P1, N=8, Completed, Inhibikase Therapeutics, Inc.

P1, N=6, Completed, Inhibikase Therapeutics, Inc.

P2, N=120, Active, not recruiting, Inhibikase Therapeutics, Inc. | Trial primary completion date: Jun 2024 --> Sep 2024

P2, N=513, Terminated, Sun Pharma Advanced Research Company Limited | Trial completion date: Mar 2024 --> Jun 2024 | Active, not recruiting --> Terminated; Terminated based on study outcomes

P2, N=120, Active, not recruiting, Inhibikase Therapeutics, Inc. | Recruiting --> Active, not recruiting

Asciminib and VK2 are suggested as a novel treatment for ABL-TKI-resistant cells since they increase treatment efficacy. Additionally, this treatment option has intriguing clinical relevance for patients who are resistant to ABL TKIs.

This pharmacovigilance study serves as a clinical reminder to physicians to be more vigilant for fluid retention-associated AEs with BCR::ABL inhibitors.

Biological studies showed that compared with Imatinib, these compounds showed significant proliferation inhibitory activities of HL-60 and K562 in cell activity assay...Compounds 4g and 4j, as potential BCR-ABL1 inhibitors, inhibit the phosphorylation of ABL1 and CRKL in a dose-dependent manner. Therefore, compounds 4g and 4j can be used as a starting point for further optimization.

Co-treatment of four BP-CML cell lines with the TKIs nilotinib or ponatinib and either BCL-2 (venetoclax), MCL-1 (S63845) or BCL-xL (A-1331852) inhibitors resulted in a synergistic reduction in cell viability and increase in phosphatidylserine (PS) presentation. Gene expression and protein level analysis suggests a protective upregulation of alternative BCL-2 prosurvival proteins in response to BH3 mimetic single-treatment in BP-CML. Our results suggest that BH3 mimetics represent an interesting avenue for further exploration in myeloid BP-CML, for which alternative treatment options are desperately sought.

Hepatic or renal impairment does not have a clinically significant impact on the PK of asciminib. Hence, dose adaptations for patients with hepatic or renal impairment are not warranted. Overall, asciminib has a manageable DDI risk at all recommended doses.

Asciminib has an excellent selectivity profile, is several-fold more potent than current approved TKIs such as nilotinib, and in vitro was active in the low nanomolar range against a spectrum of clinically observed ATP site mutations. Asciminib demonstrated efficacy in phase I studies in resistant/intolerant chronic and accelerated phase CML, including T315I mutation positive and ponatinib pretreated patients. In a phase III trial, asciminib was more active than bosutinib in a phase III trial in patients who had received 2 prior TKIs Our primary objective in this study is to determine the 1-year TFR rate after 12 months of combination therapy with imatinib plus asciminib, followed by treatment cessation, in subjects who have previously had molecular recurrence first TFR attempt...This design yields a type I error rate of 5% and power of 85% when the true TFR rate is 65%. To account for a potential dropout rate of 8% due to adverse events or loss of response, 51 patients will be enrolled to achieve the 47 patients needed.

34% had previously received ponatinib. Asciminib is a molecule with a good safety profile, with a lower rate of AEs compared to classical TKIs. However, this drug, despite its novel mechanism of action presents risk of cross-intolerance with classical TKIs for some toxicities, including hematologic toxicity, fatigue, vomiting and pancreatitis.

The treatment regimens consisted of Venetoclax in combination with either chemotherapy (Venetoclax 600mg/d with low dose Cytarabine 20mg/m2 D1-10 and/or Actinomycin D 12.5mcg/kg D1-3), or hypomethylating (HMA) agents (Venetoclax 400mg/d with Decitabine 20mg/m2 D1-5/D1-10 or Azacitidine 75mg/m2 D1-7)...Patients with targetable mutations (FLT3, N(K)RAS, BCR-ABL1) received concomitant FLT3-inhibitors, Trametinib or BCR-ABL1-inhibitors... Venetoclax based regimens produce high remission rates in both ND and R/R AML or MDS-EB2 in the real-life setting. Poor performance status, TP53 and PTPN11 mutations negatively impact OS, whereas DNMT3A, IDH2 mutations and bridging to alloSCT are associated with improved OS.

We found that the effects of ABL1 inhibitors, including imatinib, dasatinib, ponatinib, and ABL001, on growth inhibition and promoting apoptosis of Ba/F3 cells with BCR::ABL1 mutants, especially compound mutants, were weakened. GMB-475 combined with TKIs, especially dasatinib, synergistically inhibited growth, promoted apoptosis, and blocked the cell cycle of Ba/F3 cells carrying BCR::ABL1 mutants and synergistically blocked multiple molecules in the JAK-STAT pathway. In conclusion, dasatinib enhanced the antitumor effect of GMB-475; that is, the combination of PROTAC targeting ABL1 in an allosteric manner and orthosteric TKIs, especially dasatinib, provides a novel idea for the treatment of CML patients with BCR::ABL1 mutants in clinical practice.

We also identified the RET kinase pathway, targeted by AST-487, as a novel regulator of mutant hTERT promoter-driven transcription in bladder cancer cells. Collectively, our work provides new potential precision medicine approaches for cancer patients with upregulated hTERT expression, perhaps, especially those harboring mutations in both the RET gene and the hTERT promoter, such as in thyroid cancer.

Findings from this Japanese subgroup analysis of the ASCEMBL study support the use of asciminib for the treatment of Japanese patients with CML-CP previously treated with ≥2 TKIs. ClinicalTrials.gov Identifier: NCT03106779.

The combination of ruxolitinib plus blinatumomab or inotuzumab is a promising chemotherapyfree salvage regimen given outpatient for relapsed Ph-like ALL. It achieved CR in our patient prior to allo SCT with a limited side effect profi le. Further clinical trials adding ruxolitinib to front-line and next-line therapies are needed.

The final PopPK model adequately characterized the PK properties of asciminib and assessed the impact of key covariates on its exposure. The model corroborates the use of the approved asciminib dose of 80 mg total daily dose as 40 mg twice daily, and supports the use of 80 mg once daily as an alternative dose regimen to facilitate patient's compliance. TRIAL REGISTRATION NUMBER [DATE OF REGISTRATION]: First-in-human (CABL001X2101, Phase 1), ClinicalTrials.gov identifier: NCT02081378 [28 February 2014]; ASCEMBL (CABL001A2301, Phase 3), ClinicalTrials.gov identifier: NCT03106779 [10 April 2017].

P1/2 | " TAS0953/HM06 was more effective than RET multi-kinase inhibitors (cabozantinib, RXDX105, vandetanib), and equipotent to selpercatinib and pralsetinib, at inhibiting growth of patient-derived (8) and isogenic (2) cell lines harboring different RET fusions (IC50<0.1µM)... Our data show that TAS0953/HM06 is effective at inhibiting growth in vitro and in vivo of preclinical models driven by RET fusions. TAS0953/HM06 was more effective than selpercatinib at decreasing CNS disease and extending survival, at a dose that produced comparable suppression of tumor growth in extracranial disease models. TAS0953/HM06 represents a promising new therapeutic option for patients with RET fusions including those with brain metastasis and those resistant to first-generation selective RET inhibitors."

However, it is unclear exactly where asciminib will be positioned amongst the other available tyrosine kinase inhibitors (TKIs), especially ponatinib which is also available for the same indications. In this review, we discuss the available data on asciminib while exploring a number of clinical trials in progress. Finally, we provide our opinion based on the current data about where asciminib is most likely to be the optimal choice, which will hopefully assist clinicians with therapy selection.

Aims To test palbociclib and ponatinib, along with reference drugs – venetoclax, azacitidine, cytarabine+doxorubicine (chemotherapy) on 2 primary AML samples in a patient-derived xenograft model. Effect of ponatinib was only limited. This encourages further investigation of treatment efficacy in different AML subtypes and in combination with other drugs.

Advanced practitioners play a critical role in CML patient management that extends to the recognition and management of TKI-associated side effects. They should be cognizant of the potential for TKI-associated cardiotoxicities along with appropriate baseline risk assessments, active surveillance, and mitigation strategies as part of a collaborative team effort with cardio-oncologists.

No abstract available

The treatments were generally well tolerated, and the asciminib safety profile was consistent with previous studies of asciminib in the absence of probe substrates. Overall, the results indicate that asciminib (40 mg b.i.d.) is a weak inhibitor of CYP3A and CYP2C9 and has no meaningful effect on CYP2C8.

We found that the dual PI3 kinase (PI3K) and mTOR inhibitor BEZ235 and the selective pan-PI3K inhibitor copanlisib suppress proliferation of primary osteoblasts (BEZ235 IC: 0.05 μM; copanlisib IC: 0.05 μM), the osteoblast cell line CAL-72 (BEZ235 IC: 0.5 μM; copanlisib IC: 1 μM), primary umbilical vein-derived endothelial cells (BEZ235 IC: 0.5 μM; copanlisib IC: 0.5 μM), and the vascular endothelial cell line HMEC-1 (BEZ235 IC: 1 μM; copanlisib IC: 1 μM), whereas no comparable effects were seen with the mTOR inhibitor rapamycin. Furthermore, we show that BEZ235 and copanlisib cooperate with nilotinib and ponatinib in suppressing proliferation and survival of osteoblasts and endothelial cells...Together, targeting osteoblastic niche cells through PI3K inhibition may be a new effective approach to overcome niche-induced TKI resistance in CML. Whether this approach can be translated into clinical application and can counteract drug resistance of LSC in patients with CML remains to be determined in clinical trials.

Our results suggest that primitive CML leukemic cells are not dependent on BCL2 for their persistence and support that committed CML and Ph + ALL cells are dependent by BCL2 and BCR-ABL1 cooperation for their survival. The antileukemic activity of BCL2 and BCR-ABL1 dual targeting may be a useful therapeutic strategy for Ph+ ALL patients.

Chemotherapy (cytarabine+doxorubicine, AraC/Dox) 5+3 regimen served as a positive control...Interestingly, azacitidine induced the longest remission (<1% hCD45+ cells in PB), for almost 10 weeks, but only in 2/4 mice for AML#2... Significant reduction of disease burden and prolongation of overall survival (OS) were seen with palbociclib and the reference treatment venetoclax in both AMLs, and with chemotherapy in AML#1 (Fig. 1). Ponatinib prolonged OS in AML#1 but failed to provide reduction of disease burden in PB.

Moreover, pts with CML harboring the T315I mutation have limited treatment options as they are resistant to all approved TKIs except for ponatinib...In the phase III ASCEMBL trial in pts with CML in chronic phase (CP) after prior treatment with ≥2 ATP-competitive TKIs, asciminib showed superior efficacy vs bosutinib: major molecular response (MMR; BCR-ABL1 on the International Scale ≤0.1%) rate at week 24 was 25.5% vs 13.2%, respectively... The AIM4CML study is currently enrolling pts across multiple sites in the United States, with an anticipated enrollment of approximately 115 heavily pretreated pts with CML-CP. Asciminib has the potential to transform the standard of care in this pt population through its novel mechanism of action as a BCR-ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP). This study is sponsored by Novartis.

Intensive chemotherapy was administered in 80% (40/50) of whom 38% (15/40) had primary refractory disease and 48% (19/40) had previously received Fludarabine + Cytarabine + Idarubicin (FLAG-Ida) or Cytarabine + Mitoxantrone (HAM)...Additional FLT3/RAS/BCR-ABL1 inhibitors Gilteritinib, Trametinib or Dasatinib were administered in 12% (6/50)...Day 30 and Day 60 mortality rates were 8% (4/50) and 16% (8/50), respectively. Conclusions ACTIVE was effective and well tolerated in this unselected prognostically unfavourable older R/R AML patient population.

We found that the dual PI3 kinase (PI3K) and mTOR inhibitor BEZ235 and the selective pan-PI3K inhibitor copanlisib suppress proliferation of primary osteoblasts (BEZ235 IC 50 : 0.05 µM; copanlisib IC 50 : 0.05 µM), the osteoblastic cell line CAL-72 (BEZ235 IC 50 : 0.5 µM; copanlisib IC 50 : 1 µM), primary human umbilical vein endothelial cells (BEZ235 IC 50 : 0.5 µM; copanlisib IC 50 : 0.5 µM) and the endothelial cell line HMEC-1 (BEZ235 IC 50 : 1 µM; copanlisib IC 50 : 1 µM), whereas no comparable effects were seen with the mTOR inhibitor rapamycin...Furthermore, BEZ235 and copanlisib were found to overcome osteoblast-induced resistance of K562, KU812 cells, and primary CD34 + /CD38 − CML LSC against nilotinib and ponatinib...Of all other drugs tested, only the BRD4-targeting drug JQ1 was found to suppress CAL72-induced resistance in the CML cell lines KU812 and K562, suggesting that osteoblast-induced resistance of CML cells is also mediated by a BRD4-MYC pathway...In conclusion, our data show that osteoblast-induced resistance of CML stem cells is mediated by a PI3K-dependent pathway and BRD4/MYC, and that BRD4-inhibition or BRD4-degradation counteracts osteoblast-induced resistance of CML (stem) cells against BCR-ABL1 inhibitors and PD-L1 expression on CML LSC and osteoblasts. We hypothesize that checkpoint inhibition may assist in drug-induced eradication of CML LSC and thus in the development of curative drug therapies in Ph + CML.

Resistant/intolerant CML-CP after 2 lines of TKI treatment remains BCR-ABL1 dependent. The novel STAMP inhibitor asciminib demonstrates continued superior efficacy and a limited adverse event profile; myelosuppression, while more prominent, appears to be early and disease related. Secondary resistance based on loss of MMR is rare.

The final model was adapted using allometric scaling to inform dose selection for pediatric development. Clinicaltrials.

The patient was induced with I3A7 and midostaurin, with no response. Being, reinduced with MEC in association with sorafenib. Still refractory to second-line treatment, he underwent induction with Ida-Flag and started dasatinib, with a complete response on D26 and was referred to allogeneic transplant using dasatinib. Discussion The appearance of BCR-ABL1 as a secondary abnormality and the result of a Possible clonal evolution in relapsing/refractory AML has been sporadically reported in post-chemotherapy treatment and in post-therapy with FLT3 inhibitory agents. Few studies demonstrate the concomitant detection of genetic abnormalities at the time of diagnosis. In one of them, the FLT3 mutation identified was of the TKD type, unlike the aforementioned patient, in another there was an association of the NPM1 mutation, not investigated in the patient reported. Patients with BCR-ABL1-associated AML are usually refractory to conventional chemotherapy, and tyrosine kinase (ITK) inhibitor therapy alone does not seem to control the disease. In this case, with only 0.02482% of transcripts, the result was considered false positive and the patient was treated for the FLT3 mutation. After the result of karyotype and demonstrated refractoriness, ITK was associated with the treatment with excellent response. The optimal treatment for these cases is not yet established, however, recent reports suggest that the low rate of complete remission induction and the short survival of AML BCR-ABL1 cases implied better Results with chemotherapy combined with ITK followed by allogeneic transplantation, so far the only effective way to improve the survival of these patients. Ponatinib appears to be a potent ITK with pan BCR-ABL1 inhibitory activity and strong FLT3 inhibitory activity. For the case reported, with the two mutations present at baseline, the use of ponatinib in conjunction with conventional therapy, followed by allogeneic transplantation seemed an appropriate alternative. of the FLT3 and BCR-ABL mutations in the beginning of the pathology and clinical trials that promote therapeutic alternatives.