Clinical trial NCT02180724: An Open-label, Phase 2 Study of ACP-196 in Subjects With Waldenström Macroglobulinemia
Official title: An Open-label, Phase 2 Study of ACP-196 in Subjects With Waldenström Macroglobulinemia
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Waldenström Macroglobulinemia (WM)
Keywords: Bruton tyrosine kinase inhibitor
Btk
Waldenström Macroglobulinemia
WM
Waldenström
Macroglobulinemia
Lead sponsor: Acerta Pharma BV
Sponsor class: INDUSTRY
First posted: 2014-07-03
Enrollment: 107
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety, pharmacokinetics, pharmacodynamics, and activity of acalabrutinib in treating subjects with WM.

Detailed description: Clinical studies have shown that targeting the B-cell receptor (BCR) signaling pathway by inhibiting Bruton tyrosine kinase (BTK) produces significant clinical benefit in patients with non-Hodgkin lymphoma, including Waldenström macroglobulinemia (WM). Ibrutinib (IMBRUVICA®), an oral, small-molecule BTK inhibitor has been approved for the treatment for chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and WM.

Acerta Pharma BV (AcertaPharma) has developed a novel BTK inhibitor, acalabrutinib, that achieves significant oral bioavailability and potency in preclinical models.

The purpose of this study is to evaluate the safety, pharmacokinetics, pharmacodynamics, and activity of acalabrutinib in treating subjects with WM.

Eligibility criteria: Inclusion Criteria:

1. Men and women ≥18 years of age.
2. Previously treated cohort only: A confirmed diagnosis of WM, which has relapsed after, or been refractory to ≥1prior therapy for WM and which requires treatment.
3. Previously untreated cohort only: A confirmed diagnosis of previously untreated WM in subjects who require treatment and do not want to receive chemoimmunotherapy or have comorbidities that would preclude chemoimmunotherapy such as:

   * Symptomatic hyperviscosity with an IgM ≥5,000mg/dL
   * Disease-related neuropathy
4. Serum concentration of IgM, as measured by SPEP and IFE, that exceeds the upper limits of normal or measurable nodal WM (defined as the presence of ≥1lymph node that measures ≥2.0 cm in the longest diameter and ≥1.0cm in the longest perpendicular diameter).
5. ECOG performance status of ≤2.
6. Women who are sexually active and can bear children must agree to use highly effective forms of contraception during the study and for 2 days after the last dose of acalabrutinib.
7. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.
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 patient privacy regulations).

Exclusion Criteria:

1. 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 ≥2 years or which will not limit survival to \<2 years. Note: These cases must be discussed with the medical monitor.
2. A 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, or put the study outcomes at undue risk.
3. 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, or QTc \>480 msec.
4. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
5. Any immunotherapy within 4 weeks of first dose of study drug.
6. For subjects with recent chemotherapy or experimental therapy, the first dose of study drug must occur after 5 times the half-life of the agent(s).
7. Prior exposure to a BCR inhibitor (e.g., BTK,PI3K, or SYK inhibitors) or BCL-2 inhibitors (e.g., ABT-199).
8. Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids for treatment of WM or other conditions. Note: Subjects may use topical or inhaled corticosteroids or low-dose steroids (≤10 mg of prednisone or equivalent per day) as therapy for comorbid conditions. During study participation, subjects may also receive systemic or enteric corticosteroids as needed for treatment-emergent comorbid conditions.
9. Grade ≥2 toxicity (other than alopecia) continuing from prior anticancer therapy including radiation.
10. Known history of HIV or active infection with HCV or hepatitis B virus (HBV) or any uncontrolled active systemic infection.
11. Major surgery within 4 weeks before first dose of study drug.
12. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.
13. History of a bleeding diathesis (e.g., hemophilia, von Willebrand disease).
14. History of stroke or intracranial hemorrhage within 6 months before the first dose of acalabrutinib.
15. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 28 days of first dose of study drug.
16. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).
17. ANC \<0.75 x 109/L or platelet count \<50 x 109/L. For subjects with disease involvement in the bone marrow, ANC \<0.50 x 109/L or platelet count \<30x109/L.
18. Creatinine \>2.5 x institutional ULN; total bilirubin \>2.5 x ULN; or AST or ALT \>3.0 x ULN.
19. Lactating or pregnant.
20. Concurrent participation in another therapeutic clinical trial.

Primary outcomes:
measure: Overall Response Rate (ORR) of Acalabrutinib in Subjects as Assessed by Investigator Per IWWM 6th Criteria
timeFrame: Up to approximately 3.8 years. Data cut at when last patient has completed Cycle 27 (28 days per Cycle).
measure: Overall Response Rate (ORR) of Acalabrutinib in Subjects as Assessed by Investigator Per IWWM 3rd Criteria
timeFrame: Up to approximately 3.8 years. Data cut at when last patient has completed Cycle 27 (28 days per Cycle).
Secondary outcomes:
measure: Progression-free Survival (PFS) of Acalabrutinib by Investigator
timeFrame: Up to approximately 3.8 years. Data cut at last subject have completed Cycle 27 (28 days per Cycle).
measure: Overall Survival (OS) of Acalabrutinib by Investigator
timeFrame: Primary analysis occur when all subjects have completed Cycle 27 or have discontinued before Cycle 27.
measure: Summary of Duration of Response (DOR)
timeFrame: Primary analysis occur when all subjects have completed Cycle 27 or have exit the study
Other outcomes:
Locations:
city: Santa Barbara
country: United States
facility: Research Site
state: California
city: Aurora
country: United States
facility: Research Site
state: Colorado
city: Washington
country: United States
facility: Research Site
state: District of Columbia
city: Minneapolis
country: United States
facility: Research Site
state: Minnesota
city: New York
country: United States
facility: Research Site
state: New York
city: Nashville
country: United States
facility: Research Site
state: Tennessee
city: Austin
country: United States
facility: Research Site
state: Texas
city: Bedford
country: United States
facility: Research Site
state: Texas
city: Houston
country: United States
facility: Research Site
state: Texas
city: Vancouver
country: United States
facility: Research Site
state: Washington
city: Aurillac Cedex
country: France
facility: Research Site
city: Clermond Ferrand
country: France
facility: Research Site
city: Marseille CEDEX
country: France
facility: Research Site
city: Montpellier
country: France
facility: Research Site
city: Nantes
country: France
facility: Research Site
city: Paris cedex 13
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Pierre Benite Cedex
country: France
facility: Research Site
city: Poitiers
country: France
facility: Research Site
city: Reims Cedex
country: France
facility: Research Site
city: Rennes Cedex
country: France
facility: Research Site
city: Toulouse Cedex
country: France
facility: Research Site
city: Vandoeuvre-les-Nancy
country: France
facility: Research Site
city: Athens
country: Greece
facility: Research Site
city: Bologna
country: Italy
facility: Research Site
city: Milan
country: Italy
facility: Research Site
city: Novara
country: Italy
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Utrecht
country: Netherlands
facility: Research Site
city: Salamanca
country: Spain
facility: Research Site
city: Bournemouth
country: United Kingdom
facility: Research Site
city: Leeds
country: United Kingdom
facility: Research Site
city: Leicester
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Oxford
country: United Kingdom
facility: Research Site
city: Plymouth
country: United Kingdom
facility: Research Site
city: Southampton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: 1-877-240-9479 information.center@astrazeneca.com
name: AstraZeneca Clinical study Information Center
role: STUDY_DIRECTOR
References:
citation: Owen RG, McCarthy H, Rule S, D'Sa S, Thomas SK, Tournilhac O, Forconi F, Kersten MJ, Zinzani PL, Iyengar S, Kothari J, Minnema MC, Kastritis E, Aurran-Schleinitz T, Cheson BD, Walter H, Greenwald D, Chen DY, Frigault MM, Hamdy A, Izumi R, Patel P, Wei H, Lee SK, Mittag D, Furman RR. Acalabrutinib monotherapy in patients with Waldenstrom macroglobulinemia: a single-arm, multicentre, phase 2 study. Lancet Haematol. 2020 Feb;7(2):e112-e121. doi: 10.1016/S2352-3026(19)30210-8. Epub 2019 Dec 19.