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Blood, Vol. 92 No. 5 (September 1), 1998:
pp. 1532-1540
A Randomized Phase-II Study of BB-10010 (Macrophage Inflammatory
Protein- 1 ) in Patients With Advanced Breast Cancer Receiving
5-Fluorouracil, Adriamycin, and Cyclophosphamide Chemotherapy
Mark J. Clemons,
Ernest Marshall,
Jan Dürig,
Ken Watanabe,
Anthony Howell,
David Miles,
Helena Earl,
Julie Kiernan,
Audrey Griffiths,
K. Towlson,
P. DeTakats,
Nydia G. Testa,
Mark Dougal,
Michael G. Hunter,
L. Michael Wood,
Lloyd G. Czaplewski,
Andrew Millar,
T. Michael Dexter, and
Brian I. Lord
From the CRC Department of Medical Oncology and Paterson Institute
for Cancer Research, Christie Hospital, Manchester; ICRF Clinical
Oncology Unit, Guy's Hospital, London; CRC Institute of Cancer
Studies, Birmingham; Department of Medical Statistics, Christie
Hospital, Manchester; and British Biotech plc, Oxford, UK.
BB-10010 is a variant of the human form of macrophage inflammatory
protein-1 (MIP-1), which has been shown in mice to block the
entry of hematopoietic stem cells into S-phase and to increase their
self-renewal capacity during recovery from cytotoxic damage. Its use
may constitute a novel approach for protecting the quality of the stem
cell population and its capacity to regenerate after periods of
cytotoxic treatment. Thirty patients with locally advanced or
metastatic breast cancer were entered into the first randomized, parallel group controlled phase II study. This was designed to evaluate
the potential myeloprotective effects of a 7-day regimen of BB-10010
administered to patients receiving six cycles of 5-fluorouracil (5-FU),
adriamycin, and cyclophosphamide (FAC) chemotherapy. Patients were
randomized, 10 receiving 100 µg/kg BB-10010, 11 receiving 30 µg/kg
BB-10010, and nine control patients receiving no BB-10010. BB-10010 was
well-tolerated in all patients with no severe adverse events related to
the drug. Episodes of febrile neutropenia complicated only 4% of the
treatment cycles and there was no difference in incidence between the
treated and nontreated groups. Studies to assess the generation of
progenitor cells in long-term bone marrow cultures were performed
immediately preceding chemotherapy and at the end of six dosing cycles
in 18 patients. Circulating neutrophils, platelets, CD
34+ cells, and granulocyte/macrophage colony-forming cell
(GM-CFC) levels were determined at serial time points in
cycles 1, 3, and 6. The results showed similar hemoglobin and platelet
kinetics in all three groups. On completion of the six treatment
cycles, the average pretreatment neutrophil levels were reduced from
5.3 to 1.7 × 109/L in the control patients and from 4.3 to 1.9 and 4.5 to 2.5 × 109/L in the 30/100 µg/kg
BB-10010 groups, respectively. Relative to their pretreatment values,
50% of the patients receiving BB-10010 completed the treatment with
neutrophil values significantly higher than any of the controls
(P = .02). Mobilization of GM-CFC was enhanced by BB-10010
with an additional fivefold increase over that generated by
chemotherapy alone, giving a maximal 25-fold increase over pretreatment
values. Bone marrow progenitor assays before and after this standard
regimen of chemotherapy indicated little long-term cumulative
impairment to recovery from chemotherapy. Despite the limited
cumulative damage to the bone marrow, which may have minimized the
protective value of BB-10010 during this regimen of chemotherapy,
better recovery of neutrophils in the later treatment cycles with
BB-10010 was indicated in a number of patients.
© 1998 by The American Society of Hematology.
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