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).
- 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
-≥ 18 years of age.
- Eligible for and planning to receive standard fractionated RT of 60 Gy with concurrent
- 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).
- 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
- New York Heart Association grade II or greater congestive heart failure within 6
- 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
- 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