FDA Places Partial Clinical Hold on Selinexor Trials

The FDA has placed a partial clinical hold on trials of selinexor (KPT-330), which is being explored in several tumor types. Although the hold stops additional enrollment in the trials, patients who have achieved stable disease (SD) or better can continue treatment, according to Karyopharm, the company developing the agent.

“The FDA has indicated that the partial clinical hold is due to incomplete information in the existing version of the investigator's brochure (IB), including an incomplete list of serious adverse events associated with selinexor. At the FDA's request, Karyopharm has amended the IB and updated the informed consent documents accordingly and has submitted such documents to the FDA as requested,” Karyopharm reported in a statement.

The company noted the hold is not related to any new safety concerns. Now that the FDA has received the requested materials from Karyopharm, the agency will review the information and make a decision within 30 days on whether or not to lift the hold.

Selinexor links to and inhibits XPO1 (CRM1), a nuclear export protein. There is an accumulation of tumor suppressor proteins in the cell nucleus as a results of this activity, and, subsequently, the cell’s tumor suppressor function is regained and amplified, which investigators hypothesize induces apoptosis.

According to Karyopharm, over 1900 patients with various hematologic malignancies and solid tumors have received selinexor in a clinical trial. Results from the phase IIb STORM trial reported at the 2016 ASH annual meeting showed that selinexor, in combination with dexamethasone, induced a response rate of 20.5% (n = 16) among 78 heavily pretreated patients with relapsed/refractory multiple myeloma.

In 48 patients with “quad-refractory” disease, the overall response rate (ORR) was 20.8% (n = 10), and in 30 patients with “penta-refractory” disease, the ORR was 20% (n = 6). In the overall population, the median progression-free survival (PFS) and overall survival (OS) were 2.3 and 9.3 months, respectively.

In the multicenter, single-arm phase IIb STORM trial, 79 patients with heavily pretreated relapsed/refractory multiple myeloma (median of 7 prior treatment regimens) received 80 mg of oral selinexor plus 20 mg of oral dexamethasone twice weekly. Over each 4-week cycle, patients were dosed continuously (8 doses/cycle), or 3 weeks on and 1 week off (6 doses/cycle). The primary endpoint was ORR.

Sixty-one percent of patients (n = 48) were quad-refractory, meaning they had received the proteasome inhibitors (PIs) bortezomib (Velcade) and carfilzomib (Kyprolis), as well as the immunomodulatory agents (IMiDs) lenalidomide (Revlimid) and pomalidomide (Pomalyst). Thirty-nine percent of patients (n = 31) were penta-refractory, meaning they were also refractory to an anti-CD38 agent, such as daratumumab (Darzalex) or isatuximab.

The clinical benefit rate (CBR; defined as very good partial response [VGPR] + partial response [PR] + minor response [MR]) was 33% in the overall population. The VGPR, PR, and MR rates were 5%, 15%, and 13%, respectively. The SD and progressive disease (PD) rates were 35% and 12%, respectively.

Among patients receiving the 6-dose regimen, the ORR was 20%. The CBR was 29%, comprising VGPR, PR, and MR rates of 6%, 14%, and 10%, respectively. The SD and PD rates were 41% and 8%, respectively. In those receiving the 8-dose regimen, the ORR was 22%. The CBR was 41%, comprising VGPR, PR, and MR rates of 4%, 19%, and 19%, respectively. The SD and PD rates were 22% and 19%, respectively.

In patients with del(17p), the ORR was 38%. The CBR was 63%, comprising VGPR, PR, and MR rates of 13%, 25%, and 25%, respectively. The SD and PD rates were 25% and 13%, respectively.

The median time to response was 1 month and the median duration of response was 5 months. Among patients who achieved at least an MR, the median OS was not reached and the median PFS was 5.5 months.

Earlier this month, Karyopharm announced that an independent monitoring panel had determined at a planned interim analysis that the phase II 2 SOPRA study examining selinexor monotherapy in patients with relapsed/refractory acute myeloid leukemia (AML) would not meet its primary endpoint of a statistically significant improvement in OS. However, an OS benefit over physician’s choice was observed in patients who achieved a complete response (CR), and thus patients on the trial will be allowed to continue treatment after a discussion with their physician.

The SOPRA trial randomized approximately 176 patients aged 60 years or older with relapsed/refractory AML who were ineligible for intensive chemotherapy and/or transplantation to single-agent oral selinexor at 60 mg twice weekly or physician’s choice (best supportive care [BSC] alone, or BSC plus either azacitidine, decitabine, or low-dose cytosine arabinoside).

The CR with or without full hematologic recovery was 13% in the selinexor arm versus 3% in the physician’s choice arm. However, there was not a statistically significant OS benefit with selinexor.

The most common all-grade adverse events included nausea, anorexia, fatigue, vomiting, and thrombocytopenia. Rates of sepsis (4.9% vs 6.1%) and febrile neutropenia (14.7% vs 36.4%) were lower for the selinexor arm versus the physician’s choice arm.

“SOPRA is a robust, well-conducted trial and the response rates achieved with single-agent selinexor in this heavily pretreated older population have been encouraging,” Hagop Kantarjian, MD, Chair of the Department of Leukemia, The University of Texas MD Anderson Cancer Center, said in a statement accompanying the announcement of the result. “Importantly, the safety profile was as expected and the recommended phase II dose was generally well-tolerated. Unfortunately, as is common in AML, the higher response rates observed with single-agent selinexor versus physician’s choice did not translate into extended survival in the overall population of these frail and heavily pretreated patients.”

Karyopharm intends to continue exploring selinexor in AML through various combination regimens in investigator-sponsored trials.

Vogl DT, Dingli D, Cornell RF, et al. Selinexor and low dose dexamethasone (Sd) in patients with lenalidomide, pomalidomide, bortezomib, carfilzomib and anti-CD38 Ab refractory multiple myeloma (MM): STORM study. Presented at: 58th American Society of Hematology Annual Meeting; San Diego, CA; December 3-6, 2016. Abstract 491.

In quad-refractory patients the CBR was 29%, comprising VGPR, PR, and MR, rates of 4%, 17%, and 8%, respectively. The SD and PD rates were 44% and 8%, respectively. In penta-refractory patients the CBR was 40%, comprising VGPR, PR, and MR rates of 7%, 13%, and 20%, respectively. The SD and PD rates were 20% and 17%, respectively.