Clinical Trials /

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

NCT04757662

Description:

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).

Related Conditions:
  • Anaplastic Astrocytoma
  • Gliosarcoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Tadalafil to Overcome Immunosuppression During Chemoradiotherapy for IDH-wildtype Grade III-IV Astrocytoma
  • Official Title: A Phase IB Study to Use Tadalafil to Overcome Immunosuppression During Chemoradiotherapy for IDH-wildtype Grade III-IV Astrocytoma

Clinical Trial IDs

  • ORG STUDY ID: 21-x025
  • NCT ID: NCT04757662

Conditions

  • Grade III Astrocytoma
  • Grade IV Astrocytoma
  • Astrocytoma, Grade IV
  • Astrocytoma, Grade III

Interventions

DrugSynonymsArms
TadalafilCialis, AdcircaTadalafil

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
TadalafilExperimentalTadalafil 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.
  • Tadalafil

Eligibility 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.

             -≥ 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Relative change of MDSCs in peripheral blood
Time Frame: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
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Frequency of adverse events as measured by CTCAE v5.0
Time Frame:Baseline through 30 days after last dose of tadalafil (estimated to be 90 days)
Safety Issue:
Description:
Measure:Rate of severe lymphopenia
Time Frame:Within 12 weeks from start of radiation therapy
Safety Issue:
Description:-Defined as grade 3-4 lymphopenia per CTCAE v5.0 (absolute lymphocyte count < 500)
Measure:Progression-free survival (PFS)
Time Frame:12 months after completion of radiation therapy (estimated to be 14 months)
Safety Issue:
Description: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
Measure:Overall survival (OS)
Time Frame:12 months after completion of radiation therapy (estimated to be 14 months)
Safety Issue:
Description:-OS is defined as the time from enrollment in the trial until the date of death due to any cause.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Washington University School of Medicine

Last Updated

February 17, 2021