Evidence map›Paper›PMID 32062691›Full record

ArticleCancer chemotherapy and pharmacology2020

Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors.

Anthony W Tolcher, Razelle Kurzrock, Vincente Valero, Rene Gonzalez, Rebecca S Heist, Antoinette R Tan, Julie Means-Powell, Theresa L Werner, Carlos Becerra, Chenxi Wang and 8 more

Open access · greenAbstract readClinical Trial, Phase I
PubMed Publisher
In one paragraph

Article in Cancer chemotherapy and pharmacology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.

0numbers the graph read from it
0cells of the map it votes in
40citing papers in PubMed
3.2field-weighted citation impact, top 7% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

40 citing papers in PubMed, 58 citations in OpenAlex.

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  12. Medication-Induced Hyperglycemia and Diabetes Mellitus: A Review of Current Literature and Practical Management Strategies.Diabetes therapy : research, treatment and education of diabetes and related disorders · 2024
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors at 13 institutions in 2 countries.

Anthony W TolcherSouth Texas Accelerated Research Therapeutics, San Antonio, TX, USA. atolcher@nextsat.com.ORCID http://orcid.org/0000-0002-6322-9721
Razelle KurzrockDivision of Hematology and Oncology, Moores Cancer Center, University of California, San Diego, CA, USA.
Vincente ValeroDivision of Cancer Medicine, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Rene GonzalezDivision of Medical Oncology, Melanoma Research Clinics, University of Colorado Cancer Center, Aurora, CO, USA.
Rebecca S HeistMassachusetts General Hospital, Boston, MA, USA.
Antoinette R TanRutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
Julie Means-PowellSarah Cannon Research Institute, Nashville, TN, USA.
Theresa L WernerDivision of Medical Oncology, Department of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Carlos BecerraTexas Oncology, US Oncology-Baylor University Medical Center, Dallas, TX, USA.
Chenxi WangGlaxoSmithKline, Collegeville, PA, USA.
Cathrine LeonowensGlaxoSmithKline, Collegeville, PA, USA.
Shanker Kalyana-SundaramGlaxoSmithKline, Collegeville, PA, USA.
Joseph F KlehaNovartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Jennifer GauvinNovartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Anthony M D'AmelioNovartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Catherine EllisGlaxoSmithKline, Collegeville, PA, USA.
Nageatte IbrahimGlaxoSmithKline, Collegeville, PA, USA.
Li YanGlaxoSmithKline, Collegeville, PA, USA.
GlaxoSmithKline (United States) · USNovartis (United States) · USArray BioPharma (United States) · USMassachusetts General Hospital · USMerck & Co., Inc., Rahway, NJ, USA (United States) · USNexen (Canada) · CARutgers, The State University of New Jersey · USSarah Cannon · USTexas Oncology · USThe University of Texas MD Anderson Cancer Center · USUniversity of California San Diego · USUniversity of Colorado Cancer Center · USUniversity of Utah · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

purposeThis study aimed to determine the safety, tolerability, and recommended phase II doses of trametinib plus uprosertib (GSK2141795) in patients with solid tumors likely to be sensitive to MEK and/or AKT inhibition.

methodsThis was a phase I, open-label, dose-escalation, and dose-expansion study in patients with triple-negative breast cancer or BRAF-wild type advanced melanoma. The primary outcome of the expansion study was investigator-assessed response. Among 126 enrolled patients, 63 received continuous oral daily dosing of trametinib and uprosertib, 29 received various alternative dosing schedules, and 34 were enrolled into expansion cohorts. Doses tested in the expansion cohort were trametinib 1.5 mg once daily (QD) + uprosertib 50 mg QD.

resultsAdverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. Diarrhea was the most common dose-limiting toxicity; diarrhea and rash were particularly difficult to tolerate. Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib with trametinib at a concentration predicted to have clinical activity. The study was terminated early based on futility in the continuous-dosing expansion cohorts and a lack of pharmacological or therapeutic advantage with intermittent dosing. The objective response rate was < 5% (1 complete response, 5 partial responses).

conclusionsContinuous and intermittent dosing of trametinib in combination with uprosertib was not tolerated, and minimal clinical activity was observed in all schedules tested.

Indexed as

AdultAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsCohort StudiesDiaminesDose-Response Relationship, DrugFemaleFollow-Up StudiesHumansMaleMAP Kinase Kinase 1MAP Kinase Kinase 2Maximum Tolerated DoseMelanomaMiddle AgedDiaminesGSK2141795MAP2K1 protein, humanMAP2K2 protein, humanMAP Kinase Kinase 1MAP Kinase Kinase 2Proto-Oncogene Proteins c-aktPyrazolesPyridonesPyrimidinonestrametinibAKT inhibitorBRAF-wild type melanomaMEK inhibitorTrametinibTriple-negative breast cancerUprosertib

Identifiers

PMID32062691
OpenAlexW3006140059

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.