Phase I trial of mitoxantrone and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced solid malignancies

1993 ◽  
Vol 11 (4) ◽  
pp. 291-300 ◽  
Author(s):  
Joan H. Schiller ◽  
Barry Storer ◽  
Rhoda Arzoomanian ◽  
Kendra Tutsch ◽  
Dona Alberti ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Solid Malignancies ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Phase I trial of thiotepa in combination with recombinant human granulocyte-macrophage colony-stimulating factor.

1992 ◽  
Vol 10 (8) ◽  
pp. 1352-1358 ◽  
Author(s):  
P J O'Dwyer ◽  
F P LaCreta ◽  
R Schilder ◽  
S Nash ◽  
C McAleer ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Phase I Trial ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
The Mean ◽  
Macrophage Colony ◽  
Grade 3 ◽  
Stimulating Factor

PURPOSE The ability of growth factors to stimulate marrow recovery suggests their potential for use in dose intensification of cytotoxic drugs. We performed a phase I study of the alkylating agent thiotepa in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), with the goal of dose-escalation of thiotepa. Thiotepa was selected based on its capacity for dose escalation to more than 1 g/m2 in the marrow transplantation setting. PATIENTS AND METHODS The starting dose of thiotepa (75 mg/m2) was the highest dose evaluated in our previous phase I trial. Thirteen patients received 22 courses of thiotepa and GM-CSF. The dose of GM-CSF was 10 micrograms/kg subcutaneously daily in six patients and 5 micrograms/kg in seven patients. RESULTS Three patients (23%) developed grade 3 to 4 neutropenia on the first course, with a recovery to more than 1000/mm3 in 4.7 days (mean). Recovery was as rapid with the 5 micrograms/kg as it was with the 10 micrograms/kg GM-CSF dose. Thrombocytopenia grade 3 to 4 affected seven of 13 (54%) patients in the first course; counts recovered to more than 50,000/mm3 in a median of 15 days. GM-CSF at either dose did not influence markedly the severity or duration of thrombocytopenia, and did not permit dose escalation of thiotepa. Among the seven patients who received a second cycle of treatment, six of seven experienced grade 3 or 4 thrombocytopenia that lasted a median of 15.5 days. Five had thrombocytopenia that lasted more than 35 days after one to three cycles of treatment. Plasma concentrations of thiotepa and tepa were measured by gas chromatography in eight patients. The plasma elimination of thiotepa fit a two-compartment open model with a harmonic mean terminal half-life of 2.44 hours. The mean total body clearance was 217.9 mL/min/m2, and the mean steady-state volume of distribution (Vdss) was 36.8 L/m2. The half-life of tepa was 7.98 hours, and the ratio of the area under the plasma concentration versus time curve (AUC) of tepa to that of thiotepa was 0.79. CONCLUSIONS These data were consistent with our previous observations at this dose, and indicated that the severity of toxicity in these patients was not explained by aberrant pharmacokinetic indices. We conclude that, independent of effects on neutropenia, severe and cumulative platelet toxicity precludes further escalation of thiotepa dose despite the use of GM-CSF.

Novel Allogeneic Granulocyte-Macrophage Colony-Stimulating Factor–Secreting Tumor Vaccine for Pancreatic Cancer: A Phase I Trial of Safety and Immune Activation

2001 ◽  
Vol 19 (1) ◽  
pp. 145-156 ◽  
Author(s):  
Elizabeth M. Jaffee ◽  
Ralph H. Hruban ◽  
Barbara Biedrzycki ◽  
Daniel Laheru ◽  
Karen Schepers ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I Trial ◽  
Tumor Vaccine ◽  
Colony Stimulating Factor ◽  
Tumor Vaccines ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Disease Free

PURPOSE: Allogeneic granulocyte-macrophage colony-stimulating factor (GM-CSF)–secreting tumor vaccines can cure established tumors in the mouse, but their efficacy against human tumors is uncertain. We have developed a novel GM-CSF–secreting pancreatic tumor vaccine. To determine its safety and ability to induce antitumor immune responses, we conducted a phase I trial in patients with surgically resected adenocarcinoma of the pancreas. PATIENTS AND METHODS: Fourteen patients with stage 1, 2, or 3 pancreatic adenocarcinoma were enrolled. Eight weeks after pancreaticoduodenectomy, three patients received 1 × 107 vaccine cells, three patients received 5 × 107 vaccine cells, three patients received 10 × 107 vaccine cells, and five patients received 50 × 107 vaccine cells. Twelve of 14 patients then went on to receive a 6-month course of adjuvant radiation and chemotherapy. One month after completing adjuvant treatment, six patients still in remission received up to three additional monthly vaccinations with the same vaccine dose that they had received originally. RESULTS: No dose-limiting toxicities were encountered. Vaccination induced increased delayed-type hypersensitivity (DTH) responses to autologous tumor cells in three patients who had received ≥ 10 × 107 vaccine cells. These three patients also seemed to have had an increased disease-free survival time, remaining disease-free at least 25 months after diagnosis. CONCLUSION: Allogeneic GM-CSF–secreting tumor vaccines are safe in patients with pancreatic adenocarcinoma. This vaccine approach seems to induce dose-dependent systemic antitumor immunity as measured by increased postvaccination DTH responses against autologous tumors. Further clinical evaluation of this approach in patients with pancreatic cancer is warranted.

scholarly journals Phase I/II study of recombinant human granulocyte-macrophage colony- stimulating factor in aplastic anemia and myelodysplastic syndrome

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 705-713 ◽  
Author(s):  
JH Antin ◽  
BR Smith ◽  
W Holmes ◽  
DS Rosenthal
Keyword(s):  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Aplastic Anemia ◽  
Myelodysplastic Syndromes ◽  
Low Grade ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract We performed a phase I/II study of the administration of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) to patients with aplastic anemia or myelodysplastic syndrome. Doses ranging from 15 to 480 micrograms/m2 were administered as a one-hour or four-hour intravenous infusion daily for 7 days or as a 12-hour infusion for 14 days. Temporary improvements were seen in granulocyte counts, monocyte counts, and reticulocyte counts in six of eight patients with aplastic anemia and five of seven patients with myelodysplastic syndromes. The patients with myelodysplastic syndromes had larger increases in granulocyte, monocyte, and reticulocyte counts than did those with aplastic anemia, and they also had increases in the numbers of eosinophils (two of seven), immature myeloid cells (two of seven), and myeloblasts (two of seven) that were not observed in patients with aplastic anemia. There was no reduction in erythrocyte transfusion requirements, and no effect was observed on platelet counts. There was only minimal toxicity consisting of transient low- back discomfort, anorexia, myalgias/arthralgias, and low-grade fever. Our data suggest that GM-CSF is well tolerated and is more likely to result in elevations of blood counts in patients with myelodysplasia than in patients with aplastic anemia, but the role of GM-CSF therapy in these disorders remains to be determined.

Phase I trial of subcutaneous recombinant macrophage colony-stimulating factor: clinical and immunomodulatory effects.

1994 ◽  
Vol 12 (1) ◽  
pp. 97-106 ◽  
Author(s):  
R M Bukowski ◽  
G T Budd ◽  
J A Gibbons ◽  
R J Bauer ◽  
A Childs ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Mononuclear Phagocytes ◽  
Tnf Alpha ◽  
Colony Stimulating Factor ◽  
Antitumor Effects ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Dose Levels ◽  
Stimulating Factor

PURPOSE Recombinant human macrophage colony-stimulating factor (rM-CSF) has been demonstrated to control the growth, differentiation, and function of mononuclear phagocytes. Preclinical studies have indicated antitumor effects, and therefore a phase I trial of rM-CSF in patients with malignancy was initiated. The toxicity and hematologic and immunologic effects were investigated. PATIENTS AND METHODS rM-CSF was administered as a subcutaneous injection on days 1 through 5 and 8 through 12. Cycles were repeated every 28 days. Cohorts of four to seven patients received rM-CSF at dose levels from 0.1 to 25.6 mg/m2/d. Forty-two patients received 88 cycles of rM-CSF. All patients had metastatic solid tumors refractory to standard therapy. RESULTS The toxicity of rM-CSF was mild. Dose-limiting toxicity included thrombocytopenia (two patients) and iritis (one patient) occurring at a dose of 25.6 mg/m2/d. Hematologic studies demonstrated dose-related monocytosis occurring routinely at doses > or = 3.2 mg/m2/d, and thrombocytopenia. Immunologic studies demonstrated enhanced secretion of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1 beta) by monocytes after in vitro stimulation with lipopolysaccharide, and increased expression of TNF-alpha mRNA at higher rM-CSF dose levels. Pharmacokinetic studies demonstrated that the systemic clearance rate of M-CSF increases during week 1 of therapy, resulting in lower blood levels of M-CSF during the second week of therapy. CONCLUSION rM-CSF can be safely administered to patients, and has biologic activity on peripheral-blood monocytes.

Phase I Trial of Granulocyte Macrophage-Colony Stimulating Factor and Interleukin-4 as a Combined Immunotherapy for Patients With Cancer

2003 ◽  
Vol 26 (2) ◽  
pp. 171-178 ◽  
Author(s):  
Barbara J. Gitlitz ◽  
Robert A. Figlin ◽  
Sylvia M. Kiertscher ◽  
Nancy Moldawer ◽  
Frances Rosen ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Interleukin 4 ◽  
Colony Stimulating Factor ◽  
Patients With Cancer ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Combined Immunotherapy
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