Inhibitor elicits responses in cGVHD

Amandeep Salhotra, MD

STOCKHOLM—The ROCK2 inhibitor KD025 produced responses in about two-thirds of patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2 trial.

KD025 elicited improvements in Lee Symptom Scale score, and patients were able to reduce doses of corticosteroids and other immunosuppressants.

There were no serious adverse events (AEs) related to KD025 and no apparent increased risk of infection with the drug.

Amandeep Salhotra, MD, of City of Hope in Duarte, California, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S873. The research was sponsored by Kadmon Holdings, Inc.

This ongoing phase 2 trial has enrolled 48 adults with steroid-dependent or steroid-refractory cGVHD and active disease.

The patients were divided into 3 cohorts, in which they received different dose levels of KD025—200 mg daily (cohort 1), 200 mg twice daily (cohort 2), and 400 mg daily (cohort 3).

Dr Salhotra presented results in cohorts 1 (n=17) and 2 (n=16). These patients had cGVHD for a median of 18.9 months before enrollment and had received a median of 3 prior lines of cGVHD therapy. They had cGVHD involvement across all organ systems.

The median age was 50 (range, 20-63) in cohort 1 and 55 (range, 30-75) in cohort 2. The median time to cGHVD diagnosis was 9.1 months in cohort 1 and 7.7 months in cohort 2. The median time from cGVHD diagnosis to enrollment was 25.9 months and 15.8 months, respectively.

All patients in cohort 1 had at least 2 organs involved, as did 94% of patients in cohort 2. Forty-seven percent and 69%, respectively, had at least 4 organs involved.

Treatment duration

The median treatment duration was 37 weeks in cohort 1 and 33 weeks in cohort 2. Four patients in cohort 1 had cGVHD progression, as did 8 patients in cohort 2.

Seven patients in cohort 1 withdrew from the study—2 due to cancer relapse, 2 due to AEs (headache and diarrhea), 1 due to investigator decision, and 2 due to voluntary withdrawal. Three patients in cohort 2 withdrew—1 due to investigator decision and 2 due to voluntary withdrawal.

Six patients are still active in cohort 1, with a median treatment duration of 70 weeks. Five patients are still active in cohort 2, with a median treatment duration of 58 weeks.

Safety

“The adverse events were, overall, consistent with those expected in patients with chronic GVHD receiving corticosteroids,” Dr Salhotra said. “There were no treatment-related serious adverse events, and there was no increased signal of infection.”

Ninety-four percent of patients in both cohorts had AEs. Thirty-five percent of patients in cohort 1 and 63% in cohort 2 had treatment-related AEs. Twelve percent and 31%, respectively, had grade 3 or higher related AEs. Twelve percent of patients in cohort 1 had a related AE leading to discontinuation (2 events, headache and diarrhea).

Commonly reported AEs (in cohorts 1 and 2, respectively) included ALT/AST elevation (35% and 25%), upper respiratory tract infection (24% and 38%), anemia (29% and 25%), gamma-glutamyltransferase elevation (24% and 31%), diarrhea (35% and 13%), and nausea (35% and 13%).

Response

The overall response rate (ORR) was 65% (11/17) in cohort 1 and 69% (11/16) in cohort 2.

In patients with at least 2 prior lines of systemic therapy, the ORR was 65% (11/17) in cohort 1 and 64% (9/14) in cohort 2. In patients with severe cGVHD, the ORR was 67% (8/12) in cohort 1 and 64% (9/14) in cohort 2.

“Responses were rapid,” Dr Salhotra noted. “Seventy-seven percent of the responders achieved a response by the time of first assessment, which was at 8 weeks.”

“These responses were durable. Seventy-three percent (8/11) of responders in cohort 1 and 55% (6/11) of responders in cohort 2 have sustained responses for more than 20 weeks. At the 32-week endpoint, there were 45% (5/11) responders in cohort 1 and 18% (2/11) in cohort 2.”

Dr Salhotra added that responses were observed across all affected organ systems, including complete responses in upper and lower gastrointestinal systems, mouth, joints/fascia, skin, eyes, and liver.

Of the 13 responders in cohorts 1 and 2 with at least 4 organs involved, 46% (n=6) achieved responses in 4 or more organs.

In cohort 1, 73% (8/11) of responders and 83% (5/6) of non-responders had corticosteroid dose reductions. In cohort 2, 55% (6/11) of responders and 60% (3/5) of non-responders had dose reductions.

Five patients have completely discontinued steroids—4 (24%) in cohort 1 and 1 (6%) in cohort 2.

There were 6 patients each in cohorts 1 and 2 who were receiving tacrolimus. Each cohort had 5 patients (83%) who had tacrolimus dose reductions on KD025. One patient completely discontinued tacrolimus.

Sixty-five percent of patients in cohort 1 and 44% in cohort 2 had a clinically meaningful improvement in cGVHD symptoms, which was defined as at least a 7-point decrease in the Lee Symptom Scale score. Both responders and non-responders had such improvements.

Based on these results, Kadmon Holdings, Inc., is planning a pivotal study of KD025 in cGVHD, which is expected to begin in the third quarter of 2018.

Dr Salhotra said the study will enroll adults who have received at least 2 prior lines of systemic therapy for cGVHD. Patients will be randomized to receive KD025 at 200 mg daily or 200 mg twice daily. The primary endpoint will be ORR.

Amandeep Salhotra, MD

STOCKHOLM—The ROCK2 inhibitor KD025 produced responses in about two-thirds of patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2 trial.

KD025 elicited improvements in Lee Symptom Scale score, and patients were able to reduce doses of corticosteroids and other immunosuppressants.

There were no serious adverse events (AEs) related to KD025 and no apparent increased risk of infection with the drug.

Amandeep Salhotra, MD, of City of Hope in Duarte, California, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S873. The research was sponsored by Kadmon Holdings, Inc.

This ongoing phase 2 trial has enrolled 48 adults with steroid-dependent or steroid-refractory cGVHD and active disease.

The patients were divided into 3 cohorts, in which they received different dose levels of KD025—200 mg daily (cohort 1), 200 mg twice daily (cohort 2), and 400 mg daily (cohort 3).

Dr Salhotra presented results in cohorts 1 (n=17) and 2 (n=16). These patients had cGVHD for a median of 18.9 months before enrollment and had received a median of 3 prior lines of cGVHD therapy. They had cGVHD involvement across all organ systems.

The median age was 50 (range, 20-63) in cohort 1 and 55 (range, 30-75) in cohort 2. The median time to cGHVD diagnosis was 9.1 months in cohort 1 and 7.7 months in cohort 2. The median time from cGVHD diagnosis to enrollment was 25.9 months and 15.8 months, respectively.

All patients in cohort 1 had at least 2 organs involved, as did 94% of patients in cohort 2. Forty-seven percent and 69%, respectively, had at least 4 organs involved.

Treatment duration

The median treatment duration was 37 weeks in cohort 1 and 33 weeks in cohort 2. Four patients in cohort 1 had cGVHD progression, as did 8 patients in cohort 2.

Seven patients in cohort 1 withdrew from the study—2 due to cancer relapse, 2 due to AEs (headache and diarrhea), 1 due to investigator decision, and 2 due to voluntary withdrawal. Three patients in cohort 2 withdrew—1 due to investigator decision and 2 due to voluntary withdrawal.

Six patients are still active in cohort 1, with a median treatment duration of 70 weeks. Five patients are still active in cohort 2, with a median treatment duration of 58 weeks.

Safety

“The adverse events were, overall, consistent with those expected in patients with chronic GVHD receiving corticosteroids,” Dr Salhotra said. “There were no treatment-related serious adverse events, and there was no increased signal of infection.”

Ninety-four percent of patients in both cohorts had AEs. Thirty-five percent of patients in cohort 1 and 63% in cohort 2 had treatment-related AEs. Twelve percent and 31%, respectively, had grade 3 or higher related AEs. Twelve percent of patients in cohort 1 had a related AE leading to discontinuation (2 events, headache and diarrhea).

Commonly reported AEs (in cohorts 1 and 2, respectively) included ALT/AST elevation (35% and 25%), upper respiratory tract infection (24% and 38%), anemia (29% and 25%), gamma-glutamyltransferase elevation (24% and 31%), diarrhea (35% and 13%), and nausea (35% and 13%).

Response

The overall response rate (ORR) was 65% (11/17) in cohort 1 and 69% (11/16) in cohort 2.

In patients with at least 2 prior lines of systemic therapy, the ORR was 65% (11/17) in cohort 1 and 64% (9/14) in cohort 2. In patients with severe cGVHD, the ORR was 67% (8/12) in cohort 1 and 64% (9/14) in cohort 2.

“Responses were rapid,” Dr Salhotra noted. “Seventy-seven percent of the responders achieved a response by the time of first assessment, which was at 8 weeks.”

“These responses were durable. Seventy-three percent (8/11) of responders in cohort 1 and 55% (6/11) of responders in cohort 2 have sustained responses for more than 20 weeks. At the 32-week endpoint, there were 45% (5/11) responders in cohort 1 and 18% (2/11) in cohort 2.”

Dr Salhotra added that responses were observed across all affected organ systems, including complete responses in upper and lower gastrointestinal systems, mouth, joints/fascia, skin, eyes, and liver.

Of the 13 responders in cohorts 1 and 2 with at least 4 organs involved, 46% (n=6) achieved responses in 4 or more organs.

In cohort 1, 73% (8/11) of responders and 83% (5/6) of non-responders had corticosteroid dose reductions. In cohort 2, 55% (6/11) of responders and 60% (3/5) of non-responders had dose reductions.

Five patients have completely discontinued steroids—4 (24%) in cohort 1 and 1 (6%) in cohort 2.

There were 6 patients each in cohorts 1 and 2 who were receiving tacrolimus. Each cohort had 5 patients (83%) who had tacrolimus dose reductions on KD025. One patient completely discontinued tacrolimus.

Sixty-five percent of patients in cohort 1 and 44% in cohort 2 had a clinically meaningful improvement in cGVHD symptoms, which was defined as at least a 7-point decrease in the Lee Symptom Scale score. Both responders and non-responders had such improvements.

Based on these results, Kadmon Holdings, Inc., is planning a pivotal study of KD025 in cGVHD, which is expected to begin in the third quarter of 2018.

Dr Salhotra said the study will enroll adults who have received at least 2 prior lines of systemic therapy for cGVHD. Patients will be randomized to receive KD025 at 200 mg daily or 200 mg twice daily. The primary endpoint will be ORR.

Amandeep Salhotra, MD

STOCKHOLM—The ROCK2 inhibitor KD025 produced responses in about two-thirds of patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2 trial.

KD025 elicited improvements in Lee Symptom Scale score, and patients were able to reduce doses of corticosteroids and other immunosuppressants.

There were no serious adverse events (AEs) related to KD025 and no apparent increased risk of infection with the drug.

Amandeep Salhotra, MD, of City of Hope in Duarte, California, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S873. The research was sponsored by Kadmon Holdings, Inc.

This ongoing phase 2 trial has enrolled 48 adults with steroid-dependent or steroid-refractory cGVHD and active disease.

The patients were divided into 3 cohorts, in which they received different dose levels of KD025—200 mg daily (cohort 1), 200 mg twice daily (cohort 2), and 400 mg daily (cohort 3).

Dr Salhotra presented results in cohorts 1 (n=17) and 2 (n=16). These patients had cGVHD for a median of 18.9 months before enrollment and had received a median of 3 prior lines of cGVHD therapy. They had cGVHD involvement across all organ systems.

The median age was 50 (range, 20-63) in cohort 1 and 55 (range, 30-75) in cohort 2. The median time to cGHVD diagnosis was 9.1 months in cohort 1 and 7.7 months in cohort 2. The median time from cGVHD diagnosis to enrollment was 25.9 months and 15.8 months, respectively.

All patients in cohort 1 had at least 2 organs involved, as did 94% of patients in cohort 2. Forty-seven percent and 69%, respectively, had at least 4 organs involved.

Treatment duration

The median treatment duration was 37 weeks in cohort 1 and 33 weeks in cohort 2. Four patients in cohort 1 had cGVHD progression, as did 8 patients in cohort 2.

Seven patients in cohort 1 withdrew from the study—2 due to cancer relapse, 2 due to AEs (headache and diarrhea), 1 due to investigator decision, and 2 due to voluntary withdrawal. Three patients in cohort 2 withdrew—1 due to investigator decision and 2 due to voluntary withdrawal.

Six patients are still active in cohort 1, with a median treatment duration of 70 weeks. Five patients are still active in cohort 2, with a median treatment duration of 58 weeks.

Safety

“The adverse events were, overall, consistent with those expected in patients with chronic GVHD receiving corticosteroids,” Dr Salhotra said. “There were no treatment-related serious adverse events, and there was no increased signal of infection.”

Ninety-four percent of patients in both cohorts had AEs. Thirty-five percent of patients in cohort 1 and 63% in cohort 2 had treatment-related AEs. Twelve percent and 31%, respectively, had grade 3 or higher related AEs. Twelve percent of patients in cohort 1 had a related AE leading to discontinuation (2 events, headache and diarrhea).

Commonly reported AEs (in cohorts 1 and 2, respectively) included ALT/AST elevation (35% and 25%), upper respiratory tract infection (24% and 38%), anemia (29% and 25%), gamma-glutamyltransferase elevation (24% and 31%), diarrhea (35% and 13%), and nausea (35% and 13%).

Response

The overall response rate (ORR) was 65% (11/17) in cohort 1 and 69% (11/16) in cohort 2.

In patients with at least 2 prior lines of systemic therapy, the ORR was 65% (11/17) in cohort 1 and 64% (9/14) in cohort 2. In patients with severe cGVHD, the ORR was 67% (8/12) in cohort 1 and 64% (9/14) in cohort 2.

“Responses were rapid,” Dr Salhotra noted. “Seventy-seven percent of the responders achieved a response by the time of first assessment, which was at 8 weeks.”

“These responses were durable. Seventy-three percent (8/11) of responders in cohort 1 and 55% (6/11) of responders in cohort 2 have sustained responses for more than 20 weeks. At the 32-week endpoint, there were 45% (5/11) responders in cohort 1 and 18% (2/11) in cohort 2.”

Dr Salhotra added that responses were observed across all affected organ systems, including complete responses in upper and lower gastrointestinal systems, mouth, joints/fascia, skin, eyes, and liver.

Of the 13 responders in cohorts 1 and 2 with at least 4 organs involved, 46% (n=6) achieved responses in 4 or more organs.

In cohort 1, 73% (8/11) of responders and 83% (5/6) of non-responders had corticosteroid dose reductions. In cohort 2, 55% (6/11) of responders and 60% (3/5) of non-responders had dose reductions.

Five patients have completely discontinued steroids—4 (24%) in cohort 1 and 1 (6%) in cohort 2.

There were 6 patients each in cohorts 1 and 2 who were receiving tacrolimus. Each cohort had 5 patients (83%) who had tacrolimus dose reductions on KD025. One patient completely discontinued tacrolimus.

Sixty-five percent of patients in cohort 1 and 44% in cohort 2 had a clinically meaningful improvement in cGVHD symptoms, which was defined as at least a 7-point decrease in the Lee Symptom Scale score. Both responders and non-responders had such improvements.

Based on these results, Kadmon Holdings, Inc., is planning a pivotal study of KD025 in cGVHD, which is expected to begin in the third quarter of 2018.

Dr Salhotra said the study will enroll adults who have received at least 2 prior lines of systemic therapy for cGVHD. Patients will be randomized to receive KD025 at 200 mg daily or 200 mg twice daily. The primary endpoint will be ORR.