Xpovio (selinexor), developed by Karyopharm Therapeutics, is an oral treatment, used in combination with dexamethasone, for people with relapsed or refractory multiple myeloma treated with at least four prior therapies and who are not responding to several types of these therapies.

It received accelerated approval from the U.S. Food and Drug Administration (FDA) in July 2019 because of the high unmet need in these patients and benefits shown in clinical studies. But be awarded full approval, further clinical trials demonstrating its efficacy are likely required.

Xpovio is also being investigated as a potential treatment of other cancers.

How does Xpovio work?

Cells contain natural tumor suppressors that block cancer-promoting mechanisms. They act in the cell nucleus (where genetic information is stored) and suppress the activity of genes involved in cell growth and division.

One way cancer cells escape the action of tumor suppressors is by exporting them out of their nucleus. Outside the nucleus, tumor suppressors cannot work as intended.

Shuttling of proteins such as tumor suppressors out of the nucleus of cells occurs with the help of a protein called exportin 1 or XPO1. Cancer cells often produce XPO1 in large amounts to ensure the nuclear export of tumor suppressors.

Xpovio inhibits the activity of XPO1, acting to block or inhibit nuclear export to prevent the loss of tumor suppressors within cancer cells. As a result, more tumor suppressors stay inside the nucleus and act to halt cell division, thereby inhibiting tumor growth.

Xpovio in clinical trials

Accelerated FDA approval was based on data from an open-label Phase 2 clinical trial (NCT02336815) called STORM, assessing the safety and efficacy of Xpovio in combination with dexamethasone. The trial was divided into parts. The first part included relapsed or refractory multiple myeloma (RRMM) patients who failed to respond to four or five prior therapies, while the second part included only patients unresponsive to five prior therapies. A total of 202 people were given 80 mg of Xpovio and 20 mg of dexamethasone orally twice a week. The response rate to treatment was measured by assessing the amount of M-protein in patients’ blood. M-proteins are produced by myeloma cells, and lowered levels indicate a response to treatment. A partial response was defined as a more than 50% reduction in these levels from the study’s start.

A subgroup analysis of 83 patients whose disease was refractory (unresponsive) to Velcade (bortezomib), Kyprolis (carfilzomib), Revlimid (lenalidomide), Pomalyst (pomalidomide), and Darzalex (daratumumab) revealed that 25.3% of patients responded to the treatment. The median duration of response was 3.8 months, and the median time to first response was four weeks. The most common side effects for all patients included low platelet count, low white blood cell count, and low red cell blood count. Fatigue, nausea, vomiting, constipation, weight loss, and diarrhea were also reported.

A Phase 1/2 open-label clinical trial (NCT02186834) is assessing the recommended dose of Xpovio in combination with Adriamycin (doxorubicin) and dexamethasone in up to 28 RRMM patients. This trial is still active and is estimated to be completed in December 2019.

A Phase 1 open-label clinical trial (NCT02831686) is assessing the safety of Xpovio in combination with Ninlaro (ixazomib) and dexamethasone in up to 18 relapsed/refractory MM patients. The trial is also still active, and due to finish in July 2020.

A Phase 3 randomized crossover clinical trial (NCT03110562), called BOSTON, is evaluating the safety, efficacy, and effect on quality of life of Xpovio treatment (oral 100 mg dose) in combination with Velcade (subcutaneous dose of 1.3 mg/m2) and dexamethasone (oral 20mg dose), compared to Velcade and dexamethasone alone, in up to 402 adults with relapsed/refractory MM. The trial, treating patients in 35-day cycles, is also active; its estimated completion date is July 2020.

A number of clinical trials testing Xpovio are also still recruiting patients.

A Phase 1 open-label trial (NCT02199665) called SINE is recruiting up to 100 adults with RRMM at multiple sites across the U.S. It aims to find the maximum tolerated doses of Xpovio, Kyprolis, and dexamethasone; secondary goals will assess treatment efficacy.

A Phase 1/2 open-label clinical trial (NCT02780609) aims to find the maximum tolerated dose of Xpovio in combination with Alkeran (melphalan) and dexamethasone given as a conditioning regimen before autologous hematopoietic stem cell transplantation. The trial is currently recruiting up to 46 patients at the H. Lee Moffitt Cancer Center and Research Institute in Florida.

A Phase 2 open-label clinical trial (NCT03589222) aims to evaluate the response to Xpovio treatment in combination with Darzalex, Velcade, and dexamethasone. The combination will be given as a continuous therapy until disease progression or unacceptable toxicity. The trial is currently recruiting up to 62 patients at several sites in Spain.

A Phase 1/2 randomized clinical trial (NCT02343042) aims to evaluate the safety and efficacy of Xpovio in six different combinations. The medication will be combined with dexamethasone, Revlimid, Pomalyst, Velcade, Darzalex, and Kyprolis in patients with relapsed/refractory disease and those newly diagnosed with multiple myeloma. The trial is currently recruiting up to 321 adults at sites across the U.S. and Canada.

A Phase 2 open-label clinical trial (NCT03944057) called MARCH aims to assess the response rate of Xpovio treatment in combination with low-dose dexamethasone (20 mg twice weekly) in patients with multiple myeloma previously treated with Revlimid and Velcade, and refractory to prior treatment with proteasome inhibitors and immunomodulatory agents. The trial is currently recruiting up to 82 patients at the Tianjin Blood Research Institute in Tianjin, China.

 

Last updated: Nov. 14, 2019

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Özge has a MSc. in Molecular Genetics from the University of Leicester and a PhD in Developmental Biology from Queen Mary University of London. She worked as a Post-doctoral Research Associate at the University of Leicester for six years in the field of Behavioural Neurology before moving into science communication. She worked as the Research Communication Officer at a London based charity for almost two years.