Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Adagrasib

Treatment A: A single oral dose of adagrasib 400 mg (2 × 200-mg tablets) on Day 1;

Treatment B: A single oral dose of eltrombopag 75 mg

(1 × 75-mg tablet) plus adagrasib 400 mg (2 × 200-mg tablets) on Day 8.

Eltrombopag + adagrasib

A Phase 1, Open-label, One-sequence Crossover Study to Investigate the Effect of a Breast Cancer Resistance Protein Inhibitor on the Single-dose Pharmacokinetics of Adagrasib in Healthy Adult Subjects

A PK Study to Assess the Drug-drug Interaction of a BCRP Inhibitor on Adagrasib

Area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC∞)

AUC from time zero to the last quantifiable concentration (AUClast)

Maximum observed plasma concentration (Cmax)

Mirati Therapeutics Inc.

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

healthy adults with the age among 20 to 95 years old

the people who are diagnosed melanoma in NTU hospital

Shiou-Hwa Jee, M.D., Ph.D.

Jung-Ting Kao, M.D.

Melanoma is the most aggressive skin cancer, with a propensity to metastasize, and is resistant to most of the current therapeutic regimens. Incidence rate of melanoma in patients with MDM (Mal De Maleda, with SLURP-1 mutation) is much higher than normal counterpart. SLURP-1 (lymphocyte antigen 6/urokinase-type plasminogen activator receptor related protein-1) is an allosteric agonist to the nicotinic acetylcholine receptor (nAchR) and it regulates epidermal homeostasis and T-cell function. The preliminary results of comparing human peripheral blood mononuclear cells (PBMCs) from 4 affected and 15 unaffected members from the family with MDM revealed that T-cell activation was impaired in PBMCs with the heterozygous and homozygous SLURP-1 G86R mutation. (2 of affected members developed melanoma.) Since there is currently no effective treatment for metastatic melanoma, identifying novel molecular mechanisms may lead to development of new treatments for metastatic melanomas.

Previous study showed that melanoma stem cells (MSCs) are crucial in melanoma pathogenesis: 1.Melanoma contains ABCB5, CD133 and ABCG2 positive cells had enhanced tumorigenic potential. 2.Higher frequencies of cells capable of initiating melanoma xenografts when using IL2Rγ-/- NOD SCID mice. These data confirmed the interaction between T cells and MSCs.

In this project, we will investigate the roles of SLURP-1 in melanoma and MSCs. Investigating and verifying the interaction between T-cells from patients with MDM and melanoma cells to confirm the SLURP-1 function of tumorigenesis in xenotransplant mice (IL2Rγ-/- NOD SCID) model. To reveal the role of SLURP-1 silencing in melanoma cell lines by using not only A2058 , A375 and MeWo mwlanima cell lines but also ABCB5+ melanoma cells and ABCB5- melanoma cells through the tumorigenesis, apoptosis,angiogenesis, proliferation, melanosphere formation assays.

The aim of this project is to investigate the roles and molecular mechanisms of SLURP-1 in melanoma carcinogenesis, which may improve the development of novel treatments for melanoma.

Cutaneous melanoma is an aggressive neoplasm refractory to traditional therapies, especially at the metastatic stage. Furthermore, its incidence is continuously increasing during the last decade (1). Melanomas develop through a multistep process that from normal melanocytes proceeds to nevi and to radial and vertical growth phase tumors (2). During this process, melanomas are characterized by certain well-defined genetic alterations as well as frequent chromosomal aberrations associated with tumor progression (3). However, the molecular mechanisms involved in the carcinogenesis and progression of melanoma are complex and not entirely clear (4). Because of the intractability of metastatic melanomas with only 14% of the patients survive for 5 years and no effective treatments (2), understanding the underlying molecular mechanisms involved in melanoma and identifying molecular markers may lead to improvements in therapeutic approaches for metastatic melanomas.

Mal de Meleda (MDM; OMIM 248300) is a rare autosomal recessive disorder characterized by erythema and hyperkeratosis of the palms and soles, extending to the dorsal aspects of the hands and feet (known as transgrediens), and perioral erythema and psoriasiform plaques on the elbows and knees. (5-7) Homozygous mutations of the SLURP1 gene (previously known as ARS component B) encoding lymphocyte antigen 6/urokinase-type plasminogen activator receptor related protein-1 (SLURP-1) have been identified as the cause of MDM. (8-10) Mutations of the SLURP1 gene affect the expression, integrity and stability of SLURP-1 on the upper layer of the epidermis and in cultured mature keratinocytes. (11) Other studies also demonstrated that SLURP-1 acts as a positive allosteric ligand for 7-nAchR in keratinocytes, eliciting proapoptotic activity and differentiation. (12,13) As well as in epidermis and keratinocytes, the expression of SLURP-1 has been found in T cells, B cells, dendritic cells and macrophages. (14-15) Malignant melanoma (MM) has been reported to be the predominant cutaneous malignancy occurring in the hyperkeratotic area in patients with MDM. (16) The incidence of MM in MDM is significantly higher than in the general population.(17) At least six cases of MM have been reported in patients with MDM;27-29 two of the reported cases were siblings. (18) The possible explanations of the higher incidence of MM in patients with MDM include: (i) lack of proapoptotic effect of SLURP-1; (ii) defective T-cell activation and tumour monitoring; or (iii) prolonged inflammation in hyperkeratotic skin.

The previous study showed that peripheral blood mononuclear cells (PBMCs) with the heterozygous and homozygous SLURP-1 G86R mutation had defective T-cell activation. This was restored by the addition of 0•5 μg mL-1 recombinant human SLURP-1 protein. (19) Previous study showed that a putative monoclonal antibody that recognized ABCB5 was used to isolate melanoma stem cells (MSCs). (20) In this study, the investigators will investigate the roles of SLURP-1 in melanoma cells (including MSC) and also its interaction between melanoma cells and T-cells.

Aims：

1. To evaluate the significance and correlation of SLURP-1 expression in melanoma cells and melanoma metastasis in human tissues and mouse metastasis models.
2. To assess the function of the SLURP-1 protein in melanoma cells and melanoma stem cells.
3. To investigate the interaction between T-cells with SLURP-1 mutation and melanoma cells / MSCs.
4. Confirm the biological effects of SLURP-1 on melanoma cells / MSCs.
5. To investigate the relationship between SLURP-1 overexpression and melanoma cancer biology.

References

1. Gray-Schopfer V, Wellbrock C, Marais R. Melanoma biology and new target therapy. Nature 2007; 445: 851-7.
2. Miller AJ, Mihm MC. Melanoma. N Engl J Med 2006; 355: 51-65.
3. Jonsson G, et al. Genomic profiling of malignant melanoma using tiling-resolution array CGH. Oncogene 2007; 6: 4738-48.
4. Bemis LT, Chen R, Amato CM et al. MicroRNA-137 targets microphthalmia-associated transcription factor in melanoma cell lines. Cancer Res 2008; 68: 1362-8.
5. Lucker GP, Van De Kerkhof PC, Steijlen PM. The hereditary palmoplantar keratoses: an updated review and classification. Br J Dermatol 1994; 131:1-14.
6. Bergman R, Bitterman-Deutsch O, Fartasch M et al. Mal de Meleda keratoderma with pseudoainhum. Br J Dermatol 1993; 128:207-12.
7. Jee SH, Lee YY, Wu YC et al. Report of a family with mal de Meleda in Taiwan: a clinical, histopathological and immunological study. Dermatologica 1985; 171:30-7.
8. Fischer J, Bouadjar B, Heilig R et al. Mutations in the gene encoding SLURP-1 in Mal de Meleda. Hum Mol Genet 2001; 10:875-80.
9. Ward KM, Yerebakan O, Yilmaz E et al. Identification of recurrent mutations in the ARS (component B) gene encoding SLURP-1 in two families with mal de Meleda. J Invest Dermatol 2003; 120:96-8.
10. Mastrangeli R, Donini S, Kelton CA et al. ARS component B: structural characterization, tissue expression and regulation of the gene and protein (SLURP-1) associated with mal de Meleda. Eur J Dermatol 2003; 13:560-70.
11. Favre B, Plantard L, Aeschbach L et al. SLURP1 is a late marker of epidermal differentiation and is absent in mal de Meleda. J Invest Dermatol 2007; 127:301-8.
12. Grando SA. Basic and clinical aspects of non-neuronal acetylcholine: biological and clinical significance of non-canonical ligands of epithelial nicotinic acetylcholine receptors. J Pharmacol Sci 2008; 106:174-9.
13. Arredondo J, Chernyavsky AI, Webber RJ et al. Biological effects of SLURP-1 on human keratinocytes. J Invest Dermatol 2005; 125:1236-41.
14. Moriwaki Y, Yoshikawa K, Fukuda H et al. Immune system expression of SLURP-1 and SLURP-2, two endogenous nicotinic acetylcholine receptor ligands. Life Sci 2007; 80:2365-8.
15. Kawashima K, Yoshikawa K, Fujii YX et al. Expression and function of genes encoding cholinergic components in murine immune cells. Life Sci 2007; 80:2314-19.
16. Nakajima K, Nakano H, Takiyoshi N et al. Papillon-Lefèvre syndrome and malignant melanoma. A high incidence of melanoma development in Japanese palmoplantar keratoderma patients. Dermatology 2008; 217:58-62.
17. Sartore L, Bordignon M, Bassetto F et al. Melanoma in skin affected with keratoderma palmoplantaris hereditaria (mal de Meleda): treatment with excision and grafting. J Am Acad Dermatol 2009; 61:161-3.
18. Mozzillo N, Nunziata CA, Caraco C et al. Malignant melanoma developing in an area of hereditary palmoplantar keratoderma (mal de Meleda). J Surg Oncol 2003; 84:229-33.
19. Tjiu JW, Lin PJ, Wu WH et al. SLURP1 mutation-impaired T-cell activation in a family with mal de Meleda. Br J Dermatol. 2010 Sep 21
20. Schatton T, Murphy GF, Frank NY et al. Identification of cells initiating human melanomas. Nature. 2008 Jan 17;451(7176):345-9

Role of SLURP-1 in Melanoma and Melanoma Stem Cells

National Taiwan University Hospital

Pharmaceutical Solutions

The first three subjects will receive lyophilized powder reconstituted with 5 mL of 0.9% NaCl, 0.4 mg of KSP-910638G total. For the first three subjects, 3.34 mL of KSP-910638G will be discarded. The 1.66 mL of KSP-910638G remaining in the syringe will be administered by squirting it into the mouth of the subject.

Following a safety review of the first three subjects receiving 0.4 mg dose, the remaining 22 subjects will receive the full 1.2 mg dose of KSP-910638G reconstituted in 5 mL 0.9% NaCl. These 22 subjects will receive all 5 mL of the peptide solution in a syringe for administration. The agent will not be reconstituted until the subject is ready to squirt the peptide into his or her mouth via syringe. They will be asked to wait 5 minutes and then drink at least 4-8 oz of tap water.

The investigational agent to be used in this study is KSP heptapeptide, which is a fluorescently-labeled peptide composed of a 7-amino acid sequence attached via a 5 amino acid linker to a near-infrared fluorophore, IRDye800CW. (0.4 mg dose)

KSP-910638G, 0.4 mg

The investigational agent to be used in this study is KSP heptapeptide, which is a fluorescently-labeled peptide composed of a 7-amino acid sequence attached via a 5 amino acid linker to a near-infrared fluorophore, IRDye800CW. (1.2 mg dose)

KSP-910638G, 1.2 mg

Ashley E Cawthon

The purpose of this study is to evaluate the safety of orally administered KSP-910638G, a topically administered li-cor IRDye800CW labeled heptapeptide specific for human epithelial growth factor receptor 2 (HER2).

This is a Phase IA study of the safety of an orally administered KSP-910638G heptapeptide for detection of neoplastic tissues in multiple areas of the gastrointestinal tract in humans. The investigators intend to enroll 25 evaluable subjects. The investigators expect to be able to enroll about 1-2 subjects per week, so the study should take about 4-6 months to complete.

Interested, healthy subjects ages 25-100 who respond to recruitment advertising on UMHealthResearch.org and appear to be eligible based responses to inclusion/exclusion criteria questions will be scheduled for a study visit at MCRU. At the study visit, the subjects will review and sign the informed consent and eligibility will be confirmed. If eligible, subjects will provide a blood sample for clinical labs and a urine sample for urinalysis. A negative urine pregnancy test for women of child-bearing potential is required to be eligible. Eligible subjects will consume the reconstituted KSP-910638G. After 5 minutes, subjects will drink a minimum 4-8 ounces of tap water and vital signs will be taken. Subjects will remain in MCRU for observation for 30 minutes. Vital signs will be recorded after 30 minutes. Subjects are required to return to MCRU to have a repeat blood draw for clinical labs and urinalysis within 24 to 48 hours after KSP-910638G ingestion. The study team will conduct a verbal assessment for toxicity at this visit.

Study of the Safety of KSP Heptapeptide (KSP-910638G)

Study of the Safety of KSP Heptapeptide (KSP-910638G) in Humans for the Early Detection of GI Malignancies

review of laboratory values for abnormalities after intervention with KSP-910638G

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A PK Study to Assess the Drug-drug Interaction of a BCRP Inhibitor on Adagrasib	NCT05924152	Healthy Adults	Adagrasib Eltrombopag + a...	18 Years - 60 Years	Mirati Therapeutics Inc.
Role of SLURP-1 in Melanoma and Melanoma Stem Cells	NCT01281722	Melanoma;		20 Years - 95 Years	National Taiwan University Hospital
Role of SLURP-1 in Melanoma and Melanoma Stem Cells	NCT01281722	Melanoma;		20 Years - 95 Years	National Taiwan University Hospital
Study of the Safety of KSP Heptapeptide (KSP-910638G)	NCT03161418	Healthy Adults	KSP-910638G, 0.... KSP-910638G, 1....	25 Years - 100 Years	University of Michigan
Role of SLURP-1 in Melanoma and Melanoma Stem Cells	NCT01281722	Melanoma;		20 Years - 95 Years	National Taiwan University Hospital

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