- |||||||||| M7583 / EMD Serono, Telios Pharma
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) - Dec 4, 2020
P1/2, N=58, Active, not recruiting,
Trial completion date: Dec 2020 --> Dec 2021 | Trial primary completion date: Dec 2020 --> Dec 2021 N=18 --> 58
- |||||||||| Review, Journal: MDM2 inhibition: an important step forward in cancer therapy. (Pubmed Central) - Dec 1, 2020
Overall, targeting MDM2 is a promising treatment strategy, as evidenced by the increasing number of MDM2 inhibitors entering the clinic. Additional clinical investigation is needed to further elucidate the role of MDM2 inhibitors in the treatment of human cancers.
- |||||||||| Jakafi oral (ruxolitinib) / Novartis, Incyte, KRT-232 / Amgen, Kartos Therap
[VIRTUAL] An Open-Label, Global, Multicenter, Phase 1b/2 Study of KRT-232, a First-in-Class, Oral Small-Molecule Inhibitor of Murine Double Minute 2 (MDM2), Combined with Ruxolitinib in Patients Who Have Myelofibrosis and a Suboptimal Response to Ruxolitinib (Poster Hall (Virtual Meeting)) - Nov 5, 2020 - Abstract #ASH2020ASH_3885;
P1b/2
Secondary end points include spleen response (≥35% spleen volume reduction from baseline), change in Myelofibrosis Symptom Assessment Form version 4.0 Total Symptom Score, duration of response, spleen size reduction, red blood cell transfusion usage and independence, overall response rate (complete response + partial response), overall survival, progression-free survival, leukemia-free survival, safety/tolerability, and pharmacokinetics. This trial is enrolling at approximately 40 global sites (NCT04485260).
- |||||||||| KRT-232 / Amgen, Kartos Therap, Calquence (acalabrutinib) / AstraZeneca
[VIRTUAL] A Phase 1b-2 Study of KRT-232, a First-in-Class, Oral, Small Molecule Inhibitor of Murine Double Minute 2 (MDM2), in Combination with Acalabrutinib for the Treatment of Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) or R/R Diffuse Large B-Cell Lymphoma (DLBCL) (Poster Hall (Virtual Meeting)) - Nov 5, 2020 - Abstract #ASH2020ASH_3822;
P1b/2
Secondary end points include ORR, duration of response, MRD (Cohort 2 only), PFS, OS, safety/tolerability, and pharmacokinetics. [NCT04502394].
- |||||||||| Xeljanz (tofacitinib) / Pfizer, Marche Polytechnic University
[VIRTUAL] Integration of Deep Multi-Omics Profiling Veals New Insights into the Biology of Poor-Risk Acute Myeloid Leukemia (Poster Hall (Virtual Meeting)) - Nov 5, 2020 - Abstract #ASH2020ASH_3691;
Comparisons of transcriptomics with the in vitro sensitivity to drugs included in early/late phase AML clinical trials, identified signatures of response associated with MDM2 and Aurora B kinase (AZD1152-HQPA) inhibitors...Functionally, group A presented with elevated HOXA10 protein expression and enhanced in vitro response to genotoxic drugs and cell cycle inhibitors when compared to group B leukemia. Conclusions : Our study demonstrates the feasibility of simultaneously generating omics data from several different platforms and highlights that a combination of genetic and proteomic profiles may help to inform the choice of therapies based on the underlying biology of a patient’s AML.
- |||||||||| KRT-232 / Amgen, Kartos Therap
[VIRTUAL] Co-Occurring Mutation Clusters Predict Drug Sensitivity in Acute Myeloid Leukemia (Poster Hall (Virtual Meeting)) - Nov 5, 2020 - Abstract #ASH2020ASH_1941;
Cells from patients with mutations in the RAS cluster exhibited sensitivity to MEK inhibitors (Fig 1B), while cells from patients with mutations in the TP53 cluster show resistance to many drugs, including the MDM2 inhibitor AMG232 (Fig 1C)...Patients with mutations in different groups of genes show different overall survival, while cells from patients with mutations in different co-mutation groups show different drug sensitivity. The co-mutation groups may not only reflect the clonal evolution history of AML, but also serve as important features for drug sensitivity prediction.
- |||||||||| Q-Force (quercetin) / Quercegen, Temple University
[VIRTUAL] Novel therapy to target pr-recurrent glioma () - Oct 24, 2020 - Abstract #SNO2020SNO_823;
Background: Glioblastoma is a fatal infiltrative primary brain tumor, and standard care includes maximal safe surgical resection followed by radiation and Temozolomide (TMZ)...We evaluated the IC50 for several senolytics targeting multiple SCAPs, including Dasatinib, Quercetin, AMG-232, Fisetin, Onalespib, Navitoclax, and A1331852, and in senescent vs. proliferating cells... These findings suggest the potential to harness radiation-induced biology to ablate surviving quiescent cells and demonstrate Bcl-XL dependency as a potential vulnerability of surviving tumor cells after exposure to chemoradiation.
- |||||||||| A-1331852 / AbbVie, KRT-232 / Amgen, Kartos Therap
[VIRTUAL] MDM2 inhibitor synergy with BCL-XL inhibition for p53 wild type glioblastoma () - Oct 24, 2020 - Abstract #SNO2020SNO_768;
We build upon that work, demonstrating the increased rates of cell death can be augmented by MDM2 inhibition, but only in p53-WT cells. These findings highlight a novel therapeutic target for treating latent GBM tumors prior to recurrence, with the additional of MDM2 inhibition greatly increasing the efficacy of BCL-XL targeting agents.
- |||||||||| Clinical, Review, Journal: Novel Concepts of Treatment for Patients with Myelofibrosis and Related Neoplasms. (Pubmed Central) - Oct 21, 2020
Janus kinase (JAK) inhibition forms the cornerstone of the treatment of myelofibrosis (MF), and the JAK inhibitor ruxolitinib is often used as a second-line agent in patients with polycythemia vera (PV) who fail hydroxyurea (HU)...JAK inhibitor-based combinations, all of which are currently under study for MF, have been covered elsewhere in this issue. In this article, we focus on agents that have been studied as monotherapy in patients with MF, generally after JAK inhibitor resistance/intolerance, as well as several novel compounds in development for PV/ET.
- |||||||||| Review, Journal: Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives. (Pubmed Central) - Sep 4, 2020
This review is intended to provide a comprehensive and updated overview of MDM2 inhibitors and proteolysis targeting chimera (PROTAC) degraders with a particular focus on how these inhibitors or degraders are identified from starting points, strategies employed, structure-activity relationship (SAR) studies, binding modes or co-crystal structures, biochemical data, mechanistic studies, and preclinical/clinical studies. Moreover, we briefly discuss the challenges of designing MDM2/X inhibitors for cancer therapy such as dual MDM2/X inhibition, acquired resistance and toxicity of P53 activation as well as future directions.
- |||||||||| navtemadlin (KRT-232) / Kartos Therap
Enrollment closed, Enrollment change, Trial completion date: KRT-232 Compared to Ruxolitinib in Patients With Phlebotomy-Dependent Polycythemia Vera (clinicaltrials.gov) - Aug 8, 2020
P2a/2b, N=20, Active, not recruiting,
Moreover, we briefly discuss the challenges of designing MDM2/X inhibitors for cancer therapy such as dual MDM2/X inhibition, acquired resistance and toxicity of P53 activation as well as future directions. Recruiting --> Active, not recruiting | N=322 --> 20 | Trial completion date: Oct 2023 --> Oct 2022
- |||||||||| 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) - Jul 15, 2020
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.
- |||||||||| [VIRTUAL] New Therapies in Development for Myelofibrosis () - Jul 14, 2020 - Abstract #SOHO2020SOHO_149;
P1/2, P1b,
Ruxolitinib blocks excessive proliferation of hematopoietic stem cells and pro-inflammatory cytokine production, which leads to improvement in quality-of-life and spleen volume, thus prolonging survival in MF patients.2 In late 2019, another oral JAK2 inhibitor, fedratinib, was approved for intermediate-2 and high-risk MF...Interim data from the trial demonstrated reduction in spleen volume, BM fibrosis, anemia and blood transfusions, as well as total symptom score improvement in MF patients who were JAK-inhibitor naive7 or had a suboptimal response to ruxolitinib.8 Notably, preclinical studies manifested synergistic lethal activity of combined HSP90 (a chaperone of JAK2) and BET inhibitors in ruxolitinib-resistant post-MPN AML cells,6 and combination treatment of MPN cells with the HSP90 inhibitor PU-H71 and ruxolitinib synergistically reduced p-JAK2 and inhibited the JAK/STAT pathway.9 On the basis of the aforementioned preclinical findings, a phase 1b study that is assessing the safety and efficacy of PU-H71 in ruxolitinib-treated patients with primary or secondary MF (NCT03935555) is underway...Hematological responses, reduction in spleen volume, and improvement of symptoms were noted, and PRM-151 was very well tolerated.11 Bcl-2/Bcl-xL inhibition Navitoclax is an orally bioavailable inhibitor of the anti-apoptotic Bcl-2 family of proteins (primarily Bcl-xL)...Conclusions Besides the agents highlighted herein, spanning new JAK inhibitors (momelotinib, pacritinib), epigenetic modifiers (CPI-0610), and inhibitors of telomerase (imetelstat), HSP90, and HDM2, other investigational drugs, such as LCL161, parsaclisib, and KRT-232 are currently evaluated in clinical trials (Table 1). After many years with ruxolitinib as the sole drug to treat MF, it is exciting to witness many promising novel drugs, based on various biological mechanisms, enter early and late phase clinical trials and usher the way to a new era in treatment of MF.
- |||||||||| Nutlin-3 / EMD Serono, KRT-232 / Amgen, Kartos Therap
Journal, PARP Biomarker: Iduna protects HT22 cells by inhibiting parthanatos: The role of the p53-MDM2 pathway. (Pubmed Central) - Jun 18, 2020
We also investigated 2 novel p53-MDM2 pathway inhibitors, AMG 232 and Nutlin-3, which substantially reduced the protective effects of Iduna. These findings indicate that Iduna might prevent TBI by specifically inhibiting parthanatos and promoting mitochondrial function, with the p53-MDM2 pathway playing a critical role.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, cisplatin / Generic mfg., KRT-232 / Amgen, Kartos Therap
Therapeutic value of BCL2 and MDM2-p53 axis in ovarian clear cell and endometrioid carcinomas with wild type TP53 (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_2309;
We tested the anti-proliferative and apoptotic activity of venetoclax (V) alone, AMG 232 alone (A), and a combination of V plus A in ovarian clear cell carcinoma (OVISE cells) and ovarian endometrioid carcinoma cell lines (A2780 & isogenic Cisplatin resistant A2780CisR). These data strongly support the further evaluation of dual BCL2/MDM2 targeting as a therapeutic strategy for ovarian clear cell and endometrioid carcinomas patients that retain WT-TP53.
- |||||||||| Afinitor (everolimus) / Novartis
Review, Journal: ER+ metastatic breast cancer: past, present, and a prescription for an apoptosis-targeted future. (Pubmed Central) - Jan 10, 2020
Similarly, an MDM2 inhibitor, AMG-232, which induces p53 is active in early clinical trials of both liquid and advanced solid tumor patients...We reviewed not only the FDA approved current treatment approaches but also presented a discourse addressing the possibilities for novel combination strategy that can induce tumor cell apoptosis, a critical cellular mechanism delaying/denying tumor progression. Our review is unique as it presents patient data in support of our hypothesis.
- |||||||||| KRT-232 / Amgen, Kartos Therap
Journal: Potent effect of the MDM2 inhibitor AMG232 on suppression of glioblastoma stem cells. (Pubmed Central) - Dec 6, 2019
Our data provide new evidence that glioblastoma stem cells have high susceptibility to AMG232 suggesting the potential clinical implications of MDM2 inhibition for glioblastoma treatment. These will facilitate additional preclinical and clinical studies evaluating MDM2 inhibitors in glioblastoma and direct further efforts towards developing better MDM2-targeted therapeutics.
- |||||||||| M7583 / EMD Serono, Telios Pharma
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) - Nov 15, 2019
P1/2, N=18, Active, not recruiting,
N=27 --> 40 Trial completion date: Jun 2020 --> Sep 2021 | Trial primary completion date: May 2019 --> Sep 2021
- |||||||||| Jakafi oral (ruxolitinib) / Novartis, Incyte, KRT-232 / Amgen, Kartos Therap
A Randomized, Open-Label, Multicenter, Phase 2 Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of KRT-232 Compared with Ruxolitinib in Patients with Phlebotomy-Dependent Polycythemia Vera (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5908;
P2a/2b
Phlebotomy and low-dose aspirin are the standard of care for initial treatment; hydroxyurea (HU) remains the myelosuppressive agent of choice, despite the increased potential for leukemic transformation, estimated at 10% after 13 years of exposure...KRT-232 has been investigated as monotherapy and in combination with trametinib or dabrafenib in phase I studies of AML and melanoma; the most common treatment-related adverse events (TRAEs) observed in these studies were nausea, diarrhea, vomiting, decreased appetite, anemia, leukopenia, thrombocytopenia, and fatigue...Exploratory endpoints include molecular and biomarker analysis including TP53 mutational status. This trial is enrolling at multiple sites in the United States and Europe (NCT03669965, EduraCT: 2018-001672-38).
- |||||||||| Jakafi oral (ruxolitinib) / Novartis, Incyte, KRT-232 / Amgen, Kartos Therap
An Open-Label, Phase 2 Study of KRT-232, a First-in-Class, Oral Small Molecule Inhibitor of MDM2, for the Treatment of Patients with Myelofibrosis (MF) Who Have Previously Received Treatment with a JAK Inhibitor (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_4132;
P2a/2b
Median overall survival in patients who discontinue ruxolitinib is 14-16 months, highlighting the need for novel therapies targeting alternative pathways in the setting of failure or intolerance of JAK inhibitor therapy (Newberry, Blood...KRT-232 has been investigated as monotherapy and in combination with trametinib or dabrafenib in phase I studies of AML and melanoma; the most common treatment-related adverse events (TRAEs) observed were nausea, diarrhea, vomiting, decreased appetite, anemia, leukopenia, thrombocytopenia, and fatigue...The primary endpoint of the study is to determine spleen response at week 24; secondary endpoints include improvement in MPN-SAF Total Symptom Score (weeks 24 and 48), red blood cell (RBC) transfusion independence, and rates of complete remission and partial remission (IWG-ERT and ELN) at week 24 . This trial is enrolling at multiple sites in the United States and Europe (NCT03662126, EudraCT: 2018-001671-21).
- |||||||||| Increasing extent of ablation - a senolytic approach to promote apoptosis of latent glioblastoma following chemoradiation. (Ballroom Lawn) - Oct 29, 2019 - Abstract #SNO2019SNO_1272;
Current therapies, including radiation and temozolomide, are known to induce senescence in tumor cells...Given existence of multiple SCAPs, we evaluated the IC50 for several senolytic candidates including Dasatinib, Quercetin, Fisetin, AMG-232, Onalespib, A1331852, and Navitoclax in radiated vs non-radiated cells... Our findings suggest that blocking the anti-apoptotic pathway Bcl-XL in GBM cells rendered at least transiently senescent following radiation may provide an avenue to selectively ablate residual glioblastoma cells following radiation. Our data provide proof of principle that senolytic therapy may represent a previously untapped window of opportunity to increase extent of tumor ablation following completion of standard cytotoxic therapies.
- |||||||||| Jakafi oral (ruxolitinib) / Novartis, Incyte
Identifying and Treating “Progression” in Myelofibrosis () - Sep 26, 2019 - Abstract #SOHO2019SOHO_257;
P2a/2b
KRT-232 is an oral MDM2 inhibitor that has also entered the clinic in this setting (NCT03662126)...Besides CPI-0610, these include the phosphatidylinositol-3-kinase delta isoform inhibitors parsaclisib20 and umbralisib,21 the BH3-mimetic navitoclax, the heat shock protein 90 antagonist PU-H71, etc. Table 3 lists three such trials, early results from which have been presented. Like ruxolitinib failure, there is also no uniformly accepted definition of sub-optimal response to ruxolitinib, and various criteria are in use.
- |||||||||| Dual targeting of BCL2 and MDM2 as a novel therapeutic strategy in ER+ breast cancer model (Hall 1) - Sep 25, 2019 - Abstract #SABCS2019SABCS_794;
We tested the anti-proliferative and apoptotic activity of venetoclax alone, AMG 232 alone, and a combination of venetoclax plus AMG 232 along with fulvestrant in ER+ BC breast cancer cells (MCF7, Zr-75-1, & MDA-MB415). Our data reveal the potential of simultaneously targeting these two apoptosis regulators and provides a rational basis for clinical testing of this therapeutic approach for ER+ BC breast cancer patients that retain WT-TP53.
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