STAT3 antisense oligonucleotide AZD9150 in a subset of patients with heavily pretreated lymphoma: results of a phase 1b trial

Abstract

BackgroundThe Janus kinase (JAK) and signal transduction and activation of transcription (STAT) signaling pathway is an attractive target in multiple cancers. Activation of the JAK-STAT pathway is important in both tumorigenesis and activation of immune responses. In diffuse large B-cell lymphoma (DLBCL), the transcription factor STAT3 has been associated with aggressive disease phenotype and worse overall survival. While multiple therapies inhibit upstream signaling, there has been limited success in selectively targeting STAT3 in patients. Antisense oligonucleotides (ASOs) represent a compelling therapeutic approach to target difficult to drug proteins such as STAT3 through of mRNA targeting. We report the evaluation of a next generation STAT3 ASO (AZD9150) in a non-Hodgkin’s lymphoma population, primarily consisting of patients with DLBCL.MethodsPatients with relapsed or treatment refractory lymphoma were enrolled in this expansion cohort. AZD9150 was administered at 2 mg/kg and the 3 mg/kg (MTD determined by escalation cohort) dose levels with initial loading doses in the first week on days 1, 3, and 5 followed by weekly dosing. Patients were eligible to remain on therapy until unacceptable toxicity or progression. Blood was collected pre- and post-treatment for analysis of peripheral immune cells.ResultsThirty patients were enrolled, 10 at 2 mg/kg and 20 at 3 mg/kg dose levels. Twenty-seven patients had DLBCL. AZD9150 was safe and well tolerated at both doses. Common drug-related adverse events included transaminitis, fatigue, and thrombocytopenia. The 3 mg/kg dose level is the recommended phase 2 dose. All responses were seen among DLBCL patients, including 2 complete responses with median duration of response 10.7 months and 2 partial responses. Peripheral blood cell analysis of three patients without a clinical response to therapy revealed a relative increase in proportion of macrophages, CD4+, and CD8+ T cells; this trend did not reach statistical significance.ConclusionsAZD9150 was well tolerated and demonstrated efficacy in a subset of heavily pretreated patients with DLBCL. Studies in combination with checkpoint immunotherapies are ongoing.Trial registrationRegistered at ClinicalTrials.gov: NCT01563302. First submitted 2/13/2012.Electronic supplementary materialThe online version of this article (10.1186/s40425-018-0436-5) contains supplementary material, which is available to authorized users.

Progranulin sustains STAT3 hyper‐activation and oncogenic function in colorectal cancer cells

“…Antisense technology has recently emerged as a compelling therapeutic strategy to target difficult to hit proteins by downregulating their mRNA in several disease settings (Le et al, 2018;Marafini and Monteleone, 2018;Rinaldi and Wood, 2018). In particular, antitumor activity of an ASO inhibitor of STAT3 (i.e., AZD9150) was observed in two phase 1 studies in patients with highly treatmentrefractory lymphomas and non-small cell lung cancer (Hong et al, 2015;Reilley et al, 2018). However, both approaches do not overcome the issue of potential side effects related to the broad inhibition of STAT3 function.…”

Observing an Antisense Drug Complex in Intact Human Cells by in‐Cell NMR Spectroscopy

“…The phosphorothioate backbone is a standard means of increasing resistance to degradation by nucleases with preservation of RNaseH1 activity . Danvatirsen downregulates the mRNA of the transcription factor STAT3, and is currently in clinical trials, showing antitumour activity in lymphoma, non‐small‐cell lung cancer and non‐Hodgkin's lymphoma . However, understanding of intracellular trafficking and targeting processes is currently a bottleneck in ASO drug development, and until now no reliable method has allowed the study of untagged oligonucleotides or oligonucleotide structures in their active macromolecular complexes in human cells.…”

STAT3 Activation and Oncogenesis in Lymphoma

“…To date, no STAT3 inhibitors have yet been approved to treat cancer by the Food and Drug Administration (FDA), but many early-phase clinical trials are ongoing [136]. AZD9150, an antisense oligonucleotide inhibitor of STAT3, inhibits STAT3 activation in ALCL and nonsmall cell lung cancer lines and demonstrates antitumor activity in lymphoma and lung cancer patient-derived xenograft models [137]. AZD9150 is currently under clinical trials for aggressive non-Hodgkin lymphoma (NCT03527147) and nonsmall cell lung cancer (NCT03334617).…”