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Protocol Details

A Phase II Study Using ACP-196 in Patients with Relapsed/Refractory and Treatment Naive Deletion 17p CLL/SLL: Pharmacodynamic Assessment of BTK Inhibition and Anti-Tumor Response.

This study is NOT currently recruiting participants.

Summary | Eligibility | Citations | Contacts




Sponsoring Institute

National Heart, Lung and Blood Institute (NHLBI)

Recruitment Detail

Type: No longer recruiting/follow-up only
Gender: Male & Female
Min Age: 18 Years
Max Age: N/A

Referral Letter Required


Population Exclusion(s)



Biological Response Modifier Therapy;
BTK Inhibitor

Recruitment Keyword(s)



CLL (Chronic Lymphocytic Leukemia);
Small Lymphocytic Lymphoma

Investigational Drug(s)

Acalabrutinib (ACP-196)

Investigational Device(s)



Drug: ACP-196

Supporting Site

National Heart, Lung, and Blood Institute

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are mature B cell malignancies. Patients with relapsed disease and 17p deletion have a particularly aggressive disease course. Standard chemoimmunotherapy regimens for patients with relapsed/refractory disease have resulted in few durable remissions.

B cell receptor (BCR) activation is a key pathway engaged in the pathogenesis of CLL as well as in the interaction of CLL cells with the tumor microenvironment that is required for survival of CLL cells. The more aggressive forms of CLL, such as patients with relapsed/refractory disease, are characterized by stronger B cell receptor (BCR) activation. Disruption of tumor microenvironment interactions and inhibition of BCR signaling are promising therapeutic strategies in CLL. Bruton s tyrosine kinase (BTK) is a key enzyme in BCR signaling. Ibrutinib is the first BTK inhibitor that has reached the clinic and is approved as therapy for relapsed/refractory CLL. The advent of kinase inhibitors such as ibrutinib has demonstrated significantly improved responses as second line therapies as well as improved responses in patients with 17p deletion compared to standard chemoimmunotherapy regimens with long (more than two years) durable remissions in the majority of patients.

ACP-196 is an orally available, new molecule that irreversibly inhibits BTK and shows encouraging activity and acceptable safety profile in nonclinical studies. ACP-196 has shown efficacy in 3 separate models of lymphoid malignancies. Currently, this molecule is in phase 1 studies for humans with reported high response rates in the first six patients included. We believe that ACP-196, a second generation BTK inhibitor is designed to be more potent, more specific, and could overcome limitations currently seen with ibrutinib.

This study will investigate the safety and efficacy of ACP-196 for patients with CLL/SLL that have relapsed/refractory disease or treatment na(SqrRoot) ve deletion 17p. The primary endpoint is the response to ACP- 196. Biological sampling from lymph nodes, bone marrow and peripheral blood early during treatment will be used to investigate BTK inhibition in the bone marrow and lymph node compartments, the main sides for CLL progression in addition to the

circulating tumor cells.

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1. Men and women 18 years of age and older with histologically confirmed disease as defined by the following:

--CLL: clonal B-lymphocytosis geater than or equal to 5,000 cells/microL or 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 no t11;14 translocation present.

2. 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 degrees Fahrenheit for greater than or equal to 2 weeks without evidence of infection

--Night sweats for more than 1 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

--Compensated autoimmune hemolysis

3. Relapsed/refractory CLL/SLL, or treatment naive subjects with deletion 17p, TP53 mutations, or NOTCH-1 mutation.

4. ECOG performance status of less than or equal to 2

5. Absolute neutrophil count (ANC) > 500/microL, platelets > 30,000/microL

6. Female subjects who are sexually active and able to bear children must agree to use highly effective methods of contraception during the study and for 2 days after the last dose of study drug.

7. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules or tablets without difficulty and serial biopsies

8. 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)


1. Radiotherapy, radioimmunotherapy, biological therapy, chemotherapy, or investigational products in the 4 weeks prior to study drug administration.

2. Richter s transformation

3. Autoimmune hemolytic anemia or thrombocytopenia requiring steroid therapy

4. Steroids >=20 mg prednisone or equivalent for more than 3 days within the last 3 months.

5. Impaired hepatic function: total bilirubin greater than or equal to1.5 x upper limit of normal (ULN) (unless due to Gilbert's syndrome), aspartate amino transferase (AST)/ alanine aminotransferase (ALT) greater than or equal to 2.5 x institutional ULN, unless due to infiltration of the liver

6. Impaired renal function: estimated glomerular filtration rate (eGFR) less than or equal to 50 as determined by CKD-EPI equation

7. Life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of acalabrutinib oral (PO), or put the study outcomes at undue risk

8. Concomitant immunotherapy, chemotherapy, radiotherapy, corticosteroids (at dosages equivalent to prednisone > 20 mg/day), or experimental therapy

9. Active hepatitis B or hepatitis C infection

10. HIV infection

11. Female subjects: current pregnancy or unwilling to utilize effective contraceptive methods or refrain from pregnancy if of childbearing potential or currently breastfeeding

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

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

14. Individuals < 18 years old

15. Known hypersensitivity to any component of acalabrutinib

16. Any prior therapy with other BTK inhibitors

17. Requires systemic anticoagulation with coumadin (warfarin)

18. 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.

19. 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

20. Grade greater than or equal to 2 toxicity (other than alopecia) continuing from prior anticancer therapy including radiation

21. History of stroke or intracranial hemorrhage within 6 months before signing the treatment consent form

22. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of signing the treatment consent form, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or left ventricular ejection fraction (LVEF) less than or equal to 40%

23. Requires treatment with strong or moderate CY3A4/5 inhibitors (unless no alternative is available)

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Not Provided

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Principal Investigator

Referral Contact

For more information:

Clare C. Sun, M.D.
National Heart, Lung and Blood Institute (NHLBI)
NIHBC 10 - CRC BG RM 3-5132
(301) 451-7130

Susan Soto, R.N.
National Heart, Lung and Blood Institute (NHLBI)
National Institutes of Health
Building 10
Room 4-5362
10 Center Drive
Bethesda, Maryland 20892
(301) 402-0797

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: TTY Users Dial 7-1-1

Clinical Trials Number:


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