This study was conducted to evaluate the tolerability of selinexor and to establish the recommended phase II dose in an Asian population.
We investigated 4 dosing schedules. Schedule 1: twice a week dosing at 40mg/m2 in a 28-day cycle. Schedule 2: once weekly at 50mg/m2 in a 28-day cycle. Schedule 3: twice a week dosing at 40mg/m2, 2 out of 3 weeks in a 21-day cycle. Schedule 4: 3 times a week dosing at 20mg/m2 in a 28-day cycle. Adverse events were graded with the NCI Common Terminology Criteria for Adverse Events v 4.03. Pharmacodynamic assessments: nuclear-cytoplasmic localisation of p27, XPO1 cargo proteins including ki67, apoptag, cleaved caspase 3, and c-myc pre and post selinexor. Pharmacokinetic assessments were conducted in 19 individuals at doses between 40-60mg/m2.
The safest dosing was 40mg/m2 (equivalent 60mg) with no DLTs. The schedule with a 1-week drug holiday was the most tolerable for our patients. G3 adverse events included fatigue (8%), hyponatremia (23%), vomiting (5%), thrombocytopenia (5%), anemia (2%). Selinexor had a rapid oral absorption with median Tmax of 2 h with no PK accumulation after multiple doses of tested regimens. Complete responses were noted in 2 lymphoma patients. Partial responses were noted in 3 DLBCL patients, 1 Hodgkins lymphoma and thymic carcinoma. Stable disease was seen in 12 colorectal cancer patients, 3 pancreatic cancer patients, 2 thymic carcinoma patients, 1 each for ovarian cancer, hepatocellular carcinoma, cholangiocarcinoma, lung cancer, breast cancer, tongue cancer and grey zone lymphoma. An exploratory analysis on 36 colorectal cancer cases with known RAS pathway mutational status showed a median progression free survival of 86 vs 50 days, p=0.09, log-rank in RAS mutant compared to wildtype patients.
Selinexor is tolerated by Asian patients at 60mg twice a week. A 1-week drug holiday was needed as our patients could not tolerate the continuous dosing regimens because of persistent G3 fatigue, anorexia and hyponatremia. Exploratory analyses of colorectal cancer patients alluded to a clinical benefit that selinexor may have significant activity in RAS pathway activated tumors.
The authors.
This study was supported by grant funding from Karyopharm and the National Medical Research Council Singapore, National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centers of Excellence initiative.
H. Xu: Shareholder/Stockholder/Stock options: Karyopharm. All other authors have declared no conflicts of interest.