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.
Phase I portion
- Twenty-one patients were assessable for dose-limiting toxicity (DLT)
- DLT was observed in the first treated patient in cohort 1 who had grade 4 mucositis and grade 4 hand–foot syndrome
- No other DLTs was observed and the maximum tolerated dose was not determined
- Highest tested dose of BP1001 monotherapy: 90 mg/m2
- Four patients died as a result of adverse events
- After one cycle of BP1001 monotherapy
- Nine (33%) of 27 patients who had peripheral blood blasts at the start of therapy had a reduction of 50% or more in peripheral blood blasts within a median of 9 days (IQR 7–18)
- Three (10%) of 29 patients who had bone marrow blasts at the start of therapy had a reduction in bone marrow blasts of 50% or more within a median of 30 days (IQR 30–35)
- Seven (22%) patients benefitted from BP1001 monotherapy treatment and received extended cycles
Phase Ib portion
- Six patients were assessable for DLT
- No DLTs was observed
- Five (83%) of six patients had bone marrow blasts at the start of therapy had a reduction in bone marrow blasts of 50% or more within a median of 29 days (IQR 28–55)
- Two patients reached complete remission
- One patient had CR with incomplete hematological recovery
- Two patients had stable disease
- One patient died and one withdrew, both because of disease progression
- Adverse events in all patients
- Grade 3–4 adverse events (AEs): cardiopulmonary disorders (64%), fever (including neutropenic fever) and infections (44%)
- Grade 5 AEs: cardiopulmonary disorders (5%), fever (including neutropenic fever), infections (5%), and multi-organ failure (3%)
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.”