Hansoh Xinfu (flumatinib)

P1, N=100, Not yet recruiting, Jiangsu Hansoh Pharmaceutical Co., Ltd.

This cell line exhibited cross-resistance to imatinib and doxorubicin, but remained sensitive to the antiparasitic agent ivermectin, which possesses antitumoural effects. Collectively, the increased autophagy, higher expression of drug-efflux proteins and hyperactivation of the EGFR/ERK/STAT3 signalling pathway were identified as pivotal elements promoting resistance to flumatinib. The significant effects of ivermectin might offer a novel therapeutic strategy to overcome flumatinib resistance and optimize the treatment outcomes of CML.

The patient achieved clinical remission after treatment with imatinib. ETV6::ABL1 positive myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) is rare and may be misdiagnosed by conventional cytogenetical analysis. Early treatment with TKIs, particularly second-generation TKIs, may be beneficial to improve treatment results.

As far as we know, we for the first time reported a case of Ph+ ALL and EGFR mutant LUAD synchronous overlap, of which pathogenesis is related to abnormal tyrosine kinase activation. This patient was successfully treated with two different TKIs without serious adverse events.

Besides, he did not achieve a complete remission for the first two chemotherapies, until he received flumatinib combined with hyper-CVAD (B) (a dose-intensive regimen include methotrexate and cytarabine). To our knowledge, this is the first report to describe the coexistence of BMN and atypical e13a2 BCR-ABL1 transcripts in patients with MPAL. This finding will bring new understandings in the diagnosis and treatment of Ph+ MPAL.

P2, N=20, Completed, The First Affiliated Hospital of Soochow University | Recruiting --> Completed | Trial completion date: Jun 2025 --> Apr 2024 | Trial primary completion date: Jun 2023 --> Apr 2024

These findings suggest that flumatinib is a safe and effective tyrosine kinase inhibitor (TKI) for achieving CMR and MRD negativity in patients with Ph+ ALL, as supported by this small series of patients.

Prior therapies included imatinib, dasatinib, nilotinib, olverembatinib, radotinib and ponatinib. Of the 58 patients, only Grade 1 AEs were reported, including diarrhea, rash and eye edema. Conclusion Flumatinib has good efficacy and safety in the treatment of adult patients with resistant or intolerant Chronic-Phase Chronic Myeloid Leukemia, it will be a good choice for second-line or above treatment for CML-CP In clinical practice.

Mechanistically, with its structure of trifluoromethyl and pyridine flumatinib blocked BCR-ABL1 kinase autophosphorylation with much more potent activity than did imatinib and even showed higher efficacy than nilotinib against wild-type BCR-ABL1 kinase. The real-world data demonstrated that as a first-line treatment setting, flumatinib can bring patients with chronic phase CML higher rates of responses, and faster and deeper responses, indicating that flumatinib could be an alternative effective first-line treatment for CML-CP. The adverse events of flumatinib, such as cardiovascular events, abnormal liver function, and diarrhea, need to be given continuous concern in future studies.

This retrospective study had suggested promising effects of flumatinib, which showed induced high rates of CCyR and MMR or DMR in patients resistant or intolerant to imatinib. The incidence of AEs during flumatinib treatment was tolerable.

It has shown better efficacy compared to imatinib in clinical trials of CML, but few reports are available in ALL...Once the diagnosis is confirmed, the combination of flumatinib (600mg/day) and VIP-based chemotherapy regimen (Vincristine/Idarubicin/Prednisone) is given promptly...Blinatumomab is allowed to administer for MRD clearance before allo-HSCT...Achieving MRD flow negativity or CMR at 3 months and bridging allo-HSCT could further improve survival. The long-term follow-up data will be disclosed soon.

Moreover, about 80% of Ph +B-ALL patients have the IKZF1 deletion, our ChIP-seq data showed that IKZF1-encoded Ikaros protein binds to the promoter region of PTPN11 and CK2 inhibitor CX4945 as Ikaros function activator dramatically increase the Ikaros binding to the promoter of PTPN11 in B-ALL cells and Ikaros directly suppresses its promoter activity (Fig. Conclusions The combination of AZA and FLU has a synergistic anti-leukemia effect on cell proliferation arrest and apoptosis in Ph +ALL cells with IKZF1-deletion by targeting Ikaros/PTPN11/Ras oncogenic signaling. Our data provide experimental evidence for a new potential combination of AZA with FLU in the therapy of Ph +ALL and highlight the likelihood of the novel combination in ALL patients.

The 15 R/R patients (11, Ph + ALL; 4, CML-BP) received olverembatinib 30 or 40 mg on alternate days combined with VP (vindesine 4 mg once per week for 4 weeks and prednisone 1 mg/kg for 3 weeks and tapered at the fourth)...Among the 16 patients with molecular resistance to TKI-based chemotherapy (imatinib [n = 4]; dasatinib [n = 9]; flumatinib [n = 3]), 2 received olverembatinib monotherapy, 7 olverembatinib plus VP, and 7 hyper-CVAD, of whom 8 received subsequent allogeneic transplantation...Treatment-related nonhematologic severe adverse events were observed in 3 patients, including (each) stable angina pectoris, severe pneumonia, and fatal Klebsiella sepsis. Conclusions Olverembatinib-based chemotherapy is effective and safe in patients with R/R and molecular resistant Ph + ALL or CML-LBP.

In addition, if the patients were switched to flumatinib earlier, the optimal response was achieved faster. The grade 3/4 AEs were mainly hematologically related, whereas the gastrointestinal events were mostly of grade 1-2.

Flumatinib has better molecular response and tolerance in patients with primary, imatinib/dasatinib-intolerant or resistant CML. Medium-risk/high-risk in ELTS score and time to recovery from discontinuation due to haematological toxicity ≥1 month are important factors influencing achievement of better molecular response in flumatinib treatment.

P=N/A, N=200, Recruiting, Wuhan Union Hospital, China | Trial primary completion date: Dec 2022 --> Dec 2023

Flumatinib combined with chemotherapy could achieve good efficacy and safety in treating Ph+ ALL, with flumatinib in a high probability of crossing the blood-brain barrier. Flumatinib could be a superior choice to Dasatinib and Imatinib in cell experiments.

As the validated agent for the treatment of chronic myelogenous leukemia (CML), flumatinib is a novel oral tyrosine kinase inhibitor (TKI) with higher potency and selectivity for BCR-ABL1 kinase compared to imatinib...Moreover, ketoconazole, posaconazole, and isavuconazole showed more potent inhibitory effects than itraconazole, fluconazole, and voriconazole on HLM-mediated flumatinib metabolism...According to the results of in vitro and in vivo studies, the metabolism of flumatinib was inhibited by isavuconazole, suggesting that isavuconazole may raise the plasma concentration of flumatinib. Thus, it is important to take special care of the interactions between flumatinib and isavuconazole in clinical applications.

The mortality of apoptotic cells was examined by double staining with Annexin V-FITC and 7-Amino-Actinomycin D (7-AAD). The combination of AZA and FLU has a synergistic anti-leukemia effect on cell proliferation arrest and apoptosis in Ph+ALL cells. Our data provide experimental evidence for a new potential combination of AZA with FLU in the therapy of Ph+ALL and highlight the likelihood of further in vivo pre-clinical study for the potential clinical trial ofthe novel combination in ALL patients. Azacitidine, Apoptosis, Ph+ ALL, Cell cycle

At present, imatinib, nilotinib, dasatinib and flumatinib are mainly used in China. This real-world study evaluated the clinical characteristics and efficacy of different TKI drugs in the treatment of newly diagnosed CML-CP patients in China. In the first-line treatment, nilotinib is easier to achieve CCyR, 3-month EMR, 6-month ≤ 1% ,12-month MMR, MR 4 than generic imatinib. Nilotinib is easier to achieve MR4 than original imatinib.

Administration of the VAF regimen was as follows: venetoclax,100 mg d1, 200 mg d2,400 mg d3-21, orally; azacitidine ,75 mg/m2, d1-7, subcutaneously; flumatinib , 600 mg once daily continuously from d4. Once patients reached CMR after two cycles of VAF induction, they received one cycle of high-dose cytarabine based-regime consolidation and proceed to allo-HSCT if eligible... VAF is a highly effective and safe strategy to achieve early and deep molecular responsein patients with ND Ph+AL in the frontline setting, providing a potential Day ward/Out-patient treatment strategy for Ph+AL. Philadelphia chromosome, Azacitidine, Venetoclax, Acute lymphoblastic leukemia

It has shown better efficacy compared to imatinib in clinical trials of CML, but few reports are available in ALL...Once the diagnosis is confirmed, combination of flumatinib (600mg/day) and VIP-based chemotherapy regimen (Vincristine/Idarubicin/Prednisone) is administered promptly... The combination of the novel second-generation TKI flumatinib and chemotherapy is quite effective and safe in newly-diagnosed Chinese adult pts with Ph/BCR-ABL1+ ALL. This clinical trial is still ongoing, and the long-term follow-up data will be further investigated. Acute lymphoblastic leukemia, Tyrosine kinase inhibitor, BCR::ABL

In conclusion, flumatinib exhibits high efficacy and high early molecular response rate in patients newly diagnosed with CML-CP. The majority of patients obtained MMR within three months, and the adverse reactions experienced were mild and tolerable.

However, both dasatinib and nilotinib have a unique set of mutants with reduced sensitivity...There is no study that reported the efficacy of flumatinib against F359V/C mutation.We report two cases of chronic myelocytic leukemia(CML) patients with F359V/C mutation resistance to Imatinib therapy...Flumatinib may be a better choice for patients with F359V/C mutation. The online version contains supplementary material available at 10.1007/s12288-022-01585-3.

Analysis of PK parameters indicated that flumatinib exposure increased in an approximately dose-proportional manner. Further research needs to be conducted in a large sample-size study.

Later, he was given Dashatinib combined with Venetoclax, Ponatinib combined with Venetoclax,Blinatumomab, chemotherapy, CD19-CART, CD22-CART, and the disease didn't control...After chemotherapy with imatinib, the BM reached immunologic remission, and the quantitative fusion gene was continuously positive. During the period, TKI was adjusted to dasatinib and nilotinib, and the treatment was not continued due to intolerance...Flumatinib combined with chemotherapy and olverembatinib combined with chemotherapy were ineffective...After admission to our hospital, azacytidine was given in combination with VP, Venetoclax and olverembatinib... Adult relapses are difficult to treat Ph+ALL, and the chemotherapy effect is very poor, especially in elderly patients, and the tolerance to chemotherapy is also very poor. Immune targeted therapy brings new hope. The combination of Ino.

P2, N=20, Recruiting, The First Affiliated Hospital of Soochow University | N=30 --> 20

It has been demonstrated better efficacy compared to imatinib in clinical trials of CML, but few reports are available in ALL...Once the diagnosis is confirmed, combination of flumatinib (600mg/day) and VIP-based chemotherapy regimen (Vincristine/Idarubicin/Prednisone) is administered promptly...Central nervous system (CNS) prophylaxis is regularly performed by intrathecal injection of methotrexate, cytarabine, and dexamethasone after remission induction course...Conclusion The combination of the second-generation TKI flumatinib and chemotherapy is quite effective and safe in Chinese adult pts with newly diagnosed Ph/BCR-ABL1+ ALL. This clinical trial is still ongoing, and the long-term follow-up data will be further investigated.

Chidamide (CHI), a novel HDACi, is reported to be effective in hematological malignancies. Conclusions The combination of CHI with FLU has a synergistic anti-leukemia effect on cell proliferation arrest and apoptosis in Ph+ALL cells by targeting PI3K/AKT signaling through the p53/c-MYC axis. Our data provide experimental evidence for a new potential combination of CHI with FLU in the therapy of Ph+ALL, and the in vivo preclinical studies will further highlight the future clinical trial of the combination in clinic therapy of ALL.

P2, N=30, Recruiting, The First Affiliated Hospital of Soochow University

Conclusion Both single drugs of flumatinib and ABT-199 are sensitive to SUP-B15 human Ph+ B-cell ALL cells. The combination of flumatinib with ABT-199 has a synergistic effect on cell proliferation arrest and apoptosis of the cells, revealing the potential of the novel combination for therapy of Ph+ B-cell ALL.

P4, N=2400, Not yet recruiting, Jiangsu Hansoh Pharmaceutical Co., Ltd.

P4, N=200, Recruiting, Jiangsu Hansoh Pharmaceutical Co., Ltd.

P=N/A, N=200, Recruiting, Nanfang Hospital of Southern Medical University | Trial primary completion date: Jan 2022 --> Jan 2024

No abstract available

P4, N=200, Recruiting, Shenzhen Second People's Hospital | Not yet recruiting --> Recruiting

P, N=200, Recruiting, Wuhan Union Hospital, China

P4, N=200, Not yet recruiting, Shenzhen Second People's Hospital

P=N/A, N=200, Recruiting, Nanfang Hospital of Southern Medical University | Trial primary completion date: Dec 2022 --> Jan 2022

Patients receiving flumatinib achieved significantly higher rates of responses, faster and deeper responses compared with those receiving imatinib, indicating that flumatinib can be an effective first-line treatment for CML-CP. This trial was registered at www.clinicaltrials.gov as NCT02204644.