- |||||||||| Inlyta (axitinib) / Pfizer, Torisel (temsirolimus) / Pfizer, Sutent (sunitinib) / Pfizer
Trial completion date, Trial primary completion date, Stroma, Metastases: Registry For Temsirolimus, Sunitinib, And Axitinib Treated Patients With Metastatic Renal Cell Carcinoma (mRCC), Mantle Cell Lymphoma (MCL), And Gastro-Intestinal Stroma Tumor (GIST) [STAR-TOR] (clinicaltrials.gov) - Jan 19, 2022
P=N/A, N=1600, Recruiting,
Trial completion date: Dec 2023 --> Jan 2022 | Trial primary completion date: Dec 2023 --> Jan 2022
- |||||||||| Opdivo (nivolumab) / Ono Pharma, BMS, Cabometyx (cabozantinib tablet) / Takeda, Exelixis, Ipsen
Effectiveness of first-line therapy in patients with advanced non-clear renal cell carcinoma (nccRCC). (In-Person & On Demand | Level 1, West Hall - L2) - Jan 5, 2022 - Abstract #ASCOGU2022ASCO_GU_673;
This real-world data suggests an association between first-line ICI-based therapies and improved outcomes, albeit with cabozantinib not available for the indication during this time. Our data supports consensus recommendations for preferred use of ICI-based or VEGF-TKI over mTORi as first-line therapy in nccRCC.
- |||||||||| imatinib / Generic mfg.
Journal: Tyrosine kinase inhibitors reduce glucose uptake by binding to an exofacial site on hGLUT-1: Effects on F-FDG PET uptake. (Pubmed Central) - Jan 4, 2022
We evaluated the interaction of several classes of TKIs with human glucose transporter-1 (hGLUT-1) in FaDu and GIST-1 cells by measuring [ H]2-deoxy-d-glucose ([ H]2-DG) and [ H]FDG uptake...In GIST-1 cells, [ H]FDG uptake inhibition by temsirolimus and nilotinib was irreversible, whereas inhibition by imatinib, gefitinib, and pazopanib was reversible...In addition, TKIs could affect tumor [ F]FDG uptake, increasingly used as a marker of tumor response. hGLUT-1 inhibition by TKIs may have implications for routine [ F]FDG-PET monitoring of tumor response in patients.
- |||||||||| Torisel (temsirolimus) / Pfizer
Biomarker, Trial completion, Trial completion date, Trial primary completion date: FLT-PET as an Imaging Biomarker With Temsirolimus, Topotecan, and Bortezomib (clinicaltrials.gov) - Jan 4, 2022
P1, N=3, Completed,
hGLUT-1 inhibition by TKIs may have implications for routine [ F]FDG-PET monitoring of tumor response in patients. Active, not recruiting --> Completed | Trial completion date: Jun 2023 --> Dec 2021 | Trial primary completion date: Jun 2022 --> Dec 2021
- |||||||||| sirolimus / Generic mfg.
Journal, IO biomarker: Synergistic melanoma cell death mediated by inhibition of both MCL1 and BCL2 in high-risk tumors driven by NF1/PTEN loss. (Pubmed Central) - Jan 1, 2022
Because addition of the BCL2 inhibitor venetoclax resulted in compensatory upregulation of MCL1, we established a three-drug combination composed of sirolimus, venetoclax, and the MCL1 inhibitor S63845. This well-tolerated drug combination potently and synergistically induces apoptosis in both zebrafish and human NF1/PTEN-deficient melanoma cells, providing preclinical evidence justifying an early-stage clinical trial in patients with NF1/PTEN-deficient melanoma.
- |||||||||| Xeljanz (tofacitinib) / Pfizer, Marche Polytechnic University, Rhopressa (netarsudil) / Aerie Pharma
FDA event, Review, Journal: Properties of FDA-approved small molecule protein kinase inhibitors: a 2021 update. (Pubmed Central) - Dec 28, 2021
All of the eight drugs approved in 2020 fulfill Lipinski's rule of five criteria for an orally effective medicine (MW of 500 Da or less, five or fewer hydrogen bond donors, 10 or fewer hydrogen bond acceptors, calculated log of the partition coefficient of five or less) with the exception of three drugs with a molecular weight greater that 500 Da: pralsetinib (534), selpercatinib (526) and ripretinib (510). This review summarizes the physicochemical properties of all 62 FDA-approved small molecule protein kinase inhibitors.
- |||||||||| Koselugo (selumetinib) / Merck (MSD), AstraZeneca
Trial completion date, Combination therapy, Metastases: A Phase I, Open-Label, Multi-center Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD6244 (ARRY-142886) (clinicaltrials.gov) - Dec 8, 2021
P1, N=140, Active, not recruiting,
This study will guide treatment choice and optimize the future trial design for advanced or metastatic RCC. Trial completion date: Dec 2021 --> Dec 2022
- |||||||||| Torisel (temsirolimus) / Pfizer
Trial completion date, Trial primary completion date, Combination therapy, Metastases: Temsirolimus in Combination With Metformin in Patients With Advanced Cancers (clinicaltrials.gov) - Nov 24, 2021
P1, N=87, Active, not recruiting,
This was particularly evident in patients with alterations in their TSC1 or TSC2 genes. Trial completion date: Mar 2020 --> Oct 2022 | Trial primary completion date: Mar 2020 --> Oct 2022
- |||||||||| Sutent (sunitinib) / Pfizer
Journal: Metastatic Renal Cell Carcinoma Rapidly Progressive to Sunitinib: What to Do Next? (Pubmed Central) - Nov 24, 2021
Trial completion date: Mar 2020 --> Oct 2022 | Trial primary completion date: Mar 2020 --> Oct 2022 Treatment with further TKIs or mTOR inhibitors for mRCC patients primarily refractory to first-line sunitinib in the observed time period achieved very minimal benefit, suggesting avoiding TKI rechallenge and possibly preferring alternative strategies, such as immune checkpoint inhibitors, after PD to a treatment line including a TKI in this setting.
- |||||||||| Torisel (temsirolimus) / Pfizer
Clinical, Journal: Assessment of prognosis by established prognosis scores and physicians' judgement in mRCC patients: an analysis of the STAR-TOR registry. (Pubmed Central) - Nov 24, 2021
P=N/A
For poor prognosis assessed by the physician, MSKCC performed statistically better for differentiation between poor and intermediate prognosis with a median overall survival of 10.3 vs. 5.5 months (P<0.01). Physician's prognosis may be able to identify a subset of patients treated with temsirolimus with good prognosis when MSKCC-determines intermediate prognosis while the MSKCC score could identify patients which were falsely placed in the poor risk group by physicians.
- |||||||||| Trial completion date, Trial primary completion date, Tumor mutational burden, Pan tumor: Canadian Profiling and Targeted Agent Utilization Trial (CAPTUR) (clinicaltrials.gov) - Nov 9, 2021
P2, N=720, Recruiting,
Recruiting --> Completed Trial completion date: Sep 2021 --> Sep 2023 | Trial primary completion date: Sep 2021 --> Sep 2022
- |||||||||| RAPA-201 / Rapa Therap
Metabolically Reprogrammed Polyclonal Autologous Rapa-201 Cell Therapy Yields a Promising Safety and Efficacy Profile in Relapsed and Refractory Multiple Myeloma (RRMM) (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_4483;
P2
Now, we are evaluating temsirolimus for manufacture of second-generation RAPA-201 cells...Bridging chemotherapy during manufacturing (Cycle 1) and host conditioning prior to RAPA-201 infusion consisted of the 14-day PC regimen [pentostatin (4 mg/m 2 IV; days 1, 4, 8, 12; dose adjusted/omitted with renal insufficiency); cyclophosphamide (100-200 mg PO, days 1-5 and days 8-12)]...RAPA-201 therapy represents a new paradigm that utilizes stringent mTOR inhibition to reprogram Th1/Tc1 cells for enhanced metabolic fitness and induction of in vivo T cell clonal expansion, thus providing an alternative to gene-modified targeted T cell therapy. With these promising safety and efficacy results, current RAPA-201 developmental efforts are directed towards completing protocol accrual in parallel with the design and implementation of next-generation clinical trials.
- |||||||||| Taltorvic (ridaforolimus) / Takeda, Merck (MSD)
Retrospective data, Review, Journal: mTOR inhibitors and risk of ovarian cysts: a systematic review and meta-analysis. (Pubmed Central) - Nov 4, 2021
Ovarian cyst development is a common adverse event during immunosuppression treatment with mTORi. These cysts are benign conditions, but they require pelvic ultrasound follow-up and in some cases hospital admission and surgery.
- |||||||||| lenalidomide / Generic mfg.
[VIRTUAL] DETERMINING THE NUMBER OF BIASES IN SEVEN DOMAINS IN THE PHASE THREE RANDOMIZED STUDIES FOR MANTO CELL LYMPHOMA PUBLISHED BETWEEN 2010 AND 2020 () - Oct 27, 2021 - Abstract #HEMO2021HEMO_629;
Results Only 10 studies met the criteria for analysis, 3 of which were published in 2015 (2012-2018). In 7 studies, a pharmaceutical manufacturer of the drug being tested was a sponsor. In 9 studies, a new drug was being tested for the indication of MCL. Only 1 study included patients with relapsed/refractory MCL. Two studies were for transplant-eligible patients, 3 for ineligible patients, 5 included unrestricted patients (3 of them included MCL along with indolent lymphomas). The use of crossover was explained in only 1 study. Four studies were of non-inferiority. The primary endpoint was progression-free survival in five, overall survival in two, event-free survival in 1, time to next treatment in 1, and rate of complete remission in 1. All studies were open label (no placebo control) and the measurement was centralized in 4 studies. The experimental arm did better in all studies. We detected at least 1 bias in 9 studies (90%). We detected bias in ≥ 2 domains in 6 studies. The domains with the most biases were: randomization followed by external validity and outcome data. Only one of the studies resulted in approval for use in MCL (ibrutinib).Conclusion s Phase 3 randomized trials for MCL conducted between 2011 and 2020 were few despite the growing number of new drugs being approved specifically for this disease. Most of these studies have biases according to the parameters of our measurement instruments. Furthermore, heterogeneity in inclusion criteria and main outcomes prevents comparisons between them. Refractory/relapsed MCL especially is an area lacking in these studies.
- |||||||||| cisplatin / Generic mfg.
Clinical, Journal: Synergistic efficacy of inhibiting MYCN and mTOR signaling against neuroblastoma. (Pubmed Central) - Oct 22, 2021
Together, our findings demonstrate synergistic efficacy of JQ1 or OTX-015 and temsirolimus against MYCN-driven NB, by dual-inhibition of MYCN (targeting transcription) and mTOR (targeting translation). Additional preclinical evaluation is warranted to determine the clinical utility of targeted therapy for high-risk NB patients.
- |||||||||| Votrient (pazopanib) / Novartis, BeiGene, ganitumab (AMG 479) / Takeda, ImmunityBio, Torisel (temsirolimus) / Pfizer
Trial completion date, Trial primary completion date, Metastases: Implantable Microdevice for the Delivery of Drugs and Their Effect on Tumors in Patients With Metastatic or Recurrent Sarcoma (clinicaltrials.gov) - Oct 14, 2021
P1, N=20, Not yet recruiting,
Additional preclinical evaluation is warranted to determine the clinical utility of targeted therapy for high-risk NB patients. Trial completion date: Jul 2021 --> Dec 2024 | Trial primary completion date: Jul 2021 --> Dec 2024
- |||||||||| cisplatin / Generic mfg., sirolimus / Generic mfg., paclitaxel / Generic mfg.
Journal, Cancer stem cells: Survival of salivary gland cancer stem cells requires mTOR signaling. (Pubmed Central) - Oct 6, 2021
Using a panel of inhibitors of the mTOR pathway, i.e., rapamycin and temsirolimus (mTOR inhibitors), buparlisib and LY294002 (AKT inhibitors), and PF4708671 (S6K1 inhibitor), we observed consistently dose-dependent decrease in the fraction of CSC, as well as inhibition of secondary sphere formation and self-renewal in three human MEC cell lines (UM-HMC-1,-3A,-3B)...In contrast, conventional chemotherapeutic drugs (cisplatin, paclitaxel) induced preferential apoptosis of bulk tumor cells and accumulation of CSC...Transplantation of MEC cells genetically silenced for mTOR into immunodeficient mice corroborated the results obtained with temsirolimus. Collectively, these data demonstrated that mTOR signaling is required for CSC survival, and unveiled the therapeutic potential of targeting the mTOR pathway for elimination of highly tumorigenic cancer stem-like cells in salivary gland mucoepidermoid carcinoma.
- |||||||||| Torisel (temsirolimus) / Pfizer, Rituxan (rituximab) / Roche
Trial completion, Trial completion date: Bortezomib, Rituximab, and Dexamethasone With or Without Temsirolimus in Treating Patients With Untreated or Relapsed Waldenstrom Macroglobulinemia or Relapsed or Refractory Mantle Cell or Follicular Lymphoma (clinicaltrials.gov) - Oct 4, 2021
P2, N=9, Completed,
Collectively, these data demonstrated that mTOR signaling is required for CSC survival, and unveiled the therapeutic potential of targeting the mTOR pathway for elimination of highly tumorigenic cancer stem-like cells in salivary gland mucoepidermoid carcinoma. Terminated --> Completed | Trial completion date: Dec 2014 --> Sep 2021
- |||||||||| pimecrolimus topical / Generic mfg., sirolimus / Generic mfg., irinotecan / Generic mfg.
Preclinical, Journal: Rapalogues as hCES2A Inhibitors: In Vitro and In Silico Investigations. (Pubmed Central) - Sep 25, 2021
Xenografts with GHR knockout show reduced post-transplantation xenograft growth using echocardiography >6 months after transplantation, without the need for other adjuncts. Our findings demonstrate that several marketed rapalogues are potent and specific hCES2A inhibitors, and these agents can serve as leading compounds for the development of more efficacious hCES2A inhibitors to modulate the pharmacokinetic profiles and toxicity of hCES2A-substrate drugs (such as the anticancer agent irinotecan).
- |||||||||| Inlyta (axitinib) / Pfizer, Torisel (temsirolimus) / Pfizer, Sutent (sunitinib) / Pfizer
Clinical, Journal: Toxicities of axitinib, sunitinib and temsirolimus: implications for progression-free and overall survival in metastatic renal cell cancer. (Pubmed Central) - Sep 22, 2021
The following toxicities significantly predicted outcomes: hand-foot skin reaction (hazard ratio [HR] = 0.29) for PFS with axitinib; stomatitis (HR = 0.62) and pneumonitis (HR = 0.23) for PFS with temsirolimus; stomatitis (HR = 0.52) and thrombocytopenia (HR = 0.6) for OS with temsirolimus; fatigue (HR = 0.71) for PFS with sunitinib; hand-foot skin reaction (HR = 0.56) and fatigue (HR = 0.58) for OS with sunitinib. In conclusion, in metastatic renal cell cancer, axitinib, sunitinib and temsirolimus demonstrate specific toxicities that are protective OS/PFS predictors.
- |||||||||| Torisel (temsirolimus) / Pfizer
P1 data, Journal: Phase I Study of Docetaxel and Temsirolimus in Refractory Solid Tumors. (Pubmed Central) - Sep 22, 2021
Although our novel use of Bayesian Optimal Interval design using isotonic regression method to select MTD showed identical estimated DLT rates in dose levels 1 and -1, clinically our patients were not able to complete 2 cycles of this regimen without dose reductions due to myelosuppressive toxicity in either of these dose levels, and hence, escaped clinical validity. This combination regimen should not be studied further at the dose levels and schedules tested in our study.
- |||||||||| imatinib / Generic mfg., sirolimus / Generic mfg.
Review, Journal, Combination therapy: Combating TKI resistance in CML by inhibiting the PI3K/Akt/mTOR pathway in combination with TKIs: a review. (Pubmed Central) - Sep 19, 2021
Even in Imatinib, Nilotinib, and Ponatinib-resistant CML cells, a dual PI3K/mTOR inhibitor, BEZ235, showed antiproliferative activity. Therefore, by considering the literature data of these reviews and further examining some of the reported inhibitors, which proved effective against the PI3K/Akt/mTOR signaling pathway in multiple cancers, may improve the therapeutic approaches towards TKI-resistant CML cells where the respective signaling pathway gets upregulated.
- |||||||||| Cabometyx (cabozantinib tablet) / Takeda, Exelixis, Ipsen, Nexavar (sorafenib) / Bayer, Amgen
Clinical, Retrospective data, Journal: Effects of Tyrosine Kinase Inhibitors on Blood Pressure in Patients with Unresectable or Advanced Recurrent Renal Cell Carcinoma-Bayes-Mixed Treatment Comparison Meta-Analysis. (Pubmed Central) - Sep 16, 2021
Currently, 7 molecular targeted drugs(ie, sorafenib, sunitinib, axitinib, pazopanib, cabozantinib, everolimus, and temsirolimus)are available in Japan...Our analysis also showed similar results. This study demonstrated that Bayes-MTC analysis is a useful tool enabling not only direct evaluation but also indirect evaluation.
- |||||||||| Torisel (temsirolimus) / Pfizer
Clinical, Review, Journal: PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects. (Pubmed Central) - Sep 9, 2021
Currently, clinical studies evaluate inhibitors of the PI3K/AKT/mTOR axis. The main purpose of this review is to present general aspects of breast cancer, the components of the AKT signaling pathway, the factors that activate this protein kinase B, PI3K/AKT-breast cancer mutations, PI3K/AKT/mTOR-inhibitors, and the relationship between everolimus, temsirolimus and endocrine therapy.
- |||||||||| Torisel (temsirolimus) / Pfizer
Preclinical, Journal: Functional and genomic characterization of patient-derived xenograft model to study the adaptation to mTORC1 inhibitor in clear cell renal cell carcinoma. (Pubmed Central) - Jul 22, 2021
Integrated gene profiles using methylation and microarray analyses of PDX tumors suggested a global shift for the hypomethylation status including promotor regions, and showed the upregulation of several molecules that regulate the mTOR pathway in temsirolimus-resistant tumors. Present study showed the feasibility of PDX model to explore the mechanisms of mTOR resistance acquisition and suggested that genetic alterations, including that of DNMT1, which alter the methylation status in cancer cells, are one of the potential mechanisms of developing resistance to temsirolimus.
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