A Phase II Study Using Ibrutinib and Short-Course Fludarabine in Treatment-Naive CLL

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02514083
• Collaborator: (none)
• Enrollment: 29
• Location: 1
• Arm: 1
• Anticipated Duration (Months): 94.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This is a pilot phase 2 study investigating the safety and efficacy of ibrutinib combined with short-course fludarabine in previously untreated CLL patients. Ibrutinib will be given daily until disease progression or intolerable side effects occur. Fludarabine will be given in cycles 3 and 4. The primary efficacy endpoint is the rate of complete response after 6 cycles or 24 weeks. The primary safety endpoint is the rate of treatment discontinuation after 6 cycles or 24 weeks.

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma	Drug: Ibrutinib; Drug: Fludarabine	Phase 2

Detailed Description

Chronic lymphocytic leukemia (CLL) and/or small lymphocytic lymphoma (SLL) are tumors of B cells that often affect elderly patients. While the cause of CLL is still unclear, studies have indicated critical factors required for the tumor cells. First, CLL cells grow and survive because they receive signals through the B-cell receptor (BCR); and second, CLL cells benefit from interactions with other cells, especially T cells.

The stimulation through the BCR can be reduced with ibrutinib, which is an oral drug that selectively inhibits Bruton's tyrosine kinase (BTK). In clinical trials, ibrutinib demonstrated safety and high response rates in patients with high-risk disease. Ibrutinib has gained FDA approval as a treatment for CLL patients with 17p deletion and for those who had at least one prior therapy. However, single-agent ibrutinib has limitations; the drug does not eliminate all the tumor cells, and, with time, the tumor cells may become resistant. Therefore, a combination of ibrutinib with other drugs could be beneficial. Here we chose fludarabine because it is a well-tolerated drug that has been used widely to treat CLL. Also, fludarabine can kill both malignant B cells and T cells that support the growth of leukemia cells. With this approach, we hope to restore a healthier immune system.

This study will investigate the safety and efficacy of ibrutinib combined with fludarabine. This protocol is intended for previously untreated CLL patients. Ibrutinib will be given daily until disease progression or intolerable side effects occur. Fludarabine will be given only in cycles 3 and 4.

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Phase II Study Using Ibrutinib and Short-Course Fludarabine in Previously Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)
• Actual Study Start Date: Dec 9, 2015
• Actual Primary Completion Date: Oct 2, 2019
• Anticipated Study Completion Date: Oct 23, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ibrutinib and short-course fludarabine Ibrutinib 420 mg PO daily for the duration of the study Fludarabine 25 mg/m2/day IV on days 1-5 of cycles 3 and 4	Drug: Ibrutinib; Ibrutinib 420mg PO daily for the duration of the study.; Other Names: Imbruvica ; Drug: Fludarabine; Fludarabine 25 mg/m2/day IV on days 1-5 of cycles 3 and 4; Other Names: Fludara

Outcome Measures

Primary Outcome Measures

1. Rate of Complete Response at 24 Weeks [24 weeks]

   Rate of complete response at 24 weeks or after 6 cycles. Response assessment was conducted according to the guidelines from the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL).

2. Rate of Treatment Discontinuation Within the First 24 Weeks [24 weeks]

   Rate of treatment discontinuation within the first 24 weeks or 6 cycles due to intolerable side effects from study therapy

Eligibility Criteria

Criteria

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

INCLUSION CRITERIA:

1. Men and women with histologically confirmed disease as defined by the following:

• CLL: clonal B-lymphocytosis greater than or equal to 5,000 cells/microL .

• SLL: lymphadenopathy with the tissue morphology of CLL but that are not leukemic, < 5,000 cells/microL.

• Immunophenotypic profile or immunohistochemistry read by an expert pathologist as consistent with CLL. This will include CD5, CD19, and CD20 expression by the CLL cells typically also with CD23 expression, but CD23 negative cases may be included if there is an absence of t(11;14).

1. Active disease as defined by at least one of the following (IWCLL consensus criteria):

• Weight loss greater than or equal to 10% within the previous 6 months

• Extreme fatigue

• Fevers of greater than 100.5 F for greater than or equal to 2 weeks without evidence of infection

• Night sweats for more than one month without evidence of infection

• Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia

• Massive or progressive splenomegaly

• Massive nodes or clusters or progressive lymphadenopathy

• Progressive lymphocytosis with an increase of >50% over a 2-month period, or an anticipated doubling time of less than 6 months

1. Treatment naive CLL/SLL patients

-Treatment-naive CLL indicates no prior anti-CLL therapy. Anti-CLL therapy includes chemotherapies, monoclonal antibodies, and targeted agents with known or reasonably expected anti-leukemic activity.

1. Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2

2. Absolute neutrophil count (ANC) > 750/microL, platelets > 50,000/microL

3. Agreement to use acceptable methods of contraception during the study and for 90 days after the last dose of study drug if sexually active and able to bear or beget children. Female subjects of childbearing potential must have a negative serum pregnancy test upon study entry. Male and female subjects who agree to use both a highly effective method of birth control (eg, implants, injectables, combined oral contraceptives, some intrauterine devices, complete abstinence, or sterilized partner) and a barrier method (e.g. condoms, vaginal ring, sponge, etc.) during the period of therapy and for 90 days after the last dose of study drug.

4. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty

5. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local subject privacy regulations)

EXCLUSION CRITERIA:

1. Transformed CLL, including Hodgkin and non-Hodgkin lymphoma

2. Active autoimmune hemolytic anemia or thrombocytopenia

3. Known bleeding disorders

4. Impaired hepatic function: Total bilirubin greater than or equal to 1.5 times upper limit of normal unless due to Gilbert's disease, aspartate aminotransferase (AST) or alanine transaminase (ALT) greater than or equal to 2.5 times institutional upper limit of normal unless due to infiltration of liver, Child-Pugh class B or C

5. Impaired renal function: estimated glomerular filtration rate (GFR) < 30ml/min/1.73m(2) based on CKD-EPI

6. Life-threatening illness, medical condition or organ system dysfunction which, in the investigators opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib and fludarabine, or put the study outcomes at undue risk

7. Concomitant immunomodulatory therapy, chemotherapy, radiotherapy or experimental therapy

8. Active Hepatitis B or Hepatitis C infection

9. HIV infection

10. Female patients who are currently in pregnancy, or unwilling to use acceptable methods of contraception or refrain from pregnancy if of childbearing potential or currently breastfeeding. Male patients who are unwilling to follow the contraception requirements described in this protocol.

11. Psychiatric illness/social situations that would limit the patient's ability to tolerate and/or comply with study requirements.

12. Unable to understand the investigational nature of the study or give informed consent.

13. Individuals < 18 years old

14. Known hypersensitivity to any component of ibrutinib or fludarabine

15. Requires concomitant anticoagulation with Coumadin (warfarin) or other vitamin K antagonists.

16. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease-free for greater than or equal to 2 years or which will not limit survival to < 2 years

17. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction

18. History of stroke or intracranial hemorrhage within 6 months before the first dose of study drug

19. Major surgery within 4 weeks of first dose of study drug

20. Currently active, clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, Class 3 or 4 congestive heart failure as defined by New York Heart Association Functional Classification, or a history of myocardial infarction or unstable angina, or acute coronary syndrome within 6 months of screening.

21. Subjects who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior to the first dose of ibrutinib or subjects who require continuous treatment with a strong CYP3A inhibitor.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Andy Itsara, M.D., National Heart, Lung, and Blood Institute (NHLBI)

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 26, 2019

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

None provided.

• Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
• ClinicalTrials.gov Identifier: NCT02514083
• Other Study ID Numbers: 150172; 15-H-0172
• First Posted: Aug 3, 2015
• Last Update Posted: Mar 22, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by National Heart, Lung, and Blood Institute (NHLBI): Bruton's tyrosine kinase inhibitor; Fludarabine; Immune modulation
• Additional relevant MeSH terms: Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Fludarabine

Study Results

Participant Flow

Arm/Group Title	Ibrutinib With Fludarabine in Patients With CLL or SLL
Arm/Group Description	Open-label study of ibrutinib and a short-course fludarabine in previously untreated participants with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). Ibrutinib is administered orally, 420 mg daily for duration of study. Fludarabine dose is 25 mg/m2/day on days 1-5 of cycles 3 and 4.
Period Title: Overall Study
STARTED	29
COMPLETED	28
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Ibrutinib With Fludarabine in Patients With CLL or SLL
Arm/Group Description	Open-label study of ibrutinib and a short-course fludarabine in previously untreated participants with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). Ibrutinib is administered orally, 420 mg daily for duration of study. Fludarabine dose is 25 mg/m2/day on days 1-5 of cycles 3 and 4.
Overall Participants	29
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	14 48.3%
>=65 years	15 51.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.4 (10.7)
Sex: Female, Male (Count of Participants)
Female	10 34.5%
Male	19 65.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	29 100%
Unknown or Not Reported	0 0%
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	1 3.4%
White	28 96.6%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Rate of Complete Response at 24 Weeks
Description	Rate of complete response at 24 weeks or after 6 cycles. Response assessment was conducted according to the guidelines from the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL).
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

Treatment-naive CLL or SLL patients

Arm/Group Title	Ibrutinib With Fludarabine in Patients With CLL or SLL
Arm/Group Description	Open-label study of ibrutinib and a short-course fludarabine in previously untreated participants with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). Ibrutinib is administered orally, 420 mg daily for duration of study. Fludarabine dose is 25 mg/m2/day on days 1-5 of cycles 3 and 4.
Measure Participants	28
Complete response	6 20.7%
Partial response with or without lymphocytosis	21 72.4%
Stable disease	1 3.4%

2. Primary Outcome

Title	Rate of Treatment Discontinuation Within the First 24 Weeks
Description	Rate of treatment discontinuation within the first 24 weeks or 6 cycles due to intolerable side effects from study therapy
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ibrutinib With Fludarabine in Patients With CLL or SLL
Arm/Group Description	Open-label study of ibrutinib and a short-course fludarabine in previously untreated participants with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). Ibrutinib is administered orally, 420 mg daily for duration of study. Fludarabine dose is 25 mg/m2/day on days 1-5 of cycles 3 and 4.
Measure Participants	29
Treatment discontinued within 24 weeks	1 3.4%
Treatment continued for 24+ weeks	28 96.6%

Adverse Events

Time Frame	From treatment initiation until the last follow-up on study or death, whichever occurred first, assessed up to 4 years
Adverse Event Reporting Description	The AE reporting period for this study begins when the participant takes the first dose of study drug and continues until the last follow-up on the study. Participants will continue on study until disease progression or intolerable side effects occur.
Arm/Group Title	Ibrutinib With Fludarabine in Patients With CLL or SLL
Arm/Group Description	Open-label study of ibrutinib and a short-course fludarabine in previously untreated participants with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). Ibrutinib is administered orally, 420 mg daily for days 1-28 from Cycle 1 up to Cycle 27. Fludarabine dose is 25 mg/m2/day on days 1-5 of cycles 3 and 4.
All Cause Mortality
	Ibrutinib With Fludarabine in Patients With CLL or SLL
	Affected / at Risk (%)	# Events
Total	1/29 (3.4%)
Serious Adverse Events
	Ibrutinib With Fludarabine in Patients With CLL or SLL
	Affected / at Risk (%)	# Events
Total	14/29 (48.3%)
Cardiac disorders
Heart Failure	1/29 (3.4%)	1
Palpitations	1/29 (3.4%)	1
Ventricular arrhythmia	1/29 (3.4%)	1
Gastrointestinal disorders
Vomiting	1/29 (3.4%)	1
Pancreatitis	1/29 (3.4%)	1
General disorders
Death NOS	1/29 (3.4%)	1
Non-cardiac chest pain	1/29 (3.4%)	1
Hepatobiliary disorders
Cholecystitis	1/29 (3.4%)	1
Infections and infestations
Appendicitis	1/29 (3.4%)	1
Lung infection	2/29 (6.9%)	4
Sepsis	1/29 (3.4%)	1
Urinary tract infection	1/29 (3.4%)	1
Injury, poisoning and procedural complications
Post-operative Hemorrhage (Epistaxis)	1/29 (3.4%)	1
Investigations
Alanine aminotransferase increased	2/29 (6.9%)	2
Aspartate aminotransferase increased	2/29 (6.9%)	2
Metabolism and nutrition disorders
Hyponatremia	1/29 (3.4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Vulvar intraepithelial neoplasm	1/29 (3.4%)	1
Squamous cell carcinoma	4/29 (13.8%)	4
Prostate Cancer	1/29 (3.4%)	1
Triple negative Breast Cancer	1/29 (3.4%)	1
Papillary Thyroid Cancer	1/29 (3.4%)	1
Vascular disorders
Thromboembolic event	1/29 (3.4%)	1
Other (Not Including Serious) Adverse Events
	Ibrutinib With Fludarabine in Patients With CLL or SLL
	Affected / at Risk (%)	# Events
Total	29/29 (100%)
Blood and lymphatic system disorders
Leukocytosis	14/29 (48.3%)	14
Anemia	4/29 (13.8%)	4
Hematoma	2/29 (6.9%)	2
Gastrointestinal disorders
Diarrhea	13/29 (44.8%)	13
Nausea	5/29 (17.2%)	5
Vomiting	3/29 (10.3%)	3
Gastroesophageal reflux disease	2/29 (6.9%)	2
General disorders
Fatigue	9/29 (31%)	9
Pain	7/29 (24.1%)	7
Peripheral edema	7/29 (24.1%)	7
Flu like symptoms	2/29 (6.9%)	2
Infections and infestations
Shingles	5/29 (17.2%)	5
Lung infection	2/29 (6.9%)	2
Infections and infestations: other	2/29 (6.9%)	2
Productive cough	2/29 (6.9%)	2
Sinusitis	2/29 (6.9%)	2
Injury, poisoning and procedural complications
Bruising	19/29 (65.5%)	19
Investigations
White blood cell decreased	19/29 (65.5%)	19
Platelet count decresaed	14/29 (48.3%)	14
Neutrophil count decresaed	12/29 (41.4%)	12
Alanine or aspartate aminotransferase increased	4/29 (13.8%)	4
Lymphocyte count decreased	14/29 (48.3%)	14
Lymphocyte count increased	8/29 (27.6%)	8
Creatinine increased	4/29 (13.8%)	4
Weight gain	2/29 (6.9%)	2
Metabolism and nutrition disorders
Hyponatremia	2/29 (6.9%)	2
Hyperuricemia	4/29 (13.8%)	4
Hypocalcemia	4/29 (13.8%)	4
Hypophosphatemia	2/29 (6.9%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	11/29 (37.9%)	11
Myalgia	12/29 (41.4%)	12
Nervous system disorders
Headache	4/29 (13.8%)	4
Dizziness	3/29 (10.3%)	3
Renal and urinary disorders
Hematuria	2/29 (6.9%)	2
Urinary tract infection	2/29 (6.9%)	2
Respiratory, thoracic and mediastinal disorders
Epistaxis	5/29 (17.2%)	5
Cough	3/29 (10.3%)	3
Skin and subcutaneous tissue disorders
Brittle nails	8/29 (27.6%)	8
Petechiae	6/29 (20.7%)	6
Maculopapular rash	5/29 (17.2%)	5
Vascular disorders
Hypertension	9/29 (31%)	9

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.