Lomustine Arm Research Articles

CTNI-68. UPDATES ON A POTENTIALLY PIVOTAL TRIAL CNS-201: A RANDOMIZED, CONTROLLED TRIAL OF BERUBICIN VS. LOMUSTINE AFTER FIRST-LINE THERAPY FOR GLIOBLASTOMA MULTIFORME (GBM)

Abstract Berubicin, derived from doxorubicin (Dox), appears to cross the BBB and has shown significant central nervous system (CNS) uptake and anti-tumor activity. A current, potentially pivotal trial for patients with recurrent GBM after first-line therapy has completed enrollment in the US and Europe: a total of 252 patients were randomized 2:1 (Berubicin:Lomustine) after failure of prior therapy. All patients had to have certification of progression by a central reader, were Grade 4 IDH WT, and were stratified by MGMT methylation status. The primary endpoint, overall survival (OS), is maturing in this blinded trial; however, data will be presented that will document the demographics of the Berubicin and Lomustine arms, and provide a comparison of safety profiles and disposition of the patients enrolled on the study. Recently, a pre-planned non-binding futility analysis of the primary endpoint, OS, was evaluated when the trial reached ~30% of expected events (44 events). This interim analysis was performed by an independent statistician under the supervision of the Data Safety Monitoring Board (DSMB), which was additionally comprised of two oncologists. The DSMB’s charter mandated that they review the primary endpoint, OS, as well as secondary endpoints and safety data to determine whether these data for the risk-benefit profile warranted modification or discontinuation of the study. The DSMB recommended that the study continue as it was currently planned, with no modifications required, having met a pre-determined conditional endpoint. After the results of this interim analysis, CNS Pharmaceuticals completed enrollment with 252 patients evaluable for efficacy based on OS evaluations. Based on the decision of the DSMB, as well as the data presented herein, which includes comparative safety and balanced randomization of the arms, we will provide our recommendations and highlight our further development of Berubicin as a therapeutic option for patients with recurrent GBM as well as other CNS malignancies.

CTNI-35. A RANDOMIZED, CONTROLLED TRIAL OF BERUBICIN VS. LOMUSTINE AFTER FIRST-LINE THERAPY FOR GLIOBLASTOMA MULTIFORME (GBM): INTERIM RESULTS OF A PRE-PLANNED ANALYSIS OF OVERALL SURVIVAL (OS)

Abstract Berubicin is an analog of doxorubicin (Dox) that appears to cross the BBB with significant central nervous system (CNS) uptake. RESULTS: of a Phase 1 dose-escalation study with 25 patients evaluable for efficacy showed 1 complete response (14+ years), 1 partial response durable for 12 weeks, and 9 patients with stable disease for a clinical benefit rate of 44%. Our current, potentially pivotal trial for patients with recurrent GBM after first-line therapy is enrolling in the US and Europe. It is unique in that all patients must be Grade 4 IDH WT, classifying these tumors as a poorer prognostic population than Grade 4 IDH mutated. Patients are randomized in a 2:1 design of Berubicin:Lomustine and stratified by MGMT methylation status. The primary endpoint is OS. Data has been presented showing that Berubicin and Lomustine arms are balanced with respect to MGMT status and demographics, with relatively comparable safety profiles (SNO Annual Meeting 2022 Abstract #383142). A pre-planned non-binding futlity analysis of the primary endpoint, OS, is being evaluated when the trial reaches ~30% of expected events (44 events). The interim analysis will be performed by an independent statistician under the supervision of the Data Safety Monitoring Board (DSMB). The futility analysis will be based on the conditional power that the trial will be positive (e.g., statistically significant difference between treatment groups’ OS). If the conditional power is <10% then the DSMB may recommend to end the study; otherwise the study will continue as it is currently planned. The review will also include safety and secondary efficacy endpoint summaries. RESULTS: of this interim analysis will be available for the SNO annual meeting and an evaluation of its outcome will be performed, with conclusions and recommendations for the further development of Berubicin as a therapeutic option for patients with recurrent GBM.

TIPS-20 A RANDOMIZED, CONTROLLED TRIAL OF BERUBICIN, A TOPOISOMERASE II POISON THAT APPEARS TO CROSS THE BLOOD-BRAIN BARRIER (BBB), AFTER FIRST-LINE THERAPY FOR GLIOBLASTOMA MULTIFORME (GBM): PRELIMINARY RESULTS

Abstract Berubicin is a doxorubicin (Dox) analog that appears to cross the BBB with significant central nervous system (CNS) uptake. Berubicin prolongs survival in orthotopic mouse intracranial models with greater infiltration of the tumor compared to normal tissue. A Phase 1 dose-escalation study showed myelosuppression as the dose-limiting toxicity, with 1 complete response (14+ years), 1 partial response durable for 12 weeks, and 9 patients with stable disease for a clinical benefit rate of 44%. A trial of Berubicin vs Lomustine in patients with recurrent GBM after first-line therapy in the US and Europe is enrolling patients in a 2:1 randomization design of Berubicin:Lomustine. Patients will be stratified by MGMT methylation status. The primary endpoint is overall survival (OS). A pre-planned, non-binding futility analysis will be performed after approximately 30 to 50% of all planned patients have reached the primary endpoint. Currently, 97 patients are enrolled with 65 in the Berubicin arm and 32 in the Lomustine arm. At present these patients show comparable demographics, with an unmethylated MGMT population of ~60% in both arms. Patients with all grades of adverse events were 80% and 69% on the Berubicin and Lomustine arms, respectively. Grade 3-4 events were 43% (Berubicin arm) and 38% (Lomustine arm), although less than or equal to 5% of patients discontinued the study due to these events. The data available shows that Berubicin and Lomustine arms are presently balanced with relatively comparable safety profiles. The study is continuing to evaluate the efficacy of this novel drug candidate and potentially provide therapeutic options for patients after first-line therapy. An updated profile of the patient population, safety, and initial efficacy will be presented.

CTNI-52. A RANDOMIZED CONTROLLED TRIAL OF BERUBICIN, A DOXORUBICIN ANALOG THAT EFFECTIVELY CROSSES THE BLOOD-BRAIN BARRIER (BBB), AFTER FIRST-LINE THERAPY FOR GLIOBLASTOMA MULTIFORME (GBM): PRELIMINARY RESULTS

Abstract Berubicin is a doxorubicin (Dox) analog that crosses the BBB with significant central nervous system (CNS) uptake. Berubicin prolongs survival in orthotopic mouse intracranial models with greater infiltration of the tumor compared to normal tissue. A Phase 1 dose-escalation study showed myelosuppression as the dose-limiting toxicity, with 1 complete response (14+ years), 1 partial response durable for 12 weeks, and 9 patients with stable disease for a clinical benefit rate of 44%.A trial of Berubicin vs Lomustine in patients with recurrent GBM after first-line therapy in the US and EU is enrolling patients in a 2:1 randomization design of Berubicin:Lomustine. Patients will be stratified by MGMT methylation status. The primary endpoint is overall survival (OS) and secondary endpoints include progression-free survival and overall response rates. Advanced imaging technology is being utilized for consistency in the evaluation of MRI scans. An interim futility analysis to explore the relative efficacy of these drugs will be conducted after up to half of the patients enrolled have reached 6 months of therapy. Currently, 31 patients are enrolled with 21 in the Berubicin arm and 10 in the Lomustine arm. At present these patients show comparable demographics, with an unmethylated MGMT population of ~60% in both arms. Patients with all grades of adverse events were 57% and 60% on the Berubicin and Lomustine arms, respectively. Grade 3-4 events were 43% (Berubicin arm) and 30% (Lomustine arm). Less than 10% of patients discontinued the study due to adverse events.The available data to date shows that Berubicin and Lomustine arms are presently balanced with relatively comparable safety profiles. This study is continuing to evaluate the efficacy of this novel drug with the goal of providing therapeutic options for patients after first-line therapy. An updated patient population profile, safety, and initial efficacy will be presented.

Addition of Lomustine in the Treatment of Elderly Patients with Acute Myeloblastic Leukemia Improves Survival with Acceptably Increased Infectious Toxicity. a Filo Study

The LAMSA2007 trial of the French collaborative FILO group (Clinicaltrial.gov ID, NCT00590837) demonstrated the improvement of treatment results brought by the addition of lomustine for elderly (60 years old or more) fit patients with acute myeloblastic leukemia. Of 448 patients included, 222 received lomustine. Lomustine (200 mg/m² D1) was added to a standard induction (8mg/m² D1-5 idarubicin, 100 mg/m² D1-7 cytarabine) then to a consolidation schedule (8mg/m² D1-3 idarubicin, 50 mg/m² x2 D1-5 cytarabine subcut. with or without lomustine 80 mg D1) and 6 mini-reinductions (idarubicin 8 mg/m² D1 IV, cytarabine 50 mg/m²/12h D1-D5 with or without lomustine 40 mg D1), followed by a 6-months oral maintenance with 6-mercaptopurine and methotrexate.The risk of adding lomustine was to increase toxicities, mainly because of a prolonged period of neutropenia and therefore an increased risk of infectious deaths. Indeed, neutropenia lasted longer for patients receiving lomustine at all stages of therapy, from two more days during induction up to five more days during first reinduction. Surrogate markers of infection showed a higher risk for patients receiving lomustine, mainly during the first two courses of chemotherapy (induction and consolidation). During the induction phase (N=424), 358 patients presented with febrile events (50% in each group of treatment) and 265 infections were documented (135 in the lomustine group). Lower infection rates occurred during consolidation: out of 424 patients, 127 presented at least 1 fever episode over 38.5°C (79 in the lomustine group and 48 in patients without lomustine) and 103 were microbiologically documented (67 in patients receiving lomustine and 36 in patients without). The median number of days with at least two intravenous antibiotics was significantly higher for lomustine-receiving patients (median 19 days [range 0-98] versus 17 days [range 0-46] p=0.005 at induction; 3 days [range 0-49] versus 0 days [range 0-25] p<0.0001 at consolidation). The median duration of fever over 38.5°C was also significantly longer during consolidation (1 day [range 0-16] versus 0 [range 0-8], p = 0.0002) but not during induction (3 days in both groups, [range 0-44] for patients receiving lomustine and [0-24] for patients without lomustine). There was no statistical difference in the median days of treatment with anti-fungal drugs (14 days [range 0-98] vs. 13 days [range 0-56]) neither at induction nor during consolidation (0 days in both groups, ranges 0-50 and 0-65).These infectious episodes were however related neither to severity nor mortality: 16 patients (9 receiving lomustine and 7 without) died because of infections during the induction phase and 8 patients deceased from infections during the consolidation period (5 in the lomustine group). Regarding severity, 25 patients suffered from a septic shock (15 in the lomustine group), but only 9 patients died from that complication (6 in the lomustine group). During the consolidation phase, 17 patients presented a septic shock (11 while on lomustine, but only 3 deceased, and 6 without lomustine, and only one was fatal).As for microbiological documentation, the most frequent pathogens (Aspergillus, Candida, Staphylococcus, Enterobacteries, Pseudomonas) had a similar incidence in both arms. Interestingly, only Staphyloccus (25 vs 15 at induction and 27 vs 17 at consolidation) and Streptococcus (15 vs 6 at induction and 7 vs none at consolidation) seemed to be more frequent in the lomustine arm, yet without statistical significance. Infections from Enterobacter were surprisingly more frequent in the control arm at induction (36 vs 45, NS) yet more frequent in the lomustine arm at consolidation (31 vs 16, p=0.02).During the 6 mini-reinductions, less infections occurred (18 during R1, 7 in R2, 12 in R3, 5 in R4, 6 in R5 and 8 in R6), with no treatment-related death.In this trial, lomustine significantly improved the rate of complete remission after 1 cycle (75% vs 85% p= 0.01) as well as event-free survival (47% [39 - 54] vs 29% [22 - 37; p= 0.02]). We therefore keep recommending its association with standard chemotherapy in AML elderly patients, yet propose to abandon the consolidation phase because of increased toxicity. DisclosuresGuieze:GILEAD: Other: Educational Presentation; JANSSEN: Other: Educational Presentation; ABBVIE: Other: Educational Presentation. Ianotto:Novartis: Other: Grant. Jourdan:NOVARTIS: Consultancy, Honoraria. Recher:Novartis, Celgene, Jazz, Sunesis, Amgen: Consultancy; Celgene, Sunesis, Amgen, Novartis: Research Funding.

A molecular signature associated with prolonged survival in glioblastoma patients treated with regorafenib.

Patients with glioblastoma (GBM) have a dramatically poor prognosis. The recent REGOMA trial suggested an overall survival (OS) benefit of regorafenib in recurrent GBM patients. Considering the extreme genetic heterogeneity of GBMs, we aimed to identify molecular biomarkers predictive of differential response to the drug. Total RNA was extracted from tumor samples of patients enrolled in the REGOMA trial. Genome-wide transcriptome and micro (mi)RNA profiles were associated with patients' OS and progression-free survival. In the first step, a set of 11 gene transcripts (HIF1A, CTSK, SLC2A1, KLHL12, CDKN1A, CA12, WDR1, CD53, CBR4, NIFK-AS1, RAB30-DT) and 10 miRNAs (miR-93-5p, miR-203a-3p, miR-17-5p, let-7c-3p, miR-101-3p, miR-3607-3p, miR-6516-3p, miR-301a-3p, miR-23b-3p, miR-222-3p) was filtered by comparing survival between regorafenib and lomustine arms. In the second step, a mini-signature of 2 gene transcripts (HIF1A, CDKN1A) and 3 miRNAs (miR-3607-3p, miR-301a-3p, miR-93-5p) identified a subgroup of patients showing prolonged survival after regorafenib administration (median OS range, 10.6-20.8 mo). The study provides evidence that a signature based on the expression of 5 biomarkers could help identify a subgroup of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Although the presented results must be confirmed in larger replication cohorts, the study highlights potential biomarker options to help guide the clinical decision among regorafenib and other treatments in patients with relapsing GBM.

394O - Health-related quality of life (HRQoL) evaluation in the REGOMA trial: A randomized, phase II clinical trial analyzing regorafenib activity in relapsed glioblastoma patients

BackgroundREGOMA trial showed that regorafenib (REG) significantly improved OS and PFS in patients (pts) with relapsed GBM with respect to lomustine (LOM). REG showed a different toxicity profile compared to LOM. Here, we report final results of the HRQoL assessment, a secondary end point. MethodsHRQoL was measured using the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and brain module (QLQ-BN20) administered before any MRI assessments, every 8 weeks (+/- 2 weeks) until disease progression. To evaluate treatment impact on HRQoL, questionnaires at progression were excluded. Mixed-effect linear models were fitted for each of the HRQOL domain to examine the change over progression-free time within and between arms. The models included the time of questionnaire assessment, the treatment group and their interaction, as fixed effects, and a compound symmetry covariance structure for the random effects. Differences of at least 10 points were classified as a clinically meaningful change. To correct for multiple comparisons and to avoid type I error, the level of significance was set at P=0.01 (2-sided). ResultsOf 119 randomized pts, 117 participated in the HRQoL evaluation, and 114 had a baseline assessment (n=56 REG; n=58 LOM).No statistically significant differences were observed in any generic or cancer specific domain during treatment in the REG and LOM arms, or between the two arms, except for the appetite loss scale which was significantly worse in PTS treated with REG (Global mean 14.7 (SD=28.6) vs 7.6 (SD=16.0); p=0.0081). The rate of pts with a clinically meaningful worsening for appetite loss was not statistically different between the two arms (9 out of 24 and 0 out of 13 in the REG and LOM arm, respectively; p=0.02). ConclusionsIn the REGOMA trial, HRQoL did not change during regorafenib treatment. Pts treated with regorafenib and lomustine reported no significant difference in HRQoL. Legal entity responsible for the studyGiuseppe Lombardi. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

OS7.3 Health-related quality of life (HRQoL) evaluation in the REGOMA trial: a randomized, phase II clinical trial analyzing regorafenib activity in relapsed glioblastoma patients

Abstract BACKGROUND REGOMA trial showed that regorafenib (REG) significantly improved OS and PFS in patients (pts) with relapsed GBM with respect to lomustine (LOM). REG showed a different toxicity profile compared to LOM. Here, we report final results of the HRQoL assessment, a secondary end point. MATERIAL AND METHODS HRQoL was measured using the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and brain module (QLQ-BN20) administered before any MRI assessments, every 8 weeks (+/- 2 weeks) until disease progression. To evaluate treatment impact on HRQoL, questionnaires at progression were excluded. Mixed-effect linear models were fitted for each of the HRQOL domain to examine the change over progression-free time within and between arms. The models included the time of questionnaire assessment, the treatment group and their interaction, as fixed effects, and a compound symmetry covariance structure for the random effects. Differences of at least 10 points were classified as a clinically meaningful change. To correct for multiple comparisons and to avoid type I error, the level of significance was set at P=0.01 (2-sided). RESULTS Of 119 randomized pts, 117 partecipated in the HRQoL evaluation, and 114 had a baseline assessment (n=56 REG; n=58 LOM). No statistically significant differences were observed in any generic or cancer specific domain during treatment in the REG and LOM arms, or between the two arms, except for the appetite loss scale which was significantly worse in PTS treated with REG (Global mean 14.7 (SD=28.6) vs 7.6 (SD=16.0); p=0.0081). The rate of pts with a clinically meaningful worsening for appetite loss was not statistically different between the two arms (9 out of 24 and 0 out of 13 in the REG and LOM arm, respectively;p=0.02). CONCLUSION In the REGOMA trial, HRQoL did not change during regorafenib treatment. Pts treated with regorafenib and lomustine reported no significant difference in HRQoL.

Health-related quality of life (HRQoL) evaluation in the REGOMA trial: A randomized, phase II clinical trial analyzing regorafenib activity in relapsed glioblastoma patients.

2045 Background: REGOMA trial showed that regorafenib (REG) significantly improved OS and PFS in relapsed glioblastoma (GBM) patients (pts) with respect to lomustine (LOM). REG showed a different toxicity profile compared to LOM. Here, we report final results of the HRQoL assessment, a secondary end point. Methods: HRQoL was measured using the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and brain module (QLQ-BN20) administered before any MRI assessments, every 8 weeks (+/- 2 weeks) until disease progression. To evaluate treatment impact on HRQoL, questionnaires at progression were excluded. Mixed-effect linear models were fitted for each of the HRQOL domain to examine the change over progression-free time within and between arms. The models included the time of questionnaire assessment, the treatment group and their interaction, as fixed effects, and a compound symmetry covariance structure for the random effects. Differences of at least 10 points were classified as a clinically meaningful change. To correct for multiple comparisons and to avoid type I error, the level of significance was set at P = 0.01 (2-sided). Results: Of 119 randomized pts, 117 participated in the HRQoL evaluation, and 114 had a baseline assessment (n = 56 REG; n = 58 LOM). No statistically significant differences were observed in any generic or cancer specific domain during treatment in the REG and LOM arms, or between the two arms, except for the appetite loss scale which was significantly worse in PTS treated with REG (Global mean 14.7 (SD = 28.6) vs 7.6 (SD = 16.0); p = 0.0081). The proportion of pts with a clinically meaningful worsening for appetite loss was not statistically different between the two arms (9 out of 24 and 0 out of 13 in the REG and LOM arm, respectively; p = 0.0146). Conclusions: In the REGOMA trial, HRQoL did not change during REG treatment. Pts treated with REG and LOM reported no significant difference in HRQoL. Clinical trial information: NCT02926222. [Table: see text]

Abstract CT136: STELLAR: A phase 3, randomized, open-label study to evaluate the efficacy and safety of eflornithine with lomustine compared to lomustine alone in patients with anaplastic astrocytoma that progress/recur after irradiation and adjuvant temozolomide chemotherapy

Abstract Background: Eflornithine, a novel cytostatic agent, irreversibly inhibits ornithine decarboxylase, the enzyme that catalyzes the first step in the biosynthesis of putrescine that, in conjunction with, spermidine and spermine, constitute the major polyamines of mammalian cells. More than 390 patients with high-grade gliomas have been treated with eflornithine alone or in combination with a nitrosourea or PCV (procarbazine, lomustine, and vincristine) in prior US clinical trials. In a Phase 3 randomized study of adjuvant PCV compared to PCV plus eflornithine in a total of 228 evaluable patients with anaplastic glioma (AG), overall survival (OS) was improved from a median of 61.1 months for patients on PCV to 75.8 months for patients on PCV plus eflornithine (Levin, et al., 2003). The objective of the STELLAR study (NCT02796261) is to evaluate the efficacy and safety of eflornithine with lomustine vs. lomustine in patients with anaplastic astrocytoma (AA; WHO Grade 3 glioma) who progressed/recurred after surgery, irradiation and adjuvant temozolomide chemotherapy. Methods: To be eligible for STELLAR, patients must have histologically proven AA with unequivocal evidence of first AA tumor progression or recurrence ≤ 3 months prior to randomization following surgical resection or biopsy, irradiation and temozolomide chemotherapy. Radiation therapy must have been completed ≥ 6 months prior to randomization and KPS &amp;gt; 70 is required. Approximately 280 patients will be randomized 1:1 and stratified per age (≤ 45 yrs vs &amp;gt; 45 yrs), US vs Ex-US, IDH1 status (wild type vs mutant), and number of prior surgeries (biopsy only vs 1 or 2 surgical resections). Patients will receive either eflornithine 2.8 g/m2 administered orally every 8 hours on a 2 week on, 1 week off schedule, and lomustine 110 mg/m2 administered orally once every 6 weeks, or lomustine alone dosed at 110 mg/m2 administered orally once every 6 weeks. In both arms, lomustine will be limited to a maximum of 6 cycles or 12 months of therapy. in the combination arm, eflornithine therapy can be given up to 24 months. Radiologic tumor assessment will be performed per institutional standard of care. The primary endpoint will be overall survival (OS). Secondary objectives include progression free survival (PFS) and objective response rate (ORR). The study sample size was calculated by assuming true median OS of 12 months for the treatment arm receiving lomustine monotherapy. It is hypothesized true median OS will be at least 18 months for the eflornithine plus lomustine arm. Under the assumption that OS follows an exponential probability distribution for each treatment arm, such an improvement represents a true hazard ratio of 0.667 (investigational arm/control arm). Inferential comparisons of OS will be performed using a stratified log-rank test, stratifying on the randomization stratification factors. Total accrual of approximately 274 patients (137 per treatment arm), and total information of 194 deaths is estimated to provide 80% power to detect a 33% reduction in the OS failure hazard rate. The STELLAR study is currently enrolling patients in the US, Germany and Italy and is anticipated to remain open for enrollment through the first half of 2018. Citation Format: Victor A. Levin, Scott Cruickshank. STELLAR: A phase 3, randomized, open-label study to evaluate the efficacy and safety of eflornithine with lomustine compared to lomustine alone in patients with anaplastic astrocytoma that progress/recur after irradiation and adjuvant temozolomide chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT136. doi:10.1158/1538-7445.AM2017-CT136

STELLAR: A phase 3, randomized, open-label study of eflornithine with lomustine vs lomustine for patients with first recurrence of anaplastic astrocytoma after RT and adjuvant temozolomide.

TPS2081 Background: Eflornithine irreversibly inhibits ornithine decarboxylase an enzyme that catalyzes the biosynthesis of putrescine, one of 3 polyamines in mammalian cells. Over 390 patients with anaplastic gliomas (AG) received eflornithine alone, with a nitrosourea, or the PCV combination in past clinical trials. A phase 3 randomized study of adjuvant chemotherapy with PCV vs eflornithine-PCV in 228 patients with AG found a median overall survival (mOS) increase from 61.1 to 75.8 months in the eflornithine-PCV arm. Methods: Patients must have histologically proven diagnosis of WHO grade 3 anaplastic astrocytoma (AA) with unequivocal evidence of first AA tumor progression or recurrence ≤ 3 months prior to randomization following surgical resection or biopsy, RT and temozolomide chemotherapy. Patients must have RT ≥ 6 months prior to randomization and have a KPS of ≥ 70. Randomization of 280 patients will be 1:1 with stratification to: Age (≤ 45 yrs, &gt; 45 yrs), region (US, Ex-US), IDH1 status (wild, mutant), and prior surgeries (biopsy, 1-2 resections). Patients will receive eflornithine 2.8 g/m2 orally every 8 h on a 2 week on, 1 week off schedule, and lomustine 110 mg/m2 orally once every 6 weeks, or lomustine alone dosed at 110 mg/m2 orally once every 6 weeks. Lomustine will be limited to 6 cycles or 12 months of therapy. Eflornithine can be given up to 24 months in the combination arm. The primary endpoint will be OS. Secondary objectives include PFS and objective response rate (ORR) based on MRI. The study sample size was calculated by assuming true mOS of 12 months for lomustine monotherapy and true mOS of &gt; 18 months for the eflornithine plus lomustine arm. Such an improvement represents a true hazard ratio of 0.667 (investigational arm/control arm). Inferential comparisons of OS will be performed using a stratified log-rank test with 137 patients per arm and total information of 194 deaths with 80% power to detect a 33% reduction in the OS failure hazard rate. The study is open at 55 sites in the USA, Germany and Italy with an additional 10-15 sites being evaluated in 3 additional countries. Study enrollment is expected through 2018. Clinical trial information: NCT02796261.

LB-05PHASE III TRIAL EXPLORING THE COMBINATION OF BEVACIZUMAB AND LOMUSTINE IN PATIENTS WITH FIRST RECURRENCE OF A GLIOBLASTOMA: THE EORTC 26101 TRIAL

LB-05. PHASE III TRIAL EXPLORING THE COMBINATION OF BEVACIZUMAB AND LOMUSTINE IN PATIENTS WITH FIRST RECURRENCE OF A GLIOBLASTOMA: THE EORTC 26101 TRIAL W. Wick1, AA. Brandes2, T. Gorlia3, M. Bendszus1, F. Sahm1, W. Taal4, M. Taphoorn5, J. Domont6, A. Idbaih7, M. Campone8, P.M. Clement9, R. Stupp10, M. Fabbro11, F. Dubois12, C. Bais13, D. Musmeci3, M. Platten1, M. Weller10, V. Golfinopoulos3, and M. van den Bent4; University Medical Center & German Cancer Research Center, Heidelberg, Germany; Medical Oncology Department, AUSL-Bologna-IRCCS Scienze Neurologiche, Bologna, Italia; EORTC Headquarters, Brussels, Belgium; Daniel den Hoed Cancer Center, Rotterdam, The Netherlands; Medical Center Haaglanden, The Hague, The Netherlands The Netherlands; Institut Gustave Roussy, Villejuif, France; AP-HP, Hopital Universitaire La Pitie Salperiere and Sorbonne Universites, UPMC Univ Paris 06, Paris, France; Institut de Cancerologie de l’Ouest (ICO) Centre Rene Gauducheau, Saint-Herblain, France; U.Z. Leuven KU Leuven, Belgium; Zurich University Medical Center, Zurich, Switzerland; Institut regional du Cancer Montpellier, Montpellier, France; CHRU de Lille, Lille, France; Genentech Inc., South San Francisco, California, USA BACKGROUND: Phase II data from the BELOB trial indicated that the combination of bevacizumab and lomustine might produce an overall survival (OS) benefit compared with either monotherapy for patients with first progression of a glioblastoma. The primary objective of the phase III part of EORTC 26101 is to investigate whether the addition of bevacizumab to lomustine improves overall OS in patients with first progression of a glioblastoma compared to treatment with lomustine alone. METHODS: Patients with progressive disease after standard chemo-radiotherapy with temozolomide at least 3 months off the concomitant part were randomized 2:1 between lomustine 90 mg/m (cap. 160 mg) mg every six weeks plus 10 mg/kg bevacizumab every two weeks and lomustine single agent 110 mg/m (cap. 200 mg) every six weeks followed by best investigators choice at further progression. In the absence of hematological toxicity . grade 1 during the first cycle in the combination arms, the dose of lomustine could be escalated to 110 mg/m (cap 200 mg) in the second cycle. Neuroimaging according to a standard protocol was assessed locally and centrally. RESULTS: A total of 437 (288 and 149, respectively) patients were included. Median number of treatment cycles was 1 in the lomustine arm and 3 in the combination arm. With 329 OS events (75.3%) OS was not superior in the combination therapy arm (hazard ratio (HR) 0.95 (confidence interval (CI) 0.74, 1.21), p 1⁄4 0.650, analyses stratified by EORTC online randomization system), whereas locally assessed progression-free survival (PFS) was longer with the addition of bevacizumab to lomustine (HR 0.49 (CI 0.39, 0.61). Median efficacy outcomes were: OS 9.1 (8.1, 10.1) versus 8.6 (7.6, 10.4) months and PFS 4.2 (3.7, 4.3) versus 1.5 (1.5, 2.5) months in the combination arm versus the lomustine arm respectively. Toxicity was in the expected range with more events in the combination arm being also longer on treatment. Crossover to bevacizumab occurred in 35.5% of patients in the control arm; whereas 19% of patients in the combination arm continued bevacizumab at progression. CONCLUSIONS: Bevacizumab treatment in patients with progressive glioblastoma despite prolonged PFS does not confer a survival advantage. The future challenge is to identify those patients deriving benefit from that treatment. Neuro-Oncology 17:v1–v1, 2015. doi:10.1093/neuonc/nov306 Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.

O10.05 * FINAL ANALYSIS OF THE BELOB TRIAL (A RANDOMIZED PHASE II STUDY ON BEVACIZUMAB VERSUS BEVACIZUMAB PLUS LOMUSTINE VERSUS LOMUSTINE SINGLE AGENT IN RECURRENT GLIOBLASTOMA) AND FIRST RADIOLOGY REVIEW RESULTS

INTRODUCTION: Bevacizumab (BEV) is widely used in recurrent glioblastoma, alone or in combination with other agents. There is however no controlled trial to support this use. MATERIAL AND METHODS: In a Dutch multicenter randomized phase II study patients were assigned to BEV 10 mg/kg day 1, 15 and 29 iv, BEV 10 mg/kg day 1, 15 and 29 iv in combination with 110 mg/m2 lomustine orally on day 1, or lomustine 110 mg/m2 orally on day 1, in a 6- weekly schedule . Eligible were patients with histologically proven glioblastoma, first recurrence after chemo-irradiation with temozolomide, having concluded radiotherapy more than 3 months ago, with adequate bone marrow, renal and hepatic function, and WHO performance status (PS) 0-2. Primary endpoint was 9 months overall survival (OS). RESULTS: Between December 2009 and November 2011, 148 eligible patients were enrolled . Median age was 57 years (range, 24-77) and median WHO PS was 1. After a preplanned safety review after the first 8 patients the lomustine dose in the combination arm was reduced to 90 mg/m2, 44 patients were treated at this dose level. 130 patients were evaluable for response. Nine month OS [95% confidence interval] was 43% [29, 57] in the lomustine arm, 38% [25, 51] in the BEV arm, and 59% [43, 72] in the BEV/lomustine 90 arm. Objective response rate (complete or partial response) by local investigator was 5% in the lomustine arm, 38% in the BEV arm and 34% in the BEV/lomustine 90 arm. CONCLUSION: The combination bevacizumab/lomustine warrants further investigation, and is currently investigated in the randomized controlled phase III EORTC trial 26101. At the meeting the analysis based on IDH and MGMT status and the first results on the radiology review, pattern of progression and clinical impact of isolated T2/FLAIR progression will be presented.

Enzastaurin in the Treatment of Recurrent Glioblastoma: A Promise That Did Not Materialize

Enzastaurin in the Treatment of Recurrent Glioblastoma: A Promise That Did Not Materialize

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Purpose: Preclinical studies show that antiangiogenic therapy exacerbates tumor glycolysis and activates liver kinase B1/AMP kinase (AMPK), a pathway involved in the regulation of tumor metabolism. We investigated whether certain metabolism-related in situ biomarkers could predict benefit to regorafenib in the phase II randomized REGOMA trial. Patients and Methods: IHC and digital pathology analysis were used to investigate the expression in glioblastoma (GBM) sections of monocarboxylate transporter 1 and 4 (MCT1 and MCT4), associated with OXPHOS and glycolysis, respectively, phosphorylated AMPK (pAMPK), and phosphorylated acetyl-CoA carboxylase (pACC), a canonical target of AMPK activity. The status of each biomarker was associated with clinical endpoints, including overall survival (OS) and progression-free survival (PFS) in patients with relapsed GBM treated either with regorafenib or lomustine. Results: Between November 2015 and February 2017, 119 patients were enrolled (n = 59 regorafenib and n = 60 lomustine) and stratified for surgery at recurrence, and baseline characteristics were balanced. Biomarker analysis was performed in 84 patients (71%), including 42 patients of the regorafenib arm and 42 patients of the lomustine arm. Among all markers analyzed, only pACC showed predictive value in terms of OS. In fact, median OS was 9.3 months [95% confidence interval (CI), 5.6–13.2] for regorafenib and 5.5 months (95% CI, 4.2–6.6) for lomustine for pACC-positive patients, HR, 0.37 (95% CI, 0.20–0.70); log rank P = 0.0013; test for interaction = 0.0453. No statistically significant difference was demonstrated for PFS according to pACC status. Conclusions: We found that AMPK pathway activation is associated with clinical benefit from treatment with regorafenib in relapsed GBM.