Phase 2 clinical trial of VAL-083 as first-line treatment in newly-diagnosed MGMT-unmethylated glioblastoma multiforme (GBM): Halfway report

Abstract

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.

Full text

© 2020 Glioma | Published by Wolters Kluwer - Medknow 167
Original Article
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 Bacha3,4, Anne Steino3,4, Sarath Kanekal3,4, Claire Kwan3,4,
Gregory Johnson3,4, Richard Schwartz3,4, John Langlands3,4, Dennis Brown3,4, Zhong-ping Chen1
1Department 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.
2Department 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.
3Delmar Pharmaceuticals, Inc., Vancouver, Canada.
4Delmar Pharmaceuticals, Inc., Menlo Park, CA, USA.
*Contributed Equally.
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 uid 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% condence 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
Access this article online
Quick Response Code:
Website:
www.jglioma.com
DOI:
10.4103/glioma.glioma_25_19
Address for correspondence: 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.
E‑mail: chenzhp@sysucc.org.cn;
Dr. Dennis Brown,
DelMar Pharmaceuticals, Inc., Vancouver, Canada.
Email: dbrown@delmarpharma.com
This is an open access journal, and arcles are distributed under the terms of the Creave
Commons Aribuon‑NonCommercial‑ShareAlike 4.0 License, which allows others to
remix, tweak, and build upon the work non‑commercially, as long as appropriate credit
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For reprints contact: reprints@medknow.com
How to cite this article: Guo C, Yang Q, Li J, Wu S, Deng M, Du X, et al.
Phase 2 clinical trial of VAL-083 as rst-line treatment in newly-diagnosed
MGMT-unmethylated glioblastoma multiforme (GBM): Halfway report.
Glioma 2019;2:167-73.
Abstract
Received: 09-December-2019 Revised: 23-December-2019
Accepted: 27-December-2019 Published: 23-January-2020
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168
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 rst line in glioblastoma treatment, and is the rst
step in the management of patients.[1-3] 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
signicantly 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 conrmed
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.[9-12] 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 rst-line treatment with VAL-083
in combination with radiotherapy can provide improvement
in efcacy 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 conrm the recommended dose of VAL-083 in
combination with a standard-of-care radiation regimen.
Standard radiotherapy was dened 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
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Guo, et al.: VAL‑083 for the newly diagnosed GBM with MGMT unmethylation
Glioma ¦ Volume 2 ¦ Issue 4 ¦ October‑December 2019 169
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 rst 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 fulll 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 conrmed
to be MGMT unmethylated prior to enrollment.
MGMT assay
MGMT methylation-specic polymerase chain reaction (MSP)
was used to conrm the methylation status of the MGMT
promoter region. Genomic DNA was extracted from
parafn-embedded specimens according to the manufacturer’s
instructions (TianGen DNA Mini Kit, Beijing, China).
The methylation status was determined by performing the
bisulte modication, which converts unmethylated but not
methylated cytosines to uracils. The genomic DNA (50 ng)
was amplied 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
modied 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
rst 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
Table 1: Study cohort’s dose-escalation scheme
If dose-limiting
toxicity observed in
Action
Cohort 1 (20 mg/m2
per day) (n=1)
0 of 1 patient Proceed with enrollment in the next cohort
1 of 1 patient Enroll ve additional patients
1 of 6 patients Proceed with enrollment in the next cohort
≥2 of 6 patients Do not dose escalate
Cohort 2 (30 mg/m2
per day) (n=3)
0 of 3 patients Proceed with enrollment in the next cohort
1 of 3 patients Enroll three additional patients
1 of 6 patients Proceed with enrollment in the next cohort
≥2 of 6 patients Do not dose escalate
Cohort 3 (40 mg/m2
per day) (n=6)
≤1 of 6 patients Proceed with enrollment in Part 2
≥2 of 6 patients Consider lower dose for Part 2
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Glioma ¦ Volume 2 ¦ Issue 4 ¦ October‑December 2019
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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 prole
and dose–exposure relationship of VAL-083 for injection on
day 1, when given as an infusion over 60 min. Cerebrospinal
uid (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 quantiable 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
innity 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 conrmed 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 rst two cycles of
treatment [Table 3].
Pharmacokinetics
Pharmacokinetic proles 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 rst planned assessment
prior to cycle 4. At November 2, 2019, 19 patients received
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Guo, et al.: VAL‑083 for the newly diagnosed GBM with MGMT unmethylation
Glioma ¦ Volume 2 ¦ Issue 4 ¦ October‑December 2019 171
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 rst 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 rst
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.
disCussion
Glioblastoma is intrinsically inltrative 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 inltrative 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 efcacy 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 signicant 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 ve 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]
Table 2: Study patient demographics
All patients (n=23) 20 mg/m2 per day (n=1) 30 mg/m2 per day (n=19) 40 mg/m2 per day (n=3)
Age (years)
Mean±SD 48.9±12.5 33.9 50.3±13.2 46.0±4.4
Median (minimum–maximum) 53.5 (21.1–65.0) 33.9 54.7 (21.1–65.0) 44.1 (42.9–51.1)
Sex, n (%)
Male 8 (35) 1 (100) 12 (63) 2 (67)
Female 15 (65) 0 7 (37) 1 (33)
Body surface area (m2)
Mean±SD 1.69±0.17 1.64 1.67±0.17 1.70±0.27
Median (minimum–maximum) 1.67 (1.45–2.01) 1.64 1.68 (1.45–2.01) 1.67 (1.45–1.99)
Height (cm)
Mean±SD 166.5±10.1 162.0 166.4±10.3 168.7±12.5
Median (minimum–maximum) 165.0 (150.0–183.0) 162.0 168.0 (150.0–183.0) 163.0 (160–183.0)
Weight (kg)
Mean±SD 62.8±10.4 60 63.1±10.2 61.8±15.8
Median (minimum–maximum) 62.0 (46.0–80.0) 60 62.0 (49.5–80.0) 62.0 (46.0–77.5)
Karnofsky Performance Status 90 (55.25–72.25) 90 90 80
Median (minimum–maximum)
VAL-083 was administered intravenously on days 1, 2, and 3 every 21 days. SD: Standard deviation
Table 3: Frequency of dose-limiting toxicities in patients
receiving VAL-083
VAL-083 dose
(mg/m2 per day)
Number of patients
completed 42-day
treatment (2 cycles)
Number of patients
with dose-limiting
toxicities [n (%)]
20 1 0
30 18 2 (11)
40 3 1 (33)
VAL-083 was administered intravenously on days 1, 2, and 3 every 21 days
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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 benecial 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% condence 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 signicant penetration to
the brain. VAL-083 at 30 mg/m2 per day in combination with
radiotherapy has demonstrated benet 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 afliated with DelMar Pharmaceuticals
Ltd. when submitting this article for publication.
Table 4: Concentration of VAL-083 in plasma and cerebral spinal fluid
VAL-083 dose
(mg/m2 per day)
nVAL-083 concentration (ng/mL) Ratio at 2 h
cerebrospinal
fluid/plasma
Plasma maximum
concentration
Plasma at 2 h
postdose
Cerebrospinal fluid
at 2 h postdose
20 1 481.0 110.0 154 1.40
30 6 574.9±261.5 97.2±20.9 123.0±27.8 1.19±0.37
40 3 898.7±69.6 169.7±41.9 189.7±69.9 1.13±0.41
VAL-083 administered intravenously via a 60-min infusion on days 1, 2, and 3 every 21 days
Table 5: Frequency of disease progression and median progression-free survival in patients receiving VAL-083
All patients (n=22) 20 mg/m2 per day (n=1) 30 mg/m2 per day (n=18) 40 mg/m2 per day (n=3)
Number of patients progressed, n (%) 12 (55) 1 (100) 9 (50) 2 (67)
Median PFS (months)a (95% CI) 9.9 (7.3–12.0) 3.0 10.4 (6.0–12.0) 9.9 (9.3–9.9)
VAL-083 was administered intravenously on days 1, 2, and 3 every 21 days. Median PFS determined by Kaplan-Meier analysis with patients censored at
the last known date alive. Median PFS determined at cutoff date of November 2, 2019. CI: Condence interval, PFS: Progression-free survival
[Downloaded free from http://www.jglioma.com on Friday, January 24, 2020, IP: 10.232.74.22]

Guo, et al.: VAL‑083 for the newly diagnosed GBM with MGMT unmethylation
Glioma ¦ Volume 2 ¦ Issue 4 ¦ October‑December 2019 173
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