A Phase 1 Clinical Study of NXP900 in Subjects With Advanced Cancers

Обзор

This is a multi-center, first-in-human, open label, dose escalation (Part A) and expansion (Part B) Phase 1 study in subjects with advanced solid tumors and in subjects with solid tumors with selected genetic alterations that are either direct (YES1 amplification) or dependent (Hippo Pathway alterations) targets of NXP900.

Вмешательства

• Препарат NXP900
  NXP900 is an orally administered SRC/YES1 kinase inhibitor

Первичные конечные точки

• Number of patients with treatment related adverse events and/or clinical laboratory abnormalities [Срок оценки: Up to 30 days post treatment]
• Part A: Number of patients who experience Dose Limiting Toxicities (DLT) as defined in the protocol [Срок оценки: Day 28]
• Part B: Objective response rate (ORR) [Срок оценки: Up to 24 months]
• Part B: Duration of Response (DoR) [Срок оценки: Up to 24 months]
• Part B: Disease Control Rate (DCR) [Срок оценки: Up to 24 months]

Вторичные конечные точки (6)

• Area under the concentration-time curve (AUC) of NXP900 [Срок оценки: Up to 24 months]
• Maximum observed concentration (Cmax) of NXP900 [Срок оценки: Up to 24 months]
• Time to peak concentration (Tmax) of NXP900 [Срок оценки: Up to 24 months]
• Half-life (T1/2) of NXP900 [Срок оценки: Up to 24 months]
• Apparent volume of distribution at steady state (Vss/F) of NXP900 [Срок оценки: Up to 24 months]
• Apparent plasma clearance at steady state (Clss/F) of NXP900 [Срок оценки: Up to 24 months]

Критерии участия

Part A

Критерии включения

• Provide written informed consent.
• 18 years old or older.
• Advanced, metastatic, and/or progressive solid tumors for whom there is no authorized or effective therapy available, or for whom such therapies are considered inappropriate by the Investigator.
• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

Критерии исключения

• Subjects with known human epidermal growth factor receptor 2 (HER2+) overexpressing malignancies.
• Radiotherapy (except for palliative reasons), endocrine therapy, chemotherapy, or investigational agent within 28 days, (42 days for nitrosoureas, mitomycin-C) of first dose of NXP900. Subjects can continue to receive bisphosphonates due to metastatic bone disease or GnRH agonists if they have prostate cancer.
• Ongoing toxic manifestations of previous treatments > Grade 2 with the exception of alopecia and neuropathy.
• Subjects with treated brain metastases with evidence of progression within 28 days after central nervous system (CNS)-directed treatment, as ascertained by clinical examination and brain imaging (magnetic resonance imaging \[MRI\] or computed tomography \[CT\] scan) during the Screening period.
• Female subjects who can become pregnant (or are already pregnant or lactating), unless they have a negative serum pregnancy test before enrollment and agree to use at least one highly effective form of contraception .
• Male subjects with partners of childbearing potential, unless they agree to take measures not to father children by using a barrier method of contraception (condom plus spermicide).
• Major surgery from which the subject has not yet recovered.

Part B:

Критерии включения

• Provide written informed consent.
• 18 years old or older.
• Advanced, metastatic, and/or progressive solid tumors with pathogenic molecular alterations:

• Non-small cell lung cancer (adenocarcinoma); YES1, TYMS amplification or FAT1 pathogenic mutation
• Non-small cell lung cancer (squamous cell carcinoma); YES1, TYMS amplification or FAT1 pathogenic mutation
• Renal cancer; NF2 pathogenic mutation
• Mesothelioma; NF2 pathogenic mutation
• Other solid tumors with a NF2, FAT1 or LATS1 pathogenic gene mutation or TYMS, YAP1, YES1, or TAZ1 gene amplification, or cholangiocarcinoma with IDH1 or IDH2 mutations.
• Must have received 1-3 prior therapies appropriate for their tumor type and stage of disease
• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (or mRECIST 1.1 for subjects with pleural mesothelioma).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

Критерии исключения

• Subjects with the following combination of cancer type and pathogenic molecular alterations are excluded:

• Subjects with colorectal cancer, glioma, melanoma, or anaplastic thyroid conditions with BRAF mutations.
• Subjects with NSCLC with BRAF or EGFR mutations or HER2 overexpression.
• Subjects with breast cancer, gastric cancer, esophageal junction adenocarcinoma or biliary cancer with HER2 alterations,
• Subjects with anal, penile, cervical or head and neck cancers with a prior history of human papilloma virus (HPV) infection.
• Radiotherapy (except for palliative reasons), endocrine therapy, chemotherapy, or investigational agent within 28 days (42 days for nitrosoureas, mitomycin-C) prior to first dose of NXP900. Subjects can continue to receive bisphosphonates due to metastatic bone disease or GnRH agonists if they have prostate cancer.
• Ongoing toxic manifestations of previous treatments > Grade 2 with the exception of alopecia and neuropathy.
• Female subjects who can become pregnant (or are already pregnant or lactating), unless they have a negative serum pregnancy test before enrollment and agree to use at least one highly effective form of contraception .
• Male subjects with partners of childbearing potential, unless they agree to take measures not to father children by using a barrier method of contraception (condom plus spermicide).
• Major surgery from which the subject has not yet recovered.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 13 центров

• Mayo Clinic — Phoenix
• UC San Diego Moores Cancer Center — La Jolla
• Sarah Cannon Research Institute at HealthONE — Denver
• Mayo Clinic — Jacksonville
• University of Chicago — Chicago
• Mayo Clinic Rochester — Rochester
• Memorial Sloan Kettering Cancer Center — New York
• Cleveland Clinic — Cleveland
• … и ещё 5 центров

Великобритания · 2 центра

• Western General Hospital - NHS Lothian — Edinburgh
• The Royal Marsden NHS Foundation and Trust — London

Публикации

• Dash S, Hanson S, King B, Nyswaner K, Foss K, Tesi N, Harvey MJB, Navarro-Marchal SA, Woods A, Poradosu E, Unciti-Broceta A, Carragher NO, Brognard J. The SRC family kinase inhibitor NXP900 demonstrates potent antitumor activity in squamous cell carcinomas. J Biol Chem. 2024 Sep;300(9):107615. doi: 10.1016/j.jbc.2024.107615. Epub 2024 Jul 31. PMID 39089584

Идентификаторы

NCT: NCT05873686 · NXP900-101

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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