Severity: Warning
Message: fopen(/var/lib/php/sessions/ci_sessionh9gjjjb3tf9498alq5ij4qekooa30mjg): Failed to open stream: No space left on device
Filename: drivers/Session_files_driver.php
Line Number: 177
Backtrace:
File: /var/www/html/index.php
Line: 316
Function: require_once
Severity: Warning
Message: session_start(): Failed to read session data: user (path: /var/lib/php/sessions)
Filename: Session/Session.php
Line Number: 137
Backtrace:
File: /var/www/html/index.php
Line: 316
Function: require_once
Severity: Warning
Message: Undefined array key "choices"
Filename: controllers/Detail.php
Line Number: 249
Backtrace:
File: /var/www/html/application/controllers/Detail.php
Line: 249
Function: _error_handler
File: /var/www/html/index.php
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Function: require_once
Severity: Warning
Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
Line Number: 249
Backtrace:
File: /var/www/html/application/controllers/Detail.php
Line: 249
Function: _error_handler
File: /var/www/html/index.php
Line: 316
Function: require_once
Severity: Warning
Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
Line Number: 249
Backtrace:
File: /var/www/html/application/controllers/Detail.php
Line: 249
Function: _error_handler
File: /var/www/html/index.php
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Function: require_once
Severity: Warning
Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
Line Number: 249
Backtrace:
File: /var/www/html/application/controllers/Detail.php
Line: 249
Function: _error_handler
File: /var/www/html/index.php
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Function: require_once
Severity: 8192
Message: strpos(): Passing null to parameter #1 ($haystack) of type string is deprecated
Filename: models/Detail_model.php
Line Number: 71
Backtrace:
File: /var/www/html/application/models/Detail_model.php
Line: 71
Function: strpos
File: /var/www/html/application/controllers/Detail.php
Line: 252
Function: insertAPISummary
File: /var/www/html/index.php
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Function: require_once
Severity: 8192
Message: str_replace(): Passing null to parameter #3 ($subject) of type array|string is deprecated
Filename: helpers/my_audit_helper.php
Line Number: 8919
Backtrace:
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 8919
Function: str_replace
File: /var/www/html/application/controllers/Detail.php
Line: 255
Function: formatAIDetailSummary
File: /var/www/html/index.php
Line: 316
Function: require_once
Severity: Warning
Message: Undefined array key "choices"
Filename: controllers/Detail.php
Line Number: 256
Backtrace:
File: /var/www/html/application/controllers/Detail.php
Line: 256
Function: _error_handler
File: /var/www/html/index.php
Line: 316
Function: require_once
Severity: Warning
Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
Line Number: 256
Backtrace:
File: /var/www/html/application/controllers/Detail.php
Line: 256
Function: _error_handler
File: /var/www/html/index.php
Line: 316
Function: require_once
Severity: Warning
Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
Line Number: 256
Backtrace:
File: /var/www/html/application/controllers/Detail.php
Line: 256
Function: _error_handler
File: /var/www/html/index.php
Line: 316
Function: require_once
Severity: Warning
Message: Undefined array key "usage"
Filename: controllers/Detail.php
Line Number: 257
Backtrace:
File: /var/www/html/application/controllers/Detail.php
Line: 257
Function: _error_handler
File: /var/www/html/index.php
Line: 316
Function: require_once
Severity: Warning
Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
Line Number: 257
Backtrace:
File: /var/www/html/application/controllers/Detail.php
Line: 257
Function: _error_handler
File: /var/www/html/index.php
Line: 316
Function: require_once
Severity: Warning
Message: Undefined array key "usage"
Filename: controllers/Detail.php
Line Number: 258
Backtrace:
File: /var/www/html/application/controllers/Detail.php
Line: 258
Function: _error_handler
File: /var/www/html/index.php
Line: 316
Function: require_once
Severity: Warning
Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
Line Number: 258
Backtrace:
File: /var/www/html/application/controllers/Detail.php
Line: 258
Function: _error_handler
File: /var/www/html/index.php
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Function: require_once
Severity: Warning
Message: Undefined array key "usage"
Filename: controllers/Detail.php
Line Number: 259
Backtrace:
File: /var/www/html/application/controllers/Detail.php
Line: 259
Function: _error_handler
File: /var/www/html/index.php
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Function: require_once
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Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
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File: /var/www/html/application/controllers/Detail.php
Line: 259
Function: _error_handler
File: /var/www/html/index.php
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Function: require_once
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Message: Undefined array key "usage"
Filename: controllers/Detail.php
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Backtrace:
File: /var/www/html/application/controllers/Detail.php
Line: 260
Function: _error_handler
File: /var/www/html/index.php
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Function: require_once
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Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
Line Number: 260
Backtrace:
File: /var/www/html/application/controllers/Detail.php
Line: 260
Function: _error_handler
File: /var/www/html/index.php
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Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
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File: /var/www/html/application/controllers/Detail.php
Line: 260
Function: _error_handler
File: /var/www/html/index.php
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Function: require_once
Severity: Warning
Message: file_get_contents(https://...@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
Filename: helpers/my_audit_helper.php
Line Number: 143
Backtrace:
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 143
Function: file_get_contents
File: /var/www/html/application/helpers/my_audit_helper.php
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Function: simplexml_load_file_from_url
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3098
Function: getPubMedXML
File: /var/www/html/application/controllers/Detail.php
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Function: pubMedSearch_Global
File: /var/www/html/application/controllers/Detail.php
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Function: pubMedGetRelatedKeyword
File: /var/www/html/index.php
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Function: require_once
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Message: Attempt to read property "Count" on bool
Filename: helpers/my_audit_helper.php
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Backtrace:
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3100
Function: _error_handler
File: /var/www/html/application/controllers/Detail.php
Line: 574
Function: pubMedSearch_Global
File: /var/www/html/application/controllers/Detail.php
Line: 488
Function: pubMedGetRelatedKeyword
File: /var/www/html/index.php
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Function: require_once
Background: Glutamate signaling activates MAPK and PI3K/AKT pathways in tumor cells. Treatment with riluzole, a glutamate release inhibitor, has been previously shown to be safe in melanoma patients and produced biologic effects, but did not lead to radiographic responses, possibly due to poor pharmacokinetic properties. Therefore, we conducted a phase Ib trial to determine the safety and tolerability of the combination of the riluzole prodrug troriluzole (BHV-4157, trigriluzole) and the PD-1 antibody nivolumab in patients with advanced solid tumors.
Methods: Patients with advanced or refractory solid tumors and measurable disease per RECIST 1.1 were treated with increasing doses of troriluzole using a semi-Bayesian modified toxicity probability interval dose escalation procedure. Troriluzole monotherapy was orally self-administered for a 14-day lead-in period followed by continuation of troriluzole in combination with nivolumab 240 mg IV every 2 weeks. Endpoints included safety, pharmacokinetics (PK) and efficacy.
Results: We enrolled 14 patients with advanced solid tumors (melanoma = 3, NSCLC = 3, renal cell carcinoma = 2, bladder/urothelial = 2, ovarian cancer = 1, adenoid cystic carcinoma = 1, pleural mesothelial = 1, head and neck cancer = 1). Eleven patients had cancer progression on prior therapy with PD-1 or PD-L1 agent. Patients received troriluzole total daily doses from 140 to 560 mg (divided). The most common treatment-related adverse events (TRAE) occurring in ≥ 5 patients (> 35%) were transaminitis and increased lipase. DLT (dose-limiting toxicity) occurred in 3 patients: (1) grade 3 anorexia, (2) grade 3 fatigue and, (3) grade 3 atrial fibrillation. Six patients were treated at the MTD (maximum tolerated dose). No subjects discontinued treatment due to AEs. One response occurred (7%), which was a partial response in a subject who had PD-1 refractory disease. The 6-month PFS rate was 21%. PK data showed that the prodrug troriluzole was efficiently cleaved into riluzole by 2-h post-dosing in all dose cohorts tested.
Conclusion: The combination of troriluzole and nivolumab was safe and well-tolerated. The MTD of troriluzole was determined to be 420 mg total daily dose. The observed antitumor activity, primarily disease stabilization, is of interest in patients with PD-1 resistant tumors. Trial Registration ClinicalTrials.gov Identifier NCT03229278.
Download full-text PDF |
Source |
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9250196 | PMC |
http://dx.doi.org/10.1186/s40001-022-00732-w | DOI Listing |
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