Category: Rigosertib kras

Rigosertib kras

Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. A Nature Research Journal. To explore their role in cancer, we compared 5, tumor-normal genome pairs to identify snoRNAs with frequent copy number loss.

Matera, A.

rigosertib kras

Cell Biol. Kiss, T. EMBO J. Falaleeva, M. Bioessays 3546—54 Wang, C. Reichow, S. The structure and function of small nucleolar ribonucleoproteins. Nucleic Acids Res. Sahoo, T. Bhartiya, D. Systematic curation and analysis of genomic variations and their potential functional consequences in snoRNA loci.

Bellodi, C. Cell Rep. Michel, C. Cell Metab. Mannoor, K. Small nucleolar RNAs in cancer. Acta— Williams, G. Cancer 1284—88 Yin, Q. Cell 48— Rebane, A. BMC Mol. Kretz, M. Nature— Siprashvili, Z. Identification of proteins binding coding and non-coding human RNAs using protein microarrays.

BMC Genomics 13 Direct observation of individual endogenous protein complexes in situ by proximity ligation. Methods 3— Study record managers: refer to the Data Element Definitions if submitting registration or results information. The Phase I dose escalation plan will start with an accelerated titration design ATD using single patient cohorts until grade 2 toxicity is experienced.

Rigosertib escalation will occur with three dose levels dose D1: mg twice daily; dose D2: mg in the morning qAMmg in the evening qPM ; dose D3: mg twice daily; taken by mouth for 21 consecutive days of the 28 day cyclebased on previous dose escalation studies in other malignancies, while Nivolumab dose will be fixed at the standard dose mg every 2 weeks, given intravenously.

Once the MTD is determined, an additional planned 12 patients will be enrolled in the expansion phase to further study toxicity and to determine preliminary efficacy endpoints including ORR phase 2a primary endpointPFS, and OS secondary endpoints of the combination. Nivolumab will be dosed at the standard fixed dose of mg. Rigosertib escalation will occur with three dose levels dose D1: mg twice daily; dose D2: mg qAM, mg qPM; dose D3: mg twice daily.

Drug: Nivolumab Nivolumab will be dosed once ever 2 weeks twice per day cycle; standard fixed dose of mg. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies. Hide glossary Glossary Study record managers: refer to the Data Element Definitions if submitting registration or results information.

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Rigosertib Plus Nivolumab for KRAS+ NSCLC Patients Who Progressed on First-Line Treatment

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5-Azacytidine in Combination with Ruxolitinib As Therapy for Patients with MDS/MPN

Study Description. Detailed Description:. Drug Information available for: Nivolumab. FDA Resources. Arms and Interventions. Rigosertib will be dosed twice a day for 21 consecutive days, followed by 7 days off treatment each cycle duration: 28 days.

Nivolumab will be dosed once ever 2 weeks twice per day cycle; standard fixed dose of mg. Outcome Measures.

rigosertib kras

ORR is defined as achieving an objective response of either complete response or partial response. Phase 2: OS at MTD is defined as the time from the first dose of study treatment to the date of death whatever the cause. Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision.

Inclusion criteria Be willing and able to provide written informed consent for the trial.There is a high frequency of Ras mutations in cancer that leads to the belief that mutations of the Ras Pathway provide a proliferative advantage and thus is involved in the pathogenesis of cancer. As a result, targeting the Ras pathway has been the objective of scientific research for decades.

As published in the journal Cell inand now under investigation in a pivotal Phase 3 Trial, rigosertib targets the mutated RAS pathway by its interaction with Ras effector proteins containing the Ras Binding Domain.

About Onconova Therapeutics, Inc. Onconova Therapeutics, Inc. Using a proprietary chemistry platform, Onconova has created a pipeline of targeted agents designed to work against specific cellular pathways that are important in cancer cells. Onconova has three product candidates in the clinical stage and several pre-clinical programs. It is frequently associated with the presence of blasts or leukemic cells in the marrow.

This leads to low numbers of one or more types of circulating blood cells, and to the need for blood transfusions. In MDS, some of the cells in the bone marrow are abnormal dysplastic and may have genetic abnormalities associated with them. Different cell types can be affected, although the most common finding in MDS is a shortage of red blood cells anemia.

Rigosertib

Patients with higher-risk MDS may progress to the development of acute leukemia. Patents covering oral and injectable rigosertib have been issued in the US and are expected to provide coverage until at least An interim analysis in early demonstrated a promising survival signal in the intent-to-treat population as reviewed by the Independent Data Monitoring Committee.

The Committee recommended that the trial continue with an expansion in enrollment to patients based on a pre-planned sample size re-estimation. Full details of the INSPIRE trial, such as inclusion and exclusion criteria, as well as secondary endpoints, can be found on clinicaltrials. This dosage form may also support combination therapy modalities. To date, over patients have been studied with the oral formulation of rigosertib. Combination therapy of oral rigosertib with azacitidine, the standard of care in HR-MDS, has also been studied.

Currently, oral rigosertib is being developed as a combination therapy together with azacitidine for patients with higher-risk MDS who require HMA therapy. A new pivotal Phase 3 study design is under discussion with the FDA.

Onconova has attempted to identify forward-looking statements by terminology including "believes," "estimates," "anticipates," "expects," "plans," "intends," "may," "could," "might," "will," "should," "approximately" or other words that convey uncertainty of future events or outcomes. Although Onconova believes that the expectations reflected in such forward-looking statements are reasonable as of the date made, expectations may prove to have been materially different from the results expressed or implied by such forward-looking statements.

These statements are only predictions and involve known and unknown risks, uncertainties, and other factors, including Onconova's ability to continue as a going concern, the need for additional financing, the success and timing of Onconova's clinical trials and regulatory approval of protocols, our collaborations, and those discussed under the heading "Risk Factors" in Onconova's most recent Annual Report on Form K and quarterly reports on Form Q.

Any forward-looking statements contained in this release speak only as of its date. Onconova undertakes no obligation to update any forward-looking statements contained in this release to reflect events or circumstances occurring after its date or to reflect the occurrence of unanticipated events. General Contact. Related Quotes. Sign in. Sign in to view your mail. Finance Home. GlobeNewswire September 16, Presenter: Steven M. Fruchtman, M. Story continues.Rigosertib ON Naa first-in-class Ras mimetic and small-molecule inhibitor of multiple signaling pathways including polo-like kinase 1 PLK1 and phosphoinositide 3-kinase PI3Khas shown efficacy in preclinical pancreatic cancer models.

The median overall survival was 6. The median progression-free survival was 3. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations 40 cases. No correlation between mutational status and efficacy was detected. Rigosertib showed a similar safety profile to that seen in previous trials using the IV formulation. Pancreatic cancer is a devastating disease with limited treatment options that offer modest benefit in the metastatic setting [ 1 ].

In the United States, pancreatic cancer is the fourth leading cause of cancer-related death with an estimated 39 deaths and 46 new diagnoses in [ 1 ].

Few treatments for advanced pancreatic cancer have shown efficacy. Ingemcitabine became the standard first-line therapy in advanced pancreatic cancer based on a phase III trial demonstrating improved survival with gemcitabine versus 5-fluoruracil 5-FU 5. A subsequent phase III study evaluating the addition of erlotinib to gemcitabine resulted in a small but significant improvement in overall survival OS versus single-agent gemcitabine 6.

More recently, the combination of nab-paclitaxel and gemcitabine has been approved for first-line metastatic pancreatic cancer based on a phase III trial showing improved survival and response rates compared with gemcitabine alone median OS of 8. The combination of poor prognosis and limited treatment options with modest efficacy make pancreatic cancer a major focus in cancer research and treatment. Targeted therapy aimed at cell-cycle arrest offers a promising approach to improved treatment efficacy.

A potential therapeutic target involved in pancreatic oncogenesis is the polo-like kinase 1 PLK1 pathway [ 7 ]. Rigosertib, a first-in-class small-molecule inhibitor of multiple signaling pathways including phosphoinositide 3-kinase PI3K and PLK1 pathways, showed promising anti-tumor activity in solid tumor malignancies, including advanced pancreatic cancer in two phase I trials [ 89 ].

Rigosertib is believed to have dual inhibitory activity in the PI3K and PLK1 signaling pathways, leading to cell-cycle arrest and apoptosis. Recent preclinical data have shown that rigosertib achieves these pleotropic effects through the inhibition of Ras activity. Specifically, rigosertib appears to bind to the Ras-binding domain RBD of downstream effector kinases such as Raf and PI3K, leading to their inactivation [ 10 ].We need some information from you before you start using the platform.

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rigosertib kras

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rigosertib kras

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Receiving permission from our users is an important part of our compliance with international privacy regulations. Your email address will not be shared without your permission. Please refer to our privacy policy for information on how we protect your personal information.Aberrant signaling triggered by oncogenic or hyperactive RAS proteins contributes to the malignant phenotypes in a significant percentage of myeloid malignancies. Of these, juvenile myelomonocytic leukemia JMMLan aggressive childhood cancer, is largely driven by mutations in RAS genes and those that encode regulators of these proteins.

The high frequency of these genomic alterations suggests that targeting RAS signaling, either by inhibiting RAS proteins themselves, their effectors, or regulators, might be an effective strategy to combat this and other myeloid malignancies that are RAS pathway-dependent. These pre-clinical data, combined with the agent's safety profile revealed in clinical trials [ 1013 ], suggest that RGS might be an effective therapeutic in hematological malignancies that exhibit altered RAS-driven signaling and for those where there is not already a perceived clinical benefit [ 7 ].

These mice develop of an aggressive and lethal myeloproliferative neoplasm MPN with rapid onset and present with severe anemia, hepatosplenomegaly and leukocytosis [ 14 ].

Our studies show that RGS-treated mice show improvements in complete blood counts and a reduction in the degree of splenomegaly due to a decrease in erythroid cells that accumulate in the spleen. Importantly, we also show that treatment with RGS resulted in a clear survival benefit, suggesting that this compound might be useful in the treatment of myeloid disorders.

Colonies were enumerated 7 days post-plating. Representative histograms and E heatmaps depicting median fluorescence intensity MFI for one representative experiment out of 3 are shown. We also examined the phosphorylation status of STAT5, which has recently been shown to mediate the phenotypes observed in mutant and hyperactive K- and NRAS-driven hematopoietic phenotypes in animal models [ 161923 - 26 ] and is often aberrantly activated in JMML and other myeloid malignant cells treated with low concentrations of GM-CSF [ 25 ].

To determine if the phenotypic improvements observed in RGS-treated mice might enhance survival, we treated cohorts of wild-type and KRAS G12D mice with vehicle or RGS and monitored these animals over a 2-month period. Median survival was 26 days versus 48 days for the vehicle and rigosertib-treated groups, respectively, as estimated by Kaplan-Meier survival analysis.

Previous studies using compound genetically modified mouse models and small molecule inhibitors have highlighted the utility of inhibiting downstream effectors of RAS proteins in the treatment of RAS-driven myeloid malignancies [ 12192027 — 29 ]. In these instances, overall survival, as well as both disease burden and malignant phenotypes, were dramatically improved, demonstrating that blocking signals that are transmitted downstream of RAS has the potential to be clinically beneficial, even in the absence of elimination of the malignant clone.

Although the nature of this response would be considered palliative at best in the absence of improvements in erythropoiesis and anemia in the remainder of the hematopoietic compartment, patients with hematological disorders that are phenocopied here could still achieve clinical benefit from RGS. Given that RGS-treated KRAS G12D mice survived significantly longer than those treated with vehicle, it is tempting to attribute this to a reduction in spleen volume, possibly in conjunction with improvements in overall peripheral blood count.

However, as mentioned in the results section, this response is not durable and the majority of animals treated long-term 2 months ultimately succumbed to the effects of MPN as well as T-cell leukemia. It should be noted, however, that the dosing regimen used herein is a caveat of the long-term study. Hence, we were unable to determine the utility of RGS in prolonging survival of this model to the fullest extent.

KRAS G12D expression in the bone marrow results a loss of HSCs, with those that remain having enhanced repopulating ability due to increased cell cycle entry.

Cell cycle progression in myeloid progenitors is also enhanced, although these cells are unable to initiate leukemias in competitive bone marrow transplantation assays [ 1718 ]. The frequency of HSCs was significantly increased in RGS-treated animals compared to the vehicle-treated cohort, suggesting that RGS might have the ability to alter the behavior of the stem cell pool.

It is, however, unclear whether the neoplastic behavior of these cells is altered in the absence of data from bone marrow transplantation studies. The percentage of MEPs, which is decreased as a function of KRAS G12D expression [ 1617 ], was also restored to nearly normal levels in response to RGS treatment and was associated with a concomitant decrease in the abnormally high frequency of GMPs in these animals.

Given that the perceived phenotypic corrections in HSPCs within the bone marrow do not always translate into improvements in all hematopoietic tissues, use of RGS in combination with other agents that might synergize with and enhance its effect in these cell types might be of clinical benefit.

Breeding and experiments were performed under protocols approved by the Icahn School of Medicine at Mount Sinai's Institutional Animal Care and Use Committee according to federal and institutional guidelines and regulations. Polyinosinic:polycytidylic acid pIpC Sigma was resuspended at a concentration of 2.The Phase I dose escalation plan will start with an accelerated titration design ATD using single patient cohorts until grade 2 toxicity is experienced.

Rigosertib escalation will occur with three dose levels dose D1: mg twice daily; dose D2: mg in the morning qAMmg in the evening qPM ; dose D3: mg twice daily; taken by mouth for 21 consecutive days of the 28 day cyclebased on previous dose escalation studies in other malignancies, while Nivolumab dose will be fixed at the standard dose mg every 2 weeks, given intravenously.

Once the MTD is determined, an additional planned 12 patients will be enrolled in the expansion phase to further study toxicity and to determine preliminary efficacy endpoints including ORR phase 2a primary endpointPFS, and OS secondary endpoints of the combination. The last cycle of first-line treatment must occur at least 28 days prior to administration of trial drugs i.

Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesion. Specimens must be collected within 14 days prior to the start of trial. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. A female of child-bearing potential is any woman regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice who meets the following criteria: Has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 12 consecutive months i.

Exclusion Criteria - Patients may not be receiving any other investigational agents. If received as part of first line treatment, last administration of previous investigational agent must be greater than 4 weeks prior to administration of study drug combination. All other co-mutations will be allowed. Subjects with previously treated brain metastases may participate provided they are without evidence of progression for at least 4 weeks by repeat radiological imaging, clinically stable, and without requirement of steroid treatment for at least 14 days prior to first dose of study drug.

Replacement therapy e. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical or anal cancerprostate cancer on stable dose of hormonal therapy without rising prostate-specific antigen PSAand breast cancer whom have been treated with curative intent, who may be on hormonal therapy. No HIV testing is required.

A history of radiation pneumonitis in the radiation field is permitted. My Cancer Genome Data Sources. How to Give to My Cancer Genome. Detecting Gene Alterations in Cancers. Targeted Therapies. NCT Description:. Related Conditions:. Lung Adenocarcinoma. Recruiting Status:. Inclusion criteria - Be willing and able to provide written informed consent for the trial.

MTD is defined as the highest dose for which at most 1 patient out of 6 experiences a dose-limiting toxicity DLT. Phase 2: PFS is defined as the duration of time from start of treatment to the first occurrence of disease progression or death on study from any cause, whichever occurs earlier.


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