E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Waldenström Macroglobulinemia |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10047804 |
E.1.2 | Term | Waldenstrom's macroglobulinaemia recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10047805 |
E.1.2 | Term | Waldenstrom's macroglobulinaemia refractory |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the ORR of acalabrutinib in subjects with WM as assessed
by investigator. |
|
E.2.2 | Secondary objectives of the trial |
• To determine the duration of overall response (DOR) of acalabrutinib by the investigator
• to determine the progression-free survival (PFS) of acalabrutinib by the investigator
• To determine the overall survival (OS) of acalabrutinib
• To characterize the PK profile of acalabrutinib
• To characterize the safety of acalabrutinib
• To evaluate the effect of acalabrutinib in health-related quality of life
Exploratory Objective
• To evaluate the PD effects of acalabrutinib |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 ≥ 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 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). |
|
E.4 | Principal 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 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 human immunodeficiency virus (HIV) or active infection with hepatitis C virus (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 proton pump inhibitors (eg, omeprazole,esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).
17. Absolute neutrophil count (ANC) < 0.75 x 10^9/L or platelet count <50 x 10^9/L. For subjects with disease involvement in the bone marrow,ANC < 0.50 x 10^9/L or platelet count < 30 x 10^9/L.18.
18. Creatinine > 2.5 x institutional upper limit of normal (ULN); total bilirubin > 2.5 x ULN; or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3.0 x ULN
19. Lactating or pregnant.
20. Concurrent participation in another therapeutic clinical trial. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Overall Response Rate (ORR), defined as a subject achieving a Minor Response (MR) or better according to the Response Assessment Criteria for WM as assessed by investigator.
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 investigator. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
after 30 days after stop study treatment |
|
E.5.2 | Secondary end point(s) |
Efficacy:
• Duration of overall response (DOR) assessed by the investigator using Response Assessment Criteria for WM and Modified 3rd IWWM workshop criteria
• Progression-free survival (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/natural killer (NK) cell counts
• Effect of acalabrutinib on serum immunoglobulin levels
Safety:
• Frequency, severity, and relatedness of adverse events (AEs)
• Frequency of AEs requiring discontinuation of study drug or dose
reductions
Pharmacokinetics:
• Plasma pharmacokinetics of acalabrutinib
• Patient Reported Outcomes (PRO):
• Health-related quality of life
Exploratory Endpoints
Pharmacodynamics:
• BTK occupancy and biologic markers of B-cell function |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
after 30 days after stop study treatment |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Safety and Efficacy Profile |
|
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
United States |
France |
Netherlands |
Greece |
Italy |
United Kingdom |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
Last Subject, last visit. Subjects who are deriving clinical benefit from acalabrutinib may continue on the study until a rollover protocol is available. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |