| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10026798 |
| E.1.2 | Term | Mantle cell lymphomas |
| E.1.2 | System Organ Class | 100000004851 |
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| 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 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). |
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| E.2.2 | Secondary objectives of the trial |
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) |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacokinetic Sub-study
Patient demographic, pathophysiologic, and therapeutic features, such as body weight, excretory and metabolic functions, and other therapies, can alter dose-concentration relationships. The collection of relevant PK information in patients who are representative of the target population enables an assessment of these features on drug concentrations (Food and Drug Administration [FDA] 1999). Due to a short half-life, trough concentrations of acalabrutinib are generally not measurable.
Intensive PK samples will be collected for acalabrutinib, bendamustine and bendamustine metabolite from approximately 40 subjects in the PK substudy per Table 11 1 predose/before the start of the bendamustine infusion and postdose/after the start of infusion. For this subset of subjects, acalabrutinib or placebo administration for Cycle 1 Day 2, Cycle 1 Day 8, and Cycle 2 Day 2 must occur at the site. PK samples should be collected after the morning dose of acalabrutinib. The PK sampling site must be on the opposite arm from the site of bendamustine infusion. The predose samples can be taken up to 30 minutes before acalabrutinib or placebo administration. When acalabrutinib or placebo and bendamustine are administered on the same day (PK on Day 2 of Cycles 1 and 2), the 30 minute bendamustine infusion should be started immediately (within 5 minutes) after the morning dose of acalabrutinib or placebo is administered. The times of the dose administration of acalabrutinib and bendamustine and times of each PK sample will be recorded in the CRF.
Biomarker Evaluation
Peripheral blood mononuclear cells (PBMC) and tumor samples will be used for biomarker evaluations. To determine the temporal effect of study drugs on the phenotype of malignant cells in subjects, blood samples will be collected and analyzed centrally per the Schedule of Assessments.
The term “biomarker PBMC” refers to samples where PBMC will be isolated and frozen as viable cells. The PBMC may be analyzed at a future date for changes in cell surface marker expression and modulation of intracellular signaling pathways, including BTK phosphorylation. The plasma fraction from the PBMC isolation will be frozen and preserved for future measurements of soluble analytes (ie, cytokines), and/or circulating tumor DNA (ctDNA) for mutational analysis. Biomarker PBMC samples will be collected from approximately 100 subjects. Samples will be collected before treatment on the following days: Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 7 Day 1 (or after completion of BR therapy). A sample will also be collected within 7 days of a suspected CR or disease progression, or discontinuation of treatment, and at the SFU visit.
Archival or fresh tumor biopsy samples will be evaluated from all subjects to evaluate potential biomarkers related to response to therapy and/or to investigate potential mechanisms of primary resistance. Analysis of proteins, gene expression and/or mutations may be used to support this exploratory endpoint. These samples will be collected during screening only. Assays will be conducted only if subject is enrolled in study and has provided consent.
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| E.3 | Principal 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 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. 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 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). |
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| E.4 | Principal 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 components
16.Serologic status reflecting active hepatitis B or C infection
a.Subjects who are anti-HBc positive and who are surface antigen negative will need to have a negative PCR result before randomization. Those who are HbsAg positive or hepatitis B PCR positive will be excluded
b.Subjects who are hepatitis C antibody positive will need to have a negative PCR result before randomization. Those who are hepatitis C PCR positive will be excluded
17.Received a live virus vaccination within 28 days of first dose of study drug
18.History of stroke or intracranial hemorrhage within 6 months of first dose of study drug.
19.History of bleeding diathesis (eg, hemophilia or von Willebrand disease)
20.Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before first dose of study drug
21.Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug
22.Requires treatment with a strong CYP3A inhibitor/inducer
23.Requires treatment with proton pump inhibitors (eg, 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.Concurrent participation in another therapeutic clinical trial
25.Active CMV infection (active viremia as evidenced by positive PCR result for CMV DNA)
26.History of confirmed PML |
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| E.5 End points |
| E.5.1 | 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). |
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| E.5.1.1 | 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. |
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| E.5.2 | 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. |
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| E.5.2.1 | 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. |
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| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 77 |
| 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 |
| 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 |
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| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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