Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 2060-2060
    Abstract: 2060 Background: Dysregulation of the JAK/STAT pathway in newly-diagnosed high-grade gliomas (nHGG) is linked to enhanced survival and proliferation of tumor cells. Ruxolitinib, a small molecule inhibitor of JAK1, JAK2, and JAK3, limits glioma growth in preclinical models. This concept was explored in a phase I trial (NCT03514069), whose final report on toxicity is presented here. Methods: This non-randomized prospective study included 60 WHO Grade 3-4 nHGG patients who received standard of care (SOC) therapy along with ruxolitinib in a 3+3 dose-escalation design; level 1 of 10 mg BID, level 2 of 15 mg BID, level 3 of 20 mg BID, level -1 of 5 mg BID. The primary study objective was the determination of the maximum tolerated dose (MTD) of ruxolitinib in combination with chemoradiation. The secondary objective was the determination of safety, overall survival (OS), and progression-free survival (PFS). The exploratory aims were to investigate relationships between clinical outcomes and genomic signatures. Results: 60 patients were enrolled, with a median age of 60.5 years (range 22-78). 23 (38%) patients were female and 37 (62%) were male. 29 (48%) were MGMT unmethylated and received ruxolitinib with radiation of 60 Gy over 6 weeks. 31 (52%) patients were MGMT methylated and received ruxolitinib with 75 mg/m 2 of temozolomide (TMZ) with radiation of 60 Gy over 6 weeks. The 1-year OS rate was 77% for all GBM patients; 62% for arm 1 (unmethylated MGMT) and 93% for arm 2 (methylated MGMT). Median OS for arm 1 was 18.1 months (10.1, NA) and was not reached for arm 2. MTD for both cohorts was 20 mg BID. No dose-limiting toxicities were observed. Toxicities attributable to study medications included four grade 4 AEs including seizure, respiratory distress, somnolence, and thromboembolic event along with 14 grade 3 adverse events (AEs), including respiratory distress, seizure, gait disturbance, weakness, thrombocytopenia, cognitive disturbance, urinary retention, and meningitis. Conclusions: Ruxolitinib therapy is safe and feasible in combination with TMZ and radiation. Efficacy of ruxolitinib plus SOC appears promising compared to historical benchmarks for both MGMT methylated and MGMT unmethylated cohorts. A randomized phase 2 trial is planned. Clinical trial information: NCT03514069 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. e14551-e14551
    Abstract: e14551 Background: In a retrospective study, we investigated the correlation between the molecular characteristics and treatment outcomes in pts with G2-3 glioma. Methods: Pts with G2-3 glioma and known IDH mutation status who were diagnosed between 1994 and 2017 were analyzed. In most of the pts, IDH mutation was determined by immunohistochemistry only. Overall survival (OS) was defined as the date of biopsy/surgical resection to the date of last follow up or death. OS was estimated by Kaplan-Meier method and compared by log rank test. Results: 606 pts with G2 (81%) or G3 (19%) glioma were included. The median age at diagnosis was 38 years (Interquartile range 27-52), 55% of the pts were male, 83% were white, 47% had IDH-mt tumor and 67% underwent surgical resection. The median follow-up was 55.6 months (mo). The median OS (mOS) in pts with IDH mutated (mt) and IDH wild type (wt) tumor were 201 and 128 mo, respectively. The predictors of worse OS in pts with IDH-mt tumor included G3, receipt of chemotherapy or radiation therapy (RT), bilateral disease and lack of 1p/19q codeletion. The determinants of worse OS in pts with IDH-wt tumor included male gender, receipt of chemotherapy or RT, history of prior malignancy, smoking, G3, astrocytoma histology, no surgical resection, EGFR amplification, and lack of 1p/19q codeletion. The mOS by IDH, 1p/19q, and MGMT status is summarized in the table. RT and chemotherapy were more commonly used among pts who had G3 glioma and those who underwent biopsy only. Conclusions: Tumor grade continues to be a determinant of pt outcomes in the setting of molecularly defined gliomas. Presence of 1p/19q codeletion is a predictor of favorable OS in pts with G2-3 glioma. Surgical resection is a determinant of OS in pts with IDH-wt G2-3 gliomas, but not in pts with IDH-mt tumor. The worse OS in pts who were treated with RT or chemotherapy is likely due to the use of these treatment modalities in more aggressive tumors and in those who only had biopsy. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 3
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 2060-2060
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 4
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 2030-2030
    Abstract: 2030 Background: Renal cancer is the fourth most common cause of metastatic tumors to the brain. Tyrosine kinase inhibitors (TKIs) targeting VEGFR and other receptors, such as sunitinib, pazopanib, etc., have been used as first line for renal cell carcinoma brain metastasis (RCCBM). Immune Checkpoint Inhibitors (ICIs) targeting PD-L1 and CTLA-4 interactions, such as nivolumab and ipilimumab respectively, have also been used as first line treatment for RCCBM. However, the efficacy of TKIs alone, ICIs alone, or TKIs and ICIs combined as first line treatment has emerged as a topic of interest. Methods: Patients with RCCBM treated with either TKIs, ICIs, or both at our tertiary care center from 2010-2019 were evaluated. Overall Survival (OS) was measured from initiation of either TKI or ICI therapy to date of death or last follow up. The Cox proportional hazard model was used to determine differences in OS. Results: 218 patients with RCCBM were included. Of these, 32 were treated with ICIs alone, 112 were treated with TKIs alone, and 76 were treated with a combination of ICIs and TKIs. For ICI treatment alone the median age at diagnosis was 61 years (Interquartile range (IQR) 38-82), 72% of the patients were male, and 97% were white. For TKI treatment alone the median age at diagnosis was 58 years (IQR 37-82), 70% of the patients were male, and 92% were white. For the combination cohort the median age at diagnosis was 63 years (IQR 45-79), 69% of the patients were male, and 97% were white. OS for patients receiving ICI, TKI, and combination treatment had a median of 69.1, 42.7, and 126.0 months and a 2-year rate of 77%, 69%, and 93%, respectively. With ICI treatment as a reference, TKI treated patients had an OS hazard ratio of 1.32 (95% CI = 0.78 - 2.21, p = 0.30) and ICI/TKI combination had an OS hazard ratio of 0.52 (95% CI = 0.30 - 0.92, p = 0.024). Conclusions: A combination treatment of ICIs and TKIs was associated with an increase in OS when compared to treatment with either TKIs or ICIs alone in patients with RCCBM. These results should be interpreted cautiously due to treatment selection bias. Further studies need to be done to control for other patient variables such as performance status, number of intracranial lesions, and extra-cranial metastasis.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 5
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. e14009-e14009
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. e14009-e14009
    Abstract: e14009 Background: Breast cancer is the second most common cause of metastatic brain tumors. The presence of estrogen receptors (ER), and progesterone receptors (PR), and HER2 receptors have been used to guide both hormonal and targeted therapies for breast cancer. The presence or absence of these receptors may impact patient outcomes in breast cancer brain metastasis (BCBM). Methods: Patients with BCBM and known tumor marker status treated at our tertiary care center from 2010-2019 were evaluated. Overall Survival (OS) was measured from diagnosis of BCBM to date of death or last follow up. Many of these patients received multiple lines of treatment including hormonal and targeted therapies at some point during their care. The Cox proportional hazard model was used to determine differences in OS. Results: 137 patients with BCBM were included. Of these, 48 were ER or ER/PR positive (ER+), 3 were PR positive (PR+), and 47 were HER2, HER2/PR, HER2/ER, or HER2/ER/PR positive (HER2+), and 37 were triple-negative. For ER+ tumors the median age at diagnosis was 60 years (Interquartile range (IQR) 31-87) and 86% were white. For PR+ tumors the median age at diagnosis was 67 years (IQR 66-74) and 75% were white. For HER2+ tumors the median age at diagnosis was 55 years (IQR 31-84) and 79% were white. For triple-negative tumors the median age at diagnosis was 56 years (IQR 34-91) and 83% were white. OS for ER+, PR+, HER2+, and triple-negative patients had a median of 57.7, 19.8, 137.4, and 54.6 months and a 2-year rate of 76%, 33%, 82%, and 73%, respectively. With ER+ patients as a reference, PR+ patients had an OS hazard ratio of 1.49 (95% CI = 0.35 - 6.23, p = 0.59), HER2+ patients had an OS hazard ratio of 0.62 (95% CI = 0.36 - 1.06, p = 0.082), and triple-negative patients had an OS hazard ratio of 0.92 (95% CI = 0.54 - 1.57, p = 0.77). Conclusions: HER2+ tumors were associated with an increase in OS when compared to ER+, PR+, and triple-negative tumors in patients with BCBM. The OS of the other three tumor marker groups was not significantly different from one another. Further studies need to be done within tumor marker cohorts to determine the most effective treatments within those cohorts.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 6
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 2067-2067
    Abstract: 2067 Background: Novel therapeutic strategies are urgently needed in newly-diagnosed glioblastoma (GBM). Ibrutinib, an oral small molecule inhibitor of BTK, is currently being investigated for several B-cell malignancies and solid tumors. Preclinical evidence suggests ibrutinib in inhibiting cancer stem cell in glioblastoma. We sought to investigate the safety and tolerability of ibrutinib in nGBM. Methods: A non-randomized, prospective phase I trial was conducted in nGBM patients with Karnofsky performance status ≥70% and normal organ function, who received standard of care chemoradiation plus ibrutinib in a 3+3 dose-escalation design (level 1: 420 mg daily, level 2: 560 mg daily, level -1: 280 mg daily). Primary study objective was to determine maximum tolerated dose (MTD) of ibrutinib in combination with radiotherapy (RT) of 60 Gy over 6 weeks with/without 75 mg/m 2 of temozolomide (TMZ). Secondary objective was to determine safety, overall survival (OS), and progression-free survival. Results: 26 patients were enrolled, with 12 (46%) females. Median age was 61.5 years (range 76-22). 15 (58%) patients were MGMT methylated and 11 (42%) were unmethylated. Dose-limiting toxicities (DLTs) were observed at all dose levels of ibrutinib plus RT (ibru+RT) cohort. MTD of ibrutinib was noted to be 420 mg daily with RT+TMZ. All MGMT methylated and 2 unmethylated patients received ibrutinib+RT+TMZ. Remaining 9 unmethylated received ibru+RT. In ibru+RT+TMZ, median cycles of TMZ were 4 (range 0-6) and of ibrutinib were 3 (range 0-26). EGFR amplification status was available for 22 patients, of which 8 (36%) were amplified. Survival outcomes are described, stratified using log-rank test. Conclusions: 420 mg of Ibrutinib daily is safe and feasible in combination with TMZ and radiation in nGBM. Outcomes of ibrutinib appears promising compared to historical survival data in the MGMT methylated cohorts. Further trials are planned. Clinical trial information: NCT03535350 . [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 7
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 2031-2031
    Abstract: 2031 Background: Non-small cell lung cancer (NSCLC) is the most common cause of brain metastases, with 10-30% of patients developing brain metastases. EGFR is a transmembrane glycoprotein that is mutated in up to 50% of NSCLCs. First-generation EGFR tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib, are limited by blood-brain barrier (BBB) penetration and exon 20 (T790M) tumor mutations. Third-generation EGFR TKIs, such as osimertinib, have shown better BBB penetration and efficacy against T790M mutations. In this retrospective study, we evaluated the overall survival (OS) and progression-free survival (PFS) in NSCLCBM patients treated with first and third-generation EGFR TKIs. Methods: NSCLCBM patients diagnosed between 2010 and 2019 at our tertiary care center were investigated. Information regarding molecular marker status, systemic therapies, and date of progression were collected. OS was defined as the start date of systemic therapy to the date of last follow-up or death. OS and PFS were estimated by the Cox proportional model. Results: A total of 193 NSCLCBM patients with an EGFR mutation were identified. 33 EGFR mutant patients received first-generation EGFR TKIs, of which 56.7% were females, 82.1% were white, and had a median age of 63.2 years. 22 patients received third-generation EGFR TKIs, 64.1% being female, 76.9% being white, and with a median age of 71.5 years. The median OS (mOS) in patients who received first and third-generation EGFR TKIs was 59.8 months and 65.9 months respectively (p-value (p) = 0.06). The median PFS (mPFS) between the first and third-generation EGFR TKI cohorts was 44.3 months and 66.9 months respectively (p= 0.048, hazard ratio (HR) = 0.50 (95% confidence interval (CI) = 0.25, 0.99). Conclusions: Newer generation of targeted therapies in NSCLCBM have focused on overcoming previous efficacy hurdles, including BBB penetration and resistant mutations. We determined that there was a significant mPFS benefit in osimertinib compared to erlotinib or gefitinib, and a trend towards significant mOS benefit in osimertinib compared to erlotinib or gefitinib in patients with NSCLCBM. However, these results should be interpreted cautiously due to treatment selection bias, and further studies need to be conducted on brain metastases lesion size and response rates.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 8
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 2034-2034
    Abstract: 2034 Background: Non-small cell lung cancer (NSCLC) is the most common cause of brain metastases. ALK, which codes for tyrosine kinase receptors, is rearranged in 4-7% of NSCLC. First-generation ALK inhibitors have restricted efficacy due to poor blood-brain barrier (BBB) penetration and ALK-resistant tumor mutations. Second-generation ALK inhibitors have shown better BBB penetration, while third-generation ALK inhibitors were efficacious even against ALK-resistant mutations. In this retrospective study, we investigated the overall survival (OS) and progression-free survival (PFS) in NSCLCBM patients treated with first, second, and third-generation ALK inhibitors. Methods: NSCLCBM patients between 2010 and 2019 were evaluated. We analyzed data regarding molecular marker status, systemic therapies, and date of progression. OS was defined as the start date of systemic therapy to the date of last follow-up or death. The Cox proportional model was used to estimate OS and PFS. Results: A total of 90 patients had ALK gene rearrangement. 16 ALK positive patients received first-generation ALK inhibitor (crizotinib), with a median age of 59.2 years, 50% of the cohort being female and 83.3% being white. Another 17 patients received second-generation (alectinib, ceritinib, brigatinib) and third-generation ALK inhibitors (lorlatinib), with a combined median age of 52.2 years and a cohort of 52.6% females and 72.2% white patients. The 5-year OS rate was 49% (95% confidence interval (CI) = 24%, 71%) for first-generation ALK inhibitors and 76% (95% CI = 40%, 92%) for second and third-generation ALK inhibitors (p-value (p) = 0.019). The median PFS (mPFS) for patients who received first-generation ALK inhibitors was 45.3 months and for those who received second or third-generation ALK inhibitors was 180.1 months. The respective 5-year PFS rate was 43% (95% CI = 19%, 65%) and 72% (95% CI = 42%, 89%). Conclusions: Newer generations of targeted therapies in NSCLCBM have improved BBB penetration and effectiveness against resistant mutations. We determined that there was a significant 5-year OS benefit in patients who received second and third-generation ALK inhibitors compared to first-generation ALK inhibitors, and a respective trend towards significant PFS benefit in newer-generation ALK inhibitors when compared to first-generation. These results are encouraging, but the effect on intracranial lesion size and response rates should be examined in the future.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. Further information can be found on the KOBV privacy pages