| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Untreated Chronic Lymphocytic Leukemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Long term cancer of the blood |
|
| 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 | LLT |
| E.1.2 | Classification code | 10009310 |
| E.1.2 | Term | CLL |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 obinutuzumab in combination with chlorambucil (Arm A) compared with acalabrutinib in combination with obinutuzumab (Arm B) based on Independent Review Committee (IRC) assessment of progression-free survival (PFS) per International Workshop on Chronic Lymphocytic Leukemia criteria (IWCLL, Hallek 2008) with incorporation of the clarification for treatment-related lymphocytosis (Cheson 2012)—hereafter referred to as IWCLL 2008 criteria—in subjects with previously untreated chronic lymphocytic leukemia (CLL). |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of Arm A versus ACP-196 monotherapy (Arm C) based on IRC assessment of PFS per IWCLL 2008 criteria.
To compare Arm A versus Arm B and Arm A versus Arm C in terms of:
• IRC-assessed objective response rate (ORR) per IWCLL 2008 criteria.
• Time to next treatment (TTNT) (defined as the time from randomization to institution of non-protocol specified treatment for CLL).
• Overall survival (OS). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Men and women ≥ 65 years of age, or > 18 and < 65 years of age provided that they meet at least one of the following criteria:
o Creatinine clearance 30 to 69 mL/min using the Cockcroft-Gault equation.
o A score higher than 6 on the Cumulative Illness Rating Scale-Geriatric (CIRS-G) (Appendix L).
• ECOG performance status of 0, 1, or 2.
• Diagnosis of CD20+ CLL that meets published diagnostic criteria (Hallek 2008):
o Monoclonal B cells (either kappa or lambda light chain restricted) that are clonally co-expressing ≥ 1 B-cell marker (CD19, CD20, or CD23) and CD5.
o Prolymphocytes may comprise ≤ 55% of blood lymphocytes.
o Presence of ≥ 5 x 10^9 B lymphocytes/L (5000 µL) in the peripheral
blood (at any point since diagnosis).
• Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment:
o Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin < 10 g/dL) and/or thrombocytopenia (platelets < 100,000/μL).
o Massive (ie, ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
o Massive nodes (ie, ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy.
o Progressive lymphocytosis with an increase of > 50% over a 2-month period or a lymphocyte doubling time (LDT) of < 6 months. LDT may be obtained by linear regression extrapolation of absolute lymphocyte counts (ALC) obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In subjects with initial blood lymphocyte counts of < 30 x 10^9/L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections) should be excluded.
o Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy.
o Constitutional symptoms documented in the subject’s chart with supportive objective measures, as appropriate, defined as ≥ 1 of the following disease-related symptoms or signs:
- Unintentional weight loss ≥ 10% within the previous 6 months before Screening.
- Significant fatigue (ie, ECOG performance status 2; inability to
work or perform usual activities).
- Fevers higher than 100.5°F or 38.0°C for 2 or more weeks before Screening without evidence of infection.
- Night sweats for > 1 month before Screening without evidence of
infection.
• Measurable nodal disease by computed tomography (CT). Measurable nodal disease is defined as ≥ 1 lymph node > 1.5 cm in the longest diameter in a site.
• Meet the following laboratory parameters:
o Absolute neutrophil count ≥ 750 cells/μL (0.75 x 10^9/L) or ≥ 500 cells/μL (0.50 x 10^9/L) in subjects with documented bone marrow involvement and independent of growth factor support 7 days before assessment.
o Platelet count ≥ 50,000 cells/μL (50 x 10^9/L), or ≥ 30,000 cells/μL (30 x 10^9/L) in subjects with documented bone marrow involvement, and without transfusion support 7 days before assessment. Subjects with transfusion-dependent thrombocytopenia are excluded.
o Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x upper limit of normal (ULN).
o Total bilirubin ≤ 1.5 x ULN.
o Estimated creatinine clearance (ie, estimated glomerular filtration rate [eGFR] using Cockcroft-Gault) ≥ 30 mL/min.
• Able to receive all outpatient treatment, all laboratory monitoring, and all radiologic evaluations .
• Women who are sexually active and can bear children must agree to use highly effective forms of contraception while on the study and for 2 days after the last dose of acalabrutinib or 18 months after the last dose of obinutuzumab in combination with chlorambucil, whichever is longer.
• Men who are sexually active and can beget children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of obinutuzumab or chlorambucil, whichever is later.
• Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of obinutuzumab or chlorambucil, whichever is later.
• Are willing and able to adhere to the study visit schedule, understand and comply with other protocol requirements, and provide written informed consent and authorization to use protected health information. Note: vulnerable subjects, as defined in International Conference on Harmonisation (ICH), are not allowed on this protocol (eg, prisoners or institutionalized subjects). |
|
| E.4 | Principal exclusion criteria |
• Any prior systemic treatment for CLL (note: Prior localized radiotherapy is allowed).
• Known central nervous system (CNS) lymphoma or leukemia.
• Known prolymphocytic leukemia or history of, or currently suspected, Richter’s syndrome.
• Missing or incomplete documentation of FISH results reflecting the presence or absence of 17p del and the percentage of cells with the deletion in subject records before randomization.
• Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP) defined as declining hemoglobin or platelet count secondary to autoimmune destruction within the screening period or requirement for high doses of steroids (> 20 mg daily of prednisone daily or equivalent).
• Corticosteroid use > 20 mg within 1 week before first dose of study drug, except as indicated for other medical conditions such as inhaled steroid for asthma, topical steroid use, or as premedication for administration of study drug or contrast. For example, subjects requiring steroids at daily doses > 20 mg prednisone equivalent systemic exposure daily, or those who are administered steroids for leukemia control or white blood cell count (WBC) lowering are excluded.
• Major surgery within 4 weeks before first dose of study drug.
• History of prior malignancy except for the following:
o Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years before Screening and felt to be at low risk for recurrence by treating physician.
o Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer.
o Adequately treated cervical carcinoma in situ without current evidence of disease.
• 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 QTc > 480 msec at screening.
• Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
• 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 ongoing intravenous anti-infective treatment.
• Known history of infection with human immunodeficiency virus (HIV).
• Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
• Serologic status reflecting active hepatitis B or C infection. Subjects with hepatitis B core antibody positive who are surface antigen negative or who are hepatitis C antibody positive will need to have a negative polymerase chain reaction (PCR) result before randomization. Those who are hepatitis B surface antigen positive or hepatitis B PCR positive and those who are hepatitis C PCR positive will be excluded.
• History of stroke or intracranial hemorrhage within 6 months before randomization.
• History of a bleeding diathesis (eg, hemophilia, von Willebrand disease).
• Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug.
• Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).
• Breast feeding or pregnant.
• Current life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator’s opinion, could compromise the subject’s safety or put the study at risk.
• Concurrent participation in another therapeutic clinical trial.
• Requires treatment with a strong CYP3A inhibitor/inducer.
• Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the study is PFS as assessed by IRC review per IWCLL 2008 criteria. The primary analysis is a comparison of PFS between Arm A and Arm B. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy:
The first secondary endpoint is a comparison of IRC-assessed PFS between Arm A and Arm C.
Other secondary endpoints are as follows and compare Arm A versus Arm B and Arm A versus Arm C in terms of:
• ORR defined as complete remission (CR), complete remission with incomplete bone marrow recovery (CRi), nodular partial remission (nPR), or partial remission (PR) (per IWCLL 2008 criteria).
• TTNT (defined as the time from randomization to institution of non-protocol specified treatment for CLL).
• OS.
Safety:
• Frequency, severity, and relatedness of adverse events.
• Frequency of adverse events requiring discontinuation of study drug or dose reductions.
• Change in laboratory assessments. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 90 |
| 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 |
| Australia |
| Belgium |
| Brazil |
| Canada |
| Chile |
| Colombia |
| Denmark |
| France |
| Germany |
| Hungary |
| Israel |
| Italy |
| Lithuania |
| New Zealand |
| Poland |
| Spain |
| Sweden |
| United Kingdom |
| United States |
|
| 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
|
| The end of trial is defined as the point when the last subject on the study has documented disease progression or death, or has been lost of follow up, whichever occurs first. The anticipated study duration is 4.5 years including enrollment time. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| 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 | 4 |
| 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 |
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