Ac-225 Rosopatamab Tetraxetan for Prostate Cancer

Recruiting in Palo Alto (17 mi)

+3 other locations

Age: 18+

Sex: Male

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Convergent Therapeutics

Must be taking: ADT, ARSI

Must not be taking: PARP inhibitors, Anticoagulants

Disqualifiers: Superscans, Prior platinum chemotherapy, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This is a three-part study evaluating the safety and efficacy of a PSMA-directed radioantibody (rosopatamab tetraxetan, conjugated to either In-111 or Ac-225). Part 1 will consist of one administration of In-111-rosopatamab tetraxetan to characterize the biodistribution of the radioantibody to target organs and prostate cancer lesions. Participants then will be enrolled into either Part 2 (Dose Optimization) or Part 3 (Dose Escalation and Expansion) depending on their prior treatment history. Participants qualifying for Part 2 will be randomized to receive Ac-225 rosopatamab tetraxetan in a single fractionated cycle (dose administration on Day 1 and Day 15) at either 45 or 60 kBq/Kg. Participants qualifying for Part 3 must have received prior Lu-177-PSMA-radioligand therapy and will receive Ac-225 rosopatamab tetraxetan in a single fractionated cycle at 45, 55, or 60 kBq/Kg. Dose limiting toxicities (DLTs) will be monitored in Part 3 to determine the recommended phase 2 dose (RP2D), and the study may enroll additional participants to be treated with the RP2D dose level. Participants enrolled into any part will attend study visits which will include blood samples, electrocardiogram (ECG), radiographic imaging, and physical examinations along with other assessments.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on anti-coagulants or anti-platelet drugs, you may need to stop if your platelet count drops below a certain level.

What data supports the effectiveness of the drug Ac-225 Rosopatamab Tetraxetan for prostate cancer?

Research shows that treatments using Actinium-225, like Ac-225 Rosopatamab Tetraxetan, have shown promising results in treating metastatic castration-resistant prostate cancer. Actinium-225 is an alpha emitter, which means it can effectively target and kill cancer cells with potentially fewer side effects compared to other treatments. ^{1 2 3 4 5}

Is Ac-225 Rosopatamab Tetraxetan safe for humans?

Ac-225 Rosopatamab Tetraxetan, also known as 225Ac-J591, has been tested in humans for prostate cancer. It is generally well-tolerated, but some patients experienced dry mouth and blood-related side effects like anemia (low red blood cell count). ^{1 3 5 6 7}

What makes Ac-225 Rosopatamab Tetraxetan unique for prostate cancer treatment?

Ac-225 Rosopatamab Tetraxetan is unique because it uses a targeted approach by combining an anti-PSMA antibody with the alpha-emitter actinium-225, specifically targeting prostate cancer cells that overexpress PSMA, potentially offering a more precise and effective treatment for metastatic castration-resistant prostate cancer. ^{1 2 5 8 9}

Eligibility Criteria

This trial is for individuals with PSMA PET-positive castration-resistant prostate cancer. Participants must have a specific type of advanced prostate cancer and may be sorted into different parts of the study based on their previous treatments. Those who've had Lu-177-PSMA therapy go to Part 3, while others may enter Part 2.

Inclusion Criteria

PSMA PET-positive disease with specific criteria

I have previously received Lu-177-PSMA therapy.

My cancer has spread to other parts of my body, confirmed by imaging tests.

Exclusion Criteria

My bone scan shows extensive cancer spread.

I have never taken PARP inhibitors before.

I have received platinum-based chemotherapy before.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dosimetry

One administration of In-111-rosopatamab tetraxetan to characterize the biodistribution of the radioantibody to target organs and prostate cancer lesions

1 week

1 visit (in-person)

Dose Optimization

Participants receive Ac-225 rosopatamab tetraxetan in a single fractionated cycle at either 45 or 60 kBq/Kg

2 weeks

2 visits (in-person)

Dose Escalation and Expansion

Participants receive Ac-225 rosopatamab tetraxetan in a single fractionated cycle at 45, 55, or 60 kBq/Kg, with monitoring for dose limiting toxicities

2 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ac-225 Rosopatamab Tetraxetan (Radioantibody)

Trial Overview The study tests a radioantibody called rosopatamab tetraxetan, linked to radioactive elements In-111 or Ac-225. It's given in varying doses to see how well it targets cancer cells and what dose is best tolerated. The trial includes initial dosimetry, randomized dose optimization between two levels (55 or 60 KBq/kg), and dose escalation starting at 45 KBq/kg.

Participant Groups

Group I: Part 3: Dose Escalation and Expansion Experimental Treatment 3 Interventions

Participants previously treated with Lu-177-PSMA-radioligand therapy will be assigned to receive one of the three dose levels (45 kBq/kg, 55 kBq/kg, or 60 kBq/kg) depending on the dose limiting toxicities (DLTs) observed.

Group II: Part 2: 60 kBq/kg Ac-225 rosopatamab tetraxetan Experimental Treatment 1 Intervention

Group III: Part 2: 45 kBq/kg Ac-225 rosopatamab tetraxetan Experimental Treatment 1 Intervention

Group IV: Part 1: 148 ± 37 MBq In-111 rosopatamab tetraxetan Experimental Treatment 1 Intervention

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

X Cancer Omaha / Urology Cancer Center Omaha, NE

The Cleveland Clinic Foundation Cleveland, OH

Laura & Isaac Perlmutter Cancer Center New York, NY

Memorial Sloan Kettering Cancer Center New York, NY

Who Is Running the Clinical Trial?

Convergent Therapeutics Lead Sponsor

References

1. United States pubmed.ncbi.nlm.nih.gov

Prostate-Specific Membrane Antigen-Targeting Alpha Emitter via Antibody Delivery for Metastatic Castration-Resistant Prostate Cancer: A Phase I Dose-Escalation Study of 225Ac-J591. [2023] Label="PURPOSE" NlmCategory="OBJECTIVE">Novel therapies are needed to extend survival in metastatic castration-resistant prostate cancer (mCRPC). Prostate-specific membrane antigen (PSMA), a cell surface antigen overexpressed in PC, provides a validated target. This dose-escalation study investigated the safety, efficacy, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) for 225Ac-J591, anti-PSMA monoclonal antibody J591 radiolabeled with the alpha emitter actinium-225.

2. India pubmed.ncbi.nlm.nih.gov

In-House Preparation and Quality Control of Ac-225 Prostate-Specific Membrane Antigen-617 for the Targeted Alpha Therapy of Castration-Resistant Prostate Carcinoma. [2022] Ac-225 labeled with prostate-specific membrane antigen (PSMA-617), a transmembrane glycoprotein which is highly expressed in prostate carcinoma cells, is presently being considered a promising agent of targeted alpha therapy for the treatment of patients suffering from metastatic castration-resistant prostate cancer. In the present study, we report an optimized protocol for the preparation of therapeutic dose of Ac-225 PSMA-617 with high yield and radiochemical purity (RCP).

3. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Actinium-225 Prostate-Specific Membrane Antigen Radioligand Therapy in Metastatic Prostate Cancer: A Systematic Review and Metanalysis. [2023] Actinium-225 (Ac-225) labelled PSMA RLT has been tested recently in metastatic castration-resistant prostate cancer (mCRPC), with encouraging results. Ac-225, being an alpha emitter, is expected to have higher efficacy and fewer side effects compared to the beta-emitters such as Lutetium-177. We have performed a meta-analysis to assess the therapeutic responses, survival effects, and significant side effects of Ac-225 PSMA RLT in patients with mCRPC.

4. United States pubmed.ncbi.nlm.nih.gov

Preclinical Efficacy of a PSMA-Targeted Thorium-227 Conjugate (PSMA-TTC), a Targeted Alpha Therapy for Prostate Cancer. [2021] Prostate-specific membrane antigen (PSMA) is an attractive target for radionuclide therapy of metastatic castration-resistant prostate cancer (mCRPC). PSMA-targeted alpha therapy (TAT) has shown early signs of activity in patients with prostate cancer refractory to beta radiation. We describe a novel, antibody-based TAT, the PSMA-targeted thorium-227 conjugate PSMA-TTC (BAY 2315497) consisting of the alpha-particle emitter thorium-227 complexed by a 3,2-HOPO chelator covalently linked to a fully human PSMA-targeting antibody.

5. Switzerland pubmed.ncbi.nlm.nih.gov

[225Ac]Ac-SibuDAB for Targeted Alpha Therapy of Prostate Cancer: Preclinical Evaluation and Comparison with [225Ac]Ac-PSMA-617. [2022] In the present study, SibuDAB, an albumin-binding PSMA ligand, was investigated in combination with actinium-225 and the data were compared with those of [225Ac]Ac-PSMA-617. In vitro, [225Ac]Ac-SibuDAB and [225Ac]Ac-PSMA-617 showed similar tumor cell uptake and PSMA-binding affinities as their 177Lu-labeled counterparts. The in vitro binding to serum albumin in mouse and human blood plasma, respectively, was 2.8-fold and 1.4-fold increased for [225Ac]Ac-SibuDAB as compared to [177Lu]Lu-SibuDAB. In vivo, this characteristic was reflected by the longer retention of [225Ac]Ac-SibuDAB in the blood than previously seen for [177Lu]Lu-SibuDAB. Similar to [225Ac]Ac-PSMA-617, [225Ac]Ac-SibuDAB was well tolerated at 30 kBq per mouse. Differences in blood cell counts were observed between treated mice and untreated controls, but no major variations were observed between values obtained for [225Ac]Ac-SibuDAB and [225Ac]Ac-PSMA-617. [225Ac]Ac-SibuDAB was considerably more effective to treat PSMA-positive tumor xenografts than [225Ac]Ac-PSMA-617. Only 5 kBq per mouse were sufficient to eradicate the tumors, whereas tumor regrowth was observed for mice treated with 5 kBq [225Ac]Ac-PSMA-617 and only one out of six mice survived until the end of the study. The enhanced therapeutic efficacy of [225Ac]Ac-SibuDAB as compared to that of [225Ac]Ac-PSMA-617 and reasonable safety data qualify this novel radioligand as a candidate for targeted α-therapy of prostate cancer.

6. Switzerland pubmed.ncbi.nlm.nih.gov

Prostate specific membrane antigen binding radiopharmaceuticals: Current data and new concepts. [2022] Prostate specific membrane antigen (PSMA) represents a validated target for prostate cancer therapeutics. The phase III VISION study with 177lutetium (177Lu)-PSMA-617 represented a pivotal step forward and the FDA has now approved this agent in advanced metastatic castrate-resistant prostate cancer (mCRPC). A number of other PSMA targeted radiopharmaceuticals are now under development. Some of these agents are targeted to PSMA via monoclonal antibodies such as J591 and TLX591. Others are targeted to PSMA via small molecules such as PSMA-617, PSMA I&T, MIP-1095, etc. In addition to the use of various ligands, multiple isotopes are now in clinical trials. Beta emitters in development include 177Lu, 131iodide (131I), and 67copper (67Cu). Targeted alpha emitters potentially include 225actinium (225Ac), 227thorium (227Th), and 212lead (212Pb). Phase III trials are underway with both 177Lu-PSMA-617 and 177Lu-PSMA I&T in mCRPC. Single dose phase I trials are complete with 225Ac-J591 but additional data are need to launch a phase III. Data are promising with 225Ac-PSMA-617 but concerns remain over salivary and renal toxicity. Tandem therapies are also considered combining both beta and alpha-targeted therapy. Taken together the field of PSMA targeted radiopharmaceuticals is rapidly developing. The targeted alpha therapies are particularly promising and several developmental paths forward are being considered in the near future.

7. United States pubmed.ncbi.nlm.nih.gov

Effects of 225Ac-Labeled Prostate-Specific Membrane Antigen Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer: A Meta-Analysis. [2022] Prostate-specific membrane antigen (PSMA), overexpressed in prostate cancer, has become a popular target for radionuclide-based theranostic applications in the advanced stages of prostate cancer. We conducted a meta-analysis of the therapeutic effects of PSMA-targeting α-therapy (225Ac-PSMA radioligand therapy [RLT]) in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: A systematic search was performed using the keywords "mCRPC," "225Ac-PSMA," and "alpha therapy." Therapeutic responses were analyzed as the pooled proportions of patients with more than a 50% prostate-specific antigen (PSA) decline and any PSA decline. Survival outcomes were analyzed by estimating summary survival curves for progression-free survival and overall survival. Adverse events were analyzed as the pooled proportions of patients with xerostomia and severe hematotoxicity (anemia, leukocytopenia, and thrombocytopenia). Results: Nine studies with 263 patients were included in our meta-analysis. The pooled proportions of patients with more than a 50% PSA decline and any PSA decline were 60.99% (95% CI, 54.92%-66.83%) and 83.57% (95% CI, 78.62%-87.77%), respectively. The estimated mean progression-free survival and mean overall survival were 9.15 mo (95% CI, 6.69-11.03 mo) and 11.77 mo (95% CI, 9.51-13.49 mo), respectively. The pooled proportions of patients with adverse events were 62.81% (95% CI, 39.34%-83.46%) for xerostomia, 14.39% (95% CI, 7.76%-22.63%) for anemia, 4.12% (95% CI, 0.97%-9.31%) for leukocytopenia, and 7.18% (95% CI, 2.70%-13.57%) for thrombocytopenia. Conclusion: In our study, around 61% of patients had more than a 50% PSA decline and 84% of patients had any PSA decline after 225Ac-PSMA RLT. The common adverse events in 225Ac-PSMA RLT were xerostomia in 63% of patients and severe hematotoxicity in 4%-14% of patients.

8. New Zealand pubmed.ncbi.nlm.nih.gov

Lutetium Lu 177 Vipivotide Tetraxetan: First Approval. [2022] Lutetium Lu 177 vipivotide tetraxetan (PLUVICTO™, formerly known as 177Lu-PSMA-617) is a radioligand therapeutic agent that is being developed by Advanced Accelerator Applications (a subsidiary of Novartis) for the treatment of prostate-specific membrane antigen (PSMA)-expressing metastatic prostate cancer. The active part of the radiopharmaceutical is lutetium-177, which is linked to a ligand that binds to prostate-specific membrane antigen (PSMA), a transmembrane enzyme overexpressed in primary and metastatic prostate cancers. Based on efficacy results from the phase 3 VISION trial, lutetium Lu 177 vipivotide tetraxetan was approved in the USA on 23 March 2022 for the treatment of adult patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy. Regulatory review in the EU and other countries is underway. This article summarizes the milestones in the development of Lutetium Lu 177 vipivotide tetraxetan leading to this first approval as a therapeutic radioligand for mCRPC.

9. India pubmed.ncbi.nlm.nih.gov

Health-Related Quality-of-Life Outcomes with Actinium-225-Prostate-Specific Membrane Antigen-617 Therapy in Patients with Heavily Pretreated Metastatic Castration-Resistant Prostate Cancer. [2022] Label="AIMS" NlmCategory="OBJECTIVE">Actinium-225 (225Ac) labeled prostate-specific membrane antigen (PSMA)-617 is a novel treatment modality in the management of metastatic castration-resistant prostate cancer (mCRPC). The present study was conducted to assess the impact of 225Ac-PSMA-617 therapy on the quality-of-life of patients with heavily pretreated mCRPC using the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy-Prostate Symptom Index-17 (NCCN-FACT-FPSI-17) questionnaire.