scholarly journals ATIM-23. PHASE 1 DOSE ESCALATION STUDY OF CONTROLLED INTRATUMORAL VIRAL DELIVERY OF Ad-RTS-hIL-12 + ORAL VELEDIMEX IN SUBJECTS WITH RECURRENT OR PROGRESSIVE HIGH-GRADE GLIOMA

2016 ◽  
Vol 18 (suppl_6) ◽  
pp. vi22-vi23 ◽  
Author(s):  
Francois Lebel
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
High Grade Glioma ◽  
High Grade ◽  
Dose Escalation Study

A phase I study to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activities of daily oral BAL101553, a novel tumor checkpoint controller (TCC) in adult patients with progressive or recurrent glioblastoma (GBM) or high-grade glioma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2601-TPS2601
Author(s):  
Alvaro Henrique Ingles Garces ◽  
Elizabeth R. Plummer ◽  
Juanita Suzanne Lopez ◽  
Rebecca Sophie Kristeleit ◽  
Julie MacDonald ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Dose Escalation ◽  
Spindle Assembly Checkpoint ◽  
Phase 1 ◽  
High Grade Glioma ◽  
Low Grade ◽  
High Grade ◽  
Tumor Cell Death ◽  
Antitumor Activities ◽  
Dose Escalation Study

TPS2601 Background: BAL101553 (prodrug of BAL27862) is a novel TCC that promotes tumor cell death by modulating the spindle assembly checkpoint. BAL27862 is a lipophilic, small molecule (MW 387) shown in rats to penetrate the brain (1:1 plasma ratio) and has shown promising antitumor activity in orthotopic preclinical models of GBM as monotherapy or in combination with radiotherapy (RT) with/without chemotherapy. In a completed Phase 1 study with 2-h IV infusions (Days 1, 8, 15, q28d, NCT01397929 , CDI-CS-001, Lopez et al. J Clin Oncol 34, 2016 suppl; 2525), dose-limiting vascular effects were observed and appeared Cmax related. Preclinical data suggest that antiproliferative effects of BAL101553/27862 are driven by exposure (AUC); thus vascular toxicity and antitumor activity are mediated by different PK drivers. In this ongoing study (NCT02490800, CDI-CS-002), daily oral BAL101553 was initially examined in solid-tumor patients; no vascular toxicities were observed at doses up to the MAD of 30 mg QD. Given this absence, the study was amended to enroll separate cohorts of patients with progressive or recurrent GBM or high-grade glioma. Methods: This is an ongoing multicenter, open-label, Phase 1 dose-escalation study using a 3+3 design to determine the MTD, characterize dose-limiting toxicities and assess the PK, PD and antitumor activities of daily oral administration of BAL101553 in consecutive 28-day cycles at a starting dose of 8 mg QD. Patients with histologically-confirmed GBM or high-grade glioma, with progressive or recurrent disease after prior RT with/without chemotherapy, are eligible for enrollment. This includes patients with histologically-confirmed low-grade glioma with unequivocal evidence by imaging of transformation to high-grade glioma. Adverse events are assessed using CTCAEv4; tumor response by RANO (every 2 cycles). The dose escalation allows for doubling of dose levels depending on observed toxicities. PD assessments include circulating tumor cells. PK profiles are assessed throughout the first two treatment cycles. Clinical trial information: NCT02490800.

scholarly journals Gemcitabine Plus Radiation Therapy for High-Grade Glioma: Long-Term Results of a Phase 1 Dose-Escalation Study

2016 ◽  
Vol 94 (2) ◽  
pp. 305-311 ◽  
Author(s):  
Michelle M. Kim ◽  
Sandra Camelo-Piragua ◽  
Matthew Schipper ◽  
Yebin Tao ◽  
Daniel Normolle ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Dose Escalation ◽  
Phase 1 ◽  
High Grade Glioma ◽  
Long Term Results ◽  
High Grade ◽  
Dose Escalation Study

scholarly journals Phase I dose-escalation study of the PI3K/mTOR inhibitor voxtalisib (SAR245409, XL765) plus temozolomide with or without radiotherapy in patients with high-grade glioma

2015 ◽  
Vol 17 (9) ◽  
pp. 1275-1283 ◽  
Author(s):  
Patrick Y. Wen ◽  
Antonio Omuro ◽  
Manmeet S. Ahluwalia ◽  
Hassan M. Fathallah-Shaykh ◽  
Nimish Mohile ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Mtor Inhibitor ◽  
High Grade Glioma ◽  
High Grade ◽  
Dose Escalation Study

A Phase 1 Dose-Escalation Study of Oral 5-Aminolevulinic Acid in Adult Patients Undergoing Resection of a Newly Diagnosed or Recurrent High-Grade Glioma

Neurosurgery ◽  
2017 ◽  
Vol 81 (1) ◽  
pp. 46-55 ◽  
Author(s):  
Jeffrey W. Cozzens ◽  
Barbara C. Lokaitis ◽  
Brian E. Moore ◽  
Devin V. Amin ◽  
José A. Espinosa ◽  
...  
Keyword(s):  
United States ◽  
Adverse Events ◽  
Dose Level ◽  
Dose Escalation ◽  
Aminolevulinic Acid ◽  
Medical Center ◽  
Phase 1 ◽  
High Grade Glioma ◽  
The United States ◽  
High Grade

Abstract BACKGROUND: The utility of oral 5-aminolevulinic acid (5-ALA)/protoporphyrin fluorescence for the resection of high-grade gliomas is well documented. This drug has received regulatory approval in Europe but awaits approval in the United States. OBJECTIVE: To identify the appropriate dose and toxicity or harms of 5-ALA used for enhanced intraoperative visualization of malignant brain tumors, reported from a single medical center in the United States. METHODS: Prior to craniotomy for resection of a presumed high-grade glioma, individuals were given oral 5-ALA as part of a rapid dose-escalation scheme. At least 3 patients were selected for each dose level from 10 to 50 mg/kg in 10 mg/kg increments. Adverse events, intensity of tumor fluorescence, and results of biopsies in areas of tumor and the tumor bed under white light and deep blue light were recorded. RESULTS: A total of 19 patients were studied in this phase 1 study. Serious adverse events were unrelated to the ingestion of 5-ALA. At the highest dose level studied (50 mg/kg), 2 out of 6 patients were observed to have transient dermatologic redness and peeling. These were grade 1 adverse events, which were not serious enough to be dose limiting. Patients at higher dose levels (>40 mg/kg) were more likely to have strong tumor fluorescence. There were no instances of false positive fluorescence. CONCLUSION: The use of 5-ALA for brain tumor fluorescence is safe and effective to a dose of 50 mg/kg. Dose-limiting toxicity was not reached in this study.

scholarly journals ACTR-64. PHASE 2 STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS AND CLINICAL ACTIVITY OF PI3K/mTOR INHIBITOR GDC-0084 IN GBM PATIENTS WITH UNMETHYLATED O6-METHYLGUANINE-METHYLTRANSFERASE (MGMT) PROMOTER STATUS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi28-vi28
Author(s):  
Patrick Wen ◽  
John DeGroot ◽  
James Battiste ◽  
Samuel Goldlust ◽  
James Garner ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Mtor Inhibitor ◽  
Phase 1 ◽  
Mammalian Target Of Rapamycin ◽  
High Grade Glioma ◽  
Clinical Activity ◽  
High Grade ◽  
Newly Diagnosed ◽  
Open Label ◽  
Once Daily

Abstract BACKGROUND GDC-0084 is a potent, oral, selective small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin (PI3K/mTOR). GDC-0084 crosses the blood-brain barrier and achieves a brain / plasma ratio of approximately 1.0. GDC-0084 was given as once daily dosing in a phase 1 study (Wen et al, J Clin Oncol 34, 2016(15) suppl.2012) in 47 patients with recurrent high-grade gliomas. The adverse events were generally consistent with the established PI3K/mTOR inhibitor class-effects. The MTD identified was 45mg once daily. METHODS The current study is conducted in the newly diagnosed GBM patient with unmethylated MGMT promotor status upon completion of standard adjuvant XRT/TMZ. It has a 2-part design: an open-label, dose-escalation phase to assess the safety, tolerability, MTD (Part 1, followed by an expansion cohort (Part 2) commencing once MTD is established. Dose-escalation started at 60mg, and progressed in 15mg increments, per standard 3 + 3 rules. Part 2 recruits 20 patients, who are randomized to take GDC-0084 at the identified MTD, in fed and fasted states. RESULTS Part 1 of the study is complete. There were no DLTs among 3 pts treated at the 60mg. Among 6 pts treated at 75mg, DLTs were identified as hyperglycaemia (symptomatic) and oral mucositis. Adverse effects seen were generally modest, manageable and consistent with the PI3K-class. PK parameters are in line with phase 1 data. Part 2 recruitment is ongoing. CONCLUSION GDC-0084 displays a safety profile consistent with previous data in recurrent high-grade glioma but appears better tolerated in the newly diagnosed GBM setting. An MTD of 60mg is identified.

Safety and pharmacokinetics of BXQ-350 in a phase 1a and 1b trial of solid tumors and high-grade glioma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13531-e13531 ◽  
Author(s):  
Olivier Rixe ◽  
John Charles Morris ◽  
Vinay K. Puduvalli ◽  
John L. Villano ◽  
Trisha Michel Wise-Draper ◽  
...  
Keyword(s):  
Adverse Events ◽  
Dose Escalation ◽  
Phase 1 ◽  
High Grade Glioma ◽  
High Grade ◽  
Antitumor Effects ◽  
Serious Adverse Events ◽  
Blood Pressure Elevation ◽  
Saposin C ◽  
Ongoing Phase

e13531 Background: BXQ-350 is composed of the multifunctional, lysosomal-activator protein Saposin C and phosphatidylserine lipid with demonstrated antitumor effects in vitro and in vivo. In this abstract we update the safety and pharmacokinetic (PK) profile based on an ongoing Phase 1 trial. Methods: BXQ-350 was administered in a Phase 1a dose-escalation trial (NCT02859857), and an ongoing Phase 1b trial (data cut off at max of 6 cycles, 01DEC2018) to refractory solid tumor/high-grade glioma patients (pts). In Phase 1a, pts received escalating IV BXQ-350 doses of 0.7, 1.1, 1.4, 1.8, or 2.4 mg/kg on days 1, 2, 3, 4, 5, 8, 10, 12, 15, 22 (cycle 1), 29 (cycle 2), and thereafter 28-day cycles. PK was assessed over a 24-hr period following the first dose. The Saposin C level was analyzed by ELISA and PK parameters were calculated using noncompartmental methods. Results: The 1a cohort of 18 pts (age 24-69) had a median of 3 cycles and 1b cohort of 20 pts (age 31-80) had median of 2 cycles with no treatment-related serious adverse events to date. Moderately severe related adverse events (AEs, n case, n events) are reported with serious non-related events. The most common treatment-related AE was fatigue (2 at dose 1.1, 2 at 1.8, 1 at 2.4mg/kg and 3 in 1b), at 2.4 mg/kg, 1 pt had moderate blood pressure elevation. Exposures in the 1.4 and 1.8 mg/kg cohorts were less than dose-proportional, likely due to higher clearance in those groups. The overall mean clearance and half-live values were 66.8 (mL/kg/h) and 4.03 h, respectively. Conclusions: BXQ-350 has had no serious related AEs during dose-escalation or in the on-going trial supporting a tolerable safety profile at 2.4 mg/kg. Clinical trial information: NCT02859857. [Table: see text]

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