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

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.

scholarly journals Safety and tolerability of asunercept plus standard radiotherapy/temozolomide in Asian patients with newly-diagnosed glioblastoma: a phase I study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kuo-Chen Wei ◽  
Peng-Wei Hsu ◽  
Hong-Chieh Tsai ◽  
Ya-Jui Lin ◽  
Ko-Ting Chen ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Progression Free Survival ◽  
Multicenter Trial ◽  
Newly Diagnosed ◽  
Open Label ◽  
Free Survival ◽  
Asian Patients ◽  
Newly Diagnosed Glioblastoma ◽  
Secondary Endpoints

AbstractAsunercept (company code APG101 [Apogenix AG]; company code CAN008 [CANbridge Pharmaceuticals]) is a novel glycosylated fusion protein that has shown promising effectiveness in glioblastoma. This Phase I study was initiated to evaluate the tolerability and safety of asunercept in combination with standard radiotherapy and temozolomide (RT/TMZ) in Asian patients with newly diagnosed glioblastoma. This was the Phase I portion of a Phase I/II open label, multicenter trial of asunercept plus standard RT/TMZ. Adults with newly-diagnosed glioblastoma received surgical resection followed by standard RT/TMZ plus asunercept 200 mg/week (Cohort 1) or 400 mg/week (Cohort 2) by 30-min IV infusion. The primary endpoint was the safety and tolerability of asunercept during concurrent asunercept and RT/TMZ; dose-limiting toxicities were observed for each dose. Secondary endpoints included pharmacokinetics (PK) and 6-month progression-free survival (PFS6). All patients (Cohort 1, n = 3; Cohort 2, n = 7) completed ≥ 7 weeks of asunercept treatment. No DLTs were experienced. Only one possibly treatment-related treatment emergent adverse event (TEAE), Grade 1 gingival swelling, was observed. No Grade > 3 TEAEs were reported and no TEAE led to treatment discontinuation. Systemic asunercept exposure increased proportionally with dose and showed low inter-patient variability. The PFS6 rate was 33.3% and 57.1% for patients in Cohort 1 and 2, respectively. Patients in Cohort 2 maintained a PFS rate of 57.1% at Month 12. Adding asunercept to standard RT/TMZ was safe and well tolerated in patients with newly-diagnosed glioblastoma and 400 mg/week resulted in encouraging efficacy.Trial registration NCT02853565, August 3, 2016.

scholarly journals RBTT-12. A PHASE I STUDY OF EGFRVIII-DIRECTED CAR T CELLS COMBINED WITH PD-1 INHIBITION IN PATIENTS WITH NEWLY, DIAGNOSED, MGMT-UNMETHYLATED GLIOBLASTOMA: TRIAL IN PROGRESS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi221-vi221 ◽  
Author(s):  
Stephen Bagley ◽  
Arati Desai ◽  
Zev Binder ◽  
MacLean Nasrallah ◽  
Wei-Ting Hwang ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
Phase I Study ◽  
Phase 1 ◽  
Objective Response ◽  
Tumor Resection ◽  
Adjuvant Radiation ◽  
Newly Diagnosed ◽  
Car T Cells ◽  
Car T

Abstract BACKGROUND This study builds on the results of the University of Pennsylvania sponsored phase I study of a single peripheral infusion of chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor variant III (EGFRvIII) in recurrent glioblastoma (GBM) (NCT02209376). A dose of 5x108 CART-EGFRvIII cells was safe, and the cells were able to expand in the host and reach the GBM tumor in the brain. In addition, there was no cross-reactivity of CART-EGFRvIII cells with wild-type EGFR normally expressed by human tissues. Some patients required tumor resection after CAR T cell infusion. In situ evaluation of the tumor microenvironment demonstrated increased and robust expression of inhibitory molecules, such as programmed death-ligand 1 (PD-L1), compared to pre–CART-EGFRvIII tumor specimens. Therefore, we hypothesized that using a combination of CART-EGFRvIII cells and a PD-1 inhibitor would improve the outcome of the treatment. METHODS This single-center study (NCT03726515) has a single-arm, open-label, phase 1 design and will enroll 7 patients with newly diagnosed, O6-methylguanine-methyltransferase (MGMT)-unmethylated, EGFRvIII+ GBM. Following maximal safe tumor resection, patients receive a short course of adjuvant radiation with a total dose of 40 Gy administered in 15 fractions. Peripheral IV infusions of 2x108 CART-EGFRvIII cells and 200mg pembrolizumab begin 2–3 weeks after completing radiation therapy. Thereafter, subjects receive CART-EGFRvIII cells + pembrolizumab in 3-week cycles for up to 3 infusions of CART-EGFRvIII cells and 4 infusions of pembrolizumab. The primary endpoint of the study is the safety and tolerability of administering multiple infusions of CART-EGFRvIII cells in combination with pembrolizumab, as measured by the occurrence of study-related adverse events. Secondary endpoints include overall survival, progression-free survival, and objective response rate. PROGRESS: At 5 June 2019, 2 patients have been enrolled and treated on study.

scholarly journals ACTR-36. A PHASE I STUDY OF NEURAL STEM CELLS LOADED WITH AN ONCOLYTIC ADENOVIRUS FOR PATIENTS WITH NEWLY DIAGNOSED MALIGNANT GLIOMA: PRELIMINARY SAFETY AND DATA ANALYSIS

2017 ◽  
Vol 19 (suppl_6) ◽  
pp. vi8-vi8 ◽  
Author(s):  
Maciej S Lesniak ◽  
Roger Stupp ◽  
Sean Sachdev ◽  
Rimas Lukas ◽  
James Chandler ◽  
...  
Keyword(s):  
Stem Cells ◽  
Data Analysis ◽  
Neural Stem Cells ◽  
Phase I ◽  
Malignant Glioma ◽  
Phase I Study ◽  
Oncolytic Adenovirus ◽  
Newly Diagnosed

An update on phase I study of dose-escalating imatinib mesylate plus standard-dosed temozolomide for the treatment of patients with malignant glioma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1560-1560 ◽  
Author(s):  
S. Sathornsumetee ◽  
D. A. Reardon ◽  
J. A. Quinn ◽  
J. N. Rich ◽  
J. J. Vredenburgh ◽  
...  
Keyword(s):  
Phase I ◽  
Malignant Glioma ◽  
Imatinib Mesylate ◽  
Dose Escalation ◽  
Stable Disease ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Current Phase ◽  
Hematologic Toxicity ◽  
Anaplastic Gliomas

1560 Background: Imatinib mesylate, a kinase inhibitor of the PDGF receptor has been shown to decrease tumor interstitial pressure resulting in enhanced delivery of cytotoxic therapy. Recent phase II trial demonstrated promising anti-glioma activity of imatinib mesylate in combination with chemotherapy, hydroxyurea. Methods: The current phase I study is designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of imatinib mesylate when combined with temozolomide, a DNA methylator with established efficacy against gliomas. Eligibility criteria include: histologically confirmed malignant glioma; age of at least 18 years; KPS of at least 60%; less than grade 2 intratumoral hemorrhage; adequate hepatic, renal, and bone marrow function and lack of prior failure or significant toxicity following treatment with either imatinib mesylate or temozolomide. Temozolomide is dosed at 200 mg/m2 on days 4–8 of each 28-day cycle. Imatinib mesylate is administered on days 1–8 of each cycle and the dose is escalated in successive cohorts of 3–6 patients via a standard “3+3” dose escalation design. Patients are stratified based on concurrent use of enzyme-inducing anticonvulsants (EIAC) and both strata are independently escalated. Results: To date 47 patients have been enrolled including 40 with GBM and 7 with anaplastic gliomas. Median age is 53.9 years (range 28 to 72); 66% are male and 51% are on EIAC. The MTD has yet to be defined for either stratum. To date DLT of ALT elevation has been observed in one patient from non-EIAC stratum. Two patients discontinued therapy due to toxicities with one asymptomatic intracerebral hemorrhage and one severe hematologic toxicity. Pharmacokinetic sampling has been performed in approximately half of the patients. One patient completed the study (12 cycles) with stable disease. Eleven patients remain on study with one partial response and three patients have undergone more than 10 cycles of therapy with stable disease. Twenty-eight patients (59%) have developed progressive disease and discontinued therapy. Conclusions: Combination of imatinib mesylate and temozolomide is safe and well tolerated. Further accrual and dose escalation are ongoing. [Table: see text]

scholarly journals EPCT-19. A PHASE I STUDY OF RIBOCICLIB AND EVEROLIMUS FOLLOWING RADIATION THERAPY IN CHILDREN WITH NEWLY DIAGNOSED NON-BIOPSIED DIFFUSE PONTINE GLIOMAS (DIPG) AND RB+ BIOPSIED DIPG AND HIGH GRADE GLIOMAS (HGG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii307-iii307
Author(s):  
Mariko DeWire ◽  
James Leach ◽  
Christine Fuller ◽  
Peter de Blank ◽  
Trent Hummel ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Studies ◽  
High Grade ◽  
Newly Diagnosed ◽  
High Grade Gliomas ◽  
Grade 3 ◽  
Expansion Cohort

Abstract Genomic aberrations in the cell cycle and mTOR pathways have been reported in diffuse pontine gliomas (DIPG) and high-grade gliomas (HGG). Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus administered during maintenance therapy following radiotherapy was determined in the phase I study as a rolling 6 design. Ribociclib and everolimus were administered once daily for 21 days and 28 days, respectively starting two-four weeks post completion of radiotherapy. All HGG patients and any DIPG patient who had undergone biopsy were screened for RB protein by immunohistochemistry. Eighteen eligible patients enrolled (median age 8 years; range: 2–18). Six patients enrolled at dose levels 1,2, and 3 without dose limiting toxicities (DLT). Currently, five patients are enrolled at dose level 3 expansion cohort. The median number of cycles are 4.5 (range: 1–20+). Among the expansion cohort, one dose limiting toxicity included a grade 3 infection and one patient required a dose reduction in course 3 due to grade 3 ALT and grade 4 hypokalemia. The most common grade 3/4 adverse events included neutropenia. Preliminary pharmacokinetic studies on 12 patients suggest an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus following radiotherapy in newly diagnosed DIPG and HGG is anticipated to be 170 mg/m2/day x 21 days and 1.5 mg/ m2/day every 28 days which is equivalent to the adult RP2D.

Gemcitabine (G) in combination radiationtherapy (RT) in stage III–IV pancreatic cancer: first results of a current phase I study

1999 ◽  
Vol 35 ◽  
pp. S148 ◽  
Author(s):  
U. Maurer ◽  
P. Stegmeier ◽  
R. Bolte ◽  
K.P. Jungius ◽  
D. Mueller ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Phase I Study ◽  
Stage Iii ◽  
Current Phase ◽  
First Results ◽  
A Current

A phase I study of everolimus and CHOP in newly diagnosed peripheral T-cell lymphomas

2013 ◽  
Vol 31 (6) ◽  
pp. 1514-1521 ◽  
Author(s):  
Seok Jin Kim ◽  
Hye Jin Kang ◽  
Jin Seok Kim ◽  
Hyeon-Seok Eom ◽  
Jooryung Huh ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Phase I Study ◽  
Newly Diagnosed ◽  
T Cell Lymphomas ◽  
Peripheral T Cell Lymphomas

scholarly journals EPCT-06. A PHASE I STUDY OF MULTI-TARGETED THERAPY IN NEWLY DIAGNOSED OR PROGRESSIVE DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii304-iii305
Author(s):  
Muhammad Baig ◽  
Jason Johnson ◽  
Sumit Gupta ◽  
Zsila Sadighi ◽  
Wafik Zaky ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Maintenance Therapy ◽  
Phase I ◽  
Phase I Study ◽  
Diffusion Tensor ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Newly Diagnosed ◽  
Pontine Glioma ◽  
Dose Limiting Toxicity

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) constitutes 80% of pediatric brain stem tumors with a median survival of 12 months. The PI3K/AKT/mTOR pathway is a key oncogenic driver of this tumor. Targeting the chromatin dysregulation through HDAC inhibition, demonstrated benefit in vivo and vitro studies. We completed the first study as a multi-targeted therapy using SAHA and temsirolimus in pediatric DIPG. METHODS After receiving institutional IRB approval, we enrolled 6 patients on this phase I study using a 3 + 3 statistical design. Patients were divided into stratum 1 and stratum 2, based on newly diagnosed or relapsed DIPG respectively. Stratum I patients received radiation therapy concurrently with vorinostat, followed by maintenance therapy with vorinostat and temsirolimus for 10 cycles (28 day cycle), while in stratum II patients received vorinostat and temsirolimus for 12 cycles. Neuroimaging including diffusion tensor imaging were evaluated where feasible. RESULTS Three patients were enrolled in each of the stratum. One patient in stratum 1 completed therapy, 2 other demonstrated progressive disease (PD) after 4th and 1st cycle of maintenance therapy respectively. In stratum 2 all patients progressed 2 months after the start of therapy. However no dose-limiting toxicity (DLT) was noted. The patient in stratum 1 who completed therapy, remained free of PD 21 months after diagnosis with continued improvements in the volume of enhancing and T2 hyperintense disease. CONCLUSION Although no significant benefit was seen as compared to historical controls during this study, no dose limiting toxicity was noticed with this treatment.

Sign in / Sign up

Export Citation Format

Share Document