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Growth factor receptor-bound protein 2 (Grb2) is an adaptor protein involved in signal transduction of oncogenic tyrosine kinases. Oncogenic tyrosine kinases bind Grb2 and the activated signaling leads to proliferation of hematopoietic cells in leukemias. Maro Ohanian from the University of Texas, MD Anderson Cancer Center, Houston, TX, USA, and colleagues hypothesised that blocking Grb2 protein expression would inhibit the signaling pathway and thus, set back the progression of leukemia. In order to block Grb2, BP1001, a liposome-incorporated antisense oligodeoxynucleotide, was designed and tested in a phase I/Ib trial (NCT01159028). Findings of the study were published ahead of print in The Lancet Hematology.
This first single-centre, open-label, 3 + 3 dose-escalation phase I/Ib study, assessed the safety and efficacy of escalating doses of BP1001 in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML), Philadelphia-chromosome-positive chronic myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome. A total of 39 patients were enrolled and treated in this study between July 2010–February 2016.
In the phase I portion of this study, 32 patients (median age = 63; range 56–73) were treated with escalating doses of BP1001 (cohorts 1–6). Six doses levels were used twice weekly; 5 mg/m² (cohort 1; n = 13), 10 mg/m² (cohort 2; n = 6), 20 mg/m² (cohort 3; n = 3), 40 mg/m² (cohort 4; n= 3), 60 mg/m² (cohort 5; n = 3), or 90 mg/m² (cohort 6; n = 4).
In the phase Ib portion of this study, seven patients (median age = 72; range 70–76) were treated with BP1001 twice weekly plus low-dose cytarabine (cohorts 7–8). Four patients were assigned to cohort 7 receiving BP1001 (60 mg/m²) plus low-dose cytarabine (20 mg subcutaneously twice daily × 10 consecutive days) and three to cohort 8 receiving BP1001 (90 mg/m²) plus low-dose cytarabine.
The authors concluded by stating that “BP1001 was well tolerated both as monotherapy or in combination with low-dose chemotherapy” and a potential anti-leukemic activity was also observed. The authors added that “the efficacy of BP1001 plus low-dose cytarabine combination is being investigated in an ongoing phase II study (NCT02781883) in patients with previously untreated AML who are ineligible for intensive induction therapy.”
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