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

  • J Immunother Cancer. 2018 Nov 16;6(1):119. doi: 10.1186/s40425-018-0436-5.
Matthew J Reilley  1 ,  Patricia McCoon  2 ,  Carl Cook  2 ,  Paul Lyne  2 ,  Razelle Kurzrock  3 ,  Youngsoo Kim  4 ,  Richard Woessner  2 ,  Anas Younes  5 ,  John Nemunaitis  6 ,  Nathan Fowler  7 ,  Michael Curran  7 ,  Qinying Liu  7 ,  Tianyuan Zhou  4 ,  Joanna Schmidt  4 ,  Minji Jo  4 ,  Samantha J Lee  4 ,  Mason Yamashita  4 ,  Steven G Hughes  4 ,  Luis Fayad  7 ,  Sarina Piha-Paul  7 ,  Murali V P Nadella  8 ,  Xiaokun Xiao  4 ,  Jeff Hsu  4 ,  Alexey Revenko  4 ,  Brett P Monia  4 ,  A Robert MacLeod  4 ,  David S Hong  9
Affiliations
  • 1. Division of Hematology/Oncology, University of Virginia Health System, Charlottesville, VA, USA.
  • 2. Oncology, IMED Biotech Unit, AstraZeneca Pharmaceuticals, Waltham, MA, USA.
  • 3. UC San Diego Moores Cancer Center, La Jolla, CA, USA.
  • 4. Department of Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA.
  • 5. Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 6. Mary Crowley Cancer Research Center, Dallas, TX, USA.
  • 7. Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0455, Houston, TX, 77030, USA.
  • 8. Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca Pharmaceuticals, Waltham, MA, USA.
  • 9. Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0455, Houston, TX, 77030, USA. [email protected].
PMID: 30446007 DOI: 10.1186/s40425-018-0436-5
Abstract

Background: The 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.

Methods: Patients 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.

Results: Thirty 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.

Conclusions: AZD9150 was well tolerated and demonstrated efficacy in a subset of heavily pretreated patients with DLBCL. Studies in combination with checkpoint immunotherapies are ongoing.

Trial registration: Registered at ClinicalTrials.gov: NCT01563302 . First submitted 2/13/2012.

Keywords
Anti-sense oligonucleotide; Clinical trial; DLBCL; Diffuse large B-cell lymphoma; Immunotherapy; JAK-STAT; Lymphoma; STAT3.
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