navtemadlin (KRT-232)

P1/2, N=70, Terminated, 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.

P1/2, N=0, Withdrawn, Kartos Therapeutics, Inc. | Phase classification: P1b/2 --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 Withdrawn | Trial primary completion date: Dec 2025 --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

P1, N=38, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Feb 2025 | Trial primary completion date: Dec 2023 --> Aug 2023

P1, N=24, Active, not recruiting, National Cancer Institute (NCI) | Phase classification: P1b --> P1

P1, N=58, Recruiting, National Cancer Institute (NCI) | Phase classification: P1b --> P1 | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=86, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=40, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

Other tested covariates, including body weight, creatinine clearance, aspartate transaminase, alanine transaminase, bilirubin, albumin, alpha 1-acid glycoprotein, race, UGT1A1 genotype, recent ruxolitinib treatment in MF, and CYP3A4 inducer/inhibitor concomitant medications, were not significant. Tumor type influenced navtemadlin exposure with simulated exposure in R/R MF patients at the selected Phase 3 dose of 240 mg comparable to exposures in MCC patients at 180 mg, the selected Phase 2 dose for that indication. Cancer-associated inflammation and/or treatment history, as well as age and female sex, may increase navtemadlin exposure. The PD marker MIC-1 responds to navtemadlin in a concentration-dependent fashion.

Our results indicate that BTKi therapy might increase susceptibility of MPN-BP SC to MDM2i therapy, by upregulating p53 activity and dampening NF-κB signaling, and also by disrupting protective TME interactions that sustain MPN-BP SC. This novel combination merits further clinical investigation in advanced phase MPN.

A proof-of-concept study with idasanutlin (idasa), a first-generation MDM2 inhibitor and ven demonstrated manageable safety and encouraging efficacy in relapsed/refractory AML patients (Daver et al. Nvtm, a potent second-generation MDM2 inhibitor, rapidly restored p53 function, induced apoptosis in p53WT AML MOLM-13 by impeding cell cycle, viability, clonogenicity potential, and reducing both glycolysis and oxidative phosphorylation. Nvtm combined with ven significantly enhanced these effects. Importantly, this combination blocked stromal cell-mediated (contact and soluble factors) cytoprotection.

Primary endpoint for Phase 3 is PFS by blinded independent review. Current Trial Status: This study is now open to enrollment.

P1b, N=24, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2023 --> Jun 2024 | Trial primary completion date: Jul 2023 --> Jun 2024

P2, N=3, Terminated, Kartos Therapeutics, Inc. | N=38 --> 3 | Trial completion date: Nov 2025 --> Aug 2022 | Recruiting --> Terminated | Trial primary completion date: May 2025 --> Aug 2022; Unanticipated and extremely high screen failure rate. There was no evidence of safety concerns in the study.

P1b/2, N=86, Active, not recruiting, Kartos Therapeutics, Inc. | Recruiting --> Active, not recruiting

While some MDM2 inhibitors have progressed to early phase clinical trials in GBM, their efficacy, alone and in combination, is yet to be confirmed. In this article, we present an overview of MDM2 inhibitors currently under preclinical and clinical investigation, with a specific focus on the drugs being assessed in ongoing clinical trials for GBM patients.

Primary endpoint for Phase 3 is progression-free survival by blinded independent review. Results NAConclusion NA

P1/2, N=130, Active, not recruiting, Telios Pharma, Inc. | Recruiting --> Active, not recruiting

PROSPERO provides a precise way to evaluate therapy efficacy by measuring molecular drug responses using specific biomarker changes in freshly resected brain tumor samples, in addition to providing key functional insights in cellular behavior, which may ultimately complement standard, clinical biomarker evaluations.

Nvtm combined with acala has an acceptable safety profile with no DLTs in dose escalation and showedencouraging preliminary activity in BTKi-naïve R/R CLL/SLL. Two out of seven pts (29%) reported CR/CRi at ≥6 months follow-up. Ph2 expansion is ongoing.

The MDM2 inhibitor Navtemadlin arrests mouse tumor growth and potentiates radiotherapy. Our results support a threshold model for apoptosis induction that requires a high, prolonged p53 signaling for cancer cells to become apoptotic.

This review discusses the anticancer mechanism of flavonoids (quercetin, rutin, chrysin, apigenin, naringenin, silibinin, EGCG, genistein, biochanin A and C3G) through targeting molecules associated with high-grade adult-type diffuse glioma cell proliferation, apoptosis, oxidative stress, cell cycle arrest, migration, invasion, autophagy and DNA repair. Moreover, the clinical relevance of flavonoid molecular targets in high-grade adult-type diffuse gliomas is discussed with comparison to small molecules inhibitors: ralimetinib, AMG232, marimastat, hydroxychloroquine and chloroquine. Despite the positive pre-clinical results, further investigations in clinical studies are warranted to substantiate the efficacy and safety of the use of flavonoids on high-grade adult-type diffuse glioma patients.

P1b, N=48, Suspended, National Cancer Institute (NCI) | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Dec 2023

P1b/2, N=18, Active, not recruiting, Telios Pharma, Inc. | Recruiting --> Active, not recruiting | N=70 --> 18

Finally, AGM232 resulted in a significant decrease in new vessels and hemoglobin content in vivo. This study proved AMG232 inhibited glioma angiogenesis by blocking the MDM2-p53 interaction, in which the p53/RBM4/VEGFR2 pathway played an important role.

P1, N=40, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Dec 2023

P1, N=46, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Dec 2023

P1, N=86, Suspended, National Cancer Institute (NCI) | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Dec 2023

Similar results were obtained for the other two MDM2 inhibitors, AMG232 and DS-3032b, and a BCL2 inhibitor, venetoclax...Furthermore, overexpressing GATA2 conferred Idasanutlin resistance at high concentrations. Finally, we observed that combining a FLT3/IRAK dual inhibitor, pacritinib, or an IRAK1 /IL-1 receptor antagonist, anakinra, partially rescued IL-1α and IL-1β mediated drug resistance of MDM2 inhibitors. As such, we uncovered the role of leukemia-associated monocyte in driving intrinsic and extrinsic MDM2 inhibitor resistance and the potential underlying mechanisms.

Navtemadlin induces potent, threshold-dependent apoptosis in cell culture models of TP53WT myeloid malignancies at clinically relevant concentrations. Navtemadlin-induced p53 activity initiates apoptosis by activating the caspase cascade via cytochrome c release. Navtemadlin was shown to induce the expression of pro-apoptotic BCL-2 family proteins, key mediators in driving cell death.

"Tempus...announced a new collaboration to develop a companion diagnostic (CDx) test with Kartos Therapeutics...in support of its ongoing Phase II study of navtemadlin (KRT-232). Tempus’ CDx test, which will be developed on Tempus’ xT platform, will be used to identify patients with TP53 wild-type (TP53WT) Merkel cell carcinoma (MCC) who may be eligible for treatment with navtemadlin. Navtemadlin is a potent, selective, orally available MDM2 inhibitor that overcomes MDM2 dysregulation by restoring p53 activity and inducing apoptosis of TP53WT tumor cells."

P1, N=46, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

The maximum tolerated dose of AMG 232 for both arms was 120 mg. AMG 232 plus T±D exhibited a favorable PK profile. Although objective responses occurred in both arms, adding AMG 232 to T±D did not confer additional clinical benefit.

P1b/2, N=70, Recruiting, Telios Pharma, Inc. | Trial completion date: Jun 2024 --> Nov 2025 | Trial primary completion date: Jun 2022 --> Nov 2024

In addition, this combination treatment led to enhanced expression of apoptosis and autophagy-related genes in ALL cell lines. The results declared that AMG232 as an MDM-2 inhibitor could be an effective approach to enhance antitumor effects of Doxorubicin on NALM-6 cells as well as an effective future treatment for ALL patients.

Secondary endpoints include duration of response, progression-free survival, overall survival, disease control rate, and safety. This trial is ongoing and will enroll patients at approximately 40 global sites.

P2, N=38, Recruiting, Kartos Therapeutics, Inc. | Not yet recruiting --> Recruiting

Two Janus-associated kinase inhibitors (JAKi) (initially ruxolitinib and, more recently, fedratinib) have been approved as treatment options for patients who have intermediate-risk and high-risk myelofibrosis (MF), with pivotal trials demonstrating improvements in spleen volume, disease symptoms, and quality of life. To address such a high unmet therapeutic need, various non-JAKi agents are being actively explored (in combination with ruxolitinib in first-line or salvage settings and/or as monotherapy in JAKi-pretreated patients) in phase 3 clinical trials, including pelabresib (a bromodomain and extraterminal domain inhibitor), navitoclax (a B-cell lymphoma 2/B-cell lymphoma 2-xL inhibitor), parsaclisib (a phosphoinositide 3-kinase inhibitor), navtemadlin (formerly KRT-232; a murine double-minute chromosome 2 inhibitor), and imetelstat (a telomerase inhibitor). The breadth of data expected from these trials will provide insight into the ability of non-JAKi treatments to modify the natural history of MF.

Here, we evaluated combination therapy with MEK inhibitor selumetinib and MDM2 inhibitor KRT-232 in TP53 wild-type and MAPK altered colon and thyroid cancer models. In summary, combined inhibition of MEK and MDM2 upregulated p53 expression, inhibited MAPK signaling and demonstrated greater antitumor efficacy than single drug therapy in both in vitro and in vivo settings. These findings support further clinical testing of the MEK/MDM2 inhibitor combination in tumors of epithelial origin with MAPK pathway alterations.

In vivo efficacy of combination therapy was evaluated with CAL-51 and CAL-51 p53 CRISPR xenograft models. An MDM2 inhibitor (JNJ-26854165) was nominated as an effective drug in treatment for RT-resistant BC cell lines (R2 = 0.43, p value 10μm)... These results demonstrate the combination of RT and MDM2 inhibition may be an effective therapeutic strategy in patients with p53-wild type breast cancer, regardless of hormone receptor status.

P1b, N=48, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended