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

• ClinicalTrials.gov Identifier: NCT03042468
• Recruitment Status: Active, not recruiting
• First Posted: February 3, 2017
• Results First Posted: December 13, 2022
• Last Update Posted: December 13, 2022
• Sponsor: Weill Medical College of Cornell University
• Information provided by (Responsible Party): Weill Medical College of Cornell University

Tracking Information

• First Submitted Date: January 19, 2017
• First Posted Date: February 3, 2017
• Results First Submitted Date: September 30, 2022
• Results First Posted Date: December 13, 2022
• Last Update Posted Date: December 13, 2022
• Study Start Date: December 2016
• Actual Primary Completion Date: September 30, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 16, 2022)

• Number of Subjects With Dose Limiting Toxicity (DLT) of Fractionated Dose of 177Lu-PSMA-617 [ Time Frame: Assessed throughout the DLT period, up to 92 days after starting study drug. ]
  Proportion of subjects experiencing a dose limiting toxicity (DLT) of fractionated dose of 177Lu-PSMA-617 by using 3+3 dose escalation was assessed.
• Number of Subjects That Achieved Cumulative Maximum Tolerated Dose (MTD) Phase II Dose of 177Lu-PSMA-617 [ Time Frame: from first dose of study drug to at least 12 weeks of subsequent follow-up evaluations, up to 92 days ]
  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.
• Recommended Phase II Dose of 177Lu-PSMA-617 in a 2-week Dose-fractionation Regimen [ Time Frame: Duration of Phase I, up to 47 months ]
  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.

Original Primary Outcome Measures (submitted: February 1, 2017)

• Dose limiting toxicity (DLT) of fractionated dose of 177Lu-PSMA-617 by using 3+3 dose escalation will be used. [ Time Frame: at least 12 weeks of subsequent follow-up evaluations ]
• Cumulative MTD and recommended phase II dose of 177Lu-PSMA-617 in a 2-wk dose-fractionation regimen by using a 3+3 dose escalation design [ Time Frame: at least 12 weeks of subsequent follow-up evaluations ]

Current Secondary Outcome Measures (submitted: November 16, 2022)

• The Rate of PSA Decline Following Fractionated 177Lu-PSMA-617 [ Time Frame: from baseline visit to short term follow up visit, approximately 6 months ]
  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.
• Count of Patients That Had a Radiographic Response Rate Measured by RECIST 1.1 With PCWG3 Modifications [ Time Frame: 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 [ Time Frame: Duration of time on study, from baseline to last follow up visit, up to 54 months ]
  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.
• Number of CTC Count Responders [ Time Frame: Duration of study, from screening to EOS visit, up to 12 weeks ]
  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.
• Overall Survival Following Fractionated 177Lu-PSMA-617 [ Time Frame: Up to 5 years ]
  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.
• Count of Participants That Experience an Adverse Event [ Time Frame: From screening to end of study visit, up to 54 months ]

Original Secondary Outcome Measures (submitted: February 1, 2017)

• The rate of PSA decline following fractionated 177Lu-PSMA-617, PSA response will be determined by comparing the PSA levels after therapy to the baseline, pre-treatment PSA. [ Time Frame: at least 12 weeks of subsequent follow-up evaluations ]
• Radiographic response rate measured by RECIST 1.1 with PCWG3 modifications [ Time Frame: at least 12 weeks of subsequent follow-up evaluations ]
• Radiographic progression-free survival measured by PCWG3 criteria [ Time Frame: at least 12 weeks of subsequent follow-up evaluations ]
• 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 [ Time Frame: at least 12 weeks of subsequent follow-up evaluations ]
• Whole body distribution of 177Lu-PSMA-617 by performing planar/SPECT imaging of 177Lu-PSMA-617 at post-treatment follow up [ Time Frame: at least 12 weeks of subsequent follow-up evaluations ]
• Radiation dosimetry of 177Lu-PSMA-617 and correlate toxicity with radiation dosimetry by performing planar/SPECT imaging of 177Lu-PSMA-617 at post-treatment follow up [ Time Frame: at least 12 weeks of subsequent follow-up evaluations ]
• Biochemical and radiographic progression-free survival by PCWG3 criteria [ Time Frame: at least 12 weeks of subsequent follow-up evaluations ]
• Overall survival following fractionated 177Lu-PSMA-617 [ Time Frame: at least 12 weeks of subsequent follow-up evaluations ]

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: February 1, 2017)

• Disease assessment with 68Ga-PSMA-HBED-CC PET/CT prior to and following investigational treatment [ Time Frame: at least 12 weeks of subsequent follow-up evaluations ]
• Semi-quantitative PSMA expression on Circulating Tumor Cells will be collected [ Time Frame: at least 12 weeks of subsequent follow-up evaluations ]
• Genomic DNA repair pathways in relationship to outcome following fractionated dose 177Lu-PSMA-617 by collecting archival pathology tissue. [ Time Frame: at least 12 weeks of subsequent follow-up evaluations ]
• Patient reported outcomes using the Brief Pain Inventory [ Time Frame: at least 12 weeks of subsequent follow-up evaluations ]
• Patient reported outcomes using Functional Assessment Cancer Therapy-Prostate [ Time Frame: at least 12 weeks of subsequent follow-up evaluations ]

Descriptive Information

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

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:

1. 177Lu-PSMA-617 [50mCi (1.85GBq) - 300mCi (11.1GBq)] intravenous X2 doses, 2 weeks apart (Visit 1 and 2)
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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Prostate Cancer

Intervention

• Drug: 177Lu-PSMA-617
  177Lu-PSMA-617 [50mCi (1.85GBq) - 300mCi (11.1GBq)] intravenous X2 doses, 2 weeks apart (Visit 1 and 2)
• Drug: 68Ga-PSMA-HBED-CC
  68Ga-PSMA-HBED-CC [5 ±2mCi or 185 ±74MBq] intravenous during screening and at 12 weeks with standard imaging

Study Arms

Experimental: All subjects

1. 177Lu-PSMA-617 [50mCi (1.85GBq) - 300mCi (11.1GBq)] intravenous X2 doses, 2 weeks apart (Visit 1 and 2)
2. 68Ga-PSMA-HBED-CC [5 ±2mCi or 185 ±74MBq] intravenous during screening and at 12 weeks with standard imaging

Interventions:

• Drug: 177Lu-PSMA-617
• Drug: 68Ga-PSMA-HBED-CC

• Publications *: Vlachostergios PJ, Niaz MJ, Skafida M, Mosallaie SA, Thomas C, Christos PJ, Osborne JR, Molina AM, Nanus DM, Bander NH, Tagawa ST. Imaging expression of prostate-specific membrane antigen and response to PSMA-targeted beta-emitting radionuclide therapies in metastatic castration-resistant prostate cancer. Prostate. 2021 Apr;81(5):279-285. doi: 10.1002/pros.24104. Epub 2021 Jan 19.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: November 16, 2022): 50
• Original Estimated Enrollment (submitted: February 1, 2017): 46
• Estimated Study Completion Date: September 2023
• Actual Primary Completion Date: September 30, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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. ECOG performance status of 0-2
4. 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.

5. 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)
6. Have previously received taxane chemotherapy, been determined to be ineligible for taxane chemotherapy by their physician, or refused taxane chemotherapy.
7. Age > 18 years

8. 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
9. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. 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
2. Prior systemic beta-emitting bone-seeking radioisotopes
3. Brain metastases or leptomeningeal disease
4. History of deep vein thrombosis and/or pulmonary embolus within 1 month of study entry
5. 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
6. Radiation therapy for treatment of PCa ≤4 weeks of Day 1 Cycle 1
7. 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.
8. 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
9. 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.
10. Known history of known myelodysplastic syndrome

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years to 99 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03042468
• Other Study ID Numbers: 1609017542; PSMA-617 ( Other Identifier: Weill Cornell Medical College )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Weill Medical College of Cornell University
• Original Responsible Party: Same as current
• Current Study Sponsor: Weill Medical College of Cornell University
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Scott Tagawa, MD; Weill Medical College of Cornell University

• PRS Account: Weill Medical College of Cornell University
• Verification Date: November 2022