We examined the transcriptome of UM biopsies collected pre- and post-PKC inhibitor therapy and confirmed that MAPK, but not PI3K/AKT signalling, was inhibited early during treatment with the second-generation PKC inhibitor IDE196...We also show that re-activation of MAPK signalling has a dominant role in regulating PKC inhibitor responses in UM and that PI3K/AKT signalling diminishes UM cell sensitivity to PKC inhibitor monotherapy. Thus, combination therapies targeting PKC and PKC-independent signalling nodes, including PI3K/AKT activity, are required to improve responses in patients with metastatic UM.

The lead series was optimized for kinase and off target selectivity to afford a compound that is rapidly absorbed and well tolerated in preclinical species. LXS196 is being investigated in the clinic as a monotherapy and in combination with other agents for the treatment of uveal melanoma (UM), including primary UM and metastatic uveal melanoma (MUM).

P2, N=15, Active, not recruiting, Anthony Joshua, FRACP | Recruiting --> Active, not recruiting | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2023 --> Nov 2024

Currently available therapeutic approaches for Mantle Cell Lymphoma (MCL), including the Bruton Tyrosine Kinase (BTK) inhibitors ibrutinib, acalabrutinib and zanubrutinib, are not curative...In MCL, BET inhibitors, such as INCB054329 or JQ-1, have been shown to increase apoptosis through downregulation of the AKT-mTOR, ERK, and other B Cell Receptor (BCR)-triggered cascades...The most effective and tested CSNK2 chemical inhibitor is CX4945 (silmitasertib), but very recently a novel compound, SGC-CK2, has been developed...Remarkably, CK2 inactivation led to a robust reduction of the BET inhibitor-induced increase of Mcl1, and NF-kB Ser 529 phosphorylation, thus counteracting BET-inhibitors-evoked compensatory pathways that could favor apoptosis resistance. Therefore, combined CSNK2 and BET proteins inhibition could represent an innovative strategy for chemotherapy and BTKi-resistant MCL.

Our investigation reveals that darovasertib potently inhibits PKC as well as PKN/PRK, an AGC kinase family that is part of the "dark kinome." We find that downstream of the Gαq-RhoA signaling axis, PKN converges with ROCK to control FAK, a mediator of non-canonical Gαq-driven signaling. Strikingly, darovasertib synergizes with FAK inhibitors to halt UM growth and promote cytotoxic cell death in vitro and in preclinical metastatic mouse models, thus exposing a signaling vulnerability that can be exploited as a multimodal precision therapy against mUM.

These genes are associated with regulating the tumor microenvironment, proliferation and differentiation of cancer cells and poor prognosis. The effect of kinase masking in downregulating these genes in bladder cancer indicates the benefits PRKC inhibitors may have in managing these patients.

P2/3, N=380, Recruiting, IDEAYA Biosciences | Not yet recruiting --> Recruiting

Compared to other PKC inhibitors, such as sotrastaurin and enzastaurin, darovasertib is significantly more potent in inhibiting conventional (α, β) and novel (δ, ϵ, η, θ) PKC proteins and has a better tolerability and safety profile. Current Phase I/II clinical trials indicated that darovasertib, combined with the Mitogen-activated protein kinase/Extracellular (MEK) inhibitors, binimetinib or crizotinib, produced a synergistic effect of uveal melanoma. In this article, we summarize the development of drugs for treating uveal melanomas and discuss problems associated with current treatments. We also discuss the mechanism of action, pharmacokinetic profile, adverse effects, and clinical trial for darovasertib, and future research directions for treating uveal melanoma.

P2/3, N=380, Not yet recruiting, IDEAYA Biosciences

Midostaurin is used in combination with chemotherapy to treat patients with newly diagnosed FLT3-mutated acute myeloid leukemia. Hematologic outcomes (complete remission and duration of severe neutropenia) and safety outcomes (midostaurin-related any grade or grade ≥3 AEs) were nonetheless similar for patients exposed to PCZ or micafungin, as was the number of breakthrough IFIs. In waiting for randomized phase III trials of new prophylaxis regimens, these findings show that PCZ should remain the antifungal of choice for the midostaurin-treated patient.

ctDNA was reduced in almost all pts. These data support the registrational phase II/III study for potential accelerated approval in 1L HLA-A2 neg. MUM, where there are no FDA approved therapies.

Total all-cause incremental monthly costs appeared to be highest with HIC ($171,982) and similar for LIC ($60,512), gilteritinib ($47,218), other FLT3 TKIs ($43,218), and venetoclax ($77,566). Results highlight HRU and cost differences for R/R AML during first salvage therapy.

Finally, drug sensitivity prediction illustrated that cells with high TBCB expression were more responsive to ATRA and midostaurin but resistant to cytarabine, dasatinib, and imatinib. In conclusion, our findings shed light on the feasibility of TBCB as a potential predictor of poor outcome and to be an alternative target of treatment in AML.

Midostaurin was the first FDA-approved FLT3 inhibitor in 2017 in the United States and Europe for AML remedy. Next, Gilteritinib was an FDA-approved FLT3 inhibitor in 2018 and in the next year, Quizartinib was approved an as FLT3 inhibitor in Japan...Furthermore, their chemotypes, mechanism of action, and interaction mode over both wild and mutated FLT3 target proteins had been judgmentally discussed. Therefore, this review could offer inspiring future perspectives into the finding of new FLT3-related AML therapies.

P1/2, N=278, Recruiting, IDEAYA Biosciences | Trial completion date: Jul 2024 --> May 2025 | Trial primary completion date: Dec 2023 --> Oct 2024

Regarding key strategies, experts usually prefer early treatment for persistent febrile neutropenia, switching to another broad-spectrum antifungal family if azole-resistant Aspergillus is suspected, broad-spectrum azoles and echinocandins as prophylactic treatment in patients receiving midostaurin or venetoclax, and liposomal amphotericin B for breakthrough IFIs after prophylaxis with echinocandins in patients receiving new targeted therapies. For antifungals failing to reach adequate levels during the first days and suspected invasive aspergillosis, the most appropriate strategy would be to associate an antifungal from another family.

Concurrent administration of sotrastaurin and binimetinib is feasible but associated with substantial gastrointestinal toxicity. Given the limited clinical activity achieved with this regimen, accrual to the phase II portion of the trial was not initiated.

Not available.

P2, N=181, Active, not recruiting, PrECOG, LLC. | Trial primary completion date: Nov 2022 --> Oct 2023

P2, N=82, Recruiting, IDEAYA Biosciences

Tyrosine kinase inhibitors (TKI) (midostaurin, avapritinib) have changed the treatment landscape in SM...Cladribine continues to have a role for MC debulking, whereas interferon-α has a diminishing role in the TKI era...Allogeneic stem cell transplant has a role in such patients. Imatinib has a therapeutic role only in the rare patient with an imatinib-sensitive KIT mutation.

Our study strongly suggests that SH3PXD2B is a carcinogenic molecule that can be used as a biomarker for GC detection, prognosis, treatment design, and follow-up.

P3, N=777, Active, not recruiting, Stichting Hemato-Oncologie voor Volwassenen Nederland | Recruiting --> Active, not recruiting

The combination therapy of FLT3 inhibitor midostaurin and intensive chemotherapy has improved the prognosis of patients with FLT3-ITD-positive AML, which has been considered a poor prognosis for a long period...Considering the treatment strategies with diverse therapeutic modalities, the pathogenesis and clonal selection process of refractory AML, including the surrounding environment of residual leukemia cells, should be clarified. The combination of new therapies and chemotherapies is highly expected to improve the prognosis of patients with AML in the near future.

We suggest that midostaurin therapy could be a predictor for 3 years OS (85.2% with vs. 54.8% without midostaurin, P = 0.04)...Patients with TP53 ± complex karyotype or inv(3) had a dismal prognosis (7.1 months median OS). We validate the prognostic utility of the 2022 ELN classification in a real-life setting providing supportive evidences to improve risk stratification guidelines.

Currently, two FLT3 inhibitors are approved for use in patients with acute myeloid leukemia: midostaurin in the frontline setting, in combination with intensive chemotherapy; and gilteritinib as monotherapy in the relapsed refractory setting. The addition of FLT3 inhibitors to hypomethylating agents and venetoclax offers superior responses in several completed and ongoing studies, with encouraging preliminary data...A protective environment within the bone marrow makes eradication of FLT3 leukemic cells difficult, while prior exposure to FLT3 inhibitors leads to the development of alternative FLT3 mutations as well as activating mutations in downstream signaling, promoting resistance to currently available therapies. Multiple novel therapeutic strategies are under investigation, including BCL-2, menin, and MERTK inhibitors, as well as FLT3-directed BiTEs and CAR-T therapy.

Based on our identified miRNA-regulated molecular machinery, an inhibitor of PDK1/Akt BX-912, an anthracycline antibiotic daunorubicin, and a multi-targeted protein kinase inhibitor midostaurin were discovered as potential repositioning drugs for treating lung cancer. These findings have implications for improving lung cancer diagnosis, optimizing treatment selection, and discovering new drug options for better patient outcomes.

Furthermore, we demonstrated that these combinations exert a remarkable in vivo activity in UM patient-derived xenografts. Our study confirms the previously described synergy of the dual inhibition of FAK and MEK and identifies a novel combination of drugs (FAK and PKC inhibitors) as a promising strategy for therapeutic intervention in metastatic UM.

Interestingly, the FLT3 inhibitor midostaurin increases FLT3 in the membrane and SET/FLT3 binding. Therefore, our results show that SET is involved in the transport of FLT3-WT to the membrane; however, SET barely binds FLT3 in FLT3-ITD cells, contributing to its retention in the ER.

Midostaurin – an oral, multitargeted tyrosine kinase inhibitor – is approved in several countries, including Europe, where it is indicated for adult patients with newly diagnosed FLT3 mutation-positive ( FLT3+ ) AML in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy, and for patients in complete response as single-agent during maintenance therapy. None, trial in progress. Acute myeloid leukemia, Clinical trial, Pediatric

NGS-based FLT3 -ITD MRD monitoring allows for the identification of pts at high risk of relapse and death. Combining mido with intensive chemotherapy MRD- at Cy2 and EOT was achieved in a high proportion of pts; at Cy2 MRD- was the strongest independent favorable prognostic factor for relapse risk and OS. Concurrent NPM1 mut correlated with deeper molecular responses and higher rates of MRD-. .

Twenty-six pts (63%) received intensive chemotherapy (IC), 5 of whom also received midostaurin; and 3 (7%) received hypomethylating agents (HMA). In our cohort, OLD pts who received IC had no statistically significant inferior OS. However, OLD were more frequently not eligible for IC, as expected. Despite the small simple size, HMA alone did not seem to be a good alternative, as seen before the approval of venetoclax.

However, 8 (35%) pts classified as FR by ELN2017 were re-classified as IR by ELN2022.Twenty-two pts (61%) received IC (4 of whom also received midostaurin), 2 (6%) received hypomethylating agents and the remaining received only palliative support or died before any therapeutics... In our cohort neither ELN2017 nor ELN2022 was better in predicting survival and did not establish significant survival differences between risk groups, probably due to the small sample size. An important number of patientsclassified as FR in ELN2017 were reclassified in higher risk strata with ELN2022. Therefore, the latter may impact therapeutic strategies in a subgroup of pts.

DDI of posaconazole and midostaurin are clinically meaningful. TDM may serve for decision-making when DDI with strong CYP3A4 inhibitors are suspected clinically and could help to individually adapt the doses of both medications to reduce toxicity.

In the FLT3i group, Midostaurin was administered in 86/92 (93.5%) patients, while 6/92 (6.5 %) patients received Sorafenib. this study confirmed the benefit of incorporating a FLT3i in the real-life upfront intensive treatment of ND FLT3-mut AML patients. The FLAM study was supported by Daiichi-Sankyo. #CP and #GM equally contributed.

Our study suggest that the concomitant administration of PCZ and midostaurin results effective and safe for FLT3- mut AML patients. A pharmacokinetic guided approach by measuring plasma levels of both midostaurin and PCZ, in particular for those patients experiencing toxicities, might could support haematologists towards a precision medicine.