MGMT-unmethylated Glioblastoma Patients Research Articles

Abstract CT125: A phase 0/2 ‘trigger’ trial of pamiparib or olaparib plus radiotherapy in patients with newly-diagnosed or recurrent glioblastoma

Abstract Background: This Phase 0/2 clinical trial evaluates the pharmacokinetic (PK), pharmacodynamic (PD), and clinical response of newly-diagnosed and recurrent glioblastoma (GBM) patients to the PARP1/2 selective inhibitors, pamiparib and olaparib, in combination with radiotherapy. Materials/Methods: In this study, newly-diagnosed (Arm A) and recurrent GBM (Arm B) patients received 4 days of pamiparib (60 mg BID) prior to planned resection at 2-4 or 8-12 hours following the final dose. Arm C included recurrent GBM patients who received 4 days of olaparib (200 mg BID) prior to resection. In the Phase 0 component of the study total and unbound drug concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’, defined as unbound drug > 5-fold biochemical IC50 in Gd-nonenhancing tumor, determined eligibility for Phase 2. PARP inhibition was assessed via ex vivo tumor tissue radiation and quantification of PAR levels compared to non-irradiated control. When demonstrating a PK response, newly-diagnosed, MGMT-unmethylated GBM or recurrent GBM patients were eligible for Phase 2 dosing of pamiparib (Arms A and B) or olaparib (Arm C) with concurrent RT followed by maintenance pamiparib or olaparib. Results: A total of 41 patients (Arm A, n=16; Arm B, n=19; Arm C, n=6) were enrolled in the Phase 0 component of the study. In Arms A and B, mean unbound concentrations of pamiparib in Gd-nonenhancing tumor were 167.3 nM and 104.3 nM respectively, and in Arm C the mean unbound concentration of olaparib was 5.2 nM. All patients in the pamiparib arms (n=35) but only 1 of 6 patients in the olaparib Arm C exceeded the PK threshold. Radiation-induced PAR expression was 2.44-fold in untreated control vs 1.16 in Arm A (p<0.05), 0.82 in Arm B (p<0.01) and 1.11 in Arm C patients. In Arm A, 7 of 11 MGMT-unmethylated GBM patients advanced to Phase 2. Two patients were ineligible due to clinical status, 1 patient was ineligible per physician decision, and 1 patient declined to participate. In Arm B, 11 of 19 patients advanced to Phase 2. Eight patients were ineligible due to clinical status. At a mean follow-up of 5.8 months, median progression-free survival (PFS) was 5.8, 6.0, and 3.8 months for Arms A (n=7), B (n=11), and C (n=1), respectively. Grade 3+ toxicities related to pamiparib occurred in 4 patients, with 2 adverse events resulted in treatment discontinuation. No grade 3+ toxicities were documented in the olaparib arm. Conclusions: Pamiparib achieved pharmacologically-relevant concentrations in Gd-nonenhancing GBM tissue and suppressed induction of PAR levels ex vivo post-radiation. The majority of newly-diagnosed patients with MGMT-unmethylated GBM and recurrent GBM patients advanced to therapeutic dosing in this trial, and pamiparib was generally well-tolerated in these patients. Citation Format: Nader Sanai, Yu-Wei Chang, Jun Jiang, Jennifer Molloy, Chelsea Pennington-Krygier, Jocelyn Harmon, Amy Hong, John Wanebo, William Kennedy, Michael Garcia, Igor Barani, Wonsuk Yoo, Artak Tovmasyan, An-Chi Tien, Jing Li, Shwetal Mehta. A phase 0/2 ‘trigger’ trial of pamiparib or olaparib plus radiotherapy in patients with newly-diagnosed or recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT125.

Abstract CT044: A phase 0/1b study of AZD1390 plus radiotherapy in newly-diagnosed, MGMT-unmethylated glioblastoma patients

Abstract Background: ATM inhibition has been hypothesized to potentiate the effects of radiation by preventing acute phase DNA damage repair, and a Phase 1 trial of this combination in patients with GBM is ongoing (NCT03423628). To test this hypothesis, this Phase 0/1b study evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of AZD1390, a first-in-class ATM inhibitor, in combination with radiation in newly-diagnosed GBM patients (NCT05182905). Methods: Presumed newly-diagnosed GBM patients received 3 days of AZD1390 prior to planned resection at 4-6 or 23-25 hours following the final dose. Tumor tissue, cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase. ATM inhibition was assessed via ex vivo tissue radiation, quantifying pRAD50 levels compared to non-radiated control. Patients exceeding the PK threshold (2 nM unbound drug levels in Gd-non-enhancing tumor region) with unmethylated MGMT promoter were eligible for the expansion phase of study drug, combining AZD1390 with 6 weeks of radiotherapy. Results: Seventeen patients were enrolled into the study. All tested patients (n=14) exceeded the PK threshold and qualified for the expansion phase. Three patients were excluded from the PK analysis due to dosing deviation (n=1) and non-GBM diagnosis (n=2). The mean unbound concentration of AZD1390 in Gd-nonenhancing tumor was 12.4 and 4.4 pmol/g, respectively, for the 4-6 and 23-25-hours cohort. Following 5Gy ex vivo radiation of surgical specimen, pRAD50 expression was significantly suppressed in AZD1390 treated patients compared to untreated controls (median 0.2% for 4-6-hours cohorts and 1.9% for 23-25-hours cohort vs 32.3% for control cohort, average 99% and 95% reduction, respectively, p<0.01 for both cohorts vs control). As of 11/30/2023, 3 patients with unmethylated MGMT promoter are undergoing therapeutic dosing of AZD1390 plus radiotherapy, with median clinical follow-up of 2.3 months. Conclusion: AZD1390 is well-tolerated in newly-diagnosed GBM patients, achieving pharmacologically relevant concentrations in Gd-nonenhancing tumor tissue, and substantially suppressing radiation-induced increases in pRAD50 levels. These data are the first in GBM patients demonstrating AZD1390-mediated pharmacodynamic and pharmacokinetic response. Citation Format: Nader Sanai, Siddhi Desai, Tigran Margaryan, Jennifer Molloy, Costanza LoCascio, Mackenna Elliott, Jocelyn Harmon, Amy Hong, Ernesto Luna Melendez, John Wanebo, Kelly Braun, William Kennedy, Michael Garcia, Wonsuk Yoo, Artak Tovmasyan, An-Chi Tien, Shwetal Mehta. A phase 0/1b study of AZD1390 plus radiotherapy in newly-diagnosed, MGMT-unmethylated glioblastoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT044.

PATH-24. A CASE SERIES OF LONGER THAN EXPECTED SURVIVAL IN IDH-WILDTYPE, MGMT-UNMETHYLATED GLIOBLASTOMA PATIENTS

Abstract Despite interventions with surgery, radiation, and chemotherapy, Glioblastoma (GBM) remains a difficult cancer to treat. Only 6.9% of patients survive five years post-diagnosis1 and the median overall survival is reported to be in the range of 14-15 months.2Glioblastoma patients who harbor an IDH-mutation have a known improved survival rate over their IDH-wildtype counterparts and under the recent WHO 2021 Classification of CNS tumors, IDH-mutational status is now an established criteria for the classification of high-grade gliomas. MGMT methylation status is also a well-described prognostic factor in GBM. MGMT methylated patients have a more favorable prognosis and better response to conventional treatment with temozolomide.3 It is rare but there are some IDH-wildtype, MGMT-unmethylated GBM patients who survive longer than 4 years. Therefore, it is important to identify other potential favorable factors for longer survival in the unfavorable cohort of patients with IDH-wildtype and MGMT-unmethylated GBM. Case Series: Eighty-five GBM patients who had next generation sequencing completed at the University of California, Irvine were reviewed. Of 85 patients, 4 patients (4.7%) were IDH-wildtype, MGMT-unmethylated and lived longer than 4 years. We evaluated the pathology, clinical characteristics, treatment course, and molecular findings of these 4 long term GBM survivors with IDH-wildtype and MGMT-unmethylated status. Discussion: This case series of 4 cases of patients with IDH-wildtype, MGMT-unmethylated GBM with longer than expected survival did not reveal a ubiquitously prevalent molecular marker for long term survival based on review of next-generation sequencing results. 2 out of the 4 patients harbored an uncommon MTAP copy number loss mutation, which may warrant further investigation into the significance of this mutation on prognosis. 3 out of 4 patients received a vaccine-based intervention through clinical trial which may support ongoing investigation into the additional benefit this specific population of GBM patients may have from vaccine-based therapy.

Abstract CT238: Phase 2 study of dianhydrogalactitol (VAL-083) inpatients with MGMT-unmethylated, bevacizumab-naivepatients with MGMT-unmethylated, bevacizumab-naïve glioblastoma in the recurrent and adjuvant setting

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) followed by adjuvant TMZ (days 1-5 every 28 days). Almost all GBM patients experience recurrent/progressive disease, with a median survival of 3-9 months after recurrence. Second-line treatment for recurrent GBM with bevacizumab (BEV) has not improved survival, and effective therapies for GBM are lacking. Unmethylated promoter status for O6-methylguanine DNA methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with poor prognosis. VAL-083 is a bi-functional DNA-targeting agent rapidly inducing interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and cell death. VAL-083's cytotoxicity is independent of MGMT status, and VAL-083 overcomes TMZ-resistance in GBM cell lines, GBM cancer stem cells, and in vivo GBM models. The trial described here is an open-label two-arm biomarker-driven phase 2 clinical trial in MGMT-unmethylated GBM patients with either recurrent disease (Group 1) or newly diagnosed GBM patients requiring adjuvant therapy after chemoradiation with TMZ (Group 2). Patients receive VAL-083 IV at 30 or 40 mg/m2/day on days 1, 2, and 3 of a 21-day cycle. For Group 1 the primary objective of this study is to determine the effect of VAL-083 on median overall survival (mOS) in MGMT-unmethylated recurrent GBM patients compared to historical control. For Group 2, the primary objective of this study is to determine the effect of VAL-083 on progression-free survival (PFS) in newly diagnosed GBM patients requiring adjuvant therapy after chemoradiation with TMZ, compared to historical control. Secondary efficacy endpoints include progression-free survival (PFS) (Group 1), overall response rate (ORR), duration of response (DOR), and quality-of-life (QoL). Tumor response will be assessed by MRI approximately every 42 days, as per RANO criteria. The initial starting dose in this study was 40 mg/m2/day, which was subsequently reduced to 30 mg/m2/day to improve tolerance due to myelosuppression. As of January 11, 2021, 35 evaluable subjects have enrolled at a starting dose of 40 mg/m2/day, and 46 evaluable subjects have enrolled at a starting dose of 30 mg/m2/day in Group 1. In Group 2, 31 evaluable subjects had enrolled at a starting dose of 30 mg/m2/day. As anticipated from prior studies with VAL-083, myelosuppression (thrombocytopenia and neutropenia) has been the most common adverse event observed. The trial is continuing as planned, and an enrollment, efficacy and safety data update will be provided at the meeting. Clinicaltrials.gov identifier: NCT02717962 Citation Format: Barabara J. O'Brien, Carlos Kamiya-Matusoka, Shaio-Pei Weathers, WK Alfred Yung, WK Alfred Yung, Monica Loghin, Rebecca Harrison, Nazanin Majd, Stephanie Knight, Ying Yuan, Jeffrey Bacha, Dennis Brown, Anne Steino, Gregory Johnson, Sarath Kanekal, John Langlands, Lorena Lopez, Richard Schwartz, Marta Penas-Prado, John de Groot. Phase 2 study of dianhydrogalactitol (VAL-083) inpatients with MGMT-unmethylated, bevacizumab-naivepatients with MGMT-unmethylated, bevacizumab-naïve glioblastoma in the recurrent and adjuvant setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT238.

Preconditioning with INC280 and LDK378 drugs sensitizes MGMT-unmethylated glioblastoma to temozolomide: Pre-clinical assessment

Temozolomide (TMZ) therapy is the standard of care for patients with glioblastoma (GBM). Clinical studies have shown that elevated levels of DNA repair protein O (6)-methylguanine-DNA methyltransferase (MGMT) or deficiency/defect of DNA mismatch repair (MMR) genes is associated with TMZ resistance in some, but not all, GBM tumors. Another reason for GBM treatment failure is signal redundancy due to coactivation of several functionally linked receptor tyrosine kinases (RTKs), including anaplastic lymphoma kinase (ALK) and c-Met (hepatocyte growth factor receptor). As such, these tyrosine kinases serve as potential targets for GBM therapy. Thus, we tested two novel drugs: INC280 (Capmatinib: a highly selective c-Met receptor tyrosine kinase-RTK inhibitor) and LDK378 (Ceritinib: a highly selective anaplastic lymphoma kinase-ALK inhibitor), aiming to overcome TMZ resistance in MGMT-unmethylated GBM cells in in vitro cell culture models. Treatments were examined using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, caspase-3 assay and western blot analysis. Results obtained from our experiments demonstrated that preconditioning with INC280 and LDK378 drugs exhibit increased MMR protein expression, specifically MMR protein MLH1 (MutL Homolog 1) and MSH6 (MutS Homolog 6) and sensitized TMZ in MGMT-unmethylated GBM cells via suppression of ALK and c-Met expression. INC280 and LDK378 plus TMZ also induced apoptosis by modulating downstream signaling of PI3K/AKT/STAT3. Taken together, this data indicates that co-inhibition of ALK and c-MET can enhance growth inhibitory effects in MGMT-unmethylated cells and enhance TMZ sensitivity in-vitro, suggesting c-Met inhibitors combined with ALK-targeting provide a therapeutic benefit in MGMT-unmethylated GBM patients.

Abstract CT272: Phase 2 study of dianhydrogalactitol (VAL-083) in patients with MGMT-unmethylated, bevacizumab-naïve glioblastoma in the recurrent or adjuvant setting

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) followed by adjuvant TMZ (days 1-5 every 28 days). Almost all GBM patients experience recurrent/progressive disease, with a median survival of 3-9 months after recurrence. Second-line treatment for recurrent GBM with bevacizumab (BEV) has not improved survival, and effective therapies for GBM are lacking. Unmethylated promoter status for O6-methylguanine DNA methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with poor prognosis. VAL-083 is a bi-functional DNA-targeting agent rapidly inducing interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and cell death. VAL-083's cytotoxicity is independent of MGMT status, and VAL-083 overcomes TMZ-resistance in GBM cell lines, GBM cancer stem cells, and in vivo GBM models. The trial described here is an open-label two-arm biomarker-driven phase 2 clinical trial in MGMT-unmethylated GBM patients with either recurrent disease (Group 1) or newly diagnosed GBM patients requiring adjuvant therapy after chemoirradiation with temozolomide (Group 2). Patients receive VAL-083 IV at 30 or 40 mg/m2/day on days 1, 2, and 3 of a 21-day cycle. The primary objective of this study is to determine the effect of VAL-083 on median overall survival (mOS) in MGMT-unmethylated recurrent GBM patients (Group 1) compared to historical control, and progression-free survival (PFS) in newly diagnosed GBM patients requiring adjuvant therapy after chemoirradiation with temozolomide (Group 2), compared to historical control. Secondary efficacy endpoints include progression-free survival (PFS) (Group 1), overall response rate (ORR), duration of response (DOR), and quality-of-life (QoL). Tumor response will be assessed by MRI approximately every 42 days, as per RANO criteria. The initial starting dose in this study was 40 mg/m2/day, which was subsequently reduced to 30 mg/m2/day to improve tolerance due to myelosuppression. As of 21st January 2020, thirty-five (35) subjects had enrolled at a starting dose of 40 mg/m2/day, and 31 subjects had enrolled at a starting dose of 30 mg/m2/day in Group 1, and 9 subjects enrolled at a starting dose of 30 mg/m2/day in Group 2. As anticipated from prior studies with VAL-083, myelosuppression (thrombocytopenia and neutropenia) has been the most common adverse event observed. Enrollment and safety data update will be provided at the meeting. Clinicaltrials.gov identifier: NCT02717962 Citation Format: Barbara J. O'Brien, Carlos Kamiya-Matsuoka, Shiao-Pei Weathers, Alfred Yung, Monica Loghin, Rebecca Harrison, Nazanin Majd, Jeffrey A. Bacha, Dennis M. Brown, Anne Steino, Gregory Johnson, Sarath Kanekal, John Langlands, Lorena M. Lopez, Richard M. Schwartz, Marta Penas-Prado, John F. de Groot. Phase 2 study of dianhydrogalactitol (VAL-083) in patients with MGMT-unmethylated, bevacizumab-naïve glioblastoma in the recurrent or adjuvant setting [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT272.

ACTR-12. PHASE 2 STUDY OF DIANHYDROGALACTITOL (VAL-083) IN PATIENTS WITH MGMT-UNMETHYLATED, BEVACIZUMAB-NAÏVE GLIOBLASTOMA IN THE RECURRENT AND ADJUVANT SETTING

Abstract Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) followed by adjuvant TMZ (days 1–5 every 28 days. Almost all GBM patients experience recurrent/progressive disease, with a median survival after recurrence of 3–9 months. Second-line treatment for recurrent GBM with bevacizumab (BEV) has not improved survival, and effective therapies for GBM are lacking. Unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with poor patient prognosis. VAL-083 is a bi-functional DNA-targeting agent which rapidly induces interstrand DNA cross-links at N7-guanine, induces double-strand breaks and acts independent of MGMT DNA repair. The current ongoing trial is a biomarker-driven Phase 2 study in MGMT-unmethylated BEV-naïve adult GBM. The primary objective of this study is to determine the effect of VAL-083 on median overall survival (mOS) for MGMT-unmethylated GBM patients compared to historical control. Secondary efficacy endpoints include progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and quality-of-life. Thirty-five (35) subjects with recurrent GBM have received 40 mg/m2/day VAL-083 on days 1, 2, 3 of a 21-day cycle as the starting dose. Myelosuppression is the most common adverse event and a higher potential for this toxicity correlated with those patients who received a higher number of cycles of prior TMZ maintenance therapy, (>5 cycles vs. ≤5 cycles, p< 0.05). To minimize the potential for hematological toxicity in rGBM, subsequent subjects initiated treatment at 30 mg/m2/d VAL-083 x 3 consecutive days every 21 days. In addition, since TMZ is of limited value in the MGMT-unmethylated setting, a second arm in newly diagnosed GBM has been included to explore whether substituting TMZ with VAL-083 offers clinical benefit and extends the time to recurrence. Enrollment, safety data and study updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT02717962.

Clinical trials of VAL-083 in patients with chemo-resistant glioblastoma.

TPS2082 Background: Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard of care includes surgery, radiation and treatment with temozolomide (TMZ), however nearly all tumors recur and the prognosis for recurrent GBM is dismal. Most GBM tumors have unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT); a validated biomarker for TMZ-resistance. Second-line treatment with anti-angiogenic agent bevacizumab has not improved overall survival (OS) and 5-year survival is less than 3%. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent targeting N7-Guanine and inducing interstrand DNA cross-links, double-strand breaks and cell death in GBM cell lines and GBM cancer stem cells, independent of MGMT status in vitro. VAL-083 readily crosses the blood-brain barrier and accumulates in brain tumor tissue. Our recent phase I/II clinical trial in recurrent GBM patients failing both TMZ and bevacizumab, suggested that VAL-083 offers clinically meaningful survival benefits for patients with recurrent GBM and pinpointed a new dosing regimen (40 mg/m2/d on days 1,2,3 of a 21-day cycle) which was well-tolerated and was selected for study in subsequent GBM trials. Methods: These trials include i) an ongoing single-arm, biomarker driven, Phase 2 study to determine if VAL-083 treatment of MGMT-unmethylated adult GBM patients at first recurrence/progression, prior to bevacizumab improves overall survival at 9 months, compared to historical control with lomustine (clinicaltrials.gov identifier: NCT02717962). ii) A pivotal Phase 3 study in recurrent GBM after failing both TMZ and bevacizumab. The control arm will consist of a limited number of salvage chemotherapies currently used in bevacizumab-failed GBM. If successful, this study will serve as the basis for a New Drug Application (NDA) submission for VAL-083. iii) A single arm, biomarker driven, Phase 2 study to confirm the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients whose tumors are known to express high MGMT levels. The results of these studies may support a new treatment paradigm in chemotherapeutic regimens for the treatment of GBM. Clinical trial information: NCT02717962.

P09.57 Clinical trials of VAL-083 in patients with chemoresistant glioblastoma

Glioblastoma (GBM) is the most common CNS tumor. Patients with recurrent GBM have few treatment options and dismal prognosis. O6-methylguanine-DNA-methyltransferase (MGMT) is correlated with resistance to standard of care treatment with temozolomide and poor patient outcomes. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent with a distinct mechanism-of-action differentiating it from other alkylating agents used in the treatment of GBM and other CNS tumors. VAL-083 readily crosses the blood-brain barrier and accumulates in brain tumor tissue. VAL-083 has demonstrated MGMT-independent cytotoxicity in multiple GBM cell-lines and cancer stem cells and is able to overcome TMZ-resistance in vitro demonstrating a different mechanism of action. In multiple prior NCI-sponsored clinical trials VAL-083 showed promise against CNS tumors. We recently concluded a phase I/II clinical trial studying VAL-083 in recurrent GBM patients failing temozolomide and bevacizumab, and data suggests a potential for VAL-083 to offer clinically meaningful survival benefits in patients who have failed or are unlikely to respond to currently available chemotherapeutic regimens. In the phase I portion of the trial, VAL-083, 40 mg/m2/day x 3 every 21 days was well-tolerated and this dose was selected for study in the phase II expansion phase. We are initiating multiple clinical trials targeting adult patients with chemoresistant GBM due to MGMT expression. Enrollment is anticipated to be initiated in early 2017. These trials include i) a pivotal, randomized Phase 3 study measuring survival outcome compared to “physician’s choice” control, which, if successful, would serve as the basis for a New Drug Application (NDA) submission for VAL-083. The control arm will consist of a limited number of salvage chemotherapies currently utilized in bevacizumab-failed GBM. ii) A single-arm, biomarker-driven, Phase 2 study to determine if treatment of MGMT-unmethylated recurrent GBM with VAL-083 improves overall survival at 9 months, compared to historical control in bevacizumab-naïve patients (clinicaltrials.gov identifier: NCT02717962). iii) A single arm Phase 2 study to confirm the tolerability of DelMar’s dosing regimen in combination with radiotherapy and to explore the activity of VAL-083 in newly diagnosed MGMT-unmethylated GBM patients whose tumors are known to express high MGMT levels. The results of these studies may support a new treatment paradigm in chemotherapeutic regimens for the treatment of GBM. Enrollment updates and study design details will be presented at the meeting.

ACTR-42. CLINICAL TRIALS OF VAL-083 IN PATIENTS WITH CHEMORESISTANT GLIOBLASTOMA

Glioblastoma (GBM) is the most common CNS-tumor. Patients with recurrent GBM have few treatment options and dismal prognosis. O6-methylguanine-DNA-methyltransferase (MGMT) is correlated with resistance to standard-of-care treatment with temozolomide and poor patient outcomes. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent that readily crosses the blood-brain barrier and has demonstrated MGMT-independent activity in multiple GBM cell-lines and cancer stem cells, in vitro. VAL-083 showed promise against CNS-tumors in prior NCI-sponsored clinical trials. We recently concluded a phase I/II clinical trial studying VAL-083 in recurrent GBM after failing temozolomide and bevacizumab, suggesting potential of VAL-083 to offer clinically meaningful survival benefits and a promising new treatment for GBM patients who have failed or are unlikely to respond to currently available chemotherapeutic regimens. In this phase I/II trial, VAL-083, 40 mg/m2/day x 3 every 21 days was well tolerated and was selected for study in subsequent clinical trials in GBM. These trials include i) a pivotal, randomized Phase 3 study measuring survival outcomes compared to “physician’s choice” control, which, if successful, would serve as the basis for a New Drug Application (NDA) submission for VAL-083. The control arm will consist of a limited number of salvage chemotherapies currently utilized in bevacizumab-failed GBM. ii) A non-comparative, biomarker-driven, Phase 2 study to determine if treatment of MGMT-unmethylated recurrent GBM with VAL-083 improves overall survival at 9 months, compared to reported CCNU control in bevacizumab-naïve patients. iii) A single arm Phase 2 study to confirm the tolerability of DelMar’s dosing regimen in combination with radiotherapy and to explore the activity of VAL-083 in newly diagnosed MGMT-unmethylated GBM patients whose tumors are known to express high MGMT-levels. Trial designs and further details will be presented at the meeting. The results of these studies may support a new treatment paradigm in chemotherapeutic regimens for the treatment of GBM.

PC3 - 155 Phase II Study of Dianhydrogalactitol in Patients with MGMT-Unmethylated, Bevacizumab-Naïve Recurrent Glioblastoma

Glioblastoma (GBM) is the most common brain cancer. Most GBM tumors have unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT); a validated biomarker for MGMT protein-expression and ensuing temozolomide-resistance. Second-line treatment with bevacizumab has not improved overall survival (OS). Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent targeting N7-Guanine, thus MGMT-independently inducing interstrand cross-links, DNA double-strand breaks and cell-death in GBM cell-lines and cancer stem cells. VAL-083 is currently in Phase I/II clinical trial for recurrent GBM, post-TMZ and post-bevacizumab. In this Phase II clinical trial, the main goal is to assess the 9-month OS in MGMT-unmethylated, recurrent, bevacizumab-naive GBM. RATIONALE: The vast majority of GBM patients experience recurrent/progressive disease within a year from initial diagnosis and median survival after recurrence is 3-9 months. Chemotherapy regimens for these patients are lacking and there is a significant unmet medical need. Given VAL-083’s novel alkylating mechanism, promising clinical benefit, and favorable safety profile, a trial studying VAL-083 in MGMT-unmethylated recurrent GBM is warranted. METHOD: Randomized, non-comparative biomarker-driven Phase II clinical trial in MGMT-unmethylated GBM patients at first recurrence/progression, prior to bevacizumab. 48 patients will be randomized to receive VAL-083 or “standard-of-care” salvage drug lomustine. 32 patients will receive VAL-083 40mg/m2/day on days 1,2,3 of a 21-day cycle. 16 patients will receive lomustine 90 mg/m2/day on day 1 of a 42-day cycle. Patients will be followed until death or for at least 9 months from enrollment, whichever occurs earlier. Survival will be compared to the BELOB trial for recurrent MGMT-unmethylated GBM patients treated with lomustine.