Clinical Study to Investigate the Biological Activity, Safety, Tolerability, and Pharmacokinetics of Ponesimod in Subjects With Symptomatic Chronic GVHD

• Sponsor: Actelion (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02461134
• Collaborator: (none)
• Enrollment: 1
• Locations: 10
• Arm: 1
• Actual Duration (Months): 5.1
• Patients Per Site: 0.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

Chronic graft versus host diseasre (GVHD) is a serious reaction that might occur in a person (the host) who has received cells or organs (graft) from another person because the graft attacks the host's cells. Currently there are no approved therapies for chronic GVHD in the USA, and patients with chroninc GVHD are treated with immunosuppressant drugs. T-lymphocytes (a type of white blood cells) are likely to play a role in the development of chronic GVHD. Due to the capacity of ponesimod to block the traffic of T-lymphocytes, ponesimod may be a new therapeutic approach to treat chroninc GVHD.

The main objective of this study is to assess the effectiveness and safety of several doses of ponesimod in subjects with chronic GVHD who did not respond to standard available treatments.

Condition or Disease	Intervention/Treatment	Phase
Chronic Graft Versus Host Disease	Drug: Ponesimod	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Open-label, Single-arm, Intra-subject Dose-escalation Study to Investigate the Biological Activity, Safety, Tolerability, and Pharmacokinetics of Ponesimod in Subjects With Symptomatic Moderate or Severe Chronic GVHD Inadequately Responding to First or Second Line Therapy
• Actual Study Start Date: Sep 29, 2016
• Actual Primary Completion Date: Mar 2, 2017
• Actual Study Completion Date: Mar 3, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ponesimod Study treatment consists of 3 consecutive periods: 5 mg ponesimod treatment period (including up-titration), 10 mg treatment period (including up-titration) and a 20 mg treatment period.	Drug: Ponesimod; Oral film-coated tablets at the doses of 2, 3, 4, 5, 6, 7, 8, 9, 10, and 20 mg. One tablet of ponesimod at any dose will be taken orally once daily.; Other Names: ACT-128800

Outcome Measures

Primary Outcome Measures

1. Change in Peripheral Absolute Lymphocyte Count From Baseline to Week 4, 8 and 12 [From baseline to Week 12]

   The primary pharmacodynamic endpoint assesses intra-subject dose response during the first 12 weeks of treatment.

Secondary Outcome Measures

1. Incident Rate of Treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [From the first study drug intake up to 30 days after last study drug intake (Week 24)]

   This outcome measure reports the occurrence of adverse events (AEs), and serious adverse events (SAEs) during the treatment period and the follow-up period, and AEs leading to premature discontinuation of study drug. A treatment-emergent AE is any AE temporally associated with the use of study treatment whether or not considered by the investigator as related to study treatment.

Other Outcome Measures

1. Assessment of a Partial or Complete Overall Response at Week 24 [At Week 24]

   The exploratory efficacy endpoint is based on the 2014 NIH Consensus Development Project response criteria. A complete overall response is defined as a resolution of all reversible manifestations due to chronic GVHD in each organ as defined per NIH Consensus Development Project response criteria. A partial overall response is defined as improvement in a measure for at least one organ without progression in measures for any other organ.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Signed informed consent

• Symptomatic moderate or severe chronic GVHD patients in need of a change of systemic immunosuppressant (IS) therapy

• Women of child bearing potential must have a negative pregnancy test and use reliable methods of contraception

Exclusion Criteria:

• Clinically significant medical conditions including active or uncontrolled infections, new or recurrent malignancy, serious cardiac, pulmonary, or renal disease, and uncontrolled diabetes.

• Karnofsky Performance Score < 60.

• Immunosuppressant therapies other than allowed background therapy

• Anti-arrhythmic and heart rate lowering drugs.

• Any other circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Virginia Piper Cancer Institute	Scottsdale	Arizona	United States	85258
2	Moore Cancer Center - UCSD	La Jolla	California	United States	92093
3	David Geffen School of Med at UCLA	Los Angeles	California	United States	90095
4	Northwestern University	Chicago	Illinois	United States	60611
5	Indiana University Simon Cancer Center	Indianapolis	Indiana	United States	46202
6	National Cancer Institute	Bethesda	Maryland	United States	20892-1203
7	University of Minnesota - Masonic Cancer CTR CLIN TRIALS CTR	Minneapolis	Minnesota	United States	55455
8	Washington Univ School of Med, Oncology (St.Louis)	Saint Louis	Missouri	United States	63110
9	Stony Brook Univ. Medical Center	Stony Brook	New York	United States	11794
10	Fred Hutchinson Cancer Res CTR	Seattle	Washington	United States	98109-1023

Sponsors and Collaborators

• Actelion

Investigators

• Study Chair: Daniele D'Ambrosio, MD, PhD, Actelion

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 5, 2016

More Information

Publications

None provided.

• Responsible Party: Actelion
• ClinicalTrials.gov Identifier: NCT02461134
• Other Study ID Numbers: AC-058C202
• First Posted: Jun 3, 2015
• Last Update Posted: May 9, 2018
• Last Verified: Apr 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Actelion: GVHD; ponesimod
• Additional relevant MeSH terms: Graft vs Host Disease; Ponesimod

Study Results

Participant Flow

Recruitment Details	11 subjects were screened at 5 different sites. 1 subject was finally recruited into the study. The study was prematurely terminated due to poor recruitment.
Pre-assignment Detail	The protocol-defined study population included male and female subjects aged 18 to 70 years with chronic Graft versus Host disease (GVHD). It was planned to recruit 30 subjects.

Arm/Group Title	Ponesimod
Arm/Group Description	It was planned that enrolled subjects receive ponesimod in escalating doses of 5, 10 and 20 mg over the course of the treatment period of 24 weeks in total (4 weeks of 5 mg incl. up-titration, 4 weeks of 10 mg incl. up-titration and 16 weeks of 20 mg).
Period Title: Overall Study
STARTED	1
COMPLETED	0
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Ponesimod
Arm/Group Description	It was planned that enrolled subjects receive ponesimod in escalating doses of 5, 10 and 20 mg over the course of the treatment period of 24 weeks in total (4 weeks of 5 mg incl. up-titration, 4 weeks of 10 mg incl. up-titration and 16 weeks of 20 mg).
Overall Participants	1
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	1 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	1 100%
Male	0 0%
Race and Ethnicity Not Collected (Count of Participants)

Outcome Measures

1. Primary Outcome

Title	Change in Peripheral Absolute Lymphocyte Count From Baseline to Week 4, 8 and 12
Description	The primary pharmacodynamic endpoint assesses intra-subject dose response during the first 12 weeks of treatment.
Time Frame	From baseline to Week 12

Outcome Measure Data

Analysis Population Description

Due to the premature termination of the study and consequent lack of meaningful data, no analyses were performed. The statistical analysis plan issued is obsolete, it was not finalized and was therefore not executed.

Arm/Group Title	Ponesimod
Arm/Group Description	It was planned that enrolled subjects receive ponesimod in escalating doses of 5, 10 and 20 mg over the course of the treatment period of 24 weeks in total (4 weeks of 5 mg incl. up-titration, 4 weeks of 10 mg incl. up-titration and 16 weeks of 20 mg).
Measure Participants	0

2. Secondary Outcome

Title	Incident Rate of Treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	This outcome measure reports the occurrence of adverse events (AEs), and serious adverse events (SAEs) during the treatment period and the follow-up period, and AEs leading to premature discontinuation of study drug. A treatment-emergent AE is any AE temporally associated with the use of study treatment whether or not considered by the investigator as related to study treatment.
Time Frame	From the first study drug intake up to 30 days after last study drug intake (Week 24)

Outcome Measure Data

Analysis Population Description

The premature termination of the study led to a consequent lack of meaningful data. As the statistical analysis plan issued was not finalized and was not executed, no statistical analyses were performed. As there was only 1 patient enrolled in the study, the safety events reported occur with 100% frequency.

Arm/Group Title	Ponesimod
Arm/Group Description	It was planned that enrolled subjects receive ponesimod in escalating doses of 5, 10 and 20 mg over the course of the treatment period of 24 weeks in total (4 weeks of 5 mg incl. up-titration, 4 weeks of 10 mg incl. up-titration and 16 weeks of 20 mg).
Measure Participants	1
Participants with AEs	1 100%
Participants with SAEs	1 100%
Participants discontinued prematurely study drug	1 100%

3. Other Pre-specified Outcome

Title	Assessment of a Partial or Complete Overall Response at Week 24
Description	The exploratory efficacy endpoint is based on the 2014 NIH Consensus Development Project response criteria. A complete overall response is defined as a resolution of all reversible manifestations due to chronic GVHD in each organ as defined per NIH Consensus Development Project response criteria. A partial overall response is defined as improvement in a measure for at least one organ without progression in measures for any other organ.
Time Frame	At Week 24

Outcome Measure Data

Analysis Population Description

Due to the premature termination of the study and consequent lack of meaningful data, no analyses were performed. The statistical analysis plan issued is obsolete, it was not finalized and was therefore not executed.

Arm/Group Title	Ponesimod
Arm/Group Description	It was planned that enrolled subjects receive ponesimod in escalating doses of 5, 10 and 20 mg over the course of the treatment period of 24 weeks in total (4 weeks of 5 mg incl. up-titration, 4 weeks of 10 mg incl. up-titration and 16 weeks of 20 mg).
Measure Participants	0

Adverse Events

Time Frame	Study treatment was terminated on Day 81 and the subject was exposed to ponesimod for a total of 81 days (i.e., Day 1 to Day 81). None of the reported adverse events (AEs) were considered by the investigator to be related to the study drug. As there was only 1 patient enrolled in the study, all (S)AEs reported occur with 100% frequency.
Adverse Event Reporting Description	All AEs were coded using MedDRA version 19.0. No AEs were reported during the screening period.
Arm/Group Title	Ponesimod
Arm/Group Description	It was planned that enrolled subjects receive ponesimod in escalating doses of 5, 10 and 20 mg over the course of the treatment period of 24 weeks in total (4 weeks of 5 mg incl. up-titration, 4 weeks of 10 mg incl. up-titration and 16 weeks of 20 mg).
All Cause Mortality
	Ponesimod
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Serious Adverse Events
	Ponesimod
	Affected / at Risk (%)	# Events
Total	1/1 (100%)
Gastrointestinal disorders
Gastritis	1/1 (100%)	1
Haematemesis, Parainfluenza	1/1 (100%)	1
Infections and infestations
Virus infection	1/1 (100%)	1
Injury, poisoning and procedural complications
Hip fracture	1/1 (100%)	1
Other (Not Including Serious) Adverse Events
	Ponesimod
	Affected / at Risk (%)	# Events
Total	1/1 (100%)
Cardiac disorders
Atrial flutter	1/1 (100%)	1
Vascular disorders
Hypertension	1/1 (100%)	1

Limitations/Caveats

The study was terminated early due to poor recruitment with 1 subject enrolled. Due to consequent lack of meaningful data, no conclusive analyses could be performed. The statistical analysis plan is obsolete and therefore not applicable.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Any study-related publication written independently by investigators must be submitted to Actelion for review at least 30 days prior to submission for publication or presentation. Upon review, Actelion may provide comments, and may also request alterations and/or deletions for the sole purpose of protecting its confidential information and/or patent rights.