CTNI-42. PHASE I STUDY OF RUXOLITINIB WITH RADIATION AND TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GRADE III GLIOMAS AND GLIOBLASTOMA

Abstract BACKGROUND Ruxolitinib is a novel, potent, selective inhibitor of JAK1 (Janus kinase 1) and JAK2 with modest to marked selectivity against TYK2 (tyrosine kinase 2) and JAK3. Ruxolitinib interferes with the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression. METHODS Newly diagnosed patients with MGMT not hypermethylated, Glioblastoma or grade III glioma were recruited to Arm 1. Every patient received ruxolitinib and 60 Gy radiation for 6 weeks (2Gy x 30). The dose of Ruxolitinib was administered given the 3 + 3 design. Level 1 or starting dose was 10 mg twice daily, level 2 was 15 mg twice daily, level 3 was 20 mg twice daily. Patients with MGMT hypermethylated glioblastoma or grade III glioma were eligible for Arm 2. Every patient received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks. RESULTS 45 patients had survival data, 25 patients were in Arm I and 20 arm in II. The median OS and PFS were 18.2 (95% CI: 3.6-NA) months for Arm 1 and were not reached for Arm 2. OS and PFS Rate at 1 year was 61% (95% CI: 43-85%) and 51% (35-76%) for Arm 1, and 95% (85-100%) for Arm 2 (p=0.01 and p= 0.002), respectively. 9 patients had partial response, 16 patients were stable, and 28 patients had progression. CONCLUSION Patients that received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks (Arm 2) had significantly better PFS and OS than those that received ruxolitinib + radiation x 60 Gy alone..

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Phase I study of ruxolitinib with radiation and temozolomide in patients with newly diagnosed grade III gliomas and glioblastoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2060 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2060-2060

Author(s):

Yasmeen Rauf ◽

Rachel Hufsey ◽

Kathy Robinson ◽

John H. Suh ◽

Samuel T. Chao ◽

...

Keyword(s):

Survival Data ◽

Progression Free Survival ◽

Janus Kinase ◽

Rank Test ◽

Newly Diagnosed ◽

Signal Transducers ◽

Kaplan Meier ◽

Tyrosine Kinase 2 ◽

Level 1 ◽

Grade Iii

2060 Background: Ruxolitinib is a novel, potent, and selective inhibitor of JAK1 (Janus kinase 1) and JAK2 with modest to marked selectivity against TYK2 (tyrosine kinase 2) and JAK3, respectively. Ruxolitinib interferes with the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression. Dysregulation of the JAK/STAT pathway has been associated with several types of cancer and increased proliferation and survival of malignant cells. Methods: Newly diagnosed patients with unmethylated MGMT Glioblastoma or grade III glioma were recruited to Arm 1. Every patient received ruxolitinib and 60 Gy radiation for 6 weeks over 6 weeks (2Gy x 30). The dose of Ruxolitinib was administered given the 3+3 design. Level 1 or starting dose was 10 mg twice daily, level 2 was 15 mg twice daily, level 3 was 20 mg twice daily and level -1 was 5 mg twice daily. Arm 2 was started once safe dose was established for Arm 1 for each dose level. Patients with methylated MGMT glioblastoma or grade III glioma were eligible for Arm 2. Every patient received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks. Overall survival (OS) and progression-free survival (PFS) were estimate by Kaplan-Meier method and compared using log rank test. Results: 45 patients had survival data, 25 patients were Arm I and 20 arm II. The median OS and PFS were 18.2 (95% CI: 3.6-NA) months for Arm 1 and were not reached for Arm 2. OS and PFS Rate at 1 year was 61% (95% CI: 43-85%) and 51% (35-76%) for Arm 1, and 95% (85-100%) for Arm 2 (p = 0.01 and p = 0.002), respectively. Conclusions: Patients that received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks (Arm 2) had significantly better PFS and OS than those that received ruxolitinib + radiation x 60 Gy alone. Clinical trial information: NCT03514069.

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CTNI-41. PHASE I STUDY OF RUXOLITINIB WITH RADIATION AND TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GRADE III GLIOMAS AND GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.207 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii51-ii51

Author(s):

Yasmeen Rauf ◽

Rachel Hufsey ◽

Kathy Robinson ◽

John Suh ◽

Samuel Chao ◽

...

Keyword(s):

Partial Response ◽

Respiratory Distress ◽

Maximum Tolerated Dose ◽

Janus Kinase ◽

Poor Responders ◽

Newly Diagnosed ◽

Tyrosine Kinase 2 ◽

Level 1 ◽

Grade 3 ◽

Grade Iii

Abstract BACKGROUND Ruxolitinib is a novel, potent, and selective inhibitor of JAK1 (Janus kinase 1) and JAK2 with modest to marked selectivity against TYK2 (tyrosine kinase 2) and JAK3, respectively. Dysregulation of the JAK/STAT pathway has been associated with several types of cancer and increased proliferation and survival of malignant cells. METHODS Newly diagnosed patients with unmethylated MGMT Glioblastoma or grade III glioma were recruited to Arm I. Every patient received ruxolitinib and 60 Gy radiation for 6 weeks over 6 weeks (2Gy x 30). The dose of Ruxolitinib was administered given the 3 + 3 design. Level 1 or starting dose was 10 mg twice daily, level 2 was 15 mg twice daily, level 3 was 20 mg twice daily and level -1 was 5 mg twice daily. Arm two was started once safe dose was established for Arm 1 for each dose level. Patients with methylated MGMT glioblastoma or grade III glioma were eligible for Arm 2. Every patient received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks. RESULTS 30 patients were randomized to Arm I and 16 to arm II. There was one partial response in the methylated Arm and one partial response in the unmethylated arm. The maximum tolerated dose of Ruxolitinib was 20 mg BID in both methylated and unmethylated arm. There were 14 incidences of Grade 3 toxicity including respiratory distress, seizure, gait disturbance, weakness, thrombocytopenia, cognitive disturbance, urinary retention, and bacterial meningitis. There were 4 incidences of Grade 4 toxicity including seizure, respiratory distress, somnolence and thromboembolic events. CONCLUSION This is an ongoing clinical trial and final results will be presented once the trial is complete. We will perform single cell sequencing on good and poor responders, that data will be presented in the meeting.

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TYK2 in Tumor Immunosurveillance

Cancers ◽

10.3390/cancers12010150 ◽

2020 ◽

Vol 12 (1) ◽

pp. 150 ◽

Cited By ~ 4

Author(s):

Anzhelika Karjalainen ◽

Stephen Shoebridge ◽

Milica Krunic ◽

Natalija Simonović ◽

Graham Tebb ◽

...

Keyword(s):

Current Knowledge ◽

Janus Kinase ◽

Cytokine Receptor ◽

Cytokine Signaling ◽

Signal Transducers ◽

Tumor Surveillance ◽

Adaptive Immune ◽

Cancer Immunity ◽

Tyrosine Kinase 2 ◽

History Of

We review the history of the tyrosine kinase 2 (TYK2) as the founding member of the Janus kinase (JAK) family and outline its structure-function relation. Gene-targeted mice and hereditary defects of TYK2 in men have established the biological and pathological functions of TYK2 in innate and adaptive immune responses to infection and cancer and in (auto-)inflammation. We describe the architecture of the main cytokine receptor families associated with TYK2, which activate signal transducers and activators of transcription (STATs). We summarize the cytokine receptor activities with well characterized dependency on TYK2, the types of cells that respond to cytokines and TYK2 signaling-induced cytokine production. TYK2 may drive beneficial or detrimental activities, which we explain based on the concepts of tumor immunoediting and the cancer-immunity cycle in the tumor microenvironment. Finally, we summarize current knowledge of TYK2 functions in mouse models of tumor surveillance. The biology and biochemistry of JAKs, TYK2-dependent cytokines and cytokine signaling in tumor surveillance are well covered in recent reviews and the oncogenic properties of TYK2 are reviewed in the recent Special Issue ‘Targeting STAT3 and STAT5 in Cancer’ of Cancers.

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Effects of puerarin on expressions of leptin receptor mRNA, phosphoryla-ted Janus kinase 2/phosphorylated signal transducers and activators of transcription 3 proteins in the liver of rats with non-alcoholic fatty liver

Journal of Chinese Integrative Medicine ◽

10.3736/jcim20080909 ◽

2008 ◽

Vol 6 (9) ◽

pp. 921-927 ◽

Cited By ~ 3

Author(s):

PY Zheng

Keyword(s):

Fatty Liver ◽

Leptin Receptor ◽

Janus Kinase ◽

Janus Kinase 2 ◽

Alcoholic Fatty Liver ◽

Signal Transducers ◽

Receptor Mrna ◽

Transcription 3 ◽

Signal Transducers And Activators

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Investigation of JAK2V617F Mutation Prevalence in Patients with Beta Thalassemia Major

Laboratory Medicine ◽

10.1093/labmed/lmz045 ◽

2019 ◽

Cited By ~ 1

Author(s):

Zari Tahannejad Asadi ◽

Reza Yarahmadi ◽

Najmaldin Saki ◽

Mohammad Taha Jalali ◽

Ali Amin Asnafi ◽

...

Keyword(s):

Genetic Disorder ◽

Thalassemia Major ◽

Janus Kinase ◽

Jak2v617f Mutation ◽

Beta Thalassemia ◽

Common Mutation ◽

Signal Transducers ◽

Significant Difference ◽

Polymerase Chain ◽

Low Prevalence

AbstractBackgroundBeta (β)–thalassemia major is a genetic disorder with anemia and an increased level of erythropoietin by Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway. JAK plays an important role in cell signaling, and the common mutation in the JAK2 gene in myeloid disorders is called JAK2V617F.MethodsA total of 75 patients with beta (β)-thalassemia major patients, including 34 males (45%) and 41 females (55%), were enrolled in this study. The presence of the JAK2V617F mutation was assessed using the amplification-refractory mutation–polymerase chain reaction (ARMS-PCR) technique.ResultsAmong the 75 patients, 14 patients (19%) tested positive and 61 patients (81%) tested negative for JAK2V617F mutation. We observed no statistically significant difference in sex, age, genotype, and JAK2V617F mutation among patients (P> .05). However, a significant difference between blood-transfusion frequency and JAK2V617F mutation was observed (P <.05).ConclusionDue to the low prevalence of JAK2V617F mutation in thalassemia, using a larger population of the patients to investigate this mutation in ineffective erythropoiesis can be useful.

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Value of Surgical Resection in Patients with Newly Diagnosed Grade III Glioma Treated in a Multimodal Approach: Surgery, Chemotherapy and Radiotherapy

Annals of Surgical Oncology ◽

10.1245/s10434-016-5222-3 ◽

2016 ◽

Vol 23 (9) ◽

pp. 3040-3046 ◽

Cited By ~ 17

Author(s):

Federico Pessina ◽

Pierina Navarria ◽

Luca Cozzi ◽

Anna Maria Ascolese ◽

Matteo Simonelli ◽

...

Keyword(s):

Surgical Resection ◽

Multimodal Approach ◽

Newly Diagnosed ◽

Grade Iii

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CTNI-47. INTERIM RESULTS OF NCT03011671: A MULTI-INSTITUTIONAL PHASE I STUDY OF ACETAZOLAMIDE WITH TEMOZOLOMIDE IN ADULTS WITH NEWLY DIAGNOSED MGMT-METHYLATED MALIGNANT GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noab196.272 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi70-vi70

Author(s):

Bakhtiar Yamini ◽

Seán Lyne ◽

Riley Driscoll ◽

Giovanna Bernal ◽

Longtao Wu ◽

...

Keyword(s):

Phase I ◽

Malignant Glioma ◽

Phase I Study ◽

Objective Response ◽

Controlled Study ◽

Current Phase ◽

Newly Diagnosed ◽

Biomarker Analysis ◽

Secondary Endpoints ◽

Grade Iii

Abstract Preclinical studies indicate that up-regulation of carbonic anhydrase (CA) by temozolomide (TMZ), via a mechanism requiring the proto-oncogene BCL-3, promotes resistance to therapy in glioblastoma (GBM) cells. Moreover, the CA inhibitor, acetazolamide (ACZ), sensitizes patient-derived GBM cells and xenografts to TMZ. These findings led to the current Phase I study investigating the safety and efficacy of adding ACZ to adjuvant TMZ in patients with newly diagnosed, MGMT-methylated malignant glioma. 24 patients were enrolled (23 GBM and one Grade III IDH-mutant astrocytoma), median age was 53.5 and mean KPS 91. ACZ was given on days 1-21 of each adjuvant TMZ cycle (250 mg BID days 1-7, increased to 500 mg BID days 8-21). No patient experienced the primary outcome of regimen limiting toxicity (RLT) and there were only three grade III adverse events deemed likely unrelated to ACZ. For the secondary endpoints of overall and progression free survival (OS and PFS, respectively), only the 23 GBM patients were included (22 IDH-wildtype and 1 IDH-mutant). From diagnosis, median PFS was 18.8 months (95% CI: 10.4-23.0) and median OS was 25.0 months (95% CI: 19.9-28.4). Median time from diagnosis to consent was 2.9 months. As of April 2021, only 7 of 23 deaths had occurred. 2-year OS% was 68.2%. Further analysis of secondary endpoints including 6-month objective response rate (ORR) and biomarker analysis of BCL-3 by IHC will be available in the coming months. In sum, the data indicate that addition of ACZ to TMZ is safe and does not lead to reduced TMZ dosing. Also, compared to historical data, interim outcomes suggest that addition of ACZ may substantially improve PFS and 2-year overall survival. These findings support the hypothesis that ACZ acts as a chemosensitizer of alkylating chemotherapy in GBM and support examination of this regimen in a randomized, placebo-controlled study.

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Short-term outcomes associated with temozolomide vs. PCV chemotherapy for 1p/19q-codeleted WHO grade III anaplastic oligodendrogliomas: a national evaluation

10.1101/2020.03.29.20046805 ◽

2020 ◽

Author(s):

Nayan Lamba ◽

Malia McAvoy ◽

Vasileios K. Kavouridis ◽

Timothy R. Smith ◽

Mehdi Touat ◽

...

Keyword(s):

Cox Regression ◽

Long Term Results ◽

National Database ◽

Newly Diagnosed ◽

First Line ◽

Short Term ◽

Who Grade ◽

Cox Regression Analysis ◽

Pcv Chemotherapy ◽

Grade Iii

AbstractPURPOSEThe optimal chemotherapy regimen between temozolomide (TMZ) and procarbazine, lomustine, and vincristine (PCV) remains uncertain for newly-diagnosed anaplastic oligodendroglioma (AO). We therefore addressed this question using a national database.METHODSPatients newly-diagnosed with 1p/19q-codeleted W.H.O. grade III AO between 2010-2016 were identified from the National Cancer Database. Predictors of receiving first-line single-agent TMZ vs. multi-agent PCV were assessed by multivariable logistic regression. Overall survival (OS) was estimated by Kaplan-Meier techniques and evaluated by multivariable Cox regression.RESULTS1,360 AO patients were identified: 74.5% (n=1,013) treated with TMZ, 9.6% (n=131) with PCV, and 15.9% (n=216) with no chemotherapy in the first-line setting. In multivariable logistic analysis, PCV utilization increased from 2010 to 2016 (OR=1.38/year, 95%CI: 1.22-1.56, p<0.001) and was less commonly utilized in privately insured patients (OR=0.38 vs. uninsured, 95%CI: 0.15-0.97, p=0.04). In survival analyses (33.1% reached endpoint), there was no difference in unadjusted OS between TMZ (5yr-OS 60.1%, 95%CI: 55.9-64.1) and PCV (5yr-OS 61.1%, 95%CI: 45.6-73.5; p=0.42). There remained no OS difference between TMZ and PCV in the 75.9% (n=1,032) of AO patients that also received radiotherapy (p=0.51), in the Cox regression analysis adjusted by age, extent of resection, and radiotherapy (TMZ vs. PCV HR=1.31, 95%CI: 0.83-2.08, p=0.24), and in subgroup analyses that incorporate KPS or MGMT status.CONCLUSIONSIn a national database of AOs managed in the ‘real-world’ setting, there is no difference in the short-term mortality between first-line TMZ and PCV chemotherapy. These findings provide preliminary data while we await the long-term results from the CODEL trial.

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