A Multicenter Phase 2 Study of Ibrutinib in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) With 17p Deletion

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ClinicalTrials.gov Identifier: NCT01744691

Recruitment Status : Completed

First Posted : December 7, 2012

Results First Posted : June 9, 2015

Last Update Posted : February 27, 2017

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Sponsor:

Collaborator:

Janssen Research & Development, LLC

Information provided by (Responsible Party):

Pharmacyclics LLC.

Study Type	Interventional
Study Design	Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Conditions	Chronic Lymphocytic Leukemia With 17p Deletion Small Lymphocytic Lymphoma With 17p Deletion
Intervention	Drug: Ibrutinib
Enrollment	145

Participant Flow

Recruitment Details
Pre-assignment Details	One hundred forty-five subjects were enrolled and 144 subjects received at least 1 dose of PCI-32765 and constitute the all treated population and the safety analysis set.


Arm/Group Title	Ibrutinib
Arm/Group Description	All subjects received ibrutinib 420...
Arm/Group Description	All subjects received ibrutinib 420 mg (3 x 140-mg capsules) orally once daily. Ibrutinib: All subjects received ibrutinib 420 mg (3 x 140-mg capsules) orally once daily.
Period Title: Overall Study
Started	144 ^[1]
Completed	101 ^[2]
Not Completed	43
Reason Not Completed
Progressive Disease	18
Unacceptable toxicity, AE or death	18
Withdrawal of consent for treatment	3
Physician Decision	4
[1] Participants who received study treatment [2] Participants who were on study treatment at the time of the primary analysis

Baseline Characteristics

Arm/Group Title		PCI-32765
Arm/Group Description		All subjects received PCI-32765 420...
Arm/Group Description		All subjects received PCI-32765 420 mg (3 x 140-mg capsules) orally once daily. PCI-32765: All subjects received PCI-32765 420 mg (3 x 140-mg capsules) orally once daily.
Overall Number of Baseline Participants		144
Baseline Analysis Population Description		...
Baseline Analysis Population Description		One hundred forty-five subjects were enrolled and 144 subjects received at least 1 dose of PCI-32765 and constitute the all treated population and the safety analysis set.
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	144 participants
	<=18 years	0 0.0%
	Between 18 and 65 years	75 52.1%
	>=65 years	69 47.9%
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	144 participants
		64.4 (9.9)
Gender Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	144 participants
	Female	48 33.3%
	Male	96 66.7%

Outcome Measures

1.Primary Outcome


Title	Overall Response Rate
Description	The primary objective of this study is to evaluate the efficacy of ibr...
Description	The primary objective of this study is to evaluate the efficacy of ibrutinib in terms of ORR according to an Independent Review Committee (IRC). ORR based upon IRC assessment is the proportion of responders in the all treated population. Responders were subjects who achieved partial response (PR) or better, ie, complete response (CR), complete response with incomplete marrow recovery (CRi), nodule partial response (nPR) or PR, per IWCLL 2008 criteria with the clarification for treatment-related lymphocytosis.
Time Frame	The median time on study for all treated participants is 33.3 (range 0.5 - 40.1) months

Outcome Measure Data

Analysis Population Description

Efficacy analyses were performed on all 144 treated subjects. The primary analysis (PA) used IRC assessment of efficacy endpoints. In the PA, there were no differences between the IRC and investigator responses. IRC assessment was no longer performed after the PA and the final analysis result report investigator-assessed efficacy outcomes.


Arm/Group Title	Ibrutinib
Arm/Group Description:	All subjects will receive ibrutinib...
Arm/Group Description:	All subjects will receive ibrutinib 420 mg (3 x 140-mg capsules) orally once daily. ibrutinib: All subjects will receive ibrutinib 420 mg (3 x 140-mg capsules) orally once daily.
Overall Number of Participants Analyzed	144
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: % of participants with response by PI
	77.8 (70.3 to 83.8)

2.Secondary Outcome


Title	Number of Participants With Treatment Emergent Adverse Events (AEs)
Description	Number of participants who had experienced at least one treatment emer...
Description	Number of participants who had experienced at least one treatment emergent AE
Time Frame	From first dose of PCI-32765 to within 30 days of last dose for each participant or until study closure

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 dose of PCI-32765 and constitute the all treated population.


Arm/Group Title	PCI-32765
Arm/Group Description:	All subjects will receive PCI-32765...
Arm/Group Description:	All subjects will receive PCI-32765 420 mg (3 x 140-mg capsules) orally once daily. PCI-32765: All subjects will receive PCI-32765 420 mg (3 x 140-mg capsules) orally once daily.
Overall Number of Participants Analyzed	144
Measure Type: Number Unit of Measure: participants
	144

Adverse Events

Time Frame	From first dose of PCI-32765 to within 30 days of last dose
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	PCI-32765
Arm/Group Description	All subjects received PCI-32765 420...
Arm/Group Description	All subjects received PCI-32765 420 mg (3 x 140-mg capsules) orally once daily. PCI-32765: All subjects received PCI-32765 420 mg (3 x 140-mg capsules) orally once daily.
All-Cause Mortality
	PCI-32765
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events Serious Adverse Events
	PCI-32765
	Affected / at Risk (%)
Total	76/144 (52.78%)
Blood and lymphatic system disorders
Anaemia ^† 1	4/144 (2.78%)
Febrile neutropenia ^† 1	2/144 (1.39%)
Autoimmune haemolytic anaemia ^† 1	1/144 (0.69%)
Coagulopathy ^† 1	1/144 (0.69%)
Haemolytic anaemia ^† 1	1/144 (0.69%)
Immune thrombocytopenic purpura ^† 1	1/144 (0.69%)
Iron deficiency anaemia ^† 1	1/144 (0.69%)
Spontaneous haematoma ^† 1	1/144 (0.69%)
Thrombocytopenia ^† 1	1/144 (0.69%)
Cardiac disorders
Atrial fibrillation ^† 1	8/144 (5.56%)
Acute myocardial infarction ^† 1	2/144 (1.39%)
Pericarditis ^† 1	2/144 (1.39%)
Cardiac failure ^† 1	1/144 (0.69%)
Myocardial infarction ^† 1	1/144 (0.69%)
Pericardial effusion ^† 1	1/144 (0.69%)
Sinus node dysfunction ^† 1	1/144 (0.69%)
Eye disorders
Iritis ^† 1	1/144 (0.69%)
Gastrointestinal disorders
Colitis ^† 1	2/144 (1.39%)
Diarrhoea ^† 1	2/144 (1.39%)
Colitis ischaemic ^† 1	1/144 (0.69%)
Gastric ulcer haemorrhage ^† 1	1/144 (0.69%)
Gastritis ^† 1	1/144 (0.69%)
Intestinal obstruction ^† 1	1/144 (0.69%)
Oral mucosal blistering ^† 1	1/144 (0.69%)
Stomatitis ^† 1	1/144 (0.69%)
Upper gastrointestinal haemorrhage ^† 1	1/144 (0.69%)
Vomiting ^† 1	1/144 (0.69%)
General disorders
Pyrexia ^† 1	3/144 (2.08%)
Fatigue ^† 1	2/144 (1.39%)
Asthenia ^† 1	1/144 (0.69%)
General physical health deterioration ^† 1	1/144 (0.69%)
Localised oedema ^† 1	1/144 (0.69%)
Oedema peripheral ^† 1	1/144 (0.69%)
Hepatobiliary disorders
Cholecystitis ^† 1	2/144 (1.39%)
Cholecystitis acute ^† 1	1/144 (0.69%)
Hepatic function abnormal ^† 1	1/144 (0.69%)
Infections and infestations
Pneumonia ^† 1	21/144 (14.58%)
Urinary tract infection ^† 1	5/144 (3.47%)
Cellulitis ^† 1	4/144 (2.78%)
Bronchitis ^† 1	2/144 (1.39%)
Pyelonephritis ^† 1	2/144 (1.39%)
Sepsis ^† 1	2/144 (1.39%)
Septic shock ^† 1	2/144 (1.39%)
Appendicitis ^† 1	1/144 (0.69%)
Aspergillus infection ^† 1	1/144 (0.69%)
Atypical pneumonia ^† 1	1/144 (0.69%)
Bacteraemia ^† 1	1/144 (0.69%)
Campylobacter gastroenteritis ^† 1	1/144 (0.69%)
Cystitis ^† 1	1/144 (0.69%)
Empyema ^† 1	1/144 (0.69%)
Epiglottitis ^† 1	1/144 (0.69%)
Gastroenteritis clostridial ^† 1	1/144 (0.69%)
Groin abscess ^† 1	1/144 (0.69%)
Herpes simplex ^† 1	1/144 (0.69%)
Influenza ^† 1	1/144 (0.69%)
Lower respiratory tract infection viral ^† 1	1/144 (0.69%)
Lung infection ^† 1	1/144 (0.69%)
Lymphadenitis bacterial ^† 1	1/144 (0.69%)
Oropharyngeal candidiasis ^† 1	1/144 (0.69%)
Pneumocystis jirovecii pneumonia ^† 1	1/144 (0.69%)
Sinusitis fungal ^† 1	1/144 (0.69%)
Staphylococcal sepsis ^† 1	1/144 (0.69%)
Subcutaneous abscess ^† 1	1/144 (0.69%)
Varicella zoster virus infection ^† 1	1/144 (0.69%)
Injury, poisoning and procedural complications
Subdural haematoma ^† 1	3/144 (2.08%)
Alcohol poisoning ^† 1	1/144 (0.69%)
Femoral neck fracture ^† 1	1/144 (0.69%)
Meniscus injury ^† 1	1/144 (0.69%)
Muscle rupture ^† 1	1/144 (0.69%)
Post procedural haematuria ^† 1	1/144 (0.69%)
Post procedural haemorrhage ^† 1	1/144 (0.69%)
Traumatic haematoma ^† 1	1/144 (0.69%)
Metabolism and nutrition disorders
Hypercalcaemia ^† 1	1/144 (0.69%)
Hyperkalaemia ^† 1	1/144 (0.69%)
Hypomagnesaemia ^† 1	1/144 (0.69%)
Hyponatraemia ^† 1	1/144 (0.69%)
Musculoskeletal and connective tissue disorders
Arthritis ^† 1	2/144 (1.39%)
Myalgia ^† 1	2/144 (1.39%)
Osteoporosis ^† 1	2/144 (1.39%)
Arthralgia ^† 1	1/144 (0.69%)
Chondromalacia ^† 1	1/144 (0.69%)
Dactylitis ^† 1	1/144 (0.69%)
Muscular weakness ^† 1	1/144 (0.69%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Richter's syndrome ^† 1	6/144 (4.17%)
Chronic lymphocytic leukaemia ^† 1	5/144 (3.47%)
Basal cell carcinoma ^† 1	2/144 (1.39%)
Hodgkin's disease ^† 1	2/144 (1.39%)
B-cell small lymphocytic lymphoma ^† 1	1/144 (0.69%)
Lymphoma transformation ^† 1	1/144 (0.69%)
Skin papilloma ^† 1	1/144 (0.69%)
Squamous cell carcinoma of skin ^† 1	1/144 (0.69%)
Vulval cancer stage 0 ^† 1	1/144 (0.69%)
Nervous system disorders
Syncope ^† 1	2/144 (1.39%)
Cerebrovascular accident ^† 1	1/144 (0.69%)
Critical illness polyneuropathy ^† 1	1/144 (0.69%)
Encephalopathy ^† 1	1/144 (0.69%)
Haemorrhage intracranial ^† 1	1/144 (0.69%)
Psychiatric disorders
Psychotic disorder ^† 1	1/144 (0.69%)
Renal and urinary disorders
Acute kidney injury ^† 1	2/144 (1.39%)
Renal failure ^† 1	2/144 (1.39%)
Renal infarct ^† 1	1/144 (0.69%)
Reproductive system and breast disorders
Prostatomegaly ^† 1	1/144 (0.69%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion ^† 1	3/144 (2.08%)
Alveolitis allergic ^† 1	1/144 (0.69%)
Haemoptysis ^† 1	1/144 (0.69%)
Haemothorax ^† 1	1/144 (0.69%)
Interstitial lung disease ^† 1	1/144 (0.69%)
Pneumonitis ^† 1	1/144 (0.69%)
Pulmonary embolism ^† 1	1/144 (0.69%)
Pulmonary mass ^† 1	1/144 (0.69%)
Pulmonary oedema ^† 1	1/144 (0.69%)
Skin and subcutaneous tissue disorders
Livedo reticularis ^† 1	1/144 (0.69%)
Skin erosion ^† 1	1/144 (0.69%)
Stevens-Johnson syndrome ^† 1	1/144 (0.69%)
Trichodysplasia spinulosa ^† 1	1/144 (0.69%)
Vascular disorders
Arterial haemorrhage ^† 1	1/144 (0.69%)
Hypertension ^† 1	1/144 (0.69%)
Orthostatic hypotension ^† 1	1/144 (0.69%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 17.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	PCI-32765
	Affected / at Risk (%)
Total	144/144 (100.00%)
Blood and lymphatic system disorders
Anaemia ^† 1	33/144 (22.92%)
Neutropenia ^† 1	29/144 (20.14%)
Increased tendency to bruise ^† 1	23/144 (15.97%)
Thrombocytopenia ^† 1	21/144 (14.58%)
Spontaneous haematoma ^† 1	8/144 (5.56%)
Cardiac disorders
Atrial fibrillation ^† 1	16/144 (11.11%)
Eye disorders
Vision blurred ^† 1	16/144 (11.11%)
Visual acuity reduced ^† 1	12/144 (8.33%)
Dry eye ^† 1	11/144 (7.64%)
Lacrimation increased ^† 1	11/144 (7.64%)
Eye irritation ^† 1	8/144 (5.56%)
Gastrointestinal disorders
Diarrhoea ^† 1	63/144 (43.75%)
Nausea ^† 1	34/144 (23.61%)
Constipation ^† 1	21/144 (14.58%)
Dyspepsia ^† 1	18/144 (12.50%)
Vomiting ^† 1	17/144 (11.81%)
Abdominal pain ^† 1	14/144 (9.72%)
Stomatitis ^† 1	11/144 (7.64%)
Abdominal pain upper ^† 1	8/144 (5.56%)
Gastrooesophageal reflux disease ^† 1	8/144 (5.56%)
General disorders
Fatigue ^† 1	54/144 (37.50%)
Pyrexia ^† 1	31/144 (21.53%)
Oedema peripheral ^† 1	28/144 (19.44%)
Chills ^† 1	9/144 (6.25%)
Peripheral swelling ^† 1	9/144 (6.25%)
Infections and infestations
Upper respiratory tract infection ^† 1	30/144 (20.83%)
Urinary tract infection ^† 1	30/144 (20.83%)
Pneumonia ^† 1	28/144 (19.44%)
Nasopharyngitis ^† 1	18/144 (12.50%)
Sinusitis ^† 1	16/144 (11.11%)
Bronchitis ^† 1	14/144 (9.72%)
Cellulitis ^† 1	9/144 (6.25%)
Injury, poisoning and procedural complications
Contusion ^† 1	10/144 (6.94%)
Fall ^† 1	8/144 (5.56%)
Investigations
Weight increased ^† 1	20/144 (13.89%)
Weight decreased ^† 1	16/144 (11.11%)
Metabolism and nutrition disorders
Decreased appetite ^† 1	28/144 (19.44%)
Hyperuricaemia ^† 1	18/144 (12.50%)
Hyponatraemia ^† 1	11/144 (7.64%)
Hypokalaemia ^† 1	9/144 (6.25%)
Hyperglycaemia ^† 1	8/144 (5.56%)
Hypomagnesaemia ^† 1	8/144 (5.56%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	41/144 (28.47%)
Muscle spasms ^† 1	28/144 (19.44%)
Back pain ^† 1	23/144 (15.97%)
Myalgia ^† 1	17/144 (11.81%)
Pain in extremity ^† 1	15/144 (10.42%)
Musculoskeletal pain ^† 1	8/144 (5.56%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma ^† 1	13/144 (9.03%)
Nervous system disorders
Headache ^† 1	18/144 (12.50%)
Dizziness ^† 1	14/144 (9.72%)
Peripheral sensory neuropathy ^† 1	12/144 (8.33%)
Psychiatric disorders
Insomnia ^† 1	12/144 (8.33%)
Depression ^† 1	10/144 (6.94%)
Anxiety ^† 1	8/144 (5.56%)
Renal and urinary disorders
Haematuria ^† 1	9/144 (6.25%)
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	46/144 (31.94%)
Dyspnoea ^† 1	18/144 (12.50%)
Oropharyngeal pain ^† 1	13/144 (9.03%)
Epistaxis ^† 1	12/144 (8.33%)
Nasal congestion ^† 1	10/144 (6.94%)
Productive cough ^† 1	10/144 (6.94%)
Rhinorrhoea ^† 1	8/144 (5.56%)
Skin and subcutaneous tissue disorders
Night sweats ^† 1	23/144 (15.97%)
Rash maculo-papular ^† 1	13/144 (9.03%)
Rash erythematous ^† 1	12/144 (8.33%)
Rash ^† 1	11/144 (7.64%)
Skin lesion ^† 1	11/144 (7.64%)
Pruritus ^† 1	9/144 (6.25%)
Vascular disorders
Hypertension ^† 1	39/144 (27.08%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 17.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Dr. Alvina Chu
Organization:	Pharmacyclics, Inc.
Phone:	855-427-8846
EMail:	medinfo@pcyc.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

O'Brien S, Jones JA, Coutre SE, Mato AR, Hillmen P, Tam C, Osterborg A, Siddiqi T, Thirman MJ, Furman RR, Ilhan O, Keating MJ, Call TG, Brown JR, Stevens-Brogan M, Li Y, Clow F, James DF, Chu AD, Hallek M, Stilgenbauer S. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol. 2016 Oct;17(10):1409-1418. doi: 10.1016/S1470-2045(16)30212-1. Epub 2016 Sep 13.

Layout table for additonal information

Responsible Party:	Pharmacyclics LLC.
ClinicalTrials.gov Identifier:	NCT01744691
Other Study ID Numbers:	PCYC-1117-CA 2012-004476-19 ( EudraCT Number )
First Submitted:	December 3, 2012
First Posted:	December 7, 2012
Results First Submitted:	May 21, 2015
Results First Posted:	June 9, 2015
Last Update Posted:	February 27, 2017

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