A Study of Ibrutinib in Combination With Corticosteroids versus Placebo in Combination With Corticosteroids in Patients with New Onset Chronic Graft Versus Host Disease (cGVHD)

• Register: EUCTR
• Last refreshed on: 2 March 2022
• Main ID: EUCTR2016-003286-26-HU
• Date of registration: 02/03/2017
• Prospective Registration: Yes
• Primary sponsor: Pharmacyclics LLC
• Public title: A Study of Ibrutinib in Combination With Corticosteroids versus Placebo in Combination With Corticosteroids in Patients with New Onset Chronic Graft Versus Host Disease (cGVHD)
• Scientific title: A Randomized, Double-Blind Phase 3 Study of Ibrutinib in Combination With Corticosteroids versus Placebo in Combination With Corticosteroids in Subjects with New Onset Chronic Graft Versus Host Disease (cGVHD)
• Date of first enrolment: 18/04/2017
• Target sample size: 186
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-003286-26
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Austria, Canada, China, Croatia, France, Germany, Hungary, Italy, Korea, Republic of, Singapore, Spain, Taiwan, United States

Contacts

• Name: Clinical Trial Information
• Affiliation: Pharmacyclics LLC

• Name: Clinical Trial Information
• Affiliation: Pharmacyclics LLC

Key inclusion & exclusion criteria

Inclusion criteria:
Prior to randomization, each potential subject must satisfy all of the following inclusion criteria.

Disease related
1. New onset moderate or severe cGVHD as defined by the NIH Consensus Development Project Criteria (2014, see Appendix M, Appendix N and Appendix O of protocol).
2. History of an allogeneic hematopoietic cell transplant.
3. Need for systemic treatment with corticosteroids for cGVHD.
4. No previous systemic treatment for cGVHD (including extracorporeal photopheresis [ECP]).
5. Participants may be receiving other immunosuppressants for the prophylaxis or treatment of acute GVHD but if the subject is receiving prednisone for prophylaxis or treatment of acute GVHD it must be at or below 0.5 mg/kg/d.
6. Participants may have received pre-transplant BTK inhibitors for other reasons besides cGVHD such as for the treatment of leukemia or lymphoma, but must not have received a BTK inhibitor since the time of transplant.

Demographic
7. Age =12 years old.
8. Karnofsky or Lansky (subjects <16 years) performance score =60.

Laboratory
9. Adequate renal function defined as estimated Creatinine Clearance =30 mL/min (Cockcroft-Gault formula)
10. Adequate hepatic function as defined by:
- Total bilirubin =1.5 x ULN (unless of non-hepatic origin or due to Gilbert’s Syndrome) or
- Total bilirubin of > 1.5 x ULN to 3.0 x ULN if due to GVHD
11. Adequate hematological function defined as:
- Absolute neutrophil count =1.0 x 109/L and off growth factor support for 7 days
- Platelets =30 x 109/L and no transfusion for 7 days
12. PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN (unless abnormalities are unrelated to coagulopathy or bleeding disorder). When treated with warfarin or other vitamin K antagonist, then INR =3.0 (Section 6.2.3 of protocol)

Ethical/Other
13. Male and female subjects of reproductive potential who agree to use both a highly effective methods of birth control (eg, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence, or sterilized partner) and a barrier method (eg, condoms, cervical ring, sponge, etc) during the period of therapy and for 90 days for both females and males after the last dose of study drug.
Are the trial subjects under 18? yes
Number of subjects for this age range: 35
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 151
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
To be enrolled in the study, potential subjects must meet NONE of the following exclusion criteria:

Disease related
1. Received any previous systemic treatment for cGVHD with the following exception
- Corticosteroids for cGVHD received within the 72 hours prior to signing the informed consent form.
2. Inability to begin a prednisone dose =0.5 mg/kg/d for the treatment of cGVHD.
3. Presence of single-organ, genito-urinary involvement with cGVHD as the only manifestation of cGVHD.

Concurrent conditions
4. Received any investigational agent =28 days before randomization.
5. Received donor lymphocyte infusion (DLI) =56 days before randomization.
6. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
7. Any uncontrolled active systemic infection or active infection requiring systemic treatment that was ongoing =7 days before randomization. This does not include secondary prophylaxis of well controlled fungal infections, ongoing treatment of controlled viral reactivations (eg, CMV), or treatment or prophylaxis of controlled low grade central line infections (eg, Staphylococcus epidermidis).
8. Progressive underlying malignant disease or active post-transplant lymphoproliferative disease.
9. History of other malignancy (not including the underlying malignancy that was the indication for transplant), with the following exceptions:
- Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to Screening and felt to be at low risk for recurrence by treating physician
- Adequately treated nonmelanomatous skin cancer or lentigo maligna melanoma without current evidence of disease
- Adequately treated cervical carcinoma in situ without current evidence of disease
10. Subject has a concurrent illness which in the opinion of the investigator may interfere with the treatment and evaluation of the subject.
11. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia).
12. History of stroke or intracranial hemorrhage within 6 months prior to randomization.
13. Known history of human immunodeficiency virus (HIV).
14. Subject with chronic liver disease with hepatic impairment per Child-Pugh classification Class C (Appendix E). Please note that acute liver dysfunction due to cGVHD is not applicable to the evaluation of Child-Pugh classification.
15. Active hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody or hepatitis B surface antigen or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before randomization. Those who are PCR positive will be excluded.
16. Vaccinated with live, attenuated vaccines within 4 weeks of randomization.
17. Major surgery within 4 weeks of randomization.
18. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk.
19. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Chronic Graft Versus Host Disease (cGVHD)
MedDRA version: 20.1 Level: PT Classification code 10066261 Term: Chronic graft versus host disease System Organ Class: 10021428 - Immune system disorders

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Intervention(s)

Product Name: Ibrutinib 140 mg
Product Code: PCI-32765
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Ibrutinib
CAS Number: 936563-96-1
Current Sponsor code: PCI-32765
Other descriptive name: IBRUTINIB
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 140-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Name: Ibrutinib 70 mg
Product Code: PCI-32765
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Ibrutinib
CAS Number: 936563-96-1
Current Sponsor code: PCI-32765
Other descriptive name: IBRUTINIB
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 70-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: To evaluate the efficacy of ibrutinib in combination with prednisone (Arm A) versus placebo in combination with prednisone (Arm B) based on the response rate at 48 weeks (the proportion of responders [CR or PR]) as determined by NIH Consensus Development Project criteria in subjects with new onset moderate to severe cGVHD.

Primary end point(s): The primary endpoint is the response rate at 48 weeks. Response will be defined by the NIH Consensus Development Project Criteria (2014) and must occur:
- In the absence of new therapy for cGVHD
In the absence of progression of the underlying disease that was the indication for transplant, or post transplant
lymphoproliferative disease (PTLD), or death

Secondary Objective: To compare the two treatment arms in terms of the following:
Efficacy
- Response rate at 24 weeks (the proportion of responders [CR or PR]) as defined by the NIH Consensus Development Project (2014)
- Duration of response (DOR)
- Proportion of subjects obtaining steroid dose level less than 0.15 mg/kg/d at 24 weeks
- Time to withdrawal of all immunosuppressants (with the exception of ibrutinib/placebo)
- Overall survival (OS)
- Lee cGVHD symptom scale improvement

Safety
- Safety and tolerability
- Differences in steroid-related morbidities (eg, hyperglycemia, hypertension)

Timepoint(s) of evaluation of this end point: 48 weeks

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Timepoints for the secondary end points are detailed in the 'Schedule of assessments' in Appendix A of the protocol

Secondary end point(s): Secondary endpoints will assess for additional clinical benefit including Week-24 response, duration of response (DOR), corticosteroid dose reduction, time to withdrawal of all immunosuppressants, overall survival (OS) and Lee cGVHD symptom scale.

Secondary ID(s)

PCYC-1140-IM

Source(s) of Monetary Support

Pharmacyclics LLC

Ethics review

Status: Approved
Approval date: 10/04/2017
Contact:

Results

• Results available: Yes
• Date Posted: 31/03/2021
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-003286-26/results