Inclusion Criteria:
- - Signed informed consent form (ICF)
- Ability and willingness to comply with the requirement of the study protocol.
- - Histologically confirmed World Health Organization (WHO) grade IV glioma (GBM) or
gliosarcoma, IDH wild-type.
- - Documentation of MGMT unmethylated GBM per testing at any Clinical Laboratory
Improvement Amendment (CLIA) certified laboratory.
- - Patients must have undergone brain surgery or biopsy and must not have had any further
treatments following surgery.
- - Have Karnofsky performance status (KPS) of >= 60 or Eastern Cooperative Oncology Group
(ECOG) =< 2.
- - A baseline magnetic resonance imaging (MRI) of brain obtained no more than 14 days
prior to study enrollment on a stable or tapering dose of steroids no greater than 4
mg a day of dexamethasone (or equivalent dose of other steroids) for at least 3 days.
- - Patients must start treatment within 8 weeks of last brain surgical procedure (biopsy
or resection)
- Absolute neutrophil count (ANC) >= 1,500 /mcL (within 14 days prior to day 1 of the
study)
- Platelets >= 100,000/mcL (within 14 days prior to day 1 of the study)
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (within 14 days prior to day 1 of the study)
- Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated
creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine
levels > 1.5 x institutional ULN (within 14 days prior to day 1 of the study)
o Creatinine clearance should be calculated per institutional standard.
- - Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 x ULN (within 14 days prior to day 1 of the study)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
ULN (within 14 days prior to day 1 of the study)
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN (within 14
days prior to day 1 of the study)
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN (within 14 days prior to day
1 of the study)
- Have provided tissue from an archival tissue sample.
- - Female subjects of childbearing potential should have a negative serum pregnancy test
within 14 days of day 1 of the study.
- - Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile.
o Female 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.
- - STAGE I: In the case stage I patients need resection as determined by the treating
physicians during or after completion of radiation therapy (RT) and that pathology of
resected lesion is not consistent with recurrent GBM, the patient can continue on the
study (complete 6 weeks of RT + M3814) if deemed appropriate by the treating
physicians.
The tissue obtained in such circumstances will be analyzed as in Stage II
subjects. However, these cases will not count towards the 5 patients who will be
enrolled during Stage
- II. These patients will contribute to the correlative endpoints
detailed above and ORR, OS, and PFS as Stage II patients.
- - STAGE II: Patients meet above criteria, would benefit from further non-urgent surgical
resection of at least one enhancing lesion per the treating physician, and would
provide consent to undergo surgery after treatment with RT and M3814.
Exclusion Criteria:
- - Has received prior interstitial brachytherapy, implanted chemotherapy, or therapeutics
delivered by local injection or convection enhanced delivery.
Prior treatment with
Gliadel® wafers and laser interstitial thermal therapy (LITT) will be excluded. Active
treatment with the tumor treating filed devices such as Optune during radiation will
be excluded. Concurrent use of Optune during the adjuvant temozolomide cycles is
allowed.
- - Currently participating or previously participated in any other newly diagnosed GBM
therapeutic trials.
- - History of MGMT methylated status performed at any CLIA certified laboratory.
- - Any serious medical condition that interferes with adherence to study procedures.
- - Malignancies other than the disease under study within 2 years prior to Day 1 of the
study, with the exception of those with a negligible risk of metastasis or death and
with expected curative outcome (such as adequately treated carcinoma in situ of the
cervix, basal or squamous cell skin cancer, localized prostate cancer treated
surgically with curative intent, or ductal carcinoma in situ treated surgically with
curative intent) or undergoing active surveillance per standard-of-care management
(e.g., chronic lymphocytic leukemia Rai Stage 0, prostate cancer with Gleason score =<
6, and prostate-specific antigen [PSA] =< 10 mg/mL, etc).
- - Has known disease in the posterior fossa, gliomatosis cerebri, leptomeningeal disease,
extracranial disease or multicentric enhancing disease.
Multicentric disease is
defined as discrete sites of contrast enhancing disease without contiguous T2/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 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 physician.
- - 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 children within the projected
duration of the trial, starting with the screening visit.
- - Contraindication for undergoing MRIs.
- - Inability to comply with study and follow-up procedures.
- - Signs or symptoms of serious infection such as surgical wound infection, received IV
antibiotics within 2 weeks prior to Day 1 of the study.
- - Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary
tract infection or chronic obstructive pulmonary disease) are eligible.
- - Patients receiving oral antibiotics for minor infections such as urinary tract
infection are eligible.
- - History of HIV infection.
- - Administration of a live, attenuated vaccine within 4 weeks before Day 1 of the study
or anticipation that such a live, attenuated vaccine will be required during the study.
- - Influenza vaccination can be given.
Patients must not receive live, attenuated
influenza vaccine (e.g., FluMist®) within 4 weeks prior to Day 1 of the study or at
any time during the study and for 5 months after completion of adjuvant TMZ.
- - History of long QT syndrome.
- - Any other diseases, metabolic dysfunction, physical examination finding, or clinical
laboratory finding giving reasonable suspicion of a disease or condition that
contraindicates the use of M3814 or that may affect the interpretation of the results
or render the patient at high risk from treatment complications.
- - Anticipation of need for a major surgical procedure during the course of the study
(excluding patients in Stage II with planed non-urgent neuro-surgical resection)
- Subjects at increased risk for radiation toxicities, such as known active collagen
vascular disease (example; scleroderma, Sjogren's disease, etc) or other inherited
radiation hypersensitivity syndromes (example; Gorlin syndrome, Fanconi anemia,
ataxia-telangiectasia, etc.)
- Active difficulty swallowing, malabsorption or other chronic gastrointestinal disease
or conditions (including pancreas deficiency requiring Creon therapy) that may hamper
compliance and/or absorption of M3814.
- - Patients may not receive concomitant chemotherapy, immunotherapy, or radiotherapy
(other than as pertained to standard of care for GBM as described in section 1.1)
while patients are on study.
- - Prior treatment with DNA damage response inhibitors (including inhibitors of PARP,
ATR, WEE).
