JP-2022514654-A5 -

Dates

Publication Date

20221227

Application Date

20191220

Description

The overall median progression-free survival (PFS) was 5.4 months (95% CI 4.5–19.5 months, N=15), 19 months (95% CI 5.3–19.5 months) in patients who experienced partial response (PR), and 4.5 months (95% CI 1.6–5.4 months) in patients who experienced stable disease (SD). The median PFS in the most recent prior treatment was 3.2 months. All patients experienced at least one therapeutic adverse event (TEAE). These occurred in ≥10% of patients, and the most frequently observed drug-related grade >3 TEAEs were hematological and lymphatic disorders, gastrointestinal disorders, and renal disorders. In one embodiment, for example, the following items are provided. (Item 1) A method for treating a subject having H-Ras mutation squamous cell carcinoma (SCC) in combination with surgical intervention, comprising administering a therapeutically effective dose of a farnesyltransferase inhibitor (FTI) to the subject, wherein the SCC has an H-Ras mutation allele frequency (AF) greater than 20%. (Item 2) The method according to item 1, wherein the H-Ras mutation AF is greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, or greater than 60%. (Item 3) The method according to item 1 or item 2, wherein the SCC has an amino acid substitution in a codon within H-Ras selected from the group consisting of G12, G13, Q61, Q22, K117, A146, and any combination thereof. (Item 4) The method according to any one of items 1 to 3, wherein the SCC does not have a K-Ras mutation or an N-Ras mutation. (Item 5) The method according to any one of items 1 to 4, further comprising administering a radiotherapy agent or a chemotherapeutic agent to the subject. (Item 6) The method according to any one of items 1 to 5, wherein the FTI is administered before the surgical procedure. (Item 7) The method according to item 6, wherein the FTI reduces the total tumor tissue volume in the subject by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%. (Item 8) The method described in item 6, wherein the FTI changes the SCC from inoperable to operable. (Item 9) The method according to any one of items 1 to 5, wherein the FTI is administered after the surgical procedure. (Item 10) The method according to item 9, wherein the FTI reduces the risk of recurrence after the surgical procedure. (Item 11) The method according to any one of items 1 to 10, wherein the SCC is head and neck SCC (HNSCC), lung SCC (LSCC), thyroid SCC (TSCC), esophageal SCC (ESCC), bladder SCC (BSCC), cervix SCC, vulva SCC, penile SCC, cutaneous SCC, or urothelial carcinoma (UC). (Item 12) The method according to item 11, wherein the SCC is HNSCC. (Item 13) The method described in item 12, wherein the HNSCC is a tracheal HNSCC. (Item 14) The method described in item 12, wherein the HNSCC is the HNSCC of the maxilla. (Item 15) The method according to item 12, wherein the HNSCC is an oral HNSCC. (Item 16) The method according to any one of items 1 to 15, wherein the SCC is negative for human papillomavirus (HPV). (Item 17) The method according to any one of items 1 to 15, wherein the SCC is in an advanced stage or is metastatic. (Item 18) The method according to any one of items 1 to 15, wherein the SCC is recurrent. (Item 19) The SCC is refractory, according to the method described in any one of items 1 to 15. (Item 20) The method according to any one of items 1 to 19, comprising measuring the H-Ras mutation AF in a sample derived from the subject. (Item 21) The method according to item 20, wherein the H-Ras mutation AF is measured by sequencing, polymerase chain reaction (PCR), DNA microarray, mass spectrometry (MS), single nucleotide polymorphism (SNP) assay, denaturing high-performance liquid chromatography (DHPLC), or restriction enzyme fragment length polymorphism (RFLP) assay. (Item 22) The sample is tissue biopsy material, as described in item 21. (Item 23) The sample is tumor biopsy material, as described in item 21. (Item 24) The aforementioned sample is a blood sample, as described in item 21. (Item 25) The sample is isolated cells, as described in item 21. (Item 26) The method according to any one of items 1 to 25, wherein the FTI is selected from the group consisting of tipifarnib, ronafarnib, algrabine, periryl alcohol, L778123, L739749, FTI-277, L744832, CP-609, 754, R208176, AZD3409, and BMS-214662. (Item 27) The method according to item 26, wherein the FTI is tipifarnib. (Item 28) The method described in item 26, wherein the FTI is ronafarnib. (Item 29) The method described in item 26, wherein the FTI is BMS-214662. (Item 30) The FTI is administered in a dose of 0.05 to 500 mg/kg (body weight) according to any one of items 1 to 29. (Item 31) The method according to any one of items 1 to 29, wherein the FTI is administered in a daily dose of 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg,