A randomized phase II study of BB‐10010: a variant of human macrophage inflammatory protein‐1α for patients receiving high‐dose etoposide and cyclophosphamide for malignant lymphoma and breast cancer

Abstract

Summary. Macrophage inflammatory protein-1a (MIP-1a)is a chemokine that can inhibit the cell cycle progression of both primitive haemopoietic and epidermal progenitor cells. This property could potentially be exploited to attenuate both the myelosuppressive effects of chemotherapy as well as mucositis. We evaluated both the biological and clinical effects of BB-10010, a genetically engineered variant of MIP1a, in patients with malignant lymphoma or breast cancer receiving high-dose etoposide (VP 3·6 g/m 2 ) and cyclophosphamide (Cy 200 mg/kg). 52 patients were randomized to one of three cohorts. Cohort A received no BB-10010; cohorts B and C received 10 mg/kg and 100 mg/kg of BB-10010, respectively. All patients received post-chemotherapy G-CSF. BB-10010 was well tolerated. There were no significant differences between groups in recovery to an ANC > 0·5 × 10 9 /l, 1 × 10 9 /l or 1·5 × 10 9 /l, the number of days with an ANC < 0·5 × 10 9 /l, days to a platelet count >50 × 10 9 /l or 100 × 10 9 /l, or the incidence and severity of mucositis. There was no evidence of any effect of BB-10010 on colony-forming cell (CFC) or long-term culture-initiating cell (LTC-IC) mobilization, cycling activity in the marrow or on chemotherapy-induced changes in CFC or LTC-IC number both of which were in the normal range by 22 d after completion of the chemotherapy. To our knowledge this is the first report of a myelointensive regimen having no apparent long-term effect on the LTC-IC compartment. In summary, BB-10010 is safe when used in patients receiving high-dose therapy but has no effect on reducing the toxicity of such therapy.

Identification of Amino Acid Residues Critical for Aggregation of Human CC Chemokines Macrophage Inflammatory Protein (MIP)-1α, MIP-1β, and RANTES

“…Nonaggregating variants of hMIP-1␣, hMIP-1␤, and RANTES may be essential for the safe clinical evaluation of these chemokines. hMIP-1␣ D26A, also known as BB-10010, has proven to be safe and well tolerated in phase I and phase II clinical trials even after large doses (300 g/kg) have been administered by subcutaneous injection (25)(26)(27)38).…”

“…The early description of MIP-1␣ as a proinflammatory cytokine (21) has not been confirmed and it has not restricted its use in a number of in vitro (22) and in vivo models (23,24). hMIP-1␣ has a number of potential clinical uses: as a myeloprotectant during aggressive cytotoxic therapy (25)(26)(27), for the treatment of psoriasis (28), for stem cell mobilization (24,29), and for ex vivo hematopoietic stem cell expansion (30).…”

Therapeutic Use of Chemokines

“…Furthermore, phase I trials showed that BB-10010 treatment resulted in an earlier recovery of leukocyte numbers compared with a bolus injection. Unfortunately, a limited therapeutic benefit of BB-10010 treatment was recently observed in patients receiving high dose etoposide and cyclophosphamide for malignant lymphoma and breast cancer [101]. Nevertheless, additional phase II clinical studies should reveal the appropriate BB-10010 dosing regimen needed to render a therapeutic effect in cancer patients receiving cytotoxic chemotherapy.…”

Abscopal Effect of Radiation Therapy and Signal Transduction

“…Recombinant formulation for the variant was produced using a budding yeast expression system [116] from a GMP certified production site. Its myelosuppressive effect [117][118][119][120] was investigated in several clinical trials of patients receiving chemotherapy [121][122][123][124]. We previously showed that the recombinant MIP-1 variant, now called ECI301, strikingly enhanced the antitumor efficacy of subcutaneous tumor irradiation and induced an abscopal effect [104].…”