AlphaBet: Combination of Radium-223 and [177Lu]Lu-PSMA-I&T in men with metastatic castration-resistant prostate cancer (clinical trial protocol)

Abstract

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.

Alpha-Emitting Radionuclides: Current Status and Future Perspectives

“…However, due to the indirect targeting mechanism aimed at bone remodeling and the insufficient ability to couple radium-223 with binding vector molecules, radium-223 has not been successfully used in other indications [ 77 ]. Nevertheless, the side effect profile of this treatment is low and its combination with targeted beta-emitting therapy is possible [ 78 ]. With the introduction of an alpha-emitting radionuclide into clinical routine, radiation safety has been addressed in particular.…”

Advancements in PSMA ligand radiolabeling for diagnosis and treatment of prostate cancer: a systematic review

“…225 Ac-PSMA-I&T has demonstrated enhanced anti-tumor effects in patients with advanced metastatic castration-resistant prostate cancer (mCRPC) ( 67 ). A Phase I/II clinical trial named AlphaBet (NCT05383079) is underway, combining 223 Ra with 177 Lu-PSMA-I&T. This combination aims to improve outcomes for patients with mCRPC and bone metastases ( 68 ).…”

Determinants of outcome following PSMA-based radioligand therapy and mechanisms of resistance in patients with metastatic castration-resistant prostate cancer

“…Ongoing trials are also evaluating the combination of [ 177 Lu]Lu-PSMA with an additional radionuclide to cause cumulative radiation, hypothetically resulting in more profound responses. Examples include combining [ 177 Lu]Lu-PSMA-I&T with radium-223 (AlphaBet, 44 NCT05383079) or [ 225 Ac]Ac-J591(NCT04886986).…”