Prostate Cancer
Conditions
Brief summary
The purpose of the initial (phase I) portion of this study is to find a dose level and administration schedule of the study drug, 225Ac-J591, that can be given without severe side effects. The purpose of the second (phase II) portion of the study is to determine the proportion of those with PSMA-positive tumors with \>50% PSA decline following 225Ac-J591 treatment in two regimens.
Detailed description
This clinical trial is for men with progressive metastatic castration resistant prostate cancer. The purpose of this study is to find the highest dose level of the study drug, 225Ac-J591, that can be given without severe side effects. The research study is being done because the standard treatments for prostate cancer that has spread beyond the prostate gland are intended to minimize the adverse effects of the disease. These treatments, however, are not curative. Patients who choose to participate in this study will have a screening visit to determine whether or not they are eligible to participate in the study. There are two different regimens for men with progressive mCRPC with and without prior 177Lu-PSMA-RL treatment. The fractionated dose regimen is a single cycle of study drug administered on Day 1 and Day 15. The dose-limiting toxicity assessment period is 8 weeks for the fractionated dose regimen (starting from Cycle 1 Day 1). The multiple dose regimen is a single dose of 225Ac-J591 per cycle, with each cycle administered every 6 weeks up to 4 cycles. The dose-limiting toxicity assessment period is up to 9 weeks past the 2nd dose of 225Ac-J591. Following treatment, short-term follow up is planned until radiographic progression, expected to be 6 months. The study medication is called 225Ac-J591, and is administered as a single fractionated cycle day 1 and day 15 in the fractionated dose regimen and as a single dose per cycle repeated every 6 weeks in the multiple dose regimen. Upon completion of investigational treatment with 225Ac-J591, participants will undergo 68Ga-PSMA-HBED-CC injection and same day PET/CT to document treatment response. 68Ga-PSMA-HBED-CC is comprised of gallium-68, which is a positron-emitting radionuclide linked to PSMA-HBED-CC (aka PSMA11), which is a small molecule targeting PSMA. 68Ga-PSMA-HBED-CC will be administered intravenously prior to PET/CT at screening and at follow up imaging x2. Subsequent survival data and additional treatment(s) information will be captured from their routine standard of care (SOC) visits. During the other study visits, participants will undergo routine tests and procedures, such as physical examinations, and blood tests. Some blood tests will be done for research purposes only. After completion of therapy, participants may be contacted on a periodic basis to see how they are doing.
Interventions
DRUGMultiple Dose of 225Ac-J591 at 45 KBq/kg
Multiple dose of 45 KBq/kg
DRUGMultiple Dose of 225Ac-J591 at 55 KBq/kg
Multiple dose of 55 KBq/kg in dose-escalation regimen
DRUGMultiple Dose of 225Ac-J591 at 65 KBq/kg
Multiple dose of 65 KBq/kg in dose-escalation regimen
DRUGFractionated Dose of 225Ac-J591 at 45 KBq/kg
Fractionated dose of 45 KBq/kg in dose-escalation regimen
DRUGFractionated Dose of 225Ac-J591 at 55 KBq/kg
Fractionated dose of 55 KBq/kg in dose-escalation regimen
DRUGFractionated Dose of 225Ac-J591 at 60 KBq/kg
Fractionated dose of 60 KBq/kg in dose-escalation and dose-expansion regimens
DRUGFractionated Dose of 225Ac-J591 at 65 KBq/kg
Fractionated dose of 65 KBq/kg in dose-escalation regimen
DRUGFractionated Dose of 225Ac-J591 at 45 KBq/kg (Prior 177Lu-PSMA-RL)
Fractionated dose of 45 KBq/kg for cohort of participants previously treated with 177Lu-PSMA-RL
DRUGFractionated Dose of 225Ac-J591 at 50 KBq/kg (Prior 177Lu-PSMA-RL)
Fractionated dose of 50 KBq/kg for cohort of participants previously treated with 177Lu-PSMA-RL
DIAGNOSTIC_TEST68Ga-PSMA-HBED-CC injection
68Ga-PSMA-HBED-CC PET/CT before and after treatment
Sponsors
Weill Medical College of Cornell University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants were enrolled to either the multiple dose cohort or the fractionated dose cohort in parallel, after which additional participants were enrolled in a prospective fractionated dose regimen (with prior 177Lu-PSMA-RL) and additional participants were enrolled in an expansion cohort of fractionated dose regimen at the R2PD of 60 KBq/kg. In a fractionated dose cohort, participants receive the dose level of treatment during one cycle to be administered on Day 1 and Day 15. In the multiple dose cohort, participants receive the dose level of treatment administered as a single dose per cycle every 6 weeks up to 4 cycles.
Eligibility
Sex/Gender
MALE
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Histologically or cytologically confirmed adenocarcinoma of prostate 2. Documented progressive metastatic CRPC based on Prostate Cancer Working Group 3 (PCWG3) criteria, which includes at least one of the following criteria: * PSA progression * Objective radiographic progression in soft tissue * New bone lesions 3. Have serum testosterone \< 50 ng/dL. Subjects must continue primary androgen deprivation with an LHRH/GnRH analogue (agonist/antagonist) if they have not undergone orchiectomy 4. Have previously been treated with at least one of the following in any disease state: * Androgen receptor signaling inhibitor (such as enzalutamide) * CYP 17 inhibitor (such as abiraterone acetate) 5. Have previously received taxane chemotherapy (in any disease state), been determined to be ineligible for taxane chemotherapy by their physician, or refused taxane chemotherapy. 6. Age \> 18 years 7. Patients must have normal organ and marrow function as defined below: * Absolute neutrophil count \>2,000 cells/mm3 * Hemoglobin ≥9 g/dL * Platelet count \>150,000 x 109/uL * Serum creatinine \<1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/min/1.73 m2 by Cockcroft-Gault * Serum total bilirubin \<1.5 x ULN (unless due to Gilbert's Syndrome in which case direct bilirubin must be normal) * Serum AST and ALT \<3 x ULN in absence of liver metastases; \< 5x ULN if due to liver metastases (in both circumstances bilirubin must meet entry criteria) 8. ECOG performance status of 0-2 9. Ability to understand and the willingness to sign a written informed consent document 10. For patients enrolled in the post-177Lu-PSMA-RL cohorts, must have previously received either 177Lu-PSMA-617 or 177Lu-PSMA-I\&T
Exclusion criteria
1. Implantation of investigational medical device ≤4 weeks of Treatment Visit 1 (Day 1) or current enrollment in oncologic investigational drug or device study 2. Use of investigational drugs ≤4 weeks or \<5 half-lives of Cycle 1, Day 1 or current enrollment in investigational oncology drug or device study 3. Prior systemic beta-emitting bone-seeking radioisotopes (e.g. samarium-153, strontium-89) 4. For patients enrolled in the post-177Lu-PSMA-RL cohorts: prior radium-223 5. Untreated hydronephrosis 6. Known active brain metastases or leptomeningeal disease 7. History of deep vein thrombosis and/or pulmonary embolus within 1 month of C1D1 8. Other serious illness(es) involving the cardiac, respiratory, CNS, renal, hepatic or hematological organ systems which might preclude completion of this study or interfere with determination of causality of any adverse effects experienced in this study 9. Radiation therapy for treatment of PC ≤4 weeks of Day 1 Cycle 1 10. Chemotherapy for treatment of PC ≤4 weeks of Day 1 Cycle 1 11. Patients on stable dose of bisphosphonates or denosumab, which have been started no less than 4 weeks prior to treatment start, may continue on this medication, however patients are not allowed to initiate bisphosphonate/Denosumab therapy during the DLT-assessment period of the study 12. Having partners of childbearing potential and not willing to use a method of birth control deemed acceptable by the principle investigator and chairperson during the study and for 1 month after last study drug administration 13. Currently active other malignancy other than non-melanoma skin cancer. Patients are considered not to have "currently active" malignancy if they have completed any necessary therapy and are considered by their physician to be at less than 30% risk of relapse 14. Known history of myelodysplastic syndrome 15. Bone scan with confluent lesions and lack of urinary tracer consistent with a "superscan" as determined by the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicity (DLT) | Collected from Day 1 through 6 months | DLTs will be measured by utilizing the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. |
| Maximum Tolerated Dose (MTD) | Collected from Day 1 through 6 months | The dose that produces an "acceptable" level of toxicity or that, if exceeded, would put subjects at "unacceptable" risk for toxicity. MTD is defined as the dose level at which no more than two patients out of six experienced dose-limiting toxicity (DLT). |
| Recommended Phase II Dose (RP2D) of 225Ac-J591 in Fractionated Dose and Multiple Dose Regimens Both Pre- and Post-treatment With 177Lu-PSMA-RL | Collected from Day 1 through 6 months | — |
| Number of Participants With PSMA-positive Tumors With >50% PSA Decline Following 225Ac-J591 in Each Cohort Regimen | Collected from Day 1 through 6 months | Number of participants achieving greater than 50% PSA decline (relative to baseline/pre-treatment PSA). Response may occur at any time following treatment initiation and prior to going off study or initiation of new therapy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Radiographic Response | Imaging performed at timepoints from Day 1 through study completion, approximately 3 years. | Response evaluation criteria in solid tumors RECIST (Version 1.1) criteria with prostate cancer working group 3 (PCWG3) modifications to be used. |
| Overall Survival Following 225Ac-J591 Treatment | Collected from Day 1 through study completion, approximately 3 years. | Overall survival will be captured through in-clinic or telephone contact with participants |
| Change in Disease Assessment With 68Ga-PSMA-11 PET/CT Prior to and Following Investigational Treatment | Scans performed during screening period (within 30 days of Cycle 1 Day 1) and at Day 85 from Cycle 1 Day 1. | Change in Maximum SUV (SUVmax) from Baseline 68Ga-PSMA-11 PET/CT to Post-therapy (Week 12) 68Ga-PSMA-11 PET/CT. 68Ga-PSMA-11 PET/CT was utilized as part of the radiographic assessment. |
| Number of Participants With Change in Circulating Tumor Cells (CTC) Count at 12 Weeks Following 225Ac-J591 | Samples will be collected at Screening and Day 85 | CTCs will be analyzed through blood specimen collection via CellSearch methodology lab testing. Number of participants with changes in CTC count. |
| Number of Participants With Adverse Events | Collected from Day 1 through study completion, approximately 3 years | National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 is used to grade all adverse events |
| Assess Biochemical Progression-free Survival | Collected from Day 1 through study completion, approximately 3 years | PSA progression will be defined as a rise of \> 25% above either the pretreatment level or the nadir PSA level (whichever is lowest). PSA must increase by \> 2 ng/ml to be considered progression |
| Assess the Proportion With Different Levels of PSA Decline Following 225Ac-J591 | Collected from Day 1 through study completion, approximately 3 years | PSA will be monitored through serial blood draws. Response may occur at any time following treatment initiation and prior to going off study or initiation of new therapy. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJoseph R Osborne, MD
Weill Medical College of Cornell University
Participant flow
Recruitment details
Participants were enrolled in Phase I of the study only. Phase II of the study was never initiated.
Pre-assignment details
Participants were enrolled in parallel to the Multiple Dose and Fractionated Dose (without prior 177Lu-PSMA-RL) regimen cohorts first, then participants were enrolled in an expansion Fractionated Dose Post 177Lu-PSMA-RL cohort. Data are reported for Phase I, as Phase II was never initiated and will not be initiated.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 73 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 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 | 45 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 6 | 6 / 6 | 6 / 6 | 3 / 3 | 7 / 7 | 17 / 18 | 5 / 6 | 1 / 2 | 6 / 6 |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 6 / 6 | 3 / 3 | 7 / 7 | 18 / 18 | 6 / 6 | 2 / 2 | 6 / 6 |
| serious Total, serious adverse events | 1 / 6 | 1 / 6 | 1 / 6 | 0 / 3 | 2 / 7 | 5 / 18 | 1 / 6 | 0 / 2 | 2 / 6 |
Outcome results
None listed