Cancer of the Prostate, Castration-resistant Prostate Cancer, Metastatic Prostate Cancer, Progressive mCRPC, Prostatic Neoplasm
Conditions
Keywords
bone metastases, 18F-DCFPyL, PSMA PET, PSMA-avidity, biomarker, radioligand therapy, adjunct radiation therapy, dosimetry, SPECT/CT, docetaxel
Brief summary
This clinical trial was done to show whether a radioactive drug (I-131-1095) that binds to prostate-specific membrane antigen (PSMA) is useful in treating metastatic prostate cancer that is positive for PSMA. The trial enrolled men whose PSMA-positive metastatic prostate cancer had progressed while they were taking abiraterone. During the trial, all of the men took enzalutamide (standard-of-care therapy) once a day. However, some of the men also had up to 4 doses (8 weeks apart) of I-131-1095 (in addition to taking enzalutamide once a day). At specified times during the trial, all of the men had blood tests (to measure levels of prostate-specific antigen \[PSA\]) and imaging studies (to assess tumor status). The two groups of men were then compared in several ways. The main comparison was the percentage of men in each group with at least a 50% decrease in PSA levels. Other comparisons involved the response of the tumors (as seen on imaging) and overall survival. To assess safety, the number of adverse events in both groups were also compared.
Detailed description
This phase 2 clinical trial (conducted in the United States and Canada) enrolled chemotherapy-naïve men whose PSMA-positive (as shown by piflufolastat F18 imaging) metastatic prostate cancer had progressed during treatment with abiraterone. The participants were stratified by risk factors at Screening and then randomized 2:1 either to receive PSMA radioligand therapy (up to four 8-week cycles of I-131-1095) plus standard treatment with enzalutamide or to receive standard treatment with enzalutamide as monotherapy. The prostate-specific antigen (PSA) levels and radiographic response or progression (RECIST v1.1 criteria for soft tissue and PCWG3 criteria for bone) were then monitored for up to 53 weeks of randomized treatment. The primary outcome measure was PSA response rate (percentage of participants with a confirmed ≥50% decrease in serum PSA). Other outcome measures included percentage of participants with partial or complete response (radiographic), duration of response, time to progression (PSA or radiographic), time to next treatment for prostate cancer, and overall survival.
Interventions
DRUGI-131-1095
Participants received up to 4 (8-week) cycles of I-131-1095: 100 mCi for the first dose. Subsequent dose(s) were reduced to 75 mCi for participants experiencing any dose-limiting toxicities. The third and fourth therapeutic doses could be reduced to 75 mCi on the basis of dosimetry assessment after administration of 10 mCi of I-131-1095 prior to the third dosing cycle. Participants also received the label dosage of enzalutamide once daily for up to 53 weeks.
DRUGEnzalutamide
Participants received the label dosage of enzalutamide once daily for up to 53 weeks.
Sponsors
Progenics Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The study population includes patients with PSMA-avid mCRPC whose disease has progressed despite abiraterone therapy, and are planned for treatment with enzalutamide.
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male ≥ 18 years of age 2. Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features at initial diagnosis 3. Castration-resistant prostate cancer, with serum testosterone ≤ 50 ng/dL at Screening 4. Radiographic evidence of metastatic disease prior to Randomization or up to 21 days prior to Screening 5. Disease progression on prior abiraterone therapy as defined by meeting at least one of the following criteria per the investigator: 1. PSA progression as defined by a minimum of two rising PSA levels at least 1 week apart 2. Soft tissue disease progression defined by RECIST 1.1 3. Bone disease progression defined by two or more new lesions on bone scan 6. Planned to receive treatment with enzalutamide 7. Subjects who are ineligible or choose not to receive taxane-based chemotherapy based on personal preference or physician opinion. Examples of conditions that could make a patient ineligible or refuse to receive taxane-based chemotherapy, but would allow them to still be eligible to receive I-131-1095 include the following: 1. Poor performance status 2. Prior intolerance to cytotoxic agents 3. History of another malignancy suspected for recurrence or metastases 4. Other serious medical conditions such as symptomatic peripheral neuropathy CTCAE Grade 2 or higher; or clinically significant cardiovascular disease per the Investigator or treating physician 8. Subjects receiving bisphosphonate therapy must have been on stable doses for at least 4 weeks prior to Randomization 9. ECOG performance status 0-2 10. If sexually active, agree to use a medically acceptable method of birth control or sexual abstinence from the time of dosing through 28 days after the last dose of I-131-1095. Female partners must use hormonal or barrier contraception unless postmenopausal or abstinent. 11. Estimated life expectancy of at least 6 months as determined by the Investigator. 12. Able and willing to provide signed informed consent and comply with protocol requirements
Exclusion criteria
1. Received any anti-tumor therapy within 4 weeks of Randomization, with the exception of abiraterone, GnRH therapy and non-radioactive bone-targeted agents 2. Received prior chemotherapy for castration-resistant prostate cancer 3. Superscan as evidenced on baseline bone scan 4. Treatment with Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223 within 6 months prior to Randomization 5. Prior hemi-body irradiation 6. Prior PSMA-targeted radioligand therapy 7. Major surgery within 4 weeks of Randomization 8. Impaired organ function as evidenced by the following laboratory values at Screening: 1. Absolute neutrophil count \< 1500 μL 2. Platelet count \< 100,000/μL 3. Hemoglobin \< 9.5 g/dL 4. Albumin \< 3.0 g/dL (30 g/L) 5. Total bilirubin \> 2 x ULN unless in instances of known or suspected Gilbert's disease 6. AST or ALT \> 2.5 x ULN 7. Calculated creatinine clearance (CrCL) \< 30 mL/min (Cockroft-Gault equation), or currently on renal dialysis. 9. QT interval corrected for heart rate (QTc) \> 470 msec 10. Previous use of enzalutamide for more than 7 days prior to consent 11. Planned initiation of alternative therapy for prostate cancer, investigational therapy, or participation in clinical trials during the study 12. History or risk of seizure (i.e., clinically significant neurological disorder) or any other condition that contraindicates treatment with enzalutamide 13. Gastrointestinal disorder affecting absorption of oral medications 14. Known or suspected brain metastasis or active leptomeningeal disease 15. Active malignancy other than prostate cancer, with the exception of curatively treated non-melanoma skin cancer, carcinoma in situ, or non-muscle invasive bladder/urothelial cancer 16. Subjects with any medical condition or other circumstances that, in the opinion of the investigator, compromise obtaining reliable data, achieving study objectives, or completing the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PSA Response Rate | Up to 53 weeks | The percentage of participants with a PSA response according to PCWG3 criteria. PCWG3 defines PSA response as the first occurrence of a 50 percent or more decline in PSA from baseline, confirmed by a second measurement at least 3 weeks later. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Radiographic Progression Free Survival (rPFS) | Up to 5 years. | Time from randomization to the first occurrence of radiographic progression based on RECIST 1.1 for soft tissue (≥20% increase in the sum of the longest diameter of the target lesions \[relative to the smallest value recorded since the treatment started\] or the appearance of ≥1 new lesion) or PCWG3-modified RECIST 1.1 for bone, respectively, or unequivocal clinical progression, or death on study from any cause. |
| Overall Survival (OS) | Up to 5 years | Overall Survival is defined as time from randomization to death from any cause. |
| Objective Response Rate (ORR) | Up to 53 weeks | The proportion of participants who have a partial response (PR) or complete response (CR) based on RECIST 1.1 for soft tissue or PCWG3 for bone (PCWG3-modified RECIST 1.1). |
| Duration of Response | Up to 5 years. | Time from the first date of complete response (CR) or partial response (PR) to the first occurrence of radiographic progression based on PCWG3-modified RECIST 1.1, or unequivocal clinical progression. Complete response was defined as disappearance of all target lesions. Partial response was defined as ≥30% decrease from baseline in the sum of the longest diameter of target lesions. |
| Time to Initiation of Next Treatment for Prostate Cancer | Up to 5 years | Time from randomization to initiation of any new treatment for prostate cancer. |
| PSA Progression | Up to 53 weeks | Time from randomization to the date of the first PSA increase from baseline ≥ 25 percent and ≥ 2 ng/ml above nadir confirmed by a second PSA assessment defining progression ≥ 3 weeks later per PCWG3. |
Countries
Canada, United States
Participant flow
Recruitment details
Participants were recruited by physician referral at academic medical centers in the United States and Canada. Of 28 sites activated, 23 sites (16 in the United States and 7 in Canada) enrolled at least 1 participant. The study was initiated on 30May2019. The first participant consented on 07Jun2019 and last participant consented on 10Jun2022.
Pre-assignment details
A total of 177 participants were screened. Of 132 participants who underwent piflufolastat imaging, 123 met the inclusion criterion of PSMA avidity.
Participants by arm
| Arm | Count |
|---|---|
| Enzalutamide Participants received the labeled dosage of enzalutamide once daily for up to 53 weeks. | 39 |
| I-131-1095 in Combination With Enzalutamide Participants received up to 4 (8-week) cycles of I-131-1095: 100 mCi for the first dose. Subsequent dose(s) were reduced to 75 mCi for participants experiencing any of the dose-limiting toxicities. The third and fourth therapeutic doses could be reduced to 75 mCi on the basis of dosimetry assessment after administration of 10 mCi of I-131-1095 prior to the third dosing cycle.
Participants also received the label dosage of enzalutamide once daily for up to 53 weeks.. | 76 |
| Total | 115 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 8 |
| Overall Study | Death | 0 | 3 |
| Overall Study | Investigator decision | 1 | 0 |
| Overall Study | Other | 1 | 4 |
| Overall Study | Participant decision | 0 | 3 |
| Overall Study | Radiographic progression | 14 | 17 |
| Overall Study | Treatment is no longer benefiting participant | 5 | 6 |
| Overall Study | Unequivocal clinical progression | 2 | 5 |
| Overall Study | Withdrawal of consent | 2 | 1 |
Baseline characteristics
| Characteristic | Enzalutamide | Total | I-131-1095 in Combination With Enzalutamide |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 28 Participants | 85 Participants | 57 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 30 Participants | 19 Participants |
| Age, Continuous | 70.2 years STANDARD_DEVIATION 8.97 | 70.7 years STANDARD_DEVIATION 8.93 | 70.9 years STANDARD_DEVIATION 8.96 |
| Body mass index | 29.73 kg/m2 STANDARD_DEVIATION 5.35 | 29.68 kg/m2 STANDARD_DEVIATION 4.861 | 29.66 kg/m2 STANDARD_DEVIATION 4.629 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 5 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 36 Participants | 107 Participants | 71 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants |
| Height | 174.3 cm STANDARD_DEVIATION 6.52 | 174.6 cm STANDARD_DEVIATION 7.18 | 174.7 cm STANDARD_DEVIATION 7.53 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 11 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 5 Participants | 4 Participants |
| Race (NIH/OMB) White | 31 Participants | 95 Participants | 64 Participants |
| Region of Enrollment Canada | 10 Participants | 41 Participants | 31 Participants |
| Region of Enrollment United States | 29 Participants | 74 Participants | 45 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 39 Participants | 115 Participants | 76 Participants |
| Weight | 90.77 kg STANDARD_DEVIATION 18.28 | 90.64 kg STANDARD_DEVIATION 18.008 | 90.58 kg STANDARD_DEVIATION 17.467 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 39 | 3 / 76 |
| other Total, other adverse events | 37 / 39 | 72 / 76 |
| serious Total, serious adverse events | 11 / 39 | 29 / 76 |
Outcome results
Primary
PSA Response Rate
The percentage of participants with a PSA response according to PCWG3 criteria. PCWG3 defines PSA response as the first occurrence of a 50 percent or more decline in PSA from baseline, confirmed by a second measurement at least 3 weeks later.
Time frame: Up to 53 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Enzalutamide | PSA Response Rate | 10 Participants |
| I-131-1095 in Combination With Enzalutamide | PSA Response Rate | 44 Participants |
Comparison: A Cochran-Mantel-Haenszel (CMH) test with adjustment for stratification factor (prostate cancer risk factor at Screening) was carried out by using complete cases for the FAS population (missing data were not imputed for this analysis). Intermediate risk at Screening: hemoglobin (Hgb) ≥11 g/dL and LDH \<262 IU/L and ALP \<414 IU/L. High-risk at Screening: Hgb \<11 g/dL or LDH ≥262 IU/L or ALP ≥414 IU/L.p-value: 0.0025Cochran-Mantel-Haenszel
Secondary
Duration of Response
Time from the first date of complete response (CR) or partial response (PR) to the first occurrence of radiographic progression based on PCWG3-modified RECIST 1.1, or unequivocal clinical progression. Complete response was defined as disappearance of all target lesions. Partial response was defined as ≥30% decrease from baseline in the sum of the longest diameter of target lesions.
Time frame: Up to 5 years.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enzalutamide | Duration of Response | 15.1 Months |
| I-131-1095 in Combination With Enzalutamide | Duration of Response | 15.0 Months |
Comparison: Event free rates and 95% CI were estimated by using Kaplan-Meier method and Greenwood formula.p-value: 0.1823Log Rank
Secondary
Objective Response Rate (ORR)
The proportion of participants who have a partial response (PR) or complete response (CR) based on RECIST 1.1 for soft tissue or PCWG3 for bone (PCWG3-modified RECIST 1.1).
Time frame: Up to 53 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Enzalutamide | Objective Response Rate (ORR) | 4 Participants |
| I-131-1095 in Combination With Enzalutamide | Objective Response Rate (ORR) | 7 Participants |
p-value: 0.806Chi-squared
Secondary
Overall Survival (OS)
Overall Survival is defined as time from randomization to death from any cause.
Time frame: Up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enzalutamide | Overall Survival (OS) | 22.0 Months |
| I-131-1095 in Combination With Enzalutamide | Overall Survival (OS) | 18.8 Months |
Comparison: Kaplan-Meier analysis and Greenwood formula used for estimating event-free rates and 95% confidence intervals.p-value: 0.5924Log Rank
Secondary
PSA Progression
Time from randomization to the date of the first PSA increase from baseline ≥ 25 percent and ≥ 2 ng/ml above nadir confirmed by a second PSA assessment defining progression ≥ 3 weeks later per PCWG3.
Time frame: Up to 53 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enzalutamide | PSA Progression | 10 Months |
| I-131-1095 in Combination With Enzalutamide | PSA Progression | NA Months |
Comparison: Event-free rates and 95% CI were estimated by using Kaplan-Meier method and Greenwood formula.p-value: 0.6199Log Rank
Secondary
Radiographic Progression Free Survival (rPFS)
Time from randomization to the first occurrence of radiographic progression based on RECIST 1.1 for soft tissue (≥20% increase in the sum of the longest diameter of the target lesions \[relative to the smallest value recorded since the treatment started\] or the appearance of ≥1 new lesion) or PCWG3-modified RECIST 1.1 for bone, respectively, or unequivocal clinical progression, or death on study from any cause.
Time frame: Up to 5 years.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enzalutamide | Radiographic Progression Free Survival (rPFS) | 11.5 Months |
| I-131-1095 in Combination With Enzalutamide | Radiographic Progression Free Survival (rPFS) | 14.0 Months |
Comparison: Kaplan-Meier analysis and Greenwood formula used for estimating event-free rates and 95% confidence intervals.p-value: 0.5924Log Rank
Secondary
Time to Initiation of Next Treatment for Prostate Cancer
Time from randomization to initiation of any new treatment for prostate cancer.
Time frame: Up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enzalutamide | Time to Initiation of Next Treatment for Prostate Cancer | 10.9 Time to event, months |
| I-131-1095 in Combination With Enzalutamide | Time to Initiation of Next Treatment for Prostate Cancer | 18.3 Time to event, months |
Comparison: Event-free rates and 95% CI were estimated by using Kaplan-Meier method and Greenwood formula.p-value: 0.0006Log Rank