Crenolanib (a PDGFR inhibitor) inhibited AOFB-01 cell proliferation...Therefore, PDGF-A produced by microvascular proliferations and tumor cells may promote the proliferation of PDGFR-α-expressing tumor cells in canine HGOG. PDGFR-α signaling has potential as a therapeutic target.

P1, N=50, Recruiting, Etnova Therapeutics Corp.

P2, N=14, Completed, Arog Pharmaceuticals, Inc. | N=20 --> 14

P2, N=150, Recruiting, Kyowa Kirin, Inc. | Not yet recruiting --> Recruiting

P2, N=180, Recruiting, Kyowa Kirin, Inc. | Not yet recruiting --> Recruiting

Crenolanib plus intensive chemotherapy in adults with newly diagnosed FLT3-mutant AML results in high rate of deep responses and long-term survival with acceptable toxicity. A randomized trial of crenolanib versus midostaurin plus chemotherapy in younger patients is ongoing.

P2, N=30, Completed, Arog Pharmaceuticals, Inc. | Active, not recruiting --> Completed | N=48 --> 30

FLT3 tyrosine kinase inhibitors (e. g. , Crenolanib) have the potential to enforce surface expression of FLT3 by impairing its intracellular recycling, thus enhancing CAR-T mediated killing, but their use may be limited by overlapping toxicities on healthy hematopoiesis, in particular in the post-HSCT setting...In conclusion, we believe that epitope edited HSPCs may not only enable safe and effective CAR-T immunotherapies for AML, but also allow their combination with pharmacological blockade of leukemia survival/proliferative pathways to achieve synthetic lethality mechanisms, while still avoiding dose-limiting toxicities. Further exploration of immunotherapy-synergistic combinations will be fundamental to improve the outcomes of difficult-to-treat high-risk AML patients.

To evaluate the effect of FLT3 inhibitors in ALL, we treated ex vivo primary leukemic cells of 6 adult ALL patients (FLT3 mut n=4; FLT3 wt n=2) with increasing concentrations of Gilteritinib, Midostaurin, Crenolanib, Sorafenib and Quizartibin for 24, 48 and 72h. AIRC IG 2019 (Project Code: 23810). Figure 1.

P2, N=150, Not yet recruiting, Kyowa Kirin, Inc.

P2, N=180, Not yet recruiting, Kyowa Kirin, Inc.

We demonstrated that the addition of the PDGFR inhibitor, crenolanib, to TTFields further reduced cell growth in comparison to either treatment alone. Collectively, our data suggest the efficacy of TTFields in vitro and identify common signaling responses to TTFields in TMZ-sensitive and -resistant populations, which may support more personalized medicine approaches.

VEGFR-mediated signaling would be an alternative signaling pathway for the survival of OSCC cells under the disruption of EGFR signaling. These results highlight the clinical application of VEGFR inhibitors in the development of multi-molecular-targeted therapeutics against OSCC.

Our prediction and validation results indicated that the combination of the RTK inhibitors Lapatinib and Pazopanib exhibited a strong therapeutic effect in breast cancer by blocking the downstream PI3K/AKT/mTOR signaling pathway. Furthermore, we incorporated molecular features to identify potential biomarkers for synergistic drug pairs, and almost all potential biomarkers found connections between drug targets and corresponding molecular features using protein-protein interaction network. Overall, this study provides valuable insights to complement and guide rational efforts to develop drug combination treatments.

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.

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.

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.

Not available.

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

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.

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.

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.

"GeneCentric Therapeutics...announced today the initiation of its Alamance study, a multi-center bladder cancer study conducted in collaboration with investigators at Memorial Sloan Kettering Cancer Center and the University of Wisconsin – Madison Carbone Cancer Center....In this prospectively designed real-world evidence study, clinical response data and existing tumor samples are being collected from a multi-center cohort of approximately 250 patients with locally advanced or metastatic urothelial (bladder) cancer treated with FGFR-targeted therapy (e.g., erdafitinib) or other standards of care (e.g., anti-PD-(L)1 or platinum-based chemotherapy)."

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.

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

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.