Nailike (olverembatinib)

P=N/A, N=112, Recruiting, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital; The First Affiliated Hospital of Nanjing Medical University, J

P2, N=50, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China

Overall, our findings indicate the prevalence and impact of new ABL1 KD mutations in BCR::ABL1-positive ALL patients, highlighting the necessity for effective therapies targetingthese mutations.

Currently, ponatinib is the only approved tyrosine kinase inhibitor (TKI) that is effective for Ph-positive ALL with the T315I mutation...is a retrospective observational study, it offers prospects for the efficacy of chemotherapy combined with the novel third-generation TKI, olverembatinib, in these conditions, which may be validated in future prospective clinical trials...Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19804.

P3, N=40, Not yet recruiting, Ascentage Pharma Group Inc.

The safety profile was generally manageable. This study suggests that olverembatinib-based therapy is another promising option for BCR::ABL1-positive ALL in addition to ponatinib, especially for patients with MRD-positive disease and a single T315I mutation.

P=N/A, N=82, Recruiting, Institute of Hematology & Blood Diseases Hospital, China | Not yet recruiting --> Recruiting

P=N/A, N=31, Not yet recruiting, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

Coadministration with rifampin decreased these same variables by 61.27%, 74.21%, and 75.19%, respectively. These results confirm that olverembatinib is primarily metabolized by CYP3A4 in humans, suggesting that caution should be exercised with concurrent use of olverembatinib and strong CYP3A4 inhibitors or inducers.

P1, N=30, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

Four tyrosine kinase inhibitors (TKIs), imatinib, dasatinib, bosutinib, and nilotinib, are approved by the United States Food and Drug Administration (FDA) for first-line treatment of newly diagnosed CML in the chronic phase (CML-CP)...Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs except ponatinib, asciminib, and olverembatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP and failure (due to resistance) of at least two TKIs and for all patients in advanced-phase disease. Older patients who have a cytogenetic relapse post-failure on all TKIs can maintain long-term survival if they continue a daily most effective/least toxic TKI, with or without the addition of non-TKI anti-CML agents (hydroxyurea, omacetaxine, azacitidine, decitabine, cytarabine, and others).

P3, N=285, Recruiting, Ascentage Pharma Group Inc. | Not yet recruiting --> Recruiting

The third-generation TKI olverembatinib has been proven to be effective in CML patients with the T315I mutation, and it may also be effective in Ph+ acute lymphoblastic leukemia. Some new immune drugs have also shown improvement in the remission rate. Combination therapy with olverembatinib and Ino can achieve a complete molecular response in patients with relapsed and refractory Ph+ ALL with the T315I mutation.

P=N/A, N=82, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China

P=N/A, N=30, Not yet recruiting, Peking University People's Hospital | Trial completion date: Dec 2026 --> Dec 2027 | Trial primary completion date: Dec 2025 --> Dec 2026

P3, N=285, Not yet recruiting, Ascentage Pharma Group Inc.

P1, N=30, Not yet recruiting, M.D. Anderson Cancer Center

P=N/A, N=30, Not yet recruiting, Peking University People's Hospital

P1, N=100, Recruiting, Ascentage Pharma Group Inc. | N=60 --> 100

P2, N=67, Recruiting, Nanfang Hospital, Southern Medical University

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.

Figure 1. HRQOL profile

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.

Recently, such pts have new hope with the wide application of a novel third-generation TKI Olverembatinib developed in China and Blinatumomab（CD19 antibody,BITE）and INOTUZUMAB OZOGAMICIN(CD22 antibody,Ino. For heavily treated RR ABL1+B ALL pts,including those after treatment with ponatinib and other TKICART and HSCT, Olverembatinib combined with monoclonal antibodies is effective and safe. In my cases, it is particularly noteworthy that one pts ,Ph like ALL with ABL1 FG, received Olverembatinib combination BITE and achieved a surprising response, so Olverembatinib may also be effective and safe for such pts. In addition, venetoclax may be used as a sensitizer for TKI or other antitumor drugs.

The Olverembatinib involving regimen included: Olverembatinib and Venetoclax in combination with VP based low intensive chemotherapy (Vindesine /Prednisone), Olverembatinib+Blinatumomab, Olverembatinib + INO. ConclusionThis work suggests that Olverembatinib showed a profound response rate and was well tolerated in MRD clearance prior to allo-HSCT in Ph+ALL with disease recurrence and persistently MRD positive. Larger prospective studies are needed.

Common nonhematologic adverse events included hepatotoxicity, nephrotoxicity, myalgia, arthralgia, rash, and edema, of which most were mild. Conclusion Olverembatinib-based therapies are generally well tolerated and efficacious for patients with Ph/BCR-ABL1-positive acute lymphoblastic leukemia.

A similar pattern was also observed when olverembatinib was combined with doxorubicin. ConclusionsOlverembatinib, a novel, third-generation TKI, in combination with chemotherapeutic agents vincristine or doxorubicin decreased MCL-1, BCL-2, and BCL-xL and increased BAX and PUMA in a dose-dependent manner, the combinations have demonstrated synergistic antitumor effects by enhancing apoptosis and antiproliferation in Ph⁺ ALL cells, which may provide an alternative approach for treatment of patients with Ph⁺ ALL.

As for the 23-year-old female pt with CML-LBP, dasatinib was switched to olverembatinib when T315I, E255K, and E255V mutations were detected...At present, the patient maintained in CR, and blinatumomab will be used for MRD clearance before allo-HSCT...In addition, bridging allo-HSCT after deeper molecular remission could further improve survival. The safety profiles were manageable, but there is still a need to explore the optimal dose in elderly pts.

Here, we present 6 patients with CD19-positive MPAL that are successfully treated with blinatumomab in combination with venetoclax and/or azacytidine in front line setting...The patient with BCR: : ABL1 received blinatumomab in combination with olverembatinib. Intrathecal (IT) chemotherapy with cytarabine and methotrexate was administered to central nervous system (CNS) as prophylaxis treatment... The results provide preliminary evidence of effective and safe treatment with blinatumomab and venetoclax combination as first-line therapy in MPAL resulting in the achievement of normal bone marrow function with less toxicity than using conventional chemotherapy.

P1, N=62, Recruiting, Ascentage Pharma Group Inc. | Trial primary completion date: Jan 2023 --> Jan 2024

17 (30.4%) patients were pretreated with third-generation TKI (ponatinib). As of the data cutoff date, 37 (66.1%) patients continued on treatment and 19(33.9%) discontinued because of disease progression, intolerance, loss to follow-up or death. Conclusion Olverembatinib-based therapy showed strong efficacy and tolerable toxicity in advanced Ph+ leukemia.

Background: In patients (pts) with CML, the BCR::ABL1 T315I gatekeeper mutation confers treatment resistance to all approved ATP-competitive tyrosine kinase inhibitors (TKIs) except ponatinib and olverembatinib; thus pts harboring this mutation have limited treatment options. Asciminib demonstrated effectiveness in pts with CML and the T315I mutation in routine medical practice, including ponatinib pre-treated pts, a population with limited available treatment options. Effectiveness estimates were consistent with those observed in clinical trials. Although the number of pts was small, this global study reports on one of the largest cohorts of pts with CML and the T315I mutation.

Purposes Study safety and efficacy of olverembatinib or ponatinib and azacitidine (AZA) in this setting. KRAS and TP53 mutations and PFKFB3::LINC02649 fusions had predictive impact on outcomes. Determining whether adding azacitidine to a 3rd-generation TKI requires a randomized controlled trial.

The upfront use of third generation TKI ponatinib has improved the frequency of complete molecular response (CMR) and the overall survival rate to a greater extent...They received three cycles of OVP regimen(for 28 days each cycle :olverembatinib 40mg qod d1-28,Vindesine 4mg d1,8,15,22,Prednisone1mg/Kg/d d1-21,0.5mg/kg/dd22-28). Twelve intrathecal injections of cytarabine alternating with methotrexate were designed as central nervous system prophylaxis in the following therapy after the diagnosis...The trial is ongoing. we need more time to observe.

Furthermore, through analyzing patients who received TKI treatment, we observed that 3G TKIs like olverembatinib exhibited advantages in prognosis, including achieving deep molecular response, rapid remission reduction, and decreased relapse probability, for both newly diagnosed and relapsed Ph+ ALL patients...The promising outcomes observed with 3G TKIs suggest their potential as a treatment option for both newly diagnosed and relapsed Ph+ ALL patients, offering advantages in terms of molecular response depth, rapid remission, and reduced relapse risk. Further investigations are warranted to explore the clinical significance of unreported ABL1 KD mutations and validate the effectiveness of 3G TKIs against them.

There were 22 CML-CP and 23 CML-AP patients previous received 3rd Gen TKIs (ponatinib or HQP1351) or asciminib. Clinical activity of TGRX-678 was seen in all cohorts and across TKI-resistant mutations including T315I, providing a promising treatment option for CML CP/AP patients, including those who failed ponatinib or asciminib. Its unique PK properties might bring additional benefit to patients. TGRX-678 was well tolerated in heavily pretreated CML patients.

Introduction This was a multicenter, randomized, registrational phase 2 study to assess the efficacy and safety of olverembatinib compared with BAT in pts with CML-CP who were resistant and/or intolerant to 3 TKIs (imatinib [I], dasatinib [D], nilotinib [N]) in China...Pts were randomized 2:1 to investigational olverembatinib (40 mg QOD) or the BAT arm, which could be one of the following per investigator choice: TKIs (I, D, or N), interferon (IFN), hydroxyurea (HU), and homoharringtonine (HHT)...Olverembatinib was observed to be better tolerated and more effective than BAT in treating these pts. Internal study (CT.gov) numbers: HQP1351CC203 (NCT04126681).

Pts were treated with a combination of venetoclax (100 mg d1, 200 mg d2, 400 mg d3-28), olverembatinib 40 mg once every continuously other day, vincristine 1.4 mg/m2 (maximum dose 2 mg) on day 1, 8, 15, 22, and prednisone 60 mg/m2 on day 1-14; 40 mg/m2 on day 15-28 in cycle 1...Routine triple intrathecal injection (methotrexate 10 mg, cytarabine 50 mg, and dexamethasone 10 mg) was performed to prevent central nervous system involvement...Conclusion The combination of olverembatinib and venetoclax with reduced-intensity chemotherapy is a safe and effective regimen in patients with newly diagnosed Ph+ ALL. The regimen results in high rates of CMR in the absence of intensive chemotherapy or immunotherapy.

Prophylactic oral levofloxacin and posaconazole were administered from day 8 through whole myelosuppression period of every cycles. MVHO therapy was effective and reasonably well tolerated in pediatric patients with refractory or relapsed AML, suggesting that it may comprise a suitable first-line treatment option for pediatric AML patients.

In the combination cohort, pts with Ph+ B-cell precursor (BCP) ALL or lymphoid CML-BP (CML-LBP) resistant to at least 1 TKI were enrolled and received olverembatinib (30 or 40 mg) QOD in combination with blinatumomab. Internal study identifier: HQP1351-CU101. Clinicaltrials.gov identifier: NCT04260022.

Background The combination of dasatinib and blinatumomab represented a chemotherapy-free treatment approach, which had been employed in the management of newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). A recent study demonstrated that combination therapy of ponatinib with blinatumomab may achieve better efficacy, with a complete molecular response (CMR) rate of 87%...However, further clinical trials are needed to definitively establish the efficacy of this treatment approach and validate the potential benefits. This research was supported by the National Natural Science Foundation of China(NFSC82170163, 81970147), Clinical Study of Nanfang Hospital(LC2016ZD009/2019CR012).

P1, N=60, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Mar 2024 --> Dec 2026 | Trial primary completion date: Sep 2023 --> Dec 2024