Metastatic Castration-resistant Prostate Cancer, Prostate Cancer
Conditions
Keywords
mCRPC, metastatic castration-resistant prostate cancer, prostate cancer, CD-39, PD-1, A2a, A2b, SRF617, AB122, AB928, adenosine pathway, cancer, immunotherapy, phase 2, efficacy, checkpoint inhibitor, adenosine receptor antagonist
Brief summary
This trial will look at the safety and preliminary efficacy of SRF617 in combination with etrumadenant and zimberelimab in patients with metastatic castration-resistant prostate cancer (mCRPC).
Detailed description
This is a phase 2, open-label, safety and preliminary efficacy trial in patients with mCRPC using the combination of SRF617, etrumadenant (AB928), and zimberelimab (AB122).
Interventions
DRUGSRF617
SRF617 is a fully human antibody designed to inhibit the enzymatic activity of CD39.
DRUGetrumadenant
Etrumadenant is an A2aR and A2bR antagonist.
DRUGzimberelimab
Zimberelimab is a fully human anti-PD-1 monoclonal antibody.
Sponsors
Arcus Biosciences, Inc.
Surface Oncology
Coherus Oncology, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* ≥ 18 years of age. * Metastatic CRPC with castrate levels of testosterone (≤ 50 ng/dL or ≤ 1.7 nmol/L). * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. * Progressed (by PSA or radiologic criteria) during or following treatment with a novel androgen receptor signaling inhibitor (ARSI, eg, abiraterone, enzalutamide, apalutamide, darolutamide), which may have been given for either hormone-sensitive prostate cancer or CRPC. * Received 1 to 2 prior lines of taxane chemotherapy, unless the physician and patient believe the patient is medically ineligible or the patient refuses (ineligibility or refusal must be documented in the source documents). * Progressed by PSA or radiologic criteria on or during last therapy for prostate cancer. * Measurable or non-measurable disease as per radiographic evaluation. Lesions situated in a previously irradiated area are considered evaluable if progression has been demonstrated in such lesions since radiation. • Note: If disease is considered non-measurable, a minimum PSA of 1 ng/dL is required with at least 1 confirmed rise at a minimum of a 1-week interval. * Adequate hematologic function, defined as absolute neutrophil count ≥ 1.5 × 109/L, hemoglobin ≥ 9.0 g/dL, and platelet count ≥ 100 × 109/L. Transfusions are permitted to meet hemoglobin and platelet criteria. However, the patient must have a stable hemoglobin level and platelet count for ≥ 2 weeks prior to dosing without transfusion. * Adequate renal function, defined as serum creatinine clearance ≥ 30 mL/min per Cockcroft-Gault formula. * Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (≤ 3 × ULN if elevated because of Gilbert's syndrome, and ≤ 2 × ULN for patients with known liver metastases). * Aspartate aminotransferase and alanine aminotransferase \< 2.5 × ULN (\< 5 × ULN if liver metastases present). * Prothrombin time (PT) or international normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless the patient is receiving anticoagulant therapy, in which case PT/INR or aPTT must be within therapeutic range of intended use of anticoagulants.
Exclusion criteria
* Currently participating in or has participated in a trial of an investigational device or has used an investigational device within 21 days before the first dose of study drug. * Any component of small cell or neuroendocrine histology. * Previously received an anti-CD39 antibody, anti-CD39 targeted therapy, or other agent targeting the adenosine pathway. * Prior treatment with programmed death-ligand 1 (PD-L1)/programmed death receptor-1 (PD-1) inhibitors. * Prior treatment with ≥ 3 lines of taxane chemotherapy administered as a single agent or as part of a combination regimen. * Symptomatic or untreated brain metastases (including leptomeningeal metastases). Patients previously treated for brain metastases must be at least 4 weeks from completion of radiation treatment with follow-up imaging showing no progression. * Current pneumonitis with or without steroid requirement or history of pneumonitis requiring steroids. * Another malignancy other than prostate within 2 years of trial entry, except for those with a low risk of spreading or negligible risk of death such as non-melanoma skin cancer or Ta superficial bladder cancer. * Active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). * Medical conditions requiring chronic steroid (ie, \> 10 mg/day of prednisone or its equivalent). • Note: Replacement therapy (eg, levothyroxine, insulin, or physiologic corticosteroid replacement therapy for thyroid, adrenal, or pituitary insufficiency) is allowed. * Administration of a live attenuated vaccine within 6 weeks before the first dose of study drug. • Exception: Health Authority approved COVID-19 vaccines are permitted. * Any gastrointestinal condition that would preclude the use of oral medications (eg, difficulty swallowing, nausea, vomiting, or malabsorption).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Response | From the date of first dose administration to the end of treatment (maximum exposure: 168 days) | Response was defined as Prostate-Specific Antigen (PSA) decline of ≥ 50% (PSA50) and/or radiographic objective response of Complete Response (CR) or Partial Response (PR) per Prostate Cancer Working Group 3 (PCWG3) Criteria. The number of participants with response shows participants with any one or combination of these response types. * CR: Disappearance of all extranodal target lesions. All pathological lymph nodes must have decreased to \< 10 millimeters (mm) in short axis * PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum of diameters |
| Number of Participants With Adverse Events (AEs) | From date of first dose until 90 days after the last dose of treatment (maximum treatment exposure: 168 days) | An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious Adverse Events (SAEs) were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | From the date of first dose administration to the end of treatment (maximum exposure: 168 days) | DCR was defined as the percentage of participants with CR, PR, or SD lasting a minimum of 12 weeks by PCWG3 or PSA50 criteria. |
| Number of Participants With PSA50 Response | From the date of first dose administration to the end of treatment (maximum exposure: 168 days) | PSA50 response is defined as a confirmed PSA decrease from Baseline of 50% or more based on 2 consecutive assessments measured 3 to 4 weeks apart. |
| Number of Participants With PSA Decline of ≥ 30% (PSA30) Response | From the date of first dose administration to the end of treatment (maximum exposure: 168 days) | PSA30 response is defined as a confirmed PSA decrease from Baseline of 30% or more based on 2 consecutive assessments measured 3 to 4 weeks apart. |
| Time to PSA Progression | From the date of first dose administration to the end of treatment (maximum exposure: 168 days) | — |
| Radiographic Progression Free Survival (PFS) | From the date of first dose administration to the end of treatment (maximum exposure: 168 days) | — |
| Number of Participants With Response Per PCWG3 Criteria | From the date of first dose administration to the end of treatment (maximum exposure: 168 days) | The number of participants achieving CR or PR by PCWG3 criteria is reported: * CR: Disappearance of all extranodal target lesions. All pathological lymph nodes must have decreased to \< 10 millimeters (mm) in short axis * PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum of diameters * Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions from the smallest value on trial (including Baseline, if that is the smallest). The sum of diameters must also demonstrate an absolute increase of at least 5 mm. Or, the appearance of one or more lesions * Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD |
| Maximum Observed Serum Concentration of SRF617 (Cmax) | From the date of first dose administration to the end of treatment (maximum exposure: 168 days) | — |
| Minimum Observed Serum Concentration of SRF617 Prior to Administration of Subsequent Dose (Cmin) | From the date of first dose administration to the end of treatment (maximum exposure: 168 days) | — |
| Number of Participants With Antidrug Antibodies (ADAs) | From the date of first dose administration to the end of treatment (maximum exposure: 168 days) | — |
| Number of Participants With Symptomatic Skeletal Events (SSEs) | From date of first dose until 90 days after the last dose of treatment (maximum treatment exposure: 168 days) | Number of participants with SSEs per PCWG3 criteria, defined as symptomatic fracture, radiation or surgery to bone, or spinal cord compression, is reported. |
| Landmark PFS Rate | Months 6 and 12 | Landmark PFS was defined as the percentage of participants who have not developed PFS events of death or documented disease progression as determined by applicable disease criteria. |
| Duration of Response (DOR) | From the date of first dose administration to the end of treatment (maximum exposure: 168 days) | DOR was defined as the time from first documented response (PSA50 and/or CR/PR) to documented disease progression as determined by applicable disease criteria, or documented death due to any cause, whichever occured first. |
Countries
Canada, United States
Participant flow
Pre-assignment details
A total of 16 participants were enrolled. 1 participant discontinued due to an adverse event prior to the first dose and was therefore not included in the analyses. 15 participants received study treatment and were included in the analyses.
Participants by arm
| Arm | Count |
|---|---|
| SRF617 + Etrumadenant + Zimberelimab SRF617 was administered in combination with etrumadenant and zimberelimab in 28-day cycles according to the following dosing schedule:
* SRF617 1400 mg IV every q2 weeks on Days 1 and 15
* Etrumadenant 150 mg orally daily
* Zimberelimab 480 mg IV q4 weeks on Day 1 | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event prior to dosing | 1 |
| Overall Study | Death | 4 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | SRF617 + Etrumadenant + Zimberelimab |
|---|---|
| Age, Continuous | 68.9 years STANDARD_DEVIATION 8.16 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 11 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 4 / 16 |
| other Total, other adverse events | 15 / 16 |
| serious Total, serious adverse events | 7 / 16 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs)
An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious Adverse Events (SAEs) were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time frame: From date of first dose until 90 days after the last dose of treatment (maximum treatment exposure: 168 days)
Population: The Safety Analysis Set included all participants who received any amount of study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SRF617 + Etrumadenant + Zimberelimab | Number of Participants With Adverse Events (AEs) | 15 Participants |
Primary
Number of Participants With Response
Response was defined as Prostate-Specific Antigen (PSA) decline of ≥ 50% (PSA50) and/or radiographic objective response of Complete Response (CR) or Partial Response (PR) per Prostate Cancer Working Group 3 (PCWG3) Criteria. The number of participants with response shows participants with any one or combination of these response types. * CR: Disappearance of all extranodal target lesions. All pathological lymph nodes must have decreased to \< 10 millimeters (mm) in short axis * PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum of diameters
Time frame: From the date of first dose administration to the end of treatment (maximum exposure: 168 days)
Population: The Response-Evaluable Analysis Set is defined as all participants at Baseline who received study drug and had at least 1 post-Baseline response assessment or who discontinued the treatment phase because of radiographic or symptomatic disease progression (including death caused by disease progression) within 6 weeks (+ 2 week window) of the first dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SRF617 + Etrumadenant + Zimberelimab | Number of Participants With Response | 0 Participants |
Secondary
Disease Control Rate (DCR)
DCR was defined as the percentage of participants with CR, PR, or SD lasting a minimum of 12 weeks by PCWG3 or PSA50 criteria.
Time frame: From the date of first dose administration to the end of treatment (maximum exposure: 168 days)
Population: Analysis was not performed as data were not collected for this outcome measure due to early study termination
| Arm | Measure | Group | Value |
|---|---|---|---|
| Unknown | Disease Control Rate (DCR) | CR | — |
| Unknown | Disease Control Rate (DCR) | PR | — |
| Unknown | Disease Control Rate (DCR) | SD | — |
Secondary
Duration of Response (DOR)
DOR was defined as the time from first documented response (PSA50 and/or CR/PR) to documented disease progression as determined by applicable disease criteria, or documented death due to any cause, whichever occured first.
Time frame: From the date of first dose administration to the end of treatment (maximum exposure: 168 days)
Population: Analysis was not performed as data were not collected for this outcome measure due to early study termination
Secondary
Landmark PFS Rate
Landmark PFS was defined as the percentage of participants who have not developed PFS events of death or documented disease progression as determined by applicable disease criteria.
Time frame: Months 6 and 12
Population: Analysis was not performed as data were not collected for this outcome measure due to early study termination
Secondary
Maximum Observed Serum Concentration of SRF617 (Cmax)
Time frame: From the date of first dose administration to the end of treatment (maximum exposure: 168 days)
Population: Analysis was not performed as data were not collected for this outcome measure due to early study termination
Secondary
Minimum Observed Serum Concentration of SRF617 Prior to Administration of Subsequent Dose (Cmin)
Time frame: From the date of first dose administration to the end of treatment (maximum exposure: 168 days)
Population: Analysis was not performed as data were not collected for this outcome measure due to early study termination
Secondary
Number of Participants With Antidrug Antibodies (ADAs)
Time frame: From the date of first dose administration to the end of treatment (maximum exposure: 168 days)
Population: Analysis was not performed as data were not collected for this outcome measure due to early study termination
Secondary
Number of Participants With PSA50 Response
PSA50 response is defined as a confirmed PSA decrease from Baseline of 50% or more based on 2 consecutive assessments measured 3 to 4 weeks apart.
Time frame: From the date of first dose administration to the end of treatment (maximum exposure: 168 days)
Population: The Response-Evaluable Analysis Set is defined as all participants at Baseline who received study drug and had at least 1 post-Baseline response assessment or who discontinued the treatment phase because of radiographic or symptomatic disease progression (including death caused by disease progression) within 6 weeks (+ 2 week window) of the first dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SRF617 + Etrumadenant + Zimberelimab | Number of Participants With PSA50 Response | 0 Participants |
Secondary
Number of Participants With PSA Decline of ≥ 30% (PSA30) Response
PSA30 response is defined as a confirmed PSA decrease from Baseline of 30% or more based on 2 consecutive assessments measured 3 to 4 weeks apart.
Time frame: From the date of first dose administration to the end of treatment (maximum exposure: 168 days)
Population: Analysis was not performed as data were not collected for this outcome measure due to early study termination
Secondary
Number of Participants With Response Per PCWG3 Criteria
The number of participants achieving CR or PR by PCWG3 criteria is reported: * CR: Disappearance of all extranodal target lesions. All pathological lymph nodes must have decreased to \< 10 millimeters (mm) in short axis * PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum of diameters * Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions from the smallest value on trial (including Baseline, if that is the smallest). The sum of diameters must also demonstrate an absolute increase of at least 5 mm. Or, the appearance of one or more lesions * Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD
Time frame: From the date of first dose administration to the end of treatment (maximum exposure: 168 days)
Population: Analysis was not performed as data were not collected for this outcome measure due to early study termination
Secondary
Number of Participants With Symptomatic Skeletal Events (SSEs)
Number of participants with SSEs per PCWG3 criteria, defined as symptomatic fracture, radiation or surgery to bone, or spinal cord compression, is reported.
Time frame: From date of first dose until 90 days after the last dose of treatment (maximum treatment exposure: 168 days)
Population: The Safety Analysis Set included all participants who received any amount of study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SRF617 + Etrumadenant + Zimberelimab | Number of Participants With Symptomatic Skeletal Events (SSEs) | 4 Participants |
Secondary
Radiographic Progression Free Survival (PFS)
Time frame: From the date of first dose administration to the end of treatment (maximum exposure: 168 days)
Population: Analysis was not performed as data were not collected for this outcome measure due to early study termination
Secondary
Time to PSA Progression
Time frame: From the date of first dose administration to the end of treatment (maximum exposure: 168 days)
Population: Analysis was not performed as data were not collected for this outcome measure due to early study termination