Zarnestra (tipifarnib) / Kura Oncology - LARVOL DELTA

Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial) (clinicaltrials.gov) - P2 | N=1376 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: May 2026 ➔ Jan 2027

Biomarker • Trial completion date • Brain Cancer • CNS Tumor • Embryonal Tumor • Ependymoma • Ewing Sarcoma • Germ Cell Tumors • Glioma • Hematological Malignancies • Hepatoblastoma • High Grade Glioma • Langerhans Cell Histiocytosis • Lymphoma • Medulloblastoma • Nephrology • Neuroblastoma • Non-Hodgkin’s Lymphoma • Oncology • Osteosarcoma • Pediatrics • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Wilms Tumor • BRAF

FIT-001: A phase 1 clinical trial of the farnesyl transferase inhibitor KO-2806 alone or as part of combination therapy for advanced solid tumors (AACR 2024) - P1, P2 | "Recent clinical trials (NCT03719690, NCT02383927) of the FTI, tipifarnib, in patients with HRAS-mutant (HRAS-m) head and neck squamous cell carcinoma harboring high variant allele frequency mutations (VAF ≥20%), showed objective response rates of up to 50% and favorable long-term outcomes...In preclinical studies, KO-2806 has been shown to: (1) enhance tumor growth inhibition of tyrosine kinase inhibitors, including cabozantinib, in multiple clear cell renal cell carcinoma (ccRCC) cell line- and patient-derived xenograft models; and (2) enhance activity of KRAS inhibitors, including adagrasib, in KRAS mutant non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC) mouse models...Other combination arms may also be considered. The study began accrual in October 2023."

Clinical • Combination therapy • IO biomarker • Metastases • P1 data • Clear Cell Renal Cell Carcinoma • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • HRAS • KRAS

Bioinformatics analyses reveal the autophagy-related feature biomarkers in dilated cardiomyopathy with heart failure. (PubMed, Front Cardiovasc Med) - "A doxorubicin (DOX)-induced cardiomyocyte injury model was established to evaluate hub gene expression in vitro and in vivo studies. This study provides novel evidence that CTSD and SOD2 potently contribute to autophagy regulation in DCM with HF. These findings highlight their diagnostic potential for DCM with HF and lay a foundation for exploring targeted small-molecule therapies (e.g., QL-XII-47, tipifarnib-P2) to improve the disease's clinical management."

Biomarker • Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • CDKN1A • CTSD • DDIT3 • EP300 • SOD2

Tipifarnib (TIP) and alpelisib (ALP) in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC): Phase I results from KURRENT-HN (ESMO 2025) - P1/2 | "8 pts not evaluable: inability to swallow (n=2); toxicity (n=2); death, clinical progression, withdrew consent, tumor hemorrhage (n=1 each) † Of 6 pts with CR/PR, 5 pts had 1 prior tx and 1 pt had 3 prior tx ‡ Off tx prior to confirmatory scan due to: disease progression (n=2), withdrawn consent and cardiac event (n=1 each) Conclusions TIP + ALP was well tolerated with a manageable toxicity profile – noteworthy considering the known challenges of PI3Kαi combos with other targeted tx. Durable antitumor activity was observed in heavily pretx molecularly selected R/M HNSCC pts, supporting that combos (eg, FTI + PI3Kαi) targeting synergistic pathways may improve modest single tx activity."

Metastases • P1 data • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PIK3CA

Phase 2 Trial of the Farnesyltransferase Inhibitor Tipifarnib for Relapsed/Refractory Peripheral T Cell Lymphoma. (PubMed, Blood Adv) - P2 | "Tipifarnib monotherapy demonstrated encouraging clinical activity in heavily pre-treated relapsed/refractory PTCL, especially in AITL, with a manageable safety profile. ClinicalTrials.gov NCT02464228."

Journal • P2 data • Hematological Disorders • Hematological Malignancies • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • Thrombocytopenia • DNMT3A • IDH2 • RHOA

KURRENT-HN: Combination Trial of Tipifarnib and Alpelisib in Adult Recurrent/ Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC) (clinicaltrials.gov) - P1/2 | N=45 | Completed | Sponsor: Kura Oncology, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Dec 2025 ➔ Jul 2025 | Trial primary completion date: Dec 2025 ➔ Jul 2025

Biomarker • Trial completion • Trial completion date • Trial primary completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • HRAS • PIK3CA

NOXA modulates tipifarnib sensitivity in myeloid leukemia cells. (ASH 2025) - "This is consistent with clinical data in angioimmunoblastic T-cell lymphoma that suggested responses were enriched in IDH2 mutated cases. Ongoing studies will include sequencing samples from patients treated with tipifarnib in the cooperative group phase 3 study (NCI 2009-00535) to determine the incidence of IDH2 and other mutations in responders vs. non-responders."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • T Cell Non-Hodgkin Lymphoma • Targeted Protein Degradation • BCL2 • IDH2 • PMAIP1

Prevalence of HRAS mutations in metastatic head and neck squamous cell carcinoma: A preliminary study from India (ESMO Asia 2025) - "Tipifarnib, a FTase inhibitor, has been given FDA approval for high VAF HRAS positive HNSCC. HRAS mutations have been shown to have poor response to cetuximab in first-line recurrent metastatic setting... This preliminary study demonstrates a notably high prevalence (20%) of HRAS mutations among Indian patients with metastatic HNSCC highlighting the potential for integrating HRAS-targeted therapies into future clinical management protocols in India."

Metastases • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • HRAS

Using single-cell and transcriptome data to identify prognostic genes associated with SUMO-ylation and their molecular regulatory mechanisms in breast cancer. (PubMed, BMC Cancer) - "In this study, 8 SUMO-ylation related prognostic genes were identified in BRCA, namely GPC1, CAPZA1, NUDCD1, MTDH, COX7A1, PLK3, FAM43A and CEBPD, offering fresh perspectives on the prognosis of BRCA."

Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • BRCA • CD8 • FAM43A • GPC1 • MTDH

Integrative computational approach to farnesyltransferase inhibition toward anti-liver cancer drug candidate from Syzygium cumini essential oils. (PubMed, Mol Biol Res Commun) - "However, MD simulations confirmed that both essential oil compounds exhibit binding stability comparable to that of Tipifarnib. Finally, α-humulene epoxide II and bornyl acetate from S. cumini exhibit favorable drug-like properties, high predicted safety margins, and a lack of organ-specific toxicity, underscoring their suitability for further drug development."

Journal • Liver Cancer • Oncology • Solid Tumor • FNTB • HIF1A • MMP9

Farnesyltransferase inhibitors decrease matrix-vesicle-mediated mineralization in SaOS-2 cells. (PubMed, Mol Biol Rep) - "Our findings demonstrate that FTIs Lonafarnib and Tipifarnib impair MVM, highlighting the essential role of farnesylation in biomineralization."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • COL1A1 • RUNX2

Comprehensive bioinformatic analysis of HTR7: A potential biomarker for diagnosis, survival, and immunotherapy in pan-cancer. (PubMed, PLoS One) - "Furthermore, our study showed that aberrant methylation of HTR7 was associated with the infiltration of many immune cells, including Th1, Th17, DC, macrophages, etc. In cancer pathways, HTR7 could inhibit the cell cycle, DNA damage, and hormone AR pathways and activate the EMT and RAS/MAPK pathways. GO and KEGG enrichment analyses revealed that HTR7 could participate in the G protein-coupled receptor signaling pathway, serotonin receptor signaling pathway, hormone signaling, cAMP signaling pathway, etc. Several drugs, including 5-fluorouracil, gemcitabine, sunitinib, tipifarnib, and trametinib, may be sensitive to high HTR7 expression in tumors."

Biomarker • IO biomarker • Journal • Pan tumor • Oncology • CTLA4 • HAVCR2 • HTR7 • PD-1 • PD-L1 • PD-L2 • TIGIT

A phase I study of the next-generation farnesyltransferase inhibitor (FTI) KO-2806 as monotherapy in advanced solid tumors (ESMO 2025) - P1 | "The FTI tipifarnib demonstrated promising clinical activity among m HRAS tumors, supporting the potential utility of KO-2806 in these settings. Encouraging antitumor activity was observed in advanced m HRAS solid tumors with a broad therapeutic window. These data support further exploration of its combinatorial potential."

Metastases • Monotherapy • P1 data • Colorectal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Thyroid Gland Carcinoma • HRAS • KRAS

Identification of Potential Biomarkers and Drugs for Papillary Thyroid Carcinoma Using Computational Analysis and Molecular Docking. (PubMed, Curr Med Chem) - "The hub gene CCND1 and its targeting drug candidate Tipifarnib may contribute to PTC treatment."

Biomarker • Journal • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • CCND1 • LYVE1 • SOX4 • TCF4 • YBX1

Tipifarnib + Alpelisib in PIK3CA-altered Head and Neck Squamous Cell Carcinoma – KURRENT-HN Phase 1 Trial (GlobeNewswire) - "TI mechanism blocks hyperactivated mTORC1 signaling in squamous tumor cells; Manageable safety profile in HNSCC patients across multiple doses; Robust antitumor activity was observed in heavily pretreated patients with relapsed or metastatic HNSCC with PIK3CA alterations: ORR: 47% was observed at a daily dose of tipifarnib 1200 mg + alpelisib 250 mg; Alpelisib monotherapy provides modest clinical benefit (ORR: 0%; BOR: SD)1 and tipifarnib monotherapy not expected to provide clinical benefit in this population."

P1/2 data • Squamous Cell Carcinoma of Head and Neck

Wild-type RAS signaling is an essential therapeutic target in RAS-mutated cancers. (PubMed, Sci Signal) - "The farnesyltransferase inhibitor tipifarnib blocked mutant HRAS-PI3K signaling and synergized with MEK inhibitors in HRAS-mutated cells, whereas KRASG12C inhibitors blocked mutant KRAS-MEK signaling and synergized with PI3K inhibitors in KRASG12C-mutated cells. Synergy was abolished in MEFs lacking all RAS proteins and in cancer cell lines in which nonmutated RAS family members were deleted. Our data highlight the critical role of wild-type RAS family members in supporting mutant RAS signaling and its importance as a therapeutic cotarget in RAS-mutated cancers."

Journal • Oncology • KRAS • NRAS

In Vitro synergy of Farnesyltransferase inhibitors in combination with colistin against ESKAPE bacteria. (PubMed, PLoS One) - "Tipifarnib exhibited more potent antimicrobial activity against gram-negative strains than lonafarnib...In contrast, alpha-hydroxy farnesyl phosphonic acid, an FPP analog, and bempedoic acid, targeting the mevalonate pathway, showed no antibacterial activity...This might be due to a mechanism distinct from their eukaryotic targets, potentially involving the disruption of multiple biosynthetic pathways. Future studies will focus on elucidating these mechanisms of FTIs and exploring the therapeutic potential of FTI/colistin combinations against ESKAPE and other multidrug-resistant pathogens."

Journal • Preclinical • Infectious Disease • Oncology • Pneumonia

Development of a multi-indicator risk prediction model for cervical cancer associated with benzo[a]pyrene and nicotine exposure: A multi-omics study integrating toxicological analyses and molecular docking. (PubMed, Ecotoxicol Environ Saf) - "Risk prediction models based on multi-omics data and machine learning algorithms provide potential reference targets for prognosis prediction and personalised treatment of cervical cancer patients. The results of this study provide important insights into the understanding of the health risks of cervical cancer associated with Benzo[a]pyrene and Nicotine exposures and the development of preventive and therapeutic strategies for cervical cancer, which may contribute to the development of precision medicine for cervical cancer."

Journal • Cervical Cancer • Oncology • Solid Tumor • SLAMF6

Progression-Free Survival and Overall Survival in Relapsed/Refractory T-cell Lymphoma Patients on Chemotherapy vs Targeted Therapy (SOHO 2025) - "Options include chemotherapy, brentuximab, pralatrexate, romidepsin, and duvelisib...Other treatment options used were immunotherapy (n = 2), tipifarnib (n = 2), pentostatin (n = 1), MEDI-570 (n = 1), duvelisib (n = 1), and vorinostat (n = 1)... Our study showed a benefit to the use of targeted therapy in relapsed/refractory TCL that was more pronounced in the third-line setting, likely due to increased resistance to chemotherapy with repeated exposure."

Clinical • Hematological Malignancies • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • TNFRSF8

Semi-synthetic K-Ras4B protein via expressed protein ligation: A versatile platform for modifying Ras protein and investigating its biological behavior (ACS-Fall 2025) - "Tipifarnib, a farnesyltransferase inhibitor (FTIs), is an anti-tumor drug currently in phase II clinical trials...B) Understanding the mechanism of prenylation of Ras protein in Cellulo. Additionally, with the engineered synthetic farnesyl transferase substrate, C) Ras dimer will be constructed by chemoenzymatic labeling to elucidate the structure and the effect of Ras clustering in cell."

Pancreatic Adenocarcinoma • Pancreatic Cancer • Targeted Protein Degradation • KRAS • RAS

KURRENT-HN: Combination Trial of Tipifarnib and Alpelisib in Adult Recurrent/ Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC) (clinicaltrials.gov) - P1/2 | N=40 | Active, not recruiting | Sponsor: Kura Oncology, Inc. | Trial completion date: Jul 2025 ➔ Dec 2025 | Trial primary completion date: Jul 2025 ➔ Dec 2025

Biomarker • Trial completion date • Trial primary completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • HRAS • PIK3CA

Kura Oncology Reports Second Quarter 2025 Financial Results (Kura Oncology Press Release) - "Forecasted Milestones: Initiate one or more FIT-001 expansion cohorts of KO-2806 and cabozantinib in patients with advanced renal cell carcinoma in the second half of 2025. Present data from the FIT-001 Phase 1 trial evaluating KO-2806 and cabozantinib in patients with renal cell carcinoma at the 2025 ESMO Congress in October 2025. Present data from the FIT-001 Phase 1 monotherapy dose escalation of KO-2806 in patients with RAS-mutant solid tumors at the 2025 ESMO Congress in October 2025. Present data from the KURRENT-HN trial evaluating tipifarnib and alpelisib in PIK3CA-dependent HNSCC at the 2025 ESMO Congress in October 2025."

P1 data • P1/2 data • Trial status • Renal Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Farnesyltransferase Inhibitor (R115777) Targets CENPF to Inhibit Breast Cancer Bone Metastasis by Regulating the PI3k/AKT/mTOR/PTHrP Pathway. (PubMed, Clin Breast Cancer) - "Our findings highlight the potential of R115777 as a novel therapeutic strategy for preventing bone metastasis in breast cancer. By specifically targeting CENPF and modulating the PI3K-AKT-mTORC1 pathway, R115777 emerges as a promising targeted treatment option in combating the progression and metastasis of breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

A Phase 1 Clinical Trial of the Farnesyltransferase Inhibitor KO-2806 in Combination with Cabozantinib in Renal Cell Carcinoma (KCRS 2025) - P1, P2 | "Recent clinical trials (NCT03719690, NCT02383927) of the FTI tipifarnib in patients with HRAS-mutant (HRAS-m) head and neck squamous cell carcinoma harboring high variant allele frequency mutations (VAF ≥20%) showed objective response rates of up to 50% and favorable long-term outcomes...The study began accrual in October 2023, and recruitment is ongoing. Significance & Vision FIT-001 is assessing the safety, tolerability, pharmacokinetics, PD, and preliminary antitumor activity of KO-2806 in combination with cabozantinib in patients with ccRCC and non-ccRCC."

Clinical • Combination therapy • IO biomarker • P1 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Head and Neck Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • HRAS

Novel Therapies for Neurofibromatosis Type 1-Associated Inoperable Plexiform Neurofibromas: A Systematic Literature Review (ISPOR 2025) - "These reported on a total of 21 unique studies on 11 emerging therapies: 6 MEK inhibitors (selumetinib, mirdametinib, trametinib, binimetinib, FCN-159, tunlametinib) and 5 targeted anti-cancer agents (cabozantinib, tipifarnib, sorafenib, sirolimus, everolimus)... The promising results of MEK inhibitors in therapeutic trials for NF1 demonstrate that targeting the MAPK/ERK pathway is an attractive therapeutic avenue for unresectable PNs. Because selumetinib is only approved for children, future reimbursement will require advanced studies establishing MEK inhibitor efficacy in adults."

Review • Brain Cancer • Genetic Disorders • Neurofibromatosis • Oncology • Solid Tumor • NF1