Dataset Information

Safety and efficacy of 188-rhenium-labeled antibody to melanin in patients with metastatic melanoma.

ABSTRACT: There is a need for effective "broad spectrum" therapies for metastatic melanoma which would be suitable for all patients. The objectives of Phase Ia/Ib studies were to evaluate the safety, pharmacokinetics, dosimetry, and antitumor activity of (188)Re-6D2, a 188-Rhenium-labeled antibody to melanin. Stage IIIC/IV metastatic melanoma (MM) patients who failed standard therapies were enrolled in both studies. In Phase Ia, 10?mCi (188)Re-6D2 were given while unlabeled antibody preload was escalated. In Phase Ib, the dose of (188)Re-6D2 was escalated to 54?mCi. SPECT/CT revealed (188)Re-6D2 uptake in melanoma metastases. The mean effective half-life of (188)Re-6D2 was 12.4?h. Transient HAMA was observed in 9 patients. Six patients met the RECIST criteria for stable disease at 6 weeks. Two patients had durable disease stabilization for 14 weeks and one for 22 weeks. Median overall survival was 13 months with no dose-limiting toxicities. The data demonstrate that (188)Re-6D2 was well tolerated, localized in melanoma metastases, and had antitumor activity, thus warranting its further investigation in patients with metastatic melanoma.

SUBMITTER: Klein M

PROVIDER: S-EPMC3556872 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Safety and efficacy of 188-rhenium-labeled antibody to melanin in patients with metastatic melanoma.

Klein M M Lotem M M Peretz T T Zwas S T ST Mizrachi S S Liberman Y Y Chisin R R Schachter J J Ron I G IG Iosilevsky G G Kennedy J A JA Revskaya E E de Kater A W AW Banaga E E Klutzaritz V V Friedmann N N Galun E E Denardo G L GL Denardo S J SJ Casadevall A A Dadachova E E Thornton G B GB

Journal of skin cancer 20130110

There is a need for effective "broad spectrum" therapies for metastatic melanoma which would be suitable for all patients. The objectives of Phase Ia/Ib studies were to evaluate the safety, pharmacokinetics, dosimetry, and antitumor activity of (188)Re-6D2, a 188-Rhenium-labeled antibody to melanin. Stage IIIC/IV metastatic melanoma (MM) patients who failed standard therapies were enrolled in both studies. In Phase Ia, 10 mCi (188)Re-6D2 were given while unlabeled antibody preload was escalated. ...[more]

PMID: 23365757

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Project description:BackgroundRipretinib, a broad-spectrum KIT and platelet-derived growth factor receptor A switch-control tyrosine kinase inhibitor, is approved for the treatment of adult patients with advanced gastrointestinal stromal tumor as ≥ fourth-line therapy. We present the efficacy and safety of ripretinib in patients with KIT-altered metastatic melanoma enrolled in the expansion phase of the ripretinib phase I study.Patients and methodsPatients with KIT-altered metastatic melanoma were enrolled and treated with ripretinib at the recommended phase II dose of 150 mg once daily in 28-day cycles. Investigator-assessed responses according to Response Evaluation Criteria In Solid Tumors version 1.1 were carried out on day 1 of cycles 3, 5, 7, every three cycles thereafter, and at a final study visit.ResultsA total of 26 patients with KIT-altered metastatic melanoma (25 with KIT mutations, 1 with KIT-amplification) were enrolled. Patients had received prior immunotherapy (n = 23, 88%) and KIT inhibitor therapy (n = 9, 35%). Confirmed objective response rate (ORR) was 23% [95% confidence interval (CI) 9%-44%; one complete and five partial responses] with a median duration of response of 9.1 months (range, 6.9-31.3 months). Median progression-free survival (mPFS) was 7.3 months (95% CI 1.9-13.6 months). Patients without prior KIT inhibitor therapy had a higher ORR and longer mPFS (n = 17, ORR 29%, mPFS 10.2 months) than those who had received prior KIT inhibitor treatment (n = 9, ORR 11%, mPFS 2.9 months). The most common treatment-related treatment-emergent adverse events (TEAEs) of any grade in ≥15% of patients were increased lipase, alopecia, actinic keratosis, myalgia, arthralgia, decreased appetite, fatigue, hyperkeratosis, nausea, and palmar-plantar erythrodysesthesia syndrome. There were no grade ≥4 treatment-related TEAEs.ConclusionsIn this phase I study, ripretinib demonstrated encouraging efficacy and a well-tolerated safety profile in patients with KIT-altered metastatic melanoma, suggesting ripretinib may have a clinically meaningful role in treating these patients.

Project description:A pentapeptide macrocyclic ligand, KYCAR (lysyl-tyrosyl-cystyl-alanyl-arginine), has been designed as a potential chelating ligand for SPECT imaging and therapeutic in vivo agents. This study shows the synthesis and characterization of KYCAR complexes containing nonradioactive rhenium, 99mTc, or 188Re. The metal complexes were also biologically evaluated to determine in vivo distribution in healthy mice. The overall goals of this project were (1) to synthesize the Tc/Re pentapeptide complexes, (2) to identify spectroscopic methods for characterization of syn versus anti rhenium peptide complexes, (3) to analyze the ex vivo stability, and (4) to assess the biological properties of the [99mTc]TcO-KYCAR and [188Re]ReO-KYCAR complexes in vivo. Details on these efforts are provided below.MethodsNatRe/99mTc/188ReO-KYCAR complexes were synthesized, and macroscopic species were characterized via HPLC, IR, NMR, and CD. These characterization data were compared to the crystallographic data of ReO-KYC to assist in the assignment of diastereomers and to aid in the determination of the structure of the complex.ResultsThe radiometal complexes were synthesized with high purity (>95%). HPLC, IR, NMR and CD data on the macroscopic natReO-KYCAR complexes confirm the successful complexation as well as the presence of two diastereomers in syn and anticonformations. Tracer level complexes show favorable stabilities ex vivo for 2+ h.ConclusionMacroscopic metal complexes form diastereomers with the KYCAR ligand; however, this phenomenon is not readily observed on the tracer level due to the rapid interconversion. It was determined through pKa measurements that the macroscopic natReO-KYCAR complex is 0 at physiological pH. The [99mTc]TcO-KYCAR is stable in vitro while the [188Re]ReO-KYCAR shows 50% decomposition in PBS and serum. Biologically, the tracer level complexes clear through the hepatobiliary pathway. Some decomposition of both tracers is evident by uptake in the thyroid and stomach.

Dataset Information

Safety and efficacy of 188-rhenium-labeled antibody to melanin in patients with metastatic melanoma.

Publications

Safety and efficacy of 188-rhenium-labeled antibody to melanin in patients with metastatic melanoma.

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