Richards, Donald

Abstract Background Protein phosphatase (PP2A) is a multifunctional protein involved in regulation of cell cycle, DNA-damage response, and apoptosis. LB-100, a novel small molecule inhibitor of PP2A, inhibits the growth of a broad spectrum of leukemic and solid tumor cell lines. In addition, LB100 potentiates the effectiveness of cytotoxic drugs (cisplatin, docetaxel, doxorubicin, temozolomide) and radiation without significant increases in toxicity. The predominant mechanisms responsible for potentiation are inhibition of mitotic exit and homologous recombination repair. Methods This is an open label, first-time-in-human, multicenter, phase 1 study of LB-100 in patients with advanced cancer refractory to standard therapies. The first part of the study determines the maximum tolerated dose (MTD) of LB-100 as a single agent when given intravenously days 1-3 every 21 days. Utilizing a standard 3+3 design, patients (pts) are evaluated for dose limiting toxicities (DLT) through 2 cycles. Once the single agent MTD is determined, the dose will be reduced by 2 dose levels (DL) and combined with docetaxel given on day 2. Escalation will continue until the MTD of the combination is determined. Plasma sampling for pharmacokinetics of LB-100 will be collected on days 1 and 3 of cycle 1 in the MTD confirmation cohort. Results The starting dose of LB-100 was 0.25 mg/m2 and 21 pts have enrolled in part 1 of the study through six dose levels. At DL6, pts received 2.33 mg/m2 and no DLTs have been observed. One pt with metastatic colon cancer at DL6 had a grade 2 creatinine after 2 doses that resolved with hydration. This was related to LB-100 and the study was amended to increase the volume and infusion time. One pt on DL3 with stage 4 pancreas cancer had stable disease through 15 cycles of treatment and another pt on DL5 with metastatic thymoma remains on treatment through 8 cycles. Stable disease for 4-6 cycles was also observed in breast, ovarian, carcinoid and testicular cancer patients. Conclusions Rb and p53 mutations are common in malignancies leading to chromosomal instability and overexpression of the mitotic checkpoint gene Mad2. PP2A inhibition results in synthetic lethality of cancer cells overexpressing Mad2 which may be a biomarker for LB100 responsiveness. Through 6 DLs, LB-100 has been well tolerated without any DLTs and early activity has been observed with stabilization of disease in a wide variety of cancers. Correlative studies for biomarkers of response are planned. Clinical trial identifier: NCTO1837667 Citation Format: Vincent Chung, Donald Richards, Fadi Braiteh, John S. Kovach, Aaron Scott Mansfield. A phase 1 study of a novel inhibitor of protein phosphatase 2A alone or in combination with docetaxel. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A175.

Purpose To compare the progression-free survival (PFS) using a treatment regimen selected by molecular profiling (MP) of a patient's tumor with the PFS for the most recent regimen on which the patient had experienced progression (ie, patient as his own control). Patients and Methods Patients with refractory metastatic cancer had tissue samples submitted for MP in two formats including formalin-fixed tissue for immunohistochemistry and fluorescent in situ hybridization assays and immediately frozen tissue for oligonucleotide microarray (MA) gene expression assays (all performed in a Clinical Laboratory Improvement Amendments [ CLIA ] –certified laboratory). The MP approach was deemed of clinical benefit for the individual patient who had a PFS ratio (PFS on MP-selected therapy/PFS on prior therapy) of ≥ 1.3. Results In 86 patients who had MP attempted, there was a molecular target detected in 84 (98%). Sixty-six of the 84 patients were treated according to MP results. Eighteen (27%) of 66 patients had a PFS ratio of ≥ 1.3 (95% CI, 17% to 38%; one-sided, one-sample P = .007). Therefore, the null hypothesis (that ≤ 15% of this patient population would have a PFS ratio of ≥ 1.3) was rejected. Conclusion It is possible to identify molecular targets in patients' tumors from nine different centers across the United States. In 27% of patients, the MP approach resulted in a longer PFS on an MP-suggested regimen than on the regimen on which the patient had just experienced progression. Issues to be considered in interpretation of this study include limited prior experience with patients as their own controls as a study end point and overall patient attrition.