Higlights Of the American Society Of Clinical Oncology conference 2007

Reported by Hong Lan

Selected Abstracts from ASCO 2007

Summary Table
(See below for the abstracts)

AbstractNumber	Treatment	NumberOfPatients	PatientCatagory	PSF6-Month
2000	EMD121947+Temodar	52	NewGBM	65%
2001	AZD2171	30	RecurrentGBM	28%
2002	EMD121947	81	RecurrentGBM	16%
2003	Avastin+CPT11	35	RecurrentGBM	43%
2004	Vorinostat	68	RecurrentGBM	23%
2005	Erlotinib	54	RecurrentGBM	12%
2024	Erlotinib+Carboplatin	20	RecurrentGBM	NotReported(mTTP15.2wks)
2031	Temodar150mg7/7vsDaily50mg	51	NewGBM	mPFS6.8monthfor150vs3.8monthfor50
2032	Temodar150mg7/7	64	RecurrentGBM	44%
2055	Imatinib+Hydroxyurea	30	NonProgressionGBM	60%
2056	Imatinib600mg	20	RecurrentGBM	52%
2066	ICE	42	RecurrentGBM	37%
2067	Thalidomide+Procarbazine	18	RecurrentGBM	NotGood(mTTP2.1months)
2077	Avastin+CPT11	27	RecurrentHighGradeGlioma	46%
2078	Avastin+CPT11	22	RecurrentGBM	NotReported(mTTP3months)
12508	ICE	32	RecurrentGBM	31%
12521	AP12009	95	RecurrentGBM	NotReported(18mOS21%-24%)

 

Selected abstracts:

Phase I/IIa trial of cilengitide (EMD121974) and temozolomide with concomitant radiotherapy, followed by temozolomide and cilengitide maintenance therapy in patients (pts) with newly diagnosed glioblastoma (GBM).

Abstract No: 2000

Citation: Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 2000 Author(s): R. Stupp, R. Goldbrunner, B. Neyns, U. Schlegel, P. Clement, G. G. Grabenbauer, M. E. Hegi, J. Nippgen, M. Picard, M. Weller

Abstract: Background: To evaluate safety, toxicity, and efficacy of the combination of the cyclic RGD pentapeptide cilengitide (EMD121974), an inhibitor of integrins avβ3 and avβ5, in addition to standard temozolomide (TMZ) and radiotherapy (RT). Methods: 52 pts (PS 0-1: 92%, 2: 8%; median age 57 yrs) after tumor resection (n=43/83%) or biopsy (n= 9/17%) were treated with standard TMZ/RT (Stupp et al. NEJM 2005). In addition cilengitide (500 mg i.v., 2x/week) was started one week before TMZ/RT and given throughout for the duration of chemotherapy or until progression. The primary endpoint was progression free survival rate at 6 months (target: 65%). Pts were followed with MRI every 2 months. Histopathologic diagnosis and MRI imaging were independently reviewed, O6-Methylguanine- DNA methyltransferase (MGMT) promotor methylation status was assessed in 45 (86.5%) pts. Results: 46 pts (92%) completed RT, = 90% of concomitant TMZ was received by 42 pts and cilengitide by 45 pts. 20 pts (3 ongoing) completed 6 cycles of maintenance TMZ and cilengitide. Observed hematological grade 3 and 4 toxicities were: lymphopenia (28/52, 53.8%), thrombocytopenia (7/52 pt. 13.4%) and neutropenia (5/52, 9.6%). Treatment related non-hematologic grade 3/4 toxicities were reported for n=3/52 (5.7%) patients: constitutional symptoms (asthenia, fatigue, anorexia, n=3); elevated liver function tests (n=1), deep venous thrombosis and pulmonary embolism (n=1). One patient with a history of sigmoid diverticulosis experienced sigmoid perforation (grade 2). In total, 34/52 (65.4% [95% CI, 50.9-78.0%]) of the pts were progression free at 6 months. Pts with MGMT gene-promotor methylation in the tumor were more likely to reach 6 months PFS endpoint. Conclusions: The study reached its primary endpoint. The combination of the integrin inhibitor RGD peptide Cilengitide and TMZ/RT was well tolerated, PFS at 6 months is encouraging. MGMT gene promoter methylation correlates with outcome. At the time of ASCO, updated results and survival estimates after a minimum follow-up of at least 1 year will be available.

 

A phase II trial of AZD2171 (cediranib), an oral pan-VEGF receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma.

Abstract No: 2001

Citation: Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 2001

Author(s): T. Batchelor, A. G. Sorensen, M. Ancukiewicz, D. G. Duda, D. N. Louis, S. R. Plotkin, P. Ivy, P. Y. Wen, J. S. Loeffler, R. Jain

Abstract: Background: AZD2171 (cediranib) is a potent, oral pan-VEGF receptor tyrosine kinase inhibitor with a half-life of 20 hours compatible with once-daily dosing. A primary target of AZD2171, VEGFR2, is expressed on glioblastoma endothelium. We have demonstrated normalization of tumor vessels in recurrent glioblastoma patients treated with daily doses of AZD2171. Normalization has rapid onset, is reversible and is associated with alleviation of brain edema [Cancer Cell 2007; 11: 83]. Methods: In this phase II study of 30 recurrent glioblastoma subjects the primary endpoint was the proportion of patients alive and progression-free at 6 months (APF6). Secondary endpoints include radiographic response proportion; progression-free survival; overall survival and toxicity. At this time we are presenting radiographic response data and toxicity on the first 16 consecutive patients and APF6, PFS and OS on all 30 patients. Complete information will be available on all 30 patients at the time of presentation. Results: Twenty-eight patients have experienced disease progression and two patients remain in follow-up without progression. The primary and secondary endpoints are tabulated below: Only one of the first 16 patients was removed from the study due to toxicity (fatigue). Dose limiting toxicities of hypertension, fatigue and diarrhea were observed in 9/16 patients. There were no intracerebral hemorrhages. AZD2171 alleviated brain edema, a major cause of morbidity in glioblastoma patients, and had a steroid-sparing effect in the first 16 patients enrolled. Blood biomarkers were serially assessed and elevated levels of bFGF, SDF1a and viable circulating endothelial cells correlated with disease progression. Conclusions: AZD2171 has activity in patients with recurrent glioblastoma. Combination studies of AZD2171 with radiation and chemotherapy are planned. 

APF6 [95% CI] (N = 30)	Radiographic Responses (N = 16)	PFS [95% CI] (N = 30)	OS [95% CI] (N = 30)
27.6% [15.3%, 50.0%]	Partial Responses: 9/16 (56%)	111 days [71, 182]	226 days [169, NA]

 

 

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

Abstract No: 2002

Citation: Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 2002

Author(s): D. Reardon, K. Fink, B. Nabors, T. Cloughesy, S. Plotkin, D. Schiff, J. Raizer, S. Krueger, M. Picard, T. Mikkelsen

Abstract: 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.

 

Phase II trial of bevacizumab and irinotecan in the treatment of malignant gliomas.

Abstract No: 2003

Citation: Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 2003

Author(s): K. J. Goli, A. Desjardins, J. E. Herndon, J. N. Rich, D. A. Reardon, J. A. Quinn, S. Sathornsumetee, D. A. Bota, H. S. Friedman, J. J. Vredenburgh

Abstract: Background: Recurrent malignant gliomas have low response rates to current treatments. Malignant gliomas have high concentrations of VEGF receptors which are poor prognostic indicators. Bevacizumab is a humanized IgG1 monoclonal antibody to VEGF, which is synergistic with chemotherapy for most malignancies. Irinotecan is a topoisomerase 1 inhibitor with modest activity against recurrent malignant gliomas. Methods: We report the mature data for our FDA approved phase II trial of bevacizumab and irinotecan for the treatment of recurrent malignant gliomas. We enrolled 68 patients (35 with grade IV tumors and 33 with grade III tumors.) All patients had progressive disease and received prior radiation therapy and temozolomide. The first 32 patients were treated every other week with bevacizumab 10 mg/kg and irinotecan 125 mg/m2 (non EIAED) or 340 mg/m2 (EIAED). The last 36 patients were treated with irinotecan 125 mg/m2 (non EIAED) or 350 mg/m2 (EIAED) on days 1, 8, 22, and 29 and bevacizumab 15 mg/kg on days 1 and 22. Results: The regimen was well tolerated. Only 1 CNS hemorrhage occurred after 10 cycles of treatment. Eight patients were taken off study for thrombotic complications (four PE, two DVT, one TTP, one thrombotic stroke) and 2 of these patients died (one with PE and one with thrombotic stroke). Two patients were discontinued secondary to grade 2 proteinuria and 3 were discontinued because they required non-neurosurgical surgery. The response rate was 59% (38 PRs and 2 CRs). In Grade IV, the median PFS was 23 weeks (95% confidence intervals 17-34). The 6 month PFS was 43% (95% confidence intervals 29%-63%), the median overall survival was 40 weeks (95% confidence intervals 34-50). In grade III patients the median PFS was 42 weeks, the 6 month PFS was 61% (95% confidence intervals 46%-80%), the medial overall survival was 60 weeks (95% confidence intervals 37%-73%). The follow-up for the second cohort is short with similar efficacy and more toxicity. Conclusion: The combination of bevacizumab and irinotecan is safe and demonstrates superior activity against malignant gliomas.

 

N047B: NCCTG phase II trial of vorinostat (suberoylanilide hydroxamic acid) in recurrent glioblastoma multiforme (GBM).

Abstract No: 2004

Citation: Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 2004

Author(s): E. Galanis, K. A. Jaeckle, M. J. Maurer, J. M. Reid, M. M. Ames, C. Giannini, J. S. Hardwick, D. F. Moore, J. A. Zwiebel, J. C. Buckner

Abstract: Background: Vorinostat is a histone deacetylase inhibitor that represents a rational therapeutic target in GBM. Methods: Recurrent GBM patients (pts) having received = 1 prior chemo regimen for progressive disease were eligible. Vorinostat dose was 200 mg bid x 14 days q 3 weeks. We applied a phase II design which had 90% power to declare the regimen active if the study PFS6 rate was 25%, a 15% rate increase over PFS6 in historical controls (10%). Results: 68 patients were treated. Grade 3+ non-hematologic toxicity consisting mainly of fatigue, diarrhea and dehydration occurred in 23% of pts; Grade 3+ hematologic toxicity consisting mainly of thrombocytopenia occurred in 25% of pts. Intra-patient dose escalation to 300 mg bid resulted in higher incidence of grade 3+ thrombocytopenia (45%) and was aborted. Pts receiving enzyme-inducing anticonvulsants (EIAC) had significantly less grade 3 + non-hematologic toxicity (p=0.01) and grade 3/4 thrombocytopenia (p=0.04). Pharmacokinetic analysis showed lower vorninostat C-max and AUC (0-24h) values and higher vorinostat-glucuronide C-max and AUC (0-24h) values in EIAC pts, although this did not reach statistical significance. The trial met the prospectively defined primary efficacy endpoint at the planned interim analysis with 5 of the first 22 patients (23%) being progression-free at 6 mo. RNA array analysis, performed in paired baseline and post-vorinostat treatment samples in a separate subgroup of 5 surgical recurrent GBM pts, who received vorinostat for 6 doses prior to surgery, showed upregulation of E-cadherin (p=0.02), thus indicating a biologic effect of the HDAC inhibitor on the glioblastoma tumors. Histone acetylation, Akt, phospho-Akt, P21Waf1/Cip1 and P27Kip1 expression analysis in all patients and correlation with outcome is ongoing. Conclusions: Vorinostat is well tolerated in recurrent GBM patients. EIAC patients have less toxicity, likely due to increased vorinostat metabolism via glucuronidation. Interim efficacy analysis is indicative of antitumor activity. Final efficacy analysis, RNA array data and correlative tissue analysis will be reported.

 

Randomized phase II trial of erlotinib (E) versus temozolomide (TMZ) or BCNU in recurrent glioblastoma multiforme (GBM): EORTC 26034.

Abstract No: 2005

Citation: Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 2005

Author(s): M. J. Van Den Bent, A. Brandes, R. Rampling, M. Kouwenhoven, J. M. Kros, A. F. Carpentier, P. Clement, B. Klughammer, T. Gorlia, D. Lacombe

Abstract: Background: In 40-50% of GBM epidermal growth factor receptor (EGFR) is amplified, and often constitutively activated (EGFRvIII mutant). EGFR is therefore a potential therapeutic target. Previous studies suggested activity of EGFR tyrosine-kinase inhibitors in recurrent GBM, particularly in specific molecular subsets. This study explored erlotinib (E) activity in recurrent GBM. Methods: Randomized phase II trial. Eligibility criteria: histologically proven GBM, recurrent >3 months after radiotherapy, Karnofsky performance status (KPS) =70, no prior chemotherapy for recurrent disease, tissue sample for EGFR studies. Patients (pts) received E 150mg/day (300mg/day if on enzyme inducing anti-epileptic drugs [EIAEDs]), or control (TMZ 150-200mg/m2, day 1-5 q4wk or BCNU 60-80mg/m2 i.v., day 1-3 q8wk). If no significant toxicity, E was escalated to 200mg (500mg in patients on EIAEDs). The primary endpoint was 6 months' PFS in =10/50 pts on E (20%); P0 was set at 15%, and P1 at 30%. Response was assessed with Macdonald's criteria. EGFR amplification (FISH) and expression of EGFR, EGFRvIII and PTEN (immunohistochemistry [IHC]) were assessed. Results: 110 patients were randomized (54 E, 56 control: 27 TMZ; 29 BCNU). Median age 55 years; median KPS 90. All but 1 patient started treatment; median number of cycles was 2 for E, 4 for TMZ and 1 for BCNU. Grade 3/4 toxicities likely related to E: dermatological (5); hemorrhage (1). Grade 3/4 toxicities for control were mainly hematological (3 TMZ, 13 BCNU). Three pts discontinued E due to toxicity. Six-month PFS was 12% for E, 24% for control. Six and 12-month survival were 61% and 24% for E, and 63% and 26% for control. Two responses were seen on control; the best response on E was SD (n=6). Patients with EGFRvIII mutations (13 in E arm, 8 in control arm) had shorter PFS (p=0.007) and OS (p=0.004) regardless of treatment. Response to E was not correlated with EGFR expression, EGFR amplification or EGFRvIII mutation. Conclusions: This randomized, controlled phase II study did not find sufficient activity for erlotinib in the general population of recurrent GBM. The presence of EGFRvIII mutations was not predictive for response.

 

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

Abstract No: 2024

Citation: Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 2024

Author(s): J. F. De Groot, M. R. Gilbert, K. R. Hess, T. Hanna, M. Groves , C. Conrad, K. Aldape, H. Colman, V. Puduvalli, W. A. Yung

Abstract: 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.

 

A randomized phase II trial of concurrent temozolomide (TMZ) and radiotherapy (RT) followed by dose dense compared to metronomic TMZ and maintenance cis-retinoic acid for patients with newly diagnosed glioblastoma multiforme (GBM).

Abstract No: 2031

Citation: Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 2031

Author(s): J. Sul, K. S. Panageas, A. B. Lassman, A. Hormigo, C. Nolan, I. T. Gavrilovic, S. A. Grimm, L. M. DeAngelis, L. E. Abrey

Abstract: Background: Metronomic and dose dense scheduling are alternatives to conventional TMZ regimens to overcome drug resistance in part by depleting O-6 methylguanine-DNA methyltransferase (MGMT). Furthermore, metronomic TMZ may inhibit endothelial recovery and act as an anti-angiogenic therapy; dose dense TMZ increases the intensity of drug delivery. Objective: To determine the overall (OS) and progression free survival (PFS) of patients with newly diagnosed GBM treated with concurrent TMZ and RT followed by dose dense or metronomic TMZ and maintenance cis-retinoic acid. Methods: Patients with newly diagnosed, histologically confirmed GBM underwent standard RT with TMZ. Upon completion of this treatment, patients were randomized to receive dose-dense TMZ (150mg/m2, days 1-7 and 15-21 of a 28 day cycle) or metronomic TMZ (50mg/m2 daily in 28 day cycles), for 6 cycles. Maintenance cis-retinoic acid was prescribed following the 6 cycles of adjuvant TMZ. OS and PFS were calculated from date of diagnosis. Prospective correlative tissue analysis of MGMT status is planned. A Simon minimax 2-stage design was used for each cohort. If either group has 70% survival probability at 1 year, further evaluation in a phase III trial will be recommended. Results: 51 patients were randomized: 24 to metronomic, and 27 to dose dense. Median age is 57, and median KPS 90. 26 patients have progression of disease (POD), with a median follow up of 5 months. Grade 3/4 hematologic toxicity occurred in 7 patients (14%), 3 in the metronomic and 4 in the dose dense arm. Conclusions: Our patient population is comparable to that of other upfront GBM treatment trials. Metronomic and dose dense TMZ appear to be well tolerated with equivalent toxicities. Early analysis suggests that patients on the dose dense regimen may have better PFS than those on the metronomic arm. 

	All GBMs (51)	Metronomic (24)	Dose Dense (27)
Median OS (months)	Not reached	11.2	Not reached
Median PFS (months)	5.5	3.8	6.8

 

 

 

One week on/one week off regimen of temozolomide: Phase II trial in recurrent glioma.

Abstract No: 2032

Citation: Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 2032

Author(s): W. Wick, A. Wick, J. Schuth, M. Platten, G. Reifenberger, M. Weller

Abstract: Background: Evaluation of toxicity and efficacy of a one week on/one week off temozolomide regimen in patients with recurrent gliomas. Methods: Ninety adult patients (median Karnofsky performance score 90; median age 51 years) with recurrent gliomas (9 patients with low-grade gliomas, 11 with anaplastic gliomas, 64 with GBM, and 6 with other brain tumors) accrued in one center received chemotherapy with temozolomide at 150 mg/m2/d (days 1-7 and 15-21 every four weeks) with individual dose adjustments according to hematological toxicity. Results: A total of 906 treatment weeks was delivered. Grade 4 hematotoxicity according to the common terminology criteria for adverse events (CTCEA v 3.0) was observed in 24 treatment weeks (2.6%). CTCEA grade 4 lymphopenia eventually developed in 11 patients (12%). There were no cumulative lymphopenia or opportunistic infections. The progression-free survival (PFS) rate at 6 months for the patients with GBM was 43.8%. The median PFS was 24 weeks (95% CI, 17 to 26 weeks), the median survival time (MST) from diagnosis of progression was 38 weeks (95% CI, 30 to 46 weeks), the 1-year survival rate from progression was 23%. O6-methylguanine DNA methyltransferase (MGMT) gene promoter methylation in the tumor tissue was not associated with longer PFS (p=0.37, log-rank test). Conclusions: This data imply that the one week on/one week off schedule is feasible, safe and effective and clearly warrant investigation in randomized studies. In contrast, protracted low-dose temozolomide at 75 mg/m2 has been shown to be toxic, resulting in cumulative lymphopenia and opportunistic infections. Compared with protracted low-dose temozolomide 1 the one week on/one week off schedule was far less toxic. In addition this dosing schedule may circumvent the disadvantage of an unmethylated MGMT gene promoter by depleting MGMT.

 

Single center phase II trial analysing the role of imatinib/hydroxyurea in patients (pts) with pretreated non-progressive glioblastoma (GBM) as maintenance treatment.

Abstract No: 2055

Citation: Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 2055

Author(s): G. Dresemann, C. Hosius, Z. Nikolova, L. Letvak

Abstract: Background: In GBM the highest malignant brain tumor with a median survival of about 15 months dysregulated signalling of platelet derived growth factor receptors (PDGF-Rs) is implicated in pathogenesis. I/HU showed impressive efficacy and tolerability in patients (pts) with recurrent progressing GBM. In 30 pilot pts with recurrent GBM the progression free survival (PFS) at 6 and 24 months (m) was 32% and 16% respectively. Disease stabilisation (SD) in 37% was an important result. SD for more than 2 years was possible. In GBM a short period of SD after primary or relapse treatment is typical. In this phase II study the efficacy of I/HU as maintenance treatment in pts with GBM in stage of SD was analysed. Methods: From December 2003 up to June 2005 30 GBM pts with documented SD for more than 6 weeks following prior treatment, including surgery, radiotherapy and at least one chemotherapeutic regimen were included,. No enzyme-inducing anticonvulsive drugs were allowed. I dose was 600 mg od, HU dose was 1000 mg (500 mg bid) as continuous oral treatment, pts were followed up by blood cell count weekly and magnetic resonance imaging every 6 weeks. Results: All 30 pts were eligible for safety and for 6, 12 and 18 m PFS and overall survival (OS); 25 pts were male, 5 pts female, median age was 44 years (32 to 71), 24 pts had primary (de novo) and 6 pts secondary GBM. All 30 pts had prior radiotherapy, 21 pts had prior temozolomide and 9 pts non- temozolomide containing regimens. 8 pts were free from relapse, 17 pts after first and 5 pts after second relapse. The median observation time is 28 m. 6, 12 and 18 m PFS was 60% (18/30), 40% (12/30) and 30% (9/30) respectively. 6, 12 and 18 m OS is 90% (27/30), 67% (20/30) and 53% (16/30) so far. PFS for more than 24 m occurred in 3/6 pts with secondary and in 2/24 pts with primary GBM. Toxicity was low (anemia grade 3: 2 pt; grade 2: 4 pts; leucocytopenia grade 3:2 pts; grade 2: 7 pts; thrombocytopenia grade 2: 4 pts), HU dose was reduced in 8 pts, I dose in 1 pt and G-CSF was given in 8 pts, no treatment related death occurred. Conclusion: I (600 mg/d)/ HU (1000 mg/d) was well tolerated in this study. Long-term disease stabilisation was possible - especially in pts with secondary GBM. Confirmation in further investigation is required.

 

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

Abstract No: 2056

Citation: Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 2056

Author(s): F. S. Viola, A. Katz, A. Arantes, A. Gaiger, C. Vasconcellos, V. Passos, C. H. Barrios

Abstract: 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. 

 

 

Phase II study of ifosfamide, carboplatin and etoposide (ICE) in recurrent glioblastoma.

Abstract No: 2066

Citation: Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 2066

Author(s): T. Aoki, K. Nojima, T. Mizutani, M. Ishikawa, A. Takasu, N. Hashimoto

Abstract: Background: To evaluate the efficacy and tolerability of ifosfamide, carboplatin and etoposide ( ICE ) in patients with recurrent glioblastoma. Methods: This was an open-label, single-center phase II trial. Forty-two patients with first recurrent glioblastoma after surgery, standard radiotherapy and a first-line temozolomide-based or ACNU-based chemotherapy, were enrolled.The primary endpoint was progression-free survival at 6 months ( PFS-6 ), and secondary endpoints were response rate, toxicity, and survival. Chemotherapy consisted of Ifosfamide ( 700 mg / m2 on day 1, 2 and 3 ), carbopaltin ( 100 mg / m2 on day 1 ), etoposide ( 70 mg / m2 on day 1, 2, and 3 ), every 6 weeks. Results: PFS-6 was 37 %. The median PFS was 17 weeks. Response rate was 27 %. Adverse events were generally mild ( grade 1 or 2 ) and consisted mainly of alopecia. Conclusions: This regimen is well tolerated and has activity in patients with recurrent glioblastoma.

 

A phase II trial of thalidomide (Thal) and procarbazine (Pro) in adults with recurrent or progressive malignant gliomas (MG).

Abstract No: 2067

Citation: Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 2067

Author(s): G. J. Lesser, V. Stieber, D. Case, G. Enevold, R. Rosdhal, S. Tatter, T. Ellis, K. McMullen, E. Shaw, Wake Forest University Community Clinical OncologyProgram Research Base (WFURB)

Abstract: Background: Thal and Pro are among the few agents with demonstrated activity against MG. A two-stage, phase II trial was initiated within the WFURB to establish the response rate of combination Thal-Pro in patients (pts) with recurrent or progressive MG. Methods: Eligibility included pt age = 18 with measurable tumor on contrast enhanced brain scans; KPS = 60; normal liver, kidney and hematologic function; and treatment with = 2 prior regimens. Pts were required to participate in the S.T.E.P.S. Program and mandated to comply with agreed upon measures to avoid conception. Protocol therapy included Pro 250mg/m2/d x 5d q 28days and Thal 200mg/day continuously. Intrapatient dose escalation of Thal was attempted (increase by 100mg/day weekly as tolerated) to a maximum of 800mg/day. All pts received daily pyridoxine(100mg), warfarin(1mg) and stool softeners/laxatives. MRI/CT scans were performed prior to each odd cycle (every 8 weeks) to assess response based upon changes in the products of the largest bidimensional tumor diameters. Quality of life questionnaires including the FACT-Br were performed at baseline and prior to each odd cycle in all treated pts. Results: 18 pts (11 male) were enrolled (median age 50, range 27-63). One pt refused any therapy and is excluded from the analysis. The 17 treated pts received 36 cycles (median 2) of therapy. The median maximum Thal dose achieved was 400mg (range 200-800). No complete or partial responses were seen; 1 pt (6%) experienced stable disease, 14 (82%) progressed as best response and 2 (12%) were not evaluable for response. Median time to progression was 2.1 months (95% CI, 1.5-2.5). 14 pts have died; median survival was 7.6 months (95% CI, 3.5-9.4). Grade 3/4 drug related toxicity was minimal. Conclusions: Despite modest individual response rates in multiple prior phase II and III trials, the combination of Pro and Thal demonstrated no efficacy in this trial and this combination is unworthy of further investigation in pts with MG. Supported by NCI 1 U10 CA81851 and Celgene.

 

Irinotecan and bevacizumab in progressive primary brain tumors: The Cleveland Clinic experience.

Abstract No: 2077

Citation: Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 2077

Author(s): T. Kang, T. Jin, D. Peereboom

Abstract: Background: High-grade gliomas are generally resistant to modern chemotherapy. In the case of glioblastoma multiforme, median overall survival has been less than 12 months and progression free survival of less than 4 months. For patients with recurrent GBMs, the 6 month progression free survival is 15-20%. The combination of irinotecan and bevacizumab is an active regimen in the treatment of this disease. Herein we report the experiences with this regimen at our institution with the objective of identifying a therapy with a better outcome than historical results. Methods: Single institutional, retrospective review of 27 patients with recurrent or progressive high grade gliomas treated at the Cleveland Clinic Brain Tumor Institute from 7/2005 through 10/2006. Patients had progressed on at least one prior chemotherapy. Patients with prior irinotecan or bevacizumab were excluded. Patients were analyzed on an intention-to-treat basis, and outcomes estimated by the Kaplan-Meier method. Results: The median age of the group was 46 years (range 5-69). The median number of prior therapies was 2 (range 1-10). Twenty of 27 patients have progressed (74%), and 11 of 27 patients have died (41%). Kaplan-Meier estimates for outcomes are summarized in the table. Progression-free survival at 6 months is 46 %, with median of 5.1 months. Overall survival at 6 months is 84%, with median of 12.6 months. In 7 patients, treatment was terminated early prior to progression. Significant toxicities include: one patient who developed hematuria, one patient with deep venous thrombosis and one patient who experienced intracranial hemorrhage. Conclusions: Our experience suggests that the combination of irinotecan and bevacizumab improves the 6-month progression-free survival when compared to historical figures. The rate of severe toxicities is consistent with prior reports and mandates careful selection of patients. Further randomized, phase 3 studies should be done to validate these results.

6 Month Kaplan Meier Estimates .

	n	%	SE	Median (months)
Progression-Free Survival	11	46	9.8	5.1
Overall Survival	19	84	7.4	12.6
n = number of patients, SE= standard error

 

 

Bevacizumab and irinotecan in patients (pts) with recurrent glioblastoma multiforme (GBM).

Abstract No: 2078

Citation: Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 2078

Author(s): S. Raval, S. Hwang, L. Dorsett

Abstract: Background: Primary GBM exhibits overexpression or amplification of the epidermal growth factor gene. The effectiveness of bevacizumab and irinotecan in pts with relapsed GBM was first reported in 2005 (Stark-Vance, et al, Neuro-Oncol, 2005). In this report, we assess the effects of combination of bevacizumab and irinotecan on overall responses, toxicity, cognitive function and functional status in recurrent GBM pts. Methods: From August 2005 to December 2006, 22 consecutive GBM pts failed > 1 prior chemotherapy with measurable disease on MRI were included. Each patient received bevacizumab 5mg/kg IV and irinotecan 125mg/m2 IV infusion every 2 weeks until disease progression or developed unacceptable toxicity. The response was determined by MRI every 2 cycles. Cognitive function was assessed by Blessed Orientation-Memory-Concentration Test (BOMC) and functional status was assessed by Karnofsky performance status (KPS), Barthel Index (BI) and Instrumental Activities of Daily Living (IADL) prior to each cycle of treatment. Descriptive statistics analysis was used. Results: All pts failed temozolomide and radiation therapy; 1 pt had prior BCNU and 2 pts had prior irinotecan treatment. The median (M) age was 55 years (37-77) with pre treatment M KPS 80 (40-80), BOMC 7 (0-28), BI 85 (10-100) and IADL 6 (0-17); 12 pts exhibited mild (3 pts), moderate (7 pts) to severe (2 pts) cognitive impairment. The M number of cycles received was 8 (2-27); 21 pts are evaluable for MRI responses with 95.2% response rate (2CR's + 14PR's + 4 minimal responses). Seven pts have expired; the M length of survival was 4.6 months (range 1.1-15.4+) and the M time to progression was 3 months (0.5-13.8+). There were only two grade 3 thrombocytopenia and one grade 3 neutropenia. Improvement in BOMC score was seen in 15 pts (62%) with M improvement of 7 point. Improvement in functional status was seen in 18 pts (85.7%) with M improvement in KPS by 10 point, BI by 8 points and IADL by 2 point. Conclusions: The combination of bevacizumab and irinotecan is well tolerated and safe. The overall response rate was 95.2% and significant improvements in cognitive functional and functional status were demonstrated. The longer follow up will determine the impact of this most active combination.

 

Reirradiation and chemotherapy with ifosfamide, carboplatin and etoposide (ICE) for recurrent multiforme glioblastoma. 

Abstract No: 12508

Citation: Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 12508

Author(s): A. Rodica Maricela, L. N. Minea, L. Oprea, T. Georgescu, I. Isacu, A. Tarlea, X. Bacinschi

Abstract: Background:

Despite different treatment options no standard treatment regimen is yet available for patient with recurrent glioblastoma, and the prognosis remain poor. In our study our aim was to assess the efficacy of a schedule consisted in Ifosfamide plus Carboplatine plus Etoposide in recurrent multiform glioblastoma patients.

Methods:

Between January 2002 - December 2006 32 patients have been treated for recurrent glioblastoma multiforme. They were 18 male and 14 female, with median age 44.6 years old (range 22-65 years old). The ECOG was 0-1-2 , 12/14/6 patients respectively. 15 of them received chronic corticotherapy. All patients were previously irradiated and they have inoperable recurrences. After the confirmation of recurrence 30 of them could be reirradiated with 30 Gy using conformal beam radiotherapy on the tumor bed. Three weeks after completion of radiotherapy they receive six cycles of chemotherapy consisted in Ifosfamide 1000 mg/sqm day 1-3 + Carboplatin 75 mg/sqm day 1-3 + Etoposide 75 mg/sqm day 1-3 every 4 weeks, according to hematological tolerance.

Results: Reirradiation associated with ICE chemotherapy resulted in one complete remission, three partial remission, and 8 stable disease. All responders were 37.5%. 26 patients survived at least six month and 22 of them received all six cycles. One year survival rate was 21.8%. Progression-free survival at six month was 31.25%. The regimen was well tolerated with mild toxicities. Haematological toxicity gr.I-II 8 pts, gr.III-IV 3 pt; nonhaematological toxicity: fatigability gr.I-II 12 pts., gr.III-IV 2 pt, gr.III-IV 1 pt, nausea gr.I-II 9 pts, gr.III-IV 4 pt, renal toxicity grade I-II 3 patients, Neurological toxicity grade I-II 5 patients.

Conclusions:

The treatment scheme has been well tolerated. Results are similar with PCV regimen, even slightly better. This regimen should be reconsider for concomitant radiochemotherapy.

 

Results of a phase IIb study in recurrent or refractory glioblastoma patients with the TGF-beta-2 inhibitor AP 12009. 

Abstract No: 12521

Citation: Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 12521

Author(s): P. Hau, U. Bogdahn, V. E. Olyushin, A. Mahapatra, V. E. Parfenov, K. Venkataramana, S. Ludwig, P. Jachimczak, H. Heinrichs, K. Schlingensiepen

Abstract: Background: The antisense phosphorothioate oligonucleotide compound AP 12009 targets TGF-beta2. Since TMZ is now used in the adjuvant setting in GBM there is a high need for new treatment options in recurrence. In three Phase I/II dose escalation trials with AP 12009 in high-grade glioma (HGG) patients complete and long lasting tumor responses had been observed.

Methods: The study G004 is an international open-label, randomized, active controlled, dose-finding Phase IIb study. Objective is a comparison of two doses of AP 12009 and standard chemotherapy. A total of 145 patients with histopathologically confirmed recurrent or refractory HGG (WHO Grades III and IV) were randomized into three treatment arms. Patients received treatment with low dose AP 12009 (10 µM), high dose AP 12009 (80 µMM), or standard chemotherapy TMZ or PCV. AP 12009 was applied by convection-enhanced delivery during using 7-day-on, 7-day-off cycles. Maximum number of cycles was 11.

Results: Here we report on patients with recurrent or refractory glioblastoma (GBM, WHO Grade IV; AA patients see separate abstract). Out of 95 GBM patients treated, 28 pts received 10 µM AP 12009, 34 pts AP 12009 80 µM, and 33 pts standard chemotherapy (28 TMZ, 5 PCV). Median age differed between treatment groups (see table). Dose finding was achieved, as efficacy and safety results for the AP-10 group were superior to those of the AP-80 group (see table). Comparable hazard ratios for survival were seen in the three treatment groups (see table). Long lasting responses were observed in both AP 12009 groups.

Conclusions: The safety profile of AP 12009 in GBM patients was good. The durable responses in both AP 12009 groups and the survival data confirm the proof of concept obtained in Phase I/II trials for treatment of recurrent GBM patients with AP 12009.

Prognostic Factors, Safety and Survival data 

Treatment group	AP 12009 10 µM (AP-10)	AP 12009 80 µM (AP-80)	Control (TMZ or PCV)
Median age [years]	57.0	45.0	52.0
SAEs drug related	3	7	1
18-months survival [%]	21	24	18
Comparison between treatment groups	AP-10 vs. Control	AP-80 vs. Control	AP-10 vs. AP-80
Hazard Ratio of survival (95 % CI)	0.9 (0.7 - 1.3)	1.0 (0.6 - 1.6)	1.0 (0.6 - 1.7)
Hazard Ratio of survival - age adjusted (95 % CI)	1.0 (0.7 - 1.3)	0.9 (0.5 - 1.5)	1.3 (0.7 - 2.5)