Clinical Trials

Date: 2016-12-16

Type of information: Presentation of results at a congress

phase: 1b-2

Announcement: presentation of results at the 58th ASH Annual Meeting & Exposition

Company: BerGenBio (Norway)

Product: BGB324

Action mechanism:

• AXL inhibitor/ receptor tyrosine kinase inhibitor.  BGB324 is a first-in-class, highly selective small molecule inhibitor of the Axl receptor tyrosine kinase that blocks the epithelial-mesenchymal transition, which is a key driver of metastasis and drug-resistance.. Preclinical in vivo studies have shown that BGB324 has both single agent activity in leukemia and solid tumors and is very effective in preventing and reversing acquired resistance to existing therapies including cytotoxics, protein kinase inhibitors and other targeted therapies.

Disease: acute myeloid leukaemia

Therapeutic area: Cancer - Oncology

Country: Germany, Norway, USA

Trial details:

• BGBC003 is a multi-centre Phase 1b trial of BGB324, a selective inhibitor of Axl, in patients with acute myeloid leukaemia. The two part Phase 1b trial will investigate dose escalation and expansion of BGB324 in patients with refractory/relapsed acute myeloid leukaemia, at six sites in three countries (Germany, Norway, USA). The primary objective of the first part of the trial is to identify the maximum tolerated dose (MTD) of BGB324 and the secondary objectives are to identify the dose limiting toxicity (DLT), safety and tolerability and confirm the pharmacokinetics of the drug candidate. The primary objective of the second part of the trial is to identify the safety, and tolerability of BGB324, as a single agent and in combination with low dose cytarabine, with a secondary objective of determining the efficacy of BGB324 as a single agent and in combination with low dose cytarabine..
• (NCT02488408)

Latest news:

•   • On December 12, 2016, BerGenBio presented clinical and biological data from a Phase I trial of  BGB324 in acute myeloid leukaemia in an oral session at the 58th ASH Annual Meeting & Exposition in San Diego. The company regards the results as an important indicator of the clinical utility of BGB324 in AML and the possibility of selecting patients who may benefit from treatment in advance of therapy. The oral presentation was entitled BGB324, an orally available selective Axl inhibitor exerts anti-leukaemic activity in the First-in-Patient trial BGBC003 and induces unique changes in biomarker profiles (Paper 0592, Session: Acute Myeloid Leukemia: Clinical Studies: New Drugs for Older AML). It reported clinical and biological data demonstrating the impact of BGB324 on the Axl signalling pathway in leukemic blast cells.
• Furthermore, an analysis of patients T-cell lymphocyte diversification illustrated that BGB324 amplified the immune response in a proportion of patients. Twenty-five patients (twenty-two with relapsed/refractory AML and three with high risk MDS) were treated in a classical 3+3 dose escalation design. Three dose levels were explored: 400/100 mg, 600/200 mg and 900/300 mg. Treatment was generally well-tolerated and steady-state levels of BGB324 were reached between three and six days after initiation of treatment. One AML patient achieved a CRi and two achieved a PR. Four additional AML patients (25%) experienced disease stabilisation for more than four months. One MDS patient experienced a PR. Treatment with BGB324 also led to an increase in the levels of soluble Axl receptor (sAXL) which was directly correlated to compound exposure (n=13; r=0.86), indicating that Axl could be used as a biomarker of target engagement.
• Also presented was a poster that showed single cell signaling pharmacodynamics in a Phase 1 trial of BGB324 in acute myeloid leukemia (Paper 3995, Session: Acute Myeloid Leukemia: Clinical Studies: Poster III). The effect of BGB324 on intracellular signaling and the immune profile of leukaemic blasts in patients treated in the clinical study was investigated using phospho-flow cytometry. Leukemic blasts were identified using surface markers and treatment-related changes in direct and indirect downstream targets of Axl were explored. Analyses of blood samples from six patients showed rapid changes in signalling pathways downstream of Axl. In most patients, the CD117+/CD34- blast population appeared more responsive to treatment, and this cell population decreased during treatment with BGB324, suggesting that Axl inhibition may push leukemic blasts towards differentiation.
• • On November 4, 2014, BerGenBio, an oncology biopharmaceutical company, has announced that the first patient has been dosed in its multi-centre Phase 1b trial (BGBC003) of BGB324, a selective inhibitor of Axl, in patients with acute myeloid leukaemia (AML) at Haukeland University Hospital in Bergen, Norway.The study will be conducted at six sites in Norway, Germany and the United States. The Company expects data to be available from this trial in 2015. This two part Phase 1b trial will primarily investigate the safety and tolerability of BGB324 when administered as a single agent and in combination with standard of care drug (cytarabine) in patients with AML; secondary endpoints will also explore evidence of clinical response and assess novel biomarkers.
• • On April 9, 2014, BerGenBio has announced that results from its Phase Ia clinical study for lead compound, BGB324, was presented at the American Association of Cancer Research annual conference, which took place on April 5-9, 2014. The poster entitled “BGB324, a selective small molecule Axl kinase inhibitor to overcome EMT-associated drug resistance in carcinomas: Therapeutic rationale and early clinical studies”, detailed the results of a single ascending dose study, which evaluated the safety and tolerability, and pharmacokinetics of BGB324 in 32 healthy volunteers. BGB324 was shown to be safe and well tolerated in doses up to 1.5 g/daily with a predictable PK profile and long plasma half-life, allowing for different dosing options. Reported adverse events in doses up to 1 gm were no more than grade 1 in severity and were fully reversible. The most common adverse event reported was gastrointestinal in nature and occurred more frequently at higher doses (above 1 gm). The poster also included results from preclinical in vivo studies in animal models of triple negative breast cancer (TNBC), pancreatic cancer and non-small cell lung cancer (NSCLC). Data from these studies demonstrated that BGB324, in combination with targeted chemotherapeutic agents, effectively delays or blocks acquired drug resistance, leading to a significant prolonged survival in these disease models. BGB324 was also shown to block the ability of TNBC cells to initiate tumour formation, a characteristic of cancer stem cells. The company intends to initiate multi-centre Phase Ib trials in NSCLC and AML patients.
• • On December 17, 2013, BerGenBio has announced that preclinical data demonstrating that BGB324 has potential application as a novel treatment for chronic myeloid leukemia (CML), was presented at the Annual Meeting of the American Society of Hematology (ASH), which took place on December 7-10, 2013. The results suggest that BGB324 may be effective as monotherapy in treating patients with drug-resistant CML as a result of exposure to Abelson kinase (Abl) inhibitors such as imatinib, nilotinib and dasatinib, which are widely used as first line therapy in patients. Long term therapy with these agents can result in the development of resistance and new mutations. Overexpression of the Axl tyrosine kinase is known to confer resistance to treatment with imatinib. Treatment with Abl inhibitors whilst successful in eradicating malignant cells from the blood does not kill the leukemic stem cells which remain active in the bone marrow necessitating life-long treatment with these agents. In contrast treatment with BGB324 was effective in inducing programmed cell death in CML stem cells located in the marrow. The results also revealed that treatment with BGB324 was effective in treating animals infected with CML cells expressing the T315I mutation of ABL which is resistant to treatment with currently approved drugs. The data further underscores the potential of BGB324 in addressing the spread of leukemias and other resistant cancers whose biology is driven by Axl expression. BGB324 has recently completed a phase Ia clinical trial. Phase Ib clinical trials are planned in acute myeloid leukemia and non-small cell lung cancer in 2014.
• • On June 19, 2013, BerGenBio has announced the start of a Phase 1 Clinical Trial for BGB324, a first-in-class small molecule inhibitor of AXL tyrosine kinase. The Phase 1 clinical trial of BGB324 is a single ascending dose study designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of BGB324. BerGenBio in parallel is developing biomarker and PD assays for use in the clinical trials of BGB324 to quantify end points and support patient segmentation for enrollment in future studies.
• BGB324 is the first compound in BerGenBio’s pipeline to enter clinical trials, with additional compounds and drug targets at different stages of preclinical development.

Is general: Yes