Methods of treating cancer with farnesyltransferase inhibitors
Inventors
Gualberto, Antonio • SCHOLZ, Catherine Rose
Assignees
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Publication Number
US-11541045-B2
Publication Date
2023-01-03
Expiration Date
Abstract
The present invention relates to the field of cancer therapy. Specifically, provided are methods of treating cancer, for example, peripheral T-cell lymphoma (“PTCL”), with a farnesyltransferase inhibitor (FTI) that include determining whether the subject is likely to be responsive to the FTI treatment based on gene expression characteristics.
Core Innovation
The invention relates to treating angioimmunoblastic T-cell lymphoma (AITL) in a subject using tipifarnib. It describes administering tipifarnib in a specified dosing regimen within repeated 4 week treatment cycles, including 200-1200 mg twice a day and distinct timing patterns within a cycle.
The treatment approaches include dosing on days 1-7 of a 28-day treatment cycle, alternate-week scheduling in repeated 4 week treatment cycles, and dosing for 3 out of 4 weeks in repeated 4 week treatment cycles. The subject has AITL histology, including relapsed or refractory AITL, and the method further comprises administering a therapeutically effective amount of a second active agent or a support care therapy in addition to tipifarnib.
The invention also relates to cancer treatment in a subject using farnesyltransferase inhibitors, in particular tipifarnib, for predicting responsiveness and stratifying patients. It uses biomarker and gene-expression characteristics to guide use of farnesyltransferase inhibitors in treating cancers, including CXCL12, CXCR4, the CXCL12/CXCR4 expression ratio, serum circulating CXCL12, and biomarkers and genomic status such as CXCL13, PD-1, KIR3DL2, CXCL12 rs2839695, SIK3, and CENPF.
The document further describes sample-based measurement workflows for biomarkers related to FTI treatment decisions in PTCL, including immunoassay, enzyme immunoassay, immunofluorescence, flow cytometry, and measurements of protein and gene expression. Example cancer types and settings explicitly mentioned include EBV-associated nasopharyngeal carcinoma, nasopharyngeal carcinoma, esophageal cancer, ovarian cancer, sarcoma, breast cancer, pancreatic cancer, locally advanced pancreatic cancer, peripheral T-cell lymphoma including AITL, and leukemia types including AML, T-ALL, and CML.
Claims Coverage
The provided claim set includes independent claims focused on methods of treating angioimmunoblastic T-cell lymphoma (AITL) with tipifarnib. Across the independent claims, the inventive features center on a tipifarnib dose range of 200-1200 mg twice a day and distinct treatment-cycle schedules within repeated 4 week treatment cycles.
Tipifarnib dosing on days 1-7 of a 28-day treatment cycle
Administering tipifarnib to the subject at a dose of 200-1200 mg twice a day on days 1-7 of a 28-day treatment cycle.
Tipifarnib dosing in alternate weeks within repeated 4 week treatment cycles
Administering tipifarnib to the subject at a dose of 200-1200 mg twice a day in alternate weeks in repeated 4 week treatment cycles.
Tipifarnib dosing for 3 out of 4 weeks in repeated 4 week treatment cycles
Administering tipifarnib to the subject at a dose of 200-1200 mg twice a day for 3 out of 4 weeks in repeated 4 week treatment cycles.
Across the independent claims, the core coverage is treatment of AITL using tipifarnib within a defined twice-daily dose range of 200-1200 mg, with the principal differences being the cycle schedule definition. Dependent claim coverage further refines timing within a cycle, route such as oral administration, disease context such as relapsed or refractory AITL, and optional co-administration of a second active agent or support care therapy.
Stated Advantages
Predicting responsiveness to tipifarnib and stratifying patients.
Supporting prediction of responsiveness to tipifarnib using CXCL12, CXCR4, and the CXCL12/CXCR4 expression ratio.
Association between tipifarnib response/progression-free survival and biomarkers including CXCL12/CXCR4 ratio and CXCL12 3′UTR genotype (rs2839695).
Documented Applications
Treating angioimmunoblastic T-cell lymphoma (AITL) in a subject using tipifarnib.
Cancer treatment in a subject using farnesyltransferase inhibitors, in particular tipifarnib.
Guiding use of farnesyltransferase inhibitors in treating cancers using biomarker and gene-expression characteristics.
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