Efficacy and Safety of BN101 in Subjects With Chronic Graft Versus Host Disease (cGVHD)

BioNova Pharmaceuticals (Shanghai) LTD.30 enrolled

Overview

This is a phase 2, open-label, multicenter trial to evaluate the efficacy and safety of BN101 in subjects with Chronic Graft Versus Host Disease (cGVHD) after at least First Line of systemic therapy.

Approximately 30 subjects will be enrolled to receive orally administered BN101 200 mg QD (once daily) Study drug will be administered in 28-day cycles until disease progression or unacceptable toxicity. Subjects may receive study drug in the inpatient or outpatient setting. Curative Effect analysis The efficacy was analyzed based on MITT The point estimate and 95%CI of ORR were calculated based on the exact probability method of binomial distribution.If applicable, a logistic regression model will be used for multivariate analysis. Descriptive statistical analyses were provided for all secondary efficacy endpoints. The following subgroups will be analysed: * Severe cGVHD (Yes/No) * Number of organs involved (\<4 vs. ≥4) * Number of previous systemic cGVHD treatment (1 vs. ≥2) * Duration of cGVHD before inclusion (i.e., from the time of cGVHD diagnosis to the time of inclusion) * Lung Involvement (Yes/No)

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

GVHD, Chronic

Interventions

BN101DRUG

BN101 is an orally ROCK2 selective inhibitor

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Male and female subjects at least 18 years of age who have had allogenic hematopoietic cell transplant (HCT). * Previously received at least 1 and not more than 5 lines of systemic therapy for cGVHD * Receiving glucocorticoid therapy with a stable dose over the 2 weeks prior to screening; * Have persistent cGVHD manifestations and systemic therapy is indicated Exclusion Criteria: * Subject has not been on a stable dose / regimen of systemic cGVHD treatments for at least 2 weeks prior to screening. (Note: Concomitant corticosteroids, calcineurin inhibitors, sirolimus, MMF, methotrexate, rituximab, and extracorporeal photophoresis (ECP) are acceptable. Systemic investigational GVHD treatments are not permitted). * Histological relapse of the underlying cancer or post-transplant lymphoproliferative disease at the time of screening. * Current treatment with ibrutinib. Prior treatment with ibrutinib is allowed with a washout of at least 28 days prior to treatment.

Locations (7)

Peking University People's Hospital

Beijing, China

Xinqiao Hospital, Army Medical University

Chongqing, China

Guangzhou First People's Hospital

Guangzhou, China

Nanfang Hospital

Guangzhou, China

Outcomes

Primary Outcomes

Overall Response Rate (ORR)

OR was defined as the percentage of participants with complete response (CR) or partial response (PR). The OR determination of chronic graft versus host disease (cGVHD) was based on cGVHD response assessment performed by clinicians as per the 2014 National Institutes of Health (NIH) Consensus Development Project for Clinical Trials in cGVHD criteria. CR was defined as the resolution of all manifestations in each organ or site. PR was defined as the improvement in at least 1 organ or site without progression in any other organ or site; and cGVHD progression was defined as the clinically meaningful worsening in 1 or more organs regardless of improvement in other organs.

Time frame: 12 Months

Secondary Outcomes

Duration of Response (DOR)

The DOR was defined as the time (in weeks) from first documentation of response to the time of first documentation of deterioration from best response (e.g., CR to PR, or PR to LR). LOR included the response status of unchanged (LOR-U), mixed (LOR-M), or progression (LOR-P). Per the 2014 NIH Consensus Development Project for Clinical Trials in cGVHD criteria; CR was defined as the resolution of all manifestations in each organ or site; PR was defined as the improvement in at least 1 organ or site without progression in any other organ or site; LOR-M was defined as CR or PR in at least one organ accompanied by progression in another organ, LOR-U was defined as outcomes that did not meet the criteria for CR, PR, progression or mixed response, LOR-P was defined as progression in at least one organ or site without a response in any other organ or site. Kaplan-Meier was used for the analysis.

Time frame: 12 Months

Time-to-Response (TTR)

Time-to-response was measured as the time (in weeks) from first dose of study drug to the time of first documentation of response. Response was defined as the participants achieving a PR or CR at any post-baseline response assessment. Per the 2014 NIH Consensus Development Project for Clinical Trials in cGVHD criteria; CR was defined as the resolution of all manifestations in each organ or site and PR was defined as the improvement in at least 1 organ or site without progression in any other organ or site

Data from ClinicalTrials.gov

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Zhujiang Hospital of Southern Medical University

Guangzhou, China

The First Affiliated Hospital of Soochow University

Suzhou, China

The Affiliated Hospital of Xuzhou Medical University

Xuzhou, China

Time frame: 12 months

Number of Participants With Best Response in Each Individual Organ

Best response was defined as the percentage of participants with CR or PR. Response was assessed per the 2014 NIH Consensus Development Project for Clinical Trials in cGVHD criteria; CR was defined as the resolution of all manifestations in each organ or site; PR was defined as the improvement in at least 1 organ or site without progression in any other organ or site. Organ response assessment was performed on 9 individual organs: skin, eyes, mouth, esophagus, upper gastrointestinal (GI), lower GI, liver, lungs, and joints and fascia and is reported in this outcome measure.

Time frame: 12 months

Number of Participants With Change From Baseline in Overall Score on Lee cGvHD Symptom Scale at Specified Time Points

Lee cGVHD symptom scale, a patient-reported symptom scale used to measure symptom burden and has 7 subscales (Skin, Eyes and Mouth, Breathing, Eating and Digestion, Muscles and Joints, Energy, and Mental and Emotional) with ratings as follows: 0-Not at all, 1-Slightly, 2-Moderately, 3-Quite a bit, 4-Extremely, with lower values representing better outcome. Score for each subscale was normalized to a score ranged from 0 to 100, where higher score=worse symptoms. An overall Lee cGvHD score was calculated as average of these 7 subscales and it ranged from 0 to 100, where a higher score = worse symptoms. EOT visit was performed within 3 days after the participant's last dose of study drug. Baseline value was defined as valid and last non-missing value obtained within 28 days prior to participant receiving first study medication.

Time frame: Baseline and 12 months

Failure-free Survival (FFS)

Failure-free survival was defined as the time (in months) from first dose of study drug to either the start of another new systemic treatment for cGVHD, relapse of the underlying disease or death. If no such events happened, FFS was censored by last response assessment or long term follow up assessment, whichever was the latest and available. Kaplan-Meier survival method was used for the analysis.

Time frame: 12 months

Time to Next Therapy (TTNT)

The TTNT was defined as the time (in months) from first treatment to the time of new systemic cGVHD treatment. TTNT was censored by last response assessment or long term follow up assessment, whichever was earlier. Kaplan-Meier survival method was used for the analysis.

Time frame: 12months

Overall Survival (OS)

Overall survival was defined as the time (in months) from first dose of study drug to the death due to any reason. If there was no death, OS was censored by last visit, last long-term follow-up, or study cut-off date, whichever occurred first. Kaplan-Meier survival method was used for the analysis.

Time frame: 12months

Change From Baseline in Corticosteroids Dose

Baseline value was defined as valid and last non-missing value obtained within 28 days prior to participant receiving first study medication. EOT visit was performed within 7 days after the participant's last dose of study drug.

Time frame: 12months

Number of Participants With Change From Baseline in Calcineurin Inhibitor (CNI) Usage.

Calcineurin inhibitors included systemic tacrolimus and cyclosporine. Number of participants who took CNI at Baseline and had reduction and discontinuation in CNI use as compared to Baseline during the study are reported in this outcome measure. EOT visit was performed within 7 days after the participant's last dose of study drug. Baseline value was defined as valid and last non-missing value obtained within 28 days prior to participant receiving first study medication.

Time frame: 12months

Change From Baseline in in Global Severity Rating (GSR) Score by Clinician-reported cGVHD Assessment

The GSR assessment was performed by asking the participants to rate their disease severity of cGVHD symptoms on a 0 to 10-point numeric rating scale, where score 0 indicated 'not at all severe cGVHD symptoms' and score 10 indicated 'most severe cGVHD symptoms possible'. The response was defined using scores from 9 organs: skin, eyes, mouth, esophagus, upper gastrointestinal (GI) track, lower GI tract, liver, lungs, and joints and fascia plus GSR. End of treatment (EOT) visit was performed within 7 days after participant's last dose of study drug. Baseline value was defined as valid and last non-missing value obtained within 28 days prior to participant receiving first study medication. Change from Baseline was calculated as GSR score at Baseline minus the lowest GSR score on scheduled visits with possible ranges from -10 to 10. The higher the number means the better improvement in cGVHD symptoms. Only those categories in which at least 1 participant had data were reported.

Time frame: 12months

Change From Baseline in Symptom Activity by cGVHD Activity Assessment Participant Self-Report

cGVHD symptom severity was self-reported by participants. Participants were asked to rate their disease symptom severity over the last week on the following questions: skin itching at its worst, moth dryness at its worst, mouth pain at its worst, mouth sensitivity at its worst, main compliant on eyes, symptom severity on eyes. Severity rating was done on a 0 to 10-point numeric rating scare, where score 0 indicated 'not at all severe cGVHD symptoms' and score 10 indicated 'most severe cGVHD symptoms possible'. EOT visit was performed within 7 days after participant's last dose of study drug. Baseline value was defined as valid and last non-missing value obtained within 28 days prior to participant receiving first study medication. Change from Baseline was calculated as the symptom severity score at Baseline minus the lowest symptom severity score on scheduled visits minuswith possible ranges from -10 to 10. The higher the number means the better improvement in cGVHD symptoms.

Time frame: 12months