Tadalafil to Overcome Immunosuppression During Chemoradiotherapy for IDH-wildtype Grade III-IV Astrocytoma
Tadalafil to Overcome Immunosuppression During Chemoradiotherapy for IDH-wildtype Grade III-IV Astrocytoma
Increasing preclinical and clinical data have shown that myeloid-derived suppressor cells
 (MDSCs) may represent a significant driver of immunosuppression in glioblastoma (GBM, grade
 IV astrocytoma) and a potential mechanism of treatment resistance to chemoradiotherapy.
 Tadalafil, an FDA-approved drug with inexpensive cost and excellent safety profile, has been
 shown to effectively reduce MDSCs and restore T-cell activation in the peripheral blood and
 in the tumor microenvironment. The purpose of this study is to investigate the impact of
 targeting MDSCs in newly diagnosed IDH-wildtype grade III-IV astrocytoma by combining
 tadalafil with standard of care radiation therapy (RT) and temozolomide (TMZ).
Inclusion Criteria:

 -  Histologically proven diagnosis of newly diagnosed supratentorial high-grade
 astrocytoma (WHO grade III-IV), excluding astrocytoma of brainstem and cerebellum.
 Gliosarcoma or other subvariants are allowed, including the newly defined "diffuse
 astrocytoma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV"
 (Brat et al., 2018).

 -  Must have recovered from the effects of surgery, postoperative infection, and other
 complications.

 -≥ 18 years of age.

 -  Eligible for and planning to receive standard fractionated RT of 60 Gy with concurrent
 TMZ.

 -  Karnofsky performance status ≥ 60.

 -  Available archival formalin-fixed paraffin-embedded (FFPE) tumor blocks.

 -  Adequate organ and bone marrow function as defined below:

 -  Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;

 -  Platelets ≥ 100,000 cells/mm3;

 -  Hemoglobin > 9.0 g/dL (Note: the use of transfusion or other intervention to
 achieve Hgb >9.0 g/dL is acceptable);

 -  Total bilirubin ≤ 1.5 upper limit of normal (ULN)

 -  AST (SGOT) and ALT (SGPT) ≤ 3 x ULN

 -  Creatinine ≤ 1.5 ULN or creatinine clearance ≥ 60 mL/min

 -  If there is history of human immunodeficiency virus (HIV) infection, patients
 must be on effective antiretroviral therapy, and HIV viral load must be
 undetectable within 6 months of study enrollment.

 -  If there is history of chronic hepatitis B virus (HBV) infection, patients must
 have either been treated or are on suppressive therapy (as indicated), and HBV
 viral load must be undetectable.

 -  If there is history of hepatitis C virus (HCV) infection, patients must have been
 treated, and HCV viral load must be undetectable.

 -  Females of childbearing potential (defined as a female who is non-menopausal or
 surgically sterilized) must be willing to use an acceptable method of birth control
 (i.e., hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom
 with spermicide, or abstinence) for the duration of the study. Should a woman become
 pregnant or suspect she is pregnant while participating in this study, she must inform
 her treating physician immediately.

 -  Able to understand and willing to sign an IRB-approved written informed consent
 document (legally authorized representative permitted).

 Exclusion Criteria:

 -  Prior cranial RT or RT to the head and neck where potential field overlap may exist

 -  Gliomatosis, leptomeningeal, or metastatic involvement.

 -  High-grade glioma with known IDH mutation. IDH status could be determined by either
 immunohistochemistry (IDH1-R132H mutation) or sequencing (including other uncommon
 variants of IDH1 and IDH2 mutations) as evaluated routinely for clinical diagnosis
 using a CLIA-approved assay.

 -  Known severe hypersensitivity to tadalafil or other PDE5 inhibitors, including history
 of hypotension, priapism (painful erection > 4 hours duration), blindness, or hearing
 loss during prior treatment with tadalafil or other PDE5 inhibitors.

 -  Concurrent nitrate, alpha-blocker, guanylate cyclase stimulators (eg, riociguat), or
 cytochrome P-450 3A4 (CYP3A4) inhibitor use. CYP3A4 inhibitors include ketoconazole,
 itraconazole, and ritonavir.

 -  Severe, active co-morbidity, defined as follows:

 -  Unstable angina, angina requiring treatment with nitrates, positive cardiac
 stress test without evidence of subsequent effective cardiac intervention within
 90 days of planned tadalafil administration

 -  Myocardial infarction, coronary artery bypass graft surgery, or percutaneous
 coronary angioplasty or stent within the 90 days of planned tadalafil
 administration

 -  New York Heart Association grade II or greater congestive heart failure within 6
 months

 -  Serious and inadequately controlled arrhythmia

 -  Hypotension (<90/50 mm Hg) or uncontrolled hypertension (>170/100 mm Hg)

 -  Left ventricular outflow obstructions, such as aortic stenosis

 -  Stroke within the last 6 months

 -  Acute bacterial or fungal infection requiring intravenous antibiotics.

 -  Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;
 note, however, that laboratory tests for coagulation parameters are not required
 for entry into this protocol.

 -  Active peptic ulcer disease.

 -  End-stage renal disease (ie, on dialysis or dialysis has been recommended).

 -  Unilateral blindness, hereditary retinal disorder, including retinitis pigmentosa.

 -  Patients treated on any other therapeutic clinical protocols within 30 days prior to
 registration.

 -  Inability to undergo contrast-enhanced MRI (e.g., due to safety reasons, such as
 presence of a pacemaker, or severe claustrophobia).

 -  Pregnant or breastfeeding. Women of childbearing potential must have a negative
 pregnancy test within 14 days of study entry.

 -  Patients with psychiatric illness/social situations, including alcohol or drug abuse
 that in the investigator's opinion will prevent administration or completion of
 protocol therapy.