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

• Register: EUCTR
• Last refreshed on: 21 May 2018
• Main ID: EUCTR2015-005220-26-HU
• Date of registration: 20/03/2017
• Prospective Registration: Yes
• Primary sponsor: Acerta Pharma BV
• Public title: 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
• Scientific title: 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
• Date of first enrolment: 16/05/2017
• Target sample size: 546
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-005220-26
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: yes Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Belgium, Brazil, Canada, China, Czech Republic, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Japan, Korea, Republic of, Mexico, New Zealand, Peru, Poland, Romania, Russian Federation, Spain, Taiwan, Ukraine, United States, Vietnam

Contacts

• Name: ACE-LY-308 Clinical Team
• Affiliation: Acerta Pharma BV

• Name: ACE-LY-308 Clinical Team
• Affiliation: Acerta Pharma BV

Key inclusion & exclusion criteria

Inclusion criteria:
1. Men and women, = 65 years of age.
2. Pathologically confirmed MCL, with documentation of chromosome translocation t(11;14)(q13;q32) and/or overexpress 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 acalabrutinib, 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longest. Highly effective forms of contraception are defined in Section 9.2.2.
7. Men must agree to refrain from sperm donation during the study and for 6 months after the last dose of acalabrutinib, 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).
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 546

Exclusion criteria:
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 yrs before screening and felt to be at
low risk for recurrence by treating physician
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.Subjects for whom the goal of therapy is tumor debulking before stem
cell transplant
3.Any history of CNS lymphoma or leptomeningeal disease
4.Uncontrolled AIHA or ITP
5.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
6.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
7.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
8.Total bilirubin > 1.5 x ULN; or AST or ALT > 2.5 x ULN
9.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]
10.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
11.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
12.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
13.Known history of infection with HIV
14.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
15.Known history of anaphylaxis or hypersensitivity to bendamustine,
rituximab,or any of their compo

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Mantle Cell Lymphoma
MedDRA version: 20.0 Level: HLT Classification code 10026798 Term: Mantle cell lymphomas System Organ Class: 100000004851

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: Acalabrutinib
Product Code: ACP-196
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Acalabrutinib
CAS Number: 1420477-60-6
Current Sponsor code: ACP-196
Other descriptive name: ACP-196
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Trade Name: Levact
Product Name: Levact
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: BENDAMUSTINE
CAS Number: 16506-27-7
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2.5-

Trade Name: MabThera
Product Name: MabThera
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Trade Name: Bendamustine hydrochloride Accord
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: BENDAMUSTINE
CAS Number: 16506-27-7
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2.5-

Trade Name: Bendamustine hydrochloride
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: BENDAMUSTINE
CAS Number: 16506-27-7
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2.5-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Response assessments will be based on the Lugano Classification for NHL, which incorporates assessments via PET/CT and CT alone. During treatment, CT scans will be performed for tumor assessments at Week 12 (± 7 days), then every 12 weeks until Week 96 (± 7 days), and then every 24 weeks (± 7 days) thereafter.
During treatment, PET/CT scans will be performed at Weeks 12 and 24 (± 7 days), and then only to confirm CR thereafter. Subjects with confirmed CR are not required to undergo further PET/CT scans on study unless there is suspicion of disease progression.

Secondary Objective: To evaluate acalabrutinib (ACP-196) in combination with BR compared with placebo in combination with BR in terms of:
• Investigator-assessed PFS per the Lugano Classification for NHL
• Investigator-assessed ORR per the Lugano Classification for NHL
• 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.
• Overall survival (OS)
• IRC-assessed duration of response (DOR) per the Lugano Classification for NHL
• IRC-assessed time to response (TTR) per the Lugano Classification for NHL
• IRC-assessed ORR (CR + PR) per Revised Response Criteria for Malignant Lymphoma (Cheson 2007)
• PRO by Functional Assessment of Cancer Therapy Lymphoma (FACT-Lym) scale score
• PRO by the EuroQol (EQ-5D-5L) index score
• PRO by the EORTC QLQ-C30 score
• Medical Ressource utilization (MRU)

Primary end point(s): 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).

Main Objective: 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 Outcome(s)

Timepoint(s) of evaluation of this end point: Response assessments will be based on the Lugano Classification for NHL, which incorporates assessments via PET/CT and CT alone. During treatment:
CT scans will be performed for tumor assessments at Week 12 (± 7 days), then every 12 weeks until Week 96 (± 7 days), and then every 24 weeks (± 7 days) thereafter.
PET/CT scans will be performed at Weeks 12 and 24 (± 7 days), and then only to confirm CR thereafter. Subjects with confirmed CR are not required to undergo further PET/CT scans on study unless there is suspicion of disease progression

PRO assessment will be performed at screening, on Day 1 of Cycles 3, 5, and 8, then every 4 cycles until discontinuation of study treatment, and then every 12 weeks thereafter until disease progression or use of alternative anticancer therapy.

Secondary end point(s): •Investigator-assessed PFS per the Lugano Classification for NHL
•Investigator-assessed ORR (CR+PR) per the Lugano Classification for NHL
•IRC-assessed ORR (CR+PR) per the Lugano Classification for NHL
•OS
•IRC-assessed DOR per the Lugano Classification for NHL
•IRC assessed TTR per the Lugano Classification for NHL
•IRC-assessed ORR (CR + PR) per Revised Response Criteria for Malignant Lymphoma (Cheson 2007)
•PRO as measured by change in scores from baseline to each assessment using the FACT-Lym scale
•PRO as measured by change in scores from baseline to each assessment using the EQ-5D-5L index score
•PRO by change in scores from baseline to each assessment using the EORTC QLQ-C30 score
•MRU associated with the study treatment, including the number of hospitalizations, emergency department visits, blood product transfusions, and use of hematopoietic growth factors, that occur after initiation of study drug.

Secondary ID(s)

118717

ACE-LY-308

Source(s) of Monetary Support

Acerta Pharma BV