navtemadlin (KRT-232) / Amgen, Kartos Therap - LARVOL DELTA

ANTICANCER EFFECTS AND MECHANISMS OF HERBS USED IN TRADITIONAL CHINESE MEDICINE ON HUMAN LUNG CARCINOMA AND HEPATOMA CELLS (SITC 2024) - "Using our own designed algorithm based on the LINCS L1000 database, We identified two drugs, AMG232 and Nutlin-3, that had treatment effects similar to P. chinensis in A549 cells. Besides, we found that although P. chinensis affected different pathways in A549 and Huh7 cells, the triggered transcriptional factors were similar and they were associated with the cell cycle regulation. Conclusions We conclude that P. chinensis has a significant anticancer effect on both A549 and Huh7 cells, signifying its potential for clinical translation in cancer treatment after additional preclinical and clinical studies."

Gastrointestinal Cancer • Hepatocellular Cancer • Liver Cancer • Lung Cancer • Oncology • Solid Tumor • CASP3 • CASP8 • TNFA

MODULE 4: Future Directions in the Management of MF (ASH 2024) - "This program is supported by educational grants from CTI BioPharma, a Sobi Company, Geron Corporation, GSK, Incyte Corporation and Karyopharm Therapeutics.Mechanism of antitumor activity of navitoclax and biological rationale for its evaluation for MF Available efficacy and safety findings from the Phase III TRANSFORM-1 study of navitoclax in combination with ruxolitinib versus ruxolitinib alone for patients with previously untreated MF Potential role of navitoclax in the up-front setting and ongoing evaluation for relapsed/refractory (R/R) disease in the Phase III TRANSFORM-2 study Rationale for the evaluation of BET inhibitors for MF; updated findings from the Phase III MANIFEST-2 study combining pelabresib to ruxolitinib for JAK inhibitor-naïve disease Scientific justification for the evaluation of selinexor for MF; early efficacy and safety findings with selinexor as monotherapy and in combination with ruxolitinib Ongoing evaluation of the combination of..."

Oncology

Assessing the predictive value of genomic drivers for targeted therapy in glioblastoma: Insights from a pre-clinical platform (EORTC-NCI-AACR 2024) - "Representative results from dose-response curves for selected targeted agents in omics-profiled glioblastoma patient-derived models Clinical and molecular information Select driver genomic abnormalitiesMDM2 antagonists dose-reponse AAC values CDK4/6 inhibitors dose-response AAC values Patient ID Age/ Gender Rx prior to surgery OS (days) MGMT promoter Transcriptional Subclass CDKN2A TP53 MDM2 RB1 CDK4 RTK MYC fam. NF1 PTEN RG7112 AMG232 Ribociclib Abemaciclib HF2354 61 M BCNU 196 U undetermined DEL mut NC NC NC NC MYC AMP NC mut 0.05 0.02 0.10 0.08 HF2381 66 M untreated 183 M proneural NC NC AMP NC AMP NC MYC AMP NC 0.61 0.85 0.57 0.75 HF2587 56 F untreated 360 M proneural DEL NC NC NC NC NC NC mut mut 0.68 0.83 0.59 0.60 HF2927 55 F untreated 664 U classical DEL NC NC NC NC EGFR AMP, vIII NC NC DEL 0.52 0.81 0.59 0.67 HF3035 54 F untreated 352 U classical DEL NC NC NC NC MET AMP NC NC DEL 0.44 0.63 0.21 0.28 HF3055 58 M untreated 371 U classical NC NC AMP NC AMP EGFR AMP..."

Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CDKN2A • EGFR • MYCN • NF1 • PDGFRA • PTEN • RB1 • TP53

Association of cellular drug responses and metabolic profiles in adult type diffuse gliomas (EANO 2024) - " First analysis within this cohort (n =18) showed significantly lower AUC values (i.e. enhanced drug response) of panobinostat and vorinostat (HDAC inhibitors), AMG232 and RG7112 (MDM2 inhibitors), selinexor (exportin-1 inhibitor) and temsirolimus (mTOR inhibitor) in IDH-wt gliomas (all p<0.05). These first analyses showed an association between drug response and metabolism when using a holistic approach. Additionally, these results suggested a connection between metabolic pathways and drug susceptibility. In the next step, we plan to investigate the metabolic heterogeneity of IDH-wt gliomas within the tumor in more detail to find out whether there is an influence on the response to treatment."

Clinical • IO biomarker • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • XPO1

Cutaneous Merkel cell carcinoma (MCC): updates from AAD Annual Congress 2024. (EADV 2024) - "3 ) The gold- standard for the treatment of advanced MCC remains the association of radiotherapy and checkpoint inhibitors (in particular, avelumab) after radical surgery of this rare skin cancer...4 ) Several controlled studies have been made for alternative treatments with mRNA-vaccines (based on MCPyV-related LT-Ag) in comparison with target therapies (KRT-232 and others) , frequently in combination with checkpoint inhibitors... Relevant scientific progresses have been made in these years for a better knowledge of this rare skin cancer, particularly concerning its histopathological diagnosis and clinical management. However, further studies are necessary to characterize better refractory MCCs and to develop alternative treatment strategies for their care.**"

IO biomarker • Genetic Disorders • Merkel Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor

Novel Radiosensitizer Screen Identifies an Effective Strategy to Treat p53 Wild-Type Breast Cancer Models in a Hormone Independent Manner (ASTRO 2024) - "MDM2 inhibitors navtemadlin (AMG-232) and alrizomadlin (APG-115) were used in p53 wild-type and mutant models of estrogen receptor (p53-WT:MCF-7, p53-MT:T47D) and ER-negative BC (p53-WT: CAL-51, p53-MT: MDA-MB-231). These results demonstrate the combination of RT and MDM2 inhibition may be an effective therapeutic strategy in patients with p53-WT BC which represent the majority of BCs, regardless of hormone receptor status. Clinical trial development is currently underway to test this in women with locally advanced p53-WT BCs at high risk of locoregional recurrence."

Preclinical • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Oncology • Solid Tumor • ANXA5 • ER

Functional genomic approaches to understand mechanisms of drug response and resistance (EANO 2024) - "We have characterized the effect of navtemadlin, one such MDM2 inhibitor, through a window of opportunity clinical trial in patients diagnosed with HGG...In the second part of the talk, I will exemplify how genome-wide and targeted CRISPR activation screens in patient-derived HGG cell line models were able to identify putative cell programs modulating drug response in the absence of p53 inactivating mutations. Our ongoing efforts are focused on validating putative drivers of resistance to MDM2 and PPM1D inhibition in additional cell line and animal models, as well as identifying combination therapies for the upfront treatment of these tumors."

Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • PPM1D • TP53

Combination of MDM2 and Targeted Kinase Inhibitors Results in Prolonged Tumor Control in Lung Adenocarcinomas With Oncogenic Tyrosine Kinase Drivers and MDM2 Amplification. (PubMed, JCO Precis Oncol) - "These preclinical in vivo data provide a rationale for further clinical development of this combinatorial targeted therapy approach."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • MDM2 • RET • TP53

Surgical window of opportunity trial reveals mechanisms of response and resistance to navtemadlin (KRT-232) in patients with recurrent glioblastoma. (PubMed, medRxiv) - P1 | "However, combining navtemadlin with temozolomide increased apoptotic rates while sparing normal bone marrow cells in vitro, which in return underwent reversible growth arrest. Tissue sampling during this clinical trial allowed us to assess mechanisms of response and resistance associated with navtemadlin treatment in recurrent GBM. We report that clinically achievable doses of navtemadlin induce pharmacodynamic effects in tumor tissue, and suggest combinations with standard-of-care chemotherapy for durable clinical benefit."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • TP53

Testing a New Chemotherapy Drug, KRT-232 (AMG-232) in Combination With Decitabine and Venetoclax in Patients With Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=58 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Suspended ➔ Active, not recruiting

Combination therapy • Enrollment closed • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD4 • TP53

Icariin Targets p53 to Protect Against Ceramide-Induced Neuronal Senescence: implication in Alzheimer's Disease. (PubMed, Free Radic Biol Med) - "Icariin demonstrates a protective effect against ceramide-induced neuronal senescence by inhibiting the P53 pathway. This identifies a novel mechanism of action for icariin, offering a novel therapeutic approach for AD and other age-related neurodegenerative diseases."

Journal • Alzheimer's Disease • CNS Disorders • Dementia

Testing a New Chemotherapy Drug, KRT-232 (AMG-232) in Combination With Decitabine and Venetoclax in Patients With Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=58 | Suspended | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Suspended

Combination therapy • Trial suspension • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD4 • TP53

[PREPRINT] Surgical window of opportunity trial reveals mechanisms of response and resistance to navtemadlin (KRT-232) in patients with recurrent glioblastoma (medRxiv) - P1 | N=86 | NCT03107780 | "In patient-derived GBM models, the lower range of clinically achieved navtemadlin concentrations induced partial tumor cell death as monotherapy. However, combining navtemadlin with temozolomide increased apoptotic rates while sparing normal bone marrow cells in vitro, which in return underwent reversible growth arrest. These results indicate that clinically achievable doses of navtemadlin generate significant pharmacodynamic effects and suggest that combined treatment with standard-of-care DNA damaging chemotherapy is a route to durable survival benefits."

P1 data • PK/PD data • Preprint • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

Identification of RBM15 as a prognostic biomarker in prostate cancer involving the regulation of prognostic m6A-related lncRNAs. (PubMed, Eur J Med Res) - "RBM15 is involved in the regulation of prognostic lncRNAs in the risk signature and has a robust predictive ability for PCa, making it a promising biomarker in PCa."

Biomarker • Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • RBM15

Testing the Addition of KRT-232 (AMG 232) to Usual Chemotherapy for Relapsed Multiple Myeloma (clinicaltrials.gov) - P1 | N=35 | Terminated | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2024 ➔ Jul 2024 | Recruiting ➔ Terminated | Trial primary completion date: Dec 2024 ➔ Jul 2024; Inadequate accrual rate

Combination therapy • Trial completion date • Trial primary completion date • Trial termination • Hematological Malignancies • Multiple Myeloma • Oncology • Plasmacytoma • CD4 • TP53

HER4 Affects Sensitivity to Tamoxifen and Abemaciclib in Luminal Breast Cancer Cells and Restricts Tumor Growth in MCF-7-Based Humanized Tumor Mice. (PubMed, Int J Mol Sci) - "We investigated tumor cell proliferation as well as the cellular and molecular mechanisms of tamoxifen, abemaciclib, AMG232, and NRG1 treatments as a function of HER4 in vitro. However, abemaciclib-treated hormone receptor-positive breast cancer patients with tumor-associated mdm2 gene copy gains or pronounced HER4 expression showed a reduced event-free survival. Evidently, the presence of HER4 affects the efficacy of tamoxifen and abemaciclib treatment in different estrogen receptor-positive breast cancer cells, even to different extents, and is associated with unfavorable outcomes in abemaciclib-treated patients."

Journal • Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • ERBB4 • HER-2 • MDM2 • NRG1

POIESIS: Study of Navtemadlin add-on to Ruxolitinib in JAK Inhibitor-Naïve Patients With Myelofibrosis Who Have a Suboptimal Response to Ruxolitinib (clinicaltrials.gov) - P3 | N=600 | Recruiting | Sponsor: Kartos Therapeutics, Inc.

New P3 trial • Myelofibrosis

EFFECT OF NOVEL AGENTS ON THE MECHANISM OF FIBROCYTE-MEDIATED INDUCTION OF MYELOFIBROSIS (EHA 2024) - "6%, while themeans for the Ruxolitinib, Navitoclax, TL-895, Parsaclisib, and Navtemadlin groups were 49. In vitro experiments demonstrated that the novel agents examined in this studyeffectively inhibited monocyte differentiation into fibrocytes and reduced certain profibrotic cytokinelevels in the culture supernatant. Further investigation into these mechanisms is anticipated to provideinsights into the antifibrotic mechanisms underlying the action of these novel agents."

Hematological Disorders • Hematological Malignancies • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • CCL2 • CCL22 • CSF1 • CXCL1 • IFNG • IL13 • IL18 • IL1R1 • IL4 • IL6 • IL7 • TNFA

Testing a New Chemotherapy Drug, KRT-232 (AMG-232) in Combination With Decitabine and Venetoclax in Patients With Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=58 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2025 ➔ Jun 2026 | Trial primary completion date: Jun 2025 ➔ Jun 2026

Combination therapy • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD4 • TP53

Testing a New Chemotherapy Drug, KRT-232 (AMG-232) in Combination With Decitabine and Venetoclax in Patients With Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=58 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2024 ➔ Jun 2025 | Trial primary completion date: Dec 2024 ➔ Jun 2025

Combination therapy • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD4 • TP53

Pre-clinical modeling of navtemadlin pharmacokinetics (PK), pharmacodynamics (PD), and efficacy in glioblastoma, IDH-wildtype. (ASCO 2024) - "Nvtm showed significant efficacy in TP53 WT GBM flank PDX models but efficacy in orthotopic PDX was highly dependent on CNS penetration. Targeting nvtm levels based on the in vitroIC50 may significantly underestimate the in vivo effective concentration. In vivo studies showed lower intra-tumoral nvtm levels are required to significantly inhibit growth of MDM2amplified compared with non-amplified tumors."

PK/PD data • Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • ABCG2 • MDM2

Testing the Addition of an Anti-cancer Drug, Navtemadlin, to the Usual Treatments (Cytarabine and Idarubicin) in Patients With Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=24 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2024 ➔ Jun 2025 | Trial primary completion date: Jun 2024 ➔ Jun 2025

Combination therapy • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of KRT-232 When Administered Alone and in Combination With Low-Dose Cytarabine (LDAC) or Decitabine in Patients With Acute Myeloid Leukemia (AML) (clinicaltrials.gov) - P1/2 | N=70 | Terminated | Sponsor: Kartos Therapeutics, Inc. | Phase classification: P1b/2 ➔ P1/2 | Trial completion date: Jul 2024 ➔ Sep 2023 | Active, not recruiting ➔ Terminated; In September 2023, the study was terminated because of a Sponsor decision, unrelated to safety concerns.

Combination therapy • Phase classification • Trial completion date • Trial termination • Acute Myelogenous Leukemia • Essential Thrombocythemia • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • IDH1 • IDH2

Study of Navtemadlin Plus Pembrolizumab as Maintenance Therapy in Locally Advanced and Metastatic Non-Small Cell Lung Cancer (clinicaltrials.gov) - P1/2 | N=0 | Withdrawn | Sponsor: Kartos Therapeutics, Inc. | Phase classification: P1b/2 ➔ P1/2 | N=92 ➔ 0 | Trial completion date: Dec 2027 ➔ Jun 2027 | Not yet recruiting ➔ Withdrawn | Trial primary completion date: Dec 2025 ➔ Jun 2025

Enrollment change • Metastases • Phase classification • Trial completion date • Trial primary completion date • Trial withdrawal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

NRG-DT001: Navtemadlin and Radiation Therapy in Treating Patients With Soft Tissue Sarcoma (clinicaltrials.gov) - P1 | N=38 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2023 ➔ Feb 2025 | Trial primary completion date: Dec 2023 ➔ Aug 2023

Trial completion date • Trial primary completion date • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CD4 • MDM2 • MDM4 • TP53