Phase 2 Study of the Combination of Bruton's Tyrosine Kinase Inhibitor PCI-32765 and Rituximab in High-Risk Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma Patients

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01520519
• Collaborator: Pharmacyclics LLC. (Industry)
• Enrollment: 40
• Location: 1
• Arm: 1
• Actual Duration (Months): 77.4
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The goal of this clinical research study is to learn if PCI-32765 (Ibrutinib) combined with rituximab can help to control CLL and SLL. The safety of this combination will also be studied.

Ibrutinib is designed to stop a protein from working in the cells, which may cause the cancer cells to die or stop growing.

Rituximab is designed to attach to cancer cells and damage them, which may cause the cells to die.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: Rituximab; Drug: PCI-32765	Phase 2

Detailed Description

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive rituximab by vein on Days 1, 8, 15, and 22 of Cycle 1 (+ 3 days) and then on Day 1 (+/- 7 days) of Cycles 2-6.

Each cycle is 28 days.

You will take Ibrutinib capsules by mouth 1 time each day starting on Day 2 of Cycle 1. You should take it with 1 cup (8 ounces) of water.

You will also take allopurinol by mouth 1 time each day during the first 1-2 weeks of study treatment to lower the risk of side effects.

Study Visits:

On Days 7, 14, 21, and 28 of Cycle 1 (+/- 3 days):

• You will have a physical exam, including measurement of your vital signs.

• Blood (about 1 tablespoon) will be drawn for routine tests.

• You will be asked about any drugs you may be taking.

At the end of Cycles 2, 3, 4, 6, 9, and 12 (+/- 1 month):

• You will have a physical exam, including measurement of your vital signs.

• Blood (about 1 tablespoon) will be drawn for routine tests.

• You will be asked about any drugs you may be taking.

At the end of Cycles 3 or 6, and 12 (+/- 1 month), and then every 12 cycles (+/- 1 month) after that if the doctor thinks it is needed, you will have CT scans of the chest, abdomen and pelvis to check the status of the disease.

At the end of Cycles 3, 6, and 12 and then every 12 cycles (+/- 1 month) after that, you will have a bone marrow aspiration to check the status of the disease. If the doctor things these bone marrow aspirations are no longer needed, you will no longer have to have them.

Every 3 months (+/- 1 month) for Cycles 13-36 and every 6 months (+/- 1 month) after that:

• You will have a physical exam, including measurement of your vital signs.

• Blood (about 1 tablespoon) will be drawn for routine tests.

• You will be asked about any drugs you may be taking.

Length of Treatment:

You may continue taking the study drug combination of rituximab and Ibrutinib for up to 6 cycles, after which Ibrutinib will be continued for up to a total of 12 cycles. It will be possible to continue with Ibrutinib treatment beyond 12 cycles if the study doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

This is an investigational study. Ibrutinib is FDA approved and commercially available for the treatment of patients with mantle cell lymphoma, CLL and SLL. Its use in this study is investigational. Rituximab is FDA approved to treat CLL and SLL.

Up to 40 patients will take part in this study. All will be enrolled at MD Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of the Combination of the Bruton's Tyrosine Kinase Inhibitor PCI-32765 and Rituximab in High-Risk Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) Patients
• Actual Study Start Date: Feb 27, 2012
• Actual Primary Completion Date: Aug 9, 2018
• Actual Study Completion Date: Aug 9, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rituximab + PCI-32765 Rituximab (375 mg/m2) given intravenously (IV) on Day 1, Day 8, Day 15, and Day 22, then continued once every 4 weeks only on Days 1 during cycles 2 - 6. PCI-32765 started on Day 2 of cycle 1 at a dose of 420 mg (3 * 140-mg capsules) orally daily and will be continued daily.	Drug: Rituximab; 375 mg/m2 intravenously on Day 1, Day 8, Day 15, and Day 22, then continued once every 4 weeks only on Days 1 during cycles 2 - 6.; Other Names: Rituxan ; Drug: PCI-32765; 420 mg (3 * 140-mg capsules) orally started on Day 2 of cycle 1 once daily and will be continued daily.

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) [up to 50 months]

   Progression free survival defined as the time interval from treatment to progressive disease or death, whichever happens earlier. Participants in complete remission (CR), partial remission (PR) or stable disease (SD) are all counted as progression-free. Survival or times to progression functions estimated using the Kaplan-Meier method.

2. Number of Participants With a Response [7 months]

   Over all Response = complete remission (CR) + partial remission (PR). Complete remission (CR), requiring absence of peripheral blood clonal lymphocytes by immunophenotyping, absence of lymphadenopathy, absence of hepatomegaly or splenomegaly, absence of constitutional symptoms and satisfactory blood counts; positive or negative minimal residual disease (MRD); Partial remission (PR), defined as ≥ 50% fall in lymphocyte count, ≥ 50% reduction in lymphadenopathy or ≥ 50% reduction in liver or spleen, together with improvement in peripheral blood counts

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. 1.Patients must have a diagnosis of high-risk CLL/SLL and be previously treated with up to 3 lines of prior therapy. High-risk CLL and high-risk SLL is defined by the presence of a 17p deletion or 11q deletion or TP53 mutation. Any CLL and SLL patient who has a short remission duration of less than 3 years after prior first-line chemo-immunotherapy, such as the FCR regimen, also fulfills criteria of high-risk CLL/SLL, regardless of the presence or absence of cytogenetic abnormalities.

2. 2.CLL and SLL patients with 17p deletion or TP53 mutation will not be required to have received any prior therapy, given the poor outcome of CLL/SLL patients to standard frontline chemo-immunotherapy, such patients will be eligible if they are untreated or if they have received up to 3 lines of prior therapy.

3. Patients must have an indication for treatment by 2008 IWCLL Criteria.

4. Patients age > 18 years at the time of signing informed consent. Understand and voluntarily sign an informed consent. Be able to comply with study procedures and follow-up examinations.

5. Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO) performance status of 0-1.

6. Patients of childbearing potential must be willing to practice highly effective birth control (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], sexual abstinence, or sterilized partner) during the study and for 30 days after the last dose of study drug. Women of childbearing potential include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Post menopause is defined as follows: Amenorrhea >/= 12 consecutive months without another cause and a documented serum follicle stimulating hormone (FSH) level >35 mIU/mL; a male of childbearing potential is any male that has not been surgically sterilized.

7. Adequate renal and hepatic function as indicated by all of the following: Total bilirubin </=1.5 x institutional Upper Limit of Normal (ULN) except for patients with bilirubin elevation due to Gilbert's disease who will be allowed to participate; an Alanine (ALT) </=2.5 x ULN; and an estimated creatinine clearance (CrCl) of > 30 mL/min, as calculated by the Cockcroft-Gault equation unless disease related.

8. Free of prior malignancies for 3 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast.

9. A Urine Pregnancy Test (within 7 days of Day 1) is required for women with childbearing potential

Exclusion Criteria:

1. Pregnant or breast-feeding females.

2. Treatment including chemotherapy, chemo-immunotherapy , monoclonal antibody therapy, radiotherapy, high-dose corticosteroid therapy (more than 60 mg prednisone or equivalent daily), or immunotherapy within 21 days prior to enrollment or concurrent with this trial.

3. Investigational agent received within 30 days prior to the first dose of study drug or have previously taken PCI-32765. If received any investigational agent prior to this time point, drug-related toxicities must have recovered to Grade 1 or less prior to first dose of study drug.

4. Systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).

5. Patients with uncontrolled Autoimmune Hemolytic Anemia (AIHA) or autoimmune thrombocytopenia (ITP).

6. Patients with severe hematopoietic insufficiency, as defined by an absolute neutrophil count of less than 500/micro-L and/or a platelet count of less than 30,000/micro-L at time of screening for this protocol.

7. Any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver or other organ system that may place the patient at undue risk to undergo therapy with PCI-32765 and rituximab.

8. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification.

9. Significant screening ECG abnormalities including left bundle branch block, 2nd degree AV block type II, 3rd degree block, bradycardia, and QTc > 470 msec.

10. Any serious medical condition, laboratory abnormality, or psychiatric illness that places the subject at unacceptable risk if he/she were to participate in the study.

11. History of stroke or cerebral hemorrhage within 6 months.

12. Evidence of bleeding diathesis or coagulopathy.

13. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1, anticipation of need for major surgical procedure during the course of the study.

14. Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to Day 1. Bone marrow aspiration and/or biopsy are allowed.

15. Serious, non-healing wound, ulcer, or bone fracture.

16. Treatment with Coumadin. Patients who recently received Coumadin must be off Coumadin for at least 7 days prior to start of the study.

17. Any chemotherapy (e.g., bendamustine, cyclophosphamide, pentostatin, or fludarabine), immunotherapy (e.g., alemtuzumab, or ofatumumab), bone marrow transplant, experimental therapy, or radiotherapy is prohibited during therapy on this study.

18. Use of medications known to prolong QTc interval or that may be associated with Torsades de Pointes (refer to Appendix F) are prohibited within 7 days of starting study drug and during study-drug treatment.

19. Requires treatment with strong CYP3A4/5 and/or CYP2D6 inhibitors.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• Pharmacyclics LLC.

Investigators

• Principal Investigator: Jan A. Burger, MD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 13, 2012

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT01520519
• Other Study ID Numbers: 2011-0785; NCI-2012-00126
• First Posted: Jan 30, 2012
• Last Update Posted: Sep 18, 2019
• Last Verified: Sep 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by M.D. Anderson Cancer Center: Leukemia; Chronic Lymphocytic Leukemia; CLL; Small Lymphocytic Lymphoma; SLL; Rituximab; Rituxan; PCI-32765
• Additional relevant MeSH terms: Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab

Study Results

Participant Flow

Recruitment Details	Recruitment Details: February 2012 - September 2012

Arm/Group Title	Rituximab + PCI-32765
Arm/Group Description	Rituximab (375 mg/m2) given intravenously (IV) on Day 1, Day 8, Day 15, and Day 22, then continued once every 4 weeks only on Days 1 during cycles 2 - 6. PCI-32765 started on Day 2 of cycle 1 at a dose of 420 mg (3 * 140-mg capsules) orally daily and will be continued daily. Rituximab: 375 mg/m2 intravenously on Day 1, Day 8, Day 15, and Day 22, then continued once every 4 weeks only on Days 1 during cycles 2 - 6. PCI-32765: 420 mg (3 * 140-mg capsules) orally started on Day 2 of cycle 1 once daily and will be continued daily.
Period Title: Overall Study
STARTED	40
COMPLETED	40
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Rituximab + PCI-32765
Arm/Group Description	Rituximab (375 mg/m2) given intravenously (IV) on Day 1, Day 8, Day 15, and Day 22, then continued once every 4 weeks only on Days 1 during cycles 2 - 6. PCI-32765 started on Day 2 of cycle 1 at a dose of 420 mg (3 * 140-mg capsules) orally daily and will be continued daily. Rituximab: 375 mg/m2 intravenously on Day 1, Day 8, Day 15, and Day 22, then continued once every 4 weeks only on Days 1 during cycles 2 - 6. PCI-32765: 420 mg (3 * 140-mg capsules) orally started on Day 2 of cycle 1 once daily and will be continued daily.
Overall Participants	40
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	26 65%
>=65 years	14 35%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	65
Sex: Female, Male (Count of Participants)
Female	14 35%
Male	26 65%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 5%
White	37 92.5%
More than one race	0 0%
Unknown or Not Reported	1 2.5%
Region of Enrollment (participants) [Number]
United States	40 100%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	Progression free survival defined as the time interval from treatment to progressive disease or death, whichever happens earlier. Participants in complete remission (CR), partial remission (PR) or stable disease (SD) are all counted as progression-free. Survival or times to progression functions estimated using the Kaplan-Meier method.
Time Frame	up to 50 months

Outcome Measure Data

Analysis Population Description

1 participant was not evaluable for response

Arm/Group Title	Rituximab + PCI-32765
Arm/Group Description	Rituximab (375 mg/m2) given intravenously (IV) on Day 1, Day 8, Day 15, and Day 22, then continued once every 4 weeks only on Days 1 during cycles 2 - 6. PCI-32765 started on Day 2 of cycle 1 at a dose of 420 mg (3 * 140-mg capsules) orally daily and will be continued daily. Rituximab: 375 mg/m2 intravenously on Day 1, Day 8, Day 15, and Day 22, then continued once every 4 weeks only on Days 1 during cycles 2 - 6. PCI-32765: 420 mg (3 * 140-mg capsules) orally started on Day 2 of cycle 1 once daily and will be continued daily.
Measure Participants	39
Median (Full Range) [Months]	45

2. Primary Outcome

Title	Number of Participants With a Response
Description	Over all Response = complete remission (CR) + partial remission (PR). Complete remission (CR), requiring absence of peripheral blood clonal lymphocytes by immunophenotyping, absence of lymphadenopathy, absence of hepatomegaly or splenomegaly, absence of constitutional symptoms and satisfactory blood counts; positive or negative minimal residual disease (MRD); Partial remission (PR), defined as ≥ 50% fall in lymphocyte count, ≥ 50% reduction in lymphadenopathy or ≥ 50% reduction in liver or spleen, together with improvement in peripheral blood counts
Time Frame	7 months

Outcome Measure Data

Analysis Population Description

1 participant was not evaluable for response

Arm/Group Title	Rituximab + PCI-32765
Arm/Group Description	Rituximab (375 mg/m2) given intravenously (IV) on Day 1, Day 8, Day 15, and Day 22, then continued once every 4 weeks only on Days 1 during cycles 2 - 6. PCI-32765 started on Day 2 of cycle 1 at a dose of 420 mg (3 * 140-mg capsules) orally daily and will be continued daily. Rituximab: 375 mg/m2 intravenously on Day 1, Day 8, Day 15, and Day 22, then continued once every 4 weeks only on Days 1 during cycles 2 - 6. PCI-32765: 420 mg (3 * 140-mg capsules) orally started on Day 2 of cycle 1 once daily and will be continued daily.
Measure Participants	39
Count of Participants [Participants]	37 92.5%

Adverse Events

Time Frame	7 months
Arm/Group Title	Rituximab + PCI-32765
Arm/Group Description	Rituximab (375 mg/m2) given intravenously (IV) on Day 1, Day 8, Day 15, and Day 22, then continued once every 4 weeks only on Days 1 during cycles 2 - 6. PCI-32765 started on Day 2 of cycle 1 at a dose of 420 mg (3 * 140-mg capsules) orally daily and will be continued daily. Rituximab: 375 mg/m2 intravenously on Day 1, Day 8, Day 15, and Day 22, then continued once every 4 weeks only on Days 1 during cycles 2 - 6. PCI-32765: 420 mg (3 * 140-mg capsules) orally started on Day 2 of cycle 1 once daily and will be continued daily.
All Cause Mortality
	Rituximab + PCI-32765
	Affected / at Risk (%)	# Events
Total	2/40 (5%)
Serious Adverse Events
	Rituximab + PCI-32765
	Affected / at Risk (%)	# Events
Total	18/40 (45%)
Cardiac disorders
Atrial fibrillation	3/40 (7.5%)	3
Cardiac disorders - other	1/40 (2.5%)	1
Eye disorders
Eye disorders - other	1/40 (2.5%)	1
General disorders
Abdominal Pain	1/40 (2.5%)	1
Infections and infestations
Lung Infection	9/40 (22.5%)	11
Mucosal infection	1/40 (2.5%)	1
Sepsis	3/40 (7.5%)	3
Wound Infection	1/40 (2.5%)	1
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorder - other	1/40 (2.5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified	1/40 (2.5%)	1
Nervous system disorders
Intracranial hemorrhage	1/40 (2.5%)	1
Peripheral Sensory Neuropathy	1/40 (2.5%)	1
Renal and urinary disorders
Hematuria	1/40 (2.5%)	1
Renal and urinary disorders - other	1/40 (2.5%)	3
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/40 (2.5%)	1
Respiratory, thoracic and mediastinal disorders - other	1/40 (2.5%)	2
Other (Not Including Serious) Adverse Events
	Rituximab + PCI-32765
	Affected / at Risk (%)	# Events
Total	40/40 (100%)
Blood and lymphatic system disorders
Neutropenia	2/40 (5%)	2
Bleeding event	13/40 (32.5%)	13
Anemia	3/40 (7.5%)	3
Cardiac disorders
Atrial fibrillation	2/40 (5%)	2
Eye disorders
Eye disorders	3/40 (7.5%)	3
Gastrointestinal disorders
Diarrhea	10/40 (25%)	10
Nausea/vomiting	15/40 (37.5%)	15
Mucositis	3/40 (7.5%)	3
Constipation	3/40 (7.5%)	3
Dry Mouth	2/40 (5%)	2
General disorders
Fatigue	7/40 (17.5%)	7
Headache	3/40 (7.5%)	3
Infections and infestations
Lung Infection	11/40 (27.5%)	11
Investigations
Weight Gain	4/40 (10%)	4
Musculoskeletal and connective tissue disorders
Arthralgia	11/40 (27.5%)	11
Nervous system disorders
Peripheral Neuropathy	3/40 (7.5%)	3
Psychiatric disorders
Insomnia	4/40 (10%)	4
Anxiety	2/40 (5%)	2
Renal and urinary disorders
Urinary tract infection	3/40 (7.5%)	3
Respiratory, thoracic and mediastinal disorders
Upper respiratory tract infection	14/40 (35%)	14
Skin and subcutaneous tissue disorders
Alopecia	2/40 (5%)	2
Vascular disorders
Hot flashes	2/40 (5%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.