PRIMARY OBJECTIVES:
I. To characterize the safety profile and determine the maximum tolerated dose (MTD) of
tinostamustine (EDO-S101) in the adjuvant phase of therapy for patients with newly diagnosed
MGMT-promoter unmethylated glioblastoma (GB) post chemoradiation with temozolomide. (Stage 1)
II. To characterize the safety profile and determine the MTD of EDO-S101 when given as a
single agent in the concomitant phase with radiation therapy (RT) in patients with newly
diagnosed GB who are O6-methylGuanine deoxyribonucleic acid (DNA) methyltransferase
(MGMT)-promoter unmethylated. (Stage 2) III. To confirm the MTD of EDO-S101 in the
concomitant phase and adjuvant phase in an expanded population of newly diagnosed GB patients
who are MGMT-promoter un-methylated. (Dose Expansion Group)
SECONDARY OBJECTIVE:
I. To assess anti-tumor activity for patients with newly diagnosed GB who are MGMT-promoter
unmethylated based on progression-free survival (PFS), overall survival (OS), and overall
response rate (ORR).
EXPLORATORY OBJECTIVE:
I. Profiling tumor DNA, messenger ribonucleic acid (mRNA), microRNA and epigenetic profiling
(DNA methylation) and evaluation of whole exome sequencing, RNA sequencing, microRNA
sequencing and cell-free circulating tumor DNA (ctDNA) and correlate with outcome.
OUTLINE: This is a dose escalation study of tinostamustine. Patients who have completed
temozolomide (TMZ) and radiation therapy (RT) are assigned to Stage 1A or Stage 1B. Patients
who have received no treatment other than surgery are assigned to Stage 2.
STAGE 1A: Patients receive tinostamustine intravenously (IV) over 30 minutes on day 1.
Treatment repeats every 21 days for up to 12 cycles in the absence of disease progression or
unacceptable toxicity.
STAGE 1B: Patients receive tinostamustine IV over 30 minutes on days 1 and 15. Treatment
repeats every 28 days for up to 12 cycles in the absence of disease progression or
unacceptable toxicity.
STAGE 2: Patients undergo RT 5 days a week for up to 6 weeks in the absence of disease
progression or unacceptable toxicity. Patients also receive tinostamustine IV on day 1 or
days 1 and 15 (to be determined following stage 1). Treatment repeats every 21 days (day 1)
or 28 days (days 1 and 15) for up to 12 cycles in the absence of disease progression or
unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 3
months.
Inclusion Criteria:
- Be willing and able to provide written informed consent for the trial.
- Have histologically confirmed World Health Organization grade IV glioma (glioblastoma
[GB] or gliosarcoma).
- Patients must have preliminary glioblastoma (GBM) MGMT status (tumor must be MGMT
promoter unmethylated) determined prior to study entry. If initial MGMT status is
determined to be "unmethylated", by an outside institution the patient may be enrolled
and begin treatment. However, MGMT status must be retested following enrollment by
central laboratory Clinical Laboratory Improvement Act (CLIA) certified testing at MD
Anderson, if tissue is available. Confirmed IDH wildtype. The presence of an IDH
mutation will be an exclusionary criteria for trial enrollment.
- Have a performance status of >= 60 on the Karnofsky performance scale (KPS).
- If patient is on steroids, patient must be on a stable or decreasing dose of steroids
for at least 5 days at the time of baseline brain magnetic resonance imaging (MRI).
- Absolute neutrophil count (ANC) >= 1,500 /mcL (within 14 days [+3 working days] of
treatment initiation).
- Platelets >= 100,000 /mcL (within 14 days [+3 working days] of treatment initiation).
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (within 14 days [+3 working days] of treatment
initiation).
- Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration
rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =<
1.5 x upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels >
1.5 x institutional ULN (within 14 days [+3 working days] of treatment initiation).
- Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 ULN (within 14 days [+3 working days] of treatment initiation).
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
ULN (within 14 days [+3 working days] of treatment initiation).
- International normalized ratio (INR) or prothrombin time (PT), activated partial
thromboplastin time (aPTT) =< 1.5 x ULN (within 14 days [+3 working days] of treatment
initiation).
- Female subjects of childbearing potential should have a negative serum pregnancy test
within 72 hours of starting first dose of study drug.
- Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the
duration of the study. Subjects of childbearing potential are those who have not been
surgically sterilized or have not been free from menses for > 1 year.
- Male subjects should agree to use an adequate method of contraception during the
course of the study.
- Patients must have completed standard radiation therapy with concurrent TMZ and must
not have evidence of progressive disease on post treatment imaging. Progression can
only be defined using diagnostic imaging if there is new enhancement outside of the
radiation field (beyond the high-dose region or 80% isodose line) or if there is
unequivocal evidence of viable tumor on histopathologic sampling (e.g., solid tumor
areas [i.e, > 70% tumor cell nuclei in areas], high or progressive increase in MIB-1
proliferation index compared with prior biopsy, or evidence for histologic progression
or increased anaplasia in tumor). Note: Given the difficulty of differentiating true
progression from pseudoprogression, clinical decline alone, in the absence of
radiographic or histologic confirmation of progression, will not be sufficient for
definition of progressive disease in the first 12 weeks after completion of concurrent
chemoradiotherapy. (For Stage 1: post-chemoradiation group only)
- Prescribed treatment with concomitant temozolomide must be consistent with the Food
and Drug Administration (FDA) package insert. The dose must be 75 mg/m^2 daily for the
6 to 6.5 weeks of radiation therapy. If the patient missed more than 1 week of
temozolomide dosing during radiotherapy, then they are not eligible for the trial.
EDO-S101 can accentuate thrombocytopenia induced by temozolomide. Therefore, if
patients had a platelet < 75,000/mm^3 during concomitant temozolomide therapy during
radiation, they are not eligible for this trial
- NOTE: Complete blood count (CBC) should be monitored during chemoradiation and
lowest platelet count must be submitted at registration. (For stage 1:
post-chemoradiation group only)
- Patients must have undergone surgery of their GBM, and must not have had any further
treatment following surgery. A minimal interval of 7 days between the day of surgery
and the day of inclusion should be respected; a maximal interval of 31 days between
the day of surgery and the day of inclusion should be respected; the patient should
have fully clinically recovered from the surgery. (For stage 2: radiation with
concurrent and adjuvant EDO-S101 only)
- Patients must undergo surgery and must not have further treatment. (For MTD expansion
cohort only)
Exclusion Criteria:
- Has received prior interstitial brachytherapy, implanted chemotherapy, or therapeutics
delivered by local injection or convection enhanced delivery. Prior treatment with
Gliadel wafers will be excluded. Concomitant use of the Optune device will also be
excluded.
- Is currently participating or has participated in any other any other investigational
or therapeutic trial before or after chemoradiation.
- Any serious medical condition that interferes with adherence to study procedures.
- Has had prior chemotherapy, targeted small molecule therapy, within 2 weeks prior to
study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse
events due to a previously administered agent. Note: subjects with =< grade 2
neuropathy are an exception to this criterion and may qualify for the study. Note: if
subject received major surgery, they must have recovered adequately from the toxicity
and/or complications from the intervention prior to starting therapy. (For Stage 1:
post-chemoradiation group only)
- Patients with a history of a second malignancy diagnosed within three (3) years of
study enrollment or have a known additional malignancy that is progressing or requires
active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell
carcinoma of the skin, or in situ cervical cancer that has undergone potentially
curative therapy.
- New York Heart Association (NYHA) stage III/IV congestive heart failure, arrhythmias
not adequately controlled.
- Patients with prolonged corrected QT (QT) interval defined as male > 450 msec and
female > 470 msec.
- Patients who are on treatment with drugs known to prolong the QT/QTc interval. Case of
the selective serotonin reuptake inhibitors (SSRIs): Patients treated with a SSRI AND
displaying a QTc prolongation are NOT eligible in the trial. Nevertheless, there is no
need to stop or change a SSRI if a patient is on a stable dose AND with no impact on
QT/QTc interval, since it is not expected that plasma concentration of the SSRI will
be affected by the administration of EDO-S101
- Has known gliomatous meningitis, extracranial disease, or multifocal disease. Subject
has multifocal GBM, defined as discrete sites of contrast enhancing disease without
contiguous T2/fluid-attenuated inversion recovery (FLAIR) abnormality that require
distinct radiotherapy ports. Satellite lesions that are associated with a contiguous
area of T2/FLAIR abnormality as the main lesion(s) and that are encompassed within the
same radiotherapy port as the main lesion(s) are permitted.
- Has an active infection requiring systemic therapy.
- Has an ongoing or previous history of spontaneous intratumoral hemorrhage.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the screening visit.
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
Testing not required.
- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus (HCV) RNA [qualitative] is detected). (Testing
not required for stage 2 and MTD expansion cohort)
- Has received a live vaccine within 30 days prior to the first dose of trial treatment.
- Contraindication for undergoing MRIs.
- Use of any drug with histone deacetylase (HDAC) inhibiting activity.
- Use of valproate in any of its indications (epilepsy, mood disorder). Valproate, due
to its HDAC inhibiting activity is contraindicated. For those patients on valproate,
valproate will need to be discontinued and switched to a different anti-epileptic
agent or psychotropic agent. A washout period of 4 days from valproate acid will be
allowed prior to enrolling into the trial.
- Patients who missed more than 1 week of temozolomide dosing during radiotherapy. (For
Stage 1: Post-chemoradiation group only)
- Patients who had a platelet < 75,000/mm^3 during concomitant temozolomide therapy
during radiation. (For Stage 1: Post-chemoradiation group only)
- Has had any prior chemotherapy, targeted small molecule therapy. (For Stage 2:
Radiation with concurrent and adjuvant EDO-S101 and MTD Expansion cohort only).
