Newton, Massachusetts-based Karyopharm Therapeutics has published the results from its Phase 1 trial of selinexor (KPT-330) in patients with advanced solid tumors in the Journal of Clinical Oncology, revealing clinically significant anti-tumor activity for the drug. These results will serve as a basis for further clinical trials in multiple myeloma patients.
Selinexor is a novel, oral small-molecule inhibitor of the nuclear export protein XPO1 (also known as CRM1), that leads to the accumulation of tumor suppressor proteins (proteins that protect the cells from becoming cancer cells) in the nucleus, inducing apoptosis of the cancer cells, while sparing healthy cells.
The Phase 1 dose escalation trial enrolled 189 patients with advanced or metastatic solid tumors who had received at least one prior treatment and were objectively progressing at the time of enrollment, and evaluated the safety, tolerability, and recommended Phase 2 dose of orally administered selinexor.
Of the 157 patients who were evaluated for response, 47 percent showed an objective response of stable disease or better, with 17 percent experiencing stable disease for at least four months. One patient with melanoma showed complete response, and six patients — one with colorectal cancer (KRAS positive), one with melanoma, prostate cancer, thymoma, ovarian carcinoma, and cervical cancer, respectively, revealed partial response to treatment.
The most common adverse events included nausea, fatigue, anorexia, and vomiting, which were observed in about half of patients, and generally grade 1 or 2. Grade 3 and 4 toxicities included fatigue, thrombocytopenia (low levels of platelets), or low sodium concentration in the blood, events that occurred in about 15 percent of patients and were manageable with supportive care and/or treatment interruption. Several patients received treatment for more than two years without clinically significant cumulative toxicities.
The researchers identified a 60 mg dose twice a week as the recommended Phase 2 dose, due to better patient tolerability, and longer duration of therapy.
“We are very excited with the results of this completely novel mechanism for treating a variety of solid tumors.” Dr. Albiruni Razak, MB MRCPI, Medical Oncology Lead in Sarcoma at Princess Margaret Cancer Centre and Mount Sinai Hospital, and the study’s lead author, said in a press release. “Selinexor showed broad and durable disease control with clear tumor shrinkage across multiple tumor types, consistent with its mechanism of re-activing tumor suppressor proteins. We look forward to additional work in multiple solid tumors, both as a single agent and in combination with existing and emerging therapies.”
Karyopharm is now conducting several Phase 2/3 clinical trials to address selinexor efficacy in solid tumors and hematological cancers. They have initiated the SEAL Phase 2/3 study to evaluate selinexor as single agent in liposarcoma patients and expect to start the SCORE Phase 2/3 trial that will evaluate the selinexor in combination with low-dose dexamethasone and carfilzomib in multiple myeloma patients in mid-2016.
“This study achieved an important milestone in establishing the recommended Phase 2 dose of 60 mg given twice a week. This dosing regimen is supported by results from other early-stage selinexor clinical trials across a variety of indications, which showed that selinexor, dosed at approximately 60 mg, is associated with maximal overall response rates. We believe that this dose optimizes the therapeutic window, response rates and duration of treatment,” said Sharon Shacham, Ph.D., president and chief scientific officer of Karyopharm.
“Based on these encouraging single-agent data for selinexor, including partial responses and durable stable disease for greater than four months in a variety of heavily pre-treated, advanced solid tumors, we have initiated clinical studies in gynecological malignancies, glioblastoma multiforme and liposarcoma and look forward to initiating studies in combination with existing therapies and emerging therapies, such as checkpoint inhibitors,” Shacham said.