Background: Activating 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. Methods: In 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/m2. If two or more patients developed toxic effects of grade 3 or higher, that dose level was deemed toxic. The dose was escalated if it did not produce dose-limiting toxic effects, and patients would be sequentially enrolled into cohort 2 (10 mg/m2), cohort 3 (20 mg/m2), cohort 4 (40 mg/m2), cohort 5 (60 mg/m2), or cohort 6 (90 mg/m2). After completion of monotherapy, we assessed the safety and toxicity of BP1001 (60 or 90 mg/m2) in combination with 20 mg low-dose cytarabine (twice-daily subcutaneous injections) in a phase 1b study in patients with refractory or relapsed acute myeloid leukaemia (ie, those who were refractory to at least one previous therapy regimen and no more than one previous salvage regimen). The objectives of this study were to establish the toxicity and tolerance of escalating doses of BP1001 monotherapy in patients with refractory or relapsed leukaemia, to assess the maximum tolerated dose of BP1001, and to determine the optimal biologically active dose of BP1001, defined as a 50% reduction in Grb2 expression in circulating leukaemia cells. We also aimed to assess the in-vivo pharmacokinetics of BP1001 and tumour response. The study is completed and is registered with ClinicalTrials.gov, number NCT01159028. Findings: Between 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/m2. The most common grade 3–4 adverse events were cardiopulmonary disorders (25 [64%] of 39 patients), and fever (including neutropenic fever) and infections (17 [44%] patients). Grade 5 adverse events were cardiopulmonary disorders (two [5%] of 39 patients), fever (including neutropenic fever) and infections (two [5%] of 39 patients), and multi-organ failure (one [3%] of 39 patients). 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 while receiving BP1001 montherapy. 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 while receiving BP1001 monotherapy. Per investigator's assessment, seven (22%) of 32 patients benefited from BP1001 monotherapy and had extended cycles of treatment. Of seven patients receiving BP1001 plus low-dose cytarabine combination therapy, two had complete remission, one had complete remission with incomplete haematological recovery, and two had stable disease with no dose-limiting toxicity; one patient died and one withdrew, both because of disease progression. There were eight deaths; none were treatment related. Interpretation: BP1001 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. Funding: Bio-Path Holdings Inc.
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