Tadalafil to Overcome Immunosuppression During Chemoradiotherapy for IDH-wildtype Grade III-IV Astrocytoma

• Status: Recruiting
• Trial end date: 2023-07-31
• Target enrollment: 0
• Participant gender: All

Summary

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).

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Washington University School of Medicine
• Collaborator: The Curtis L. Brown Glioblastoma Research Fund
• Treatments: Tadalafil

Criteria

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 sufficiently that they can proceed with RT and TMZ.

-≥ 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.