dubermatinib (TP-0903)

Thus, TP-0903 and ZEB1 knockdown sensitised TNBC cells to ART, likely via different pathways. Synergistic interactions between TP-0903 and ART indicate that combination approaches involving these compounds can have therapeutic prospects for TNBC treatment.

P1, N=177, Completed, Sumitomo Pharma America, Inc. | Phase classification: P1a --> P1

We also found that AXL-STAT3 inhibition can impede the recruitment of TAMs in a xenograft mouse model, thereby suppressing tumor growth. These findings suggest the potential application of AXL-STAT3-related markers to quantitatively assess metastatic potential and inform therapeutic strategies in lung cancer.

When we treated high and low PNP expressing CLL B-cells from untreated patients with drugs known to be active in CLL, interestingly we found high PNP expressing CLL B-cells are sensitive to Bcl2 inhibitor venetoclax and AXL kinase inhibitor TP-0903 versus low PNP expressing CLL B-cells...However treatment of CLL B-cells from untreated patients cultured alone or co-cultured with BMSCs with TYMS inhibitor raltitrexed did not show any killing indicating an alternate role of TYMS in BMSC cultured CLL B-cells...In conclusion, these results indicate that active purine and pyrimidine metabolism in CLL B-cells augmented by the BM environment can support CLL B-cell survival and drug resistance and possible induction of EMT components. Future studies are underway to understand the role and regulation of PNP and TYMS in CLL disease progression and drug resistance for both untreated and treated CLL patients.

Although the 1 st stage in the Ph2 portion of the trial was terminated early after treating only 11 patients with 25 mg TP-0903 + dec, the trial still achieved 3 of the 4 required CR responses needed to move onto the 2 nd stage. Additionally, 3 other patients in this group achieved responses of CRh (1) and CRi (2). This combination regimen is encouraging, considering the high risk and poor outcome of patients with TP53 m and/or CK AML.

We assessed the activity of AXL inhibitor TP-0903 in reducing tumor growth... Targeting TBK1 enhances the efficacy of AXL-targeted therapy in aggressive breast cancer by suppressing the paracrine effect of CCR5/CCL5 axis. This combination represents a novel and effective therapy modulating the TME of aggressive breast cancer, which warrants further investigation in the clinical setting.

P1b/2, N=3, Completed, Uma Borate | Recruiting --> Completed | N=80 --> 3

P1a, N=177, Completed, Sumitomo Pharma Oncology, Inc. | Active, not recruiting --> Completed | Trial completion date: Dec 2022 --> Jun 2022 | Trial primary completion date: Dec 2022 --> Jun 2022

The combination of TP-0903 and decitabine was additive in vitro, and in vivo significantly prolonged median survival compared to single-agent treatments in mice xenografted with HL-60 (vehicle, 46 days; decitabine, 55 days; TP-0903, 63 days; combination, 75 days) or MV4-11 (R248W) (51 days; 62 days; 81 days; 89 days) (p < 0.001). Together, these results provide scientific premise for the clinical evaluation of TP-0903 in combination with decitabine in TP53 mutant AML.

Initial results with DL1 suggest that TP-0903/dec shows preliminary clinical activity in the prognostically poor TP53m/complex karyotype AML sub-group, with 4 pts achieving MRD negative status out of 6 patients who achieved a CR/CRh/CRi (66%). After further patients were treated on DL1, the toxicity profile and correlative data supported the de-escalation to DL-1 as the RP2D. The Ph2 study is ongoing to determine the clinical activity of this new RP2D (DL-1).

P1b/2, N=80, Recruiting, Uma Borate | N=46 --> 80

P1a, N=177, Active, not recruiting, Sumitomo Dainippon Pharma Oncology, Inc | Trial completion date: Dec 2021 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Dec 2022

Next therapy (n=9) consisted of Richter transformation treatment (n=2), chemotherapy plus continued I+V (n=1), anti-CD20 plus continued I+V (n=1), duvelisib + I (n=1), TP-0903 + I (n=1), reIntroduction of I at disease progression after previously stopping I during I+V therapy (n=1), and reIntroduction of I (n=1) or V (n=1) at disease progression after previously stopping I+V...Eight pts required additional treatment, consisting of PI3K inhibitor (n=2), anti-CD20 added to I+V (n=1), CAR-T (n=1), anti-CD20 with (n=1) or without (n=1) bendamustine added to continued I, and Richter transformation treatment (n=2)...In the double-refractory setting, repurposing both drugs as combination I+V therapy can be a useful strategy, despite the short-term disease control, for pts where clinical trial options are limited or not available. Further examination of these approaches in larger cohorts and understanding the operative resistance mechanisms in pts with double-refractory disease are key next studies.

To determine the effect of targeting TBK1 and AXL pathways in vivo, we injected control or TBK1 KO murine 4T1.2 TNBC cells into BALB/c mice and assessed the efficacy of the AXL inhibitor TP-0903 in reducing the tumor growth... Targeting TBK1 could enhance the sensitivity of aggressive breast cancer cells to AXL-targeted therapy in vitro and in vivo . Our preliminary TME data suggest that combined AXL and TBK1 inhibition enhances the anti-tumor immune environment by upregulating secretion of CXCL16 by tumor cells, resulting in the increased recruitment of cytotoxic CD8 + T cells. In future studies, we will further elucidate the role that CXCL16 upregulation plays in this novel synergy.

Recombinant human Gas6 protein and inhibitor TP-0903 were used to activate and inhibit the Gas6/Axl signaling pathway, respectively...Activity of Gas6/Axl signaling pathway was shown to be positively associated with cell proliferation by Cell Counting Kit 8 and clone formation assays. In conclusion, the Gas6/Axl signaling pathway was revealed to promote the proliferation, migration and invasion and inhibit the apoptosis of lung adenocarcinoma cells, which serve important roles in the progression of lung adenocarcinoma.

Finally, we discovered that bevacizumab and TP-0903 inactivated the Smad 2/3 signaling pathway in TGF-β1-exposed SW480 and HCT116 cells. Therefore, we suggest that treatment of bevacizumab and TP-0903 inhibits TGF-β1-induced EMT of colon cancer cells through inactivation of the Smad 2/3 signaling pathway.

Patients were given lapatinib and T for 18 weeks (Luminal-HER2+ patients were additionally given hormonotherapy). On our preclinical models, we showed that combination of TP-0903 and T abrogate tumor growth in acquired resistant models to T in PDXs. We postulate AXL as a promising new therapeutic strategy to overcome resistance to antiHER2 therapies

P1a, N=177, Active, not recruiting, Sumitomo Dainippon Pharma Oncology, Inc | Trial completion date: Dec 2020 --> Dec 2021 | Trial primary completion date: Dec 2020 --> Dec 2021

We also showed that TP-0903 had ex vivo activity in primary AML cells with recurrent mutations including MLL-PTD, ASXL1, SRSF2, and WT1, which are associated with poor prognosis or promote clinical resistance to AML-directed therapies. Our preclinical studies demonstrate that TP-0903 is a multikinase inhibitor with potent activity against multiple drug-resistant models of AML that will have an immediate clinical impact in a heterogeneous disease like AML.

P1b/2, N=46, Recruiting, Bhavana Bhatnagar | Not yet recruiting --> Recruiting

In summary, Axl-RTK inhibition with TP-0903 demonstrates a direct suppression of inhibitory monocytes, which in turn enhances CART cell function. Our findings support the strategy of further refining and testing the novel and potent combination of Axl-RTK inhibition and CART cell therapy for the treatment of B cell malignancies.

P1b/2, N=46, Not yet recruiting, Bhavana Bhatnagar | Initiation date: Sep 2020 --> Dec 2020

Patient-derived organoids (PDO) obtained from tumors with high AXL and JAK1 were sensitive to TP-0903 and ruxolitinib (JAK inhibitor) treatments, supporting the CyTOF findings. Patient-derived organoids (PDOs) obtained from tumors with high AXL and JAK1 were sensitive to TP-0903 and ruxolitinib (JAK inhibitor) treatments supporting the CyTOF findings. This study shows that single-cell proteomic profiling of treatment-naïve lung tumors, coupled with ex vivo testing of PDOs, identifies continuous AXL, TGF-β and JAK1-STAT3 signal activation in select tumors that may be targeted by combined AXL-JAK1 inhibition.

Metformin is an anti-diabetic drug known to have anticancer activity by inhibiting mechanistic target of rapamycin (mTOR); however, other molecular mechanisms may also be involved...Furthermore, metformin augmented the suppressive effects of a small-molecule AXL inhibitor TP-0903 on the growth of OCI/AML3 and K562 cells and prevented doxorubicin-induced AXL activation in K562 cells, which induces chemoresistance in leukemia cells, thus potentiating doxorubicin anti-proliferative effects. Given that metformin also downregulated expression of TYRO3 and phosphorylation of MERTK, these findings indicate that anti-leukemic effects exerted by metformin could be partly due to the inhibition of TAM kinases. Thus, metformin has a clinical potential for patients with leukemia cells positive for AXL and the other TAM proteins as well as activated mTOR.

Clinical activity included 4 PRs: 2 NSCLC (1 pt 37mg/m2 dubermatinib+TKI, 1 pt 50mg dubermatinib+nivolumab), 1 melanoma pt. Funding: Tolero Pharmaceuticals, Inc. Clinical trial identification: NCT02729298 JAPIC ID: JapicCTI-194793.

P1a, N=177, Active, not recruiting, Sumitomo Dainippon Pharma Oncology, Inc | Recruiting --> Active, not recruiting | Trial completion date: Sep 2020 --> Dec 2020 | Trial primary completion date: Apr 2020 --> Dec 2020

AXL plays a role in EMT, treatment resistance, and metastasis in MBM, resulting in poor survival. Our findings suggest TP-0903 is effective in reducing cell migration, inhibit metastasis, and can be a potential therapeutic option in MBM. Research Funding: City of Hope Young Investigator Award

P1/2, N=3, Active, not recruiting, Tolero Pharmaceuticals, Inc. | Recruiting --> Active, not recruiting | N=108 --> 3 | Trial completion date: Apr 2021 --> Jun 2020 | Trial primary completion date: Jan 2021 --> Jun 2020

AXL was downregulated by siRNA and a selective tyrosine kinase (TK) AXL inhibitor (TP-0903). Our results suggest: 1) RCLs were more proliferative and showed mesenchymal-like enriched phenotype; 2) AXL-HER2 dimer was identified as a potential mechanism of secondary resistance to Trastuzumab; 3) genetic and pharmacological AXL inhibition restored sensitivity to Trastuzumab in in vitro models; 4) AXL expression was associated with worse prognosis in our HER2+ trastuzumab-treated BC patients and validated in silico . These results showed AXL as a prognostic factor and a potential therapeutic target in HER2+ patients with resistance to Trastuzumab and AXL overexpression.