Zarnestra (tipifarnib) / Kura Oncology - LARVOL DELTA

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

Molecular profiling of head and neck cancers (HNCs): Genetic heterogeneity, immune landscape, and therapeutic targets. (ASCO 2025) - "HRAS mutations offer potential for targeted therapy with tipifarnib, a farnesyltransferase inhibitor. EGFR alterations, though rare, have proven challenging to effectively target with EGFR-specific therapies such as cetuximab or tyrosine kinase inhibitors, underscoring the critical need for innovative strategies to exploit this target... This study underscores the genetic heterogeneity of HNCs, pointing to deregulated pathways involved in cell cycle control, apoptosis, and DNA repair as promising targets for future therapeutic development and personalized treatment strategies. Also this study points towards a subset of patients who may derive a greater benefit with immunotherapy, based on TMB/PDL1. ESCAT TIER distribution of the molecular alterations detected in head and neck cohort (N=273)."

Heterogeneity • IO biomarker • Tumor mutational burden • Head and Neck Cancer • Microsatellite Instability • Oncology • Solid Tumor • BCL2 • BRAF • CCND1 • CDKN2A • FGF19 • FGF3 • FGF4 • FGFR1 • HER-2 • HRAS • MET • MSI • PIK3CA • PLAG1 • TMB • TP53

Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial (clinicaltrials.gov) - P2 | N=5 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Apr 2025 ➔ Sep 2027

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

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) | N=2316 ➔ 1376 | Trial completion date: Jun 2025 ➔ May 2026 | Trial primary completion date: Jun 2025 ➔ Mar 2025

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

Kura Oncology Reports First Quarter 2025 Financial Results (GlobeNewswire) - "Forecasted Milestones:...(i) 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; (ii) Present data from the FIT-001 Phase 1 trial evaluating KO-2806 and cabozantinib in patients with renal cell carcinoma in the second half of 2025; (iii) Present data from the FIT-001 Phase 1 monotherapy dose escalation of KO-2806 in patients with RAS mutations in the second half of 2025; (iv) Present data from the KURRENT-HN trial evaluating tipifarnib and alpelisib in PIK3CA-dependent head and neck squamous cell carcinoma (HNSCC) in the second half of 2025."

Clinical data • Trial status • Renal Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

HRAS Mutations in Head and Neck Carcinomas in Japanese Patients: Clinical Significance, Prognosis, and Therapeutic Potential. (PubMed, Int J Mol Sci) - "HRAS knockdown with siRNA suppressed the in vitro migration ability of HRAS mutation-positive cells but not that of HRAS mutation-negative cells. In conclusion, a positive HRAS mutation could be an indicator of distant metastasis and poor prognosis, as well as a potential therapeutic target."

Journal • Head and Neck Cancer • Lung Cancer • Oncology • Salivary Gland Cancer • Solid Tumor • HRAS • 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. | Recruiting ➔ Active, not recruiting

Enrollment closed • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • HRAS • PIK3CA

Effects and molecular mechanisms of farnesyltransferase inhibitor tipifarnib on platelet activation. (PubMed, J Pharmacol Exp Ther) - "SIGNIFICANCE STATEMENT: Farnesyltransferase inhibitor tipifarnib regulates platelet activity by inhibiting thromboxane A2 generation through the modulation of protein kinase B and extracellular signal-regulated kinase phosphorylation. Given the dual role of platelets in both thrombosis and cancer progression, tipifarnib's ability to modulate these pathways highlights its potential as a therapeutic agent in preventing thromboembolic complications in patients with cancer."

Journal • Cardiovascular • Hematological Disorders • Oncology • Thrombosis

Anti-PD1 prolongs the response of PI3K and farnesyl transferase inhibition in HRAS- and PIK3CA-mutant head and neck cancers. (PubMed, Neoplasia) - "These findings underscore the critical role of antitumor immunity, particularly CD8+T cell activity, in the efficacy of tipifarnib alone and in combination with alpelisib. The triple combination of tipifarnib, alpelisib, and anti-PD1 treatment showed superior antitumor activity and extended survival in preclinical models, suggesting its potential as a therapeutic strategy for HNSCC patients with HRAS- and PIK3CA-mutation."

IO biomarker • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • CD8 • HRAS • PIK3CA

Kura Oncology Reports Fourth Quarter and Full Year 2024 Financial Results (GlobeNewswire) - "Present data from the dose escalation portion of KURRENT-HN trial evaluating tipifarnib and alpelisib in PIK3CA-dependent head and neck squamous cell carcinoma (HNSCC) in the second half of 2025."

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

Impaired MC3T3-E1 osteoblast differentiation triggered by oncogenic HRAS is rescued by the farnesyltransferase inhibitor Tipifarnib. (PubMed, Sci Rep) - "In this study, we created stable doxycycline inducible cell lines overexpressing HRAS G12 mutants in MC3T3-E1 preosteoblast cell line and analyzed their impact on osteoblast differentiation. At the molecular level, Tipifarnib was not able to block HRAS activation, but impaired HRAS localization to the plasma membrane, and inhibited MAPK activation and Opn expression. Thus, HRAS abundance/activation and its potential crosstalk with OPN may be more critical for osteogenic differentiation than previously assumed."

Journal • CNS Disorders • Developmental Disorders • Oncology • Osteoporosis • Psychiatry • Rheumatology • HRAS • TNFSF11

Functional-proteomics-based investigation of the cellular response to farnesyltransferase inhibition in lung cancer. (PubMed, iScience) - "Additionally, we identified a synergistic drug combination involving tipifarnib and a ferroptosis inducer and discovered PTP4A1 as a regulator of interferon signaling. Our data, covering 15,080 proteins, offer valuable insights for future studies of farnesylation and FTIs."

Journal • Eye Cancer • Lung Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • GNA11 • GNAQ • NRAS

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=2316 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Sep 2027 ➔ Jun 2025 | Trial primary completion date: Sep 2027 ➔ Jun 2025

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

2025 Anticipated Clinical Data Highlights (GlobeNewswire) - "(i) FIT-001 Phase 1 data of KO-2806 monotherapy in HRAS-mutant and KRAS-mutated solid tumors (2H 2025); (ii) FIT-001 Phase 1 data of KO-2806 in combination with cabozantinib in renal cell carcinoma (RCC) (2H 2025); (iii) KURRENT-HN Phase 1 data of tipifarnib in combination with alpelisib in PIK3CA-dependent head and neck squamous cell carcinoma (HNSCC) (2H 2025)."

P1 data • Renal Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

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 | Recruiting | Sponsor: Kura Oncology, Inc. | Trial completion date: Sep 2024 ➔ Jul 2025 | Trial primary completion date: Sep 2024 ➔ Jul 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

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=2316 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Active, not recruiting

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

Integrated proteomics and connectivity map-based analysis reveal compounds with a potential antiviral effect against Japanese encephalitis virus infection in a mouse model. (PubMed, FEBS J) - "Based on the CMap score, we chose the top three compounds (Tipifarnib, Ly303511 and MDL11939) with CMap scores of -91.83, -88.18 and -91.15, respectively...Our results highlight Ly303511 and MDL11939 as promising host-targeted inhibitors of JEV infection and pathogenesis. Moreover, our results favor the combination of Ly303511 and MDL11939 therapy to improve clinical symptoms and reduce JEV-induced damage, thus warranting inclusion in clinical studies."

Journal • Preclinical • CNS Disorders • CNS Tumor • Infectious Disease • Neuroblastoma • Oncology • Solid Tumor

Tipifarnib and Naxitamab for Relapsed/Refractory Neuroblastoma (clinicaltrials.gov) - P2 | N=98 | Recruiting | Sponsor: Giselle Sholler | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor

Dissecting the Implications of Calumenin in Malignancy and Heterogeneity of the Microenvironment of Clear Cell Renal Cell Carcinoma Using Multi-Omics Data. (PubMed, Phenomics) - "Sensitivity analysis of common chemotherapeutic drugs showed that high expression of CALU could sensitize chemotherapeutic drugs such as 5Z-7-Oxozeaenol, AMG-706 and Cytarabine, but could lead to drug resistance to chemotherapeutic drugs such as Embelin, Salubrinal and Tipifarnib. Thus, our results indicate that CALU could be a biomarker and designing personalized treatment approaches for ccRCC patients. The online version contains supplementary material available at 10.1007/s43657-024-00169-7."

Heterogeneity • IO biomarker • Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • CD4 • CD8

Tipifarnib and Naxitamab for Relapsed/Refractory Neuroblastoma (clinicaltrials.gov) - P2 | N=98 | Not yet recruiting | Sponsor: Giselle Sholler | Trial completion date: Aug 2035 ➔ Dec 2035 | Trial primary completion date: Aug 2030 ➔ Dec 2030

Trial completion date • Trial primary completion date • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor

Kura Oncology Reports Third Quarter 2024 Financial Results (GlobeNewswire) - "Forecasted Milestones: (i) Report topline results from the KOMET-001 registration-directed trial of ziftomenib in NPM1-mutant R/R AML in early 2025; (ii) Present data from the KURRENT-HN trial of tipifarnib in combination with alpelisib in PIK3CA-dependent head and neck squamous cell carcinoma (HNSCC) in the first half of 2025."

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

An Innovative Telomere-associated Prognosis Model in AML: Predicting Immune Infiltration and Treatment Responsiveness. (PubMed, Curr Med Chem) - "This innovative TRG scoring model demonstrates considerable predictive value for AML patient prognosis, offering valuable insights for optimizing treatment strategies and personalized medicine approaches. The identified TRGs and associated scoring models could aid in risk stratification and guide tailored therapeutic interventions in AML patients."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CD4 • RPA2 • SMA4 • SMN1

Therapeutic Potental of Quinolin-2H-one Hybrids as Anticancer Agents. (PubMed, Mini Rev Med Chem) - "Tipifarnib and Dovitinib are quinolin-2-one hybrids used to treat cancer, possessing imidazole and benzimidazole heterocyclic rings. The current review presents information on the different quinolin-2-one hybrids and their effect on different cancer cell lines. It also imparts knowledge of the structural requirements for designing novel anticancer agents."

Journal • Gene Therapies • Oncology

Signaling effect, combinations, and clinical applications of triciribine. (PubMed, J Chemother) - "Triciribine (TCN) is a tricyclic nucleoside. Although a single dose of TCN demonstrated limited activity in solid tumors at the clinical level, combinations of TCN with various agents, such as specific inhibitors, tyrosine kinase inhibitor dasatinib, ErbB inhibitor tipifarnib, IGF1-R inhibitor NVP-AEW541, mTORC1 inhibitor RAD-001, TNF-related apoptosis-inducing ligand, PPARγ agonist, 1,25(OH)2D3, gemcitabine, and paclitaxel, have been reported to be efficient against various malignancies such as pancreatic, breast, prostate cancer, insulinoma, gut neuroendocrine tumor, and hepatocellular carcinoma at the preclinical level. Other than malignancies, through Akt inhibition activity, TCN has also been demonstrated potential for treating lung injuries, including those encountered in COVID-19 infections."

Journal • Review • Breast Cancer • Endocrine Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatocellular Cancer • Hepatology • Infectious Disease • Neuroendocrine Tumor • Novel Coronavirus Disease • Oncology • Pancreatic Cancer • Prostate Cancer • Respiratory Diseases • Solid Tumor • IGF1

Paraneoplastic leukocytosis induces NETosis and thrombosis in bladder cancer PDX model. (PubMed, Am J Cancer Res) - "UC-PDX-LN1, originating from bladder cancer, exhibited two druggable targets - HRAS and ERCC2 - responding well to chemotherapy and targeted therapy, though not to tipifarnib, an HRAS inhibitor...Clinical observations in bladder cancer patients revealed PNL in 1.61% of cases (35/2162) with associated poor prognosis. These findings propose a novel approach, advocating for the combination of anticancer/NETosis/thrombosis strategies for managing UC patients presenting with PNL in clinical settings."

Journal • Bladder Cancer • Cardiovascular • Genito-urinary Cancer • Hematological Disorders • Oncology • Solid Tumor • Thrombosis • Urothelial Cancer • CSF2 • CSF3 • ERCC2 • HRAS