Phase I Dose-escalation Study of Fractionated 177Lu-PSMA-617 for Progressive Metastatic CRPC

Study Overview
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Brief Summary
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The purpose of this study is to find the highest dose level of the study drug, 177Lu-PSMA-617 that can be given without severe side effects for advanced prostate cancer.

Detailed Description
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Phase I dose escalation study with 177Lu-PSMA-617 using dose fractionation regimen will be performed in patients with documented progressive metastatic CRPC. The cumulative 177Lu dose [100 mCi (3.7 GBq) - 600 mCi (22.2 GBq)] will be escalated in up to 6 different dose levels (3 + 3 study design). Additional 10 subjects will be enrolled at the MTD dose level to further assess safety and tolerability and to obtain a preliminary assessment of efficacy. The study will enroll adult males 18 years of age or older with documented progressive metastatic CRPC. The primary objectives are: - To determine the dose limiting toxicity (DLT) of fractionated dose of 177Lu-PSMA-617 - To determine the maximal tolerated and recommended phase II dose of 177Lu-PSMA-617 in a 2-week dose-fractionation regimen Subjects will receive the following study interventions: 177Lu-PSMA-617 [50mCi (1.85GBq) - 300mCi (11.1GBq)] intravenous X2 doses, 2 weeks apart (Visit 1 and 2) 68Ga-PSMA-HBED-CC [5 ±2mCi or 185 ±74MBq] intravenous during screening and at 12 weeks with standard imaging Subjects will be on this study from screening to end of study (day 85). The treatment phase comprises of 8 visits over 12 weeks. Patients will be followed until death for survival assessment. Patients removed from study for unacceptable adverse events will be followed until resolution or stabilization of the adverse event. All tests and procedures performed on this study are routine and standard of care except: 68Ga-PSMA-HBED-CC PET/CT scan, administration of investigational agent 177Lu-PSMA-617, research blood samples (CTCs for research, cell-free DNA sample), and PSMA testing on archive tissue.

Official Title
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Phase I/ll Dose-escalation Study of Fractionated Dose 177Lu-PSMA-617 for Progressive Metastatic Castration Resistant Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: 177Lu-PSMA-617
* Drug: 68Ga-PSMA-HBED-CC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of prostate 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 ECOG performance status of 0-2 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. Have previously been treated with at least one of the following: Androgen receptor signaling inhibitor (such as enzalutamide) CYP 17 inhibitor (such as abiraterone acetate) Have previously received taxane chemotherapy, been determined to be ineligible for taxane chemotherapy by their physician, or refused taxane chemotherapy. Age > 18 years Patients must have normal organ and marrow function as defined below: Absolute neutrophil count >2,000 cells/mm3 Hemoglobin ≥9 g/dL (independent of transfusion and/or growth factors within 1 month prior to registration) Platelet count >150,000 x 109/uL (independent of transfusion and/or growth factors within 3 months prior to randomization) 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 <1.5 x ULN Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Use of investigational drugs or implantation of investigational medical device ≤4 weeks of Cycle 1, Day 1 or current enrollment in investigational drug or device study Prior systemic beta-emitting bone-seeking radioisotopes Brain metastases or leptomeningeal disease History of deep vein thrombosis and/or pulmonary embolus within 1 month of study entry 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 Radiation therapy for treatment of PCa ≤4 weeks of Day 1 Cycle 1 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. 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 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. Known history of known myelodysplastic syndrome

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All subjects<br>177Lu-PSMA-617 [50mCi (1.85GBq) - 300mCi (11.1GBq)] intravenous X2 doses, 2 weeks apart (Visit 1 and 2) 68Ga-PSMA-HBED-CC [5 ±2mCi or 185 ±74MBq] intravenous during screening and at 12 weeks with standard imaging | Drug: 177Lu-PSMA-617<br>* 177Lu-PSMA-617 [50mCi (1.85GBq) - 300mCi (11.1GBq)] intravenous X2 doses, 2 weeks apart (Visit 1 and 2)<br>Drug: 68Ga-PSMA-HBED-CC<br>* 68Ga-PSMA-HBED-CC [5 ±2mCi or 185 ±74MBq] intravenous during screening and at 12 weeks with standard imaging<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Dose Limiting Toxicity (DLT) of Fractionated Dose of 177Lu-PSMA-617 | Proportion of subjects experiencing a dose limiting toxicity (DLT) of fractionated dose of 177Lu-PSMA-617 by using 3+3 dose escalation was assessed. | Assessed throughout the DLT period, up to 92 days after starting study drug. | 
| Number of Subjects That Achieved Cumulative Maximum Tolerated Dose (MTD) Phase II Dose of 177Lu-PSMA-617 | This outcome is measuring the number of subjects that achieved MTD. MTD is defined as the highest dose level with an observed incidence of DLT in no more than one out of six patients treated at a particular dose level. If no DLTs were experienced, then a recommended phase II dose was determined in 2-wk dose-fractionation regimen by using a 3+3 dose escalation design, as no MTD was observed. | from first dose of study drug to at least 12 weeks of subsequent follow-up evaluations, up to 92 days | 
| Recommended Phase II Dose of 177Lu-PSMA-617 in a 2-week Dose-fractionation Regimen | Recommended Phase II dose was determined based on the results of the Phase I portion of the study. Since no Maximum Tolerated Dose was achieved given that no Dose Limiting Toxicities occurred, the Recommended Phase II dose was determined based on the Cohort 5 dose. | Duration of Phase I, up to 47 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Rate of PSA Decline Following Fractionated 177Lu-PSMA-617 | Proportion of patients with PSA decline following treatment (fractionated 177Lu-PSMA-617) with the RP2D of fractionated dose 177Lu-PSMA-617 (Phase II). PSA response will be determined by comparing the PSA levels after therapy to the baseline, pre-treatment PSA. | from baseline visit to short term follow up visit, approximately 6 months | 
| Count of Patients That Had a Radiographic Response Rate Measured by RECIST 1.1 With PCWG3 Modifications |  | From start of study to progression of disease with at least 12 weeks of subsequent follow-up evaluations, up to 54 months | 
| Progression-free Survival Measured by PCWG3 (Prostate Cancer Working Group3) Criteria | Progression Free Survival, with progression determined based by Radiographic and Biochemical response. Biochemical response was assessed by comparing the PSA levels after therapy to the baseline, pre-treatment PSA. Declines of ≥ 30% confirmed by a second PSA value ≥2 weeks later, are reported. | Duration of time on study, from baseline to last follow up visit, up to 54 months | 
| Number of CTC Count Responders | Changes in CTC count as measured by CellSearch and the rate of favorable CTC count and LDH at 12 weeks following fractionated 177Lu-PSMA-617. All subjects in this study will get blood samples drawn (at screening and EOS visit) for CTC enumeration by CellSearch methodology. Participants whose CTC counts drop to less than 5 or stay below 5 (responders) vs. those who remain at least 5 or above (non-responders) at EOS visit are analyzed. | Duration of study, from screening to EOS visit, up to 12 weeks | 
| Overall Survival Following Fractionated 177Lu-PSMA-617 | Overall survival was defined as the time from start of 177Lu-PSMA-617 to the date of death from any cause, or last date of follow up. | Up to 5 years | 
| Count of Participants That Experience an Adverse Event |  | From screening to end of study visit, up to 54 months |