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

NCT04757662 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: 202103257
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief 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).

Conditions

Grade III Astrocytoma; Grade IV Astrocytoma; Astrocytoma, Grade IV; Astrocytoma, Grade III

Outcome Measures

Primary Outcomes (2)

• Relative change of MDSCs in peripheral blood

  Baseline, week 6 of RT, before the start of adjuvant TMZ (approximately 4-6 weeks after the end of RT), before the 3rd cycle of adjuvant TMZ (or approximately 3 months after the end of RT if no planned 3rd cycle of adjuvant TMZ), time of progression

• Frequency of adverse events as measured by CTCAE v5.0

  Baseline through 30 days after last dose of tadalafil (estimated to be 90 days)

Secondary Outcomes (4)

• Rate of severe lymphopenia

  Within 12 weeks from start of radiation therapy

• Progression-free survival (PFS)

  12 months after completion of radiation therapy (estimated to be 14 months)

• Overall survival (OS)

  12 months after completion of radiation therapy (estimated to be 14 months)

• Number of imaging changes on heterogeneity diffusion imaging (HDI)

  Baseline and 4-6 weeks after end of radiation therapy (estimated to be 12 weeks)

Study Arms (1)

Tadalafil

EXPERIMENTAL

* Tadalafil will be given orally once daily for a total of 60 days at a weight-normalized dose as follows: * 10 mg/day if weight ≤63.5 kg * 15 mg/day if weight \>63.5 kg and ≤104.3 kg * 20 mg/day for weight \>104.3 kg * Standard of care fractionated radiation therapy (RT) to 60 Gy in 30 daily fractions will be administered in this study. * Concurrent temozolomide (TMZ) will be administered as per standard of care, i.e., continuously (Monday through Sunday) from Day 1 of RT to the last day of RT at a daily oral dose of 75 mg/m\^2 at the discretion of treating medical oncologist. * Adjuvant therapy will administered as per standard of care. Typically, this consists of adjuvant TMZ initiated 4 to 6 weeks after completion of RT for 6 cycles at 150-200 mg/m\^2 PO per day on Days 1-5 of every 28-day cycle. Tumor-treating fields or Optune device (Novocure) as per routine clinical care during adjuvant TMZ is permitted at the discretion of the treating physician.

Drug: Tadalafil

Interventions

Tadalafil DRUG

Tadalafil is commercially available and will be purchased by the Siteman Cancer Center and distributed to participants free of charge.

Also known as: Cialis, Adcirca

Tadalafil

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically proven diagnosis of newly diagnosed supratentorial high-grade astrocytoma (WHO grade III-IV), excluding astrocytoma of brainstem and cerebellum. However, supratentorial astrocytoma with extension to the brainstem and cerebellum is allowed at discretion of the PI. 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Astrocytoma; Glioblastoma

Interventions

Tadalafil

Condition Hierarchy (Ancestors)

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Carbolines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indole Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 3-Ring

Study Officials

• Jiayi Huang, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 12, 2021
• First Posted: February 17, 2021
• Study Start: May 14, 2021
• Primary Completion: June 7, 2023
• Study Completion: June 7, 2023
• Last Updated: June 13, 2023

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)