Adenosine Signaling Modulation and Immune Checkpoint Inhibition With Hormone Sensitive Oligometastatic Prostate Cancer (SBRT-AMICO)

• ClinicalTrials.gov Identifier: NCT05915442
• Recruitment Status: Recruiting
• First Posted: June 23, 2023
• Last Update Posted: May 7, 2024
• Sponsor: Catherine Spina
• Collaborator: Arcus Biosciences, Inc.
• Information provided by (Responsible Party): Catherine Spina, Columbia University

Tracking Information

• First Submitted Date: June 7, 2023
• First Posted Date: June 23, 2023
• Last Update Posted Date: May 7, 2024
• Actual Study Start Date: July 1, 2023
• Estimated Primary Completion Date: December 1, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 6, 2024)

Biochemical recurrence-free survival at 12-months [ Time Frame: 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.

Original Primary Outcome Measures (submitted: June 14, 2023)

Proportion of Participants free of progressive disease at 6 months [ Time Frame: 6 months ]

To evaluate efficacy of study treatment if >91% of subjects (21 of 23) are free of progressive disease by measuring percentage of subjects free of progressive disease after at 6 months start of treatment. Progressive disease is defined as one of the following (1) At least a 20% increase in the sum of the longest diameter (LD) of the target lesion compared to smallest sum of LD recorded since treatment start, or (2) 1 or more new lesions on CT or nuclear bone scan or (3) > 25% increase in PSA concentration measured in peripheral blood from nadir or total PSA > 50 ng/mL.

Current Secondary Outcome Measures (submitted: May 6, 2024)

• Biochemical recurrence-free survival at 6-months [ Time Frame: 6 months ]
  To estimate the proportion of men treated with quemliclustat + etrumadenant + zimberelimab + SBRT who are free from biochemical failure at 6-months.
• To estimate treatment response based on CT at 6-months [ Time Frame: 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.
• To estimate treatment response based on nuclear bone scan at 6-months. [ Time Frame: 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.
• To estimate treatment response based on PSMA-PET scan at 6-months. [ Time Frame: 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.
• Proportion of patients who start ADT. [ Time Frame: 6, 12 months and 3 years. ]
• To estimate pain over time. [ Time Frame: Every 12 weeks for 3.5 years ]
  Quantify pain using a numeric 10-point scale using the Brief Pain Inventory (BPI) every 12 weeks from time of enrollment.
• To assess the safety and tolerability of oligometastasis-directed SBRT + quemliclustat + etrumadenant + zimberelimab. [ Time Frame: 6, 12 months and 3 years ]
  Adverse events graded by CTCAE v5.0.

Original Secondary Outcome Measures (submitted: June 14, 2023)

• Proportion of Participants free of progressive disease at 12 months [ Time Frame: 12 months ]
  To estimate the proportion of men treated with quemliclustat + etrumadenant + zimberelimab + SBRT who are free of progressive disease at 12 months as defined by target lesion(s) and PSA response at 12 months.
• Prostate Specific Antigen (PSA) Response [ Time Frame: 12 weeks ]
  Defined as average PSA change at 12 weeks compared to value on Day 0 (as per Prostate Cancer Working Group 3 PCWG3 criteria) and/or maximal PSA decline.
• Local Control Rate, free of progression of target lesion(s) at 6 months and 12 months [ Time Frame: 6 and 12 months ]
  To estimate Local Control (LC) rate, based on radiographic response by irradiated target lesion(s) including stable disease (SD), partial response (PR), and complete response (CR).
• Progression-free survival (PFS) [ Time Frame: 3.5 years ]
  To estimate the progression-free survival (PFS) in patients treated with oligometastasis-directed SBRT + quemliclustat + etrumadenant + zimberelimab based on progression of disease (target lesion(s), PSA) and death.
• Treatment Response based on nuclear bone scans at 6 and 12 months. [ Time Frame: 6 and 12 months ]
  To estimate treatment response based on nuclear bone scans
• Treatment Response based on CT at 6 and 12 months. [ Time Frame: 6 and 12 months ]
  To estimate treatment response based on CT scans
• Treatment Response based on PSA measured in the peripheral blood at 6 and 12 months. [ Time Frame: 6 and 12 months ]
  To estimate treatment response based on PSA concentration (ng/mL) measured in peripheral blood.
• ADT-Free Survival [ Time Frame: 3.5 years ]
  To determine ADT-free survival in patients treated with oligometastasis-directed SBRT + quemliclustat + etrumadenant + zimberelimab. This will be quantified based on the length of time patients remain off of androgen deprivation therapy (ADT), measuring the time between study enrollment and initiation of ADT at time of PD.
• Pain over time [ Time Frame: 3.5 years ]
  Quantify pain on a numeric 10-point scale using the Brief Pain Inventory (BPI) form every 12 weeks starting at time of enrollment.
• Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: 3.5 years ]
  To assess the safety and tolerability of oligometastasis-directed SBRT + quemliclustat + etrumadenant + zimberelimab based on adverse events reported according to CTCAE v5.0 grade.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Adenosine Signaling Modulation and Immune Checkpoint Inhibition With Hormone Sensitive Oligometastatic Prostate Cancer
• Official Title: Phase II Single Arm Study Testing SBRT, Adenosine Signaling Modulation (AB680, AB928), and Immune Checkpoint Inhibition (AB122) for Men With Hormone Sensitive Oligometastatic Prostate Cancer

Brief Summary

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.

Detailed 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).

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description:

Simon Two-Stage design: In the first stage, trial will enroll 14 patients. If two or more patients show progression at 6 months, the study is terminated at the end of stage I. However, if 13 of the 14 remain free from progressive disease at 6 months, then the study would move onto the second stage. In this stage, n=9 additional patients will be enrolled, for a total of 23 total. If 21 of the 23 patients remain progression-free at 6 months, then the null hypothesis is rejected, and we will consider the addition of quemliclustat, etrumadenant, and zimberelimab to SBRT worthy of further study.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Oligometastatic Prostate Cancer

Intervention

• Drug: Quemliclustat
  100mg IV once every two weeks
  Other Name: AB680
• Drug: Etrumadenant
  150 mg orally (PO) once a day (QD)
  Other Name: AB928
• Drug: Zimberelimab
  240 mg IV once every two weeks starting within 1 week of completing metastasis-directed SBRT
  Other Name: AB122
• Radiation: Stereotactic Body Radiation Therapy
  Standard of care metastasis-directed hypofractionated radiotherapy treatment starting 4 weeks (+/- 1 week) of starting Etrumadenant and Quemliclustat
  Other Name: SBRT

Study Arms

Experimental: Treatment with quemliclustatm, etrumadenant, zimberelimab and SBRT

Subjects with metastatic prostate cancer will receive quemliclustat and etrumadenant for 4 weeks prior to metastasis-directed SBRT (Stereotactic Body Radiation Therapy). Within one week of completing SBRT, subjects will also start zimberelimab.

Interventions:

• Drug: Quemliclustat
• Drug: Etrumadenant
• Drug: Zimberelimab
• Radiation: Stereotactic Body Radiation Therapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 14, 2023): 23
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2028
• Estimated Primary Completion Date: December 1, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Patient must have histologically confirmed adenocarcinoma of the prostate.
2. Patient's primary prostate cancer tumor treated with surgery and/or radiation (+/- ADT).
3. 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.
4. Prostate-specific antigen (PSA) > 0.5 ng/mL but < 50ng/ml
5. PSA doubling time (PSADT) < 15 months (using all available PSA values from time of relapse)
6. Testosterone > 125 ng/mL
7. Age ≥18 years.
8. Patient must have life expectancy > 12 months.
9. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

10. Normal organ and marrow function as defined below:

    • leukocytes ≥3,000/mcL
    • absolute neutrophil count ≥1,500/mcL
    • platelets ≥100,000/mcL
    • total bilirubin within normal institutional limits
    • aspartate transaminase (AST)(serum glutamic-oxaloacetic transaminase (SGOT))/alanine transaminase (ALT)(serum glutamic-pyruvic transaminase (SGPT) ) ≤2.5 × institutional upper limit of normal creatinine, within normal institutional limits

11. 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.

    • Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
    • A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

    Highly effective contraceptive measures include:

    • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal
    • Progestogen only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable
    • Intrauterine device
    • Intrauterine hormone-releasing system
    • Surgical sterilization
    • The male participant is vasectomized (with documented medical confirmation of surgical success) and is the sole sexual partner of the WOCBP participant
    • Female partner of the male participant has undergone bilateral tubal ligation
    • Complete sexual abstinence defined as refraining from heterosexual intercourse during the entire period of risk associated with study treatment. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant.
12. Male participants should refrain from donating sperm for 180 days after the last dose of the study drugs.
13. Patient must have the ability to understand and the willingness to sign written informed consent.

Exclusion Criteria:

1. 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.
2. 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.
3. Spinal cord compression or impending spinal cord compression.
4. Pulmonary and/or liver metastases > 1.0cm in largest dimension.
5. 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.
6. Use of other investigational agents or treatment protocol.
7. 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.
8. Inability to swallow medications.
9. Malabsorption condition that would alter the absorption of orally administered medications.
10. Grade ≥ 3 hemorrhage or bleeding event within 28 days prior to initiation of study treatment.
11. 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.
12. 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.
13. 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.

14. Due to the potential risk for drug-drug interactions with etrumadenant, participants must not have had:

    1. Oral treatment with strong inhibitors of breast cancer resistance protein (BCRP) (e.g., cyclosporin A, eltrombopag) or BRCP substrates with a narrow therapeutic window, administered orally (e.g., prazosin, rosuvastatin) within 4 weeks or 5 drug-elimination half-lives of the drug (whichever is longer) prior to initiation of study treatment.
    2. Oral treatment with strong inhibitors of P-glycoprotein (P-gp) substrates (e.g., itraconazole, quinidine, verapamil, dronedarone, ranolazine) or P-gp with a narrow therapeutic window, administered orally (e.g., digoxin) within 4 weeks or 5 drug-elimination half-lives of the drug (whichever is longer) prior to initiation of study treatment.
    3. Treatment with known strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, and St. John's Wort) or strong CYP3A4 inhibitors (e.g., clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment.
    4. Treatment with known strong UDP-glucuronosyltransferases (UGTs) of UGT1A1, 1A4, 1A9 and 2B4 inhibitors (e.g., atazanavir) within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to the initiation of study treatment.
    5. Treatment with known sensitive substrates of BSEP within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to the initiation of study treatment.
    6. Treatment with known sensitive substrates of OCT2 within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to the initiation of study treatment.
    7. Treatment with known sensitive substrates of MATE1 within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to the initiation of study treatment.
15. Immunosuppression (e.g., solid organ transplant on immunosuppression).
16. No known HIV, or active with Hepatitis C Virus (HCV) or Hepatitis B Virus (HBV).
17. Active autoimmune disease.
18. 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.
19. Inability to lie flat to tolerate computed tomography (CT) simulation study and oligometastasis-directed stereotactic body radiotherapy (SBRT).
20. Use of any live vaccines against infectious diseases within 28 days of first dose of investigational products.
21. Refusal to sign informed consent.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years to 99 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Catherine S. Spina, MD, PhD; 212-305-7406; css2190@cumc.columbia.edu

Contact: Research Nurse Navigator; 212-342-5162; cancerclinicaltrials@cumc.columbia.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05915442
• Other Study ID Numbers: AAAU4675
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Catherine Spina, Columbia University
• Original Responsible Party: Same as current
• Current Study Sponsor: Catherine Spina
• Original Study Sponsor: Same as current
• Collaborators: Arcus Biosciences, Inc.

Investigators

• Principal Investigator: Catherine S. Spina, MD, PhD; Columbia University

• PRS Account: Columbia University
• Verification Date: May 2024