Vorinostat, temozolomide, and bevacizumab for patients with recurrent glioblastoma: A phase I/II trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2027-2027 ◽  
Author(s):  
Katherine B. Peters ◽  
James J. Vredenburgh ◽  
Annick Desjardins ◽  
Henry S. Friedman ◽  
James Emmett Herndon ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Phase I ◽  
Bowel Perforation ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Time Interval ◽  
Open Label ◽  
Eligibility Criteria ◽  
Recurrent Gbm

2027 Background: Prognosis for recurrent glioblastoma (GBM) remains poor with median survival between 3 to 6 months. Use of anti-vascular endothelial growth factor inhibitor, bevacizumab (BEV), has advanced this area of research, but continued studies have focused on whether the addition of other chemotherapies can improve efficacy in recurrent GBM. Vorinostat, a small molecule inhibitor of histone deactylase (HDAC), has anti-tumor activity directly through HDAC inhibition and indirectly by promoting anti-angiogenesis. Its good oral bioavailability and favorable toxicity profile make it a promising additive agent to standard therapy. Thus, we evaluated the efficacy of vorinostat in combination with BEV and daily temozolomide (TMZ) in recurrent GBM. Methods: This was a phase I/II open-label, single arm study in recurrent GBM patients. Primary endpoint was 6-month progression free survival (PFS). Secondary endpoints were safety/tolerability, radiographic response, PFS, and overall survival of recurrent GBM patients treated with BEV plus daily TMZ and vorinostat. Chief eligibility criteria included age ≥ 18 years, KPS ≥ 70, time interval ≥ four weeks from previous treatment, and maximum of 2 prior progressions. Dosing regimen was as follows: BEV 10 mg/kg IV every two weeks, TMZ 50 mg/m2 po daily, and vorinostat 400 mg po for 7 days on then 7 days off in a 28 day cycle. Results: 46 recurrent GBM patients were enrolled with 42 of those patients receiving a vorinostat dose of 400 mg. Most common grade 2 and above toxicities were leukopenia (36%), neutropenia (29%), fatigue (24%), and thrombocytopenia (19%). Serious toxicities included 4 grade 4 toxicities (grade 4 hyperglycemia, pulmonary embolism, bowel perforation and intracranial hematoma) and 1 patient expired on day of informed consent due to pulmonary embolism (grade 5). With a median follow-up of 11.3 months (95% CI: 10.1, 13.1 months), the 6-month PFS was 52.4% (95% CI: 36.4%, 66.1%). Best radiographic responses were 2 complete responses, 17 partial responses, 20 stable responses, and 1 radiographic progression. Conclusions: In summary, combination of BEV, daily TMZ, and vorinostat has promising efficacy on recurrent GBM with reasonable toxicity/safety.

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 multicenter, 3-arm, open-label, phase IIa clinical trial to evaluate the safety and efficacy of tanibirumab (VEGFR2 mAb), in patients with recurrent glioblastoma (GBM).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13522-e13522 ◽  
Author(s):  
Lawrence Cher ◽  
Anna K. Nowak ◽  
George Iatropoulos ◽  
Weon Sup Lee ◽  
Seon Young Lee ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Signal Transduction Pathway ◽  
Study Drug ◽  
Current Data ◽  
Recurrent Glioblastoma ◽  
Open Label ◽  
Eligibility Criteria ◽  
Impaired Wound Healing ◽  
Safety And Efficacy ◽  
Recurrent Gbm

e13522 Background: Treatment of recurrent GBM remains a challenge. The VEGF signal transduction pathway is upregulated in GBM. We evaluated Tanibirumab, a mAb to VEGFR2, in an open-label, dose-escalation, 3-arm, Phase 2a clinical trial. Primary and secondary endpoints were determining safety and efficacy (6-month PFS, ORR, DCR and OS). Methods: Eligibility criteria included age ≥19 yrs at 1st or 2nd recurrence of GBM, measurable disease, KPS≥80, and no prior bevacizumab. Patients were enrolled in 3 arms: Arm 1 (8mg/kg d1,8,15/q28 days); Arm 2 (12mg/kg d1,8,15/q28 days) and Arm 3 (12mg/kg weekly). Response evaluation with MRI (RANO criteria) including DCE, was performed every 2 cycles. Results: 12 patients were enrolled over 10 months from 2 sites: 3 patients each in Arms 1 & 2; 6 in Arm 3. The median age was 50 years and 8 were male. 6 patients had second recurrence. At 1st infusion, 8 out of 12 were on baseline corticosteroids. 10 patients have progressed. No dose limiting toxicities (DLT) were observed. Cutaneous hemangiomas (CH) were frequent (83% of patients) and all G2 or less. No drug-related G3 or 4 AEs were observed. All SAEs were unrelated to the study drug apart from G2 bleeding haemangioma and G2 cerebral haemorrhage. Expected AEs with anti-angiogenic drugs (hypertension; impaired wound healing) were not observed. Among 12 patients allocated to Arm 1, 2 and 3, no objective radiological responses were observed. 3 patients demonstrated stable disease (SD); 2 patients had SD beyond 4 cycles and are still receiving treatment at weeks 45 (Arm 1) & 20 (3). This was correlated with the highest expression of VEGFR2 using immunohistochemistry on archival tumour and blood vessels. Only 2 patients needed to initiate or increase corticosteroids for control of tumor edema while on treatment. Current data are immature to determine time to event efficacy endpoints (PFS,OS). Conclusions: Tanibirumab can be safely administered to patients with recurrent GBM, with CH being common. SD was seen in 2 patients up to 10+ months, with some indication that VEGFR2 expression may be a response biomarker. Clinical trial information: NCT03033524.

Safety and efficacy study of retifanlimab and epacadostat in combination with radiation and bevacizumab in patients with recurrent glioblastoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2070-TPS2070
Author(s):  
Jian Li Campian ◽  
Christopher Abraham ◽  
Jingqin Luo ◽  
Grayson Talcott ◽  
Ruth Katumba ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Treatment Options ◽  
Single Agent ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Open Label ◽  
Eligibility Criteria ◽  
Safety And Efficacy

TPS2070 Background: Recurrent glioblastoma (rGBM) after chemoradiotherapy has a dismal outcome with very limited treatment options. Addition of reirradiation to bevacizumab appears to improve progression-free survival (PFS) but does not improve overall survival (OS). Immune checkpoint inhibitors of programmed cell death-1 (PD-1) pathway appear to have limited single-agent activity for rGBM due to its immunesuppressive microenvironment. Indoleamine 2,3 dioxygenase 1 (IDO1) is an inducible and rate-limiting enzyme that catabolizes tryptophan (Trp) into kynurenine (Kyn). IDO1 is over-expressed in 50̃90% of GBM patients, and high IDO1 levels correlate with reduced OS. Epacadostat is a highly potent and selective oral inhibitor of IDO1 and may increase tumor sensitivity to anti-PD-1 blockade. Retifanlimab is a humanized anti-PD-1 monoclonal antibody directed against PD-1. The purpose of this study is to evaluate the safety and efficacy of combining retifanlimab plus or minus epacadostat with reirradiation and bevacizumab for rGBM patients. Methods: This is an open-label nonrandomized phase II study of two sequential cohorts for bevacizumab-naïve adults with rGBM: retifanlimab + bevacizumab+ radiation (cohort A), and retifanlimab + epacadostat + bevacizumab + radiation (cohort B). Each cohort will enroll 24 evaluable patients. Key eligibility criteria include candidates for reirradiation and bevacizumab, age ≥ 18 years, Karnofsky performance status ≥ 60%, and dexamethasone dose ≤ 4 mg/day. The primary endpoint is OS. Secondary endpoints include PFS, neurologic functions, and toxicity. The correlative endpoints include studies assess the anti-glioma immune response, serum Kyn/Trp ratio, and RNA expression of IDO1 and PD-L1 from available tissue. The trial is actively enrolling. At the time of abstract submission, 16 of the planned 24 patients in Cohort A have been enrolled. Clinical trial information: NCT03532295. [Table: see text]

scholarly journals ACTR-26. SAFETY AND EFFICACY OF BEVACIZUMAB PLUS TTFIELDS IN PATIENTS WITH RECURRENT GLIOBLASTOMA (GBM): DATA FROM A PHASE II CLINICAL TRIAL

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi18-vi18 ◽  
Author(s):  
Jaleh Fallah ◽  
Rekha Chaudhary ◽  
Lisa Rogers ◽  
Wei (Auston) Wei ◽  
Cathy Brewer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Disease Progression ◽  
Muscle Weakness ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Open Label ◽  
Safety And Efficacy ◽  
Phase 2 Clinical Trial ◽  
Recurrent Gbm

Abstract BACKGROUND Studies of bevacizumab monotherapy and TTFields monotherapy have shown activity but limited clinical benefit in patients with recurrent GBM. In an open label, single-arm, phase 2 clinical trial, the safety and efficacy of the combination of bevacizumab and TTFields was studied in patients with recurrent GBM. METHOD Bevacizumab-naïve patients with histologically confirmed GBM or other grade IV glioma, with recurrent disease after radiotherapy and temozolomide chemotherapy, were eligible. Bevacizumab dose was 10mg/kg intravenously every 2 weeks and TTFields was worn at least 18 hours daily. The primary endpoint was safety, progression-free survival at 6 months (PFS6) and overall survival at 12 months (OS12). Treatment was continued until disease progression or unacceptable toxicity. Survival outcomes were assessed using the Kaplan-Meier method. Treatment-related adverse events were reported according to CTCAE, v4.0 criteria. RESULTS 25 patients were enrolled and 23 were eligible for data analysis: 18 (78%) men and 5 (22%) women, median age 60 years (range 17–78). 21 patients were Caucasian, 1 was African American and 1 of unknown race. Median follow-up was 6.0 months (range 2.4–22). Seven patients (30 %) had disease progression. Median PFS was 9.9 (95% CI: 6.7-NA) months. PFS rate at 6 months (PFS6) was 71% (95% CI: 0.54–0.94). Median overall survival was 9.9 (95%CI 7.3-NA) months. OS rate at 12 months (OS12) was 42% (95%CI 0.24–0.74). 7 patients (30%) had grade 3 toxicity (cough, dysphagia, muscle weakness, hyperglycemia, hypertension, psychosis, seizure, lymphopenia, transaminitis). 1 patient developed grade 4 muscle weakness in the lower extremities. CONCLUSION Treatment with the combination of bevacizumab and TTFields in patients with recurrent GBM is safe and feasible and has shown clinical efficacy.

Phase II trial of sorafenib combined with dacarbazine in metastatic melanoma patients

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8012-8012 ◽  
Author(s):  
P. Lorigan ◽  
P. Corrie ◽  
D. Chao ◽  
P. Nathan ◽  
T. Ahmad ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Metastatic Melanoma ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Study Drug ◽  
Progression Free Survival ◽  
Open Label ◽  
Eligibility Criteria ◽  
Stage 1

8012 Background: Sorafenib inhibits tumor cell proliferation and angiogenesis through blockade of multiple kinases including Raf, VEGFR-2/-3, and PDGFR-β. In Phase I/II trials, sorafenib was generally well tolerated as a monotherapy or in combination with other agents. A Phase I study in combination with dacarbazine (DTIC) showed encouraging activity, which warranted this Phase II study. Methods: This multi-center, open-label, two-stage (30 patients in Stage 1; 52 in Stage 2), uncontrolled Phase II trial was performed to evaluate the primary endpoints of efficacy (according to RECIST) and tolerability of sorafenib in combination with DTIC in patients with advanced metastatic melanoma. Eligibility criteria included ECOG 0 or 1, life expectancy ≥12 weeks, adequate bone marrow, liver, and renal function. Oral sorafenib 400 mg twice daily (bid) was administered with repeated 3-week cycles of DTIC 1000 mg/m2. Results: At this interim end of Stage 1 analysis, 30 patients with metastatic melanoma had been treated (median age 61 years [range 30–78]; 73.3% male; 96.7% white). Five (16.7%) patients had PR as best response (two confirmed, three currently unconfirmed), 13 (43.3%) had SD, 10 (33.3%) had PD, and two (6.7%) were unevaluable for tumor response. The patients with confirmed PR continue on study drug at 6.4 months. Median progression-free survival for all patients was 3.6 months (range 0.9–6.1 months). The most frequently reported drug-related adverse events (AEs) were dermatologic (rash/desquamation [43%], hand-foot skin reaction [HFS, 33%]); gastrointestinal (constipation [47%], nausea [37%], diarrhea [27%]); constitutional (fatigue [43%]); and blood/bone marrow (neutrophils [40%], platelets [30%]). The most common grade 3/4 drug-related AEs were blood/bone marrow (neutrophils [23%], platelets [17%]), and fatigue (7%), while HFS and hypertension were observed in <5%. Conclusions: Continuous sorafenib 400 mg bid is generally well tolerated and shows promising preliminary anti-tumor activity in combination with DTIC. No toxicities were observed above those expected from either agent alone. Updated results will be presented, including the decision whether to proceed to Stage 2 of the study. [Table: see text]

Phase IIa trial of cilengitide (EMD121974) single-agent therapy in patients (pts) with recurrent glioblastoma (GBM): EMD 121974-009

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2002-2002 ◽  
Author(s):  
D. Reardon ◽  
K. Fink ◽  
B. Nabors ◽  
T. Cloughesy ◽  
S. Plotkin ◽  
...  
Keyword(s):  
Karnofsky Performance Status ◽  
Performance Status ◽  
Single Agent ◽  
Progression Free Survival ◽  
Median Number ◽  
Recurrent Glioblastoma ◽  
Tumor Control ◽  
Clinical Activity ◽  
Open Label ◽  
Recurrent Gbm

2002 Background: Our phase IIa study evaluated the safety, toxicity, and clinical activity of the cyclic RGD pentapeptide cilengitide (EMD121974), an inhibitor of integrins avβ3 and avβ5, as a single agent at doses of 500 and 2000 mg in pts with recurrent GBM. Methods: In this multicenter, open-label, randomized, uncontrolled study, pts with GBM and measurable disease that had relapsed after previous temozolomide and radiotherapy were randomized to receive cilengitide at either 500 mg or 2000 mg i.v., 2x/week, until progression. Neurologic exams were performed after every cycle (4 weeks) and MRIs were performed every other cycle. Central, blinded pathology and radiology reviews were performed. The primary endpoint was Progression Free Survival (PFS) at 6 months (6-mth PFS). Secondary endpoints included response, survival, time to disease progression, safety, tolerability and pharmacokinetics (PK). Results: 81 pts accrued (median Karnofsky Performance Status 80%; median age 57 yrs) at 15 sites including 41 at the 500 mg and 40 at the 2000 mg dose levels. Demographic and pretreatment variables were comparable between dose level cohorts. The median number of infusions was 16 [range, 4–179]. PK studies revealed significantly greater exposures among the 2000 mg cohort. Treatment related NCI CTC grade 3 adverse events (AEs) included elevated transaminases (at 500 mg), arthralgia/ myalgia (at 500 mg), and weight increase/ edema (at 2000 mg) in 1 patient, respectively. No grade 4 therapy related AEs were reported. One CTC grade 2 cerebral hemorrhage was reported in a pt at progression. The 6- mth PFS was 16.1% (n=13/81 pts). 10 pts (12.3 %, n=4 with 500 mg, n=6 with 2000 mg) received 12 or more cycles. Six pts (7.4%) remain progression-free and on treatment. Median Overall Survival (mOS) was 6.5 mths [95% CI: 5.2–9.3 mths] in the 500 mg arm and 9.9 mths [95% CI, 6.3–15.7 mths] in the 2000 mg arm. Although not statistically significant, there was a trend towards better tumor control in pts receiving 2000 mg 2x/week. Conclusions: Cilengitide was well tolerated and demonstrated single agent activity in recurrent GBM, with long term disease stabilization in a subset of pts. [Table: see text]

Interim analysis of a phase I/II study of panobinostat in combination with bevacizumab for recurrent glioblastoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2013-2013 ◽  
Author(s):  
Eudocia Quant Lee ◽  
David A. Reardon ◽  
David Schiff ◽  
Jan Drappatz ◽  
Alona Muzikansky ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Interim Analysis ◽  
Safety Data ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Recurrent Glioblastoma ◽  
Free Survival ◽  
Deacetylase Inhibitor ◽  
Recurrent Gbm

2013 Background: Bevacizumab is frequently used to treat recurrent GBM, but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects in GBM and may work synergistically with bevacizumab. We conducted a multicenter phase I/II trial of panobinostat in combination with bevacizumab in patients with recurrent GBM. Methods: In the phase II trial, patients with recurrent GBM were treated with oral panobinostat 30 mg three times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. The primary endpoint was 6-month progression-free survival (PFS6) and the study was powered to discriminate between a 35% and 55% PFS6 rate (85% power at an alpha level of 0.07). A planned interim analysis specified suspension of accrual and careful data review if 12 or more of the first 21 patients accrued to the study progress within 6 months of initiating treatment. Patients with recurrent GBM enrolled in the phase I study at the maximum tolerated dose (which is the phase II dose) were eligible for inclusion in the interim analysis. Results: Thirteen of the first 21 patients accrued to the GBM arm of the study had progressed within 6 months of initiating study treatment. The study was closed to further accrual and a planned interim analysis was performed. Median age was 53 (range 22-66) and median KPS was 80% (60%-100%). PFS6 rate was 33.9% [95% CI 12.8, 56.5), median was PFS 5 months [95% CI 3 months, NR], and median OS was 342 days [95% CI 203 days, NR]. Five patients (23.8%) achieved partial responses. Conclusions: Although reasonably well-tolerated, this phase I/II study of panobinostat and bevacizumab in recurrent GBM did not meet criteria for continued accrual and the study was closed. Updated outcome and safety data will be presented at the meeting. Study Supported by: Novartis and Genentech Clinical trial information: NCT00859222.

scholarly journals Phase I trial of intranasal NEO100, highly purified perillyl alcohol, in adult patients with recurrent glioblastoma

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Axel H Schönthal ◽  
David M Peereboom ◽  
Naveed Wagle ◽  
Rose Lai ◽  
Anna J Mathew ◽  
...  
Keyword(s):  
Overall Survival ◽  
Adverse Events ◽  
Phase I ◽  
Progression Free Survival ◽  
The United States ◽  
Perillyl Alcohol ◽  
Recurrent Glioblastoma ◽  
Intranasal Delivery ◽  
Isocitrate Dehydrogenase 1 ◽  
Recurrent Gbm

Abstract Background Better treatments for glioblastoma (GBM) patients, in particular in the recurrent setting, are urgently needed. Clinical trials performed in Brazil indicated that intranasal delivery of perillyl alcohol (POH) might be effective in this patient group. NEO100, a highly purified version of POH, was current good manufacturing practice (cGMP) manufactured to evaluate the safety and efficacy of this novel approach in a Phase I/IIa clinical trial in the United States. Methods A total of 12 patients with recurrent GBM were enrolled into Phase I of this trial. NEO100 was administered by intranasal delivery using a nebulizer and nasal mask. Dosing was 4 times a day, every day. Four cohorts of 3 patients received the following dosages: 96 mg/dose (384 mg/day), 144 mg/dose (576 mg/day), 192 mg/dose (768 mg/day), and 288 mg/dose (1152 mg/day). Completion of 28 days of treatment was recorded as 1 cycle. Adverse events were documented, and radiographic response via Response Assessment in Neuro-Oncology (RANO) criteria was evaluated every 2 months. Progression-free and overall survival were determined after 6 and 12 months, respectively (progression-free survival-6 [PFS-6], overall survival-12 [OS-12]). Results Intranasal NEO100 was well tolerated at all dose levels and no severe adverse events were reported. PFS-6 was 33%, OS-12 was 55%, and median OS was 15 months. Four patients (33%), all of them with isocitrate dehydrogenase 1 (IDH1)-mutant tumors, survived &gt;24 months. Conclusion Intranasal glioma therapy with NEO100 was well tolerated. It correlated with improved survival when compared to historical controls, pointing to the possibility that this novel intranasal approach could become useful for the treatment of recurrent GBM.

Phase I/II study of sorafenib and temsirolimus for patients with recurrent glioblastoma (GBM) (NABTC 05–02)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2006-2006 ◽  
Author(s):  
P. Y. Wen ◽  
T. Cloughesy ◽  
J. Kuhn ◽  
K. Lamborn ◽  
L. E. Abrey ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Single Agent ◽  
Recurrent Glioblastoma ◽  
Molecular Therapy ◽  
Dose Finding ◽  
Pharmacokinetic Data ◽  
Eligibility Criteria ◽  
Grade 3 ◽  
Recurrent Gbm

2006 Background: The activity of targeted molecular therapy with single agents has been disappointing in GBM. Combination therapy simultaneously targeting both the PI3k/Akt/mTOR and the MAP kinase pathway may be more effective. Methods: The North American Brain Tumor Consortium conducted a phase I/II study of sorafenib (VEGFR/PDGFR/Raf inhibitor) in combination with temsirolimus (mTOR inhibitor) in recurrent GBM. Eligibility criteria included histologically proven GBM, radiologic progression, > 18 years old, KPS > 60, adequate bone marrow reserve, and organ function. There was no limit on the number of prior relapses for phase I and no more than two prior relapses for phase II. No enzyme-inducing antiepileptic drugs were allowed. Dose-finding used a standard 3 + 3 design with the MTD defined as the dose with DLTs in 1/6 or fewer patients. The primary endpoint for the phase II component was PFS6 (p0 = 15%; p1 = 35%). A 2-stage design was used. If > 4 of the initial 19 patients achieved PFS6, an additional 14 patients would be accrued for a total of 33 patients. Results: In phase I, 13 patients were enrolled. Median age was 50 years (32–59); median prior chemotherapy 1 (1–3). The initial doses were sorafenib 200 mg bid and temsirolimus 25 mg intravenously once weekly. The MTD was 400 mg bid of sorafenib daily combined with 25 mg of temsirolimus weekly. At this dose 1/6 patients had a DLT (grade 3 thrombocytopenia). Other grade 3 or 4 toxicities included transaminitis, hypophosphatemia, fatigue, diarrhea, and hyperlipidemia. Pharmacokinetic data were similar to that for single agent sorafenib and temsirolimus suggesting that there were no significant interaction between the two drugs. In phase II, 19 patients were accrued to stage I. Median age 50 years (24–64); median prior relapses 1 (range 1–2). One patient was found not to have GBM on central review. No patient remained progression free at 6 months, although two patients stopped treatment prior to 26 weeks for other than progression (alternative therapy, cerebral ischemia). As result, the study was terminated and did not proceed to the second stage. Conclusions: The combination of sorafenib and temsirolimus was moderately well-tolerated but did not demonstrate sufficient efficacy in recurrent GBM to warrant further investigation. No significant financial relationships to disclose.

scholarly journals Machine-Learning-Based Radiomics MRI Model for Survival Prediction of Recurrent Glioblastomas Treated with Bevacizumab

Diagnostics ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1263
Author(s):  
Samy Ammari ◽  
Raoul Sallé de Chou ◽  
Tarek Assi ◽  
Mehdi Touat ◽  
Emilie Chouzenoux ◽  
...  
Keyword(s):  
Machine Learning ◽  
Therapeutic Option ◽  
Binary Classification ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Machine Learning Algorithms ◽  
Survival Prediction ◽  
Classification Models ◽  
Angiogenic Therapy ◽  
Recurrent Gbm

Anti-angiogenic therapy with bevacizumab is a widely used therapeutic option for recurrent glioblastoma (GBM). Nevertheless, the therapeutic response remains highly heterogeneous among GBM patients with discordant outcomes. Recent data have shown that radiomics, an advanced recent imaging analysis method, can help to predict both prognosis and therapy in a multitude of solid tumours. The objective of this study was to identify novel biomarkers, extracted from MRI and clinical data, which could predict overall survival (OS) and progression-free survival (PFS) in GBM patients treated with bevacizumab using machine-learning algorithms. In a cohort of 194 recurrent GBM patients (age range 18–80), radiomics data from pre-treatment T2 FLAIR and gadolinium-injected MRI images along with clinical features were analysed. Binary classification models for OS at 9, 12, and 15 months were evaluated. Our classification models successfully stratified the OS. The AUCs were equal to 0.78, 0.85, and 0.76 on the test sets (0.79, 0.82, and 0.87 on the training sets) for the 9-, 12-, and 15-month endpoints, respectively. Regressions yielded a C-index of 0.64 (0.74) for OS and 0.57 (0.69) for PFS. These results suggest that radiomics could assist in the elaboration of a predictive model for treatment selection in recurrent GBM patients.

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