- |||||||||| alrizomadlin (APG-115) / Ascentage Pharma, navtemadlin (KRT-232) / Kartos Therap, serdemetan (JNJ-26854165) / J&J
MDM2 inhibition as a non-hormone dependent radiosensitizing strategy in p53 wild-type breast cancer models (Section 10) - Mar 9, 2022 - Abstract #AACR2022AACR_3067;
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.
- |||||||||| idasanutlin (RO5503781) / Roche
Journal: Fluorine-18 Labeling of the MDM2 Inhibitor RG7388 for PET Imaging: Chemistry and Preliminary Evaluation. (Pubmed Central) - Feb 19, 2022
Our results suggest that RG7388 is a promising molecular scaffold for F-labeled probe development for MDM2. Additional labeling strategies and functionalizing locations on RG7388 are under development to improve binding affinity and in vivo stability of the F-labeled compound to make it more amenable for PET imaging of MDM2 in vivo.
- |||||||||| M7583 / EMD Serono, Telios Pharma
Enrollment closed, Enrollment change, Combination therapy, Monotherapy: MS200662_0001: Phase I/II, FIH, Dose Escalation Trial of TL-895 and Expansion of TL-895 Monotherapy and Combination Therapy With Navtemadlin in Tx-Na (clinicaltrials.gov) - Feb 17, 2022
P1/2, N=80, Active, not recruiting,
Additional labeling strategies and functionalizing locations on RG7388 are under development to improve binding affinity and in vivo stability of the F-labeled compound to make it more amenable for PET imaging of MDM2 in vivo. Recruiting --> Active, not recruiting | N=58 --> 80
- |||||||||| Review, Journal: SOHO State of the Art Updates and Next Questions: Identifying and Treating "Progression" in Myelofibrosis. (Pubmed Central) - Feb 9, 2022
Over the last decade, the Janus kinase (JAK) 1/2 inhibitor ruxolitinib has become widely established as the cornerstone of pharmacologic therapy for most patients with myelofibrosis (MF), providing dramatic and durable benefits in terms of splenomegaly and symptoms, and prolonging survival...The regulatory approval of fedratinib has introduced an important option in the postruxolitinib setting. Fortunately, a plethora of novel agents, both new JAK inhibitors and drugs from other classes, eg, bromodomain and extraterminal (BET), murine double minute 2 (MDM2) and telomerase inhibitors, activin receptor ligand traps, BH3-mimetics and more, are poised to greatly expand the therapeutic armamentarium for patients with MF if successful in pivotal trials.
- |||||||||| Clinical, P2 data, Journal: Emerging drugs for the treatment of myelofibrosis: phase II & III clinical trials. (Pubmed Central) - Jan 27, 2022
Ruxolitinib and fedratinib are approved JAK2 inhibitors that have produced meaningful benefits in terms of spleen reduction and symptom improvement, but there remain several unmet needs...Specifically, we cover novel JAK inhibitors (momelotinib and pacritinib), and agents that target bromodomain and extra-terminal domain (pelabresib), the antiapoptotic proteins BCL-2/BCL-xL (navitoclax), MDM2 (navtemadlin), phosphatidylinositol 3-kinase (parsaclisib), or telomerase (imetelstat)...Future evaluation of agents must be judged on their potential to modify disease progression, which current JAK2 inhibitors lack. Combination therapy, possibly with an immunotherapeutic agent might serve as key components of future myelofibrosis treatment options.
- |||||||||| navtemadlin (KRT-232) / Kartos Therap
Phase classification, Enrollment change, Trial completion date, Trial primary completion date, Combination therapy: NOTOS: Navtemadlin (KRT-232) With or Without Anti-PD-1/Anti-PD-L1 for the Treatment of Patients With Merkel Cell Carcinoma (clinicaltrials.gov) - Jan 27, 2022
P1b/2, N=115, Recruiting,
Combination therapy, possibly with an immunotherapeutic agent might serve as key components of future myelofibrosis treatment options. Phase classification: P2 --> P1b/2 | N=46 --> 115 | Trial completion date: Dec 2021 --> Aug 2025 | Trial primary completion date: Jun 2021 --> Nov 2024
- |||||||||| navtemadlin (KRT-232) / Kartos Therap
Trial completion date, Trial primary completion date, Combination therapy: Testing the Addition of KRT-232 (AMG 232) to Usual Chemotherapy for Relapsed Multiple Myeloma (clinicaltrials.gov) - Jan 6, 2022
P1, N=40, Recruiting,
N=20 --> 86 | Trial completion date: Dec 2021 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Dec 2022 Trial completion date: Dec 2021 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Dec 2022
- |||||||||| navtemadlin (KRT-232) / Kartos Therap
Single-cell drug activity mapping in glioblastoma identifies extended drug response heterogeneity and therapy-induced cellular plasticity (Room 208) - Nov 16, 2021 - Abstract #SNO2021SNO_1169;
By applying an optimised GBM-specific and therapy-tailored antibody panel, we measured therapeutic activity upon exposure to ionising radiation (RT) or a small molecule MDM2 inhibitor (AMG232) in a cohort of patient-derived GBM cell lines (n=14)...Accordingly, we identified highly variable fractions of responsive tumour and microenvironmental cell populations in a patient-specific way. The ability to measure drug activity at single-cell resolution in a patient-tailored manner by applying a genotype-agnostic method, paves the way for advanced precision cancer medicine in GBM by offering a novel approach to more precisely select eligible patients for prospective clinical trials.
- |||||||||| navtemadlin (KRT-232) / Kartos Therap
Optimizing MDM2 inhibition for the treatment of high-grade glioma (Exhibit Hall D) - Nov 16, 2021 - Abstract #SNO2021SNO_396;
Treatment with KRT232 upregulated both cell cycle arrest and apoptotic cellular responses, with unique temporal and transcriptional differences correlated with MDM2/4 or PPM1D status. In other tumors resistance to MDM2i is mainly mediated by TP53 mutations, but in a subset of chronic KRT232-treated glioma models we noted lack of TP53 mutations and identified cell state and transcriptional changes as potentially more treatable mediators of resistance.
- |||||||||| navtemadlin (KRT-232) / Kartos Therap
Navtemadlin (KRT-232), a Small Molecule MDM2 Inhibitor, Is More Effective Than Decitabine Against Myeloproliferative Neoplasm-Blast Phase in a Patient-Derived Xenograft Model (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_5280;
Furthermore, toxicity (body weight loss, intestinal pathology) was observed in mice receiving high dose of navtemadlin and decitabine simultaneously, but not when either drug was administered alone. In conclusion, navtemadlin monotherapy, which activates p53, depletes leukemia cell counts and prolongs survival of MPN-BP PDX mice and is a promising agent for patients with WT TP53 MPN-BP.
- |||||||||| navtemadlin (KRT-232) / Kartos Therap
A Phase 1b/2 Study of Navtemadlin (KRT-232), a Murine Double Minute 2 Inhibitor, Combined with a BCR-ABL Tyrosine Kinase Inhibitor in Patients with Relapsed/Refractory, TP53WT, Ph+ Chronic Myeloid Leukemia (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_4196;
P1b/2
The primary endpoints of phase 2 are the rate of major cytogenetic response at 6 months in Arms A and B and major hematologic response in Arm C. Secondary endpoints include duration of response, rate of complete hematologic response, progression-free and overall survival, and safety. This trial is ongoing and will enroll patients at approximately 45 global sites in North America, Europe, and Asia.
- |||||||||| azacitidine / Generic mfg.
Development of an MDM2 Degrader for Treatment of Acute Leukemias (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_3458;
These agents such as RG7388 and AMG232 have shown efficacy as monotherapy and in combination...XY-27 also shows efficacy when combined with other chemotherapeutic agents such as azacytidine and cytarabine...( c ) Induction of apoptosis in primary AML cells treated with XY-27 at 1μM using a co-culture system for 3 days. *p<.05
- |||||||||| cisplatin / Generic mfg.
[VIRTUAL] SCREENING AND IDENTIFICATION OF NOVEL CHEMOTHERAPY AGENTS IN PLATINUM- RESISTANT OVARIAN CANCER () - Aug 26, 2021 - Abstract #IGCS2021IGCS_493;
Neither telaglenastat, savolitinib, nor AMG-232 exhibit any appreciable cytotoxicity; however, mithramycin demonstrates cytotoxicity in the low nanomolar range in several representative ovarian cancer cell lines, including two platinum-resistant lines. The potential therapeutic benefit of mithramycin warrants further preclinical evaluation.
- |||||||||| navtemadlin (KRT-232) / Kartos Therap, milademetan (RAIN-32) / Rain Therap
[VIRTUAL] The MDM2/p53 Axis is a Therapeutic Vulnerability in Malignant Pleural Mesothelioma (ePoster Hall) - Aug 9, 2021 - Abstract #IASLCWCLC2021IASLC_WCLC_1279;
Conclusion MDM2 inhibitors selectivity and potently inhibit in vitro and in vivo growth of MPM cell lines bearing WT TP53. In light of the fact that there are no approved therapies following MPM treatment failure with standard cytotoxic agents or anti-PD1-based immunotherapy, the MDM2/p53 axis represents an attractive target for further clinical exploration in this disease.
- |||||||||| Nutlin-3 / EMD Serono, THR-18 - D / Pharm, KRT-232 / Kartos Therap
Journal: Single-molecule analysis of interaction between p53TAD and MDM2 using aerolysin nanopores. (Pubmed Central) - Jun 30, 2021
Taken together, our results elucidate a novel mechanism of single-molecule sensing for analyzing PPIs and their inhibitors using aerolysin nanopores. This novel methodology may contribute to remarkable improvements in drug discovery targeted against undruggable PPIs.
- |||||||||| imatinib / Generic mfg.
[VIRTUAL] Managing TKI Resistance: New Options () - May 20, 2021 - Abstract #SOHO2021SOHO_186;
Resistance to imatinib occurs in 10–15% and to second-generation TKiin <10% of patients in the first-line setting...Detection of some ABL KD mutations may help to decide between the second-generation TKIs dasatinib, nilotinib, and bosutinib or the third-generation TKiponatinib...The allosteric inhibitor asciminib has demonstrated clinical efficacy in multi-resistant patients, including those with a T315imutation, and favorable safety profile...A small-molecule inhibitor of MDM2, KRT232, is being tested in combination to dasatinib or nilotinib for patients resistant to at least two lines of treatment. These new strategies will be presented and discussed.
- |||||||||| [VIRTUAL] Potential New Therapeutic Approaches for Myelofibrosis () - May 20, 2021 - Abstract #SOHO2021SOHO_158;
Targeting the p53-HDM2 Axis KRT-232 is a first-in-class, potent, bioavailable inhibitor of HDM2 (key negative regulator of p53) that was assessed in a phase 2 study (KRT-232-101) and showed promising clinical efficacy and tolerability in TP53-wild type patients with MF who failed ruxolitinib treatment.17 A randomized phase 3 trial comparing KRT-232 (240 mg on days 1–7/28-day cycle) to BAT in MF patients refractory /resistant to JAK inhibitors has been launched...In the phase 2 study IMbark, the higher dose of imetelstat (9.4 mg/ kg) yielded a median overall survival of 29.9 months in patients with intermediate-2 or high-risk MF relapsed/refractory to JAK inhibitors.18 In light of the aforementioned promising result, a pivotal international phase 3 trial (IMpactMF) was launched to evaluate the survival advantage – an unprecedented trial endpoint for investigational MF medications – that imetelstat may confer to JAK-inhibitor-refractory MF patients.19 Conclusions The era of JAK1/2 inhibitor monotherapies in MF has ushered the way to the clinical development of a suite of promising novel medications spanning various biological mechanisms (for example, inhibitors of BET, HDM2, BCL-2/ BCL-XL, and telomerase, among others). Several highly promising candidates are currently evaluated in regulatory phase 3 clinical trials in the frontline and second line settings; these studies may lead to approval of novel medications that will significantly improve the current MF treatment paradigm.
- |||||||||| KRT-232 / Kartos Therap
[VIRTUAL] BOREAS: A global phase 3 study of KRT-232, a first-in-class murine double minute 2 (MDM2) inhibitor in TP53WT relapsed/refractory (R/R) myelofibrosis (MF). () - Apr 28, 2021 - Abstract #ASCO2021ASCO_1266;
P2/3
Clinical Trial Registry Number: NCT03662126 Funding: Kartos Therapeutics, Inc Background: The prognosis for patients (pts) with MF who have primary resistance to or who have progressed after treatment with ruxolitinib (RUX) is poor (median OS is ̃13 months), highlighting the unmet need for novel treatments in this setting...BAT options include hydroxyurea, chemotherapy, or supportive care (including; but not limited to: corticosteroids and androgens); treatment selection is at the discretion of the investigator...Key secondary endpoints are ≥50% reduction in TSS rate at Week 24 (per MFSAF v4.0), PFS, OS, best overall SVR ≥35%, and duration of spleen response . Enrollment is planned at 137 sites in 21 countries in North and South America, Europe, and Asia-Pacific.
- |||||||||| M7583 / EMD Serono, Telios Pharma
Enrollment open, Trial completion date, Trial primary completion date, Combination therapy, Monotherapy: MS200662_0001: Phase I/II, FIH, Dose Escalation Trial of TL-895 and Expansion of TL-895 Monotherapy and Combination Therapy With Navtemadlin in Tx-Na (clinicaltrials.gov) - Apr 14, 2021
P1/2, N=58, Recruiting,
Enrollment is planned at 137 sites in 21 countries in North and South America, Europe, and Asia-Pacific. Active, not recruiting --> Recruiting | Trial completion date: Sep 2021 --> Feb 2024 | Trial primary completion date: Sep 2021 --> Feb 2024
- |||||||||| M7583 / EMD Serono, Telios Pharma
Enrollment open: TL-895 and KRT-232 Study in Acute Myeloid Leukemia (clinicaltrials.gov) - Apr 12, 2021
P1b/2, N=58, Recruiting,
Active, not recruiting --> Recruiting | Trial completion date: Sep 2021 --> Feb 2024 | Trial primary completion date: Sep 2021 --> Feb 2024 Not yet recruiting --> Recruiting
- |||||||||| KRT-232 / Amgen, Kartos Therap, serdemetan (JNJ-26854165) / J&J
[VIRTUAL] The role of MDM2 inhibition in the radiosensitization of ER+ breast cancers () - Mar 11, 2021 - Abstract #AACR2021AACR_3658;
yH2AX immunofluorescence was used to measure dsDNA breaks.Results: A MDM2 inhibitor (JNJ-26854165) was nominated as an effective drug in treatment for RT-resistant BC cell lines (R2 = 0.43, p-value <0.01) in our novel radiosensitizer screen...AMG-232 and RT combined led to an increase in apoptosis compared to RT alone in ER+ p53 WT cells but not p53 MT cells...G1 cell cycle arrest was a secondary effect of MDM2 inhibition and radiation. Experiments investigating the role of dsDNA breaks in radiosensitization are ongoing.Conclusions: Our novel radiosensitizer screen identifies MDM2 as a potential mediator of radioresistance in ER+ BC in a p53-dependent manner and suggests that MDM2 targeting concurrent with RT may represent a tractable clinical strategy in women with locally advanced ER+, p53 WT BC.
- |||||||||| KRT-232 / Amgen, Kartos Therap
Journal, PD(L)-1 Biomarker, IO biomarker: AMG-232 sensitizes high MDM2-expressing tumor cells to T-cell-mediated killing. (Pubmed Central) - Feb 11, 2021
MDM2 inhibition lowered expression of Interleukin-6, a pro-inflammatory pro-tumorigenic cytokine. Our data support targeting MDM2 in tumors with overexpression or amplification of MDM2 as a precision therapy approach to overcome drug resistance including hyper-progression in the context of immune checkpoint therapy.
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