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

  • STATUS
    Recruiting
  • End date
    Jul 31, 2023
  • participants needed
    16
  • sponsor
    Washington University School of Medicine
Updated on 15 September 2021
cancer
karnofsky performance status
chemoradiotherapy
neutrophil count
temozolomide
astrocytoma
gliosarcoma

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).

Details
Condition Astrocytoma, Glioma, Glioblastoma Multiforme, glioblastoma, astrocytoma, anaplastic
Treatment Tadalafil
Clinical Study IdentifierNCT04757662
SponsorWashington University School of Medicine
Last Modified on15 September 2021

Eligibility

Yes No Not Sure

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
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
Clear my responses

How to participate?

Step 1 Connect with a study center
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar

Primary Contact

site

0/250

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider

Loading...

Browse trials for

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

user name

Added by • 

 • 

Private

Reply by • Private
Loading...

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.
Loading...

No annotations made yet

Add a private note
  • abc Select a piece of text from the left.
  • Add notes visible only to you.
  • Send it to people through a passcode protected link.
Add a private note