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This study will evaluate the safety and effectiveness of a combination of study drugs including zimberelimab, etrumadenant, and quemliclustat in combination with metastasis-directed irradiation in men with hormone sensitive oligometastatic prostate cancer.
The study aims to test the hypothesis that targeted inhibition of the adenosine signaling axis (quemliclustat (CD73 antagonist) + etrumadenant (A2AR/A2BR antagonist)) and immune checkpoint inhibition (zimberelimab, α-PD-1) in combination with metastasis-directed stereotactic body radiation therapy (SBRT) will improve local control, progression-free survival (PFS), and hormone therapy-free survival and mitigate immunosuppressive changes to the tumor microenvironment (TME), compared to SBRT alone.
Full description
The optimal therapeutic approach to men with oligometastatic (1-3 or 1-5 sites of metastatic disease) prostate cancer is ever more important as advanced imaging technologies are becoming standard of care, providing clinicians with the tools to accurately diagnose and localize oligometastatic prostate cancer. Hence, methods to improve the local curative potential of stereotactic body radiation therapy (SBRT) is a timely and important opportunity. In addition, previous data suggest that the adenosine A2A pathway may be a particularly attractive avenue for intervention in the context of radiation, thus influencing multiple suppressive populations within the tumor microenvironment (TME).
Immunotherapy based on the PD-1/PD-L1 signaling axis is a mainstay of therapy across multiple types of malignancies. This study aims to evaluate the effectiveness of a PD-1 inhibitor (zimberelimab) in combination with a selective dual antagonist of A2aR and A2bR (etrumadenant) and an anti-CD73 (quemliclustat). Immune checkpoint inhibitors and targeted inhibitors of the adenosine signaling axis modulate the TME and aspects of the systemic immune system to overcome tumor-induced immune suppression and improve responses to therapy.
This study aims to determine the effect of etrumadenant, quemliclustat and zimberelimab [experimental] when given with ablative radiation (SBRT)[standard of care] on the oligoprogressive disease (hormone sensitive oligometastatic prostate cancer), defined by being free from radiographic progression of irradiated target metastases and PSA (prostate surface antigen) response at 6 months. PSA response, local control, progression-free survival (PFS), treatment response, ADT-free survival, time-to-pain, and safety and tolerability will also be measured. By employing a Simon Two-Stage design, the trial will test whether or not etrumadenant + quemliclustat and zimberelimab combined with ablative radiation (SBRT) will improve PFS compared to SBRT alone (ORIOLE).
Enrollment
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Inclusion criteria
Patient must have histologically confirmed adenocarcinoma of the prostate.
Patient's primary prostate cancer tumor treated with surgery and/or radiation (+/- ADT).
Patients must have one to three asymptomatic metastatic tumors of the bone or soft tissue that developed in the preceding 6 months that are < 5cm or < 250 cm3.
Prostate-specific antigen (PSA) > 0.5 ng/mL but < 50ng/ml
PSA doubling time (PSADT) < 15 months (using all available PSA values from time of relapse)
Testosterone > 125 ng/mL
Age ≥18 years.
Patient must have life expectancy > 12 months.
Eastern Cooperative Oncology Group (ECOG) performance status 0-2
Normal organ and marrow function as defined below:
Male participants with female partners of childbearing potential are required to use highly effective contraceptive measures which include condom use. A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. A female partner of is considered a woman of childbearing potential (WOCBP) following menarche and until becoming postmenopausal unless permanently sterile.
Highly effective contraceptive measures include:
Male participants should refrain from donating sperm for 180 days after the last dose of the study drugs.
Patient must have the ability to understand and the willingness to sign written informed consent.
Exclusion criteria
Patient may not have had prior systemic therapy, with the exception of androgen deprivation therapy (ADT) associated with treatment of the primary prostate tumor or with salvage radiation therapy. The ADT could not exceed 3-years in duration and must have occurred greater than 6 months before time of enrollment.
Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
Spinal cord compression or impending spinal cord compression.
Pulmonary and/or liver metastases > 1.0cm in largest dimension.
History of malignancy other than prostate cancer within 2 years prior to screening, except for malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as nonmelanoma skin carcinoma or ductal carcinoma in situ.
Use of other investigational agents or treatment protocol.
Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to initiation of study treatment with the exception of patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
Inability to swallow medications.
Malabsorption condition that would alter the absorption of orally administered medications.
Grade ≥ 3 hemorrhage or bleeding event within 28 days prior to initiation of study treatment.
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan.
Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
Positive total hepatitis B core antibody (HBcAb) test at screening. Patients can be eligible if positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening. The HBV test will be performed only for participants who have a positive total HBcAb test. Due to safety concerns related to viral activation, development of a secondary malignancy, as well as the potential for increased treatment-related toxicity, eligible participants must not have evidence of chronic viral infection at screening.
Due to the potential risk for drug-drug interactions with etrumadenant, participants must not have had:
Immunosuppression (e.g., solid organ transplant on immunosuppression).
No known HIV, or active with Hepatitis C Virus (HCV) or Hepatitis B Virus (HBV).
Active autoimmune disease.
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
Inability to lie flat to tolerate computed tomography (CT) simulation study and oligometastasis-directed stereotactic body radiotherapy (SBRT).
Use of any live vaccines against infectious diseases within 28 days of first dose of investigational products.
Refusal to sign informed consent.
Primary purpose
Allocation
Interventional model
Masking
23 participants in 1 patient group
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Central trial contact
Catherine S. Spina, MD, PhD; Research Nurse Navigator
Data sourced from clinicaltrials.gov
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