Inclusion Criteria:
1. Histopathologically proven diagnosis of WHO grade 3-4 glioma. 2. Tumor with one or more putatively pathogenic mutations or homozygous deletion in the
genes associated with DDR or genomic instability, as listed below, will be eligible
for the study. Genetic analysis on tumor tissue should be performed with
next-generation-sequencing (NGS) based analysis to screen for the following genomic
aberrations, which included,
1. IDH mutation. 2. PTEN mutation. 3. "BRCAness" signature (ATM, ATR, BAP1, BRCA1, BRCA2, CDK12, CHEK1, CHEK2, FANCA,
FANCC, FANCD2, FANCE, FANCF, PALB2, NGS1, WRN, RAD50, RAD51B, RAD51C, RAD51D,
MRE11A, BLM, BRIP1) The molecular profiling results will be considered eligible
for screening only if they are performed in laboratories accredited by the
College of American Pathologists (CAP) and certified to meet Clinical
Laboratory Improvement Amendments (CLIA).
3. Patients will be eligible if the original histology was lower-grade glioma and a
subsequent diagnosis of glioblastoma or gliosarcoma is made.
4. Patients who did not have recent surgery for their glioblastoma must have shown
unequivocal radiographic evidence for tumor progression by contrast-enhanced MRI
scan (or CT scan for patients with non-compatible devices) within 21 days prior to
registration. Patients who did have surgery with a post-operative contrast-enhanced
scan falling outside the 5-week window prior to registration, must have a repeat MRI
scan (or CT scan for patients with non-compatible devices) within 21 days prior to
registration.
5. Patients must have passed an interval of 6 months or greater between completion of
prior radiotherapy and registration. If patients have not passed an interval of at
least 6 months, they may still be eligible if they meet one or more of the following
criteria:
1. New areas of tumor outside the original radiotherapy fields as determined by
the investigator, or. 2. Histologic confirmation of tumor through biopsy or resection, or. 3. Nuclear medicine imaging, MR spectroscopy, or MR perfusion imaging consistent
with true progressive disease, rather than radiation necrosis obtained within
28 days of registration AND an interval of at least 90 days between completion
of radiotherapy and registration.
6. Patients unable to undergo MR imaging because of non-compatible devices can be
enrolled provided CT scans are obtained and are of sufficient quality. Patients
without non-compatible devices may not use CT scans performed to meet this
requirement.
7. Prior history of standard dose CNS radiation of 50-60Gy in 25-30 fractions, or 40Gy
in 15 Fractions.
8. Patients must have recovered from the toxic effects of prior therapy, and there must
be a minimum time of 28 days prior to registration from the administration of any
investigational agent or prior cytotoxic therapy with the following exceptions:
1. 14 days from administration of vincristine. 2. 42 days from administration of nitrosoureas. 3. 21 days from administration of procarbazine. 9. Patients having undergone recent resection of their high-grade glioma (within 5
weeks prior to registration) must have recovered from the effects of surgery. For
CNS related core or needle biopsies, a minimum of 7 days must have elapsed prior to
registration.
10. Residual disease following resection of recurrent glioblastoma is not mandated for
eligibility into the study. To best assess the extent of residual disease
post-operatively, a post- operative or intra-operative MRI scan (or CT scan for
patients with non-compatible devices) must be performed prior to registration.
11. At least 18 years of age.
12. World Health Organisation (WHO) performance status 0-2 with no deterioration over
the previous 2 weeks and a minimum life expectancy of 12 weeks. 13. Normal bone marrow and organ function as defined below:
1. Marrow: Hemoglobin ≥10.0 gm/dL, absolute granulocyte count (AGC) ≥1,000/mm3
platelets ≥100,000/mm3, absolute lymphocyte count ≥1000/mm3.
2. Hepatic: Serum/plasma total bilirubin ≤1.5 x upper limit of normal (ULN) with
the exception of <2.9 mg/dL for patients with Gilbert's disease, ALT (SGPT) and
AST (SGOT) ≤2.5 x ULN.
3. Renal: Serum/plasma creatinine (sCr) ≤1.5 x upper limit of normal, or
creatinine clearance (CrCl) ≥50 mL/min.
4. Serum/plasma albumin > 3.0 gm/dL. 14. For female patients of childbearing potential, agreement (by patient and/or partner)
to use a highly effective form(s) of contraception that results in a low failure
rate (< 1% per year) when used consistently and correctly, and to continue its use
for 5 months after the last dose of study treatments. Such methods include: combined
(estrogen and progestogen containing) hormonal contraception, progestogen-only
hormonal contraception associated with inhibition of ovulation together with another
additional barrier method always containing a spermicide, intrauterine device (IUD),
intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized
partner (on the understanding that this is the only one partner during the whole
study duration), and sexual abstinence.
15. Ability to understand and willingness to sign an IRB approved written informed
consent document.
Exclusion Criteria:
1. Prior therapy with PARP inhibitor. 2. Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 1 year (for example, carcinoma in situ of the breast, oral cavity,
or cervix are all permissible).
3. Severe, active co-morbidity, defined as follows:
1. Unstable angina and/or congestive heart failure requiring hospitalization
within the last 6 months prior to registration. 2. Transmural myocardial infarction within the last 6 months prior to registration. 3. History of stroke or transient ischemic attack within 6 months prior to
registration.
4. Significant vascular disease (e.g., aortic aneurysm, history of aortic
dissection) or clinically. 5. Significant peripheral vascular disease.
6. Acute bacterial or fungal infection requiring intravenous antibiotics at the
time of registration. 7. Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness
requiring. 8. Hospitalization or precluding study therapy at the time of registration. 9. Hepatic insufficiency resulting in clinical jaundice and/or coagulation
defects; note, however, that laboratory tests for liver function other than
screening panel and. 10. Coagulation parameters are not required for entry into this protocol.
11. Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition;
note, however, that HIV testing is not required for entry into this protocol.
The need to exclude patients with AIDS from this protocol is necessary because
the treatments involved in this protocol may be significantly
immunosuppressive. Protocol-specific requirements may also exclude
immuno-compromised patients.
