An Open-label, Phase 2 Study of ACP-196 in Subjects With Waldenström Macroglobulinemia

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

Study Overview

• Status: Active, not recruiting
• Conditions: Waldenström Macroglobulinemia (WM)
• Intervention / Treatment: Drug: Acalabrutinib (ACP-196)

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.

• Study Type: Interventional
• Enrollment (Actual): 107
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Aurillac Cedex, France, 15002
    • Research Site
  • Clermond Ferrand, France, 63003
    • Research Site
  • Marseille CEDEX, France, 13273
    • Research Site
  • Montpellier, France, 34295
    • Research Site
  • Nantes, France, 44093
    • Research Site
  • Paris, France, 75015
    • Research Site
  • Paris cedex 13, France, 75651
    • Research Site
  • Pierre Benite Cedex, France, 69495
    • Research Site
  • Poitiers, France, 86021
    • Research Site
  • Reims Cedex, France, 51092
    • Research Site
  • Rennes Cedex, France, 35000
    • Research Site
  • Toulouse Cedex, France, 31059
    • Research Site
  • Vandoeuvre-les-Nancy, France, 54500
    • Research Site
• Greece
  • Athens, Greece, 11528
    • Research Site
• Italy
  • Bologna, Italy, 40138
    • Research Site
  • Milan, Italy, 20162
    • Research Site
  • Novara, Italy, 28100
    • Research Site
• Netherlands
  • Amsterdam, Netherlands, 1105AZ
    • Research Site
  • Utrecht, Netherlands, 2508GA
    • Research Site
• Spain
  • Salamanca, Spain, 37007
    • Research Site
• United Kingdom
  • Bournemouth, United Kingdom, BH7 7DW
    • Research Site
  • Leeds, United Kingdom, LS9 7TF
    • Research Site
  • Leicester, United Kingdom, LE1 7RH
    • Research Site
  • London, United Kingdom, SW3 6JJ
    • Research Site
  • London, United Kingdom, NW1 2BU
    • Research Site
  • Oxford, United Kingdom, OX3 7LE
    • Research Site
  • Plymouth, United Kingdom, PL6 8DH
    • Research Site
  • Southampton, United Kingdom, SO16 6YD
    • Research Site
• United States
  • California
    • Santa Barbara, California, United States, 93105
      • Research Site
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Research Site
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Research Site
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Research Site
  • New York
    • New York, New York, United States, 10021
      • Research Site
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Research Site
  • Texas
    • Austin, Texas, United States, 78705
      • Research Site
    • Bedford, Texas, United States, 76022
      • Research Site
    • Houston, Texas, United States, 77030
      • Research Site
  • Washington
    • Vancouver, Washington, United States, 98684
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Previously Treated; Subjects previously treated with Waldenström Macroglobulinemia N=92	Drug: Acalabrutinib (ACP-196); Other Names: Acalabrutinib
Experimental: Treatment Naïve; Subjects with treatment-naïve Waldenström Macroglobulinemia. N=14	Drug: Acalabrutinib (ACP-196); Other Names: Acalabrutinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) of Acalabrutinib in Subjects as Assessed by Investigator Per IWWM 6th Criteria	ORR defined as the rate of subjects achieving a Miner Response (MR) or better including complete response (CR), very good partial response (VGPR), partial response (PR) and MR; The definition of responses are evaluated by investigators using both Modified 6th criteria (refer to protocol table 4-2 , 4-3) and Modified 3rd International Workshop of Waldenström Macroglobulinemia (IWWM) criteria (refer to protocol table 4-4 and table 4-5 for definition). For Modified 6th criteria, MR is defined as (1) monoclonal IgM protein is detectable, (2) no new signs or symptoms of active disease, (3) and patient has >=25% but < 50% reduction in serum monoclonal IgM level from baseline. PR and VGPR both require (1) and (2) as MR, but PR also requires the >=50% and <90% reduction in serum monoclonal IgM level as well as reduction in extramedullary disease. VGPR requires >= 90% reduction in serum IgM and complete resolution of extramedullary disease.	Up to approximately 3.8 years. Data cut at when last patient has completed Cycle 27 (28 days per Cycle).
Overall Response Rate (ORR) of Acalabrutinib in Subjects as Assessed by Investigator Per IWWM 3rd Criteria	ORR defined as the rate of subjects achieving a Miner Response (MR) or better including complete response (CR), very good partial response (VGPR), partial response (PR) and MR; The definition of responses are evaluated by investigators using both Modified 6th criteria (refer to protocol table 4-2 , 4-3) and Modified 3rd International Workshop of Waldenström Macroglobulinemia (IWWM) criteria (refer to protocol table 4-4 and table 4-5 for definition). For Modified 6th criteria, MR is defined as (1) monoclonal IgM protein is detectable, (2) no new signs or symptoms of active disease, (3) and patient has >=25% but < 50% reduction in serum monoclonal IgM level from baseline. PR and VGPR both require (1) and (2) as MR, but PR also requires the >=50% and <90% reduction in serum monoclonal IgM level as well as reduction in extramedullary disease. VGPR requires >= 90% reduction in serum IgM and complete resolution of extramedullary disease.	Up to approximately 3.8 years. Data cut at when last patient has completed Cycle 27 (28 days per Cycle).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS) of Acalabrutinib by Investigator	Kaplan-Meier (K-M) estimates of the PFS assessments and its 95% confidence interval are provided using both modified 3rd and 6th IWWM criteria by investigator. K-M estimates at a certain time (ex. all subjects complete Cycle 27) provides the estimated percentage of the subjects who are still alive or have not progressed by the given time over all patients at risk. Per 6th IWWM criteria, the progressive disease is defined as >= 25% increase in serum IgM level with an absolute increase of at least 500 mg/dL from lowest nadir (requires confirmation on at least 2 consecutive measurements at least 4 weeks apart) and/or progression of clinical features attributable to the disease. Per modified 3rd IWWM criteria, besides IgM requirement as 6th criteria, it could also includes progression of clinically significant disease related symptoms and/or death from any cause or initiation of a new anti-neoplastic therapy.	Up to approximately 3.8 years. Data cut at last subject have completed Cycle 27 (28 days per Cycle).
Overall Survival (OS) of Acalabrutinib by Investigator	Outcome Measure was pre-specified to summarize data per investigator assessment with respect to subject's vital/survival status is presented in the RRF and irrespective of iWWM 3rd or 6th criteria. Kaplan-Meier (K-M) estimates at a certain time (ex. all subjects complete Cycle 27) provides the estimated percentage of the subjects who are still alive by the given time over all patients at risk.	Primary analysis occur when all subjects have completed Cycle 27 or have discontinued before Cycle 27.
Summary of Duration of Response (DOR)	DOR is defined as the interval from the first documentation of Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR) or Minor Response (MR) to the earlier of the first documentation of definitive PD or death from any cause. The summary statistics are provided for DOR.	Primary analysis occur when all subjects have completed Cycle 27 or have exit the study

Collaborators and Investigators

• Sponsor: Acerta Pharma BV
• Investigators: Study Director: AstraZeneca Clinical Study Information Center, 1-877-240-9479 information.center@astrazeneca.com

Publications and helpful links

General Publications

• 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. Erratum In: Lancet Haematol. 2021 Apr;8(4):e249.

Helpful Links

• Related Info
• Related Info
• SAP

Study record dates

Study Major Dates

• Study Start (Actual): September 8, 2014
• Primary Completion (Actual): October 1, 2019
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: June 30, 2014
• First Submitted That Met QC Criteria: July 1, 2014
• First Posted (Estimated): July 3, 2014

Study Record Updates

• Last Update Posted (Estimated): January 19, 2024
• Last Update Submitted That Met QC Criteria: January 18, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Bruton tyrosine kinase inhibitor; Btk; WM; Macroglobulinemia; Waldenström Macroglobulinemia; Waldenström
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Waldenstrom Macroglobulinemia; Antineoplastic Agents; Acalabrutinib
• Other Study ID Numbers: ACE-WM-001; 2014-003212-36 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No