Phase 2 Randomized Trial of Flexible Dosing Schedule of 177Lu-PSMA-617 for the Treatment of Metastatic Castration-Resistant Prostate Cancer (FLEX-MRT)

Phase 2RecruitingNCT06216249

Jonsson Comprehensive Cancer Center90 enrolled

Overview

In advanced metastatic castration resistant prostate cancer (mCRPC) progressing after chemotherapy and androgen receptor (AR)-targeted therapy 177Lu-PSMA-617 is an effective treatment. 177Lu-PSMA-617 RLT is administered with a fixed schedule: 6 treatment cycles, administered every 6 weeks. However, the optimum number of cycles of 177Lu-PSMA in patients who show good response remains unknown. Some patients may benefit from more than 6 cycles of therapy. Additionally, some patients experience a complete or almost complete response before the last cycle. It is unclear whether these patients benefit from the subsequent remaining treatment cycle(s). A treatment holiday period would spare these patients some exposure to the therapy agent and avoid potentially unnecessary toxicity when treatment efficacy is already maximal and additional treatment effect cannot be expected. This randomized phase 2 study compares a group of patients treated with LuPSMA on a flexible and extended dosing schedule including "treatment holiday" periods (investigational arm, up to 12 cycles, as described below) to a control group treated with a fixed dosing schedule of 6 treatments cycles maximum administered every 6 weeks. The flexible dosing schedule in the investigational arm will be based on single photon emission computed tomography (SPECT)/computed tomography (CT) response assessments obtained 24h after injection of LuPSMA therapy cycle. The response assessment during treatment holiday period will be based on positron emission tomography/computed tomography (PET/CT) every 12 weeks. Single-time point SPECT/CT dosimetry protocol at every cycle will be performed and will allow to determine the number of cycles that subjects may receive under the study without exceeding the kidney dose threshold.

PRIMARY OBJECTIVE: I. To assess a potential survival benefit (2-year survival rate) of patients treated with Lu 177 vipivotide tetraxetan (177Lu-PSMA-617) therapy on a flexible dosing schedule including up to 12 cycles and potential "treatment holiday" periods in comparison to patients treated with the standard fixed dosing schedule of maximum 6 treatment cycles every 6 weeks. SECONDARY OBJECTIVES: I. To determine the safety of the flexible/extended schedule of 177Lu-PSMA-617 therapy. II. To compare the overall survival (OS) of the flexible/extended schedule of 177Lu-PSMA-617 therapy to the standard-of-care schedule of 177Lu-PSMA-617 therapy. III. To compare the progression-free survival (PFS) of the flexible/extended schedule of 177Lu-PSMA-617 therapy to the standard-of-care schedule of 177Lu-PSMA-617 therapy. IV. To compare the disease control rate (DCR) of the flexible/extended schedule of 177Lu-PSMA-617 therapy to the standard-of-care schedule of 177Lu-PSMA-617 therapy. V. To compare the impact on bone pain level of the flexible/extended schedule of 177Lu-PSMA-617 therapy to the standard-of-care schedule of 177Lu-PSMA-617 therapy. VI. To compare the impact on health-related quality of life of the flexible/extended schedule of 177Lu-PSMA-617 therapy to the standard-of-care schedule of 177Lu-PSMA-617 therapy. EXPLORATORY OBJECTIVE: I. To determine the dosimetry in organs and tumor lesions of the flexible/extended schedule of 177Lu-PSMA-617 therapy. OUTLINE: Patients are randomized to one of 2 arms. ARM I: Patients receive 177Lu-PSMA-617 intravenously (IV) once every 6 weeks on study. Treatment repeats every 6 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo post-therapeutic SPECT/CT at every cycle. The flexible dosing schedule in the investigational arm will be based on prostate specific antigen (PSA) and SPECT/CT response assessments obtained 24h after injection of LuPSMA therapy cycle. Based on their response to therapy, patients may be eligible for "treatment holiday" periods. The monitoring during treatment holiday period will be based on PSMA PET/CT every 12 weeks. If disease progresses patients will re-enter the dosing schedule for up to 12 cycles total, every 6 weeks. Patients also receive gallium Ga-68 gozetotide (68Ga-PSMA-11) IV and undergo prostate-specific membrane antigen positron emission tomography/CT (PSMA PET/CT) on the trial. ARM II: Patients receive 177Lu-PSMA-617 IV once every 6 weeks on study. Treatment repeats every 6 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo post therapeutic SPECT/CT throughout the trial. Patients also receive 68Ga-PSMA-11 IV and undergo PSMA PET/CT on the trial. Upon completion of study treatment, patients are followed up every 3 months for 24 months from after first cycle of study treatment.

Eligibility

Sex: MALEMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Patients must have prostate cancer proven by histopathology * Patients must have ≥ 1 metastatic lesion by any imaging (CT, magnetic resonance imaging \[MRI\], bone scan, PET) * Patients must have received at least one regimen of chemotherapy for mCRPC * Patients must have received at least one androgen-receptor signaling inhibitors (ARSI) * Patients must be eligible by PSMA PET VISION criteria. PSMA PET/CT must be performed within 8 weeks of planned first cycle of 177Lu-PSMA-617 * White blood cell (WBC) ≥ 2,500/ul * Platelets (PLT) ≥ 100,000/ul * Hemoglobin (Hb) ≥ 9.0 g/dl * Absolute neutrophil count (ANC) ≥ 1,500 ul * Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 * Patients must be adults ≥ 18 years of age * Patients must have the ability to understand and sign an approved informed consent form (ICF) * Patients must have the ability to understand and comply with all protocol requirements Exclusion Criteria: * Prior cycle of 177Lu-PSMA-617 therapy * Less than 6 weeks between last myelosuppressive therapy (including docetaxel, cabazitaxel, strontium-89, samarium-153, rhenium-186, rhenium-188, radium-223, hemi-body irradiation) and first cycle of 177Lu-PSMA-617 therapy * Glomerular filtration rate (GFR) \< 50 ml/min * Urinary tract obstruction or marked hydronephrosis

Outcomes

Primary Outcomes

2-year survival rate

Will be assessed patients treated with 177Lu-PSMA-617 therapy on a flexible dosing schedule (investigational arm) in comparison to patients treated with the standard fixed dosing schedule of maximum 6 treatments cycles every 6 weeks (control arm). Will be reported using descriptive statistics by means of number and percentage of patients dead 24 months after the first cycle.

Time frame: From the date of the first cycle of Lu 177 vipivotide tetraxetan (177Lu-prostate-specific membrane antigen [PSMA]-617) therapy, up to 2 years

Secondary Outcomes

Incidence of adverse events

Will be assessed by Common Terminology Criteria for Adverse Events (CTCAE). Descriptive statistics (number and percentage) will be reported separately for adverse events (AE) in total and serious adverse events (SAE) based on CTC. These descriptive statistics will be presented for the whole treatment as well as separate for each cycle. In addition, the relationship of AE to the study drug (related, not related) will be reported. Both results from laboratory test, physical examinations and patients surveys will be included. Distribution of each result will be compared between both groups using appropriate tests (e.g., Mann-Whitney U test).

Time frame: Up to 12 cycles and treatment holiday periods, assessed up to 24 months after first cycle of study treatment

Overall survival

Group comparisons performed using appropriate tests including survival analyses (Kaplan-Meier estimator). Descriptive analyses (median, standard deviation) is used.

Time frame: From the date of the first cycle injection of 177Lu-PSMA-617 until death, assessed up to 24 months after first cycle of study treatment

Progression-free survival (PFS)

Group comparisons performed using appropriate tests including survival analyses (Kaplan-Meier estimator). Descriptive analyses (median, standard deviation) is used. Radiographic progression defined as the date of progression on single photon emission computed tomography (SPECT) by visual increase in tumor volume ≥ 30% compared to baseline ± new sites of disease and/or new sites of prostate-specific membrane antigen (PSMA)-negative disease progression on diagnostic computed to computed tomography (CT) or on PSMA positron emission tomography (PET)/CT. Prostate specific antigen (PSA) progression is the date when a ≥ 25% increase in PSA and an increase of 2 ng/mL or more from the nadir is documented and confirmed by a second consecutive value obtained 3 or more weeks later. Clinical progression defined as marked escalation in cancer related pain, immediate need for initiation of new anticancer treatment, and marked deterioration in Eastern Cooperative Oncology Group (ECOG) performance.

Time frame: The date of the first cycle injection of 177Lu-PSMA-617 to the date of first evidence of progression, or death from any cause, whichever occurs first, assessed up to 24 months after first cycle of study treatment

Disease control rate (DCR)

Will be defined as the proportion of patients achieving radiographic stable disease (SD), partial response (PR) or complete response (CR). CR is defined as absence of PSMA-avid tumor on either imaging modality. On SPECT/CT, PR is defined as a \> 30% reduction in visual tumor volume at all sites of involved disease compared to baseline cycle #1, no new sites of PSMA-avid tumor and no new sites of PSMA-negative tumor on diagnostic CT, and SD is defined as no change \> 30% in visual tumor volume compared to baseline cycle #1, no new sites of PSMA-avid tumor and no new sites of PSMA-negative tumor on diagnostic CT. Respective response groups on PSMA PET/CT are defined by Response Evaluation Criteria in Prostate-specific membrane antigen PSMA PET/CT criteria. Descriptive analysis will be used to determine the DCR.