Liposomal Grb2 antisense oligodeoxynucleotide (BP1001) in patients with refractory or relapsed haematological malignancies: a single-centre, open-label, dose-escalation, phase 1/1b trial.

backgroundActivating mutations of tyrosine kinases are common in leukaemias. Oncogenic tyrosine kinases use the growth factor receptor-bound protein 2 (Grb2) for signal transduction, leading to activation of mitogen-activated protein kinase (MAPK) 1 and MAPK3 (ERK2 and ERK1). We hypothesised that inhibition of Grb2 would suppress ERK1 and ERK2 activation and inhibit leukaemia progression. To inhibit Grb2, a liposome-incorporated antisense oligodeoxynucleotide that blocks Grb2 protein expression, BP1001, was developed. We report the first phase 1 findings of BP1001.

methodsIn this single-centre, open-label, dose-escalation phase 1/1b trial, we enrolled participants (aged ≥18 years) with refractory or relapsed acute myeloid leukaemia, Philadelphia-chromosome-positive chronic myeloid leukaemia (in chronic, accelerated, or blast phase), acute lymphoblastic leukaemia, or myelodysplastic syndrome, at MD Anderson Cancer Center (Houston, TX, USA). We used a 3 + 3 dose escalation strategy, with at least three patients enrolled at each dose level. We administered BP1001 intravenously, twice weekly, for 28 days, with a starting dose of 5 mg/m

findingsBetween July 23, 2010, and Feb 23, 2016, we enrolled and treated 39 patients, of whom 27 were assessable for dose-limiting toxicity. The first patient treated had mucositis and hand-foot syndrome, which were assessed as possibly related to BP1001 and counted as a dose-limiting toxicity. We noted no other dose-limiting toxicities, and a maximum tolerated dose was not identified. The highest tested dose of BP1001 was 90 mg/m

interpretationBP1001 is well tolerated, with early evidence of anti-leukaemic activity in combination with low-dose cytarabine. To further explore this anti-leukaemic activity, the efficacy of BP1001 plus low-dose cytarabine combination is being investigated in an ongoing phase 2 study in patients with previously untreated acute myeloid leukaemia who are ineligible for intensive induction therapy.

fundingBio-Path Holdings Inc.