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 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 First-in-Human Phase I Study to Evaluate the Brain-Penetrant PI3K/mTOR Inhibitor GDC-0084 in Patients with Progressive or Recurrent High-Grade Glioma

2020 ◽  
Vol 26 (8) ◽  
pp. 1820-1828 ◽  
Author(s):  
Patrick Y. Wen ◽  
Timothy F. Cloughesy ◽  
Alan G. Olivero ◽  
Kari M. Morrissey ◽  
Timothy R. Wilson ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Mtor Inhibitor ◽  
High Grade Glioma ◽  
High Grade ◽  
The Brain

scholarly journals AT-32A PHASE I DOSE-ESCALATION STUDY OF GEMCITABINE PLUS STANDARD RADIATION THERAPY FOR MALIGNANT HIGH GRADE GLIOMAS

2014 ◽  
Vol 16 (suppl_5) ◽  
pp. v15-v15 ◽  
Author(s):  
Michelle Kim ◽  
Matthew Schipper ◽  
Yue Cao ◽  
Larry Junck ◽  
Aaron Mammoser ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Phase I ◽  
Dose Escalation ◽  
High Grade ◽  
Dose Escalation Study ◽  
High Grade Gliomas

scholarly journals First in Human Phase I Trial of Dual Vector (HSV1-TK, Flt3L) Immunotherapy For The Treatment of Newly Diagnosed High-Grade Glioma: Initial Results

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Daniel A Orringer ◽  
Oren Sagher ◽  
Jason Heth ◽  
Shawn L Hervey-Jumper ◽  
Aaron Mammoser ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Phase I ◽  
Dose Escalation ◽  
Central Element ◽  
High Grade Glioma ◽  
High Grade ◽  
Newly Diagnosed ◽  
Dual Vector ◽  
The Brain

Abstract INTRODUCTION An inadequate immune response is increasingly recognized as a central element in the pathogenesis of high-grade glioma. Based on our prior work, we hypothesized that dendritic cell dysfunction plays a key role in poor anti-brain tumor immunity. To stimulate a robust immune response against high-grade glioma, we developed a strategy to recruit dendritic cells to the brain and induce tumor cytotoxicity. We chose Flt3L to attract dendritic cells to the brain and HSV1-TK (plus valacyclovir) to kill tumor cells and make antigens available to dendritic cells. Studies in animal models of glioma reveal that Flt3L and HSV1-TK combination therapy results in infiltration of gliomas by dendritic cells, generation of immune cytotoxicity and memory, and the recognition of tumor neoantigens by immune cells. METHODS Based on compelling preclinical data, we executed a first-in-human phase I dose escalation trial of HSV1-TK or Flt3L dual adenoviral therapy for the treatment of newly diagnosed malignant gliomas. Vectors were injected into the tumor cavity following resection. The trial consisted of a dose escalation of both vectors, starting at 1 × 10∧9 iu and increasing to 1 × 10∧11 iu through a total of 6 combinations administered to 6 cohorts of 3 patients each. Two cycles of 14 d each of valacyclovir were administered to activate HSV1-TK cytotoxicity on postoperative days 1 and 56. All patients received Stupp protocol chemoradiation. RESULTS The experimental treatment was well tolerated, and at this time the MTD has not been reached. Additionally, preliminary analysis suggests that the dual-vector therapy provides a potent survival advantage when evaluated against contemporary and historical controls. Updated progression free survival and overall survival, AEs, and SAEs will be communicated at the time of presentation. CONCLUSION Flt3L/HSV1-TK dual vector immunotherapy is well tolerated and may prolong survival in high-grade glioma patients. Further evaluation in a larger-scale, multi-center trial is justified.

scholarly journals Phase I dose-escalation study of the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat in patients with advanced malignancy

Oncotarget ◽  
2016 ◽  
Vol 7 (41) ◽  
pp. 67521-67531 ◽  
Author(s):  
Haeseong Park ◽  
Ignacio Garrido-Laguna ◽  
Aung Naing ◽  
Siqing Fu ◽  
Gerald S. Falchook ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Hdac Inhibitor ◽  
Mtor Inhibitor ◽  
Dose Escalation Study ◽  
Advanced Malignancy

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 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.

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