Novel agent shows promising activity in heavily pretreated NHL

 

 

Lobby view at ASCO 2014

©ASCO/Rodney White

 

CHICAGO—The novel, oral selective inhibitor of nuclear transport known as selinexor (KPT-330) can safely be given as monotherapy to patients with heavily pretreated non-Hodgkin lymphoma (NHL), according to a presentation at the 2014 ASCO Annual Meeting.

“Selinexor has favorable pharmacokinetic and pharmacodynamic characteristics,” said presenter Martin Gutierrez, MD, of the John Theurer Cancer Center at Hackensack University Medical Center in New Jersey.

Selinexor is a slowly reversible, selective inhibitor of nuclear transport that inhibits XPO1, which is elevated in NHL, chronic lymphocytic leukemia (CLL), and other malignances.

“It shows single-agent anti-tumor activity across all NHL types, with durable cancer control of more than 9 months [and] marked activity across germ cell B (GCB), non-germ cell B, and double-hit diffuse large B-cell lymphoma (DLBCL),” Dr Gutierrez said.

He provided an update of the ongoing phase 1 dose-escalation study at the meeting as abstract 8518.

The study now includes 51 patients, half of whom have NHL. Their median age is 60 years.

The patients received selinexor across 8 dose levels, ranging from 3 mg/m² to 60 mg/m². Dosing at 60 mg/m² twice weekly is ongoing, and the maximum-tolerated dose has not been reached.

Among the 43 evaluable patients, the disease control rate was 74%, the overall response rate was 28%, and the complete response rate was 5%.

“All patients who had their disease controlled had a reduction in lymph nodes and some degree of activity across all dose levels,” Dr Gutierrez said. “GCB and non-GCB patients responded similarly.”

The length of response was up to 632 days in the DLBCL group.

Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.

The investigators found a higher incidence of side effects in the first treatment cycle. The dosing schedule was interrupted and reduced to maintain steady state levels.

“The results suggest that an intermittent dosing schedule optimally induces a steady state with maximal induction of XPO1 mRNA,” Dr Gutierrez said.

There were 3 dose-limiting toxicities, including 1 multiple myeloma patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.

ASCO discussant Owen O’Connor, MD, from Columbia University Medical Center in New York, commented, “These clinical data are interesting with a provocative target. I applaud the investigators for doing a trial across a diversity of B- and T-cell lymphomas . . . . The results suggest a potential effect in a rare subset of lymphoma patients that have little treatment options.”

Frontline trials of selinexor are planned, including patients with Richter transformation and follicular lymphoma.

Selinexor recently received orphan drug status from the US Food and Drug Administration for the treatment of DLBCL.

 

 

Lobby view at ASCO 2014

©ASCO/Rodney White

 

CHICAGO—The novel, oral selective inhibitor of nuclear transport known as selinexor (KPT-330) can safely be given as monotherapy to patients with heavily pretreated non-Hodgkin lymphoma (NHL), according to a presentation at the 2014 ASCO Annual Meeting.

“Selinexor has favorable pharmacokinetic and pharmacodynamic characteristics,” said presenter Martin Gutierrez, MD, of the John Theurer Cancer Center at Hackensack University Medical Center in New Jersey.

Selinexor is a slowly reversible, selective inhibitor of nuclear transport that inhibits XPO1, which is elevated in NHL, chronic lymphocytic leukemia (CLL), and other malignances.

“It shows single-agent anti-tumor activity across all NHL types, with durable cancer control of more than 9 months [and] marked activity across germ cell B (GCB), non-germ cell B, and double-hit diffuse large B-cell lymphoma (DLBCL),” Dr Gutierrez said.

He provided an update of the ongoing phase 1 dose-escalation study at the meeting as abstract 8518.

The study now includes 51 patients, half of whom have NHL. Their median age is 60 years.

The patients received selinexor across 8 dose levels, ranging from 3 mg/m² to 60 mg/m². Dosing at 60 mg/m² twice weekly is ongoing, and the maximum-tolerated dose has not been reached.

Among the 43 evaluable patients, the disease control rate was 74%, the overall response rate was 28%, and the complete response rate was 5%.

“All patients who had their disease controlled had a reduction in lymph nodes and some degree of activity across all dose levels,” Dr Gutierrez said. “GCB and non-GCB patients responded similarly.”

The length of response was up to 632 days in the DLBCL group.

Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.

The investigators found a higher incidence of side effects in the first treatment cycle. The dosing schedule was interrupted and reduced to maintain steady state levels.

“The results suggest that an intermittent dosing schedule optimally induces a steady state with maximal induction of XPO1 mRNA,” Dr Gutierrez said.

There were 3 dose-limiting toxicities, including 1 multiple myeloma patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.

ASCO discussant Owen O’Connor, MD, from Columbia University Medical Center in New York, commented, “These clinical data are interesting with a provocative target. I applaud the investigators for doing a trial across a diversity of B- and T-cell lymphomas . . . . The results suggest a potential effect in a rare subset of lymphoma patients that have little treatment options.”

Frontline trials of selinexor are planned, including patients with Richter transformation and follicular lymphoma.

Selinexor recently received orphan drug status from the US Food and Drug Administration for the treatment of DLBCL.

 

 

Lobby view at ASCO 2014

©ASCO/Rodney White

 

CHICAGO—The novel, oral selective inhibitor of nuclear transport known as selinexor (KPT-330) can safely be given as monotherapy to patients with heavily pretreated non-Hodgkin lymphoma (NHL), according to a presentation at the 2014 ASCO Annual Meeting.

“Selinexor has favorable pharmacokinetic and pharmacodynamic characteristics,” said presenter Martin Gutierrez, MD, of the John Theurer Cancer Center at Hackensack University Medical Center in New Jersey.

Selinexor is a slowly reversible, selective inhibitor of nuclear transport that inhibits XPO1, which is elevated in NHL, chronic lymphocytic leukemia (CLL), and other malignances.

“It shows single-agent anti-tumor activity across all NHL types, with durable cancer control of more than 9 months [and] marked activity across germ cell B (GCB), non-germ cell B, and double-hit diffuse large B-cell lymphoma (DLBCL),” Dr Gutierrez said.

He provided an update of the ongoing phase 1 dose-escalation study at the meeting as abstract 8518.

The study now includes 51 patients, half of whom have NHL. Their median age is 60 years.

The patients received selinexor across 8 dose levels, ranging from 3 mg/m² to 60 mg/m². Dosing at 60 mg/m² twice weekly is ongoing, and the maximum-tolerated dose has not been reached.

Among the 43 evaluable patients, the disease control rate was 74%, the overall response rate was 28%, and the complete response rate was 5%.

“All patients who had their disease controlled had a reduction in lymph nodes and some degree of activity across all dose levels,” Dr Gutierrez said. “GCB and non-GCB patients responded similarly.”

The length of response was up to 632 days in the DLBCL group.

Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.

The investigators found a higher incidence of side effects in the first treatment cycle. The dosing schedule was interrupted and reduced to maintain steady state levels.

“The results suggest that an intermittent dosing schedule optimally induces a steady state with maximal induction of XPO1 mRNA,” Dr Gutierrez said.

There were 3 dose-limiting toxicities, including 1 multiple myeloma patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.

ASCO discussant Owen O’Connor, MD, from Columbia University Medical Center in New York, commented, “These clinical data are interesting with a provocative target. I applaud the investigators for doing a trial across a diversity of B- and T-cell lymphomas . . . . The results suggest a potential effect in a rare subset of lymphoma patients that have little treatment options.”

Frontline trials of selinexor are planned, including patients with Richter transformation and follicular lymphoma.

Selinexor recently received orphan drug status from the US Food and Drug Administration for the treatment of DLBCL.