Dishan H. Gunawardana,2 Russell L. Basser, genitor cells increased in response to rhLIF. In stage 2, Ian D. Davis, Jonathan Cebon, Paul Mitchell, platelet recovery to baseline levels was earlier for patients ؍ ␮ < Craig Underhill, Trevor J. Kilpatrick, receiving higher doses of rhLIF ( 4.0 g/kg/day; P 0.02). The neutrophil nadir after chemotherapy was less severe in Katrina Reardon, Michael D. Green, Peter Bardy, patients receiving >4.0 ␮g/kg/day of rhLIF. In stages 1 and Pene Amor, David Crump, Siobhan Ng, 2, increases in C reactive protein were seen at higher doses. Roger L. Nation, and C. Glenn Begley Several patients developed evidence of autonomic dysfunc- Centre for Developmental Cancer Therapeutics,3 Parkville, Victoria tion, in particular impotence and episodic hypotension. The 3050 [D. H. G., R. L. B., I. D. D., J. C., P. M., C. U., T. J. K., K. R., dose-limiting toxicities were hypotension and rigors. Phar- M. D. G., S. N.]; Department of Hematology, Institute of Medical and macokinetic studies demonstrated a short half-life (1–5 h) Veterinary Science, Adelaide, South Australia [P. B.]; Amrad Operations, Richmond, Victoria, Australia [P. A., D. C.]; Centre for independent of dose. Pharmaceutical Research, University of South Australia, North Conclusions: We demonstrated a biological effect of Terrace, Adelaide, South Australia [R. L. N.]; and Centre for Child rhLIF on blood progenitor cells, C reactive protein levels, Health Research, University of Western Australia, TVW Telethon and hemopoietic recovery after chemotherapy. Institute for Child Health Research and Western Australian Institute for Medical Research, West Perth, Western Australia [C. G. B.] INTRODUCTION ABSTRACT LIF4 is a cytokine with a broad range of in vitro and Purpose: Leukemia inhibitory factor (LIF) is a pleio- in vivo biological effects. The molecule was first described as tropic molecule of the interleukin 6 family of cytokines. We an inducer of monocytic differentiation in the leukemic cell aimed to examine the safety, pharmacokinetics, and biolog- line M1 (1, 2). LIF is a member of a cytokine family that also ical effects of recombinant human LIF (rhLIF, emfilermin) includes IL-6, IL-11, oncostatin M, ciliary neurotrophic fac- in patients with advanced cancer. tor, and cardiotrophin 1. These cytokines have overlapping Experimental Design: In stage 1 of the study, 34 patients biological activities and act through receptors that share a received rhLIF or placebo (3:1 ratio) at doses of 0.25–16.0 common signaling molecule, the gp130 subunit (3). The other ␮g/kg/day or 4.0 ␮g/kg three times daily for 7 days. In stage subunit of the LIFR complex is the LIFR␤ chain. Expression 2, 40 patients received rhLIF or placebo, either once daily of LIFR␤ determines which cells respond to LIF, because for 14 days commencing the day after chemotherapy (0.25– gp130 is expressed ubiquitously (4). Ligand binding to the 8.0 ␮g/kg/day) or for 7 days commencing the day before receptor complex results in activation of intracellular signal- chemotherapy (4.0 ␮g/kg three times daily). The chemother- ing via the Janus-activated kinase/signal transducers and apy was cisplatin 75 mg/m2 and paclitaxel 135 mg/m2. activators of transcription pathway. Results: In stage 1, platelet counts increased in most Receptors for LIF are expressed on hemopoietic cells patients, including those who received placebo. Blood pro- (macrophages and megakaryocytes), hepatocytes, osteoblasts, preadipocytes, embryonic stem cells, myoblasts, and neuronal cells (5, 6). However, the in vitro biological effects of LIF vary depending on the cell type, so that for example LIF stimulates Received 3/21/02; revised 1/3/03; accepted 1/7/03. differentiation in M1 cells and inhibits differentiation in embry- The costs of publication of this article were defrayed in part by the onic stem cells. In vivo studies in mice have shown that LIF payment of page charges. This article must therefore be hereby marked produces a 2-fold increase in bone marrow megakaryocytes with advertisement in accordance with 18 U.S.C. Section 1734 solely to a dose-dependent increase in platelet numbers (7). Increased indicate this fact. 1 Supported in part by Amrad Operations and the National Health and Medical Research Council, Canberra. P. A. and D. C. were employed by Amrad Operations, whose potential product was studied in the present work. 2 To whom requests for reprints should be addressed, at Department of 4 The abbreviations used are: LIF, leukemia inhibitory factor; IL, inter- Hematology and Medical Oncology, Royal Melbourne Hospital, leukin; LIFR, leukemia inhibitory factor receptor; rh, recombinant hu- Parkville, Victoria 3050, Australia. Phone: 613-9342-7695; Fax: 613- man; ECOG, Eastern Cooperative Oncology Group; tds, three times 9347-7508; E-mail: [email protected]. daily; Epo, erythropoietin; ESR, erythrocyte sedimentation rate; PBPC, 3 Affiliated with: Ludwig Institute Oncology Unit, Austin Repatriation peripheral blood progenitor/stem cell; GM-CFC, granulocyte-macroph- Medical Centre, Heidelberg, Victoria; the Department of Hematology age colony-forming cell; G-CSF, granulocyte colony-stimulating factor; and Medical Oncology, Rotary Bone Marrow Research Laboratories, GM-CSF, granulocyte macrophage colony-stimulating factor; SCF, Royal Melbourne Hospital, Parkville, Victoria, Australia; Walter and stem cell factor; Meg-CFC, megakaryocyte colony-forming cell; Cmax, Eliza Hall Institute for Medical Research, Parkville, Victoria, Australia; maximum concentration; AUC, area under the plasma concentration- and the Department of Hematology and Medical Oncology, Western time curve; Cl, clearance; Vd, volume of distribution; t1/2, half-life; Hospital, Footscray, Victoria, Australia. BFU-E, blast-forming unit (erythroid). Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2003 American Association for Cancer Research. Clinical Cancer Research 2057 platelet levels have also been observed in primates (8). The action of LIF on nerve cells has also been examined in animal models. Direct application of LIF to sites of nerve transection improved survival of both sensory and motor neurons (9, 10). Nerve transection has been shown to increase expression of LIF and IL-6, and is associated with retrograde axonal transport of LIF (11). LIF has also been shown to retard progression of motor neuron disease in a murine model of this disorder (12). Other biological effects of LIF include induction of acute phase proteins (8), reduced lipoprotein lipase activity, and os- teoblast stimulation (13). Emfilermin is rhLIF produced in Escherichia coli. Admin- Fig. 1 Protocol schema. In stage 1, patients were randomized to re- istration of a single s.c. dose in healthy volunteers found that ceive rhLIF or placebo in a 3:1 ratio, which drug was then administered rhLIF was safe and well tolerated up to doses of 4 ␮g/kg.5 for 7 days. This was followed by a period of at least 7 days and maximum of 28 days observation. Stage 2 consisted of chemotherapy Here we report results of a randomized, blinded, placebo- that, in the majority of patients, was followed by study drug adminis- controlled, Phase I dose escalation study to test the safety and tered daily for 14 days. One cohort of patients (4.0 ␮g/kg tds rhLIF) pharmacokinetics of rhLIF administered before and after chem- received study drug from the day before chemotherapy and for a total of otherapy in patients with advanced cancer. 7 days. PATIENTS AND METHODS Patients. Eligible patients were those with advanced can- ␮ cer at least 18 years of age, ECOG performance status of 0–2, the 4.0 g/kg tds cohort. Patients continuing from stage 1 to absolute neutrophil count of Ն1.5 ϫ 109/liter, hemoglobin level stage 2 remained on the same dose of rhLIF, with the exception ␮ of Ն90 g/liter, and platelet count of 120–500 ϫ 109/liter. that patients who received 16.0 g/kg/day in stage 1 were given Ն 8.0 ␮g/kg/day in stage 2. Adequate renal (creatinine Cl 1.2 ml/sec) and hepatic (biliru- 2 Յ ␮ Chemotherapy consisted of paclitaxel 135 mg/m given bin 25 mol/liter) function were also required. Exclusion 2 criteria included surgery, radiotherapy, or chemotherapy within over3hbyi.v. infusion, followed by cisplatin 75 mg/m i.v. 4 weeks of study entry, prior irradiation to Ͼ30% of estimated over 1 h, with mannitol 10% i.v. over 15 min. Premedication for red marrow volume, and uncontrolled brain metastases. chemotherapy was 20 mg of dexamethasone given p.o. the night The study was approved by the Institutional Ethics Com- before chemotherapy and again on the morning of chemother- mittees of the participating hospitals. Each patient gave in- apy, 50 mg ranitidine i.v., 12.5 mg promethazine i.v. or equiv- formed consent before treatment. alent, and 24 mg ondansetron i.v. The study drug was commenced the day after chemother- Study Design apy for patients in the once daily cohorts and given for a total of 14 days. Patients receiving 4.0 ␮g/kg tds began treatment with The study design is shown in Fig. 1. rhLIF or placebo the day before chemotherapy, and continued Stage 1. The study was double-blinded with respect to for a total of 7 days. Study involvement was completed after one rhLIF (emfilermin is the International Nonproprietary Name cycle of chemotherapy, but patients were able to receive addi- issued by the WHO for rhLIF produced in E. coli). Patients were tional chemotherapy cycles (but without rhLIF) at the discretion randomized to rhLIF or placebo in a 3:1 ratio. A computerized of the investigator. During the study, the use of cytokines other randomization schedule was used. Patients received study drug than rhLIF such as filgrastim, sargramostim, or Epo was not alone given s.c.