A Phase IB Study to Use Tadalafil to Overcome Immunosuppression During Chemoradiotherapy for IDH-wildtype Grade III-IV Astrocytoma
Overview
- Phase
- Phase 1
- Intervention
- Tadalafil
- Conditions
- Grade III Astrocytoma
- Sponsor
- Washington University School of Medicine
- Enrollment
- 18
- Locations
- 1
- Primary Endpoint
- Frequency of adverse events as measured by CTCAE v5.0
- Status
- Completed
- Last Updated
- 2 years ago
Overview
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).
Investigators
Eligibility Criteria
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 ≥
- •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);
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
Arms & Interventions
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.
Intervention: Tadalafil
Outcomes
Primary Outcomes
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)
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
Secondary Outcomes
- Rate of severe lymphopenia(Within 12 weeks from start of radiation therapy)
- Overall survival (OS)(12 months after completion of radiation therapy (estimated to be 14 months))
- Progression-free survival (PFS)(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))