A phase 1 study of the combination of BH3-mimetic, navitoclax, and mTORC1/2 inhibitor, vistusertib, in patients with advanced solid tumors Journal Article

  

Authors:	Scott, S. C.; Farago, A.; Lai, W. V.; Zahurak, M.; Rudek, M. A.; Murray, J.; Carducci, M. A.; Uziel, T.; Takebe, N.; Gore, S. D.; Rudin, C. M.; Hann, C. L.
Article Title:	A phase 1 study of the combination of BH3-mimetic, navitoclax, and mTORC1/2 inhibitor, vistusertib, in patients with advanced solid tumors
Abstract:	Purpose: To determine the, safety, tolerability and recommended phase 2 dosing of the combination of navitoclax, a dual Bcl-2/xL inhibitor, and vistusertib, a TORC1/2 inhibitor. Methods: Patients with advanced solid tumors received navitoclax plus vistusertib following a 3 + 3 dose escalation design. To mitigate thrombocytopenia, a known toxicity of navitoclax, all patients received lead-in dosing of navitoclax alone at 150 mg orally daily for a minimum of 7 days. In addition to safety and tolerability, pharmacokinetics of navitoclax and vistusertib were evaluated. Results: 14 patients received combination treatment which was well-tolerated at dose level 1 (navitoclax 150 mg orally daily plus vistusertib 35 mg orally twice daily). The main dose-limiting toxicity, grade 3 serum aminotransferase elevation, occurred in two of five patients at dose level 2 (navitoclax 250 mg orally daily plus vistusertib 35 mg orally twice daily). Navitoclax and vistusertib exposures appeared consistent with levels reported in prior studies of each agent. No responses were observed among the 8 response evaluable patients. Conclusions: A tolerable dose of navitoclax at 150 mg orally daily plus vistusertib at 35 mg orally twice daily was identified in patients with advanced solid tumors and established as the recommended phase 2 dose (RP2D). Further efficacy assessment of this combination, in a planned phase 2 expansion in patients with relapsed small cell lung cancer, was terminated due to discontinuation of vistusertib. Trial registration: NCT03366103 (First posted December 8, 2017). © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2025.
Keywords:	adult; clinical article; controlled study; aged; middle aged; clinical trial; fatigue; advanced cancer; area under the curve; diarrhea; dose response; hypophosphatemia; side effect; antineoplastic agent; anorexia; neoplasm; neoplasms; protein bcl 2; breast cancer; anemia; nausea; thrombocytopenia; vomiting; antineoplastic combined chemotherapy protocols; antineoplastic activity; pathology; dose-response relationship, drug; pyrimidines; abdominal pain; alanine aminotransferase blood level; aminotransferase blood level; aspartate aminotransferase blood level; dyspnea; alanine aminotransferase; aspartate aminotransferase; bilirubin; maculopapular rash; sulfonamide; sulfonamides; colon cancer; uterine cervix cancer; morpholines; mesothelioma; xerostomia; time to maximum plasma concentration; drug blood level; maximum tolerated dose; phase 1 clinical trial; aniline compounds; drug therapy; indoles; pyrimidine derivative; indole derivative; bilirubin blood level; proto-oncogene proteins c-bcl-2; lymphocyte count; oral mucositis; platelet count; hypocalcemia; small cell lung cancer; appendix cancer; benzamide derivative; benzamides; loose feces; hypertransaminasemia; mammalian target of rapamycin complex 1; navitoclax; mammalian target of rapamycin complex 2; thrush; aniline derivative; morpholine derivative; activated partial thromboplastin time; humans; human; male; female; article; solid malignant neoplasm; vistusertib; maximum concentration; mechanistic target of rapamycin complex 1; mechanistic target of rapamycin complex 2
Journal Title:	Cancer Chemotherapy and Pharmacology
Volume:	95
ISSN:	0344-5704
Publisher:	Springer
Date Published:	2025-02-25
Start Page:	37
Language:	English
DOI:	10.1007/s00280-025-04760-1
PUBMED:	39998620
PROVIDER:	scopus
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85218992208&doi=10.1007%2fs00280-025-04760-1&partnerID=40&md5=e7de0307f4dd969baa0dd242f632d502
Notes:	Article -- Source: Scopus

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