Molecularly Targeted Therapy for Advanced Cancer

Overseen By Julie L Sutcliffe, Phd

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of California, Davis

Must not be taking: Warfarin

Disqualifiers: Congestive heart failure, Active infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 5

Duration: 1 day

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase I study to evaluate the safety and efficacy of the \[68Ga\]Ga DOTA-5G and \[177Lu\]Lu DOTA-ABM-5G theranostics pair in patients with metastatic cancer.

What data supports the effectiveness of the treatment [68Ga]Ga DOTA-5G and [177Lu]Lu DOTA-ABM-5G for advanced cancer?

Research on similar treatments, like 177Lu-PSMA-617, shows that lutetium-based therapies can extend survival and improve quality of life in prostate cancer patients. These treatments work by targeting specific proteins on cancer cells, delivering radiation directly to the tumor, which suggests potential effectiveness for other cancers as well. ^{1 2 3 4 5}

Is the molecularly targeted therapy for advanced cancer, including [68Ga]Ga DOTA-5G and [177Lu]Lu DOTA-ABM-5G, generally safe in humans?

The safety data for similar treatments, like [177Lu]Lu-DOTA-PSMA-GUL and [177Lu]Lu-scFvD2B, show that they are generally safe in preclinical studies, with rapid clearance from non-target tissues and minimal liver accumulation, but they do have a slow wash-out from kidneys. These findings suggest a favorable safety profile, but further clinical studies are needed to confirm safety in humans. ^{1 2 3 6 7}

How does the drug [68Ga]Ga DOTA-5G and [177Lu]Lu DOTA-ABM-5G differ from other treatments for advanced cancer?

This drug is unique because it combines a diagnostic agent ([68Ga]Ga DOTA-5G) with a therapeutic agent ([177Lu]Lu DOTA-ABM-5G), allowing for both imaging and treatment of cancer. The use of gallium-68 for imaging and lutetium-177 for therapy targets specific cancer cells, potentially improving treatment precision and effectiveness. ^{1 3 8 9 10}

Research Team

Julie Sutcliffe

Principal Investigator

University of California, Davis

Eligibility Criteria

This trial is for patients with metastatic cancer. Specific eligibility criteria are not provided, but typically participants would need to be in good health aside from their cancer and have a life expectancy that allows them to complete the study.

Inclusion Criteria

My scans show at least one cancer spot that stands out clearly.

My cancer has worsened after treatment as shown by scans.

I can take care of myself but might not be able to do heavy physical work.

Exclusion Criteria

I am on warfarin for blood thinning.

I have not had treatment for another cancer, except skin or early breast/cervical cancer, in the last 2 years.

I have severe heart failure.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Imaging

Participants undergo [68Ga]Ga DOTA-5G PET/CT scans to confirm eligibility for the [177Lu]Lu DOTA-ABM-5G therapy

2 hours

1 visit (in-person)

Treatment

Participants receive a single dose of [177Lu]Lu DOTA-ABM-5G therapy

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

60 days

2 visits (in-person)

Treatment Details

Interventions

• [68Ga]Ga DOTA-5G and [177Lu]Lu DOTA-ABM-5G

Trial Overview The study is testing [68Ga]Ga DOTA-5G and [177Lu]Lu DOTA-ABM-5G theranostics pair. It's a Phase I trial, which means it's the first time these treatments are being tested in humans to check safety and how well they work.

Participant Groups

Group I: [177Lu]Lu DOTA-ABM-5G single dose therapy study Experimental Treatment 1 Intervention

Patients will be undergo \[68Ga\]Ga DOTA-5G PET/CT scans to confirm eligibility for the \[177Lu\]Lu DOTA-ABM-5G therapy. Patients with sufficient lesion uptake of \[68Ga\]Ga DOTA-5G PET/CT will be offered therapy.

Who Is Running the Clinical Trial?

University of California, Davis

Lead Sponsor

Trials

958

Recruited

4,816,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Findings from Research

The novel radiopharmaceutical 177Lu-DOTA-PSMA-GUL targets prostate cancer cells by binding to the prostate-specific membrane antigen (PSMA) and shows promising pharmacokinetics, with an average elimination half-life of 0.30 to 0.33 hours in rats.

Tissue distribution studies revealed that 177Lu-DOTA-PSMA-GUL is primarily eliminated through the kidneys, with significant accumulation in the prostate, indicating its potential effectiveness as a targeted therapy for prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of pharmacokinetics and tissue distribution of a novel lutetium-labeled PSMA-targeted ligand, 177Lu-DOTA-PSMA-GUL, in rats by using LC-MS/MS. Song, CH., Kim, K., Kang, E., et al.[2022]

The newly developed 177Lu-scFvD2B radiopharmaceutical shows improved pharmacokinetic properties, with high stability and yield, and demonstrates better binding and internalization in PSMA-positive prostate cancer cells compared to negative controls.

In vivo studies in mice indicate that 177Lu-scFvD2B has a favorable biokinetic profile, with rapid clearance from non-target tissues and sustained uptake in tumors, suggesting its potential for effective radiation therapy in advanced prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of 177Lu-scFvD2B as a Potential Immunotheranostic Agent for Tumors Overexpressing the Prostate Specific Membrane Antigen. Carpanese, D., Ferro-Flores, G., Ocampo-Garcia, B., et al.[2021]

The study successfully converted a gallium-68 imaging agent into a lutetium-177 therapeutic agent for prostate cancer, demonstrating strong PSMA binding affinity comparable to the FDA-approved [177Lu]Lu-PSMA-617.

Biodistribution studies in mice showed that the new agent [177Lu]Lu-7 had a longer blood half-life and higher tumor uptake than both [177Lu]Lu-4 and [177Lu]Lu-PSMA-617, indicating its potential for improved therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New PSMA-Targeting Ligands: Transformation from Diagnosis (Ga-68) to Radionuclide Therapy (Lu-177). Zha, Z., Choi, SR., Li, L., et al.[2022]

In a phase II trial involving men with metastatic, castration-resistant prostate cancer, Lutetium-177 PSMA-617 was shown to extend survival and enhance quality of life for patients whose disease progressed despite standard treatments.

This study highlights the potential of targeted radionuclide therapy as an effective option for patients with advanced prostate cancer, suggesting a promising new avenue for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radionuclide Treatment Yields Responses in mCRPC. [2020]

The maximum tolerated dose (MTD) of (177)Lu-J591 for treating androgen-independent prostate cancer was determined to be 70 mCi/m², with multiple doses of 30 mCi/m² being well tolerated by patients.

The treatment showed promising biological activity, with 4 patients experiencing significant declines in prostate-specific antigen (PSA) levels and 46% of patients achieving PSA stabilization, indicating potential effectiveness in targeting prostate cancer metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of 177lutetium-labeled J591, a monoclonal antibody to prostate-specific membrane antigen, in patients with androgen-independent prostate cancer. Bander, NH., Milowsky, MI., Nanus, DM., et al.[2022]

The targeted alpha-particle therapy [225Ac]Ac-DOTA-TATE showed promising efficacy in delaying tumor growth in small animal models of lung neuroendocrine neoplasms, indicating its potential for treating patients who are resistant to standard therapies like [177Lu]Lu-DOTA-TATE.

In toxicity studies, [225Ac]Ac-DOTA-TATE demonstrated a high safety profile with no significant adverse effects in most animals, although higher doses led to chronic nephropathy, highlighting the need for careful dosing in clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of [225Ac]Ac-DOTA-TATE for treatment of lung neuroendocrine neoplasms. Tafreshi, NK., Pandya, DN., Tichacek, CJ., et al.[2022]

177Lu-DOTA-Peptide 2, a new radioantagonist, showed high stability and selective binding to somatostatin receptors in HT-29 colorectal cancer cells, indicating its potential for targeted therapy.

The study demonstrated that 177Lu-DOTA-Peptide 2 has a low internalization rate and a high tumor uptake, making it a promising candidate for radionuclide therapy in treating somatostatin receptor-positive tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical study of a new 177Lu-labeled somatostatin receptor antagonist in HT-29 human colorectal cancer cells. Behnammanesh, H., Erfani, M., Hajiramezanali, M., et al.[2023]

The novel chelator picaga, when used in the 177Lu-picaga-Alb53-PSMA construct, demonstrated significant tumor regression and increased median survival (54 days) in prostate-specific membrane antigen (PSMA)-expressing tumor xenografts compared to other treatments.

In a comparative study, 177Lu-picaga-Alb53-PSMA outperformed both the vehicle and other radiotherapeutics, indicating its potential as a more effective option for targeted radiotherapy in cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of 177Lu and 47Sc Picaga-Linked, Prostate-Specific Membrane Antigen-Targeting Constructs for Their Radiotherapeutic Efficacy and Dosimetry. Vaughn, BA., Loveless, CS., Cingoranelli, SJ., et al.[2022]

The study successfully developed two new PSMA-targeting agents, (R)-[68Ga/177Lu]-DOTAGA and (S)-[68Ga/177Lu]-DOTAGA, which can be used for both imaging and therapy in prostate cancer, showing high binding affinity to PSMA.

While both isomers demonstrated similar biological behavior in terms of cell uptake and biodistribution in tumor-bearing mice, the (S)-isomer formed complexes with Lu more quickly, which could be important for future radionuclide therapy development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and Evaluation of 68Ga- and 177Lu-Labeled (R)- vs (S)-DOTAGA Prostate-Specific Membrane Antigen-Targeting Derivatives. Zhao, R., Ploessl, K., Zha, Z., et al.[2021]

The newly developed PSMA-targeting ligands [(68)Ga/(177)Lu]DOTAGA-ffk(Sub-KuE] show high affinity and specific internalization in prostate cancer cells, indicating their potential for effective diagnostic imaging and therapy.

These ligands demonstrated favorable pharmacokinetics, including low non-specific uptake and high tumor accumulation in LNCaP-tumor-bearing mice, suggesting they could be highly effective in managing prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and preclinical evaluation of DOTAGA-conjugated PSMA ligands for functional imaging and endoradiotherapy of prostate cancer. Weineisen, M., Simecek, J., Schottelius, M., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Determination of pharmacokinetics and tissue distribution of a novel lutetium-labeled PSMA-targeted ligand, 177Lu-DOTA-PSMA-GUL, in rats by using LC-MS/MS. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Development of 177Lu-scFvD2B as a Potential Immunotheranostic Agent for Tumors Overexpressing the Prostate Specific Membrane Antigen. [2021]

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

New PSMA-Targeting Ligands: Transformation from Diagnosis (Ga-68) to Radionuclide Therapy (Lu-177). [2022]

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

Radionuclide Treatment Yields Responses in mCRPC. [2020]

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

Phase I trial of 177lutetium-labeled J591, a monoclonal antibody to prostate-specific membrane antigen, in patients with androgen-independent prostate cancer. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of [225Ac]Ac-DOTA-TATE for treatment of lung neuroendocrine neoplasms. [2022]

7. Iran pubmed.ncbi.nlm.nih.gov

Preclinical study of a new 177Lu-labeled somatostatin receptor antagonist in HT-29 human colorectal cancer cells. [2023]

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

Evaluation of 177Lu and 47Sc Picaga-Linked, Prostate-Specific Membrane Antigen-Targeting Constructs for Their Radiotherapeutic Efficacy and Dosimetry. [2022]

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

Synthesis and Evaluation of 68Ga- and 177Lu-Labeled (R)- vs (S)-DOTAGA Prostate-Specific Membrane Antigen-Targeting Derivatives. [2021]

10. Germany pubmed.ncbi.nlm.nih.gov

Synthesis and preclinical evaluation of DOTAGA-conjugated PSMA ligands for functional imaging and endoradiotherapy of prostate cancer. [2022]