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.
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).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
23
100mg IV once every two weeks
150 mg orally (PO) once a day (QD)
240 mg IV once every two weeks starting within 1 week of completing metastasis-directed SBRT
Standard of care metastasis-directed hypofractionated radiotherapy treatment starting 4 weeks (+/- 1 week) of starting Etrumadenant and Quemliclustat
Columbia University Irving Medical Center / NewYork-Presbyterian Hospital
New York, New York, United States
RECRUITINGBiochemical recurrence-free survival at 12-months
Biochemical recurrence is defined as a 0.2 ng/ml increase in PSA above the post-SBRT PSA nadir. Patient will be followed until biochemical recurrence, death, or end of study, whichever comes first. Patients who are alive and biochemical recurrence free will be censored at the last PSA measurement date.
Time frame: 12 months
Biochemical recurrence-free survival at 6-months
To estimate the proportion of men treated with quemliclustat + etrumadenant + zimberelimab + SBRT who are free from biochemical failure at 6-months.
Time frame: 6 months
To estimate treatment response based on CT at 6-months
Report the percentage of patients with PD, CR, PR, and SD based on CT imaging among patients treated with oligometastasis-directed SBRT + quemliclustat + etrumadenant + zimberelimab at 6-months.
Time frame: 6 months
To estimate treatment response based on nuclear bone scan at 6-months.
Report the percentage of patients with PD, CR, PR, and SD based on nuclear bone scan among patients treated with oligometastasis-directed SBRT + quemliclustat + etrumadenant + zimberelimab at 6-months.
Time frame: 6-months
To estimate treatment response based on PSMA-PET scan at 6-months.
Report the percentage of patients with PD, CR, PR, and SD based on PSMA-PET scan among patients treated with oligometastasis-directed SBRT + quemliclustat + etrumadenant + zimberelimab at 6-months.
Time frame: 6-months
Proportion of patients who start ADT.
Time frame: 6, 12 months and 3 years.
To estimate pain over time.
Quantify pain using a numeric 10-point scale using the Brief Pain Inventory (BPI) every 12 weeks from time of enrollment.
Time frame: Every 12 weeks for 3.5 years
To assess the safety and tolerability of oligometastasis-directed SBRT + quemliclustat + etrumadenant + zimberelimab.
Adverse events graded by CTCAE v5.0.
Time frame: 6, 12 months and 3 years
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