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

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.

SUBMITTER: Reilley MJ

PROVIDER: S-EPMC6240242 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Reilley Matthew J MJ McCoon Patricia P Cook Carl C Lyne Paul P Kurzrock Razelle R Kim Youngsoo Y Woessner Richard R Younes Anas A Nemunaitis John J Fowler Nathan N Curran Michael M Liu Qinying Q Zhou Tianyuan T Schmidt Joanna J Jo Minji M Lee Samantha J SJ Yamashita Mason M Hughes Steven G SG Fayad Luis L Piha-Paul Sarina S Nadella Murali V P MVP Xiao Xiaokun X Hsu Jeff J Revenko Alexey A Monia Brett P BP MacLeod A Robert AR Hong David S DS

Journal for immunotherapy of cancer 20181116 1

<h4>Background</h4>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 lim ...[more]

PMID: 30446007

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Project description:Patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) following autologous stem cell transplant (ASCT) remain a management challenge with few reliably effective treatments. Lenalidomide, an immunomodulatory drug approved for patients with myelodysplastic syndrome with del(5q), multiple myeloma, and mantle cell lymphoma, has demonstrated some activity in patients with R/R cHL, though the toxicity of traditional doses and schedules has been a barrier to consistent use. Low dose continuous (LDC) schedules have emerged as promising, with a more favorable safety profile. We report herein that LDC schedules are associated with a far more tolerable toxicity profile, and exhibit at least equivalent efficacy in this patient population. We report that patients diagnosed with R/R cHL who previously underwent, or were not candidates for, ASCT and/or clinical trials, were administered daily LDC lenalidomide (20 mg orally with dose reduction for toxicity). Among the 19 patients included in this analysis, 11% of patients achieved a partial response (PR), with no documented complete responses (CR). A total of 12 (63%) patients maintained stable disease (SD), with 7 patients (37%) remaining in SD for more than 6 months. The clinical benefit rate (comprised of CR, PR, and SD for greater than 6 months) was 47% (7 out of 19 patients). The median progression-free survival and overall survival of all patients were 9.4 months (range, 4.6-14.4 months) and 90 months (range, 63.6-166.8 months), respectively. In general, the treatment was well tolerated, with grade 3 or 4 adverse events consisting of neutropenia (n = 4), and one case each of thrombocytopenia, fatigue, rash, creatinine elevation, aspartate transaminase/alanine transaminase elevation, and treatment related secondary malignancy. In a heavily treated R/R cHL patient population, daily LDC lenalidomide was associated with a high disease control rate with a favorable toxicity profile.

Dataset Information

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

Publications

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

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