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| ORIGINAL ARTICLE |
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| Year : 2019 | Volume
: 2
| Issue : 4 | Page : 167-173 |
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Phase 2 clinical trial of VAL-083 as first-line treatment in newly-diagnosed MGMT-unmethylated glioblastoma multiforme (GBM): Halfway report
Chengcheng Guo1, Qunying Yang1, Jiawei Li1, Shaoxiong Wu2, Meiling Deng2, Xiaojing Du2, Ke Sai1, Xiaobing Jiang1, Zhenghe Chen1, Ji Zhang1, Fuhua Lin1, Jian Wang1, Yinsheng Chen1, Chao Ke1, Xiangheng Zhang1, Xue Ju1, Yonggao Mou1, Jeffrey Bacha3, Anne Steino3, Sarath Kanekal3, Claire Kwan3, Gregory Johnson3, Richard Schwartz3, John Langlands3, Dennis Brown3, Zhong-ping Chen1
1 Department of Neurosurgery/Neuro-Oncology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong Province, China
2 Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong Province, China
3 Delmar Pharmaceuticals, Inc., Vancouver, Canada; Delmar Pharmaceuticals, Inc., Menlo Park, CA, USA
| Date of Submission | 09-Dec-2019 |
| Date of Acceptance | 27-Dec-2019 |
| Date of Web Publication | 23-Jan-2020 |
Correspondence Address:
Dr. Dennis Brown
DelMar Pharmaceuticals, Inc., Vancouver, Canada
Prof. Zhong-ping Chen
Department of Neurosurgery/Neuro-Oncology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou 510060, Guangdong Province
China
 Source of Support: None, Conflict of Interest: Jeffrey Bacha was not affiliated with DelMar Pharmaceuticals Ltd. when submitting this article for publication.  | 5 |
DOI: 10.4103/glioma.glioma_25_19
Background and Aim: Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) gene, which confers a limited response to standard-of-care treatment with temozolomide (TMZ), resulting in a lower survival. Dianhydrogalactitol (VAL-083) is a novel bi-functional DNA-targeting agent that induces interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated repair of the O6 guanine alkylator TMZ. A Phase 2 study has been initiated for VAL-083 in newly diagnosed MGMT unmethylated GBM. Subjects and Methods: The study has two parts: part 1 is a dose–escalation and induction format to enroll up to ten patients in which they received VAL-083 at 20, 30, or 40 mg/m2 per day for 3 days every 21 days concurrently with standard radiation treatment and VAL-083 for up to eight additional cycles. Part 2 comprises an expansion phase to enroll up to twenty additional patients. This study was performed with approval by the Institutional Review Board of Sun Yat-sen University Cancer Center (B2016-058-01) on January 13, 2017, and registered with the ClinicalTrials.gov (NCT03050736) on February 13, 2017. Results: After completion of dose escalation, VAL-083, 30 mg/m2 per day, in combination with radiation therapy, was generally safe and well tolerated. At the cutoff date, 23 patients had been enrolled, 14 of whom had been treated in the expansion phase. Consistent with prior studies, myelosuppression was the most common adverse event. Pharmacokinetic assessment indicated that the levels of VAL-083 were as high in the cerebrospinal fluid as in plasma, 2 h postinfusion. Of the 22 patients who had reached their four precycle magnetic resonance imaging assessments, 12 were assessed with disease progression, with a median progression-free survival of 9.9 (95% confidence interval 7.3–12.0) months for all the patients studied. Conclusion: These preliminary data support VAL-083 as a potentially valuable treatment option for newly diagnosed GBM.
Keywords: Adjuvant, chemotherapy, dianhydrogalactitol, glioblastoma multiforme, O-6-methylguanine-DNA methyltransferase, phase 2, Stupp regimen, temozolomide
How to cite this article:
Guo C, Yang Q, Li J, Wu S, Deng M, Du X, Sai K, Jiang X, Chen Z, Zhang J, Lin F, Wang J, Chen Y, Ke C, Zhang X, Ju X, Mou Y, Bacha J, Steino A, Kanekal S, Kwan C, Johnson G, Schwartz R, Langlands J, Brown D, Chen Zp. Phase 2 clinical trial of VAL-083 as first-line treatment in newly-diagnosed MGMT-unmethylated glioblastoma multiforme (GBM): Halfway report. Glioma 2019;2:167-73 |
How to cite this URL:
Guo C, Yang Q, Li J, Wu S, Deng M, Du X, Sai K, Jiang X, Chen Z, Zhang J, Lin F, Wang J, Chen Y, Ke C, Zhang X, Ju X, Mou Y, Bacha J, Steino A, Kanekal S, Kwan C, Johnson G, Schwartz R, Langlands J, Brown D, Chen Zp. Phase 2 clinical trial of VAL-083 as first-line treatment in newly-diagnosed MGMT-unmethylated glioblastoma multiforme (GBM): Halfway report. Glioma [serial online] 2019 [cited 2023 May 28];2:167-73. Available from: http://www.jglioma.com/text.asp?2019/2/4/167/276698 |
Chengcheng Guo & Qunying Yang - Contributed Equally.
| Introduction | |  |
Glioblastoma multiforme (GBM) is the most common malignant and aggressive brain cancer with an incidence of 2–3/100,000 persons/year. Patients with GBM have a poor prognosis and a 5-year overall survival (OS) rate of 9.8%. Tumor resection represents the first line in glioblastoma treatment, and is the first step in the management of patients.[1],[2],[3] Current standard (Stupp regimen) was established by the EORTC-NCIC trial, including the usage of temozolomide (TMZ) with concurrent radiation followed by the six cycles of adjuvant TMZ chemotherapy after the maximal surgical tumor resection.[4] The Stupp regimen significantly improves the survival of newly diagnosed GBM patients, with a median OS of 14.6 months when TMZ is combined with radiation compared to those receiving radiation alone (12.1 months), and the 2-year survival was 26.5% versus 10.4%. Furthermore, patients with an unmethylated promoter for the gene encoding O-6-methylguanine-DNA methyltransferase (MGMT) had more aggressive prognosis and resistance to TMZ, with a median progression-free survival (PFS) of 10.3 months in patients with GBM with methylated MGMT promoter versus 5.3 months in patients with unmethylated MGMT promoter.[5] Overall, 68.9% of the patients with GBM with methylated MGMT promoter were progression free at 6 months versus 40.0% of patients with GBM with an unmethylated MGMT promoter. The median OS was also longer in patients with GBM with methylated MGMT promoter than those with unmethylated MGMT promoter; 21.7 months versus 12.7 months, respectively. This difference in outcome for GBM patients with methylated versus unmethylated MGMT promoter has been confirmed more recently in a study that demonstrated a median PFS in patients with GBM of 6.9 months for those with unmethylated MGMT promoter versus 11.6 months for those with methylated MGMT.[5],[6] In Stupp study,[5] the median OS was also longer in patients with GBM with methylated MGMT promoter than those with unmethylated MGMT promoter, 20.9 months versus 16.0 months, respectively. Given the aggressive biological nature of GBM, particularly in patients with unmethylated MGMT promoter, there is an urgent need to develop effective new therapies.
Dianhydrogalactitol (VAL-083) is a “ first-in-class” bi-functional DNA-targeting agent that introduces interstrand DNA cross-links at the N7-position of guanine leading to DNA double-strand breaks and cancer cell death. This involves S-phase-dependent DNA double-strand breaks and homologous recombination DNA repair.[7],[8] VAL-083 has demonstrated clinical activity against a range of cancers, including GBM and ovarian cancer in clinical trials sponsored by the U.S. National Cancer Institute.[9],[10],[11],[12] The antitumor activity of VAL-083 has been shown to be unaffected by the common mechanisms of chemoresistance, including MGMT, in cancer cell models and animal studies.[13],[14]
As a result, this clinical trial in newly diagnosed GBM patients with an unmethylated promoter for the gene encoding MGMT was designed to determine if first-line treatment with VAL-083 in combination with radiotherapy can provide improvement in efficacy over the historical standard-of-care TMZ plus radiotherapy.
| Subjects and Methods | | |
Study design
This was a single-arm, open-label study to determine the safety and the maximal tolerated dose of VAL-083 in combination with a standard-of-care radiation regimen when used to treat newly diagnosed GBM in patients with unmethylated promoter of the MGMT gene. Pharmacokinetic properties of VAL-083 in this population and tumor responses to treatment were also evaluated. This study was performed after approval by the Institutional Review Board of Sun Yat-sen University Cancer Center (B2016-058-01) on January 13, 2017. All patients had the ability to sign and provide written informed consent prior to any study-related procedure. This study was registered with the ClinicalTrials.gov (NCT03050736) on February 13, 2017.
The study was conducted in two parts:
Part 1: Dose confirmation comprised a series of three cohorts to confirm the recommended dose of VAL-083 in combination with a standard-of-care radiation regimen. Standard radiotherapy was defined as conformal, fractionated focal radiation at a dose of 2 Gy/fraction given once daily 5 days/week (Monday through Friday) over a period of 6 weeks (the induction period), for a total dose of 60 Gy. VAL-083 (DelMar Pharmaceuticals, Inc., Menlo Park, CA, USA) was administered concurrently with radiation therapy, intravenously daily for 3 days, commencing on the 1st day of radiotherapy (study days 1–3), with a repeated 3-day cycle (cycle #2) administered on study days 22–24 of radiation therapy. If radiation therapy was delayed, cycle #2 of VAL-083 was also delayed so that it was given concurrently with radiation therapy. VAL-083 was administered such that the intravenous VAL-083 infusion was completed approximately 60 min prior to the radiation therapy.
After completion of the 6-week radiotherapy regimen, on approximately study day 43 or thereafter, the patients commenced adjuvant maintenance therapy with VAL-083 alone, administered intravenously daily for 3 days every 21 days (cycles 3–10), at the same assigned dose, for up to eight maintenance cycles, such that the patients could receive a maximum of 10 cycles of VAL-083 during induction as adjuvant therapy.
Dose escalation of VAL-083 proceeded in three sequential cohorts, consisting patients receiving 20, 30, and 40 mg/m2 per day for 3 days every 21 days. Dose escalation was followed in accordance with the scheme outlined in [Table 1].
All patients who had received at least one dose of VAL-083 were evaluable for safety and determination of the maximal tolerated dose.
For Part 2 (expansion stage), the same dosing and radiation schedule as in Part 1 was utilized. The dose of VAL-083 studied in Part 2 was determined from Part 1 (30 mg/m2 per day for 3 days every 21 days).
Per protocol, patients in either part of the study continued to receive VAL-083 at the assigned dosage and were followed for the safety and indications of activity, as long as the patient continued to demonstrate response or stable disease and tolerated therapy, for a maximum of eight cycles. Patients responding to VAL-083 therapy at the end of the prescribed treatment period were permitted to continuously receive VAL-083.
In both parts of the study, baseline cranial magnetic resonance imaging (MRI) was obtained within 3 weeks prior to commencing radiation therapy, 3 weeks after completing radiation therapy (prior to VAL-083 cycle 4), and then every 3 months, while the patient remained in the study, or more frequently if clinically indicated. The same method was utilized for all response assessments.
Patients
Patients, 18–70 years of age, with documented unmethylated MGMT gene promoter status and histologically proven newly diagnosed supratentorial GBM were enrolled in our study. In addition, patients who had received no prior chemotherapy, radiation therapy, or immunotherapy for their brain tumor; those had an interval of ≥2 weeks but ≤7 weeks after surgery or biopsy before the first administration of study treatment; those who recovered from the effects of surgery, postoperative infection, and other complications before study registration and stable or decreasing dose of steroids >5 days prior to randomization; those who fell under World Health Organization Karnofsky performance status[15] ≥70%, expected survival ≥2 months, and normal hematologic, renal, and hepatic functions (absolute neutrophil count ≥1500/mm3; platelet count ≥100,000/mm3; hemoglobin ≥10 g/dL; liver function values <2.5 times the upper limit of normal for the laboratory; bilirubin <2 times the upper limit of normal for the laboratory; and serum creatinine ≤1.5 times the upper limit of normal or creatinine clearance >50 mL/min [measured or calculated by the Cockcroft–Gault formula])[16] at screening were included in the study. Contraindications to participation included active or uncontrolled infection, other coexistent malignant disease, and pregnancy or lactation.
Patients were excluded from trial participation if they had prior chemotherapy and radiation; had used Gliadel® wafer during the operation; had a history of active peptic ulcer within the last 6 months before enrollment; were pregnant or breastfeeding; had uncontrolled hypertension; had inability to undergo MRI evaluation; those on current alcohol dependence or drug abuse; had known hypersensitivity to study treatment; those who were unable or unwilling to fulfill the study requirements; or those unwilling to provide informed consent.
All patients provided written informed consent prior to participating in the current study. All patients were confirmed to be MGMT unmethylated prior to enrollment.
MGMT assay
MGMT methylation-specific polymerase chain reaction (MSP) was used to confirm the methylation status of the MGMT promoter region. Genomic DNA was extracted from paraffin-embedded specimens according to the manufacturer's instructions (TianGen DNA Mini Kit, Beijing, China). The methylation status was determined by performing the bisulfite modification, which converts unmethylated but not methylated cytosines to uracils. The genomic DNA (50 ng) was amplified using primers designed to detect the methylated or unmethylated sequences by MSP. MSP was performed according to the manufacturer's protocol (EZ DNA Methylation Gold kit, Zymo Research, Irvine, CA, USA). The primers were specific for either the methylated or modified unmethylated DNA, as previously described.[17] DNA obtained from normal peripheral blood lymphocytes served as the negative control, and enzymatically methylated DNA from peripheral blood lymphocytes was used as the positive control. Ten microliters of each 50-μL MSP product was directly loaded onto nondenaturing 6% polyacrylamide gels, stained with ethidium bromide, and examined under ultraviolet illumination.
Safety and dose-limiting toxicity assessment
All adverse events were graded utilizing the National Cancer Institute Common Toxicity Criteria version 4.0.[18] Patients in the Part 1 stage were evaluable for dose-limiting toxicity (DLT) if they completed cycle one or experienced a DLT during the first two cycles of treatment with VAL-083 during the period of radiation therapy. The following treatment-related adverse events were considered a DLT during cycles 1 and 2: any Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with hemorrhage; absolute neutrophil count nadir <500/μL or platelet count <50,000/μL, lasting for >5 days; absolute neutrophil count <500/μL with fever (febrile neutropenia); treatment delays of >3 weeks for hematologic toxicity; any Grade 3 or 4 nonhematologic toxicity due to treatment with the exception of alopecia, nausea, and vomiting; Grade 3 or 4 nausea or vomiting while receiving an optimal antiemetic regimen for prophylaxis and management; and treatment delays of >3 weeks for toxicity.
Clinical and radiographic assessment
At baseline, all patients received a physical examination and clinical assessment, and medical history was obtained. These assessments involved vital signs, performance status, and routine laboratory studies including hematology, coagulation, kidney function and liver function, urinalysis, pregnancy test, chest X-ray, electrocardiogram, and whole-brain MRI. Vital signs and laboratory assessments were conducted prior to each treatment cycle. Whole-brain MRI was repeated prior to cycle 4 and every 3 months thereafter. Tumors were evaluated by the investigator using the Response Assessment in NeuroOncology criteria.[19] Response was measured by a reduction in tumor size.
Pharmacokinetics analysis
The objectives were to determine the pharmacokinetic profile and dose–exposure relationship of VAL-083 for injection on day 1, when given as an infusion over 60 min. Cerebrospinal fluid (CSF) analysis was undertaken to obtain a single-point concentration of VAL-083 in CSF. On cycle 1, day 1, at each dose level, blood was collected predose; 15 ± 5, 30 ± 5, 60 ± 10, 120 ± 10, 240 ± 15, and 360 ± 15 min after the end of intravenous injection of study drug; and immediately prior to cycle 1, day 2 dosing. For CSF, cycle 1, day 3 blood for VAL-083 plasma concentration was collected 15 ± 5 min after the end of intravenous injection of study drug. Plasma pharmacokinetic parameters were determined for cycle 1 day 1 at each dose level via noncompartmental analysis using WinNonlin version 2.0 (Pharsight Co., Certara, NJ, USA) or newer version. Predose plasma concentration (Ctrough) determined directly from the concentration–time profile, day 1; maximum observed concentration (Cmax) on day 1; time of observed Cmax (Tmax) on day 1; area under the concentration–time curve from predose (time 0) to the time of the last quantifiable concentration (area under the curve [AUC] AUClast) on day 1 calculated using the linear-log trapezoidal rule; area under the concentration–time curve extrapolated to infinity calculated using the linear-log trapezoidal rule (AUCinf) on day 1; total oral body clearance at steady state (CL/F) calculated as dose/AUC day 1; mean residence time calculated (AUMC/AUC) where AUMC is area under the moment curve; Vz: the apparent volume of distribution during the terminal phase; Lambda z (λz): the terminal elimination rate constant determined by selection of at least three decreasing data points on the terminal phase of the concentration–time curve on day 1; and terminal elimination half-life (T1/2) on day 1 determined from 0.693/λz.
Statistical analysis
MedCalc Ver 9.3.1 (MedCalc Inc., Mariakerke, Belgium) was used in all statistical analyses. The primary safety objective of the study was to determine the maximal tolerated dose and to describe the safety and tolerability of VAL-083 in combination with a standard-of-care radiation regimen.
The efficacy objective in both parts of the study was to determine the activity of VAL-083 in newly diagnosed unmethylated MGMT GBM patients. Outcome assessment will be performed based on tumor response to treatment, PFS, PFS at 6 months, and overall survival (OS), compared to historical results in the target population. The median PFS and OS were estimated by the Kaplan–Meier analysis. For disease response, the frequency of best response (complete response, partial response, and stable disease) of the treatment was determined. Pharmacokinetic parameters were computed by noncompartmental analysis.
| Results | | |
Patient demographics
Demographics for all patients enrolled in the study are described in [Table 2]. The median age was 53.5 (range: 21.1–65.0) years; 8/23 (35%) were male; the mean body surface area was 1.69 ± 0.17 m2; and the median Karnofsky performance status was 90 (range 70–100).
As of November 2, 2019, a total of 23 patients had been treated in the study. Dose escalation cohorts evaluating doses of 20, 30, and 40 mg/m2 per day on days 1, 2, and 3 of a 21-day cycle were completed. As myelosuppression was observed at the dose of 40 mg/m2 per day, the dose of VAL-083 was reduced to 30 mg/m2 daily on days 1, 2, and 3 every 21 days, administered concurrently with radiation therapy. This dose was selected for the Part 2 of the study. To date, 14 patients have been treated in the expansion phase with a starting dose of 30 mg/m2 per day.
Safety
Myelosuppression (decreased platelet, neutrophil, lymphocyte, and white cell counts) was confirmed to be the most common adverse event. Additional adverse events included anemia, decreased red cell count and increased liver function enzymes, and fatigue. Hematological adverse events generally resolved spontaneously; serious adverse events possibly related to VAL-083 were reported in 4/23 (17%) of patients. Three DLTs were in patients who completed the first two cycles of treatment [Table 3]. | Table 3: Frequency of dose-limiting toxicities in patients receiving VAL-083
Click here to view |
Pharmacokinetics
Pharmacokinetic profiles were determined on day 1 of cycle 1 for each patient. Maximum concentration and AUC were broadly linear with respect to dose; the terminal elimination half-life was 0.8 h. Data obtained to date indicate that overall the concentration of VAL-083 was as high in CSF as in plasma at 2 h postinfusion [Table 4].
Efficacy
The best response was determined by the investigator for patients who had completed their first planned assessment prior to cycle 4. At November 2, 2019, 19 patients received at least one assessment prior to initiating cycle 4 and beyond. There were 9/19 (43%) patients assessed as complete response, 8/19 (48%) assessed as stable disease, and 2/19 (10%) assessed as progressive disease. There were two patients who have not yet reached prior-to-cycle 4 assessment and two patients discontinued or died before the first planned assessment time point (prior to cycle 4).
As of the cutoff date of November 2, 2019, for all patients including completed and active treatment patients, the median number of cycles of VAL-083 received was 8, and nine patients received >10 cycles.
For the 22 patients who had completed at least their first assessment at the cutoff date, 12 were assessed with disease progression. The median PFS for patients who had shown disease progression by MRI assessment is summarized in [Table 5]. | Table 5: Frequency of disease progression and median progression-free survival in patients receiving VAL-083
Click here to view |
| Discussion | | |
Glioblastoma is intrinsically infiltrative and destructive in the brain with poor prognosis, with a median OS of 14.6 months with radiation and TMZ chemotherapy combined.[14] Standard therapy for patients with malignant gliomas has traditionally involved maximal surgical resection/debulking of the primary tumor (if feasible), followed by radiation therapy with concurrent and the adjuvant TMZ of 5 days for 28 days.[10] However, radical resection surgery is virtually impossible, due to the infiltrative nature of the tumor and critical nature of the surrounding central nervous system tissue.
Treatment of GBM has limited new promising approaches over the Stupp regimen, especially in patients with an unmethylated promoter for the gene encoding MGMT. The MGMT gene resides on chromosome 10q26 and is responsible for this DNA repair protein, which removes alkyl groups from the O6 position of guanine. The prognostic value of MGMT promoter methylation status has been determined in previous clinical trials.[5],[6],[20] The 2-year OS in MGMT-unmethylated patients was 22.7% compared to 46% in MGMT-methylated patients.[5] Attempts to improve the efficacy have used dose–dense usage of TMZ, trying to modulate the MGMT expression. However, the median OS (14.6 months for the Stupp regimen vs. 13.3 months for the dose–dense regimen, P = 0.44) and the PFS (5.1 months for the Stupp regimen vs. 6.0 months for the dose–dense regimen, P = 0.15) did not provide any overall improvement in survival outcomes.[21]
Responses to the antivascular endothelial growth factor antibody, bevacizumab, have led to significant improvements in PFS. However, bevacizumab treatment in patients with recurrent glioblastoma does not confer a survival advantage despite prolonged PFS.[21],[22] Furthermore, bevacizumab has been reported to induce a more invasive tumor phenotype,[23] and a meta-analysis of five recurrent GBM trials concluded that outcome following bevacizumab failure is poor.[24] The median OS in bevacizumab-failed GBM has been reported to be approximately 2–5 months.[25]
A Phase II study of bevacizumab and erlotinib, and epidermal growth factor receptor, a tyrosine kinase inhibitor, based on the Stupp regimen, showed that the sequential treatment did not increase the OS for the unmethylated GBM patients with 13.2 months of OS and 9.2 months of PFS.[26] Neither the “CORE” trial including Cilengitide[27] nor the “Glarius” trial[28] including the Stupp regimen sequential with bevacizumab and irinotecan showed any beneficial result for unmethylated GBM patients.
VAL-083 is water soluble and is administered by intravenous infusion. Studies in rodents have demonstrated that VAL-083 crosses the blood–brain barrier, where it accumulates in the brain tumor tissue preferentially.[29] In the current study, VAL-083 has been measured in the CSF of patients 2 h after the end of infusion, and levels have been found to be at least as high as those in plasma at the same time point.
The main adverse event in patients receiving VAL-083 has been myelosuppression. The maximum dose evaluated in this study was 40 mg/m2 per day and was associated with myelosuppression and lower overall tolerability. As a result, 30 mg/m2 per day for 3 days in a 3-week cycle was used in the dose–escalation part of this study.
In the ongoing evaluation of the study data, VAL-083 has shown favorable efficacy in this patient population with respect to median PFS. During our mid-point data review (November 2, 2019), the overall median PFS for VAL-083 was 9.9 (95% confidence interval [CI]: 7.3–12.0) months with 12/22 (54%) patients progressed and for those receiving the intended treatment dose of 30 mg/m2 was 10.4 (95% CI: 6.0–12.0) months, with 9/18 (50%) patients progressed. In the Stupp regimen, the median PFS was 5.3–6.9 months in unmethylated MGMT GBM patients.[5],[6] These median PFS times are longer than the PFS previously reported and are close to the PFS for the methylated MGMT TMZ patients (10.3–11.6 months).[5],[6]
While we look forward to the completion of enrollment of patients in this study, these preliminary results support our optimism that VAL-083 can provide a valuable option than currently available treatments for patients with unmethylated MGMT glioblastoma.
| Conclusion | | |
VAL-083 at 30 mg/m2 per day for 3 days every 21 days in combination with radiation therapy is generally safe and well tolerated, and multiple treatment cycles in the adjuvant setting have been achieved. Adverse events have been shown to be consistent with those of prior studies. Levels of VAL-083 measured in the CSF at 2 h postinfusion were as high as those measured in plasma, demonstrating significant penetration to the brain. VAL-083 at 30 mg/m2 per day in combination with radiotherapy has demonstrated benefit with respect to disease progression over standard-of-care TMZ in the same setting. These preliminary data support the premise that VAL-083 has the potential to provide a valuable treatment option for such patients.
Financial support and sponsorship
Nil.
Institutional review board statement
This study was approved by the Institutional Review Board of Sun Yat-sen University Cancer Center (B2016-058-01) on January 13, 2017, China, and registered with the ClinicalTrials.gov (NCT03050736) on February 13, 2017.
Declaration of participant consent
The authors certify that they have obtained the appropriate participant consent form. In the forms, the participants have given their consent for the participants' images and other clinical information to be reported in the journal. The participants understood that their names and initials would not be published and due efforts would be made to conceal their identity.
Conflicts of interest
Jeffrey Bacha was not affiliated with DelMar Pharmaceuticals Ltd. when submitting this article for publication.
| References | | |
| 1. | |
| 2. | Stupp R, Tonn JC, Brada M, Pentheroudakis G; ESMO Guidelines Working Group. High-grade malignant glioma: ESMO Clinical Practice Guidelines for diagnosis, trea tment and follow-up. Ann Oncol 2010;21 Suppl 5:v190-3.  |
| 3. | Tonn JC, Thon N, Schnell O, Kreth FW. Personalized surgical therapy. Ann Oncol 2012;23 Suppl 10:x28-32. |
| 4. | Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96. |
| 5. | Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352:997-1003. |
| 6. | Tanguturi SK, Trippa L, Ramkissoon SH, Pelton K, Knoff D, Sandak D, et al. Leveraging molecular datasets for biomarker-based clinical trial design in glioblastoma. Neuro Oncol 2017;19:908-17. |
| 7. | Zhai B, Steino A, Bacha J, Brown D, Daugaard M. Molecular mechanisms of dianhydrogalactitol (VAL-083) in cancer treatment. Cancer Res 2016;76:2985. |
| 8. | Zhai B, Steinø A, Bacha J, Brown D, Daugaard M. Dianhydrogalactitol induces replication-dependent DNA damage in tumor cells preferentially resolved by homologous recombination. Cell Death Dis 2018;9:1016. |
| 9. | Eagan RT, Ames MM, Powis G, Kovach JS. Clinical and pharmacologic evaluation of split-dose intermittent therapy with dianhydrogalactitol. Cancer Treat Rep 1982;66:283-7. |
| 10. | Eagan RT, Dinapoli RP, Hermann RC Jr, Groover RV, Layton DD Jr, Scott M. Combination carmustine (BCNU) and dianhydrogalactitol in the treatment of primary brain tumors recurring after irradiation. Cancer Treat Rep 1982;66:1647-9. |
| 11. | Institóris E, Szikla K, Otvös L, Gál F. Absence of cross-resistance between two alkylating agents: BCNU vs. bifunctional galactitol. Cancer Chemother Pharmacol 1989;24:311-3. |
| 12. | Schabel FM Jr., Trader MW, Laster WR Jr, Wheeler GP, Witt MH. Patterns of resistance and therapeutic synergism among alkylating agents. Antibiot Chemother (1971) 1978;23:200-15. |
| 13. | Fouse SD, Steino A, Butowski N, Bacha JA, Kanekal S, Dos Santos N, et al. Dianhydrogalactitol inhibits the growth of glioma stem and non-stem cultures, including temozolomide-resistant cell lines, in vitro and in vivo. Neuro Oncol 2015;16:v83. |
| 14. | Hu K, Fotovati A, Chen J, Triscott J, Bacha J, Brown D, et al. Abstract 811: VAL083, a novel N7 alkylating agent, surpasses temozolomide activity and inhibits cancer stem cells providing a new potential treatment option for glioblastoma multiforme. Cancer Res 2012. |
| 15. | Schag CC, Heinrich RL, Ganz PA. Karnofsky performance status revisited: Reliability, validity, and guidelines. J Clin Oncol 1984;2:187-93. |
| 16. | Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41. |
| 17. | Qiu ZK, Shen D, Chen YS, Yang QY, Guo CC, Feng BH, et al. Enhanced MGMT expression contributes to temozolomide resistance in glioma stem-like cells. Chin J Cancer 2014;33:115-22. |
| 18. | US Department of Health and Human Services. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. National Institutes of Health/National Cancer Institute. 2009. |
| 19. | Wen PY, Cloughesy TF, Ellingson BM, Reardon DA, Fine HA, Abrey L, et al. Report of the Jumpstarting Brain Tumor Drug Development Coalition and FDA clinical trials neuroimaging endpoint workshop (January 30, 2014, Bethesda MD). Neuro Oncol 2014;16 Suppl 7:vii36-47. |
| 20. | Li D, Chen Y, Guo C, Zhang X, Sai K, Ke C, et al. Real-world management and survival outcomes of patients with newly diagnosed gliomas from a single institution in China: A retrospective cohort study. Glioma 2019;2:96-104. [Full text] |
| 21. | Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: A randomized phase III clinical trial. J Clin Oncol 2013;31:4085-91. |
| 22. | Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 2014;370:699-708. |
| 23. | de Groot JF, Mandel JJ. Update on anti-angiogenic treatment for malignant gliomas. Curr Oncol Rep 2014;16:380. |
| 24. | Reardon DA, Desjardins A, Peters K, Gururangan S, Sampson J, Rich JN, et al. Phase II study of metronomic chemotherapy with bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy. J Neurooncol 2011;103:371-9. |
| 25. | Iwamoto FM, Abrey LE, Beal K, Gutin PH, Rosenblum MK, Reuter VE, et al. Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma. Neurology 2009;73:1200-6. |
| 26. | Raizer JJ, Giglio P, Hu J, Groves M, Merrell R, Conrad C, et al. A phase II study of bevacizumab and erlotinib after radiation and temozolomide in MGMT unmethylated GBM patients. J Neurooncol 2016;126:185-92. |
| 27. | Nabors LB, Fink KL, Mikkelsen T, Grujicic D, Tarnawski R, Nam DH, et al. Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: Results of the open-label, controlled, randomized phase II CORE study. Neuro Oncol 2015;17:708-17. |
| 28. | Schäfer N, Proescholdt M, Steinbach JP, Weyerbrock A, Hau P, Grauer O, et al. Quality of life in the GLARIUS trial randomizing bevacizumab/irinotecan versus temozolomide in newly diagnosed, MGMT-nonmethylated glioblastoma. Neuro Oncol 2018;20:975-85. |
| 29. | Levin VA, Freeman-Dove MA, Maroten CE. Dianhydrogalactitol (NSC-132313): Pharmacokinetics in normal and tumor-bearing rat brain and antitumor activity against three intracerebral rodent tumors. J Natl Cancer Inst 1976;56:535-9. |
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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