Outcomes and Prognostic Factors in Recurrent Glioma Patients Enrolled Onto Phase II Clinical Trials

1999 ◽  
Vol 17 (8) ◽  
pp. 2572-2572 ◽  
Author(s):  
Eric T. Wong ◽  
Kenneth R. Hess ◽  
Mary Jo Gleason ◽  
Kurt A. Jaeckle ◽  
Athanassios P. Kyritsis ◽  
...  
Keyword(s):  
Phase Ii ◽  
Proportional Hazards ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Recurrent Glioblastoma ◽  
Recurrent Glioma ◽  
Dominant Factor ◽  
Karnofsky Performance Score ◽  
Phase Ii Trials ◽  
Recurrent Glioblastoma Multiforme

PURPOSE: To determine aggregate outcomes and prognostic covariates in patients with recurrent glioma enrolled onto phase II chemotherapy trials. PATIENTS AND METHODS: Patients from eight consecutive phase II trials included 225 with recurrent glioblastoma multiforme (GBM) and 150 with recurrent anaplastic astrocytoma (AA). Their median age was 45 years (range, 15 to 82 years) and their median Karnofsky performance score was 80 (range, 60 to 100). Prognostic covariates were analyzed with respect to tumor response, progression-free survival (PFS), and overall survival (OS) by multivariate logistic and Cox proportional hazards regression analyses. RESULTS: Overall, 34 (9%) had complete or partial response, whereas 80 (21%) were alive and progression-free at 6 months (APF6). The median PFS was 10 weeks and median OS was 30 weeks. Histology was a robust prognostic factor across all outcomes. GBM patients had significantly poorer outcomes than AA patients. The APF6 proportion was 15% for GBM and 31% for AA, whereas the median PFS was 9 weeks for GBM and 13 weeks for AA. Results were also significantly poorer for patients with more than two prior surgeries or chemotherapy regimens. CONCLUSION: Histology is a dominant factor in determining outcome in patients with recurrent glioma enrolled onto phase II trials. Future trials should be designed with separate histology strata.

Differential response rates in early-phase cancer clinical trials (EPCCT).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3133-3133
Author(s):  
Rozana Abdul Rahman ◽  
Neethu Billy Graham Mariam ◽  
Hitesh Mistry ◽  
Sreeja Aruketty ◽  
Matt Church ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Performance Status ◽  
Objective Response ◽  
Progression Free Survival ◽  
Response Rates ◽  
Primary Objective ◽  
Cox Proportional Hazards ◽  
Sustained Response ◽  
Phase Ii Trials ◽  
Significant Difference

3133 Background: The primary objective of EPCCT (phase I and non-randomised phase II trials) is to determine the safety and tolerability of new therapeutic agents. Response rates (RR) in these trials have typically been reported at around 10-15%. Increasingly RR and survival outcomes are now investigated in EPCCT as primary or secondary objectives. Methods: Retrospective data analysis was performed on patients (pts) enrolled onto an EPCCT between January 2018 and December 2019 at The Christie NHS Foundation Trust, UK. Data on demographics, prior systemic treatment, sites of disease, performance status, comorbidities, types of therapy, RR, progression free survival (PFS), and overall survival (OS) were collected. Statistical analyses were performed with univariable and multivariable models. Objective response rate (ORR) was defined as the proportion of pts with complete response (CR) and partial response (PR). Duration of response (DOR) was from initial response to progressive disease (PD). Disease control rate (DCR) was defined as CR+PR+ stable disease (SD). Results: A total of 247 pts were treated across 46 EPCCTs. Median age 61 years; 57% female. Sixty-six percent of pts had ≥2 lines of treatment and the majority were ECOG PS 0/1 (98%). Eighty-one percent of pts had ≥2 sites of metastatic disease, and 13 major tumour types were included. Monotherapy trials (159 pts) were predominantly targeted therapies (TT; 60%), or immunotherapies (IO; 20%). Combination therapy trials (88 pts) were TT-based (68%) or IO-based (32%). Data for RR analyses was available for 231 pts. ORR across all trials was 15% (CR 2%) and DCR was 63%. The median DOR was 8.3 months (mos) (95% CI: 7.0 – 9.7) with 28% of pts responding for >6 mos and 7% for >12 mos. ORR in pooled IO treated pts was 27%, DCR was 65% with sustained response >6 mos seen in 37% of these pts. ORR in pooled TT treated pts was 9.4%, DCR was 60% and sustained response > 6 mos seen in 25% of pts. ORR for IO v TT treated pts was significantly different, p=0.007 (pearson chi square), but no significant difference was seen for DCR. Median PFS for all patients was 5.0 mos (95% CI: 4.1 – 6.0) and OS was 10.4 mos (95% CI: 8.4 – 13.0). OS for those with a PR is not reached (HR for PR v PD, 0.006 (95% CI: 0.002 – 0.18). Pts with SD appear to have significantly better OS compared to those with PD (14.6 v 4.2 mos, HR 0.2 (95% CI: 0.1 – 0.3). Multivariable Cox proportional hazards analysis for OS was significant for male gender (HR 1.9, p=0.002), presence of liver metastasis (HR 2.0, p=0.001), low Hb (HR 0.8, p=0.03) and log (LDH) (HR 1.9, p<0.001). Conclusions: Two-thirds of pts enrolled on EPCCTs benefitted in terms of DCR with significant OS improvement in those with PR and SD. Higher ORR were seen in pts receiving IO-based treatments however DCR was similar in IO and TT pts. Gender, presence of liver metastases, Hb count and LDH level contributed significantly to survival differences.

scholarly journals Days gained response discriminates treatment response in patients with recurrent glioblastoma receiving bevacizumab-based therapies

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Kyle W Singleton ◽  
Alyx B Porter ◽  
Leland S Hu ◽  
Sandra K Johnston ◽  
Kamila M Bond ◽  
...  
Keyword(s):  
Treatment Response ◽  
Proportional Hazards ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Recurrent Glioblastoma ◽  
Response To Therapy ◽  
Cytotoxic Therapy ◽  
Kaplan Meier ◽  
Recurrent Gbm

Abstract Background Accurate assessments of patient response to therapy are a critical component of personalized medicine. In glioblastoma (GBM), the most aggressive form of brain cancer, tumor growth dynamics are heterogenous across patients, complicating assessment of treatment response. This study aimed to analyze days gained (DG), a burgeoning model-based dynamic metric, for response assessment in patients with recurrent GBM who received bevacizumab-based therapies. Methods DG response scores were calculated using volumetric tumor segmentations for patients receiving bevacizumab with and without concurrent cytotoxic therapy (N = 62). Kaplan–Meier and Cox proportional hazards analyses were implemented to examine DG prognostic relationship to overall (OS) and progression-free survival (PFS) from the onset of treatment for recurrent GBM. Results In patients receiving concurrent bevacizumab and cytotoxic therapy, Kaplan–Meier analysis showed significant differences in OS and PFS at DG cutoffs consistent with previously identified values from newly diagnosed GBM using T1-weighted gadolinium-enhanced magnetic resonance imaging (T1Gd). DG scores for bevacizumab monotherapy patients only approached significance for PFS. Cox regression showed that increases of 25 DG on T1Gd imaging were significantly associated with a 12.5% reduction in OS hazard for concurrent therapy patients and a 4.4% reduction in PFS hazard for bevacizumab monotherapy patients. Conclusion DG has significant meaning in recurrent therapy as a metric of treatment response, even in the context of anti-angiogenic therapies. This provides further evidence supporting the use of DG as an adjunct response metric that quantitatively connects treatment response and clinical outcomes.

Bevacizumab Plus Irinotecan in Recurrent Glioblastoma Multiforme

2007 ◽  
Vol 25 (30) ◽  
pp. 4722-4729 ◽  
Author(s):  
James J. Vredenburgh ◽  
Annick Desjardins ◽  
James E. Herndon ◽  
Jennifer Marcello ◽  
David A. Reardon ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Phase Iii ◽  
Vascular Endothelial ◽  
Recurrent Glioblastoma Multiforme ◽  
Initial Cohort ◽  
Endothelial Growth Factor

Purpose The prognosis for patients with recurrent glioblastoma multiforme is poor, with a median survival of 3 to 6 months. We performed a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan. Patients and Methods This phase II trial included two cohorts of patients. The initial cohort, comprising 23 patients, received bevacizumab at 10 mg/kg plus irinotecan every 2 weeks. The dose of irinotecan was based on the patient's anticonvulsant: Patients taking enzyme-inducing antiepileptic drugs (EIAEDs) received 340 mg/m2, and patients not taking EIAEDs received 125 mg/m2. After this regimen was deemed safe and effective, the irinotecan schedule was changed to an accepted brain tumor regimen of four doses in 6 weeks, in anticipation of a phase III randomized trial of irinotecan versus irinotecan and bevacizumab. The second cohort, comprising 12 patients, received bevacizumab 15 mg/kg every 21 days and irinotecan on days 1, 8, 22, and 29. Each cycle was 6 weeks long and concluded with patient evaluations, including magnetic resonance imaging. Results The 6-month progression-free survival among all 35 patients was 46% (95% CI, 32% to 66%). The 6-month overall survival was 77% (95% CI, 64% to 92%). Twenty of the 35 patients (57%; 95% CI, 39% to 74%) had at least a partial response. One patient developed a CNS hemorrhage, which occurred in his 10th cycle. Four patients developed thromboembolic complications (deep venous thrombosis and/or pulmonary emboli). Conclusion Bevacizumab and irinotecan is an effective treatment for recurrent glioblastoma multiforme and has moderate toxicity.

Evaluation of glioblastoma tumor microenvironment after treatment with pembrolizumab.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2559-2559 ◽  
Author(s):  
Nazanin Majd ◽  
Heather Y. Lin ◽  
Ying Yuan ◽  
Kristin Alfaro-Munoz ◽  
Kathy Hunter ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Proportional Hazards ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Recurrent Glioblastoma ◽  
T Cell Response ◽  
Rank Test ◽  
Recurrent Gbm

2559 Background: Neoadjuvant pembrolizumab improved outcome of patients with recurrent Glioblastoma (GBM) in two early phase clinical trials. However, several large phase II/III studies in patients with newly diagnosed and recurrent GBM failed to demonstrate a therapeutic benefit of anti-PD-1 therapy. Therefore, identification of biomarkers of response is crucial for appropriate patient selection and further clinical development of anti-PD-1 therapy. We reported the outcome of our window-of-opportunity clinical trial of neoadjuvant pembrolizumab in 15 patients with recurrent GBM, demonstrating rare CD8+ T cells and abundant of CD68+ macrophages in GBM tissue after 3 weeks of anti-PD-1 treatment (NCT02337686). In the current study, we compared tumor infiltrating lymphocyte (TIL) and PD-L1 scores, known biomarkers of response to anti-PD-1 therapy in other cancers, in pre-trial vs. on-trial tumor tissue and associated these markers with survival. Methods: We determined TIL score (morphological assessment of the presence or absence of TILs, 0-3) and PD-L1 H score (defined as [1*1+ %]+[2*2+ %]+[3*3+ %], 0-200) and correlated these with survival. The Wilcoxon signed rank test was used to compare levels of PD-L1 H or TIL scores between pre-trial and on-trial specimens. The Cox proportional hazards models were used to assess associations between correlative markers and progression free survival or overall survival (OS). Results: The on-trial TIL level (median: 3) was significantly higher than the pre-trial TIL level (median: 1) (p = 0.031). However the difference between pre-trial and on-trial PD-L1 levels was not statistically significant (p > 0.9). Patients whose on-trial PD-L1 H score was ≥ 3 trended toward a longer OS than those with a PD-L1 H score < 3 (HR [95% CI] = 0.225 [0.043, 1.183]) (p = 0.0782). Conclusions: Although GBM tissue lacks abundant T cells, treatment with pembrolizumab increases trafficking of T cells to the tumor microenvironment, which is necessary but not sufficient to induce an effector T-cell response. Elevated PD-L1 expression may be a biomarker of response to anti-PD1 therapy in GBM, which needs confirmation in larger studies. Further genomic, transcriptomic, and methylation profiling of the pre-trial and on-trial tissues is ongoing. Clinical trial information: NCT02337686 .

Phase II Study of Imatinib Mesylate Plus Hydroxyurea in Adults With Recurrent Glioblastoma Multiforme

2005 ◽  
Vol 23 (36) ◽  
pp. 9359-9368 ◽  
Author(s):  
David A. Reardon ◽  
Merrill J. Egorin ◽  
Jennifer A. Quinn ◽  
Jeremy N. Rich ◽  
Idharan Gururangan ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Imatinib Mesylate ◽  
Phase Ii ◽  
Cox Regression ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Recurrent Glioblastoma Multiforme ◽  
Cox Regression Analysis

Purpose We performed a phase II study to evaluate the combination of imatinib mesylate, an adenosine triphosphate mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme (GBM). Patients and Methods Patients with GBM at any recurrence received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme-inducing antiepileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Assessments were performed every 28 days. The primary end point was 6-month progression-free survival (PFS). Results Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. With a median follow-up of 58 weeks, 27% of patients were progression-free at 6 months, and the median PFS was 14.4 weeks. Three patients (9%) achieved radiographic response, and 14 (42%) achieved stable disease. Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS. The most common toxicities included grade 3 neutropenia (16%), thrombocytopenia (6%), and edema (6%). There were no grade 4 or 5 events. Concurrent EIAED use lowered imatinib mesylate exposure. Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients, suggesting an effect of hydroxyurea. Conclusion Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM.

Phase II study of combination carboplatin and erlotinib in patients with recurrent glioblastoma multiforme

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2024-2024 ◽  
Author(s):  
J. F. De Groot ◽  
M. R. Gilbert ◽  
K. R. Hess ◽  
T. Hanna ◽  
M. Groves ◽  
...  
Keyword(s):  
Phase Ii ◽  
Primary Endpoint ◽  
Tumor Tissue ◽  
Phase Ii Study ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Credible Interval ◽  
Recurrent Glioblastoma ◽  
Clinical Activity ◽  
Recurrent Glioblastoma Multiforme

2024 Background: Targeting the epidermal growth factor receptor (EGFR) in glioblastoma is effective in a subset of patients whose tumors express the phosphatase and tensin homolog (PTEN) tumor suppressor gene and overexpress the EGF variant vIII receptor. Therefore, this study was designed to assess the clinical activity of the EGFR inhibitor erlotinib when combined with carboplatin and to determine molecular predictors of response. The primary endpoint is progression-free survival (PFS). To be eligible for the study, patients had to have recurrent, histologically confirmed glioblastoma or gliosarcoma, no more than two prior relapses, a KPS = 60, and no enzyme-inducing anticonvulsants. Methods: In this ongoing phase II study, patients are given carboplatin intravenously on day 1 of every 28-day cycle to achieve a target AUC of 6 (mg x ml/min) based on creatinine clearance. Erlotinib is administered orally once daily throughout the 28-day cycle at 150 mg/day with dose escalation to 200 mg/day, as tolerated. Patients undergo clinical and MRI assessment every 4 weeks. The primary endpoint is median PFS using a Bayesian time-to-event design. To determine histologic correlates of response, tumor tissue is undergoing immunohistochemical evaluation for known markers of response to EGFR inhibitors, including PI3K/AKT and PTEN status. Results: Of the first 20 patients enrolled, 17 were evaluable and all had failed temozolomide-based therapy. The median age is 56 years, and the median KPS is 80. The median time to progression is 15.2 weeks with a 95% credible interval of 8.0 to 28.4 weeks. These results compare favorably with historical data (median of 9.0 weeks, 95% CI of 8.1 to 10.1 weeks). Bayesian analysis using computer-based simulations indicate a high probability (69%) that the median PFS in our study is at least 3 weeks longer than the historical median PFS. Grade 3 and 4 toxicities included fatigue, leukopenia, thrombocytopenia and rash requiring dose reductions. Conclusions: The results from this ongoing study suggest that the combination of carboplatin and erlotinib has promising activity in patients with recurrent glioblastoma who have failed temozolomide-based therapy. Tumor tissue is being analyzed to determine molecular markers of response. [Table: see text]

Randomized Phase II Study of Cilengitide, an Integrin-Targeting Arginine-Glycine-Aspartic Acid Peptide, in Recurrent Glioblastoma Multiforme

2008 ◽  
Vol 26 (34) ◽  
pp. 5610-5617 ◽  
Author(s):  
David A. Reardon ◽  
Karen L. Fink ◽  
Tom Mikkelsen ◽  
Timothy F. Cloughesy ◽  
Alison O'Neill ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Antitumor Activity ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Recurrent Glioblastoma Multiforme ◽  
Wide Range ◽  
First Recurrence ◽  
Arginine Glycine Aspartic Acid

PurposeCilengitide, an inhibitor of αvβ3 and αvβ5 integrin receptors, demonstrated minimal toxicity and durable activity across a wide range of doses administered to adults with recurrent glioblastoma multiforme (GBM) in a prior phase I study. The current multicenter phase II study was conducted to evaluate the activity and safety of cilengitide in GBM patients at first recurrence.Patients and MethodsEligible patients were randomly assigned to receive either 500 or 2,000 mg of cilengitide twice weekly on a continuous basis. Patients were assessed every 4 weeks. The primary end point was 6-month progression-free survival (PFS) rate. Secondary end points included PFS, overall survival (OS), and radiographic response, as well as quality-of-life and pharmacokinetic assessments.ResultsEighty-one patients were enrolled, including 41 on the 500-mg arm and 40 on the 2,000-mg arm. The safety profile of cilengitide was excellent, with no significant reproducible toxicities observed on either arm. Antitumor activity was observed in both treatment cohorts but trended more favorably among patients treated with 2,000 mg, including a 6-month PFS of 15% and a median OS of 9.9 months.ConclusionCilengitide monotherapy is well tolerated and exhibits modest antitumor activity among recurrent GBM patients. Additional studies integrating cilengitide into combinatorial regimens for GBM are warranted.

Phase II trial of sorafenib (S) and erlotinib (E) in unresectable pancreas cancer (UPC): Final results and correlative findings.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 191-191 ◽  
Author(s):  
Dana Backlund Cardin ◽  
Laura Williams Goff ◽  
Emily Chan ◽  
Melanie Holloway ◽  
Pamela McClanahan ◽  
...  
Keyword(s):  
Phase Ii ◽  
Primary Endpoint ◽  
Proportional Hazards ◽  
Phase Ii Trial ◽  
Synergistic Effects ◽  
Progression Free Survival ◽  
Outcome Data ◽  
Cox Proportional Hazards ◽  
Serum Samples ◽  
Pre Treatment

191 Background: The MAP kinase pathway plays a central role in PC pathogenesis. Blockade of this pathway at multiple levels using S and E is attractive mechanistically. S also targets VEGF receptors. Evidence suggests that dual blockade of both EGFR and VEGF pathways has potential for additive, if not synergistic, effects. This phase II trial was designed to evaluate the efficacy of the combination of S and E in patients (pts) with UPC. An exploratory correlative study analyzing pre-treatment serum samples using a proteomic mass-spectrometry test (VeriStrat), previously shown to correlate with outcomes in lung cancer pts treated with E or the combination of E and S, was performed to evaluate the possible clinical utility of the test in pts with UPC. Methods: Pts with UPC received S 400mg daily along with E 150mg daily as primarily second-line therapy (first-line was allowed). Primary endpoint was 8-week progression free survival (PFS) rate. Pre-treatment serum sample analysis by proteomic test was done blinded to clinical and outcome data; the endpoints were PFS and overall survival (OS). Difference between groups was assessed using log-rank p values; hazard ratios (HR) were obtained from Cox proportional hazards models. Results: Thirty-seven pts received study drugs and were included in the survival analysis. Eight-week PFS rate 0.47 (95% CI 0.32-0.67) did not meet the primary endpoint of a rate of ≥ 0.70. Thirty two pts were included in the correlative analysis. VeriStrat “Good” pts had superior PFS and OS compared to VeriStrat “Poor” pts (Table). Conclusions: This study did not meet the primary endpoint and this drug combination will not be further pursued. In this small retrospective analysis the proteomic classification was significantly associated with clinical outcomes (PFS and OS), meriting further evaluation. This will include a companion study to an ongoing phase I study evaluating gemcitabine, erlotinib and dasatinib in UPC (NCT01660971). Clinical trial information: NCT00837876. [Table: see text]

scholarly journals Days Gained Response Discriminates Treatment Response in Patients with Recurrent Glioblastoma Receiving Bevacizumab-based Therapies

2019 ◽  
Author(s):  
Kyle W. Singleton ◽  
Alyx B. Porter ◽  
Leland S. Hu ◽  
Sandra K Johnston ◽  
Kamila M. Bond ◽  
...  
Keyword(s):  
Treatment Response ◽  
Proportional Hazards ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Recurrent Glioblastoma ◽  
Response To Therapy ◽  
Cytotoxic Therapy ◽  
Kaplan Meier ◽  
Recurrent Gbm

AbstractPurposeAccurate assessments of patient response to therapy are a critical component of personalized medicine. In glioblastoma multiforme (GBM), the most aggressive form of brain cancer, tumor growth dynamics are heterogenous across patients, complicating assessment of treatment response. This study aimed to analyze Days Gained (DG), a burgeoning model-based dynamic metric, for response assessment in patients with recurrent GBM who received bevacizumab-based therapies.Experimental DesignDays Gained response scores were calculated using volumetric tumor segmentations for patients receiving bevacizumab with and without concurrent cytotoxic therapy (N=62). Kaplan-Meier and Cox proportional hazards analyses were implemented to examine DG prognostic relationship to overall (OS) and progression-free survival (PFS) from the onset of treatment for recurrent GBM.ResultsIn patients receiving concurrent bevacizumab and cytotoxic therapy, Kaplan-Meier analysis showed significant differences in OS and PFS at previously identified DG cutoffs consistent with previous DG analyses using gadolinium-enhanced T1 weighted MR imaging. DG scores for bevacizumab monotherapy only approached significance for PFS. Cox regression showed that increases of 25 DG were significantly associated with a 12.5% reduction in OS hazard for concurrent therapy patients and a 4.4% reduction in PFS hazard for bevacizumab monotherapy.ConclusionDays Gained has significant meaning in recurrent therapy as a metric of treatment response, even in the context of anti-angiogenic therapies. This provides further evidence supporting the use of DG as an adjunct response metric that quantitatively connects treatment response and clinical outcomes.

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