Mechanisms of Resistance to PSMA Radioligand Therapy

Mechanisms of Resistance to PSMA Radioligand Therapy: Radiation Resistance Versus Dose

This is a multicenter, correlative study to existing Lutetium based prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) trials and uses.

Study Overview

• Status: Recruiting
• Conditions: Prostate Cancer
• Intervention / Treatment: Procedure: Single-photon emission computed tomography; Procedure: Blood Draw; Procedure: Tumor Biopsy

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the relationship between whole body tumor absorbed dose and response Lutetium based prostate-specific membrane antigen-targeted radioligand therapy (177Lu-PSMA-RLT).

II. To determine the relationship between Post-Operative Radiation Therapy Outcomes Score (PORTOS) score and response to 177Lu-PSMA-RLT.

III. To determine the relative importance of radiation dose (whole body tumor absorbed dose) and radiation sensitivity (PORTOS score) as a marker of response to 177Lu-PSMA-RLT.

EXPLORATORY OBJECTIVES:

I. To develop novel signature of radiation sensitivity.

II. To evaluate tumor biopsies to understand mechanisms of resistance.

III. To understand utility of post-cycle 4 single-photon emission computed tomography (SPECT/CT) to evaluate treatment response.

Study participants will undergo a biopsy and blood draw prior to the initiation of planned therapy, as well as SPECT/CT imaging performed after the first and fourth treatments. One SPECT/CT scan will be performed 24 (+/- 6) after the first treatment, and after the fourth treatment, a 24 +/- 6-hour post-treatment SPECT/CT will be performed. Additionally, study participants may choose to undergo optional biopsy and blood draw at time of progression.

• Study Type: Observational
• Enrollment (Estimated): 125

Contacts and Locations

• Study Contact: Name: Maya Aslam; Phone Number: (415) 514-8987; Email: Maya.Aslam@ucsf.edu

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • Recruiting
      • University of California, Los Angeles
      • Principal Investigator: Matthew Rettig, MD
      • Principal Investigator: Johannes Czernin, MD
    • San Francisco, California, United States, 94143
      • Recruiting
      • University of California, San Francisco
      • Contact: Maya Aslam; Phone Number: 415-514-8987; Email: Maya.Aslam@ucsf.edu
      • Contact: Phone Number: 877-827-3222; Email: cancertrials@ucsf.edu
      • Principal Investigator: Thomas Hope, MD
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering
      • Principal Investigator: Lisa Bodei, MD
      • Principal Investigator: Michael Morris, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Participants will be selected from patients enrolled on Lutetium based PSMA-RLTs and expected to receiving at least four cycles of PSMA-RLT

Description

Inclusion Criteria:

1. Initiating treatment with Lutetium based PSMA-targeted RLT.
2. Participants must have a PSMA-avid lesion that is accessible to biopsy. Biopsy of newly emerging radiographic metastases is desired and preferable to the biopsy of previously existing lesions whenever possible. Newly emerging lesions are defined as those that are absent on a previous scan, or those demonstrating unequivocal progression since initiation of the last treatment. Biopsies will be performed according to local institutional standards.
3. Patients on warfarin, aspirin, or other anti-coagulants are eligible provided they are deemed able to tolerate discontinuation of anti-coagulation for at least five days prior to the biopsy. Conversion to low molecular weight heparin prior to biopsy is permitted per local standard operating procedures, provided there is approval by the interventional radiologist or the PI.
4. Age >=18 years.
5. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Patients with significant congenital or acquired bleeding disorders (eg von Wildebrand's disease, acquired bleeding factor inhibitors).
2. Patients who are not able to undergo additional study related imaging procedures.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Participants undergoing 177Lu-PSMA-617 treatment; Participants undergoing PSMA targeted radioligand therapy with at least four cycles of treatment planned will undergo the following: SPECT/CTs will be performed 24 hours after the first treatment and after the fourth treatment, a tumor biopsy will be performed prior to the first 177Lu-PSMA radioligand therapy, a blood will be drawn prior to treatment for future research, and an optional tumor biopsy and blood draw for future research, may also be obtained at time of progression.

Procedure: Single-photon emission computed tomography; Imaging procedure; Other Names: SPECT/CT; Procedure: Blood Draw; Blood draw for future research tests (45-60 mL).; Procedure: Tumor Biopsy; Guided biopsy of lesion; Other Names: Biopsy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean whole body tumor absorbed dose (WB Dose) across all metastatic lesions	The unit density sphere model will be implemented using OLINDA, a second-generation personal computer software for internal dose assessment in nuclear medicine to measure mean dose across all metastatic lesions. This approach uses the three time-point SPECT/CTs to create a whole-body dose map, which can then be segmented. Using OLINDA, the total dose to each tumor will be calculated as the integral of activity over time estimated out to 500 hours. Dose will be calculated in gray (Gy).	Up to 6 months
Median PORTOS score	PORTOS is a gene signature that predicts salvage radiation success. A PORTOS score of zero (called a "low" PORTOS) means it predicts no benefit from salvage radiotherapy. A PORTOS greater than zero (called a "high" PORTOS score) predicts a benefit from salvage radiation.	Up to 6 months

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: National Cancer Institute (NCI); Prostate Cancer Foundation
• Investigators: Principal Investigator: Thomas Hope, MD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Actual): October 21, 2021
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: June 22, 2022
• First Submitted That Met QC Criteria: June 22, 2022
• First Posted (Actual): June 28, 2022

Study Record Updates

• Last Update Posted (Actual): January 10, 2024
• Last Update Submitted That Met QC Criteria: January 8, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Radioligand Therapy
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms
• Other Study ID Numbers: 19553; R01CA235741-03 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No