- |||||||||| ASTX295 / Otsuka
ASTX295 a Novel Potent MDM2 Antagonist Induces More Than One Mechanism of Programmed Cell Death (PCD) in Lymphoid Malignancies (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_3881;
P1/2
Previous studies have shown in vitro activity in acute myeloid leukemia both alone and in combination with decitabine...Activity of ASTX295 was compared with AMG232 and Idasanutlin...ASTX295 in combination with the specific BCL2 inhibitor Venetoclax in the GRANTA519 cell line (CI value 0.2) and KARPAS384 (CI value 0.4) demonstrated strong synergy, despite as monotherapy resulting in <50% fall in viability...ASTX295 like other MDM2i showed synergy with BCL2i in DLBCL and MCL models. ASTX295 induced multiple forms of PCD; the precise form of non-caspase dependent PCD remains under investigation.
- |||||||||| navtemadlin (KRT-232) / Kartos Therap
Results from the Randomized, Multicenter, Global Phase 3 BOREAS Study: Navtemadlin Versus Best Available Therapy in JAK Inhibitor Relapsed/Refractory Myelofibrosis (Harbor Ballroom DEFG (Manchester Grand Hyatt San Diego)) - Nov 6, 2024 - Abstract #ASH2024ASH_2278;
P2/3, P3
Pts were randomized 2 : 1 to receive navtemadlin monotherapy 240 mg once-daily (Day 1-7/28-day cycle) or BAT (monotherapy or combinations : hydroxyurea, chemotherapy, IMiDs, and supportive care; JAKi were excluded)...Baseline characteristics were well balanced between the arms and included : int-1/int-2/high-risk MF per DIPSS (34%/50%/15%), median spleen volume of 2310 cm3, median TSS of 20.8, prior therapy range of 1-6 (99% had ruxolitinib [rux]), median time from initial MF diagnosis was 47.6 months, 34% of pts had platelets <100x109/L, 48% had a bone marrow fibrosis of grade 3, 70% had the JAK2V617F driver mutation, and 77% had ?1 high molecular risk mutation (?2 in 23%)...The rate of SVR35 and TSS50 at Week 24 was three-fold and two-fold higher with navtemadlin vs BAT, validating the novel approach of MDM2 inhibition in pts with MF. Further studies of navtemadlin in MF are warranted, including as add-on therapy to rux treatment in JAKi-naive pts who have a suboptimal response to rux (POIESIS; NCT06479135).
- |||||||||| MODULE 4: Future Directions in the Management of MF (Manchester Grand Hyatt San Diego, Seaport Ballroom EFGH; In-Person; Virtual) - Oct 5, 2024 - Abstract #ASH2024ASH_130;
Biomarkers of disease modification and associated clinical correlations will be further explored with navtemadlin as add-on therapy to ruxolitinib treatment in JAKi-na 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-na
- |||||||||| Nutlin-3 / EMD Serono, navtemadlin (KRT-232) / Kartos Therap
Anticancer effects and mechanisms of herbs used in traditional Chinese medicine on human lung carcinoma and hepatoma cells (Exhibit Halls AB - George R. Brown Convention Center) - Oct 4, 2024 - Abstract #SITC2024SITC_705;
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.Download figure Open in new tab Download powerpoint Abstract 701 Figure 1
- |||||||||| navtemadlin (KRT-232) / Kartos Therap
Functional genomic approaches to understand mechanisms of drug response and resistance (Alsh) - Sep 24, 2024 - Abstract #EANO2024EANO_52;
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.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, navtemadlin (KRT-232) / Kartos Therap
Enrollment closed, Combination therapy: Testing a New Chemotherapy Drug, KRT-232 (AMG-232) in Combination With Decitabine and Venetoclax in Patients With Acute Myeloid Leukemia (clinicaltrials.gov) - Sep 4, 2024
P1, N=58, Active, not recruiting,
These preclinical in vivo data provide a rationale for further clinical development of this combinatorial targeted therapy approach. Suspended --> Active, not recruiting
- |||||||||| Bavencio (avelumab) / EMD Serono, navtemadlin (KRT-232) / Kartos Therap
Cutaneous Merkel cell carcinoma (MCC): updates from AAD Annual Congress 2024. (Poster Area) - Aug 5, 2024 - Abstract #EADV2024EADV_2909;
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.**
- |||||||||| navtemadlin (KRT-232) / Kartos Therap
Trial completion date, Trial termination, Trial primary completion date, Combination therapy: Testing the Addition of KRT-232 (AMG 232) to Usual Chemotherapy for Relapsed Multiple Myeloma (clinicaltrials.gov) - Aug 1, 2024
P1, N=35, Terminated,
However, further studies are necessary to characterize better refractory MCCs and to develop alternative treatment strategies for their care.** Trial completion date: Dec 2024 --> Jul 2024 | Recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Jul 2024; Inadequate accrual rate
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, navtemadlin (KRT-232) / Kartos Therap
Trial completion date, Trial primary completion date, Combination therapy: Testing a New Chemotherapy Drug, KRT-232 (AMG-232) in Combination With Decitabine and Venetoclax in Patients With Acute Myeloid Leukemia (clinicaltrials.gov) - Jun 27, 2024
P1, N=58, Recruiting,
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. Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Jun 2025 --> Jun 2026
- |||||||||| navtemadlin (KRT-232) / Kartos Therap
Phase classification, Trial completion date, Trial termination, Combination therapy: 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) - Mar 22, 2024
P1/2, N=70, Terminated,
In vivo studies showed lower intra-tumoral nvtm levels are required to significantly inhibit growth of MDM2amplified compared with non-amplified tumors. 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.
- |||||||||| navtemadlin (KRT-232) / Kartos Therap
Phase classification, Enrollment change, Trial completion date, Trial withdrawal, Trial primary completion date, Metastases: Study of Navtemadlin Plus Pembrolizumab as Maintenance Therapy in Locally Advanced and Metastatic Non-Small Cell Lung Cancer (clinicaltrials.gov) - Mar 22, 2024
P1/2, N=0, Withdrawn,
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. 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
- |||||||||| navtemadlin (KRT-232) / Kartos Therap
Trial completion date, Trial primary completion date: NRG-DT001: Navtemadlin and Radiation Therapy in Treating Patients With Soft Tissue Sarcoma (clinicaltrials.gov) - Mar 3, 2024
P1, N=38, Active, not recruiting,
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 Trial completion date: Dec 2023 --> Feb 2025 | Trial primary completion date: Dec 2023 --> Aug 2023
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, navtemadlin (KRT-232) / Kartos Therap
Phase classification, Trial completion date, Trial primary completion date, Combination therapy: Testing a New Chemotherapy Drug, KRT-232 (AMG-232) in Combination With Decitabine and Venetoclax in Patients With Acute Myeloid Leukemia (clinicaltrials.gov) - Jan 5, 2024
P1, N=58, Recruiting,
Phase classification: P1b --> P1 Phase classification: P1b --> P1 | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 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 3, 2024
P1, N=40, Recruiting,
Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024 Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024
- |||||||||| navtemadlin (KRT-232) / Kartos Therap, M7583 / EMD Serono, Telios Pharma
TL-895, a Highly Selective, Covalent Inhibitor of Bruton (SDCC - Halls G-H) - Nov 3, 2023 - Abstract #ASH2023ASH_5967;
P1/2, P2
Our results indicate that BTKi therapy might increase susceptibility of MPN-BP SC to MDM2i therapy, by upregulating p53 activity and dampening NF-?B signaling, and also by disrupting protective TME interactions that sustain MPN-BP SC. This novel combination merits further clinical investigation in advanced phase MPN.
- |||||||||| navtemadlin (KRT-232) / Kartos Therap
Trial completion date, Trial primary completion date, Combination therapy: Testing the Addition of an Anti-cancer Drug, Navtemadlin, to the Usual Treatments (Cytarabine and Idarubicin) in Patients With Acute Myeloid Leukemia (clinicaltrials.gov) - Oct 16, 2023
P1b, N=24, Active, not recruiting,
Importantly, this combination blocked stromal cell-mediated (contact and soluble factors) cytoprotection. Trial completion date: Jul 2023 --> Jun 2024 | Trial primary completion date: Jul 2023 --> Jun 2024
- |||||||||| navtemadlin (KRT-232) / Kartos Therap
Enrollment change, Trial completion date, Trial termination, Trial primary completion date: KRT-232 in Subjects With Relapsed or Refractory Small Cell Lung Cancer (clinicaltrials.gov) - Aug 16, 2023
P2, N=3, Terminated,
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.
- |||||||||| MODULE 3: Future Directions in the Management of MF (LEVEL 3, MEAL THEATER 1; Virtual) - Aug 11, 2023 - Abstract #SOHO2023SOHO_338;
This activity is supported through independent medical education grants from Bristol Myers Squibb, CTI Biopharma Corp, and GlaxoSmithKline. Mechanism of antitumor activity of navitoclax and biological rationale for its evaluation in patients with MF, Published research with navitoclax alone and in combination with ruxolitinib for MF; ongoing Phase III studies, Rationale for the inhibition of BET proteins in patients with MF; mechanisms of action of pelabresib and BMS-986158, Early clinical trial findings and ongoing research with BET inhibitors as monotherapy and in combination with JAK2 inhibitors for MF, Mechanism of action of, available data with and ongoing evaluation of luspatercept as monotherapy or combined with a JAK2 inhibitor for patients with MF and anemia; current role, if any, Published activity and safety data with and ongoing investigation of other novel agents and strategies (eg, bomedemstat, zilurgisertib, selinexor, navtemadlin) in MF,
- |||||||||| navtemadlin (KRT-232) / Kartos Therap
Enrollment open, Metastases: Study of Navtemadlin as Maintenance Therapy in TP53WT Advanced or Recurrent Endometrial Cancer (clinicaltrials.gov) - Aug 7, 2023
P2/3, N=268, Recruiting,
Mechanism of antitumor activity of navitoclax and biological rationale for its evaluation in patients with MF, Published research with navitoclax alone and in combination with ruxolitinib for MF; ongoing Phase III studies, Rationale for the inhibition of BET proteins in patients with MF; mechanisms of action of pelabresib and BMS-986158, Early clinical trial findings and ongoing research with BET inhibitors as monotherapy and in combination with JAK2 inhibitors for MF, Mechanism of action of, available data with and ongoing evaluation of luspatercept as monotherapy or combined with a JAK2 inhibitor for patients with MF and anemia; current role, if any, Published activity and safety data with and ongoing investigation of other novel agents and strategies (eg, bomedemstat, zilurgisertib, selinexor, navtemadlin) in MF, Not yet recruiting --> Recruiting
- |||||||||| Review, Journal: MDM2 Inhibition in the Treatment of Glioblastoma: From Concept to Clinical Investigation. (Pubmed Central) - Jul 29, 2023
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.
- |||||||||| M7583 / EMD Serono, Telios Pharma
Enrollment closed, 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) - Jul 13, 2023
P1/2, N=130, Active, not recruiting,
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. Recruiting --> Active, not recruiting
- |||||||||| navtemadlin (KRT-232) / Kartos Therap
Preclinical, Journal: Single-cell molecular profiling using ex vivo functional readouts fuels precision oncology in glioblastoma. (Pubmed Central) - May 16, 2023
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.
- |||||||||| navtemadlin (KRT-232) / Kartos Therap, Calquence (acalabrutinib) / AstraZeneca
A PHASE 1B/2 STUDY OF NAVTEMADLIN COMBINED WITH ACALABRUTINIB IN BTK INHIBITOR NA (Poster area) - May 12, 2023 - Abstract #EHA2023EHA_2239;
P1b/2
Myelofibrosis, Ruxolitinib, TP53, Apoptosis Nvtm combined with acala has an acceptable safety profile with no DLTs in dose escalation and showedencouraging preliminary activity in BTKi-na
- |||||||||| Jakafi (ruxolitinib) / Novartis, Incyte, navtemadlin (KRT-232) / Kartos Therap
ADDING NAVTEMADLIN (NVTM) TO RUXOLITINIB (RUX) POTENTIATES APOPTOSIS IN MYELOBLASTS FROM PATIENTS (PTS) WITH MYELOFIBROSIS (MF) (Poster area) - May 12, 2023 - Abstract #EHA2023EHA_1261;
The combination leverages complementary mechanisms converging on apoptotic cell death by inhibiting transient p21-mediated cell-cycle arrest, Mcl-1 and Bcl-xL protein expression. Our data show how rux can synergize with nvtm to hasten apoptosis and reduce tumor escape, which may offer improved clinical benefit for rux treated MF pts with suboptimal response.
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