Phase II trial of high dose imatinib in recurrent glioblastoma multiforme (GBM) with platelet derived growth factor receptor (PDGFR) expression

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2056-2056 ◽  
Author(s):  
F. S. Viola ◽  
A. Katz ◽  
A. Arantes ◽  
A. Gaiger ◽  
C. Vasconcellos ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Significant Proportion ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Initial Therapy ◽  
Recurrent Glioblastoma ◽  
High Dose ◽  
Recurrent Glioblastoma Multiforme ◽  
Disease Stabilization ◽  
Ecog Ps

2056 Background: GBM are the most common primary brain tumors in adults. Despite available treatment they carry a poor prognosis with recurrences in most patients (pts) after initial therapy. PDGF signaling has been postulated to play a role in GBM transformation. We have demonstrated that PDGFRβ is expressed in tumor cells in 50% and in peritumoral endothelial cells in 65% of GBM (Barrios et al, abstract 11518, Proc ASCO 2006). Imatinib, an inhibitor of PDGFRa/β kinase activity could have therapeutic activity in these cases. Methods: We evaluated Imatinib in pts with recurrent GBM (previous radiation and chemotherapy) selected by PDGFR expression. Analysis of PDGFRa/β was performed by standard IHC. Positivity was considered in case of any qualitative expression. Pts were treated with 800 mg/day of Imatinib until tumor progression. All were on steroids and taking enzyme inducing antiepileptic drugs. Response was determined by MRI with spectroscopy and perfusion every 8 weeks according to RECIST criteria. Results: Twenty pts were enrolled (18 GBM, 2 AA). Median age: 51 (21–74), 7 were females. ECOG-PS at inclusion: 0 (3), 1 (10), 2 (7). All pts had expression of PDGFRa and 55% expressed PDGFRβ. Response data are available for all 20 pts. Main adverse events (all grade 1–2) were: edema (55%), nausea (50%), diarrhea and fatigue (35% each). We did not observe any PR but 13 pts (65%) showed disease stabilization. Median progression-free survival was 7.8 months with 60.8% of pts alive at 6 months; 6 months PFS was 52.2%. Conclusions: Imatinib was well tolerated in this group of poor prognosis highly pre-treated GBM pts demonstrating disease stabilization in a significant proportion of cases. These results, in a limited sample, compare favorably with historical data in similar populations. Selection of pts according to the specific molecular expression of their tumor may lead to better therapeutic results. No significant financial relationships to disclose.

Phase I/II dose-escalation study of VB-111, an antiangiogenic gene therapy, in patients with recurrent glioblastoma multiforme.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS2102-TPS2102 ◽  
Author(s):  
Andrew Jacob Brenner ◽  
Yael Cohen ◽  
James J Vredenburgh ◽  
Katherine B. Peters ◽  
Eyal Breitbart ◽  
...  
Keyword(s):  
Overall Survival ◽  
Glioblastoma Multiforme ◽  
Phase I ◽  
Dose Escalation ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
High Dose ◽  
Recurrent Glioblastoma Multiforme ◽  
Dose Escalation Study ◽  
Recurrent Gbm

TPS2102 Background: VB-111 is an anti-angiogenic agent consisting of a non-replicating adenovirus vector (Ad-5) with a modified murine pre-proendothelin promoter leading to apoptosis of tumor vasculature by expressing a fas-chimera transgene in angiogenic endothelial cells. In a phase I/II dose-escalation study, safety and efficacy of VB-111 in patients with recurrent Glioblastoma Multiforme (GBM) were evaluated. Methods: VB-111 was administered as a single intravenous infusion at escalating doses from 1x1012 to 3x1012 viral particles (VPs), followed by repeat doses of 3x1012 or 1x1013every 2 months. Assessments included safety, pharmacokinetics, tumor response (RANO criteria) and overall survival (OS). Results: Twenty eight patients aged 26 – 74 years at 3 medical centers in the US received up to 8 repeat doses of VB-111. The median OS was 360 [range: 70-574] and 266 days [range: 28-664] for patients receiving at least one dose of 1x1013VPs (high dose) vs. subjects who received lower doses, respectively (p NS). Progression free survival was 87 vs 55 days for patients who received high dose and for lower doses, respectively (p = 0.01). Median follow-up was 232 days. Three patients had a partial response (PR) at 82, 86 and 408 days post initial VB-111 dosing. Twenty one of the patients who progressed on VB-111 treatment received bevacizumab off study; 7 of the 15 evaluable patients (47%) had a PR compared to 30% expected according to literature. VB-111 was safe and well tolerated, 53 adverse events were reported, 14 were classified as possibly related to VB-111. All events were of CTCAE grade 1-2 except one grade 3 pulmonary embolism. There were no study related deaths. One patient developed peri-tumoral edema, which resolved with corticosteroid therapy. Events occurring in > 10% of the patients included headache and fatigue. Conclusions: VB-111 was safe and well tolerated in patients with recurrent GBM with repeat doses of up to 1x1013 VPs. Tumor responses were seen. Overall survival was about 3 months longer than historical data in recurrent GBM, including standard of care anti-angiogenic agents. Data suggests that VB-111 potentiates the response to bevacizumab given at further progression. Clinical trial information: NCT01260506.

A phase II trial of gefitinib in patients (pts) with progressive metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4043-4043 ◽  
Author(s):  
T. J. Hobday ◽  
K. Holen ◽  
R. Donehower ◽  
J. Camoriano ◽  
G. Kim ◽  
...  
Keyword(s):  
Phase Ii ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Target Lesion ◽  
Eligibility Criteria ◽  
Minor Response ◽  
Islet Cell Carcinoma ◽  
Disease Stabilization ◽  
Ecog Ps

4043 Background: Systemic treatment options for progressive metastatic NET, including islet cell carcinoma (ICC) and carcinoid tumor (CT), are limited. These tumors frequently express the epidermal growth factor receptor (EGFR). Gefitinib, a small-molecule inhibitor of the EGFR tyrosine kinase, has been shown to inhibit the growth of NET cell lines. Methods: Eligibility criteria included: radiographic progression by RECIST criteria, ECOG PS ≤ 2, ≤ 1 prior chemotherapy, and good organ function. Prior interferon and prior or concurrent octreotide (if disease progression documented on stable dose) were allowed. Pts received gefitinib 250 mg po daily. We evaluated 6 month (mos) progression-free survival (PFS) in two cohorts (ie, CT and ICC) using separate 2-stage phase II designs. 6 mos PFS rates of 30% (CT) and 10% (ICC) were considered promising. Results: 96 pts were enrolled: (57 CT, 39 ICC). For pts evaluable for the primary endpoint, 23 of 38 (61%) CT pts and 9 of 29 (31%) pts with ICC were progression-free at 6 mos. 1 PR and one minor response (MR = 20–29% decrease in sum of target lesion diameters) were observed in 40 CT pts; 2 PR and 1 MR in 31 ICC pts. In addition, 32% (12/38) of CT and 14% (4/29) of ICC pts had stable disease on study for a duration that exceeded by at least 4 months the time to progression documented prior to study entry. Grade 3–4 toxicity was infrequent with fatigue (6%), diarrhea (5%) and rash (3%) most common. Evaluation of markers of the EGFR pathway on tumor tissue will be presented. Conclusions: Gefitinib is well-tolerated and results in prolonged disease stabilization in pts with prior documented objective progression of CT and ICC, with rare objective responses. Supported by NOI CM17104. No significant financial relationships to disclose.

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]

scholarly journals MLK3 Is Associated With Poor Prognosis in Patients With Glioblastomas and Actin Cytoskeleton Remodeling in Glioblastoma Cells

2021 ◽  
Vol 10 ◽  
Author(s):  
Yan Zhu ◽  
Jin-Min Sun ◽  
Zi-Chen Sun ◽  
Feng-Jiao Chen ◽  
Yong-Ping Wu ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Poor Prognosis ◽  
Molecular Mechanisms ◽  
Growth Factor Receptor ◽  
Recurrent Glioblastoma ◽  
Migration And Invasion ◽  
Breast Cancers ◽  
Recurrent Glioblastoma Multiforme ◽  
Genetic Ablation ◽  
Cytoskeleton Organization

Mixed lineage kinase 3 (MLK3) has been implicated in human melanoma and breast cancers. However, the clinical significance of MLK3 in human gliomas and the underlying cellular and molecular mechanisms remain unclear. We found that MLK3 proteins were highly expressed in high-grade human glioma specimens and especially prevalent in primary and recurrent glioblastoma multiforme (GBM). High levels of MLK3 mRNA were correlated with poor prognosis in patients with isocitrate dehydrogenase (IDH)-wild-type (wt) gliomas. Furthermore, genetic ablation of MLK3 significantly suppressed the migration and invasion abilities of GBM cells and disrupted actin cytoskeleton organization. Importantly, MLK3 directly bound to epidermal growth factor receptor kinase substrate 8 (EPS8) and regulated the cellular location of EPS8, which is essential for actin cytoskeleton rearrangement. Overall, these findings provide evidence that MLK3 upregulation predicts progression and poor prognosis in human IDH-wt gliomas and suggest that MLK3 promotes the migration and invasion of GBM cells by remodeling the actin cytoskeleton via MLK3-EPS8 signaling.

A stratified phase II study of cetuximab for the treatment of recurrent glioblastoma multiforme: Preliminary results

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1558-1558 ◽  
Author(s):  
J. Sadones ◽  
C. Chaskis ◽  
E. J. Joosens ◽  
L. A. Dhondt ◽  
J. Baurain ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Gene Copy Number ◽  
Growth Factor Receptor ◽  
Recurrent Glioblastoma ◽  
Gene Copy ◽  
Recurrent Glioblastoma Multiforme ◽  
Egfr Gene ◽  
Recurrent Gbm

1558 Background: The Epidermal Growth Factor Receptor (EGFR) gene is frequently amplified and mutated in high-grade gliomas. We are investigating the activity of the EGFR-targeted monoclonal antibody cetuximab for the treatment of patients (pts) with recurrent glioblastoma multiforme (GBM) following surgery, radiotherapy and chemotherapy. Methods: Adult pts with recurrent GBM are allocated to two parallel treatment strata according to the amplification status of the EGFR gene (determined by FISH). According to a Simon two-stage phase II study design 1 response in 13 pts/stratum is required to continue recruitment and complete the second stage of pt recruitment. Cetuximab is administered at 400 mg/m2 (2 hour infusion) day 1 and 250 mg/m2 day 8 and for all subsequent weekly doses (1 hour infusion). Results: Between May and December 2005, 17 pts were recruited (10 without EGFR-ampl, 4 with EGFR-ampl and 3 under investigation); 4F/13M; median age 51 years, range 32–67). Recruitment is ongoing. Sixteen pts initiated study treatment; 1 pt withdrew consent before the initiation of therapy. Treatment related toxicity in the first 94 treatment cycles consisted of grade 1/2 folliculitis/dermitis in all treated pts. Grade 3 adverse events consisted of thrombocytopenia (n=1 pt), diminished consciousness (n=1 pt), dizziness/confusion (n=1 pt), infectious bronchopneumonia (n=1 pt), and infectious cellulitis (n=1 pt). Thirteen pts have been evaluated for response ≤ week 8 of study treatment. Eleven pts had progression of disease. Two patients had SD at 8 weeks (follow-up is ongoing). Conclusions: These preliminary data suggest that cetuximab can be safely administered to pretreated patients with recurrent GBM. Updated results regarding safety and activity as well as a correlative study of EGFR and PTEN expression and gene copy number of the GBM and response to cetuximab will be presented at the meeting. No significant financial relationships to disclose.

Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma: A phase II study of the Belgian Group of Digestive Oncology.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 245-245 ◽  
Author(s):  
I. Borbath ◽  
A. Ceratti ◽  
C. Verslype ◽  
A. Demols ◽  
T. Delaunoit ◽  
...  
Keyword(s):  
Skin Rash ◽  
Phase Ii ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Skin Toxicity ◽  
Standard Of Care ◽  
Egfr Expression ◽  
Prior Systemic Therapy ◽  
Ecog Ps

245 Background: Cholangiocarcinomas (CCK) are uncommon tumors with an increasing incidence and a poor prognosis. Epidermal growth factor receptor (EGFR) expression and activation in CCK have been demonstrated. Methods: We conducted a multicenter phase II trial combining cetuximab (Ctx), an anti-EGFR chimerized IgG1 monoclonal antibody, to gemcitabine (Gem). Patients with either locally advanced (LA) or metastatic (M) CCK (excluding gallbladder) were included; no prior systemic therapy was allowed. Ctx was administrated at the initial dose of 400 mg/m2 and further injections at 250 mg/m2 every 7 days, and Gem was administrated at 1000 mg/m2 on days 1, 8, and 15 every 4 weeks. The primary endpoint was the progression-free survival (PFS) rate at 6 months. A Simon 2-stage design was used. We hypothesized that Gem/Ctx would improve 6 month-PFS rate from 20% to 40%. We needed 3 patients with PFS ≥ 6 months from the first 13 to further include a total of 43 patients. Results: Forty-four patients with advanced CCK (41% LA/59%M) were enrolled from 09/2008 to 01/2010. Median age was 61.5 years (range 40-86) and baseline ECOG PS was 0 for 68% and 1 for 32% of the patients. Forty-three percent of the patients had prior surgery. Forty-six percent of the patients were free from progression at 6 months. Median PFS was 5.8 months (95% CI, 4.4-7.4 m) and median overall survival was 11.6 months (95% CI, 8.7-14.6 m). Nine patients (20.9%) had partial response with a median duration of 5 months (range 2-10 m). Disease control rate (PR + SD > 8 weeks) was 81.4%. The most common grades 3/4 related-toxicities were haematological abnormalities (47.7%), skin rash (13.6%) and fatigue (11.3%). Due to toxicity, 6 patients discontinued study treatment; 14 and 3 patients had a Gem and Ctx dose reduction respectively. Among the nine responders, 8 experienced a skin rash of at least grade 2, suggesting a relationship between skin toxicity and efficacy. Conclusions: Our study met its endpoint, i.e., a PFS rate of 46% at 6 months, suggesting that Gem-Ctx combination had promising activity with a manageable toxicity profile in advanced CCK. Adding Ctx to the new standard of care Gem-cisplatin deserves further investigations in CCK. [Table: see text]

Testing targeted demethylation to overcome resistance to epidermal growth factor receptor (EGFR) blocking agents in wild-type (wt) KRAS metastatic colorectal cancer patients (mCRC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3057-3057 ◽  
Author(s):  
Ignacio Garrido-Laguna ◽  
Kimberly McGregor ◽  
Mark Wade ◽  
John R. Weis ◽  
Laura Burr ◽  
...  
Keyword(s):  
Cpg Island ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Median Number ◽  
Response To Therapy ◽  
Small Subset ◽  
Cpg Island Methylator Phenotype ◽  
Pik3ca Mutations ◽  
Previously Treated ◽  
Ecog Ps

3057 Background: Panitumumab, a monoclonal antibody against EGFR, led to improved progression-free survival (PFS) in patients with (wt)KRAS mCRC. However, the benefit of panitumumab is limited to a not yet identified small subset of (wt)KRAS patients. The CpG island methylator phenotype (CIMP-high) is present in 15-20% of CRC patients. Epigenetic silencing through methylation of PTEN and/or genes in the EGFR pathway might play a role in resistance to therapy. We assessed whether decitabine (a hypomethylating agent) reverted resistance to anti-EGFR therapies. Methods: Patients (n=19) with (wt)KRAS mCRC previously treated with anti-EGFR therapies were enrolled. Patients were treated with decitabine 45mg/kg IV on day (d)1 and d15 and panitumumab 6mg/kg IV on d8 and d22 q28days. Peripheral blood, skin biopsies and buccal smear samples were collected on d1, d8, d15 and d22 to assess methylation changes in PTEN, RASSF1A and SOCS-1 in response to therapy. Tumors were analyzed for PIK3CA mutations using PCR-based DNA sequencing of exon 9 and 20 by PCR as well as for PTEN by immunohistochemistry. Results: Median age was 53 (range 31-72). Eleven (58%) patients were female; 15 (79%) had ECOG PS 1; 3 (16%) had ECOG PS 2; and 1 had ECOG PS 0. Median number of previous therapies was 4. The most common toxicities were rash (68%), hypomagnesemia (26%) and neutropenia (10%) (all grade 1-2). The most common grade 3-4 toxicities were neutropenic fever (5%) and hypomagnesemia (5%). Of 19 (wt)KRAS mCRC patients previously treated with anti-EGFR therapies, 2 (11%) had a partial response (PR) (-50% and -30%, respectively) and 3 (16%) had stable disease (SD) >4 months (7.8, 5.9 and 4.2 months). Both responders were (wt)PIK3CA and (wt)PTEN. Clinical benefit rate (PR+SD) was 27%. Median PFS was 60 days (95% CI 45.4-74.5), similar to median PFS after last anti-EGFR therapy, 61d (95% CI 50.6-71.3). Conclusions: Panitumumab + decitabine is an active combination in a subset of patients with mCRC previously treated with anti-EGFR therapies (2 PRs in this population). Efficacy assessment in an anti-EGFR therapy naïve population is warranted. Methylation studies are ongoing.

An interim evaluation of efficacy and safety of the combination of panitumumab, gemcitabine, and irinotecan in patients with advanced or metastatic cholangiocarcinoma: A phase II study.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 328-328
Author(s):  
Weijing Sun ◽  
Davendra Sohal ◽  
Kristine Mykulowycz ◽  
Ursina R. Teitelbaum ◽  
Nevena Damjanov ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Tumor Stage ◽  
Infusion Reaction ◽  
Primary Objective ◽  
Over Expression ◽  
Epidermal Growth ◽  
Efficacy Criteria ◽  
Tissue Specimens ◽  
Ecog Ps

328 Background: Cholangiocarcinoma is an aggressive neoplasm. Current chemotherapy approaches suggest that combinations may be superior to single agents in this disease. Over-expression of epidermal growth factor receptor (EGFR) is associated with tumor stage and prognosis. This study was designed to evaluate the efficacy and tolerability of the combination of panitumumab, a monoclonal anti-EGFR antibody, with gemcitabine and irinotecan in patients with advanced and metastatic cholangiocarcinoma. Methods: Pts with advanced unresectable or metastatic cholangiocarcinoma, ECOG PS 0-2, and adequate liver, kidney and bone marrow function were treated with panitumumab (9 mg/kg) on day 1, gemcitabine (1000 mg/m2/100 min) iv and irinotecan (100 mg/m2) iv on days 1 and 8 of a 21-day cycle. Tissue specimens were collected based on availability for future biomarker analyses. The primary objective was to evaluate the 5-month progression-free survival (PFS) rate. The secondary objectives include overall response rate (ORR), overall survival rate (OS) and toxicity of the combination. Results: There have been 24 (of planned 42) pts recruited to the study. Toxicity of the combination was assessed in all enrolled pts. There were no treatment related deaths. The most common gr 3 or higher toxicity was were neutropenia (10 pts [40%]), thrombocytopenia (6 pts, [25%]), skin rash (4 pts [17%]) and diarrhea (3 pts, [12%]). One pt developed a gr 2 infusion reaction, which was considered related to panitumumab. Efficacy was evaluated in 20 pts. Among them, there were 2 CR, 6 PR, and 10 SD (with disease control rate of 90%), and 2 PD (assessed by RECIST criteria). Two pts went on to have surgical resection. Eight pts had ≥ 10 cycles of the therapy, and dose modification/interruption were needed for some of these pts. Conclusions: The data of this on-going study showed encouraging results of the combination of panitumumab with gemcitabine and irinotecan in both tolerability and efficacy. The pre-specified efficacy criteria to continue enrollment were met. Further analysis by biomarker status (KRAS/BRAF/EGFR) is forthcoming.

Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict efficacy of axitinib for treatment of advanced hepatocellular carcinoma (HCC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15656-e15656 ◽  
Author(s):  
Po-Hsiang Huang ◽  
Bang-Bin Chen ◽  
Zhong-Zhe Lin ◽  
Ying-Chun Shen ◽  
Yee Chao ◽  
...  
Keyword(s):  
Liver Tumors ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
University Hospital ◽  
Advanced Hepatocellular Carcinoma ◽  
Quantitative Parameter ◽  
Sorafenib Treatment ◽  
Dce Mri ◽  
Advanced Hcc ◽  
Disease Stabilization

e15656 Background: Axitinib, a potent inhibitor of vascular endothelial growth factor receptor, has moderate antitumor efficacy for advanced HCC. Vascular response (VR) measured by DCE-MRI has been demonstrated to correlate with efficacy of systemic therapy for advanced HCC. Methods: Patients enrolled into a phase 2 trial of axitinib as second-line therapy for advanced HCC (NCT01273662) with liver tumors evaluable by DCE-MRI were included. Patients must have documented progression on or intolerance to sorafenib and Child-Pugh class A liver function. The primary endpoint was disease stabilization, defined as complete or partial response per RECIST1.1 or stable disease lasting for 8 weeks without progression of tumor-related symptoms. The quantitative parameter Ktrans and semi-quantitative parameter peak, measured by DCE-MRI at baseline and after 2 weeks of axitinib treatment, were used to evaluate VR, defined by a greater than 40% decrease of Ktrans or peak. Results: From April 2011 to March 2016, 40 patients were enrolled at National Taiwan University Hospital and 5 at Taipei Veterans General Hospital, all had documented progression after sorafenib treatment. Disease stabilization rate was 62.2% (95% CI 48.0-76.4). Median progression-free survival (PFS) and overall survival (OS) were 2.2 months (95% CI 0.3-4.1) and 10.1 months (95% CI 3.6-16.5) respectively. 33 patients were evaluable for VR. VR evaluated by peak was significantly associated with better PFS (5.5 vs. 1.8 months, HR 0.41, 95% CI 0.16-1.02, p = 0.04) and OS (13.0 vs. 5.8 months, HR 0.28, 95% CI 0.09-0.85, p = 0.02). Treatment-related adverse events were compatible with previous reports of axitinib. Conclusions: VR measured by DCE-MRI may help identify HCC patients most likely to benefit from axitinib treatment. Clinical trial information: NCT01273662. [Table: see text]

High-dose BCNU with autologous bone marrow rescue for recurrent glioblastoma multiforme

1981 ◽  
Vol 54 (4) ◽  
pp. 455-460 ◽  
Author(s):  
Fred H. Hochberg ◽  
Leroy M. Parker ◽  
Tak Takvorian ◽  
George P. Canellos ◽  
Nicholas T. Zervas
Keyword(s):  
Bone Marrow ◽  
Autologous Bone Marrow ◽  
Mass Effect ◽  
Recurrent Glioblastoma ◽  
High Dose ◽  
Recurrent Glioblastoma Multiforme ◽  
Content Type ◽  
Autologous Bone ◽  
High Doses ◽  
Transient Elevation

✓ Eleven patients with recurrent malignant glioma were treated with single high doses of BCNU ranging from 600 to 1400 mg/sq m. To prevent the characteristic late myelosuppression observed after conventional doses of BCNU, autologous bone marrow harvested just before drug treatment was infused 24 to 36 hours after therapy. Higher doses of BCNU causes earlier and more profound myelosuppression; one patient died of pancytopenia, breakdown of the gut epithelium, and Clostridium septicemia 10 days after receiving 1400 mg/sq m of BCNU. All patients experienced transient emesis; four developed transient elevation of hepatic enzymes, two reversible interstitial pulmonary infiltrates, and two who received 1400 mg/sq m BCNU suffered irreversible cortical damage. Eight patients receiving 600 to 1200 mg/sq m demonstrated reconstitution of polymorphonuclear leukocytes and platelets within at least 30 days after treatment. With a follow-up time of up to 19 months, four patients improved, three stabilized, and three deteriorated and died. The median survival time was 7 months. Computerized tomography performed on patients receiving constant corticosteroids showed diminished contrast enhancement and mass effect in eight patients. High-dose BCNU at doses up to 1200 mg/sq m with marrow rescue is a feasible approach to the treatment of patients with glioblastoma.

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