177Lu-J591 and 177Lu-PSMA-617 Combination for mCRPC

Study Overview
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Brief Summary
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Phase I dose escalation study with combination of 177Lu-J591 and 177Lu-PSMA-617 using a dose-fractionated regimen will be performed in patients with documented progressive metastatic CRPC. The cumulative 177Lu-J591 dose for each subject will be 2.7 GBq/m2 (73 mCi/m2) of 177Lu with 20 mg J591 and the cumulative 177Lu-PSMA-617 dose for each subject will vary (depending on the Cohort) from 3.7 GBq (100 mCi) to 18.5 GBq (500 mCi). The 177Lu-PSMA-617 dose will be escalated in up to 6 different dose levels (3+3 dose-escalation study / de-escalation design). For the phase II portion, a minimum number of 14 patients will be enrolled at MTD (including those enrolled at MTD in Phase I) and a maximum of 24.

Detailed Description
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This is an open-label, single-center Phase I dose-escalation study designed to determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of combination of 177Lu-J591 and 177Lu-PSMA-617 in a two-week dose-fractionation regimen. 177Lu-J591 will be given at a moderate dose previously demonstrated to be safe x2 infusions two weeks apart. For 177Lu-PSMA-617 the dose escalation will start at 3.7 GBq (100 mCi) and escalate in increments of 1.85 GBq (50 mCi) for each dose to a planned maximum of 9.25 GBq (250 mCi) x2 doses, 2 weeks apart. Should there be unacceptable toxicity at the initial dose level, we will de-escalate to dose level -1 (1.85 GBq / 50 mCi per dose). After the phase I study has established a MTD, the Phase II, single-arm trial will start. Patients must have documented progressive metastatic CRPC disease based on Prostate Cancer Working Group 3 (PCWG3) criteria in order to be eligible for enrollment. Upon meeting the inclusion and exclusion criteria and signing the informed consent and HIPPA form, subjects will undergo the screening. As part of the screening, subjects will get a single dose of 68Ga-PSMA-HBED-CC and will have a PET/CT. Nuclear Medicine physician(s) will review the PET/CT scans to document PSMA expression at tumor site(s). Subjects will have Lutetium-177 Planar/SPECT Imaging on Day 8 (±1 day) after the first dose of 177Lu-J591 + 177Lu-PSMA-617. Optimal images will be performed on selected consenting subjects between the initial treatment visit #1 on Day 1 and Day 4 and prior to treatment visit #2 on D15 ±1. Subjects will be closely monitored for AEs (weekly x2 weeks, then every 2 weeks for one month, at 8 and 12 weeks, and then every 4 weeks for next 3 months). Upon completion of investigational treatment with dose-fractionation regimen of the combination of 177Lu-J591 + 177Lu-PSMA-617, subjects will undergo 68Ga-PSMA-HBED-CC injection and same day PET/CT at the end of study visit to document treatment response. Subsequently survival data and additional treatment(s) information will be captured from their routine Standard of care (SOC) visits. .

Official Title
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Phase I/II Dose-Escalation Trial of Combination Fractionated-dose 177Lu-J591 and 177Lu-PSMA-617 in Patients With Metastatic Castration-Resistant Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: 177Lu-PSMA-617
* Drug: 177Lu-J591
* 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: i. PSA progression ii. Objective radiographic progression in soft tissue iii. 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 bilateral 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 Platelet count >150,000 x 109/L 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 in the absence of liver metastases; <3 x ULN if due to liver metastases (in both circumstances bilirubin must meet entry criteria) Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria Implantation of investigational medical device ≤4 weeks of Treatment visit #1 (Day 1) or current enrollment in oncologic investigational drug or device study Use of investigational drugs ≤4 weeks or <5 half-lives of Treatment visit # 1(Day 1) or current enrollment in investigational oncology drug or device study Prior systemic beta-emitting bone-seeking radioisotopes Known active brain metastases or leptomeningeal disease History of deep vein thrombosis and/or pulmonary embolus within 1 month of Treatment visit #1 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 PC ≤4 weeks of Treatment visit #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

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 [1.85 GBq (50 mCi) - 9.25 GBq (250 mCi)] x2 doses, 2 weeks apart (Treatment Visit #1 and #2), IV administration 177Lu-J591 [1.35 GBq/m2 or 36.5 mCi/m2] x2 doses, 2 weeks apart (Treatment Visit #1 and #2), IV administration 68Ga-PSMA-HBED-CC [185 ±74 MBq or 5 ±2 mCi] intravenous during screening and at 12 weeks (±1 week) with standard imaging | Drug: 177Lu-PSMA-617<br>* [1.85 GBq (50 mCi) - 9.25 GBq (250 mCi)]<br>Drug: 177Lu-J591<br>* [1.35 GBq/m2 or 36.5 mCi/m2]<br>Drug: 68Ga-PSMA-HBED-CC<br>* [185 ±74MBq or 5 ±2 mCi]<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Dose Limiting Toxicity (DLT) of Combination Therapy in a 2-Week Dose-Fractionation Regimen | Dose limiting toxicity of combination therapy was determined by monitoring for adverse events following therapy | Approximately 3 months after enrollment | 
| Cumulative Maximum Tolerated Dose (MTD) and/or Recommended Phase II Dose (RP2D) of Combination Therapy in a 2-Week Dose-Fractionation Regimen | Cumulative maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of combination therapy was determined by monitoring dose-limiting toxicity and adverse events in the dosing or treatment cohorts | Approximately 3 months after enrollment | 
| The Proportion With PSA Decline Following the Dose-Fractionated Combination Therapy by Comparing the Change in PSA Levels After Therapy to the Baseline, Pre-Treatment PSA. | The proportion of patients with PSA decline following treatment with the combination of 177Lu-J591 and 177Lu-PSMA-617 was determined by comparing PSA levels prior to and following radionuclide therapy | At baseline and at 2 weeks on therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Radiographic Response by RECIST 1.1 With Prostate Cancer Working Group 3 (PCWG3) Modifications | Radiographic response rate was determined by scoring follow-up scans after therapy; RECIST 1.1 criteria with PCWG3 modifications were utilized | At the efficacy (scan) visit time point (12 weeks) | 
| Biochemical Progression-Free Survival by PCWG3 Criteria | Biochemical progression-free survival was determined from date of first therapy to date of progression by PSA | Through study completion, up to 26 months | 
| Radiographic Progression-Free Survival by PCWG3 Criteria | Radiographic progression-free survival was determined from date of first treatment to date of progression on follow-up imaging | Through study completion, up to 26 months | 
| Overall Survival Following Treatment With the Combination of 177Lu-J591 and 177Lu-PSMA-617 in a 2-Week Dose-Fractionation Regimen | Overall survival following treatment with the combination of 177Lu-J591 and 177Lu-PSMA-617 was determined from date of first treatment to date of death | Through study completion, up to 26 months | 
| Changes in CTC Count as Measured by CellSearch | Patients' circulating tumor cell counts were obtained prior to and following therapy | At the efficacy (scan) visit time point (12 weeks) | 
| Rate of Favorable CTC Count as Measured by Cell Search | Patients' circulating tumor cell counts were obtained prior to and following therapy | At the efficacy (scan) visit time point (12 weeks) | 
| Rate of Favorable LDH Count | Patient's LDH values were monitored prior to and following therapy | During treatment phase, then every 4 weeks until radiographic progression, assessed up to 6 months |