Study of the Bruton's Tyrosine Kinase Inhibitor in Subjects With Relapsed/Refractory Marginal Zone Lymphoma

• Sponsor: Pharmacyclics LLC. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01980628
• Collaborator: Janssen Research & Development, LLC (Industry)
• Enrollment: 63
• Locations: 25
• Arm: 1
• Duration (Months): 46
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Phase 2, open-label, non-randomized, monotherapy study to evaluate the safety and efficacy of ibrutinib in subject with relapsed/refractory Marginal Zone Lymphoma (MZL).

Condition or Disease	Intervention/Treatment	Phase
Marginal Zone Lymphoma; B-cell Lymphoma	Drug: ibrutinib	Phase 2

Detailed Description

Ibrutinib is a first-in-class, potent, orally administered covalent inhibitor of Bruton's tyrosine kinase (BTK). Inhibition of BTK blocks downstream B-cell receptor (BCR) signaling pathways and thus prevents B-cell proliferation. In vitro, ibrutinib inhibits purified BTK and selected members of the kinase family with 10-fold specificity compared with non-BTK kinases. Phase 1 and 2 studies of ibrutinib in B-cell malignancies demonstrate modest toxicity and significant single agent activity in a variety of B-cell malignancies, including NHL.

Study Design

• Study Type: Interventional
• Actual Enrollment: 63 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Open-Label, Phase 2 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Subjects With Relapsed/Refractory Marginal Zone Lymphoma
• Study Start Date: Dec 1, 2013
• Actual Primary Completion Date: Jul 1, 2016
• Actual Study Completion Date: Oct 2, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ibrutinib ibrutinib capsules: 560 mg once daily	Drug: ibrutinib; Other Names: PCI-32765

Outcome Measures

Primary Outcome Measures

1. ORR (Overall Response Rate) [Analysis was conducted with the cutoff date of 02 Nov 2017, with a median follow-up time of 33.1 months.]

   ORR is defined as the proportion of subjects who achieved complete response (CR), partial response (PR). Response criteria are as outlined in the International Working Group Criteria for NHL, Cheson (2007), with disease assessments performed by an independent review committee (IRC). Per Cheson: CR is defined as disappearance of all evidence of disease. PR is defined as regression of measurable disease and no new sites.

Secondary Outcome Measures

1. DOR (Duration of Response) [Analysis was conducted with the cutoff date of 02 Nov 2017, with a median follow-up time of 33.1 months.]

   The DOR analyses is performed on the subset of subjects that achieve CR or PR as determined by IRC. DOR is calculated as the duration of time from the date of first response to the date of progression or death due to any cause.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion criteria:

• Histologically documented marginal zone lymphoma including splenic, nodal, and extranodal sub-types; subjects with splenic MZL must have an additional measurable lesion, nodal or extranodal, as described in inclusion criteria 5

• Previously received one or more lines of therapy including at least one CD20-directed regimen (either as monotherapy or as chemoimmunotherapy) with documented failure to achieve at least PR or documented PD after, the most recent systemic treatment regimen

• Men and women ≥18 years of age

• ECOG performance status of ≤2

• ≥1 measurable lesion site on CT scan (>1.5 cm in longest dimension). Lesions in anatomical locations (such as extremities or soft tissue lesions) that are not well visualized by CT may be measured by MRI instead. (Subjects with spleen-only disease are considered as not having measurable disease.)

• Life expectancy of >3 months, in the opinion of the investigator

Key Exclusion criteria:

• Medically apparent CNS lymphoma or leptomeningeal disease

• History of other malignancies except adequately treated non melanoma skin cancer, curatively treated in-situ cancer, or other solid tumors curatively treated with no evidence of disease for ≥2 years

• History of allogeneic stem-cell (or other organ) transplantation

• Any chemotherapy, anticancer antibodies, or other systemic anticancer therapy within 21 days of the first dose of study drug

• Any external beam radiation therapy within 6 weeks prior to the first dose of the study drug

• Concurrent use of warfarin or other vitamin K antagonists

• Concurrent use of a strong CYP3A inhibitor. Subjects who have received a strong CYP3A inhibitor prior to entering the study must have discontinued therapy for at least 5 half lives of the prohibited medication.

• Recent infection requiring IV anti-infective treatment that was completed ≤14 days before the first dose of study drug

• Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to CTCAE Grade 0 or 1, or to the levels dictated in the eligibility criteria with the exception of alopecia

• Inadequate organ function as defined on laboratory tests

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Site Reference ID/Investigator# 837	Tucson	Arizona	United States	85719
2	Site Reference ID/Investigator# 047	Duarte	California	United States	91010
3	Site Reference ID/Investigator# 377	Santa Monica	California	United States	90095
4	Site Reference ID/Investigator# 763	West Palm Beach	Florida	United States	33401
5	Site Reference ID/Investigator# 033	Atlanta	Georgia	United States	30322
6	Site Reference ID/Investigator# 370	Chicago	Illinois	United States	60611
7	Site Reference ID/Investigator# 195	Detroit	Michigan	United States	48202
8	Site Reference ID/Investigator# 350	New Hyde Park	New York	United States	11042
9	Site Reference ID/Investigator# 745	New York	New York	United States	08724
10	Site Reference ID/Investigator # 200	New York	New York	United States	10065
11	Site Reference ID/Investigator # 407	New York	New York	United States	10065
12	Site Reference ID/Investigator# 220	Hershey	Pennsylvania	United States	17033
13	Site Reference ID/Investigator# 348	Seattle	Washington	United States	98109
14	Site Reference ID/Investigator# 560	Ghent	Oost-vlaanderen	Belgium
15	Site Reference ID/Investigator# 737	Rouen Cedex 1	Haute-normandie	France
16	Site Reference ID/Investigator# 735	Paris Cedex 10	Ile-de-france	France
17	Site Reference ID/Investigator# 750	Lille Cedex	NORD Pas-de-calais	France
18	Site Reference ID/Investigator# 749	La Roche-sur-Yon Cedex 9	PAYS DE LA Loire	France
19	Site Reference ID/Investigator# 736	Nantes cedex 1	PAYS DE LA Loire	France
20	Site Reference ID/Investigator# 142	Pierre Bénite Cedex	Rhone-alpes	France
21	Site Reference ID/Investigator# 742	Rennes cedex 9		France
22	Site Reference ID/Investigator# 669	Mainz	Rheinland-Pfalz	Germany
23	Site Reference ID/Investigator# 030	Manchester	England	United Kingdom
24	Site Reference ID/Investigator# 814	Oxford	England	United Kingdom
25	Site Reference ID/Investigator# 368	Plymouth	England	United Kingdom

Sponsors and Collaborators

• Pharmacyclics LLC.
• Janssen Research & Development, LLC

Investigators

• Study Director: Isaiah Dimery, MD, Pharmacyclics LLC.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Pharmacyclics LLC.
• ClinicalTrials.gov Identifier: NCT01980628
• Other Study ID Numbers: PCYC-1121-CA
• First Posted: Nov 11, 2013
• Last Update Posted: Oct 16, 2019
• Last Verified: Oct 1, 2019

• Keywords provided by Pharmacyclics LLC.: MZL; NHL; SMZL; NMZL; MALT
• Additional relevant MeSH terms: Lymphoma; Lymphoma, B-Cell, Marginal Zone

Study Results

Participant Flow

Arm/Group Title	Ibrutinib
Arm/Group Description	Subjects receive daily dose of 560 mg of ibrutinib capsules.
Period Title: Overall Study
STARTED	63
COMPLETED	0
NOT COMPLETED	63

Baseline Characteristics

Arm/Group Title	Ibrutinib
Arm/Group Description	Subjects receive a daily dose of 560 mg of ibrutinib capsules
Overall Participants	63
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	27 42.9%
>=65 years	36 57.1%
Sex: Female, Male (Count of Participants)
Female	37 58.7%
Male	26 41.3%
Race/Ethnicity, Customized (Count of Participants)
White	53 84.1%
Black	6 9.5%
Asian	1 1.6%
Unknown	3 4.8%

Outcome Measures

1. Primary Outcome

Title	ORR (Overall Response Rate)
Description	ORR is defined as the proportion of subjects who achieved complete response (CR), partial response (PR). Response criteria are as outlined in the International Working Group Criteria for NHL, Cheson (2007), with disease assessments performed by an independent review committee (IRC). Per Cheson: CR is defined as disappearance of all evidence of disease. PR is defined as regression of measurable disease and no new sites.
Time Frame	Analysis was conducted with the cutoff date of 02 Nov 2017, with a median follow-up time of 33.1 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm, Intent to Treat Population
Arm/Group Description
Measure Participants	63
Mean (95% Confidence Interval) [Percentage of Participants]	46 73%

2. Secondary Outcome

Title	DOR (Duration of Response)
Description	The DOR analyses is performed on the subset of subjects that achieve CR or PR as determined by IRC. DOR is calculated as the duration of time from the date of first response to the date of progression or death due to any cause.
Time Frame	Analysis was conducted with the cutoff date of 02 Nov 2017, with a median follow-up time of 33.1 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ibrutinib
Arm/Group Description	Patients receive daily dose of 560 mg of ibrutinib capsules.
Measure Participants	63
Median (95% Confidence Interval) [Months]	NA

Adverse Events

Time Frame	From the time of first ibrutinib dose until 30 days following the last dose of study drug
Adverse Event Reporting Description	For "At Risk" we considered 60 because it was the efficacy population (with N=60) is used for OS
Arm/Group Title	Ibrutinib
Arm/Group Description	ibrutinib capsules: 560 mg once daily
All Cause Mortality
	Ibrutinib
	Affected / at Risk (%)	# Events
Total	17/63 (27%)
Serious Adverse Events
	Ibrutinib
	Affected / at Risk (%)	# Events
Total	29/63 (46%)
Blood and lymphatic system disorders
Autoimmune Haemolytic Anaemia	2/63 (3.2%)
Haemolytic Anaemia	1/63 (1.6%)
Cardiac disorders
Atrial Fibrillation	1/63 (1.6%)
Pericardial Effusion	1/63 (1.6%)
Cardiac Failure Congestive	1/63 (1.6%)
Gastrointestinal disorders
Pancreatitis	1/63 (1.6%)
Stomatitis	1/63 (1.6%)
General disorders
Asthenia	1/63 (1.6%)
Multiple Organ Dysfunction Syndrome	1/63 (1.6%)
Non-Cardiac Chest Pain	1/63 (1.6%)
Pyrexia	1/63 (1.6%)
Hepatobiliary disorders
Cholelithiasis	1/63 (1.6%)
Infections and infestations
Pneumonia	5/63 (7.9%)
Cellulitis	2/63 (3.2%)
Sepsis	2/63 (3.2%)
Escherichia Sepsis	1/63 (1.6%)
Infection	1/63 (1.6%)
Influenza	1/63 (1.6%)
Listeria Sepsis	1/63 (1.6%)
Lung Infection	1/63 (1.6%)
Parainfluenzae Virus Infection	1/63 (1.6%)
Injury, poisoning and procedural complications
Ankle Fracture	1/63 (1.6%)
Bronchial Injury	1/63 (1.6%)
Metabolism and nutrition disorders
Dehydration	1/63 (1.6%)
Fluid Overload	1/63 (1.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lymphoma	1/63 (1.6%)
Marginal Zone Lymphoma	1/63 (1.6%)
Nervous system disorders
Cerebral Haemorrhage	1/63 (1.6%)
Cervical Radiculopathy	1/63 (1.6%)
Transient Ischaemic Attack	1/63 (1.6%)
Renal and urinary disorders
Acute Kidney Injury	1/63 (1.6%)
Respiratory, thoracic and mediastinal disorders
Pneumothorax	1/63 (1.6%)
Dyspnoea	1/63 (1.6%)
Eosinophilic Pneumonia	1/63 (1.6%)
Hypoxia	1/63 (1.6%)
Pleural Effusion	1/63 (1.6%)
Pneumonitis	1/63 (1.6%)
Pulmonary Embolism	1/63 (1.6%)
Respiratory Failure	1/63 (1.6%)
Haemoptysis	1/63 (1.6%)
Organising Pneumonia	1/63 (1.6%)
Vascular disorders
Hypotension	1/63 (1.6%)
Embolism	1/63 (1.6%)
Other (Not Including Serious) Adverse Events
	Ibrutinib
	Affected / at Risk (%)	# Events
Total	63/63 (100%)
Blood and lymphatic system disorders
Anaemia	23/63 (36.5%)
Thrombocytopenia	15/63 (23.8%)
Increased Tendency To Bruise	12/63 (19%)
Cardiac disorders
Atrial Fibrillation	5/63 (7.9%)
Eye disorders
Vision Blurred	4/63 (6.3%)
Dry Eye	4/63 (6.3%)
Gastrointestinal disorders
Diarrhoea	30/63 (47.6%)
Nausea	20/63 (31.7%)
Dyspepsia	12/63 (19%)
Abdominal Pain	10/63 (15.9%)
Constipation	10/63 (15.9%)
Abdominal Pain Upper	7/63 (11.1%)
Stomatitis	8/63 (12.7%)
Vomiting	7/63 (11.1%)
Abdominal Discomfort	4/63 (6.3%)
Abdominal Distension	4/63 (6.3%)
General disorders
Fatigue	29/63 (46%)
Oedema Peripheral	15/63 (23.8%)
Pyrexia	12/63 (19%)
Asthenia	6/63 (9.5%)
Pain	4/63 (6.3%)
Infections and infestations
Upper Respiratory Tract Infection	16/63 (25.4%)
Sinusitis	13/63 (20.6%)
Bronchitis	7/63 (11.1%)
Urinary Tract Infection	9/63 (14.3%)
Oral Herpes	5/63 (7.9%)
Conjunctivitis	4/63 (6.3%)
Cystitis	4/63 (6.3%)
Cellulitis	7/63 (11.1%)
Pneumonia	6/63 (9.5%)
Ear Infection	4/63 (6.3%)
Viral Upper Respiratory tract	4/63 (6.3%)
Injury, poisoning and procedural complications
Fall	10/63 (15.9%)
Contusion	7/63 (11.1%)
Skin Abrasion	6/63 (9.5%)
Investigations
Weight Decreased	9/63 (14.3%)
Blood Alkaline Phosphatase Increased	5/63 (7.9%)
Blood Creatinine Increased	4/63 (6.3%)
Metabolism and nutrition disorders
Decreased Appetite	11/63 (17.5%)
Hyperglycaemia	10/63 (15.9%)
Hyperuricaemia	10/63 (15.9%)
Hypoalbuminaemia	11/63 (17.5%)
Hypokalaemia	9/63 (14.3%)
Hypocalcaemia	7/63 (11.1%)
Hyponatraemia	5/63 (7.9%)
Dehydration	4/63 (6.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	15/63 (23.8%)
Muscle Spasms	13/63 (20.6%)
Pain In Extremity	10/63 (15.9%)
Back Pain	7/63 (11.1%)
Musculoskeletal Pain	5/63 (7.9%)
Myalgia	4/63 (6.3%)
Joint Swelling	4/63 (6.3%)
Nervous system disorders
Dizziness	14/63 (22.2%)
Headache	13/63 (20.6%)
Psychiatric disorders
Anxiety	11/63 (17.5%)
Depression	4/63 (6.3%)
Renal and urinary disorders
Haematuria	7/63 (11.1%)
Dysuria	4/63 (6.3%)
Respiratory, thoracic and mediastinal disorders
Cough	16/63 (25.4%)
Dyspnoea	13/63 (20.6%)
Epistaxis	8/63 (12.7%)
Nasal Congestion	6/63 (9.5%)
Oropharyngeal Pain	4/63 (6.3%)
Productive Cough	4/63 (6.3%)
Rhinorrhoea	4/63 (6.3%)
Sinus Congestion	3/63 (4.8%)
Pleural Effusion	5/63 (7.9%)
Skin and subcutaneous tissue disorders
Rash Maculo-Papular	11/63 (17.5%)
Pruritus	9/63 (14.3%)
Ecchymosis	6/63 (9.5%)
Night Sweats	6/63 (9.5%)
Alopecia	5/63 (7.9%)
Dry Skin	4/63 (6.3%)
Erythema	4/63 (6.3%)
Rash Erythematous	4/63 (6.3%)
Hyperhidrosis	4/63 (6.3%)
Petechiae	4/63 (6.3%)
Vascular disorders
Hypertension	10/63 (15.9%)
Hypotension	4/63 (6.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Agreement restrictions can vary and typically include (but are not limited to): Required submission of all material for sponsor review at least thirty days prior to the proposed date of any presentation or submission. Materials must remove Proprietary Information, excluding Data /Study results. All Sponsor's comments are required to be included. Sponsor may delay the presentation/submission upon Sponsor review of materials that are being proposed for presentation/submission.