A phase 1-2 trial of sitravatinib and nivolumab in clear cell renal cell carcinoma following progression on antiangiogenic therapy

Msaouel, Pavlos; Goswami, Sangeeta; Thall, Peter F.; Wang, Xuemei; Yuan, Ying; Jonasch, Eric; Gao, Jianjun; Campbell, Matthew T.; Shah, Amishi Yogesh; Corn, Paul G.; Tam, Alda L.; Ahrar, Kamran; Rao, Priya; Sircar, Kanishka; Cohen, Lorenzo; Basu, Sreyashi; Duan, Fei; Jindal, Sonali; Zhang, Yuwei; Chen, Hong; Yadav, Shalini S.; Shazer, R.; Der-Torossian, Hirak; Allison, James P.; Sharma, Padmanee; Tannir, Nizar M.

doi:10.1126/scitranslmed.abm6420

Cited by 37 publications

(26 citation statements)

References 43 publications

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“…Furthermore, recent studies revealed some unique characteristics of sitravatinib. Sitravatinib possesses the ability to reduce immunosuppressive myeloid cells and potentiate immune checkpoint blockade in preclinical and clinical models [ 22 , 23 ]. The combination of sitravatinib and anti–programmed death-1 (PD-1) therapy has demonstrated high clinical activity with manageable toxicity in oral cavity cancer and renal cancer [ 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…Sitravatinib possesses the ability to reduce immunosuppressive myeloid cells and potentiate immune checkpoint blockade in preclinical and clinical models [ 22 , 23 ]. The combination of sitravatinib and anti–programmed death-1 (PD-1) therapy has demonstrated high clinical activity with manageable toxicity in oral cavity cancer and renal cancer [ 22 , 23 ]. Sitravatinib has also been shown to block the chemotherapeutic drug efflux function of ABCB1 and ABCG2 at submicromolar concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…Sitravatinib is a novel potent broad-spectrum TKI with immunomodulatory effects, which can block the phosphorylation of PDGFRα, PDGFRβ, IGF1-R and c-Met [21,22]. It has exerted effective antitumor activity and good safety in clinical trials of various solid tumors such as sarcoma, breast cancer and clear cell renal carcinoma [23][24][25]. No studies have yet assessed the efficacy of sitravatinib in hematologic malignancies.…”

Section: Introductionmentioning

confidence: 99%

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Sitravatinib as a potent FLT3 inhibitor can overcome gilteritinib resistance in acute myeloid leukemia

Zhang

Wang

et al. 2023

Biomark Res

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Background Gilteritinib is the only drug approved as monotherapy for acute myeloid leukemia (AML) patients harboring FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation throughout the world. However, drug resistance inevitably develops in clinical. Sitravatinib is a multi-kinase inhibitor under evaluation in clinical trials of various solid tumors. In this study, we explored the antitumor activity of sitravatinib against FLT3-ITD and clinically-relevant drug resistance in FLT3 mutant AML. Methods Growth inhibitory assays were performed in AML cell lines and BaF3 cells expressing various FLT3 mutants to evaluate the antitumor activity of sitravatinib in vitro. Immunoblotting was used to examine the activity of FLT3 and its downstream pathways. Molecular docking was performed to predict the binding sites of FLT3 to sitravatinib. The survival benefit of sitravatinib in vivo was assessed in MOLM13 xenograft mouse models and mouse models of transformed BaF3 cells harboring different FLT3 mutants. Primary patient samples and a patient-derived xenograft (PDX) model were also used to determine the efficacy of sitravatinib. Results Sitravatinib inhibited cell proliferation, induced cell cycle arrest and apoptosis in FLT3-ITD AML cell lines. In vivo studies showed that sitravatinib exhibited a better therapeutic effect than gilteritinib in MOLM13 xenograft model and BaF3-FLT3-ITD model. Unlike gilteritinib, the predicted binding sites of sitravatinib to FLT3 did not include F691 residue. Sitravatinib displayed a potent inhibitory effect on FLT3-ITD-F691L mutation which conferred resistance to gilteritinib and all other FLT3 inhibitors available, both in vitro and in vivo. Compared with gilteritinib, sitravatinib retained effective activity against FLT3 mutation in the presence of cytokines through the more potent and steady inhibition of p-ERK and p-AKT. Furthermore, patient blasts harboring FLT3-ITD were more sensitive to sitravatinib than to gilteritinib in vitro and in the PDX model. Conclusions Our study reveals the potential therapeutic role of sitravatinib in FLT3 mutant AML and provides an alternative inhibitor for the treatment of AML patients who are resistant to current FLT3 inhibitors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sitravatinib as a potent FLT3 inhibitor can overcome gilteritinib resistance in acute myeloid leukemia

Zhang

Wang

et al. 2023

Biomark Res

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“…A recent basic study showed novel histone methyltransferase EZH2 inhibitor can further reduce progression of urothelial carcinoma [32]. A translational study showed that combination therapy with the novel TKI sitravatinib and the anti-PD-1 immune checkpoint inhibitor improved the median progression-free survival for patients with kidney cancer [33]. Widespread availability of novel and favorable treatments can be appreciable at the population level to reduce the mortality rate of patients with all three cancers.…”

Section: Discussionmentioning

confidence: 99%

Secular trends of morbidity and mortality of prostate, bladder, and kidney cancers in China, 1990 to 2019 and their predictions to 2030

Huang

Luo

et al. 2022

BMC Cancer

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Background Prostate, bladder and kidney cancers are common age-related genitourinary cancers. China's population is aging at an increasing rate, so predicting the morbidity and mortality of prostate, bladder, and kidney cancer in China is of great significance to provide epidemiological evidence for forward planning and implementation of national health policies. Methods Numbers of incidences and deaths by cancer (prostate, bladder and kidney), sex (male and female) and age groups from 1990 to 2019 were extracted from the Global Burden of Disease (GBD) Study. We applied Bayesian age-period-cohort models to predict incidences and deaths to 2030. We also calculated Age-standardized incidence rate (ASIR) and mortality rate (ASMR), their trends were quantified by estimated average percentage change (EAPC) and 95% confidence interval (CI). Results Predictions suggest that by 2030, there will be 315,310 prostate cancer cases, 192,390 bladder cancer cases and 126,980 kidney cancer cases. The ASIRs will increase to 25.54/100,000 for prostate cancer (EAPC: 2.88, 95% CI, 2.84, 2.93), 7.54/100,000 for bladder cancer (EAPC: 2.58, 95% CI, 2.54, 2.61) and 5.63/100,000 for kidney cancer (EAPC: 4.78, 95% CI, 4.54, 5.02). Number of deaths in 2030 will be 81,540, 61,220, and 41,940, respectively. Different ASMR changes are observed, the ASMR for prostate cancer will drop to 7.69/100,000 (EAPC: -0.29, 95% CI, -0.31, -0.27), the ASMR for bladder cancer will stabilize at 2.49/100,000 (EAPC: 0.00, 95% CI, -0.02, 0.03), the ASMR of kidney cancer will increase to 1.84/100,000 (EAPC: 3.45, 95% CI, 3.22, 3.67). From 1990 to 2030, higher numbers of cases and rates are reported among males and in the 60 plus age group, both ASIR and ASMR of bladder and kidney cancers presents progressively widening differences between both males and females and between the < 60 and the ≥ 60 age groups. Conclusion Morbidity and mortality of the three genitourinary cancers are predicted to increase further over the next decade. It highlights the need for timely development and implementation of optimal health policies to curb the epidemic trends.

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“…Despite several successful applications, such as the recent trial examples of Tidwell et al (2021) [35] and Msaouel et al (2022) [36], the use of model-based phase I-II designs has been fairly limited. One major reason for this limited use is that these designs are statistically and computationally complicated.…”

Section: Dose Optimization For Car T-cell Therapiesmentioning

confidence: 99%

Novel bayesian adaptive early phase designs to accelerate the development of CAR T-cell therapy

Yuan

Chen

2022

Hematology and Oncology Discovery

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Chimeric antigen receptor (CAR) T-cell therapy has revolutionized cancer treatment, particularly for hematopoietic malignancies. CAR T-cell therapy is a living drug with fundamentally different characteristics from those of other therapies. For example, CAR T-cell therapy efficacy may not increase with dose, and dose-limiting toxicity is rarely observed in the therapeutic dose range. Consequently, the conventional trial design paradigm is not suitable for the development of CAR T-cell therapy. Here, we review and introduce the phase I-II trial design paradigm to optimize the dose of CAR T-cell therapy on the basis of both toxicity and efficacy. We describe several novel Bayesian model-assisted designs, including BOIN12 and U-BOIN, which are simple to implement and have excellent operating characteristics for identifying the optimal biological dose for CAR T-cell therapy. Examples and software are provided to facilitate the use of these novel designs to accelerate the development of CAR T-cell therapy.

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A phase 1-2 trial of sitravatinib and nivolumab in clear cell renal cell carcinoma following progression on antiangiogenic therapy

Cited by 37 publications

References 43 publications

Sitravatinib as a potent FLT3 inhibitor can overcome gilteritinib resistance in acute myeloid leukemia

Sitravatinib as a potent FLT3 inhibitor can overcome gilteritinib resistance in acute myeloid leukemia

Secular trends of morbidity and mortality of prostate, bladder, and kidney cancers in China, 1990 to 2019 and their predictions to 2030

Novel bayesian adaptive early phase designs to accelerate the development of CAR T-cell therapy

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