A phase 1 study of the safety, pharmacokinetics and pharmacodynamics of escalating doses followed by dose expansion of the selective inhibitor of nuclear export (SINE) selinexor in Asian patients with advanced or metastatic malignancies.

Purpose: This phase 1 study aims to evaluate the tolerability and the recommended phase 2 dose of selinexor in Asian patients with advanced or metastatic malignancies. Experimental Design: A total of 105 patients with advanced malignancies were enrolled from two sites in Singapore (National University Hospital and the National Cancer Centre, Singapore) from 24 February 2014 to 14 January 2019. We investigated four dosing schedules of selinexor in a 3 + 3 dose escalation design with an additional Phase 1b expansion cohort. Adverse events were graded with the NCI Common Terminology Criteria for Adverse Events v 4.03. Pharmacodynamic assessments included nuclear cytoplasmic localization of p27, XPO1 cargo proteins pre and post selinexor dosing and pharmacokinetic assessments were conducted at doses between 40 and 60 mg/m2. Results: In our Asian patient cohort, dosing at 40 mg/m2 given 2 out of 3 weeks, was the most tolerable for our patients. At this dose level, grade 3 adverse events included fatigue (8%), hyponatremia (23%), vomiting (5%), thrombocytopenia (5%), and anaemia (2%). Selinexor had a rapid oral absorption with median Tmax of 2 h and no PK accumulation after multiple doses of tested regimens. Complete responses were seen in two lymphoma patients. Partial responses were noted in three diffuse large B cell lymphomas, one Hodgkin's lymphoma and thymic carcinoma patient, respectively. Conclusion: Selinexor is tolerated by Asian patients at 40 mg/m2 twice a week given 2 out of 3 weeks. A 1-week drug holiday was needed as our patients could not tolerate the current approved continuous dosing regimens because of persistent grade 3 fatigue, anorexia and hyponatremia.

Imaging paradigms in assessment of rectal carcinoma: loco-regional and distant staging.

The role of imaging in the management of rectal malignancy has progressively evolved and undergone several paradigm shifts. Unlike a few decades ago when the role of a radiologist was restricted at defining the longitudinal extent of the tumour with barium enema, recent advances in imaging techniques permit highly accurate locoregional and distant staging of the disease as well as prognostication on those who are likely to have a postoperative recurrence. Computed tomography (CT) has always been the mainstay of imaging when evaluating for distant metastasis, with the advent of positron emission tomography/CT improving its specificity. In rectal malignancy, it is the local extent of the disease that often influences the surgical decision making and need for neoadjuvant therapy. Although endoscopic ultrasound has been the traditional technique for determining the depth of tumour invasion, over the last decade magnetic resonance imaging (MRI) has emerged as a very effective tool for accurate T-staging. This review intends to address the status of various imaging modalities and their advantages and limitations in detection, pretreatment staging, and assessment of therapeutic efficacy in rectal cancer, with emphasis on MRI of high spatial resolution.