Molecularly Targeted Therapy for Advanced Cancer
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: University of California, Davis
Must not be taking: Warfarin
Disqualifiers: Congestive heart failure, Active infection, others
No Placebo Group
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.12345
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.12367
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.138910
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.
See 10 more
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.
See 9 more
Trial 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 (Radiopharmaceutical)
Trial OverviewThe 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
1Treatment groups
Experimental Treatment
Group I: [177Lu]Lu DOTA-ABM-5G single dose therapy studyExperimental Treatment1 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
The University of California Davis Comprehensive Cancer CenterSacramento, CA
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Who Is Running the Clinical Trial?
University of California, DavisLead Sponsor
National Institutes of Health (NIH)Collaborator
References
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]Prostate specific membrane antigen (PSMA) is known to be overexpressed in prostate cancer cells, providing as a diagnostic and therapeutic target for prostate cancer. A lutetium-labeled PSMA targeted ligand, 177Lu-DOTA-PSMA-GUL is a novel radiopharmaceutical, which has been developed for the treatment of prostate cancer. While the GUL domain of 177Lu-DOTA-PSMA-GUL binds to the antigen, the beta-emitting radioisotope, 177Lu-labeled DOTA, interacts with prostate cancer cells. However, the in vivo pharmacokinetics of intact 177Lu-DOTA-PSMA-GUL has never been characterized. This study aimed to evaluate the pharmacokinetics and tissue distribution of the radiopharmaceutical in rats by using its stable isotope-labeled analog, 175Lu-DOTA-PSMA-GUL. A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of 175Lu-DOTA-PSMA-GUL was developed and validated. Following intravenous injection, the plasma concentration-time profiles of 175Lu-DOTA-PSMA-GUL showed a multi-exponential decline with the average elimination half-life of 0.30 to 0.33 h. Systemic exposure increased with the dose and renal excretion is the major elimination route. Tissue distribution of 175Lu-DOTA-PSMA-GUL was most substantial in kidneys, followed by the prostate. The developed LC-MS/MS assay and the in vivo pharmacokinetic data of 175Lu-DOTA-PSMA-GUL would provide helpful information for further clinical studies to be developed as a novel therapeutic agent for prostate cancer.
Development of 177Lu-scFvD2B as a Potential Immunotheranostic Agent for Tumors Overexpressing the Prostate Specific Membrane Antigen. [2021]The clinical translation of theranostic 177Lu-radiopharmaceuticals based on inhibitors of the prostate-specific membrane antigen (PSMA) has demonstrated positive clinical responses in patients with advanced prostate cancer (PCa). However, challenges still remain, particularly regarding their pharmacokinetic and dosimetric properties. We developed a potential PSMA-immunotheranostic agent by conjugation of a single-chain variable fragment of the IgGD2B antibody (scFvD2B) to DOTA, to obtain a 177Lu-labelled agent with a better pharmacokinetic profile than those previously reported. The labelled conjugated 177Lu-scFvD2B was obtained in high yield and stability. In vitro, 177Lu-scFvD2B disclosed a higher binding and internalization in LNCaP (PSMA-positive) compared to PC3 (negative control) human PCa cells. In vivo studies in healthy nude mice revealed that 177Lu-scFvD2B present a favorable biokinetic profile, characterized by a rapid clearance from non-target tissues and minimal liver accumulation, but a slow wash-out from kidneys. Micro-SPECT/CT imaging of mice bearing pulmonary microtumors evidenced a slow uptake by LNCaP tumors, which steadily rose up to a maximum value of 3.6 SUV at 192 h. This high and prolonged tumor uptake suggests that 177Lu-scFvD2B has great potential in delivering ablative radiation doses to PSMA-expressing tumors, and warrants further studies to evaluate its preclinical therapeutic efficacy.
New PSMA-Targeting Ligands: Transformation from Diagnosis (Ga-68) to Radionuclide Therapy (Lu-177). [2022]Prostate-specific membrane antigen (PSMA) is a promising target for the diagnosis and radionuclide therapy of prostate cancer. This study reports conversion of a previously reported 68Ga-imaging agent, [68Ga]Ga-P16-093, to a Lu-177 radionuclide therapeutic agent. Substitution of the HBED-CC metal chelating group with DOTA(GA)2 led to P17-087 (4) and P17-088 (7). Both agents showed excellent PSMA binding affinity (IC50 = 10-30 nM) comparable to that of recently FDA-approved [177Lu]Lu-PSMA-617 (Pluvicto). Biodistribution studies in PSMA expressing tumor bearing mice showed that [177Lu]Lu-4 exhibited very high tumor uptake and a fast blood clearance similar to those of [177Lu]Lu-PSMA-617. Conversely, [177Lu]Lu-7, containing an albumin binder, extended its blood half-life and exhibited significantly higher uptake and longer tumor residence time than [177Lu]Lu-4 and [177Lu]Lu-PSMA-617. The switch from chelator HBED-CC to DOTA(GA)2 and the switch from the imaging isotope gallium-68 to the therapeutic isotope lutetium-177 have successfully transformed a PSMA-targeting agent from diagnosis to promising radionuclide therapeutic agents.
Radionuclide Treatment Yields Responses in mCRPC. [2020]In a phase II, single-arm prospective trial, a novel, targeted radionuclide called Lutetium-177 PSMA-617 extended survival and improved quality of life in men with metastatic, castration-resistant prostate cancer whose disease advanced despite standard therapy.
Phase I trial of 177lutetium-labeled J591, a monoclonal antibody to prostate-specific membrane antigen, in patients with androgen-independent prostate cancer. [2022]To determine the maximum tolerated dose (MTD), toxicity, human anti-J591 response, pharmacokinetics (PK), organ dosimetry, targeting, and biologic activity of (177)Lutetium-labeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 ((177)Lu-J591) in patients with androgen-independent prostate cancer (PC).
Preclinical evaluation of [225Ac]Ac-DOTA-TATE for treatment of lung neuroendocrine neoplasms. [2022]Label="PURPOSE">There is significant interest in the development of targeted alpha-particle therapies (TATs) for treatment of solid tumors. The metal chelator-peptide conjugate, DOTA-TATE, loaded with the β-particle emitting radionuclide 177Lu ([177Lu]Lu-DOTA-TATE) is now standard care for neuroendocrine tumors that express the somatostatin receptor 2 (SSTR2) target. A recent clinical study demonstrated efficacy of the corresponding [225Ac]Ac-DOTA-TATE in patients that were refractory to [177Lu]Lu-DOTA-TATE. Herein, we report the radiosynthesis, toxicity, biodistribution (BD), radiation dosimetry (RD), and efficacy of [225Ac]Ac-DOTA-TATE in small animal models of lung neuroendocrine neoplasms (NENs).
Preclinical study of a new 177Lu-labeled somatostatin receptor antagonist in HT-29 human colorectal cancer cells. [2023]Label="OBJECTIVES" NlmCategory="OBJECTIVE">Somatostatin receptor-positive neuroendocrine tumors have been targeted using various peptide analogs radiolabeled with therapeutic radionuclides for years. The better biomedical properties of radioantagonists as higher tumor uptake make these radioligands more attractive than agonists for somatostatin receptor-targeted radionuclide therapy. In this study, we tried to evaluate the efficiency of Luthetium-177 (177Lu) radiolabeled DOTA-Peptide 2 (177Lu-DOTA-Peptide 2) as a new radioantagonist in HT-29 human colorectal cancer in vitro and in vivo.
Evaluation of 177Lu and 47Sc Picaga-Linked, Prostate-Specific Membrane Antigen-Targeting Constructs for Their Radiotherapeutic Efficacy and Dosimetry. [2022]Lu-177-based, targeted radiotherapeutics/endoradiotherapies are an emerging clinical tool for the management of various cancers. The chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) remains the workhorse for such applications but can limit apparent molar activity or efficient charge modulation, which can impact target binding and, as a consequence, target efficacy. Previously, our lab had developed the small, rare earth selective bifunctional chelator, picaga, as an efficient bifunctional chelator for scandium and lutetium isotopes. Here, we assess the performance of these constructs for therapy in prostate-specific membrane antigen (PSMA)-expressing tumor xenografts. To assess the viability of picaga conjugates in conjunction with long in vivo circulation, a picaga conjugate functionalized with a serum albumin binding moiety, 177Lu-picaga-Alb53-PSMA, was also synthesized. A directly comparative, low, single 3.7 MBq dose treatment study with Lu-PSMA-617 was conducted. Treatment with 177Lu-picaga-Alb53-PSMA resulted in tumor regression and lengthened median survival (54 days) when compared with the vehicle (16 days), 47Sc-picaga-DUPA-, 177Lu-picaga-DUPA-, and 177Lu-PSMA-617-treated cohorts (21, 23, and 21 days, respectively).
Synthesis and Evaluation of 68Ga- and 177Lu-Labeled (R)- vs (S)-DOTAGA Prostate-Specific Membrane Antigen-Targeting Derivatives. [2021]Prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer cells and therefore is an attractive target for prostate cancer diagnosis and radionuclide therapy. Recently, published results from clinical studies using a new PSMA-targeting PET imaging agent, [68Ga]Ga-PSMA-093 ([68Ga]Ga-HBED-CC-O-carboxymethyl-Tyr-CO-NH-Glu), support the development of this agent for the diagnosis of prostate cancer. In this study, the HBED-CC chelating group in PSMA-093 was replaced by stereoselective (R)- or (S)-DOTAGA. This chelating group serves not only for chelating 68Ga but is also amendable for complexing other radioactive metals for radionuclide therapy. The corresponding optically pure (R)- and (S)-[68Ga/177Lu]-DOTAGA derivatives, (R)-[68Ga/177Lu]-13 and (S)-[68Ga/177Lu]-13, were successfully prepared. Comparison of radiolabeling, binding affinity, cell uptake, and biodistribution between the two isomers was performed. Radiolabeling of (R)-[177Lu]Lu-13 and (S)-[177Lu]Lu-13 at 50 °C suggested that rates of complex formation were time-dependent and the formation of (S)-[177Lu]Lu-13 was distinctly faster. The rates of complex formation for the corresponding 68Ga agents were comparable between structural isomers. The natGa and natLu equivalents showed high binding PSMA affinity (IC50 = 24-111 nM), comparable to that of the parent agent, [natGa]Ga-PSMA-093 (IC50 = 34.0 nM). Results of cell uptake and biodistribution studies in PSMA-expressing PC3-PIP tumor-bearing mice appeared to show no difference between the labeled (R)- and (S)-isomers. This is the first time that a pair of [68Ga/177Lu]-(R)- and (S)-DOTAGA isomers of PSMA agents were evaluated. Results of biological studies between the isomers showed no noticeable difference; however, the distinctions on the rate of Lu complex formation should be considered in the development of new 177Lu-DOTAGA-based radionuclide therapy agents in the future.
Synthesis and preclinical evaluation of DOTAGA-conjugated PSMA ligands for functional imaging and endoradiotherapy of prostate cancer. [2022]Due to its high expression in prostate cancer, PSMA (prostate-specific membrane antigen) represents an ideal target for both diagnostic imaging and endoradiotherapeutic approaches. Based on a previously published highly specific PSMA ligand ([(68)Ga]DOTA-FFK(Sub-KuE)), we developed a corresponding metabolically stable 1,4,7,10-tetraazacyclododececane,1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA) construct for theranostic treatment of prostate cancer.