An Open-label, Phase 2 Study of ACP-196 in Subjects with Waldenström Macroglobulinemia1

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Acerta Pharma B.V.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

28 Sep 2015 → ongoing

Decision date (initial)

2024-08-20

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Acerta Pharma BV

External identifiers

EU CT number

2023-509356-34-00

EudraCT number

2014-003212-36

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacokinetic, Pharmacodynamic, Therapy

To determine the ORR of acalabrutinib in subjects with WM as assessed by the investigator.

Secondary objectives 6

1. To determine the duration of overall response (DOR) of acalabrutinib by the investigator
2. To determine the progression-free survival (PFS) of acalabrutinib by the investigator
3. To determine the overall survival (OS) of acalabrutinib
4. To characterize the PK profile of acalabrutinib
5. To characterize the safety of acalabrutinib
6. To evaluate the effect of acalabrutinib in health-related quality of life

Conditions and MedDRA coding

Waldenström Macroglobulinemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

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 ≥ 1 prior 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 ≥ 5,000 mg/dL •Disease-related neuropathy
4. Serum concentration of IgM, as measured by serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE), that exceeds the upper limits of normal or measurable nodal WM (defined as the presence of ≥1 lymph node that measures ≥ 2.0 cm in the longest diameter and ≥ 1.0 cm in the longest perpendicular diameter).
5. Eastern Cooperative Oncology Group (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. Highly effective forms of contraception are defined in the protocol.
7. This criterion was removed as of Protocol Amendment 7.
8. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules or tablets without difficulty.
9. 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 20

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 left ventricular ejection fraction (LVEF) ≤ 40%, or QTc > 480 msec.
4. 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.
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 (eg, Btk, phosphoinositide-3 kinase [PI3K], or Syk inhibitors) or BCL-2 inhibitors (eg, 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 (eg, 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 (eg, phenprocoumon) within 28 days of first dose of study drug.
16. Requires treatment with PPIs (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Note: this criterion no longer applies to patients who have switched from acalabrutinib capsules to tablets
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 <30 x109/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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. ORR, defined as a subject achieving a MR or better according to the response assessment criteria for WM as assessed by the investigator
2. ORR, defined as a subject achieving a MR or better according to the response assessment criteria defined by modified 3rd IWWM workshop criteria as assessed by the investigator

Secondary endpoints 4

1. Efficacy: •DOR assessed by the investigator using response assessment criteria for WM and modified 3rd IWWM workshop criteria • PFS assessed by the investigator using response assessment criteria for WM and Modified 3rd IWWM workshop criteria • Overall survival (OS) •Effect of acalabrutinib on peripheral T/B/NK cell counts •Effect of acalabrutinib on serum immunoglobulin levels
2. Safety: •Frequency, severity, and relatedness of AEs •Frequency of AEs requiring discontinuation of study drug or dose reductions
3. Pharmacokinetics: •Plasma pharmacokinetics of acalabrutinib
4. Patient Reported Outcomes (PRO): •Health-related quality of life

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Acerta Pharma B.V.

Sponsor organisation

Acerta Pharma B.V.

Address

Kloosterstraat 9

City

Oss

Postcode

5349 AB

Country

Netherlands

Scientific contact point

Organisation

Acerta Pharma B.V.

Contact name

Global Clinical Lead

Public contact point

Organisation

Acerta Pharma B.V.

Contact name

Global Clinical Lead

Third parties 3

Locations

3 EU/EEA countries · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 22 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications