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

A Phase IB Study to Use 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).

Study Overview

• Status: Completed
• Conditions: Astrocytoma, Grade III; Astrocytoma, Grade IV; Grade IV Astrocytoma; Grade III Astrocytoma
• Intervention / Treatment: Drug: Tadalafil

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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.
  • 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Tadalafil; 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 kg15 mg/day if weight >63.5 kg and ≤104.3 kg20 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; Tadalafil is commercially available and will be purchased by the Siteman Cancer Center and distributed to participants free of charge.; Other Names: Cialis; Adcirca

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of severe lymphopenia	-Defined as grade 3-4 lymphopenia per CTCAE v5.0 (absolute lymphocyte count < 500)	Within 12 weeks from start of radiation therapy
Progression-free survival (PFS)	PFS is defined as the time from enrollment in the trial until time of disease progression or death from any cause.; Progression will measured per standard clinical care based on the Response Assessment in Neuro-Oncology (RANO) working group guideline	12 months after completion of radiation therapy (estimated to be 14 months)
Overall survival (OS)	-OS is defined as the time from enrollment in the trial until the date of death due to any cause.	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)

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Jiayi Huang, M.D., Washington University School of Medicine

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): May 14, 2021
• Primary Completion (Actual): June 7, 2023
• Study Completion (Actual): June 7, 2023

Study Registration Dates

• First Submitted: February 12, 2021
• First Submitted That Met QC Criteria: February 12, 2021
• First Posted (Actual): February 17, 2021

Study Record Updates

• Last Update Posted (Estimated): June 13, 2023
• Last Update Submitted That Met QC Criteria: June 12, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Astrocytoma; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Tadalafil
• Other Study ID Numbers: 202103257

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No