A Phase 3, Randomized, Double-blind, Placebo-controlled, Multicenter Study of Bendamustine and Rituximab (BR) Alone Versus in Combination with Acalabrutinib (ACP-196) in Subjects with Previously Untreated Mantle Cell Lymphoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Acerta Pharma B.V.

Participant type

Patients

Age range

65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

14 Jul 2017 → ongoing

Decision date (initial)

2024-06-03

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2023-509354-58-00

EudraCT number

2015-005220-26

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenetic, Pharmacodynamic, Therapy, Pharmacokinetic, Efficacy, Safety

To evaluate the efficacy of acalabrutinib (ACP-196) in combination with bendamustine and rituximab (BR) compared with placebo in combination with BR based on Independent Review Committee (IRC) assessment of progression-free survival (PFS) per the Lugano Classification for Non Hodgkin Lymphoma (NHL) (Cheson 2014) in subjects with previously untreated mantle cell lymphoma (MCL)

Secondary objectives 7

1. To evaluate acalabrutinib (ACP-196) in combination with BR compared with placebo in combination with BR in terms of: 1. Investigator-assessed PFS per the Lugano Classification for NHL
2. Investigator-assessed ORR per the Lugano Classification for NHL
3. IRC-assessed overall response rate (ORR), defined as a subject achieving either a partial response (PR) or complete response (CR) per the Lugano Classification for NHL
4. Overall survival (OS)
5. IRC-assessed duration of response (DOR) per the Lugano Classification for NHL
6. IRC-assessed time to response (TTR) per the Lugano Classification for NHL
7. Pharmacokinetic (PK) characteristics of acalabrutinib and its active metabolite (ACP-5862), alone and when given in combination with bendamustine

Conditions and MedDRA coding

Mantle Cell Lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Men and women, ≥65 years of age.
2. Pathologically confirmed MCL, with documentation of chromosome translocation t(11;14)(q13;q32) and/or overexpression of cyclin D1 in association with other relevant markers (eg, CD5, CD19, CD20, PAX5).
3. MCL requiring treatment and for which no prior systemic anticancer therapies have been received.
4. Presence of radiologically measurable lymphadenopathy and/or extranodal lymphoid malignancy.
5. ECOG performance status of ≤2.
6. Men who are sexually active and can beget children must agree to use highly effective forms of contraception during the study and for 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longest.
7. Men must agree to refrain from sperm donation during the study and for 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longest.
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).

Exclusion criteria 26

1. History of prior malignancy except for the following: a. Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening and felt to be at low risk for recurrence by treating physician. Note: Provided they meet other eligibility criteria, subjects who are receiving hormonal therapy alone are allowed to enroll on study. b. Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled nonmelanomatous skin cancer. c. Adequately treated carcinoma in situ without current evidence of disease.
2. Prothrombin time/INR or aPTT (in the absence of a Lupus anticoagulant) > 2.0 x ULN. Exception: Subjects receiving warfarin are excluded; however, those receiving other anticoagulant therapy who have a higher INR/aPTT may be permitted to enroll to this study after discussion with the medical monitor.
3. Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
4. Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment), or intravenous anti infective treatment within 2 weeks before first dose of study drug.
5. Known history of infection with HIV.
6. Ongoing immunosuppressive therapy, including systemic (eg, IV or oral) corticosteroids within 2 weeks before the first dose of study drug. Note: Subjects may use topical or inhaled corticosteroids or low dose steroids (≤ 20 mg prednisone equivalent/day for ≤ 2 weeks) as a therapy for comorbid conditions. During study participation, subjects may also receive systemic (eg, IV or oral) corticosteroids as needed for treatment emergent comorbid conditions.
7. Known history of anaphylaxis or hypersensitivity to bendamustine, rituximab, or any of their components.
8. Subjects for whom the goal of therapy is tumor debulking before stem cell transplant.
9. Any history of CNS lymphoma or leptomeningeal disease.
10. Uncontrolled AIHA or ITP.
11. Major surgical procedure within 28 days before first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
12. Significant cardiovascular disease such as uncontrolled or untreated symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of first dose of study drug, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or QTc > 480 msec (calculated using Friderica's formula: QT/RR0.33) at screening. Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll on study.
13. ANC < 1.0 x 109/L or platelet count < 75 x 109/L; for subjects with disease involvement in the bone marrow, ANC < 0.75 x 109/L or platelet count < 50 x 109/L. Subjects will only be considered eligible if peripheral blood counts can be maintained independent of growth factors or transfusions during the screening period.
14. Total bilirubin > 1.5 x ULN; or AST or ALT > 2.5 x ULN.
15. Estimated creatinine clearance of < 50 mL/min, calculated using the formula of Cockcroft and Gault [(140-age)•mass (kg)/(72•creatinine mg/dL)•multiply by 0.85 if female].
16. 16. Serologic status reflecting active hepatitis B or C infection.
17. 17. Received a live virus vaccination within 28 days of first dose of study drug.
18. 18. History of stroke or intracranial hemorrhage within 6 months of first dose of study drug.
19. 19. History of bleeding diathesis (e.g., hemophilia or von Willebrand disease).
20. 20. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before first dose of study drug.
21. 21. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug.
22. 22. Requires treatment with a strong cytochrome P450 3A (CYP3A) inhibitor/inducer.
23. 23. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.
24. 24. Concurrent participation in another therapeutic clinical trial.
25. 25. Active cytomegalovirus (CMV) infection (active viremia as evidenced by positive polymerase chain reaction [PCR] result for CMV DNA).
26. 26. History of confirmed progressive multifocal leukoencephalopathy (PML).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint of the study is PFS as assessed by IRC per the Lugano Classification for NHL. The primary analysis is a comparison of PFS between Arm 1 (acalabrutinib plus BR) and Arm 2 (placebo plus BR).

Secondary endpoints 7

1. Investigator-assessed PFS per the Lugano Classification for NHL
2. Investigator-assessed ORR (CR+PR) per the Lugano Classification for NHL
3. IRC-assessed ORR (CR+PR) per the Lugano Classification for NHL
4. OS
5. IRC-assessed DOR per the Lugano Classification for NHL
6. IRC assessed TTR per the Lugano Classification for NHL
7. PK characteristics of acalabrutinib and its active metabolite (ACP-5862), alone and when given in combination with bendamustine

Investigational products

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

Test 1

Comparator 2

Placebo 1

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

Clinical Study Information Center

Public contact point

Organisation

Acerta Pharma B.V.

Contact name

Clinical Study Information Center

Third parties 15

Locations

9 EU/EEA countries · 52 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 80 files

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

Application history

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