Background[177Lu]Lu-PSMA is a radioligand therapy used in metastatic castration-resistant prostate cancer (mCRPC). Despite a survival benefit, the responses for many patients receiving [177Lu]Lu-PSMA are not durable, and all patients eventually develop progressive disease. The bone marrow is the most common site of progression. Micrometastases in this area likely receive an inadequate dose of radiation, as the emitted beta-particles from 177Lu travel an average range of 0.7 mm in soft tissue, well beyond the diameter of micrometastases. Radium-223 (223Ra) is a calcium-mimetic and alpha-emitting radionuclide approved for use in men with mCRPC with bone metastases. The range of emitted alpha particles in soft tissue is much shorter (≤100 μm) with high linear energy transfer, likely more lethal for osseous micrometastases. We anticipate that combining a bone-specific alpha-emitter with [177Lu]Lu-PSMA will improve eradication of micrometastatic osseous disease, and thereby lead to higher and longer responses.MethodsThis is a single-center, single-arm phase I/II trial evaluating the combination of 223Ra and [177Lu]Lu-PSMA-I&T in men with mCRPC. Thirty-six patients will receive 7.4 GBq of [177Lu]Lu-PSMA-I&T, concurrently with 223Ra in escalating doses (28 kBq/kg – 55kBq/kg), both given intravenously every six weeks for up to six cycles. Eligible patients will have at least two untreated bone metastases visible on bone scintigraphy, and PSMA-positive disease on PSMA PET scan. Patients must have adequate bone marrow and organ function and be willing to undergo tumor biopsies. Patients with discordant disease visible on FDG PET scan (defined as FDG positive disease with minimal or no PSMA expression and no uptake on bone scan) will be excluded. Other key exclusion criteria include the presence of diffuse marrow disease, prior treatment with 223Ra or [177Lu]Lu-PSMA, or more than one prior line of chemotherapy for prostate cancer. The co-primary objectives of this study are to determine the maximum tolerated dose of 223Ra when combined with [177Lu]Lu-PSMA-I&T and the 50% PSA response rate.ConclusionThe AlphaBet trial is a phase I/II study combining 223Ra with [177Lu]Lu-PSMA-I&T in patients with mCRPC. We aim to enroll the first patient in Q3 2022, and recruitment is anticipated to continue for 24 months.Study registrationNCT05383079.
TPS278 Background: [177Lu]Lu-PSMA-617 was recently FDA-approved for use in the post-taxane, post-antiandrogen setting in pts with mCRPC. Despite conferring a survival benefit, for many the treatment response is short, and progression is inevitable. One of the likely mechanisms limiting the durability of responses to [177Lu]Lu-PSMA-617 is heterogeneity in tumor PSMA expression. This can be screened for visually using PSMA and FDG PET/CT scans and inspecting for discordant disease, however, micrometastatic disease is unable to be evaluated in this way. In addition, [177Lu]Lu-PSMA-617 may not effectively target micrometastatic disease due to the longer path length of beta emitters. Cabazitaxel has radiosensitizing properties that may enhance the cytotoxic effect of [177Lu]Lu-PSMA-617, whilst also treating any PSMA-negative disease. We hypothesize that the combination of [177Lu]Lu-PSMA-617 and cabazitaxel will be well tolerated and lead to more durable responses. Methods: This single-centre, single-arm phase I/II trial will enrol 32-38 pts with mCRPC to evaluate the safety and preliminary efficacy of cabazitaxel and [177Lu]Lu-PSMA-617 in combination. Up to 6 doses of [177Lu]Lu-PSMA-617 (7.4 GBq) will be administered intravenously every 6 weeks. Cabazitaxel will be given concurrently (dose range 12.5mg/m2 - 20mg/m2), on Day 2 and Day 23 of each 6-week cycle. The dose of cabazitaxel will be escalated using a traditional 3+3 design. Key eligibility criteria include a diagnosis of mCRPC with PSMA-positive disease on PSMA PET/CT (SUVmax ≥15), with no evidence of diffuse marrow disease or sites of discordance on FDG PET/CT. Pts must have progressed after prior docetaxel and a second-generation antiandrogen, have adequate bone marrow and organ function and an ECOG performance status of 0-1. The primary objective is to establish the maximum tolerated dose of cabazitaxel and [177Lu]Lu-PSMA-617. Secondary objectives include measuring the frequency and severity of adverse events, assessment of efficacy through PSA 50% response rate, radiographic and PSA progression-free survival, overall survival, objective tumor response rate, and evaluation of pain and health-related quality of life over the first 12 months. Bloods will be taken at baseline, during treatment and at progression for ctDNA analysis, the results of which will be correlated with baseline pt and disease characteristics, and response outcomes, to determine biomarkers of treatment response and resistance. Pt recruitment commenced in August 2022 and will continue for 18 months. Clinical trial information: NCT05340374 .
TPS397 Background: Multi-parametric magnetic resonance imaging (MRI) has an established role for the diagnosis of clinically significant prostate cancer (sPCa), with superior diagnostic accuracy compared with transrectal ultrasound guided prostate biopsy alone. PRIMARY demonstrated significant improvement in sensitivity (97% vs 83%) and negative predictive value (91% vs 72%) with the addition of [68Ga]Ga-PSMA-11 PET/CT (PSMA PET/CT) vs MRI alone. Furthermore, 38% of patients with PI-RADS 2 or 3 were true negative on PSMA PET/CT, a population which may potentially benefit from avoiding transperineal prostate biopsy (TPPB). We hypothesize that the addition of PSMA PET/CT is non-inferior to MRI for the detection of sPCa in men with PI-RADS 2-3 disease, while providing the advantages of reducing unnecessary biopsies and limiting to targeted-only TPPB. Methods: This multi-centre, two-arm, randomized controlled, phase III trial will recruit 660 men with high clinical suspicion of sPC. Participants will be randomized in a 1:1 ratio in permuted blocks, stratified by center. In the experimental arm, participants will undergo a pelvic PSMA PET/CT. Local and central reviewers will interpret independently, based on the PRIMARY Score. Participants with a positive result will undergo targeted-TPPB, whereas those with negative PSMA PET/CT will avoid biopsy. In the control arm, all participants undergo template-TPPB. Patients will continue follow-up for subsequent clinical care for up to two years post-randomization. Key eligibility criteria include an MRI result of PI-RADS 2 with at least one red flag [PSA density >0.1, abnormal digital rectal examination (DRE), strong family history, BRCA mutation, PSA >10, PSA doubling time <36 months, PSA velocity >0.75/year], or PI-RADS 3, having never undergone a prostate biopsy, <cT3 on DRE, and PSA ≤20 ng/mL. The co-primary objectives are to estimate the percentage difference in sPCa between the experimental and control arms, and the percentage of participants who avoid TPPB in the experimental arm. The primary endpoints will be analyzed on the intention-to-treat principle. The main secondary objectives are the percentage difference between arms in insignificant prostate cancer, in complications following biopsy, in health-related quality of life, generalized anxiety, cancer worry, as well as the health economics impact. Patient enrolment began in March 2022, with recruitment expected to take 36 months. Clinical trial information: NCT05154162 .
TPS281 Background: [177Lu]Lu-PSMA is an effective class of therapy for men with metastatic castration-resistant prostate cancer (mCRPC); however, progression is inevitable. The limited durability of response is partially explained by the presence of micrometastatic deposits. Single tumor cells and micrometastases are energy-sheltered deposits receiving low absorbed radiation, due to the ~0.7mm mean path-length of Lutetium-177 (177Lu). Terbium-161 (161Tb) has abundant emission of Auger electrons that deposit a higher concentration of radiation over a shorter path, particularly to single tumor cells and micrometastases. 161Tb has shown superior in-vitro and in-vivo results in comparison with 177Lu. We hypothesize that [161Tb]Tb-PSMA-I&T will deliver effective radiation to sites of metastatic prostate cancer with an acceptable safety profile. Methods: This single-center, single-arm, phase I/II trial will recruit 30 to 36 men with progressive mCRPC. The phase I dose-escalation is designed with a 3+3 model to establish the safest dose of [161Tb]Tb-PSMA-I&T (dose levels: 4.4, 5.5 and 7.4 GBq). The maximum tolerated dose (MTD) will be defined as the highest dose level at which a dose-limiting toxicity occurs in less than 1/3 or 2/6 participants. The phase II dose-expansion will include 24 participants at the MTD. Up to six cycles of [161Tb]Tb-PSMA-I&T will be administered intravenously every six weeks, with each subsequent dose for each patient reduced by 0.4GBq. Key eligibility criteria include a diagnosis of mCRPC with progression after at least one line of taxane chemotherapy and a second-generation anti-androgen, PSMA-positive disease on PSMA PET/CT (SUVmax ≥20), no sites of discordance on FDG PET/CT, adequate bone marrow, hepatic and renal function, ECOG performance status ≤2, and no prior treatment with another radioisotope. The co-primary objectives are to establish the MTD of [161Tb]Tb-PSMA-I&T, and safety profile [CTCAE v5.0]. Secondary objectives include measuring absorbed radiation dose [Gray], evaluating anti-tumour activity [PSA 50% response rate, radiographic and PSA progression-free survival, overall survival, objective response rate], and evaluation of pain [BPI-SF] and health-related quality of life [FACT-P and FACT-RNT] over the first 12 months after treatment commences. Exploratory objectives include ctDNA analysis at baseline, during treatment and at progression, and optional tissue biopsies, to determine biomarkers of treatment response and resistance. Patient enrolment began in October 2022, with recruitment expected to continue for 24 months. Clinical trial information: NCT05521412 .
TPS280 Background: [177Lu]Lu-PSMA-I&T (LuPSMA) is a small molecule radioligand that delivers radiation via beta-particulate emission to cells expressing prostate-specific membrane antigen (PSMA). Despite a survival benefit in mCRPC, responses for many are not durable, with the majority of pts developing progressive osseous disease. Due to the lack of crossfire radiation in micrometastatic disease, small cancer cell clusters in the bone marrow may not receive an adequate dose of radiation from 177Lu to induce cytotoxic double-stranded DNA breaks. Alpha-emitters have a shorter path length (≤100 µm) and higher linear energy transfer, making them better suited for treating micrometastatic disease. As a calcium-mimetic, radium-223 (223Ra) is a bone-specific alpha-emitter which targets osteoblastic bone metastases. We hypothesise that the combination of LuPSMA with 223Ra will be well tolerated and lead to improved response durability. Methods: This phase I/II, single-arm, single-centre study will enrol 36 patients with mCRPC who have progressed on a prior second-generation antiandrogen. Up to 6 cycles of LuPSMA (7.4 GBq) and 223Ra (28 kBq/kg - 55 kBq/kg) will be given intravenously every 6 weeks, along with background androgen deprivation and bone protective therapy. Key eligibility criteria include a diagnosis of mCRPC with at least two untreated bone metastases visible on bone scintigraphy and PSMA-positive disease on PSMA PET/CT (SUVmax ≥20). Sites of FDG-positive disease must be either PSMA-positive or have increased uptake on bone scan. Other eligibility criteria include an ECOG status of 0-2, and adequate bone marrow and organ function. Patients treated with more than one line of chemotherapy for metastatic prostate cancer are not eligible. Blood samples and biopsies will be taken at baseline, on treatment, and at progression to develop tumor- and immune-based biomarkers that predict treatment response and associated survival benefit. A traditional 3+3 dose-escalation model will be utilized initially, escalating the dose of 223Ra. The dose of LuPSMA will remain fixed. The co-primary objectives of this study are to determine the maximum tolerated dose of 223Ra when combined with LuPSMA, and the 50% PSA response rate. Secondary objectives include measuring the frequency and severity of adverse events, assessment of efficacy through overall, radiographic and PSA progression-free survival, overall survival, objective tumor response rate, and evaluation of pain and health-related quality of life. Enrolment commenced in September 2022 and will continue for 24 months. Clinical trial information: NCT05383079 .
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.