5-(4-amino-1-propan-2-yl-3-pyrazolo[3-4-d]pyrimidinyl)-1-3-benzoxazol-2-amine and Neuroendocrine-Tumors

This was a two-stage phase II trial of a mTORC1/2 inhibitor (mTORC: mammalian target of rapamycin complex) Sapanisertib (TAK228) in patients with rapalog-resistant pancreatic neuroendocrine tumors (PNETs) (NCT02893930). Approved rapalogs such as everolimus inhibit mTORC1 and have limited clinical activity, possibly due to compensatory feedback loops. Sapanisertib addresses the potential for incomplete inhibition of the mTOR pathway through targeting of both mTORC1 and mTORC2, and thus to reverse resistance to earlier rapamycin analogues. In stage 1, patients received sapanisertib 3 mg by mouth once daily on a continuous dosing schedule in 28-day cycle. This trial adopted a two-stage design with the primary objective of evaluating objective tumor response. The first stage would recruit 13 patients in order to accrue 12 eligible and treated patients. If among the 12 eligible patients at least 1 patient had an objective response to therapy, the study would move to the second stage of accrual where 25 eligible and treated patients would be enrolled. This study activated on February 1, 2017, the required pre-determined number of patients (n = 13) had entered by November 5, 2018 for the first stage response evaluation. The accrual of this trial was formally terminated on December 27, 2019 as no response had been observed after the first stage accrual. Treatment-related grade 3 adverse events were reported in eight (61%) patients with hyperglycemia being the most frequent, in three patients (23%). Other toxicities noted in the trial included fatigue, rash diarrhea, nausea, and vomiting. The median PFS was 5.19 months (95% CI [3.84, 9.30]) and the median OS was 20.44 months (95% CI [5.65, 22.54]). Due to the lack of responses in Stage 1 of the study, the study did not proceed to stage 2. Thus the potential to reverse resistance was not evident.

Topics: Humans; Mechanistic Target of Rapamycin Complex 1; MTOR Inhibitors; Neuroectodermal Tumors, Primitive; Neuroendocrine Tumors; Pancreatic Neoplasms; Protein Kinase Inhibitors; Sirolimus

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Humans; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice, Nude; Neuroendocrine Tumors; Pancreatic Neoplasms; Promoter Regions, Genetic; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Signal Transduction; Thromboplastin; TOR Serine-Threonine Kinases; Tumor Burden; Xenograft Model Antitumor Assays

Patients with pancreatic neuroendocrine tumors (PNET) commonly develop advanced disease and require systemic therapy. However, treatment options remain limited, in part, because experimental models that reliably emulate PNET disease are lacking. We therefore developed a patient-derived xenograft model of PNET (PDX-PNET), which we then used to evaluate two mTOR inhibitor drugs: FDA-approved everolimus and the investigational new drug sapanisertib. PDX-PNETs maintained a PNET morphology and PNET-specific gene expression signature with serial passage. PDX-PNETs also harbored mutations in genes previously associated with PNETs (such as

Topics: Animals; Benzoxazoles; Cell Line, Tumor; Drug Resistance, Neoplasm; Everolimus; Humans; Mice, Nude; Neuroendocrine Tumors; Organometallic Compounds; Pancreatic Neoplasms; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays