Grade III AstrocytomaPhase 1NCT04757662
Tadalafil to Overcome Immunosuppression During Chemoradiotherapy for IDH-wildtype Grade III-IV Astrocytoma
A Phase 1 study testing Tadalafil in people with Grade III Astrocytoma and Grade IV Astrocytoma, run by Washington University School of Medicine at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Grade III Astrocytoma, Grade IV Astrocytoma, Astrocytoma, Grade IV
- What is being tested?
- Tadalafil
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 18 participants
- Where
- 1 siteUnited States
- Study dates
- 14 May 2021to 7 Jun 2023
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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).
Who cannot join
- 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:
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- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Washington University School of Medicine
St Louis, Missouri, 63110
About this study
Official title: 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).
- Conditions
- Grade III Astrocytoma, Grade IV Astrocytoma, Astrocytoma, Grade IV, Astrocytoma, Grade III
- Being tested
- Tadalafil
- Medical subject headings
- Astrocytoma, Glioblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TadalafilDrug
Also called Cialis, Adcirca
Tadalafil is commercially available and will be purchased by the Siteman Cancer Center and distributed to participants free of charge.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Tadalafil |
What is being measured
The primary outcome is the main question the study is designed to answer.
Relative change of MDSCs in peripheral blood
Measured: 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
Measured: Baseline through 30 days after last dose of tadalafil (estimated to be 90 days)
Secondary outcomes (4)
Rate of severe lymphopenia
-Defined as grade 3-4 lymphopenia per CTCAE v5.0 (absolute lymphocyte count < 500)
Measured: 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
Measured: 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.
Measured: 12 months after completion of radiation therapy (estimated to be 14 months)
Number of imaging changes on heterogeneity diffusion imaging (HDI)
Measured: Baseline and 4-6 weeks after end of radiation therapy (estimated to be 12 weeks)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Feb 2021
- Study start14 May 2021
- Primary completion7 Jun 2023
- Study completion7 Jun 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Grade III AstrocytomaStudies of the same condition, open and under way.
- More trials run by Washington University School of MedicineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 18 participants (actual)
Sponsor and investigators
- Lead sponsor
- Washington University School of Medicine
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Jiayi Huang, M.D., Principal investigator, Washington University School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04757662
- Sponsor's protocol ID
- 202103257
- Status last verified
- Jun 2023
- First submitted
- 12 Feb 2021
- Last updated
- 13 Jun 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 13 Jun 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase IB Study to Use Tadalafil to Overcome Immunosuppression During Chemoradiotherapy for IDH-wildtype Grade III-IV Astrocytoma
- ClinicalTrials.gov ID
- NCT04757662
- Acronym / sponsor ID
- 202103257
- Conditions
- Grade III Astrocytoma, Grade IV Astrocytoma, Astrocytoma, Grade IV, Astrocytoma, Grade III
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 18 participants (actual)
- Lead sponsor
- Washington University School of MedicineUniversity, hospital or other
- Study start
- 14 May 2021 (actual)
- Primary completion
- 7 Jun 2023 (actual)
- Study completion
- 7 Jun 2023 (actual)
- First posted
- 17 Feb 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Tadalafil | Experimental | Drug: 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 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (18 listed)
- 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.
Key exclusion criteria (22 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TadalafilAlso: Cialis, AdcircaTadalafil is commercially available and will be purchased by the Siteman Cancer Center and distributed to participants free of charge. | Drug | Tadalafil |
Primary outcome
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
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)
4 secondary outcomes
Rate of severe lymphopenia
Time frame: Within 12 weeks from start of radiation therapy
Progression-free survival (PFS)
Time frame: 12 months after completion of radiation therapy (estimated to be 14 months)
Overall survival (OS)
Time frame: 12 months after completion of radiation therapy (estimated to be 14 months)
Number of imaging changes on heterogeneity diffusion imaging (HDI)
Time frame: Baseline and 4-6 weeks after end of radiation therapy (estimated to be 12 weeks)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Jun 2023.
- Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of MedicineLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jiayi Huang, M.D. principal investigator
Washington University School of Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Tadalafil in people with Grade III Astrocytoma and Grade IV Astrocytoma, run by Washington University School of Medicine at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 18 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Jun 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Jun 2023.